Split (3)

train · 29.5k rows

FEATURE_phases list	FEATURE_enrollmentCount int64	FEATURE_allocation string	FEATURE_interventionModel string	FEATURE_primaryPurpose class label	FEATURE_masking class label	FEATURE_healthyVolunteers bool	FEATURE_sex class label	FEATURE_oversightHasDmc bool	FEATURE_briefSummary string	FEATURE_detailedDescription string	FEATURE_conditions string	FEATURE_conditionsKeywords string	FEATURE_protocolPdfText string	FEATURE_numArms int64	FEATURE_armDescriptions string	FEATURE_armGroupTypes list	FEATURE_numInterventions int64	FEATURE_interventionTypes list	FEATURE_interventionDescriptions string	FEATURE_interventionNames string	FEATURE_numLocations int64	FEATURE_locationDetails string	LABEL_ct_level_ade_population int64	LABEL_sum_dosing_errors int64	LABEL_dosing_error_rate float32	LABEL_wilson_label int64	METADATA_nctId string	METADATA_overallStatus class label	METADATA_completionDate date32	METADATA_startDate date32	METADATA_leadSponsorName string	METADATA_leadSponsorClass class label	METADATA_hasProtocol bool	METADATA_hasSap bool	METADATA_hasIcf bool	METADATA_protocolPdfLinks string	METADATA_count_Accidental overdose int64	METADATA_count_Incorrect dose administered int64	METADATA_count_Intentional overdose int64	METADATA_count_Multiple drug overdose int64	METADATA_count_Overdose int64	METADATA_wilson_lower_bound float32
[ 3 ]	20	RANDOMIZED	PARALLEL	0TREATMENT	1SINGLE	false	0ALL	false	The purpose of this study is to assess the 1 month safety and tolerability after multiple oral doses of AZD1656 in patients with Type 2 Diabetes Mellitus Treated with Insulin	null	Type II Diabetes	Type II Diabetes	null	2	arm 1: Dose titration of oral suspension during 4 days to a tolerable dose given twice daily. Subjects will thereafter be treated with this dose twice daily for another 24 days arm 2: Dose titration of oral suspension during 4 days to a tolerable dose given twice daily. Subjects will thereafter be treated with this dose twice daily for another 24 days	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: Tolerable dose given twice daily intervention 2: Tolerable dose given twice daily	intervention 1: AZD1656 intervention 2: Placebo	1	Chula Vista \| California \| United States \| -117.0842 \| 32.64005	20	0	0	0	NCT00856908	1COMPLETED	2009-08-01	2009-02-01	AstraZeneca	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 4 ]	71	null	PARALLEL	0TREATMENT	0NONE	false	2MALE	false	Testosterone replacement treatment is the most effective way of treating hypogonadism in men. Acrux has a propriety testosterone replacement product, Testosterone MD-Lotion and this study will assess the occurrence of skin safety events for a further two months of continuous use of the Testosterone MD-Lotion® (cutaneous solution) after completion of the MTE08 (NCT00702650) trial.	null	Hypogonadism		null	1	arm 1: In this open-label extension of the MTE08 trial, participants received Testosterone Metered Dose (MD)-Lotion for 60 days (dosing from Day 121 of the MTE08 trial to Day 180 of the MTE09 trial). Participants in MTE08 initially received 3.0 milliliters (mL) (60 micrograms \[mg\]) of 2% Testosterone MD-Lotion, and may have had their dose of testosterone adjusted upwards or downwards. Doses could be titrated to one of the following: 1.5 mL (30 mg) of 2% Testosterone MD-Lotion applied daily by 2 doses to the axilla (1.5 mL to one axilla). 3.0 mL (60 mg)of 2% Testosterone MD-Lotion applied daily by 2 doses to the axilla (1.5 mL to each axilla). 4.5 mL (90 mg)of 2% Testosterone MD-Lotion applied daily by 3 doses to the axilla (2 x 1.5 mL to one axilla and 2 x 1.5 mL to the other axilla). 6.0 (120 mg)of 2% Testosterone MD-Lotion applied daily by 4 doses to the axilla (2 x 1.5 mL to each axilla).	[ 0 ]	1	[ 0 ]	intervention 1: 30 mg to 120 mg administered topically once daily for 60 days	intervention 1: Testosterone MD-Lotion	11	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Tuscon \| Arizona \| United States \| N/A \| N/A Burbank \| California \| United States \| -118.30897 \| 34.18084 Colorado Springs \| Colorado \| United States \| -104.82136 \| 38.83388 New Britain \| Connecticut \| United States \| -72.77954 \| 41.66121 Ocala \| Florida \| United States \| -82.14009 \| 29.1872 Boise \| Idaho \| United States \| -116.20345 \| 43.6135 Shawnee Mission \| Kansas \| United States \| -94.66583 \| 39.02 Shreveport \| Louisiana \| United States \| -93.75018 \| 32.52515 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412	71	0	0	0	NCT00857454	1COMPLETED	2009-08-01	2008-10-01	Eli Lilly and Company	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3 ]	127	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	null	The purpose of this study is to investigate if AZD2066 can relieve the pain arising from painful diabetic neuropathy compared to placebo.	null	Pain Diabetic Neuropathy	Pain Diabetic Neuropathy PDN Analgesia Efficacy	null	2	arm 1: None arm 2: None	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: Capsule, once daily, 12 mg AZD2066 day 1-4 and 18 mg AZD2066 day 5-28. intervention 2: Capsule, once daily	intervention 1: AZD2066 intervention 2: Placebo	19	Bella Vista \| Arkansas \| United States \| -94.27134 \| 36.4807 National City \| California \| United States \| -117.0992 \| 32.67811 Walnut Creek \| California \| United States \| -122.06496 \| 37.90631 Clearwater \| Florida \| United States \| -82.8001 \| 27.96585 DeLand \| Florida \| United States \| -81.30312 \| 29.02832 Lauderdale Lakes \| Florida \| United States \| -80.20838 \| 26.16647 Miami \| Florida \| United States \| -80.19366 \| 25.77427 Orlando \| Florida \| United States \| -81.37924 \| 28.53834 Pembroke Pines \| Florida \| United States \| -80.22394 \| 26.00315 Madisonville \| Kentucky \| United States \| -87.49889 \| 37.3281 Owing Mills \| Maryland \| United States \| N/A \| N/A Bingham Farms \| Michigan \| United States \| -83.27326 \| 42.51587 Willingboro \| New Jersey \| United States \| -74.86905 \| 40.02789 Albany \| New York \| United States \| -73.75623 \| 42.65258 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Indiana \| Pennsylvania \| United States \| -79.15253 \| 40.62146 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Houston \| Texas \| United States \| -95.36327 \| 29.76328 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412	127	0	0	0	NCT00857623	1COMPLETED	2009-08-01	2009-02-01	AstraZeneca	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3 ]	30	NA	SINGLE_GROUP	0TREATMENT	0NONE	true	0ALL	false	This study is being performed to evaluate the functionality of a device (Sufentanil NanoTab® PCA System) that has been developed for use by patients to self-administer the ARX-F01 pain medication (Sufentanil NanoTab 15 mcg) for the treatment of post-operative pain after undergoing knee replacement surgery. Another goal of this study is to assess the safety and effectiveness of this non-invasive, sublingual route of administration of ARX-F01 in decreasing the amount of pain that a patient experiences following knee replacement surgery.	null	Pain, Postoperative		null	1	arm 1: None	[ 0 ]	1	[ 0 ]	intervention 1: 15 mcg Sufentanil NanoTab taken sublingually q 20 minutes as needed for pain for 12 hours	intervention 1: Sufentanil NanoTab PCA System/15 mcg	3	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Vero Beach \| Florida \| United States \| -80.39727 \| 27.63864 Houston \| Texas \| United States \| -95.36327 \| 29.76328	30	0	0	0	NCT00859313	1COMPLETED	2009-08-01	2009-04-01	Talphera, Inc	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 0 ]	20	RANDOMIZED	PARALLEL	7BASIC_SCIENCE	4QUADRUPLE	true	0ALL	true	The goal of this study is to determine if Echinacea purpurea stimulates the immune system. For the study, 20 healthy adults will be randomized to receive Echinacea purpurea or placebo for 10 days. Blood will be drawn to assess immune markers just before beginning the study medication, during the 10 day course of medication and after completing the course of medication. It is postulated that adults receiving the Echinacea will have evidence of immune stimulation and those receiving placebo will not.	null	Upper Respiratory Tract Infections	Echinacea prevention immune modulation	null	2	arm 1: None arm 2: None	[ 1, 2 ]	2	[ 2, 0 ]	intervention 1: Echinacea purpurea 100 mg/ml, 25 ml daily in 2 divided doses for 10 days intervention 2: placebo 25 ml daily in 2 divided doses for 10 days	intervention 1: Echinacea purpurea intervention 2: placebo	1	Kenmore \| Washington \| United States \| -122.24401 \| 47.75732	20	0	0	0	NCT00860795	1COMPLETED	2009-08-01	2009-03-01	University of Washington	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 3 ]	38	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	null	This is an open label, multi-centre, dose ranging study to assess efficacy, safety and pharmacokinetics of eltrombopag in thrombocytopenic subjects with chronic liver disease.	null	Liver Diseases		null	3	arm 1: eltrombopag 12.5 mg/day arm 2: eltrombopag 25 mg/day arm 3: eltrombopag 37.5 mg/day	[ 0, 0, 0 ]	2	[ 0, 0 ]	intervention 1: eltrombopag 12.5 mg tablet once a day intervention 2: eltrombopag 25 mg tablet once a day	intervention 1: eltrombopag 12.5 milligrams (mg) tablet intervention 2: eltrombopag 25 mg tablet	10	Fukuoka \| N/A \| Japan \| 130.41667 \| 33.6 Fukuoka \| N/A \| Japan \| 130.41667 \| 33.6 Fukuoka \| N/A \| Japan \| 130.41667 \| 33.6 Fukuoka \| N/A \| Japan \| 130.41667 \| 33.6 Fukuoka \| N/A \| Japan \| 130.41667 \| 33.6 Kagoshima \| N/A \| Japan \| 130.55 \| 31.56667 Kumamoto \| N/A \| Japan \| 130.69181 \| 32.80589 Kumamoto \| N/A \| Japan \| 130.69181 \| 32.80589 Nagasaki \| N/A \| Japan \| 129.88333 \| 32.75 Ōita \| N/A \| Japan \| 131.6 \| 33.23333	38	0	0	0	NCT00861601	1COMPLETED	2009-08-01	2009-01-01	GlaxoSmithKline	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 2 ]	22	null	CROSSOVER	null	2DOUBLE	true	0ALL	false	Insulin lispro and regular human insulin are Food and Drug Administration (FDA)-approved medications for the treatment of diabetes mellitus. Recombinant human hyaluronidase (rHuPH20) is approved by the FDA as an aid to the absorption and dispersion of other injectable drugs. In this study, rHuPH20 will be co-administered with both insulin lispro and regular human insulin in order to determine if it improves the absorption of these insulins to more closely mimic the body's natural increase in insulin in response to a meal.	The purpose of this study is to compare the pharmacokinetics (absorption, distribution, breakdown and elimination) of regular human insulin + recombinant human hyaluronidase (rHuPH20) versus insulin lispro alone, and to compare the pharmacokinetics of insulin lispro + rHuPH20 versus insulin lispro alone. The effects of regular human insulin + rHuPH20, insulin lispro + rHuPH20, and insulin lispro alone on the body will be evaluated by blood glucose measurements and by calculating the rate at which a glucose solution is infused to maintain blood glucose within a certain range. The safety and tolerability of insulin lispro with and without rHuPH20 and regular human insulin with rHuPH20 will be studied. The study drugs will be administered by subcutaneous (under the skin) injection.	Diabetes Mellitus	rHuPH20 Recombinant Human Hyaluronidase Insulin Lispro Regular Human Insulin	null	1	arm 1: All participants were randomized to 1 of 6 treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA), each of which was comprised of the same 3 interventions (A, B, and C). Intervention A: a single, subcutaneous (SC) injection of 0.15 units per kilogram (U/kg) insulin lispro with 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase (rHuPH20) Intervention B: a single, SC injection of 0.15 U/kg regular human insulin (RHI) with 3.75 ng/kg rHuPH20 Intervention C: a single, SC injection of 0.15 U/kg insulin lispro alone There was a washout period of 3 to 14 days between interventions. The treatment sequence (ABC, ACB, BAC, BCA, CAB, or CBA) was repeated once so that each participant received up to 6 injections.	[ 0 ]	3	[ 0, 0, 0 ]	intervention 1: None intervention 2: None intervention 3: None	intervention 1: Insulin Lispro intervention 2: Regular Human Insulin intervention 3: rHuPH20	1	Chula Vista \| California \| United States \| -117.0842 \| 32.64005	63	0	0	0	NCT00862849	1COMPLETED	2009-08-01	2009-03-01	Halozyme Therapeutics	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 5 ]	12	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	This study evaluates the penetration through the blood-brain-barrier of trospium chloride at plasma steady state (Day 10) in elderly subjects with overactive bladder symptoms. Trospium levels in cerebrospinal fluid (CSF) and peak and trough plasma levels will be measured. Baseline and day 10 post-dose neurocognitive testing will be compared using a reliable change index to assess if any study subject shows evidence of a clinically and statistically significant change in memory.	null	Elderly Pharmacokinetics Overactive Bladder		null	1	arm 1: Trospium Chloride Extended Release, 60 mg	[ 0 ]	1	[ 0 ]	intervention 1: Extended release, 60 mg, oral daily	intervention 1: Trospium Chloride	1	Glendale \| California \| United States \| -118.25508 \| 34.14251	12	0	0	0	NCT00863551	1COMPLETED	2009-08-01	2009-04-01	Allergan	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 4 ]	186	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	This study will assess the safety and efficacy of aliskiren plus hydrochlorothiazide (HCTZ) in patients who do not achieve controlled blood pressure levels after treatment with another specified antihypertensive medication. There was an optional study extension for the first eligible 60 patients who wanted to participate that contains the triple therapy with amlodipine 5 mg and aliskiren 300 mg plus HCTZ 25 mg.	Title of study extension: An open-label, multicenter extension to evaluate the efficacy and safety of a 4 week therapy with amlodipine 5 mg and aliskiren 300 mg plus HCTZ 25 mg in hypertensive patients not adequately responding to a 4 week therapy each with the combinations of candesartan 32 mg plus hydrochlorothiazide 25 mg followed by aliskiren 300mg plus hydrochlorothiazide 25 mg	Hypertension	Hypertension aliskiren cardiovascular diseases	null	1	arm 1: None	[ 0 ]	3	[ 0, 0, 0 ]	intervention 1: 4 weeks treatment with candesartan 32 mg (two 16 mg tablets) plus hydrochlorothiazide 25 mg (two 12.5 mg tablets) taken orally with water in the morning between 7 and 10 am. intervention 2: Patients with uncontrolled mean sitting diastolic blood pressure (msDBP ≥ 90 mm Hg) at the end of Phase 1 were treated for 4 weeks with aliskiren 300 mg plus hydrochlorothiazide 25 mg in a single tablet taken orally with water in the morning between 7 and 10 am. intervention 3: The first 60 patients with uncontrolled mean sitting systolic or diastolic blood pressure (msDBP ≥ 90 mm Hg and/or msSBP ≥ 140 mm Hg) at the end of Phase 2 were offered 4 weeks treatment with aliskiren 300 mg plus HCTZ 25 mg in a single tablet plus an amlodipine 5 mg tablet taken orally with water in the morning between 7 and 10 am.	intervention 1: Candesartan+HCTZ - Phase 1 intervention 2: Aliskiren+HCTZ - Phase 2 intervention 3: Aliskiren+HCTZ+amlodipine - Phase 3	1	Chemnitz \| N/A \| Germany \| 12.92922 \| 50.8357	370	0	0	0	NCT00867490	1COMPLETED	2009-08-01	2009-03-01	Novartis	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 2 ]	11	NON_RANDOMIZED	CROSSOVER	0TREATMENT	0NONE	true	1FEMALE	false	The purpose of this study is to determine the oral dose level at which the investigative drug, Proellex, is able induce menstruation.	The purpose of this study is to determine the oral dose level at which the investigative drug, Proellex, is able to suppress endogenous progesterone in women. It is believed that giving Proellex in the early/mid-luteal phase of the cycle will suppress the effects of endogenous progesterone triggering the end of the cycle and inducing menstruation as happens naturally	Amenorrhea	Menstruation	null	5	arm 1: Initiation-Placebo Cycle-Five (5) placebo capsules will be dispensed to subjects to self-administer for five days starting on cycle day 18. arm 2: First Cycle (3 mg)- Five (5) 3 mg capsules of Proellex will be dispensed to subjects to self-administer for five days starting on cycle day 18. arm 3: Second Cycle (6 mg)-Subjects, who have not experienced menses, will have their dose of Proellex escalated, and be dispensed ten (10) 3 mg capsules of Proellex to self-administer 2, 3 mg capsules each day for five days starting on cycle day 18. arm 4: Third Cycle (12 mg)-Subjects, who have not experienced menses, will have their dose of Proellex escalated, and be dispensed twenty (20) 3 mg capsules of Proellex to self-administer 4, 3 mg capsules for five days starting on cycle day 18. arm 5: Fourth Cycle (25 mg)-Subjects, who have not experienced menses, will be dispensed five (5) 25 mg capsules of Proellex to self-administer for five days starting on cycle day 18.	[ 2, 0, 0, 0, 0 ]	2	[ 0, 0 ]	intervention 1: Placebo, 1 capsule daily for five days intervention 2: Proellex, one 3, 6, 12 or 25 mg capsule daily for five days	intervention 1: Placebo intervention 2: Proellex	1	Houston \| Texas \| United States \| -95.36327 \| 29.76328	0	0	0	0	NCT00881608	6TERMINATED	2009-08-01	2009-02-01	Repros Therapeutics Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 5 ]	12	NA	SINGLE_GROUP	7BASIC_SCIENCE	0NONE	false	0ALL	false	This study was designed to use a sensitive neuroendocrine probe, the Dexamethasone/Corticotropin-Releasing Hormone (DEX/CRH) test, in a sample of healthy adults with insomnia. The primary aim was to assess cortisol reactivity before and after long-term (6 weeks) administration of eszopiclone. It was hypothesized that treatment with eszopiclone would result in a significant reduction in plasma cortisol response to the DEX/CRH test following treatment of insomnia with standard dose of eszopiclone.	see above	Insomnia		null	1	arm 1: Standard dosing of drug for 6 weeks for insomnia	[ 0 ]	1	[ 0 ]	intervention 1: 6 weeks standard oral therapy	intervention 1: eszopiclone	1	Providence \| Rhode Island \| United States \| -71.41283 \| 41.82399	12	0	0	0	NCT00889200	1COMPLETED	2009-08-01	2007-05-01	Butler Hospital	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 2, 3 ]	65	RANDOMIZED	PARALLEL	0TREATMENT	1SINGLE	false	0ALL	false	This study is designed to evaluate the pharmacokinetics, tolerability, and safety of exenatide once weekly suspension in both healthy subjects and in subjects with type 2 diabetes. The study will also evaluate efficacy in the type 2 diabetes patients. Development of this exenatide once weekly presentation would eliminate the need to reconstitute the product prior to use.	null	Type 2 Diabetes Mellitus	diabetes exenatide once weekly Byetta Amylin Lilly	null	3	arm 1: A single 10-mg dose of exenatide once weekly suspension given to healthy participants via 3 subcutaneous (SC) injections at Day 1. arm 2: On Day 1, participants with type 2 diabetes mellitus treated with diet and exercise alone or with a stable regimen of metformin, thiazolidinedione (TZD), or a combination of metformin or TZD were randomized to receive weekly injections of exenatide suspension for 12 weeks. arm 3: On Day 1, participants with type 2 diabetes mellitus treated with diet and exercise alone or with a stable regimen of metformin, thiazolidinedione (TZD), or a combination of metformin or TZD were randomized to receive weekly injections of medium-chain triglycerides (MCT)-diluent placebo for 12 weeks.	[ 0, 0, 2 ]	3	[ 0, 0, 10 ]	intervention 1: subcutaneous injection, 10.0 mg, single injection intervention 2: subcutaneous injection, 2.0 mg, once a week for 12 weeks intervention 3: subcutaneous injection, volume equivalent to Cohort 2 experimental intervention, once a week for 12 weeks	intervention 1: exenatide once weekly intervention 2: exenatide once weekly intervention 3: Placebo	1	Lincoln \| Nebraska \| United States \| -96.66696 \| 40.8	65	0	0	0	NCT00894322	1COMPLETED	2009-08-01	2009-04-01	AstraZeneca	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 0 ]	44	RANDOMIZED	PARALLEL	null	3TRIPLE	true	0ALL	false	The purpose of this research is to validate the common administration of oral midazolam to children prior to voiding cystourethrogram (VCUG) to see if this will significantly decrease children's anxiety and make the experience less traumatic.	null	Vesicoureteral Reflux	Midazolam VCUG Anxiety	null	2	arm 1: Both patients who are VCUG naive and patients who have had a previous VCUG are given oral midazolam prior to undergoing the VCUG. arm 2: Both patients who are VCUG naive and patients who have had a previous VCUG are given an oral placebo prior to undergoing the VCUG.	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: Children are randomized to receive oral midazolam .5 mg/kg prior to undergoing VCUG intervention 2: Children are randomized to receive a placebo prior to undergoing VCUG	intervention 1: midazolam intervention 2: placebo	1	St Louis \| Missouri \| United States \| -90.19789 \| 38.62727	44	0	0	0	NCT00894465	6TERMINATED	2009-08-01	2006-08-01	Washington University School of Medicine	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 0 ]	4	NA	SINGLE_GROUP	7BASIC_SCIENCE	0NONE	true	0ALL	false	Hypothesis: Low dose aspirin does not change exhaled inflammatory breath mediators in normal subjects.	Aim: 1. To study the effect of low dose aspirin on exhaled breath inflammatory mediators 2. To compare the change to that seen in diseased states such as asthma and Lymphangioleiomyomatosis (LAM) We will interview healthy volunteers to confirm that they do not have any major underlying medical conditions such as heart disease, diabetes, stroke and bleeding disorders. We will collect breath condensate before and after two weeks of low dose over the counter enteric coated aspirin 81 mg/day therapy. Side effects are extremely rare at this dose, but include bleeding, heart burn and allergic reaction.	Healthy	healthy volunteers aspirin Normal healthy subjects	null	1	arm 1: Low dose daily aspirin in healthy volunteers for two weeks	[ 0 ]	1	[ 0 ]	intervention 1: 81 mg orally daily for two weeks	intervention 1: aspirin	1	Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843	4	0	0	0	NCT00898222	1COMPLETED	2009-08-01	2009-05-01	Brigham and Women's Hospital	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 2 ]	24	RANDOMIZED	CROSSOVER	null	0NONE	true	0ALL	false	To demonstrate bioequivalence of a 2.5 mg saxagliptin/500 mg metformin (glucophage) immediate release (IR) fixed dose combination (FDC) tablet to the 2.5 mg saxagliptin tablet and 500 mg metformin IR tablet co-administered to healthy subjects in a fasted and in a fed state.	null	Type 2 Diabetes Mellitus		null	4	arm 1: Participants were randomized to receive oral co-administration of a 2.5 mg tablet of saxagliptin plus a 500 mg tablet of metformin immediate release (IR) under fasted conditions (S + M \[fasted\]) followed by a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fed conditions (S/M \[fed\]) followed by S/M under fasting conditions (S/M \[fasted\]) followed by S + M under fed conditions (S + M \[fed\]) arm 2: Participants were randomized to receive S/M (fasted) followed by S + M (fasted) followed by S + M (fed) followed by S/M (fed) arm 3: Participants were randomized to receive S + M (fed) followed by S/M (fasted) followed by S/M (fed) followed by S+M (fasted) arm 4: Participants were randomized to receive S/M (fed) followed by S+M (fed) followed by S+M (fasted) followed by S/M (fasted)	[ 0, 0, 0, 0 ]	4	[ 0, 0, 0, 0 ]	intervention 1: Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fasted conditions intervention 2: Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fasting conditions intervention 3: Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fed conditions intervention 4: Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fed conditions	intervention 1: Co-administration of Saxagliptin and Metformin IR, Fasted intervention 2: Saxagliptin/Metformin, Fasting intervention 3: Co-administration of Saxagliptin and Metformin IR, Fed intervention 4: Saxagliptin/Metformin, Fed	1	Lincoln \| Nebraska \| United States \| -96.66696 \| 40.8	96	0	0	0	NCT00899470	1COMPLETED	2009-08-01	2009-06-01	AstraZeneca	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 4 ]	45	RANDOMIZED	CROSSOVER	0TREATMENT	3TRIPLE	false	0ALL	false	The objective of this study was to establish that an optimal dose of Quillivant XR oral suspension would result in a significant reduction in signs and symptoms of ADHD compared to placebo treatment in pediatric patients ages 6-12 years with ADHD.	null	Attention Deficit Hyperactivity Disorder	Hyperactivity Attention Deficit Disorder ADHD Pediatric Patients Quillivant methylphenidate	null	2	arm 1: None arm 2: None	[ 0, 2 ]	3	[ 0, 0, 0 ]	intervention 1: Oral Suspension 25mg/5mL; 20-60 mg/day intervention 2: Matching Placebo Oral Suspension 25mg/5mL; 20-60 mg/day intervention 3: Matching placebo was a solution that was identical in taste and appearance to the Active drug that was used in this study.	intervention 1: Quillivant Oral Suspension XR intervention 2: Placebo intervention 3: Placebo	2	Irvine \| California \| United States \| -117.82311 \| 33.66946 Las Vegas \| Nevada \| United States \| -115.13722 \| 36.17497	135	0	0	0	NCT00904670	1COMPLETED	2009-08-01	2009-04-01	Pfizer	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 5 ]	16	RANDOMIZED	CROSSOVER	9OTHER	0NONE	true	0ALL	false	This study will compare the amount of bronchial tube relaxation from the Formoterol medicine contained in the Symbicort pressure Metered Dose Inhaler(pMDI)(a combination of Budesonide, a steroid, and Formoterol, a drug which relaxes the bronchial smooth muscle. The comparison will be using the pMDI in the usual fashion to the pMDIs and a spacer which allows more time for breathing in the medication. Breathing tests will be measured over a 12 hour period for the comparison.	Sixteen subjects will receive treatment in a cross-over design. They will inhale Symbicort 160/4.5 two inhalations in the manner prescribed in the approved package insert. The second intervention will be the inhalation of Symbicort 160/4.5 two inhalations through a valved holding chamber (Aero Chamber Plus). Breathing tests including spirometry will be measured at various time periods over a 12-hour time frame in each intervention. Comparison will be made of the two periods to demonstrate that the use of the valved holding chamber does not adversely affect the bronchodilation of the formoterol component of the combination drug.	Asthma	Asthma Formoterol Long Acting Beta Adrenergic Bronchodilator Symbicort Aerochamber	null	2	arm 1: The intervention in this group will use inhalation from the pMDI containing budesonide/formoterol pMDI 160/4.5 2 inhalations as approved. (FDA approved product information) without a spacer. The pulmonary function tests (PFTs) will be collected at baseline and for a period of 12 hours post inhalation of 2 inhalation of budesonide /formoterol; pMDI160/5. arm 2: The intervention in this group will use the pMDI budesonide/formoterol 160/4.5 with a valve holding chamber spacer device, Aerochamber Plus which is the intervention being studied The PFTs will be collected at baseline and for a period of 12 hours post inhalation of 2 inhalation of Symbicort 160/5. This is the intervention to be studied for comparison to the non-spacer inhalations..	[ 5, 0 ]	2	[ 0, 1 ]	intervention 1: The asthmatic subjects will receive budesonide/formoterol pMDI 160/4.5 pMDI 2 inhalations used in conventional fashion, and have pulmonary function measured over 12 hours who are expected to show bronchodilation. intervention 2: Symbicort 160/4.5 2 inhalations will be administered through a valved holding chamber, Aerochamber Plus, Pulmonary functions will be measured over 12 hours in asthmatic subjects who are expected to show bronchodilation.	intervention 1: pMDI budesonide/formotrol 160/4.5 is in group 1 intervention 2: Symbicort 160/4.5 plus Aerochamber Plus included in group 2	1	El Paso \| Texas \| United States \| -106.48693 \| 31.75872	32	0	0	0	NCT00915538	1COMPLETED	2009-08-01	2009-07-01	Western Sky Medical Research	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 3 ]	92	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	true	The purpose of this study is to evaluate the antihypertensive efficacy and safety of Fimasartan (BR-A-657•K) during 24 hours by dose in patients with mild to moderate essential hypertension.	Fimasartan(BR-A-657-K), a selective blocker of AT1 receptor subtype, showed the rapid and potent antihypertensive effect in many hypertensive models. Phase I study, Fimasartan(BR-A-657-K) 20mg \~ 480mg single dosing with healthy subjects, demonstrated that the Fimasartan(BR-A-657-K) was very safe and well tolerated. Another phase I study, Fimasartan(BR-A-657-K) 120mg and 360mg dosing for 7 days, also showed that Fimasartan(BR-A-657-K) was safe and tolerable though one temporal adverse event was observed in high dose. A Randomized, Double-blind, Valsartan-referenced, Parallel Grouped, Therapeutic Exploratory Clinical Study to Evaluate the Antihypertensive Efficacy of Fimasartan(BR-A-657•K) during 24hoursby dose in Patients with Mild to Moderate Essential Hypertension. Approximately 90 patients will be enrolled over 12 months in 5 centers nationwide. After 2 weeks of placebo run-in period, all subjects will be randomized into one of the following 3 groups. Subjects will take test/control drug for 8 weeks of treatment period. If subjects take any antihypertensive medications before screening, the subjects will have 1 week of wash-out period. Group I : Fimasartan 60mg group. Group II : Fimasartan 120mg group Group III : Valsartan 80mg group	Essential Hypertension	Fimasartan Essential Hypertension 24hour ABPM Population PK	null	3	arm 1: Fimasartan 60 mg group arm 2: Fimasartan 120 mg group arm 3: Reference (Valsartan 80 mg) group	[ 0, 0, 1 ]	3	[ 0, 0, 0 ]	intervention 1: Fimasartan 60 mg intervention 2: Fimasartan 120 mg intervention 3: Reference (Valsartan 80 mg)	intervention 1: Fimasartan 60 mg group intervention 2: Fimasartan 120 mg group intervention 3: Reference (Valsartan 80 mg) group	0	null	92	0	0	0	NCT00922441	1COMPLETED	2009-08-01	2008-12-01	Boryung Pharmaceutical Co., Ltd	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 5 ]	139	RANDOMIZED	PARALLEL	null	4QUADRUPLE	false	0ALL	false	The purpose of the study is to compare the sedation profile one hour after dose administration between Seroquel IR and Seroquel XR.	null	Bipolar Depression	inpatient bipolar depression quetiapine Seroquel IR Seroquel XR safety tolerability	null	2	arm 1: Quetiapine 25, 100, 200 and 300 mg arm 2: Quetiapine 50, 200, 300	[ 1, 1 ]	2	[ 0, 0 ]	intervention 1: Oral, 3 tablets daily: (2 x 25 mg + 1 x 50 mg) at one time each day intervention 2: Oral, 3 tablets daily: (2 x 25 mg + 1 x 50 mg) at one time each day	intervention 1: Quetiapine Immediate Release intervention 2: Quetiapine Extended Release	0	null	139	0	0	0	NCT00926393	1COMPLETED	2009-08-01	2009-06-01	AstraZeneca	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3 ]	122	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	0ALL	false	The purpose of this study was to evaluate analgesic efficacy and safety of hydrocodone/acetaminophen compared to placebo in moderate to severe pain following molar extraction.	Dosing started within 6 hours after completion of third molar extraction. Study drug was given once every 6 hours for 12 hours (for a total of 2 doses). Participants were randomized to receive placebo or active drug (either experimental drug or comparator). The total dose was the same for both groups receiving active drug, but was given as either 1 dose of extended-release tablets (experimental drug), or 2 doses of immediate-release tablets (active comparator).	Pain		null	3	arm 1: 1 dose of 1 ABT-712 extended-release tablet plus 1 placebo tablet, followed by 1 dose of 2 placebo tablets, administered once every 6 hours for 12 hours (for a total of 2 doses). arm 2: 2 doses of 1 hydrocodone/acetaminophen immediate-release tablet plus 1 placebo tablet, administered once every 6 hours for 12 hours (for a total of 2 doses). arm 3: 2 doses of 2 placebo tablets, administered once every 6 hours for 12 hours (for a total of 2 doses).	[ 0, 1, 2 ]	3	[ 0, 0, 0 ]	intervention 1: ABT-712 extended-release tablet intervention 2: Hydrocodone/acetaminophen immediate-release tablet intervention 3: Placebo tablet	intervention 1: ABT-712 Extended-release intervention 2: Hydrocodone/Acetaminophen Immediate-release intervention 3: Placebo	3	Austin \| Texas \| United States \| -97.74306 \| 30.26715 San Marcos \| Texas \| United States \| -97.94139 \| 29.88327 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078	122	0	0	0	NCT00935311	1COMPLETED	2009-08-01	2009-06-01	AbbVie (prior sponsor, Abbott)	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 2 ]	24	RANDOMIZED	CROSSOVER	7BASIC_SCIENCE	0NONE	true	0ALL	false	The study will be an open-label, randomized, 2-period, 2-treatment, 2-sequence, cross-over, single-dose study employing administration of two PF-02341066 formulations in the fasted state to healthy adult volunteers.	null	Healthy	bioavailability, capsule, tablet, healthy volunteer	null	2	arm 1: None arm 2: None	[ 0, 0 ]	2	[ 0, 0 ]	intervention 1: A 250-mg single dose of PF-02341066 administered as 1 x 50-mg Powder-in-Capsule and 2 x 100-mg Powder-in-Capsules intervention 2: A 250-mg single dose of PF-02341066 administered as 1 x 50-mg Immediate Release Tablet and 2 x 100-mg Immediate Release Tablets	intervention 1: PF-02341066 intervention 2: PF-02341066	1	New Haven \| Connecticut \| United States \| -72.92816 \| 41.30815	48	0	0	0	NCT00939731	1COMPLETED	2009-08-01	2009-07-01	Pfizer	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 4 ]	473	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	false	The purpose of the study is to assess the efficacy and safety of 300 IR sublingual tablet of grass pollen allergen extract compared to placebo in adult patient with allergic rhinoconjunctivitis.	Allergy is one of the most common chronic disease in the world currently affecting between 10% and 25% of the general population. Allergies to pollens characteristically result in seasonal rhinitis symptoms and allergic rhinoconjunctivitis is characterized by sneezing, congestion, rhinorrhea, nasal or palatal itching and itchy, watery, red and swollen eyes. Even if several drugs effectively manage allergic rhinoconjunctivitis symptoms, immunotherapy is considered more appropriate for patients in whom these symptoms are not optimally controlled with relief medications. In the study, each of the six rhinoconjunctivitis symptoms (sneezing, runny nose, itchy nose, nasal congestion, itchy eyes, watery eyes) will be evaluated daily and relief medication intake (oral antihistamines, eye drop antihistamine, nasal corticosteroid, oral corticosteroid) reported daily during the grass pollen season. Efficacy and good safety profile of 300IR SLIT tablet administered once per day for approximately six months (starting 4 months before and over the season) will be demonstrated during the grass pollen season compared to placebo.	Allergic Rhinitis Due to Grass Pollens	allergic rhinoconjunctivitis	null	2	arm 1: 300 IR grass pollen allergen extract tablet arm 2: Pacebo tablet	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: 300 IR grass pollen allergen extract tablet taken daily for approximately 6 months starting 4 months before the grass pollen season and over the grass pollen season intervention 2: Placebo sublingual tablet taken daily for approximately 6 months starting 4 months before the grass pollen season and over the grass pollen season	intervention 1: 300 IR intervention 2: Placebo	19	Normal \| Illinois \| United States \| -88.99063 \| 40.5142 Lexington \| Kentucky \| United States \| -84.47772 \| 37.98869 Owensboro \| Kentucky \| United States \| -87.11333 \| 37.77422 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Ypsilanti \| Michigan \| United States \| -83.61299 \| 42.24115 Columbia \| Missouri \| United States \| -92.33407 \| 38.95171 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Warrensburg \| Missouri \| United States \| -93.73605 \| 38.76279 Billings \| Montana \| United States \| -108.50069 \| 45.78329 Missoula \| Montana \| United States \| -113.994 \| 46.87215 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Eugene \| Oregon \| United States \| -123.08675 \| 44.05207 Lake Oswego \| Oregon \| United States \| -122.67065 \| 45.42067 Medford \| Oregon \| United States \| -122.87559 \| 42.32652 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 Vancouver \| Washington \| United States \| -122.66149 \| 45.63873	473	0	0	0	NCT00955825	1COMPLETED	2009-08-01	2008-10-01	Stallergenes Greer	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 2 ]	40	RANDOMIZED	CROSSOVER	7BASIC_SCIENCE	0NONE	true	2MALE	false	The major aim of this study is to investigate and compare the drug amount delivered to the body after sequential application of 2 rotigotine transdermal patches from 2 different manufacturing sites.	null	Healthy Volunteers	Rotigotine Neupro®	null	2	arm 1: Two single applications of rotigotine patches from two different manufacturing sites in the order A-B separated by a washout phase of at least 5 days arm 2: Two single applications of rotigotine patches from two different manufacturing sites in the order B-A separated by a washout phase of at least 5 days	[ 0, 0 ]	1	[ 0 ]	intervention 1: Rotigotine 4.5 mg/10 cm\^2 patch applied for 24 hours	intervention 1: rotigotine transdermal patch (Neupro®)	1	Neuss \| North Rhine-Westphalia \| Germany \| 6.68504 \| 51.19807	79	0	0	0	NCT00957944	1COMPLETED	2009-08-01	2009-07-01	UCB Pharma	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3 ]	4	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	1FEMALE	true	An open label, extension study for subjects completing the ZPU-003 Ext 1 study.	This is an open label, extension study for subjects completing the ZPU-003 Ext 1 study and an off-drug interval (menses), prior to the start of the first 16-week dosing cycle. Subjects will receive a 50 mg Proellex® daily dose. Total study participation for ZPU-003 Ext 2 (Extension 2) may be up to three 4 month drug cycles separated by off drug intervals.	Uterine Fibroids	Uterine fibroids	null	1	arm 1: 25 mg Proellex daily	[ 0 ]	1	[ 0 ]	intervention 1: one 25 mg capsules	intervention 1: 25 mg Proellex	1	Houston \| Texas \| United States \| -95.36327 \| 29.76328	0	0	0	0	NCT00958893	6TERMINATED	2009-08-01	2008-06-01	Repros Therapeutics Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 5 ]	53	RANDOMIZED	PARALLEL	0TREATMENT	1SINGLE	true	0ALL	false	This is a randomized, half-face study. On 1 side of the face, the subject will apply 1 of the 2 test products, clindamycin and benzoyl peroxide or dapsone gel and the contra lateral side of the face will remain non-treated to serve as a control.	This is a single-blind (blinded expert grader), parallel group, randomized, half-face study being conducted at one clinical site. On 1 side of the face, the subject will apply 1 of the 2 test products, clindamycin and benzoyl peroxide or dapsone gel and the contra lateral side of the face will remain non-treated to serve as a control. Approximately 25-30 male and female healthy subjects without facial acne, aged 18 to 45, will be randomly assigned to each product. The eligible subjects who qualify will be entered into a 2-week treatment phase. The first of application of the study medication will be supervised at the site, Monday through Friday of each week. Any additional applications should be applied by the subjects at home each evening and the times of application recorded on a diary card. Subjects will apply the study product at home on Saturdays and Sundays and record the times of application on a diary card. A blinded expert grader will rate comparative product tolerance during the study before study product is applied. Instrumentation measurements of TEWL will be utilized to evaluate product mildness. Duplicate sebum samples will be taken from the left and right forehead areas and assessed. Subject will complete questionnaires and all adverse events will be recorded.	Acne Vulgaris		null	2	arm 1: Once-daily applications of clindamycin/BPO gel to the randomized side of the face either left or right. arm 2: Twice-daily applications of dapsone gel to one side of the face.	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: Daily applications, to the randomized side of the face either left or right, of clindamycin and benzoyl peroxide intervention 2: Twice-daily applications of dapsone gel	intervention 1: clindamycin and benzoyl peroxide intervention 2: Dapsone gel	1	Broomall \| Pennsylvania \| United States \| -75.35658 \| 39.9815	52	0	0	0	NCT00964366	1COMPLETED	2009-08-01	2009-07-01	Stiefel, a GSK Company	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3 ]	55	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	Background: Repeated episodes of bleeding from gastrointestinal vascular malformations refractory to endoscopic or surgical therapy often pose a major therapeutic challenge. Methods: The investigators performed a randomized, parallel controlled study of thalidomide as a therapy for recurrent gastrointestinal bleeding due to vascular malformation. Patients with at least six episodes of bleeding in the prior year due to vascular malformation were randomly grouped, prescribed a four-month regimen of either 25 mg of thalidomide or 100 mg of iron orally four times daily, and monitored for at least one year. The primary end point was defined as the patients whose rebleeds decreased from baseline by ≥ 50% at 12 months and the cessation of bleeding. Rebleeding was defined based on a positive fecal occult blood test (FOBT) (monoclonal colloidal gold color technology) at any visit after treatment. Secondary outcomes included the participants dependent on blood transfusions and changes from baseline in transfused packed red cell units, bleeding episodes, bleeding durations, and hemoglobin levels at 12 months. Statistical significance was defined at P \< 0.05.	Protocol Description: This is an exploratory, randomized, parallel controlled study of thalidomide for recurrent gastrointestinal bleeding from vascular malformations. Informed consent was taken from all subjects and the Institute Ethics Committee approved the study protocol. All procedures were in accordance with the Declaration of Helsinki. The study was supported by no pharmaceutical funding. Study design and Intervention: From Nov. 2004 to Nov. 2007, patients with repeated episodes of chronic gastro-intestinal bleeding due to vascular malformations identified by oesophagogastroduodenoscopy, capsule endoscope or double-balloon endoscope were enrolled (according our enrollment criteria). The patients were randomly assigned to receive a four-month course of either 25 mg of thalidomide or 100mg iron orally at daily time 6 a.m.,12 noon,6 p.m. and 10 p.m., respectively. Randomization was performed through the proc plan procedure of Statistical Analysis Software (SAS), using the method of randomly permuted blocks of 4. Within each block, the number of patients allocated to each of the two treatments was equal. Each patient who met the inclusion criteria was consecutively assigned a random number in chronological order, which allocated him or her to one of the treatment groups. A blinded research nurse supervised patient randomization and drug administration. In the case of an adverse event, the study medication was temporarily or permanently discontinued based on subject inclination and toxicity intolerance. Concomitant therapies, such as blood transfusions and other symptomatic treatments like iron supplementation, were performed in both groups as necessary during the four-month treatment and subsequent follow-up periods. Blood transfusion was indicated and recorded when the hemoglobin (Hb) level reached \< 7.0 g/dl. Red-cell transfusions were administered according to patient Hb level as follows: 2 units were administered for 6.1 g/dl ≥ Hb ≤ 7.0 g/dl, 3 units for 5.1 g/dl ≥ Hb ≤ 6.0 g/dl, and 4 units for Hb \< 5.0 g/dl. Iron was provided for patients with 7.0 g/dl ≥ Hb ≤ 11.0 g/dl. After the four-month treatment course, all patients discontinued study medications except for cases where symptomatic treatments were necessary as described above. Assessment of response and adverse events: The primary end point was defined as the patients whose rebleeds decreased from baseline by ≥ 50% at 12 months and the cessation of bleeding. Rebleeding was defined based on a positive fecal occult blood test (FOBT) (monoclonal colloidal gold color technology) at any visit after treatment. Secondary outcomes included the participants dependent on blood transfusions and changes from baseline in transfused packed red cell units, bleeding episodes, bleeding durations, and hemoglobin levels at 12 months. Adverse events included any unfavorable change in health, including abnormal laboratory findings, during the study or follow-up period. Evaluation of Patients and Follow-up: * Certified research nurses collected information on the demographics and medical and social histories of all patients enrolled in the study. * After screening and baseline evaluations, the patients were closely monitored in the hospital for at least one week. They were then followed twice monthly during the four-mouth course of treatment and once a month thereafter. * Clinical follow-up was performed by qualified doctors. At all visits, the bleeding-related parameters (number and duration), a physical examination was performed and laboratory values were obtained for FOBT, complete blood counts, serum chemistries, and hepatic and renal function. Neuropathy and other adverse events were also assessed. * Patients were advised to refrain from any other non-prescribed medicines, especially rebleeding-related medications such as aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), anti-platelet drugs, anticoagulants, and Chinese medications (with salicylates), gingko, or Echinacea. Measurement of Vascular Endothelial Growth Factor (VEGF) in Sera: Laboratory assays for VEGF were performed at baseline and after the four-month treatment course in the thalidomide group, by a technician blinded to the assignment and final assessment. Three milliliters of serum of peripheral venous blood samples were centrifuged (3000 r/min at 4°C, 10 min), extracted, separated into freezing tubes, and stored at -70°C for no more than 4 months. Plasma VEGF levels (in pg/ml) were determined in duplicate using sandwich ELISA kits (R\&D Systems, USA) in a laboratory of the Shanghai Research Institute of Digestive Disease. Samples from each patient were batch-tested in a single run. For quality control, all samples were retested two more times in a subsequent run to confirm the results of the first run. Statistical Analysis: To our knowledge, no similar such study has previously been performed, and we were thus unable to refer to published studies to determine our samples. To this end, we performed an unpublished preliminary study. Response in the iron-control group and thalidomide group reached 10% and 80%, due to loose inclusion criteria (bleeding history was not restricted). For this study, we estimated that the primary outcome (the proportion of subjects whose number of yearly bleeds had decreased by ≥ 50%) would occur in 10% of the control group and 80% of the thalidomide group patients. An equally divided sample of 11 subjects was deemed sufficient for detecting the primary end point, with a type I error (two-sided) of 5% and a power of 90%. Assuming a 10% volunteer attrition rate to follow-up, we established a target sample size of 13 per group (calculated with nquery advisor software 5.0). Analyses of the responses and adverse events were performed on all registered patients according to the intention-to-treat principle. Statistical analysis was performed by a blinded biostatistician with the Statistical Product and Service Solutions (SPSS) 13.0 software package. We simultaneously analyzed the primary endpoint of the full analysis set (FAS) and per protocol set (PPS). Continuous variables were compared using a two-sample independent t-test or Wilcoxon rank-sum test. Categorical variables were compared using the chi-squared and Fisher's exact tests. A paired t-test was employed to compare differences in plasma VEGF levels before and after thalidomide treatment. The Breslow-Day test was used to test for the heterogeneity of treatment effects across strata. All reported P-values are two-sided. Data are reported as the mean ± standard deviation (SD) or median (range) for continuous variables and number (%) for categorical variables. Since adjustments to the control group were minimal, we also reported point estimates and 95% confidence intervals (CIs). For all outcomes, a P-value of \< 0.05 was considered statistically significant.	Obscure Gastrointestinal Bleeding Angiodysplasia Gastric Antral Vascular Ectasia Thalidomide	vascular malformation gastrointestinal bleeding thalidomide	null	2	arm 1: None arm 2: None	[ 1, 5 ]	2	[ 0, 0 ]	intervention 1: Patients were randomly assigned to receive a four-month course of 25 mg of thalidomide (Pharmaceutical Co., Ltd. of Chang-zhou, China). Medications were taken orally four times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m. intervention 2: Patients were randomly assigned to receive a four-month course of 100 mg of iron (Pharmaceutical Co., Ltd. of Nanjing, China). Medications were taken orally four times daily at 6 a.m., 12 noon, 6 p.m., and 10 p.m.	intervention 1: Thalidomide intervention 2: Iron	0	null	55	0	0	0	NCT00964496	1COMPLETED	2009-08-01	2004-11-01	Shanghai Jiao Tong University School of Medicine	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 2 ]	30	RANDOMIZED	CROSSOVER	0TREATMENT	0NONE	true	0ALL	false	The primary objective was to investigate whether multiple-dose administration of ESL 800 mg once daily affects the pharmacokinetics of simvastatin, a substrate of CYP34A.	This was a single centre, two-way crossover, randomised, open-label study in 24 healthy volunteers. The volunteers will receive an oral single-dose of simvastatin 80 mg on two occasions - once administered alone and once after treatment with an oral once-daily dose of 800 mg of ESL for 14 days -, separated by a washout period of 3 weeks or more	Epilepsy	Eslicarbazepine acetate simvastatin	null	2	arm 1: Simvastatin 80mg treatment period followed by Simvastatin 80 mg + eslicarbazepine acetate 800 mg treatment period arm 2: Simvastatin 80mg + eslicarbazepine acetate 800 mg treatment period followed by Simvastatin 80 mg treatment period	[ 0, 0 ]	2	[ 0, 0 ]	intervention 1: None intervention 2: None	intervention 1: Eslicarbazepine acetate intervention 2: Simvastatin	1	Rennes \| N/A \| France \| -1.67429 \| 48.11198	90	0	0	0	NCT00987558	1COMPLETED	2009-08-01	2009-06-01	Bial - Portela C S.A.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 4 ]	10	NON_RANDOMIZED	PARALLEL	1PREVENTION	1SINGLE	true	0ALL	false	Study to determine the sunscreen protection factor (SPF) and ultraviolet A protection factor (PFA) of 2 sunscreen products containing the combination of zinc oxide and avobenzone with and without ensulizole.	null	Sun Protection	Sunscreens	null	2	arm 1: Following Food and Drug Administration (FDA) guidelines for SPF testing, exposure control and product-protected site erythema responses are scored after 16 to 24 hours post-exposure to full spectrum light (Ultraviolet B radiation \[UVB\] and UVA). arm 2: Determination of Ultraviolet A Protection Factor (PFA). Following FDA guidelines, test sites exposed to UVA are scored for pigmentation responses 2 to 4 hours post-exposure.	[ 0, 0 ]	3	[ 0, 0, 0 ]	intervention 1: Sunscreen formula containing 15% Zinc Oxide, 3% Avobenzone, and 1% Ensulizole intervention 2: Sunscreen formula containing 15% Zinc Oxide and 3% Avobenzone intervention 3: 8% Homosalate Standard SPF 4 Sunscreen	intervention 1: Sunscreen Test Code: V53-028 intervention 2: Sunscreen Test Code: V53-030 intervention 3: Standard SPF 4 Sunscreen	0	null	10	0	0	0	NCT01001975	1COMPLETED	2009-08-01	2009-07-01	Bayer	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 0 ]	10	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	1FEMALE	true	The purpose of this study is to determine the feasibility of a short term administration of a targeted therapy (i.e., anastrozole) in women with newly diagnosed early invasive or non invasive breast cancer during the interval between their breast biopsy and surgery. Anastrozole is a form of hormonal therapy which is part of the standard treatment for hormone sensitive breast cancer in postmenopausal women. This clinical model is being used to evaluate the biologic effects of this drug on a specific molecular pathway called the PI3K/AKT signaling pathway.	Several clinical models are being explored for use in the phase I/II evaluation of targeted therapies for breast cancer. Biological markers can be measured in early stage invasive cancers in a presurgical model involving a short term intervention. In this model, women with newly diagnosed early invasive breast cancer receive a study drug during the interval between diagnostic breast biopsy and surgical resection. Tumor tissue obtained from the biopsy and surgical specimens are used to measure pre and post treatment molecular markers, respectively. The main advantages of this model include the ability to obtain direct information on molecular response in tumor tissue and elucidate drug mechanisms of action, the large patient population to draw from with early stage breast cancer, and the lack of unnecessary invasive procedures. We plan to conduct a pilot study of 10 postmenopausal women with newly diagnosed estrogen receptor (ER) positive invasive or non invasive breast cancer who will receive oral anastrozole 1mg daily for two weeks in the interval between diagnostic breast biopsy and definitive breast surgery. Patients will be identified by the breast surgeon or mammographer performing the breast biopsy. Patients with histologically confirmed ER+ invasive or non invasive breast cancer will be recruited by the medical oncologist and will start anastrozole two weeks prior to their scheduled surgery. The primary objective of this study is to demonstrate the feasibility of this presurgical model for evaluating targeted therapies for breast cancer. Secondary endpoints include changes in tissue levels of the proliferation marker Ki67 and proteins involved in PI3K/AKT signaling.	Invasive Breast Cancer	Postmenopausal women ER+ Estrogen positive PR+ Progesterone positive	null	1	arm 1: 1mg daily for two weeks in the interval between diagnostic breast biopsy and definitive breast surgery.	[ 0 ]	1	[ 0 ]	intervention 1: 1mg PO daily for two weeks prior to scheduled surgery	intervention 1: Anastrozole	1	New York \| New York \| United States \| -74.00597 \| 40.71427	10	0	0	0	NCT01004744	1COMPLETED	2009-08-01	2007-07-01	Columbia University	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 5 ]	142	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	The purpose of this study is to evaluate the safety and efficacy of Osmotic Release Oral System (OROS) methylphenidate in participants with Attention Deficit Hyperactivity Disorder (ADHD).	This is an open-label (all people involved know the identity of the intervention), single arm, multicenter (when more than one hospital or medical school team work on a medical research study), prospective study (study following participants forward in time) to evaluate the efficacy and safety of OROS methylphenidate in participants with ADHD (behavior disorder originating in childhood in which the essential features are signs of developmentally inappropriate inattention, impulsivity, and hyperactivity). The study duration will be of 12 weeks per participant, which is divided into 2 parts Screening (within 14 days before study commences on Day -1) and treatment (8 weeks and will include titration period \[from the initiation of the study treatment to determination of the individual's maintenance dose\] and maintenance period \[at least 4 weeks after determination of maintenance dose\]). Participants will receive initial dose depending on their body weight. OROS methylphenidate hydrochloride (HCL) will be given orally once daily at an initial dose of 18 milligram (mg) for participants below 30 kilogram (kg) and 27 mg for those over 30 kg of body weight. The dose will be increased by 9 mg or 18 mg every week for up to Week 8, followed by a maximum maintenance dose of 54 mg orally once daily up to Week 12 during which the dose can be decreased by 9 mg depending on tolerability. Efficacy will be evaluated by Korean Version, ADHD Rating Scale (K-ARS) total score and Clinical Global Impression)-Severity / Impression rating scale CGI-S/I. Participants safety will be monitored throughout the trial.	Attention Deficit Disorder With Hyperactivity	Attention Deficit Hyperactivity Disorder Methylphenidate Hydrochloride	null	1	arm 1: None	[ 0 ]	1	[ 0 ]	intervention 1: OROS methylphenidate hydrochloride (HCL) will be given orally once daily at an initial dose of 18 milligram (mg) for participants below 30 Kilogram (kg) and 27 mg for those over 30 kg of body weight. The dose will be increased by 9 mg or 18 mg every week for up to Week 8, followed by a maximum maintenance dose of 54 mg orally once daily up to Week 12 during which the dose can be decreased by 9 mg depending on tolerability.	intervention 1: Osmotic Release Oral System (OROS) Methylphenidate Hydrochloride	0	null	136	0	0	0	NCT01012622	1COMPLETED	2009-08-01	2008-09-01	Janssen Korea, Ltd., Korea	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 5 ]	270	RANDOMIZED	PARALLEL	0TREATMENT	1SINGLE	false	1FEMALE	false	The purpose of this study is to determine if the 2 gram single dose of metronidazole is as effective as the 7 day 500 mg BID dose for treatment of Trichomonas vaginalis (TV) among HIV-infected women.	This is a Phase IV equivalency trial as both doses of metronidazole are listed in the the Centers for Disease Control and Prevention Treatment Guidelines for the treatment of T vaginalis.	Trichomonas Infections HIV Infections		null	2	arm 1: Metronidazole 2 gm single dose arm 2: Metronidazole 500 mg dose x 7 days	[ 1, 1 ]	1	[ 0 ]	intervention 1: 2 gm single dose versus 7 day 500 mg BID dose	intervention 1: Metronidazole	5	New Orleans \| Louisiana \| United States \| -90.07507 \| 29.95465 New Orleans \| Louisiana \| United States \| -90.07507 \| 29.95465 Jackson \| Mississippi \| United States \| -90.18481 \| 32.29876 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Houston \| Texas \| United States \| -95.36327 \| 29.76328	270	0	0	0	NCT01018095	1COMPLETED	2009-08-01	2005-05-01	Tulane University Health Sciences Center	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 4 ]	793	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	false	The aim of this trial is to assess the efficacy of 0416 Ointment in the Treatment of Atopic Dermatitis. Treatment medication will be administered as follows: Apply a thin layer of ointment to affected skin areas twice daily and rub in gently and completely. Study medication will be applied twice a day, approximately 12 hours apart, for approximately 2 weeks.	null	Atopic Dermatitis	Atopic Dermatitis	null	3	arm 1: Test product that contains the active pharmaceutical ingredient arm 2: Reference product that contains active pharmaceutical ingredient arm 3: Placebo that contains no active pharmaceutical ingredient	[ 0, 1, 2 ]	3	[ 0, 0, 0 ]	intervention 1: Topical 0416 test product applied twice daily for 2 weeks intervention 2: Vehicle of 0416 test product applied twice daily for 2 weeks intervention 3: Reference Product for 0416 test product. Apply twice daily for 2 weeks.	intervention 1: 0416 intervention 2: Vehicle of 0416 test product intervention 3: tacrolimus ointment 0.1%	1	Melville \| New York \| United States \| -73.41512 \| 40.79343	793	0	0	0	NCT01053247	1COMPLETED	2009-08-01	2008-01-01	Fougera Pharmaceuticals Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 4 ]	27	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	true	1FEMALE	true	Safety and efficacy study of 25 and 50 mg doses of Proellex	The study is intended to provide more abundant safety and efficacy data of both the 25 and 50 mg doses of Proellex than ZPU-301, ZPU-302, ZPU-303 and ZPU-304 alone.	Uterine Fibroids	Uterine Fibroids	null	2	arm 1: 2, 25 mg capsules arm 2: 1, 25 mg capsule	[ 1, 1 ]	2	[ 0, 0 ]	intervention 1: 2, 25 mg capsules once per day intervention 2: 1, 25 mg capsule once per day	intervention 1: Proellex intervention 2: Proellex	4	Boynton Beach \| Florida \| United States \| -80.06643 \| 26.52535 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Houston \| Texas \| United States \| -95.36327 \| 29.76328	0	0	0	0	NCT01069120	6TERMINATED	2009-08-01	2009-04-01	Repros Therapeutics Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 4 ]	899	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	false	The aim of this trial is to assess the efficacy of 0417 Ointment in the Treatment of Atopic Dermatitis. Treatment medication will be administered as follows: Apply a thin layer of ointment to affected skin areas twice daily and rub in gently and completely. Study medication will be applied twice a day, approximately 12 hours apart, for approximately 4 weeks.	null	Atopic Dermatitis	Atopic Dermatitis	null	3	arm 1: Test product that contains the active pharmaceutical ingredient arm 2: Reference product that contains the active pharmaceutical ingredient arm 3: Placebo that contains no active pharmaceutical ingredient	[ 0, 1, 2 ]	3	[ 0, 0, 0 ]	intervention 1: Topical 0417 test product applied twice daily for 4 weeks intervention 2: Vehicle of 0417 test product applied twice daily for 4 weeks intervention 3: Reference product for 0417 test product. Apply twice daily for 4 weeks	intervention 1: 0417 intervention 2: Vehicle of 0417 test product intervention 3: Tacrolimus Ointment 0.03%	1	Melville \| New York \| United States \| -73.41512 \| 40.79343	899	0	0	0	NCT01139450	1COMPLETED	2009-08-01	2008-01-01	Fougera Pharmaceuticals Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3, 4 ]	336	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	The purpose of this study was to evaluate the long-term safety and efficacy of alogliptin and Thiazolidine administered once daily (QD) for 40 consecutive weeks in participants who completed a phase 2/3 Thiazolidine add on study.	Both insulin hyposecretion and insulin-resistance are considered to be involved in the development of type 2 diabetes mellitus. Takeda is developing SYR-322 (alogliptin) for the improvement of glycemic control in patients with type 2 diabetes mellitus. Alogliptin is an inhibitor of the dipeptidyl peptidase IV (DPP-IV) enzyme. DPP-IV is thought to be primarily responsible for the degradation of 2 peptide hormones released in response to nutrient ingestion. It is expected that inhibition of DPP-IV will improve glycemic control in patients with type 2 diabetes. To evaluate the long-term safety and efficacy of alogliptin, participants in the present study were enrolled from a core phase 2/3 thiazolidine add on study (SYR-322/CCT-004; NCT01318070).	Type 2 Diabetes Mellitus	Diabetes Mellitus - Type 2 Diabetes Mellitus Drug Therapy	null	2	arm 1: None arm 2: None	[ 1, 1 ]	2	[ 0, 0 ]	intervention 1: Alogliptin 12.5 mg, tablets, orally, once daily and Pioglitazone 15 mg or 30 mg, tablets, orally, once daily for up to 40 weeks. intervention 2: Alogliptin 25 mg, tablets, orally, once daily and Pioglitazone 15 mg or 30 mg, tablets, orally, once daily for up to 40 weeks.	intervention 1: Alogliptin and pioglitazone intervention 2: Alogliptin and pioglitazone	0	null	331	0	0	0	NCT01318122	1COMPLETED	2009-08-01	2008-05-01	Takeda	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 4 ]	571	RANDOMIZED	PARALLEL	0TREATMENT	1SINGLE	false	0ALL	false	The aim of the study is to evaluate the non-inferiority of BF-200 ALA (Ameluz) in the treatment of actinic keratosis (AK) with photodynamic therapy (PDT) compared to Metvix.	This was a randomized, observer-blind, multinational, comparator and placebo-controlled parallel group, (3:3:1 ratio) study to compare the efficacy and safety of BF-200 ALA with the comparator Metvix® (methyl-\[5-amino-4-oxopentanoate\]) and placebo, for the treatment of AK with PDT.	Actinic Keratosis		null	3	arm 1: Topical application of BF-200 ALA gel containing 78 mg/g 5-aminolevulinic acid (ALA). Application of a 1 mm thick layer covering each lesion and a 0.5 cm to 1 cm surrounding margin. arm 2: Topical application of MAL cream (Metvix) containing 160 mg/g methyl-aminolevulinate (MAL). Application of a 1 mm thick layer covering each lesion and a 0.5 cm to 1 cm surrounding margin. arm 3: Topical application of matched Placebo to BF-200 ALA gel (without containing active ingredient) ). Application of a 1 mm thick layer covering each lesion and a 0.5 cm to 1 cm surrounding margin.	[ 1, 1, 2 ]	3	[ 0, 0, 0 ]	intervention 1: topical treatment for photodynamic therapy combining drug application and after a 3 h incubation subsequent illumination with a broad or narrow spectrum light source. intervention 2: topical treatment for photodynamic therapy combining drug application and after a 3 h incubation subsequent illumination with a broad or narrow spectrum light source. intervention 3: topical treatment for photodynamic therapy combining vehicle application and after a 3 h incubation subsequent illumination with a broad or narrow spectrum light source.	intervention 1: BF-200 ALA intervention 2: MAL Cream intervention 3: Vehicle	0	null	570	0	0	0	NCT02799069	1COMPLETED	2009-08-01	2008-04-01	Biofrontera Bioscience GmbH	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3 ]	196	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	false	The purpose of this study is to assess the efficacy and safety of a single dose of an ibuprofen 600 mg extended release formulation in post-operative dental pain. There is concern that the manufacturing process may affect the performance characteristics of the selected prototype. Therefore, two formulations of this prototype manufactured by two different processes, \[roller compaction\] and \[wet granulation\] will be included in this study. The preferred prototype manufactured by two different methods will be compared to placebo and each other. This study will also characterize the pharmacokinetic/pharmacodynamic relationship with these formulations.	null	Pain	Extended-release ibuprofen	null	4	arm 1: 1 x 600 mg ibuprofen IR/ER-roller compaction caplet arm 2: 1 x 600 mg ibuprofen IR/ER-Wet granulation caplet arm 3: 1x 220 mg naproxen sodium (Aleve caplet) arm 4: 1 x placebo caplet	[ 0, 0, 1, 2 ]	4	[ 0, 0, 0, 0 ]	intervention 1: None intervention 2: None intervention 3: None intervention 4: None	intervention 1: ibuprofen intervention 2: ibuprofen intervention 3: naproxen intervention 4: Placebo	1	Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078	196	0	0	0	NCT00913627	1COMPLETED	2009-08-05	2009-05-07	Pfizer	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 2, 3 ]	27	NON_RANDOMIZED	SEQUENTIAL	1PREVENTION	0NONE	false	0ALL	false	The purpose of this study is to explore a treatment that potentially enhances the delivery of chemotherapy to tumors in participants with superficial bladder cancer. The investigational medication to be studied is an enzyme called ChemophaseTM (recombinant human hyaluronidase, rHuPH20). Chemophase is being specifically developed for use with other anticancer drug to increase the local penetration of the anticancer drug for the treatment of superficial bladder cancer. In this study, Chemophase will be given in combination with mitomycin C directly into the bladder. Mitomycin C is an anti-tumor drug that is commonly used to treat superficial bladder cancer. It is envisioned that Chemophase with mitomycin C may potentially increase the local penetration of mitomycin C into remaining cancer cells following surgery to treat superficial bladder cancer.	The primary objectives of this study are to: 1. determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of escalating doses of Chemophase in combination with mitomycin (mitomycin C, MMC) administered as weekly intravesical instillations for five weeks, and 2. establish the dose of Chemophase with MMC recommended for future studies. The secondary objectives of this study are to: 1. assess the pharmacokinetics of intravesical administration of MMC alone and in combination with intravesical administration of Chemophase, 2. for those participants treated at the MTD, assess the safety and tolerability of intravesical administration of MMC with Chemophase over up to 7 additional maintenance treatments every 3 months following the initial six weekly instillations, and 3. observe participants for any preliminary evidence of anti-tumor activity of MMC and Chemophase when combined. Study participants will receive six weekly study treatments administered intravesically (at Weeks 1 through 6) followed by post-treatment evaluations, at Weeks 8 and 12. The 12 participants treated at MTD will continue to receive combination therapy every three months until the end of Year 2 or until the time of documented tumor recurrence, whichever occurs first. For other participants, long-term follow-up after Week 12 will consist of disease monitoring of participants by telephone and will be performed every three months beginning three months after last study treatment for two years and then every six months thereafter, until bladder tumor recurrence.	Bladder Cancer	Non-invasive bladder cancer Chemophase Intravesical administration Superficial Bladder Cancer	Prot_000.pdf: Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 1 of 89 Version 4.0 26 Feb 2009 Clinical Trial Protocol Title: A Phase I-IIa, Multicenter, Open-Label, Multiple Dose, Safety, Tolerability and Pharmacokinetic Study of Recombinant Human Hyaluronidase (Chemophase) in Combination with Mitomycin in Patients with Non- Muscular-Invasive Bladder Cancer Protocol Number: HZ2-05-01 Version Number: 4.0 Version Date: 26 February 2009 Supersedes: Version 3.0, 30 April 2007 Version 2.0, 17 March 2006 Version 1.0, 29 August 2005 Sponsor: Halozyme Therapeutics, Inc. (Halozyme) 11588 Sorrento Valley Road, Suite 17 San Diego, California 92121 Tel: This document and the information it contains is the property of Halozyme Therapeutics, Inc. and is provided for the sole and exclusive use of Investigators of this clinical investigation. The information in this document may not be disclosed unless such disclosure is required by Federal or applicable State Law or Regulations or unless there is prior written consent from Halozyme Therapeutics, Inc. Subject to the foregoing, this information may be disclosed only to those persons involved in the clinical investigation who have a need to know, and who share the obligation not to further disseminate this information. NCT # NCT00318643 Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 2 of 89 Version 4.0 26 Feb 2009 TABLE OF CONTENTS TABLE OF CONTENTS.............................................................................................. 2 Tables ..................................................................................................................... 5 Figures .................................................................................................................... 5 1. STUDY SYNOPSIS ............................................................................................. 6 2. STUDY SCHEDULE OF EVENTS .................................................................... 12 3. GLOSSARY AND ABBREVIATIONS .............................................................. 15 4. BACKGROUND AND RATIONALE ................................................................ 16 4.1. Introduction to Hyaluronidases, rHuPH20, and Chemophase ..................... 16 4.2. Background on Non-Muscular-Invasive Bladder Carcinoma ......................... 17 4.3. Rationale for Use of Chemophase in Bladder Cancer .................................... 19 5. STUDY OBJECTIVES ....................................................................................... 23 5.1. Primary Objectives ...................................................................................... 23 5.2. Secondary Objectives .................................................................................. 23 6. STUDY DESIGN ............................................................................................... 24 6.1. Overview of Study Design ........................................................................... 24 6.2. Number of Patients...................................................................................... 25 6.3. Patient Recruitment ..................................................................................... 25 6.4. Treatment Summary .................................................................................... 26 6.5. Study Duration ............................................................................................ 27 7. STUDY POPULATION ..................................................................................... 27 7.1. Inclusion Criteria......................................................................................... 27 7.2. Exclusion Criteria ....................................................................................... 28 7.3. Prohibitions and Restrictions during the Study ............................................. 29 7.4. Contraindications, Warnings and Precautions with Regard to MMC Administration ............................................................................................ 29 8. STUDY METHODS AND PROCEDURES ........................................................ 30 8.1. Designated Laboratories: Central, Local, PK, and Biomarker Labs............... 30 8.2. Procedures Prior to Screening (Day -28 to Day -1) ....................................... 31 8.3. Screening Procedures (Day -28 to Day -1).................................................... 31 8.4. Patient Registration and Replacement of Patients ......................................... 33 8.5. Patient Randomization Procedures and Blinding........................................... 34 8.6. Treatment Procedures on Day 1/Week 1....................................................... 34 8.7. Treatment Procedures Week 2 through Week 6 ............................................ 35 8.8. Dose-Limiting Toxicity (DLT) .................................................................... 36 8.9. Escalation to Next Dose Cohort, Stopping Rules, and Determination of MTD 37 8.10. Premature Termination of Treatment/Withdrawal of Patients .................... 39 8.11. Post-Treatment Procedures at Week 8 ...................................................... 39 8.12. Post-Treatment Procedures at Week 12 .................................................... 40 8.13. Long-Term Maintenance Therapy and Follow-Up (Following Week 12) ... 41 9. STUDY MEDICATIONS AND ADMINISTRATION......................................... 42 Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 3 of 89 Version 4.0 26 Feb 2009 9.1. Mitomycin (Mitomycin C, MMC)................................................................ 42 9.1.1. Supply of MMC................................................................................... 42 9.1.2. Storage and Stability of MMC .............................................................. 43 9.1.3. Procedures for Proper Handling and Disposal of MMC ......................... 43 9.1.4. Preparation of MMC for Intravesical Instillation ................................... 43 9.2. Chemophase (rHuPH20).............................................................................. 44 9.2.1. Formulation and Supply of Chemophase............................................... 44 9.2.2. Storage and Stability of Chemophase.................................................... 44 9.2.3. Preparation of Chemophase for Intravesical Instillation ......................... 44 9.3. Dosing Schedule and Procedure for Intravesical Instillation of MMC with and without Chemophase ................................................................................... 46 10. ADVERSE EVENTS AND SAFETY MONITORING ..................................... 48 10.1. AE Definitions ........................................................................................ 48 10.2. Pre-Treatment-Emergent Adverse Events ................................................. 50 10.2. Laboratory Abnormalities as Adverse Events ........................................... 50 10.3. Classification of Adverse Events by Severity............................................ 51 10.4. Classification of Adverse Events by Relationship to Study Drug Administration ........................................................................................ 51 10.5. Known Toxicity Profiles of MMC and Chemophase ................................. 53 10.5.1. Known Toxicity Profile of MMC ......................................................... 53 10.5.2. Known Toxicity Profile of Chemophase ............................................... 55 10.6. Reporting of Adverse Events ................................................................... 56 10.6.1. Reporting of Serious Adverse Events.................................................... 56 10.6.2. Duration of Follow-Up of Adverse Events ............................................ 57 10.6.3. Other Information on t he Reporting of Adverse Events ......................... 57 10.6.4. Reporting of Safety Information to the Institutional Review Board ........ 58 10.7. Pregnancy ............................................................................................... 58 10.8. Concomitant Medications and Procedures ................................................ 58 11. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................... 59 11.1. Study Hypotheses .................................................................................... 59 11.2. Patient Data Sets for Analysis .................................................................. 60 11.3. Endpoints and Statistical Analyses ........................................................... 60 11.4. Sample Size Considerations ..................................................................... 61 11.5. PK Analyses and Neutralizing Antibodies to rHuPH20 ............................. 61 12. REGULATORY/ADMINISTRATIVE PROCEDURES AND DOCUMENTATION...................................................................................... 61 12.1. Ethics ...................................................................................................... 61 12.2. Institutional Review Board and Approval ................................................. 62 12.3. Informed Consent .................................................................................... 63 12.4. Laboratory Accreditation ......................................................................... 64 12.5. Drug Accountability ................................................................................ 64 12.6. Protocol Compliance and Protocol Deviations .......................................... 65 12.7. Protocol Amendments ............................................................................. 65 12.8. Data Collection and Case Report Forms ................................................... 66 12.9. Study Initiation, Monitoring and Closeout Visits and Reports ................... 66 Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 4 of 89 Version 4.0 26 Feb 2009 12.10. Study Documentation and Retention of Records ....................................... 68 12.11. Investigator’s Final Report....................................................................... 69 12.12. Financial D isclosure ................................................................................ 69 12.13 Disclosure of Data and Publication........................................................... 69 13. REFERENCES ............................................................................................... 70 14. APPENDICES ................................................................................................ 71 Appendix A. TNM Staging of Bladder Cancer ........................................................ 72 Appendix B. Karnofsky Performance Status ........................................................... 74 Appendix C. United Stages Package Insert for Mitomycin....................................... 75 Appendix D. Canadian Package Insert for Mitomycin ............................................. 76 Appendix E. United Kingdom Summary of Product Characteristics for Mitomycin .. 84 Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 5 of 89 Version 4.0 26 Feb 2009 Tables Table 6.1-A. Dose Cohorts ......................................................................................... 24 Table 9.2-A. Volume of Chemophase Withdrawn from Vial for Intravesical Administration ........................................................................................................... 45 Table 9.3-A. Dosing Schedule for MMC and Chemophase .......................................... 47 Table 10.5-A. Probability Estimates of Treatment Complications from Intravesical MMC .................................................................................................................................. 54 Figures Figure 8.9-A. Flow Diagram of Dose Escalation Schema ............................................. 38 Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 6 of 89 Version 4.0 26 Feb 2009 1. STUDY SYNOPSIS Protocol No. HZ2-05-01 Study Title A Phase I-IIa, Multicenter, Open-Label, Multiple Dose, Safety, Tolerability and Pharmacokinetic Study of Recombinant Human Hyaluronidase (Chemophase) in Combination with Mitomycin in Patients with Non- Muscular-Invasive Bladder Cancer Sponsor Halozyme Therapeutics, Inc. (Halozyme) 11588 Sorrento Valley Road, Suite 17 San Diego, CA 92121 Office: Primary Objectives • Determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of escalating doses of Chemophase in combination with mitomycin (mitomycin C, MMC) administered as weekly intravesical ins tillations for five weeks • Establish the dose of Chemophase with MMC recommended for future studies Secondary Objectives • Assess the pharmacokinetics of intravesical administration of MMC alone and in combination with intravesical administration of Chemophase • For those patients treated at the MTD, assess the safety and tolerability of intravesical administration of MMC with Chemophase over up to 7 additional maintenance treatments every 3 months following the initial six weekly instillations. • Observe patients for any preliminary evidence of anti-tumor activity of MMC and Chemophase when combined Study Design Phase I-IIa, open-label, multicenter, dose-escalation, safety, tolerability and pharmacokinetics study. Long-term follow-up information will be collected to help make a preliminary assessment of possible anti-tumor activity. Study Medications • Chemophase (hyaluronidase, human recombinant; rHuPH20) • Mitomycin (Mitomycin C, MMC) Duration Study patients will receive six (6) weekly study treatments (at Weeks 1 through 6) followed by post-treatment evaluations, at Weeks 8 and 12. The 12 patients treated at MTD will continue to receive combination therapy every three months until the end of Year 2 or until the time of documented tumor recurrence, whichever occurs first. For other patients, long-term follow-up after Week 12 will consist of disease monitoring of patients by telephone and will be performed every three (3) months beginning three months after last study treatment for two years following day 1 or until bladder tumor recurrence, whichever occurs first. Patient Population Patients with initial pr esentation or recurrence of Stage Ta , T1 or Tis, any grade, bladder cancer after TURBT Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 7 of 89 Version 4.0 26 Feb 2009 Planned Total Sample Size Up to 36 evaluable patients will be enrolled. It is anticipated that no more than a total of 44 patients will need to be enrolled. An evaluable patient is one who receives all protocol-specified six weekly intravesical treatments with at least a 90-minute retention and has had MMC plasma concentration determinations and safety assessments adequate for the determination of tolerability. Patients not meeting these criteria, including those withdrawn prematurely for reasons other than toxicity, will be replaced. Groups of either 3 or 6 patients will participate in each of the five individual dose cohorts in the dose escalation phase of the study. Once the MTD has been established, 6 additional evaluable patients will be enrolled at the MTD dose level, yielding a total of 12 evaluable patients at MTD upon which to confirm safety and tolerability of the MTD regimen. Intravesical Administration, Dose-Escalation Scheme, and Stopping Rules Cohort Week 1 Dosing Weekly Dosing Week 2 through Week 6 1 MMC 40 mg/20 mL 20,000 U Chemophase with MMC 40 mg/20 mL 2 MMC 40 mg/20 mL 60,000 U Chemophase with MMC 40 mg/20 mL 3 MMC 40 mg/20 mL 200,000 U Chemophase with MMC 40 mg/20 mL 4 MMC 40 mg/20 mL 400,000 U Chemophase with MMC 40 mg/20 mL 5 MMC 40 mg/20 mL 800,000 U Chemophase with MMC 40 mg/20 mL A dose-limiting toxicity (DLT) is defined as either (a) plasma MMC concentration ≥ 100 ng/mL, (b) National Cancer Institute (NCI) Common Terminology Criteria (CTC) (Version 3 or current version) AE Grade 3 or higher toxicity, or (c) new, treatment-emergent diagnosis of bladder fibrosis. Each intravesical administration will remain in the bladder for two hours after instillation. In each cohort, at Week 1 patients will receive MMC 40 mg alone (without Chemophase) in 20 mL of sterile water. If no DLT is observed prior to Week 2, this first treatment will be followed by five weekly intravesical instillations (at Weeks 2 through 6) of Chemophase at the dose specified by the assigned cohort followed by MMC 40 mg in 20 mL of sterile water. All 3 patients within a given cohort may begin treatment simultaneously. The next higher dose cohort can be immediately opened for patient enrollment if, at the time all 3 patients in a given cohort have completed the fourth (4th) instillation of MMC (i.e., third instillation of MMC plus Chemophase), there is: • no NCI CTC adverse event Grade 2 or higher toxicity, • no MMC plasma concentration ≥ 100 ng/mL, and • no new, treatment-emergent, diagnosis of bladder fibrosis. Note that an NCI CTC adverse event Grade 2 toxicity will delay opening the next higher dose cohort to enrollment until safety data are reviewed from all six Because this study is being conducted at more than one study center, the enrollment of patients, assignment to cohorts, and opening of each sequential cohort will be controlled centrally for all study centers by Halozyme. Each time a new patient is consented for the study, the study center must weekly instillations for all 3 patients in that cohort. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 9 of 89 Version 4.0 26 Feb 2009 • Absolute neutrophils count (ANC) ≥ 2,500 cells/mm3, • Platelet count ≥ 150,000/mm3, and • Hemoglobin ≥ 10.0 g/dL. 10. Urinalysis showing no clinically significant abnormalities except those attributable to bladder cancer. 11. For men and women of child-producing potential, agreement to use an effective contraceptive method during the treatment period of the study. 12. Signed, written IRB-approved informed consent. Exclusion Criteria 1. History or previous diagnosis of bladder fibrosis. 2. Total bladder capacity estimated at cystoscopy to be < 150 mL. 3. Urinary incontinence of a severity that would compromise the ability of the patient to retain the study drug intravesical instillation for two hours. 4. Severe irritative voiding symptoms such as urgency, frequency, or nocturia. 5. Known other malignant disease except squamous or basal cell skin cancer unless the malignancy has been in complete remission off therapy for at least 5 years. 6. Major surgery, other than TURBT and diagnostic surgery, within 28 days prior to Day 1/Week 1. 7. Active, uncontrolled bacterial, viral, or fungal infections, including urinary tract infection. 8. Treatment with radiation therapy, surgery, chemotherapy, or investigational therapy within one (1) month prior to Day 1/Week 1 on study (two [2] months for nitroureas or MMC), unless given as standard treatment for bladder cancer and provided that patient is free of all treatment-related toxicities as of Day 1/Week 1. 9. Known infection with HIV. 10. Known active infection with hepatitis B or hepatitis C. 11. Serious disease (e.g., hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor (Halozyme). 12. History of a hypersensitivity or idiosyncratic reaction to, or other contraindication to, mitomycin. 13. Known allergy to bee or vespid venom. 14. Known coagulation disorder or bleeding tendency. 15. Treatment with heparin or anticipation of heparin treatment during the treatment period in this study. 16. Unwillingness or inability to comply with procedures required in this protocol. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 10 of 89 Version 4.0 26 Feb 2009 Therapy Prohibited During Study The following therapies are prohibited from the time of enrollment through Week 12 of the study: • treatment with heparin, • any intravesical therapy except for MMC and Chemophase, and • any potentially myelosuppressive therapy. For the MTD patients who are receiving continued study drug treatments after Week 12, the following therapies are prohibited for the duration for study drug treatment: • any intravesical therapy except for MMC and Chemophase, and • any potentially myelosuppressive therapy. Pre-Study, Standard of Care, Procedures • Transurethral resection of bladder tumors (TURBT), with cystoscopy and estimate of bladder capacity • Intravesical standard of care therapy, if indicated • Histopathology report Safety and Efficacy Assessments • Signed informed consent • Karnofsky performance status • Complete medical history • Detailed urologic history • Physical examination • Vital signs • Concomitant medication assessment • Pregnancy test (women of child-bearing potential) • CBC w ith differential • Clinical c hemistries • Urinalysis and urine dipstick evaluation • Urine biomarkers (NMP22®BladderChek® Test and UroVysionTM) • Electrocardiogram, 12-lead • Adverse event collection/toxicity assessment • Blood collection for assay of levels of MMC and rHuPH20, and neutralizing antibodies to rHuPH20 • Cystoscopy, with estimate of bladder capacity, urine cytology • Long-term follow-up disease monitoring Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 11 of 89 Version 4.0 26 Feb 2009 Data Analysis This is a Phase I-IIa study of Chemophase in humans, and is not powered for formal statistical comparisons. The sample size of 3 to 6 patients per dose cohort is standard for the determination of safety and tolerability in many initial c linical trials for oncology indications. Once the MTD has been established, 6 additional evaluable patients will be enrolled at the MTD dose level, yielding a total of 12 evaluable patients at MTD upon which to confirm safety and tolerability of the MTD regimen. It is believed that 12 patients will provide an adequate sample size to establish the tolerability of this dose regimen for subsequent clinical trials and possibly provide a preliminary estimate of anti-tumor activity. The primary endpoint in this study is the rate of toxicities observed with the combination of Chemophase and MMC. The primary statistical analysis will consist of point estimates and the 95% confidence intervals constructed around the point estimates. All safety data will be examined, such as adverse event s (including overall incidence by treatment group), physical examination findings and vital signs, laboratory data, plasma MMC concentration, and ECGs. Descriptive statistics will be used to summarize all safety variables. The MTD will be determined based on DLTs. Based on the long-term follow-up monitoring, the data will be assessed for the median time to tumor recurrence, and the one-year, two-year, etc. rate of recurrence. Recurrences will be characterized with regard to the number of tumors, TNM stage, and grading. Information on tumor progression will be summarized. The data collected on the urine biomarker, comparing baseline to Week 8 values, will be summarized. PK Assessments Blood samples for assay of rHuPH20 (Weeks 2 & 6: predose and 1, 2, and 3 hrs postdose), MMC (Weeks 1, 2, 5 & 6: predose and 1, 2, and 3 hrs postdose) and neutralizing antibodies to rHuPH20 (Weeks 1 & 6; will only analyze Week 1 if Week 6 assay is positive). Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 13 of 89 Version 4.0 26 Feb 2009 1. Required prior to any protocol-specified activities and before consenting patient for screening. 2. TURBT, along with cystoscopy and estimate of bladder capacity performed within Day -42 to Day -1 (i.e., TURBT must be done no more than 42 days prior to Day 1) 3. Bladder capacity will be estimated at the time of cystoscopy. For the baseline study prior to Day 1, the cystoscopy performed at the time of TURBT is acceptable. There must be a urine cytology for Screening collected more than 5 days after the TURBT and within two weeks prior to the date of enrollment in this study. 4. In women of child-bearing potential. 5. CBC, chemistries and urinalysis must be performed within 7 days prior to Day 1, Week 1. 6. CBC at these Week 1 through Week 6 visits must be performed and results known prior to each study drug administration 7. Clinical chemistries consist of sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, calcium, glucose, albumin, total protein, uric acid, phosphorus, AST, ALT, alkaline phosphatase, GGT, total bilirubin, and creatine kinase. 8. Results of urine dipstick showing no evidence of urinary tract infection must be known prior to each study drug administration. 9. Urine biomarkers consisting of the NMP22® BladderChek® Test performed in clinic on a urine specimen obtained between midnight and noon, and collected more than 5 days after cystoscopy/TURBT, and UroVysionTM sample collected in clinic and sent to central vendor for analysis. 10.12-Lead ECG up to 42 days prior to Day 1; preoperative ECG obtained for TURBT is acceptable. 11.Blood samples sent to vendor lab for immediate processing; assays for rHuPH20 (Wks 2 & 6: predose and 1, 2, and 3 hrs postdose), MMC (Wks 1, 2, 5 & 6: predose and 1, 2, and 3 hrs postdose) and neutralizing antibodies (Wks 1 & 6; will only analyze Wk 1 if Wk 6 assay is positive). 12.Includes information collected by telephone survey (or at c linic visit) on any cystoscopy, urine cytology, bladder biopsy, tumor recurrence, and treatment administered for bladder cancer. Note: Weekly visits are expected to occur at 7-day intervals, +/- 3 days, counting from Day 1, Week 1. Note: For the purpose of this study, tumor recurrence is defined as a biopsy that histologically confirms the recurrence of bladder carcinoma. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 15 of 89 Version 4.0 26 Feb 2009 3. GLOSSARY AND ABBREVIATIONS Abbreviations Term AE Adverse event AJCC American Joint Committee on Cancer ALT Alanine transaminase (SGPT) ANC Absolute neutrophil count API Active pharmaceutical ingredient AST Aspartate transaminase (SGOT) AUA American Urological Association BCG Bacillus Calmette-Guérin BUN Blood urea nitrogen CAP College of American Pathologists CAS Registry Chemical Abstracts Service Registry CFR Code of Federal Regulations CHO Chinese hamster ovary CI Confidence interval CLIA Clinical Laboratory Improvement Amendments CRF Case report form CTC Common Terminology Criteria CTCAE Common Terminology Criteria for Adverse Events DLT Dose-limiting toxicity EC Ethics Committee ECG Electrocardiogram FDA Food and Drug Administration FISH Florescence in situ hybridization GCP Good Clinical Practice GGT Gamma glutamyltransferase GPI Glycosyl-phosphatidylinositol HIPAA Health Insurance Portability and Accountability Act IB Investigator’s Brochure IC50 Inhibition Concentration 50% ICF Informed consent form ICH International Conference on Harmonization IRB Institutional Review Board ITT Intent-to-treat MedDRA Medical Dictionary of Regulatory Activities mg Milligram mL Milliliter MMC Mitomycin C, Mitomycin MTD Maximum tolerated dose NAB Neutralizing antibody NCI National Cancer Institute NMP Nuclear matrix protein PHI Protected Health Information PK Pharmacokinetic RBC Red blood cells rHuPH20 Recombinant human hyaluronidase SAE Serious adverse event SGOT Serum glutamic oxaloacetic transaminase (AST) SGPT Serum glutamic pyruvate transaminase (ALT) Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 16 of 89 Version 4.0 26 Feb 2009 SOC System Organ Class SPC Summary of Product Characteristics T24 T24 human bladder cancer cell line TNM Tumor Node Metastasis TURBT Transurethral resection of bladder tumor ULN Upper limit of the normal range USAN United States Adoptive Name WBC White blood cells U.S. United States 4. BACKGROUND AND RATIONALE 4.1. Introduction to Hyaluronidases, rHuPH20, and Chemophase Mammalian hyaluronidase preparations differing in source, species, and manufacturing process have been the subject of multiple investigations and regulatory approvals in Europe, the United States, and Asia. The extent of human administration of these products in the U.S. has been estimated to be in the tens of millions of patients. Additionally, patients have been treated with other regulatory-approved preparations of hyaluronidase in Europe and Asia. Collectively, this usage spans more than 50 years of clinical history in humans. The U.S. Food and Drug Administration (FDA) contracted a review of the efficacy and safety of several hyaluronidase drug products through a program known as the Drug Efficacy Study Implementation (DESI). The studies were conducted by the National Academy of Sciences and the National Research Council. The DESI review findings published in the Federal Register (September 23, 1970; 35(185):14800-1) established that hyaluronidase injection was “effective” for the following indications: For use as an adjunct to increase the absorption and dispersion of other injected drugs; for hypodermoclysis; as an adjunct in subcutaneous urography; for improving the resorption of radiopaque agents. The DESI review also concluded that hyaluronidase was “probably effective” for the following indications: As an aid in retrobulbar and cone injection infiltrative anesthesia in ocular surgery; as an adjunct in reducing painful swelling by resorption of locally accumulated fluid; for hastening the onset of action and diffuseability of local anesthetics; in minimizing tumefaction during surgery; and for reducing postoperative edema and ecchymosis. The hyaluronidase drugs included in the DESI reviews included injectable hyaluronidase preparation derived from bovine testes. Replacing animal-derived slaughterhouse products with recombinant human biotechnology-developed materials potentially alleviates risks associated with animal pathogens, transmissible spongiform encephalopathies, and allergy and immunogenicity to foreign proteins. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 17 of 89 Version 4.0 26 Feb 2009 Chemophase is a formulation that contains a highly purified human hyaluronidase, rHuPH20, which is a glycoprotein enzyme generated by recombinant DNA technology. PH20 is a neutral pH-active hyaluronidase enzyme that degrades hyaluronan under physiologic conditions, but is normally locked on the plasma membrane through a glycosyl-phosphatidylinositol (GPI) moiety anchor. Therefore, Halozyme developed a recombinant soluble GPI-anchor deletion mutant form of the human PH20 hyaluronidase (rHuPH20) that, in non-human primates, does not elicit gross or histologic toxicity, neutralizing antibodies, or inflammatory responses at the site of injection across a three- log therapeutic dose range. rHuPH20is a 447-amino acid single chain polypeptide with N-linked and O-linked glycan structures. rHuPH20is synthesized in Chinese hamster ovary (CHO) cells that have been transfected with a plasmid containing the DNA sequence encoding the GPI-anchor deleted human PH20 hyaluronidase. The protein is purified through a series of chromatographic steps that results in a purified protein with high specific activity. rHuPH20 is up to 100-times more pure than slaughterhouse-derived hyaluronidases based on specific activity. rHuPH20 degrades hyaluronan by hydrolysis of the β-1,4 linkage between the C1 position of N-acetyl glucosamine and the C4 position of glucuronic acid. 4.2. Background on Non-Muscular-Invasive Bladder Carcinoma Non-muscular-invasive transitional bladder carcinomas are those tumors that have not infiltrated beyond the lamina propria, and consist of American Joint Committee on Cancer (AJCC) TNM classifications Ta (non-invasive papillary tumor confined to the urothelium), T1 (tumor penetrating the below the basement membrane and infiltrating the lamina propria subepithelial connective tissue), and Tis (Cis, carcinoma in situ, “flat tumor”) (see Appendix A). The histology of bladder carcinoma is often characterized as Grade 1 ( low, or well differentiated), Grade 2 (intermediate, or moderately differentiated), and Grade 3 (high, or poorly differentiated). Non-muscular-invasive bladder carcinoma has a high rate of tumor recurrence within the bladder, which requires repetition of surgery and medical therapy. The rate of recurrence of superficial (non-muscular-invasive) bladder cancer is reported to range from 40% to 85% [1]. The FDA’s Oncology Drugs Advisory Committee concluded in 1988 that as a general rule, over 50% of recurring patients will have recurrence within the first year [2]. The American Urologic Association (AUA) Bladder Cancer Guidelines Panel concluded in 1999 that intravesical treatment-related reductions in the probability of recurrence were detected within the first year of observation in most studies and the observed reductions were carried forward into subsequent years [3]. With tumor recurrence comes an increased risk of tumor progression and the possibility of medical/surgical treatment complications and anesthesia complications and their effect on t he patient’s quality of life. Most non-muscular-invasive bladder cancers are initially treated with transurethral surgical resection of the bladder tumor (TURBT), and less commonly with fulguration Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 18 of 89 Version 4.0 26 Feb 2009 and/or laser therapy. Following resection, adjuvant intravesical chemotherapy or immunotherapy is commonly used to prevent recurrences and eradicate residual disease. The most commonly administered intravesical therapies are bacillus Calmette-Guérin (BCG) and mitomycin (Mitomycin C, MMC). Other intravesical agents include thiotepa, doxorubicin, epirubicin, valrubicin, and interferon. Both intravesical BCG and intravesical MMC following TURBT have been shown in randomized clinical trials to statistically reduce the rate of tumor recurrence when compared to TURBT alone [3]. For patients with established bladder cancer of any grade, Stage Ta or T1, with or without Tis, who have not had prior intravesical therapy, the AUA includes a “Guideline” of “Intravesical instillation of either BCG or mitomycin is recommended for treatment of CIS and for treatment after endoscopic removal of T1 tumors and high-grade Ta tumors” [3]. Additionally, the AUA includes an “Option” of “Adjuvant intravesical chemotherapy or immunotherapy is an option for treatment after endoscopic removal of low-grade Ta bladder cancers.” Thus, both BCG and MMC have a role in the intravesical therapy of patients. However, there remains a substantial rate to tumor recurrence after intravesical therapy, and therefore an unmet medical need for therapy that is safe and more effective in preventing tumor recurrences and also tumor progression. BCG is widely used for intravesical immunotherapy, and has become first-line treatment for Stage Tis. The most serious side effect of BCG is sepsis, and the most common side effects are cystitis and hematuria. BCG may cause irritative voiding symptoms in about two-thirds of patients, and flu-like symptoms/systemic side effects in about one quarter of patients [3]. MMC is a purple antibiotic isolated from the broth of Streptomyces caespitosus and was initially investigated as an antibiotic. Later found to selectively inhibit the synthesis of DNA as an alkylating agent, MMC was studied as an anti-tumor agent. The AUA Bladder Cancer Guidelines Panel found that based on randomized clinical trials, intravesical MMC conferred about a 15% reduction in tumor recurrence compared to TURBT alone [3]. Despite the clinical trial data supporting the safety and effectiveness of MMC for bladder carcinoma, MMC has not been approved by the United States FDA for intravesical therapy of bladder cancer. The approved product label in the U.S. (see Appendix C) states that “Mitomycin for Injection is not recommended as single-agent, primary therapy. It has been shown to be useful in the therapy of disseminated adenocarcinoma of the stomach or pancreas in proven combinations with other approved chemotherapeutic agents and as palliative treatment when other modalities have failed.” When used to treat bladder carcinoma in the U.S., MMC is typically administered by intravesical instillation at doses of 20 to 40 mg at a concentration of 1-2 mg/ml in a f inal volume of 20 to 40 ml for a residence time of 1 to 2 hours. MMC is approved for use in Canada (see Appendix D) and the United Kingdom (see Appendix E) as a single agent “as topical therapy for superficial (no invasion beyond the lamina propria) transitional cell carcinoma of the urinary bladder. Efficacy has been demonstrated both in patients who have had no prior intravesical chemotherapy Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 19 of 89 Version 4.0 26 Feb 2009 and in those who have failed such therapy with thiotepa and other neoplastic agents.” The approved dose is 20 to 40 mg in 30 to 60 mL of sterile water given intravesically once weekly for up t o eight weeks. Patients are advised to abstain from liquids for 12 hours prior to therapy. The patient is catheterized, the bladder is drained, and MMC is instilled. The solution should be retained for two hours, during which time the patient may rotate positions every 15 minutes to promote maximum area of contact in the bladder. The approved dose in the U.K. for treatment of tumors is 20 to 40 mg dissolved in 20 t o 40 [mL, sic] of diluent weekly or three times a week for a total of 20 doses. Mitomycin is also approved in the U.K. for prevention of recurrent superficial bladder tumors, with various doses having been used, including 20 mg in 20 mL of diluent every two weeks and 40 mg in 40 mL of diluent monthly or three monthly. Myelosuppression is the major dose-limiting toxicity after intravenous MMC administration, and may be cumulative, occurring any time within eight weeks of onset of therapy, often with a late onset at 3 to 4 weeks, with recovery by 8 to 10 weeks. With a moderately high molecular weight of 329 daltons, MMC is not well absorbed through the bladder urothelium and therefore the risk of myelosuppression is very low. Myelosuppression has not been noted with intravesical administration [4]. In 55 patients treated with doses of 20 t o 40 mg of MMC by intravesical instillation, serial plasma samples collected during and 30 minutes after therapy contained no detectable MMC at an assay limit of 10 t o 100 ng/mL [5]. Based on data from intravenous administration, a serum MMC concentration of 400 ng/mL has been cited as predictive of myelosuppression [6]. Dalton et al. studied the pharmacokinetics of MMC in 10 patients after TURBT given six weekly instillations of 20 mg MMC in 40 mL water and found that at the first cycle (Treatment 1), maximal plasma concentrations of MMC during and up to four hours after instillation averaged 43 ng/mL (range 2.1 to 180.5 ng/mL) [7]. The concentrations measured at the subsequent Treatments 2, 4, and 6 were at least four-fold lower than those in Treatment 1 and in most cases were below the detection limit of 0.5 ng/mL. Thus, plasma levels were well below the 400 ng/mL level known to be predictive of myelosuppression, and MMC absorption in subsequent treatments was less than during the first treatment. Intravesical MMC may cause irritative voiding symptoms (e.g., dysuria, frequency/nocturia) in about 35% to 42% of patients, hematuria in about 16%, and skin rash in about 13% as the most common side effects [3]. Bladder fibrosis with a reduction in bladder capacity is an uncommon but known complication of generally long-term intravesical MMC therapy, the incidence of which appears to correlate directly with the cumulative MMC dose and correlate inversely with the time interval between a second tumor resection and the first MMC instillation [8]. 4.3. Rationale for Use of Chemophase in Bladder Cancer Chemophase (recombinant human hyaluronidase, rHuPH20) is being developed as a novel chemoadjuvant to enhance the delivery of chemotherapy to tumors in patients with various solid tumor malignancies (e.g., bladder, breast, colon, lung, and prostate) that accumulate hyaluronan (also known as hyaluronic acid). Clinical trials of animal-derived, Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 20 of 89 Version 4.0 26 Feb 2009 bovine hyaluronidase PH20 in hundreds of patients have shown promise in enhancing chemotherapy regimens using adjunctive hyaluronidase in previously chemo-refractory patients. However, the animal-derived hyaluronidases have been impaired by immunologic limitations upon repeat administration. Chemophase (recombinant human hyaluronidase) Solution for Intravesical Instillation is being specifically developed for use as an adjuvant with MMC in non-muscular-invasive bladder carcinoma following TURBT. It is envisioned that the Chemophase product would be administered with MMC as an adjuvant to increase the local penetration of MMC into residual malignant disease following TURBT. By reducing tumor recurrence rates, Chemophase adjuvant therapy with MMC could provide clinical benefit for patients by limiting repeated surgical resections and possible complications from medical and surgical treatment and anesthesia. Furthermore, reduced recurrence rates may conceivably limit the progression of disease such that the need for cystectomy or systemic chemotherapy may be delayed or eliminated. Nonclinical pharmacology studies have shown that rHuPH20 enhances the dispersion of co-administered molecules up to 200 nm in diameter in a dose-dependent fashion, decreasing in relation to the increasing size of co-administered molecules, and rHuPH20 increases hydraulic conductivity more than ten-fold. Application of rHuPH20 to T24 human bladder tumor cells in vitro effectively removes pericellular hyaluronan and allows direct contact with tumor cell membranes, an effect confirmed to be due to degradation of hyaluronan, which rapidly regenerated upon removal of rHuPH20 from the culture media. Incubation with rHuPH20 dramatically increased the doxorubicin penetration into T24 bladder cancer multicellular tumor spheroid cores. rHuPH20 induced a dose-dependent, up t o 2.5-fold change in the IC50 for MMC in T24 bladder cancer cell monolayers, and a 7.8-fold change in IC50 for spheroids, thereby increasing the sensitization of bladder tumor aggregates to MMC by increasing the penetration into the inner cellular layers. Application of rHuPH20 to human osteosarcoma orthotopic xenograft models resulted in a significant reduction in tumor interstitial fluid pressure within one hour of administration. As increased interstitial fluid pressure is a key factor limiting bulk fluid flow in solid tumors, it is reasonable to conclude that rHuPH20 warrants testing as an adjunct to chemotherapy agents to increase the therapeutic index of those agents. Three nonclinical toxicology studies have been conducted to assess the toxicity of co-administration of rHuPH20 with MMC. A GLP study in 60 rats of the acute intravenous administration of MMC and rHuPH20 found transient slight decreases in the weight in female animals receiving rHuPH20, but no overt toxicity following the administration of rHuPH20 alone or in combination with MMC at any dose level. A GLP study in 60 rats of the local tolerance of repeated exposure to intravesical MMC and rHuPH20 found that six weekly intravesical instillations of rHuPH20 alone at 6,000 units and MMC 0.4 mg (2 mg/mL) combined with rHuPH20 at dose levels of 0, 60, 600, and 6,000 units were well tolerated and no toxicity was observed. A GLP study in 48 New Zealand white rabbits of the tolerance of a single intravesical instillation of MMC Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 21 of 89 Version 4.0 26 Feb 2009 (8 mg/animal) and rHuPH20 (4,000, 40,000 and 160,000 units/animal) found the study drug treatment well-tolerated without evidence of test article-related toxicity. In addition, a GLP study in s ix rhesus monkeys of the local tolerance of repeated exposure to intravesical rHuPH20 alone (without MMC) found no toxicity. As an adjuvant to intravesically administered MMC, animal-derived, bovine hyaluronidase has been previously studied in clinical trials in at least 43 patients with bladder carcinoma. The rationale for the adjuvant use of PH20 in this setting is that the pharmacologic activity of hyaluronidase as a spreading agent could increase the penetration of MMC into residual hya luronan-rich bladder tumors, thereby increasing the effectiveness of MMC in killing residual malignant cells and reducing the risk of tumor recurrence. In 1986, Maier and Baumgartner published a series of 20 patients undergoing TURBT or multiple transurethral biopsies receiving a single dose of 20 mg intravesical MMC in 20 mL distilled water, 10 of whom received intravesical bovine hyaluronidase 200,000 units added to the dissolved MMC [9]. Serum levels of MMC were assayed at 30 and 60 minutes after instillation and found to range from < 1 t o 31.5 ng/mL. The systemic absorption of MMC was not affected by hyaluronidase. The mean MMC concentrations at 30 minutes were 14.2 ± 8.4 ng/mL for MMC alone and 13.4 ± 6.5 ng/mL for MMC with hyaluronidase. The respective mean concentrations at 60 minutes were 10.9 ± 7.1 ng/mL and 10.0 ± 6.4 ng/ mL. The highest serum level overall, 31.5 ng/mL, was measured in a patient not given hyaluronidase. Thus, MMC concentrations in this study remained below one tenth of 400 ng/mL, the critical systemic level that is believed to be predictive of myelosuppression [6]. This study concluded that hyaluronidase at a dose of 200,000 units does not enhance the systemic absorption of MMC given as a perioperative intravesical instillation. In 1989, Maier and Baumgartner published a larger, double-blind, randomized trial of 56 patients who had undergone TURBT and were randomized equally to multiple doses of either intravesical MMC 20 mg in 20 mL or the same dose of MMC plus 200,000 units of bovine hyaluronidase [10]. Twenty patients were Stage Ta, 27 were T1, and nine were T2. Twenty-nine patients were Grade 1, 22 were Grade 2, and five were Grade 3. Thirty- one patients were treated for primary tumors and 25 for recurrences. The treatment groups were comparable statistically. Intravesical instillations were started approximately one week after TURBT and given every two weeks for the first six months, followed by every four weeks until the end of two years (total of about 30 instillations per patient). Cystoscopy with lavage cytology follow-up was scheduled every three months for the first two years, and then biannually thereafter. Of the 28 patients treated with MMC alone (who received a total of 788 instillations), five (17.8%) had side effects, including four with cystitis and one with skin rash. Of the 28 patients treated with MMC and hyaluronidase (who received a total of 750 instillations), four (14.2%) had side effects, including three with cystitis and one with skin rash. There was no significant alteration in white blood count during therapy. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 22 of 89 Version 4.0 26 Feb 2009 A total of 32.1% (9/28) of MMC monotherapy patients had recurrent tumors over a median observation period of 21.1 months, compared to 7.1% (2/28) of MMC plus hyaluronidase patients over a median observation of 20.2 months (p < 0.05). The nine tumor recurrences in the MMC monotherapy group were detected at a mean of 11 months (range 6 to 24 months) compared to a mean of 13 months (6 and 20 months) for the two recurrences for MMC plus hyaluronidase. The nine MMC monotherapy recurrences were the same stage and grade as the primary tumor for four patients, downstaged for three, and upstaged for two. Both recurrences in the MMC plus hyaluronidase group were downstaged. This study, which consisted of a large number of exposures (about 30 per patient) over a relatively long duration (two years), concluded a significant additive benefit of hyaluronidase when given with MMC for the prevention of recurrent bladder tumors without an increase in adverse effects. In 1992, Hobarth, Maier and Marberger published long-term follow-up of 43 patients undergoing TURBT of Ta-T1 bladder tumors treated with intravesical bovine hyaluronidase plus MMC [11]. Twenty-four patients were Stage T1 and 19 were Stage Ta. Twenty-eight patients were Grade 1, 14 were Grade 2, and one was Grade 3. Thirty- seven patients had primary tumors and six had recurrent tumors. Beginning approximately one week after TURBT, these patients received 200,000 units of hyaluronidase along with 20 mg of MMC intravesically every two weeks for six months, then every four weeks until the end of two years. The tumor recurrence rate was 25% (11/43) over a mean follow-up of 48.5 months (range 42 to 66 months). These data compared favorably to a retrospective study of 63 comparable patients who demonstrated a tumor recurrence rate of 52.5% during and after two years of intravesical MMC monotherapy. Side effect of the combination therapy were observed in a total of 14% (6/43) of patients, and consisted of bacterial cystitis (6.9%), chemocystitis (4.6%), and skin allergy (2.3%). No patients were withdrawn due to side effects. This study concluded that the considerable reduction in tumor recurrence rate observed with hyaluronidase plus MMC compared to that seen after MMC monotherapy and the absence of any evidence of an increase in local side effects justify the application of hyaluronidase in this c linical setting. The authors postulated that, like other tumor cells, malignant transitional urothelial cells might be surrounded by a halo of hyaluronan, and destruction of this protective halo by hyaluronidase would explain the local enhancement of the anti-tumor effect of MMC. A Phase I safety, tolerability, and PK single-administration clinical trial (HZ2-05-02) of a low dose (20,000 units) of Chemophase with 40 mg MMC administered intravesically in a targeted sample size of five evaluable patients who had undergone transurethral resection of bladder tumor (TURBT) for transitional cell bladder cancer Stage Ta , T1 or Tis (any grade), were free of known bladder cancer recurrence, and were being monitored for recurrence of superficial transitional cell bladder cancer was initiated in August 2005 and completed enrollment on 2 March 2006. All five patients completed the study. There were no deaths, serious AEs, AEs judged to be possibly or more related to either study drug, moderate or severe AEs, premature withdrawals, or dose-limiting toxicities. The only three AEs reported in the study were, by MedDRA Preferred Terms, Influenza, Urinary tract infection, and Acne. All plasma samples for MMC were below the lower Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 23 of 89 Version 4.0 26 Feb 2009 limit of quantitation (10 ng/mL) and all plasma samples of PH20 were below the lower limit of quantitation (10 U/mL). In summary, the previous human experience with bovine hyaluronidase administered as an adjunct to intravesical MMC collectively in at least 43 patients, based on two clinical trials and a larger sample size follow-up publication, demonstrated no increase in toxicity and no increase in systemic absorption of MMC, but did show a statistically significant and clinically meaningful benefit in the prevention of tumor recurrences. The bovine hyaluronidase studies are important in establishing the anticipated safety and efficacy of the investigation of Chemophase as an adjunct in the treatment of bladder cancer. The nonclinical data for rHuPH20 in various tumor models including the T24 human bladder cancer cell line and the tolerability of co-administered rHuPH20 with mitomycin in two animal species (rats and rabbits) provide additional support for the study of Chemophase as an adjunct to the treatment of bladder carcinoma. Taken together, the nonclinical findings for rHuPH20 and the human clinical trial data for bovine hyaluronidase support the rationale for the anticipated safety and the potential efficacy of Chemophase administered intravesically along with MMC for non-muscular-invasive bladder carcinoma. 5. STUDY OBJECTIVES 5.1. Primary Objectives • Determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of escalating doses of Chemophase in combination with mitomycin (Mitomycin C, MMC) administered as weekly intravesical instillations for five weeks. • Establish the dose of Chemophase with MMC recommended for future studies. 5.2. Secondary Objectives • Assess the pharmacokinetics of intravesical administration of MMC alone and in combination with intravesical administration of Chemophase. • For those patients treated at the MTD, assess the safety and tolerability of intravesical administration of MMC with Chemophase over up to 7 additional maintenance treatments every 3 months following the initial six weekly instillations. • Observe patients for any preliminary evidence of anti-tumor activity of MMC and Chemophase when combined. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 24 of 89 Version 4.0 26 Feb 2009 6. STUDY DESIGN 6.1. Overview of Study Design This is a Phase I-IIa multiple dose study of intravesical treatment with the combination of Chemophase and MMC. All patients will receive six weekly intravesical instillations of chemotherapy. The 12 patients treated at MTD will continue to receive combination therapy every three months until the end of Year 2 from Day 1 or until the time of documented tumor recurrence, whichever occurs first. For the purpose of this study, tumor recurrence is defined as a biopsy that histologically confirms the recurrence of bladder carcinoma. All patients will be assigned to a single dose cohort, and the escalating dose cohorts will be enrolled sequentially after the safety and tolerability of the immediately preceding cohort has been ascertained. On Day 1 of Week 1, all patients in all cohorts (Cohorts 1 through 5) will receive MMC 40 mg/20 mL monotherapy via intravesical administration. In Weeks 2 through 6, patients will receive weekly intravesical administrations of a combination of MMC and Chemophase, in cohorts with escalating doses of Chemophase while the MMC dose remains constant at 40 mg/20 mL (see Table 6.1-A). Table 6.1-A. Dose Cohorts Cohort Week 1 Dosing Weekly Dosing Week 2 through Week 6 1 MMC 40 mg/20 mL 20,000 U Chemophase followed by MMC 40 mg/20 mL 2 MMC 40 mg/20 mL 60,000 U Chemophase followed by MMC 40 mg/20 mL 3 MMC 40 mg/20 mL 200,000 U Chemophase followed by MMC 40 mg/20 mL 4 MMC 40 mg/20 mL 400,000 U Chemophase followed by MMC 40 mg/20 mL 5 MMC 40 mg/20 mL 800,000 U Chemophase followed by MMC 40 mg/20 mL Post-treatment evaluations will be performed at Weeks 8 and 12. The 12 patients treated at MTD will continue to receive combination therapy every three months until the end of Year 2 from Day 1 or until the time of documented tumor recurrence, whichever occurs first. For all patients, long-term follow-up after Week 12 w ill consist of disease monitoring of patients by telephone (or at clinic visits for those patients still being treated at MTD) and will be performed every three months beginning three months after the last study treatment for two years and then every six months thereafter until the time of bladder tumor recurrence. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 25 of 89 Version 4.0 26 Feb 2009 6.2. Number of Patients Up to 36 evaluable patients will be enrolled in this study. It is anticipated that no more than a total of 44 patients will need to be enrolled to achieve this number of evaluable patients. Groups of either 3 or 6 patients will participate in each of the f ive individual dose cohorts in the dose escalation phase of the study. Once the MTD has been established (see Section 8.9), 6 additional evaluable patients will be enrolled at the MTD dose level, yielding a total of 12 evaluable patients at MTD upon which to confirm safety and tolerability of the MTD regimen. An evaluable patient is one who: • has received all protocol-specified six weekly intravesical treatments with at least a 90-minute retention, and • has had MMC plasma concentration determinations and safety assessments adequate for the determination of safety and tolerability. Each patient not meeting all these criteria for evaluability, including patients withdrawn prematurely for reasons other than toxicity, will be replaced by t he enrollment of an additional patient. 6.3. Patient Recruitment Patients will be recruited by each Investigator at each study center from their private practice, their institution or through referrals. Prior to consenting/enrolling patients, the Investigator will obtain Institutional Review Board (IRB) review and approval of the clinical investigation, including this protocol accompanied by t he Investigator’s Brochure (IB), the informed consent form, and any material provided to patients and any other advertising for study patients. Prior to patient screening and enrollment in this study, all patients must have had transurethral resection of bladder tumor(s) (TURBT) according to standard of care within 42 days prior to Day 1/ Week 1, followed by intravesical standard of care under the judgment of the patient’s physician and subsequent histopathology report following TURBT, which will be used to determine if the prospective patient meets the bladder carcinoma staging and grading eligibility criteria for this study. A Screening Log must be maintained at each site documenting all patients screened for participation in this study and noting reasons for non-enrollment and/or ineligibility. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 26 of 89 Version 4.0 26 Feb 2009 6.4. Treatment Summary This study will involve one (1) intravesical dose of MMC followed by five (5) subsequent weekly intravesical dose administrations of a combination of a fixed dose of MMC preceded by t he dose of Chemophase defined by the assigned dose cohort. The 12 patients treated at MTD will continue to receive combination therapy every three months until the end of Year 2 from Day 1 or until the time of documented tumor recurrence, whichever occurs first. In each cohort, at Week 1 patients will receive MMC 40 mg alone (without Chemophase) in 20 mL of sterile water. If no dose-limiting toxicity (DLT, see Section 8.8) is observed during the course of this and subsequent study drug treatments, this first treatment will be followed by five weekly intravesical instillations (at Weeks 2 through 6) of Chemophase at the dose specified by the assigned cohort followed by MMC 40 mg in 20 mL of sterile water. All 3 patients within a given cohort may begin treatment simultaneously. The next higher dose cohort can be immediately opened for patient enrollment if, at the time all 3 patients in a given cohort have completed the fourth (4th) instillation of MMC ( i.e., third instillation of MMC plus Chemophase), there is: • no NCI CTC adverse event Grade 2 or higher toxicity, • no MMC plasma concentration ≥ 100 ng/ mL, and • no new, treatment-emergent, diagnosis of bladder fibrosis. Note that an NCI CTC adverse event Grade 2 toxicity will delay opening the next higher dose cohort to enrollment until safety data are reviewed from all six weekly instillations for all 3 patients in that cohort. Because this study is being conducted at more than one study center, the enrollment of patients, assignment to cohorts, and opening of each sequential cohort will be controlled centrally for all study centers by Halozyme. Each time a new patient is consented for the study, the study center must immediately fax the updated Screening Log to Halozyme or its designee. In turn, Halozyme or its designee will keep all centers immediately apprised of the number of patients enrolled and patients in screening, so that new patients are not consented if there is no possibility of enrollment because there is no room for additional patients in the ongoing cohort. At the time a patient has fulfilled all eligibility criteria, the study center must fax a completed Enrollment/Registration Form to Halozyme or its designee, in response to which Halozyme or its designee will provide authorization to dose and confirmation of the dose cohort to which the new patient will be assigned (see Section 8.4). Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 27 of 89 Version 4.0 26 Feb 2009 6.5. Study Duration Study patients will receive six (6) weekly study treatments (at Weeks 1 through 6) followed by post-treatment evaluations, at Weeks 8 and 12. The 12 patients treated at MTD will continue to receive combination therapy every three months until the end of Year 2 from Day 1 or until the time of documented tumor recurrence, whichever occurs first. For all patients, long-term follow-up after Week 12 w ill consist of disease monitoring of patients by telephone (or at clinic visits for MTD patients continuing on study drug treatment) and will be performed every three (3) months beginning three months after last study treatment to the end of two years and 29 days following Day 1 or until bladder tumor recurrence, whichever occurs first. 7. STUDY POPULATION 7.1. Inclusion Criteria Patients must satisfy all of the following inclusion criteria in order to be enrolled in the study. 1. Patients with initial • Bilirubin ≤ 1.5 times upper limit of normal, and presentation or recurrence of Stage Ta , T1 or Tis, any grade, bladder cancer after TURBT. 2. TURBT within 42 days prior to Day 1/Week 1. 3. Karnofsky Performance Status ≥ 80% (see Appendix B). 4. Life expectancy at least 3 years. 5. Age ≥ 18 years. 6. A negative pregnancy test (if female of child-bearing potential). 7. Acceptable liver function within 7 days defined as: • AST (SGOT), ALT (SGPT), and Alkaline phosphatase ≤ 2.5 times upper limit of normal. 8. Acceptable renal function within 7 days defined as: • Serum creatinine ≤ 1.5 times upper limit of normal, OR • Calculated creatinine clearance ≥ 40 mL/min/1.73 m2. 9. Acceptable hematologic status within 7 days defined as: • Absolute neutrophils count (ANC) ≥ 2,500 cells/mm3, • Platelet count ≥ 150,000/mm3, and • Hemoglobin ≥ 10.0 g/dL. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 28 of 89 Version 4.0 26 Feb 2009 10. Urinalysis showing no clinically significant abnormalities except those attributable to bladder cancer. 11. For men and women of child-producing potential, agreement to use an effective contraceptive method during the treatment period of the study. 12. Signed, written IRB-approved informed consent. 7.2. Exclusion Criteria Patients satisfying any one or more of the following exclusion criteria must not be enrolled in this study. 1. History or previous diagnosis of bladder fibrosis. 2. Total bladder capacity estimated at cystoscopy to be < 150 mL. 3. Urinary incontinence of a severity that would compromise the ability of the patient to retain the study drug intravesical instillation for two hours. 4. Severe irritative voiding symptoms such as urgency, frequency, or nocturia. 5. Known other malignant disease except squamous or basal cell skin cancer unless the malignancy has been in complete remission off therapy for at least 5 years. 6. Major surgery, other than TURBT and diagnostic surgery, within 28 days prior to Day 1/Week 1. 7. Active, uncontrolled bacterial, viral, or fungal infections, including urinary tract infection. 8. Treatment with radiation therapy, surgery, chemotherapy, or investigational therapy within one (1) month prior to Day 1/Week 1 on study (two [2] months for nitroureas or MMC), unless given as standard treatment for bladder cancer and provided that patient is free of all treatment-related toxicities as of Day 1/Week 1. 9. Known infection with HIV. 10. Known active infection with hepatitis B or hepatitis C. 11. Serious disease (e.g., hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor (Halozyme). 12. History of a hypersensitivity or idiosyncratic reaction to, or other contraindication to, mitomycin. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 29 of 89 Version 4.0 26 Feb 2009 13. Known allergy to bee or vespid venom. 14. Known coagulation disorder or bleeding tendency. 15. Treatment with heparin or anticipation of heparin treatment during the treatment period in this study. 16. Unwillingness or inability to comply with procedures required in this protocol. 7.3. Prohibitions and Restrictions during the Study The following therapies are prohibited from the time of enrollment through Week 12 of the study: • treatment with heparin, • any intravesical therapy except for MMC and Chemophase, and • any potentially myelosuppressive therapy. For the MTD patients who are receiving continued study drug treatments after Week 12, the following therapies are prohibited for the duration for study drug treatment: • any intravesical therapy except for MMC and Chemophase, and • any potentially myelosuppressive therapy. 7.4. Contraindications, Warnings and Precautions with Regard to MMC Administration The administration of MMC in this protocol is guided in part by the approved product labeling for MMC. MMC is not approved by the United States FDA for intravesical administration but is approved for other indications. For the convenience of the Investigator, a representative U.S. package insert for MMC is provided in Appendix C and a representative Canadian package insert and United Kingdom SPC, which do allow for intravesical administration, may be found in Appendices D and E, respectively. These package inserts and SPC are current as of the date of this protocol version. It is the responsibility of the Investigator to refer to the product label that is current as of the time of treatment and management decisions. A boxed warning in the U.S. package insert notes that MMC should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available. This boxed warning further provides information about bone marrow suppression contributing to overwhelming infections in an already immunocompromised patient, and about hemolytic uremic syndrome. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 30 of 89 Version 4.0 26 Feb 2009 According to the U.S. package insert, MMC is contraindicated in patients who have demonstrated a hypersensitive or idiosyncratic reaction to MMC in the past. MMC is a lso contraindicated in patients with thrombocytopenia, coagulation disorder, or an increase in bleeding tendency due to other causes. The Canadian package insert includes the same contraindications, and adds leukopenia. Warnings in the U.S. package insert include the need for careful and frequent observation of patients during and after MMC therapy. The U.S. package insert, specific to intravenous administration of MMC, further warns about a high incidence of myelosuppression, the need for regular monitoring of hematologic laboratory parameters, and advising patients of this potential toxicity. Patients receiving MMC should be observed for evidence of renal toxicity, and MMC should not be given to patients with a serum creatinine greater than 1.7 mg/mL. The U.S. package insert further states that bladder fibrosis/contraction has been reported with intravesical administration (not an FDA-approved route of administration), which in rare cases has required cystectomy. The Canadian package insert adds warnings that MMC is a potent drug and should be used only by physicians experienced with cancer chemotherapeutic drugs. MMC should not be administered to any patient with a white blood cell count below 4,000/mm3 or a platelet count less than 150,000/mm3 or to patients with serious infections. The safety of MMC in pregnant women has not been established, and teratological changes have been noted in animal studies of MMC. It is not known if MMC is found in human breast milk, and it is recommended that women receiving MMC not breastfeed. The Investigator is referred to the full package insert(s) as the definitive, comprehensive, and most up-to-date guide to the administration of MMC. 8. STUDY METHODS AND PROCEDURES 8.1. Designated Laboratories: Central, Local, PK, and Biomarker Labs A combination of a central laboratories and laboratories local to each study center will be used in this study. The central laboratories will receive and analyze all samples that are not tied to the need for an immediate evaluation of potential myelosuppression of treated patients. It is preferable that only one local laboratory be specified and used at each individual study center. The local laboratory will receive and analyze blood drawn for a complete blood count (CBC) and differential on a “stat” basis on Week 1/Day 1, Week 2/Day 8, Week 3/Day 15, Week 4/Day 22, Week 5/Day 29, and Week 6/Day 36. For consistency, At each dosing visit, intravesical dosing with study medication(s) must not be done until CBC and differential results are known, and the ANC is confirmed to be ≥ 1,500/mm3 and the platelet count confirmed to be ≥ 75,000/mm3. In addition, at each dosing visit and before any dose of study medication, a urine dipstick must be performed at the study center and the results known to not show evidence of urinary tract infection. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 31 of 89 Version 4.0 26 Feb 2009 all protocol-specified CBCs will be performed at the local laboratory, including the CBCs at Screening, Week 8 and Week 12. Samples obtained for pharmacokinetic assays of MMC and rHuPH20and for assessment of antibodies to rHuPH20 will be sent to a separate central laboratory for analysis. For the urine biomarkers, the NMP22® BladderChek® Test will be performed in clinic and the UroVysion test will be obtained in the clinic and sent to a central vendor lab for analysis. 8.2. Procedures Prior to Screening (Day -28 to Day -1) TURBT(s) must be done on a ll patients no more than 42 days prior to Day 1/Week 1. Post-operatively, patients are expected to receive standard of care as determined by their physician, which may or may not include intravesical therapy with MMC. The surgical operative notes and the histopathology report (or content of information therein) from the TURBT must be available to the Investigator prior to performing any screening procedures and prior to having any patient sign the informed consent document. Cystoscopy within 42 days prior to Day 1/Week 1 (generally performed at the time of TURBT) accompanied by an estimation of bladder capacity will be used to qualify patients for this study. There must be a urine cytology during Screening collected more than 5 days after the TURBT and within two weeks prior to the date of enrollment in this study. As noted in Section 2.0, the Schedule of Events for this study, activities taking place prior to consenting the patient (e.g., TURBT with cystoscopy and urine cytology, post- operative standard of care, and histopathology reading and report) are not protocol- specified activities, but are prerequisites before a patient can be consented for this study. 8.3. Screening Procedures (Day -28 to Day -1) As shown in Section 2.0, Schedule of Events, the following activities are to be completed during this period. • Verification from source documents (medical record, TURBT notes, cystoscopy notes, histopathology report) that patient meets the disease-defining criteria in Section 7.1, for (1) patient with initial presentation or recurrence of Stage Ta, T1 or Tis, any grade, bladder cancer after TURBT. The specific TNM stage will be recorded. • Assess for exclusion criteria (see Section 7.2), including but not limited to incontinence, irritative voiding symptoms, history of bladder fibrosis, known other malignant disease, other recent surgery and therapies, active infection, concurrent serious disease, known coagulation disorder, use of or anticipated use of heparin, and willingness and ability to comply with protocol procedures. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 32 of 89 Version 4.0 26 Feb 2009 • Informed Consent: The Investigator or one of the study staff must explain the study protocol to prospective study patients and have them read and ask questions regarding the informed consent form (ICF). This discussion must include, among other topics, the need for an effective contraception method during the treatment phase if this study. If the patient agrees to participate, they must sign and date the informed consent form and have it witnessed. Each patient must receive a copy of the signed informed consent. • Karnofsky performance status ≥ 80% (see Appendix B). • Complete medical history. • Detailed urologic history. This will include a complete description of the number, estimated size and gross appearance of tumors removed at TURBT; and the area and depth of involvement of the bladder mucosa after TURBT; the anatomic location of the tumor(s); estimated bladder capacity; histopathology; tumor stage and grade; prior history of bladder cancer; etc. • Complete physical exam. • Vital signs (blood pressure, heart rate, respiratory rate, oral temperature, height, and weight). • Concomitant medications. Concomitant medications taken during the time period beginning 28 days prior to initial dosing, on Day 1/Week 1, through the Week 12 assessment (and, for MTD patients continuing on study drug treatment, through the last study drug instillation) will be collected (see Section 10.8). • Pregnancy test (if patient is female and of child-bearing potential). • CBC with differential within 7 da ys of Day 1/Week 1. • Clinical chemistries within 7 days of Day 1/Week 1. Clinical chemistries consist of sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, calcium, glucose, albumin, total protein, uric acid, phosphorus, AST, ALT, alkaline phosphatase, GGT, total bilirubin, and creatine kinase. • Urinalysis within 7 days of Day 1/Week 1. • Electrocardiogram. A 12-lead ECG w ithin 42 days of Day 1/Week 1 must be available. An ECG performed within this timeframe in preparation for the TURBT is acceptable. • Tests for HIV and hepatitis if there is suspicion or unclear history of infection with HIV or active infection with hepatitis B or hepatitis C. Patient with known Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 33 of 89 Version 4.0 26 Feb 2009 history of infection with HIV or active infection with hepatitis B or hepatitis C are not eligible for enrollment. 8.4. Patient Registration and Replacement of Patients Because this study is being conducted at more than one study center, the enrollment of patients, assignment to cohorts, and opening of each sequential cohort will be controlled centrally for all study centers by Halozyme. Each time a new patient is consented for the study, the study center must immediately fax the updated Screening Log to Halozyme or its designee. In turn, Halozyme or its designee will keep all centers immediately apprised of the number of patients enrolled and patients in screening, so that new patients are not consented if there is no possibility of enrollment because there is no room for additional patients in the ongoing cohort. At the time a patient has fulfilled all eligibility criteria (see Sections 7.1 and 7.2) and if there is room for a patient to be enrolled in the study, the study center must fax an updated Enrollment/Registration Form to Halozyme or its designee. Halozyme or its designee will review the information, confirm eligibility, and assign a patient identification number. Patient identification numbers will be set aside for use at each study center. Halozyme or its designee will fax a Registration Form to the clinical study center, providing authorization to dose and confirmation of the dose cohort to which the new patient will be assigned. The study center must not begin dosing any new patient without this prior Registration Form authorization from Halozyme or its designee • has received all protocol-specified six weekly intravesical treatments, and . A copy of the Screening Log and Enrollment/Registration Forms will be kept on file at Halozyme or its designee and at the study center in the Investigator Files. If the next patient is to be enrolled as the first patient in a new, higher dose cohort, the procedures discussed in Section 8.9 must be followed. Patients not meeting all evaluability criteria will be replaced. An evaluable patient is one who: • has had MMC plasma concentration determinations and safety assessments adequate for the determination of safety and tolerability. Each patient not meeting all these criteria for evaluability, including patients withdrawn prematurely for reasons other than toxicity, will be replaced by t he enrollment of an additional patient. In the event that a patient withdraws from the study prematurely, every effort will be made to document the reason for termination and obtain follow-up safety data. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 34 of 89 Version 4.0 26 Feb 2009 8.5. Patient Randomization Procedures and Blinding No randomization or blinding will be involved, as this is an open-label non-randomized study. See Section 7.4 for patient registration procedures. 8.6. Treatment Procedures on Day 1/Week 1 As shown in Section 2.0, Schedule of Events, the following activities are to be completed on this day. • Verification of all inclusion and exclusion criteria (see Sections 7.1 and 7.2) • Karnofsky performance status (see Appendix B). • Interim medical history (this history is for the interim period of time since the medical history previously performed, between Days -28 and Day -1). • Targeted physical exam (this physical exam is targeted at observations on a review of systems and follow-up of any findings on the previous physical exam). • Vital signs (blood pressure, pulse, oral temperature, and weight). • Concomitant medications. • Predose CBC with differential. The local lab will receive and analyze blood drawn for a CBC and differential on a “stat” basis. Intravesical dosing with study medication(s) on an individual patient basis on a given treatment day must not be done until CBC and differential results are known and the ANC is confirmed to be ≥ 1,500/mm3 and the platelet count is ≥ 75,000/mm3. • Predose clinical chemistries. These blood samples will be drawn at the same time as the CBC and differential. Samples will be sent to the central lab for analysis. • Predose urinalysis. A urine sample will be obtained from each patient prior to intravesical dosing with study medication and sent to the central lab for analysis. • Predose urine dipstick analysis. In addition to the full urinalysis at Day 1, a urine dipstick analysis is performed on t he day of dosing, and the results must be known with no evidence of urinary tract infection prior to study drug dosing . • Urine biomarkers for bladder carcinoma. The NMP22® BladderChek® Test will be performed in clinic on a urine specimen obtained between midnight and noon, and collected more than five days after cystoscopy/TURBT. The UroVysion test will be obtained in the clinic and sent to a central vendor lab for analysis. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 35 of 89 Version 4.0 26 Feb 2009 • Intravesical instillation of MMC (see Sections 9.1 and 9.3). All blood and urine samples must be obtained and results for CBC with differential and urine dipstick analysis must be known prior to intravesical dosing of MMC . • Blood collection for pharmacokinetics (PK) for MMC and for antibodies. Blood samples will be drawn, sent to the appropriate laboratory, and assays performed immediately for MMC PK at the following timepoints: predose, and 1 hour, 2 hours and 3 hours after intravesical instillation of MMC. Blood will be collected predose for assessment of neutralizing antibodies, but will be analyzed only if the Week 6/Day 36 assay for antibodies is positive. • Adverse events/toxicity assessment. Assessment for AEs will commence after the initial exposure to MMC at this visit, and continue during the study (see Sections 10.1 through 10.6). 8.7. Treatment Procedures Week 2 through Week 6 As shown in Section 2.0, Schedule of Events, the following activities are to be completed on the clinic visit days at each of these weekly visits. • Karnofsky performance status (see Appendix B). • Interim medical history (this history is for the interim period of time since the previous medical history). • Targeted physical exam (this physical exam is targeted at observations on a review of systems and follow-up of any findings on the previous physical exam). • Vital signs (blood pressure, pulse, oral temperature, and weight). • Concomitant medications. • Predose CBC with differential. The local lab will receive and analyze blood drawn for a CBC and differential on a “stat” basis. Intravesical dosing with study medication(s) on an individual patient basis on a given treatment day must not be done until CBC and differential results are known and the ANC is confirmed to be ≥ 1,500/mm3 and the platelet count is ≥ 75,000/mm3. • Predose clinical chemistries. These blood samples will be drawn at the same time as the CBC and differential. Samples will be sent to the central lab for analysis. • Predose urine dipstick analysis. A urine dipstick analysis is performed on t he day of dosing, and the results must be known with no evidence of urinary tract infection prior to study drug dosing . Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 36 of 89 Version 4.0 26 Feb 2009 • Intravesical instillation of MMC with the appropriate dose of Chemophase (see Sections 9.1 through 9.3). All blood and urine samples must be obtained and results for CBC with differential and urine dipstick analysis must be known prior to intravesical dosing of Chemophase and MMC . • Blood collection for pharmacokinetics (PK) for MMC and rHuPH20 and for antibodies. Blood samples will be drawn, sent to vendor laboratory, and assays performed immediately for MMC and rHuPH20 PK on the following schedule:  Week 2/Day 8 : Both MMC and rHuPH20 at predose, and 1, 2 and 3 hours postdose after intravesical instillation of MMC.  Week 5/Day29 : MMC only at predose, and 1, 2 and 3 hours postdose after intravesical instillation of MMC.  Week 6/Day 36 : Both MMC and rHuPH20 at predose, and 1, 2 and 3 hours postdose after intravesical instillation of MMC.  Week 6/Day 36 : B lood collected for neutralizing antibodies at 3 hours postdose after intravesical instillation of MMC.  T he plasma concentration of MMC must be known to be < 100 ng/mL for a given patient prior to the next intravesical dosing of study medications (see Section 8.8). • Adverse events/toxicity assessment (see Sections 10.1 through 10.6). 8.8. Dose-Limiting Toxicity (DLT) A dose-limiting toxicity (DLT) is defined as any of the following: • plasma MMC concentration ≥ 100 ng/mL, • National Cancer Institute (NCI) Common Terminology Criteria (CTC) (Version 3 or current version) adverse event Grade 3 or higher toxicity (see http://ctep.cancer.gov/reporting/ctc.html) [12], or • new, treatment-emergent diagnosis of bladder fibrosis. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 37 of 89 Version 4.0 26 Feb 2009 8.9. Escalation to Next Dose Cohort, Stopping Rules, and Determination of MTD In each cohort, at Week 1, patients will receive MMC 40 mg in 20 mL of sterile water alone (without Chemophase). If no dose-limiting toxicities (DLTs) are observed (see Section 8.8) during this and subsequent study drug treatments, this will be followed by five weekly instillations (Week 2 t hrough Week 6) of the specified dose of Chemophase followed by MMC 40 mg in 20 mL as long as no DLTs are observed with the previous instillations. A flow diagram of the dose escalation schema and stopping rules is provided in Figure 8.9-A. If at any time during the study, 1 of the 3 patients in a given cohort experiences a DLT, an additional 3 patients will be enrolled in that same cohort before consideration of enrolling the next higher dose cohort. If 2 or more out of 3 patients, or 2 or more out of 6 patients, in a given cohort experience a DLT, that dose will be declared not tolerated and 3 additional patients will be enrolled in the next lower dose cohort. If 0 or 1 patient at the highest cohort studied to date experiences a DLT, 3 additional patients will be enrolled at that same dose. If the dose in a given cohort is found to be not tolerated after dosing has begun in the next higher dose cohort, all patients in that next higher dose cohort will be immediately dose reduced to the highest dose cohort that has not been determined to be intolerable. The maximum tolerated dose (MTD) is defined as the dose level at which ≤ 2 of 6 patients experience a DLT. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 39 of 89 Version 4.0 26 Feb 2009 8.10. Premature Termination of Treatment/Withdrawal of Patients The Investigator must guard the patient’s welfare and should discontinue study drug treatment at any time that this action appears to be in the patient’s best interest. Patients may discontinue study drug treatment and may withdraw or be removed from the study at any time. Possible reasons for such actions may include, but are not limited to, the following: • Dose-limiting toxicity, as defined in Section 8.8. • Clinical need for concomitant or ancillary therapy that is not permitted during the study (e.g., intravesical therapy other than study medications) (see Section 7.3). • Unrelated intercurrent illness that in the judgment of the Investigator will significantly affect assessments of clinical status. • Pregnancy (see Section 10.7). • General or specific changes in the patient’s condition that in the judgment of the Investigator render the patient unacceptable for further study drug treatment. • Patient’s request to withdraw. • Unwillingness or inability to comply with study requirements. It is the right and duty of the Investigator to interrupt the treatment of any study patient whose health or well-being may be threatened by continuation in this study. Such patients should have study drug treatment discontinued, rather than be continued under a modified treatment regimen that is not within the specifications of this protocol. Once a study patient has received MMC or Chemophase under this protocol, the patient must be followed for safety as required in the protocol (see Section 10). In the event that a study patient withdraws from the study prematurely, every effort will be made to document the reason for premature termination and obtain follow-up safety data. The specific reason for and date of the premature discontinuation will be documented in the CRFs. The date of the last dose of study medications will also be documented. Should the enrollment rate lag or significant numbers of clearly non-eligible and/or non- evaluable patients be entered in the study, Halozyme may elect to terminate the study. Halozyme also has the right to terminate the study at any time for non-adherence to protocol, unavailability of the Investigator or his or her study staff for Halozyme or its designated monitoring personnel, or for administrative reasons, at any time. 8.11. Post-Treatment Procedures at Week 8 As shown in Section 2.0, Schedule of Events, the following activities are to be completed on the Week 8 clinic visit day. • Karnofsky performance status (see Appendix B). • Complete physical exam Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 40 of 89 Version 4.0 26 Feb 2009 • Vital signs (blood pressure, pulse, oral temperature, and weight). • Concomitant medications. • Pregnancy test if female patient of child-bearing potential. • CBC with differential. • Clinical chemistries. • Urinalysis. • 12-Lead electrocardiogram. • Urine biomarkers for bladder carcinoma. The NMP22® BladderChek® Test will be performed in clinic on a urine specimen obtained between midnight and noon, and collected more than five days after cystoscopy/TURBT. The UroVysion test will be obtained in the clinic and sent to a central vendor lab for analysis. • Adverse events/toxicity assessment (see Sections 10.1 through 10.6). 8.12. Post-Treatment Procedures at Week 12 As shown in Section 2.0, Schedule of Events, the following activities are to be completed at the Week 12 clinic visit day. • Karnofsky performance status (see Appendix B). • Interim medical history (this history is for the interim period of time since the previous medical history). • Targeted physical exam (this physical exam is targeted at observations on a review of systems and follow-up of any findings on the previous physical exam). • Vital signs (blood pressure, pulse, oral temperature, and weight). • Concomitant medications. • Cystoscopy with bladder tumor assessment, accompanied by urine cytology and estimate of bladder capacity. • CBC with differential. • Clinical chemistries. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 41 of 89 Version 4.0 26 Feb 2009 • Adverse events/toxicity assessment (see Sections 10.1 through 10.6). 8.13. Long-Term Maintenance Therapy and Follow-Up (Following Week 12) Long-term follow-up for disease monitoring for all patients will start 3 months after the last of the weekly study drug treatments for every study patient and be performed every three (3) months for two (2) years after Day 1 or until the time of first bladder tumor recurrence if earlier (see Section 2.0, Schedule of Events). For the purpose of this study, tumor recurrence is defined as a biopsy that histologically confirms the recurrence of bladder carcinoma. It is expected that patients will be receiving standard of care according to the judgment of the Investigator and/or the patient’s other physician(s). For all patients NOT treated at the MTD The 12 patients treated at MTD will continue to receive combination therapy at the same dose as during their six weekly treatments every three months until the end of Year 2 or until the time of documented tumor recurrence, whichever occurs first. Thus, they are intended to receive up to seven maintenance treatments in addition to the six initial weekly treatments. The maintenance treatments are intended to immediately follow the standard of care clinic evaluations and cystoscopies for monitoring of tumor recurrence. As shown in Section 2.0, Schedule of Events, the following activities are to be completed every three months after the Week 12 clinic visit to the end of 2 years from Day 1 for those patients still being treated at MTD. , there are no protocol-required activities during this 2years term except for first recurrence status and survival. • Interim medical history (this history is for the interim period of time since the previous medical history). • Targeted physical exam (this physical exam is targeted at observations on a review of systems and follow-up of any findings on the previous physical exam). • Vital signs (blood pressure, pulse, oral temperature, and weight). • Concomitant medications. • Cystoscopy (standard of care for monitoring of tumor recurrence), with urine cytology and estimate of bladder capacity. • Predose CBC with differential. The local lab will receive and analyze blood drawn for a CBC and differential on a “stat” basis. Intravesical dosing with study medication(s) on an individual patient basis on a given treatment day must not be done until CBC and differential results are known and the ANC is confirmed to be ≥ 1,500/mm3 and the platelet count is ≥ 75,000/mm3. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 42 of 89 Version 4.0 26 Feb 2009 • Predose urine dipstick analysis. A urine dipstick analysis is performed on t he day of dosing, and the results must be known with no evidence of urinary tract infection prior to study drug dosing . • After completion of cystoscopy and if no clinical contraindication, intravesical instillation of MMC with the defined MTD dose of Chemophase. Hematology and urine samples must be obtained and results for CBC with differential and urine dipstick analysis must be known prior to intravesical dosing of Chemophase and MMC . • Adverse events/toxicity assessment (see Sections 10.1 through 10.6). Also as shown in Section 2.0, Schedule of Events, the following activities are to be completed 6 weeks before the every-three-month v isits after the Week 12 clinic visit for those patients still being treated at MTD • Urine biomarkers for bladder carcinoma. The NMP22® BladderChek® Test will be performed in clinic on a urine specimen obtained between midnight and noon, and collected more than five days after cystoscopy/TURBT. The UroVysion test will be obtained in the clinic and sent to a central vendor lab for analysis. If either biomarker results are suggestive of tumor recurrence, it is anticipated that the patient will be brought back for a clinic evaluation as soon as possible, and undergo cystoscopic evaluation, if indicated. . 9. STUDY MEDICATIONS AND ADMINISTRATION 9.1. Mitomycin (Mitomycin C, MMC) 9.1.1. Supply of MMC Commercially available MMC will be obtained through Halozyme and provided to the Investigator for this study. For the convenience of the Investigator, a representative U.S. package insert for MMC is provided in Appendix C, and a representative Canadian package insert and United Kingdom SPC for MMC are provided in Appendices D and E, respectively, current as of the date of this protocol version. It is the responsibility of the Investigator to refer to the appropriate product label that is current as of the time of treatment and management decisions. As noted in the U.S. package insert, MMC for injection is a sterile dry mixture of mitomycin and mannitol, which, when reconstituted in sterile water, provides a solution. MMC is supplied in individually-boxed vials of 5 mg, 20 mg, and 40 mg strengths. For this clinical trial, MMC will be supplied in 40 mg vials. Each 40 mg vial of MMC contains mannitol 80 mg. Each vial will be labeled with the study protocol number and the statement “Caution: New Drug – Limited by Federal Law to Investigational Use.” The label will designate a space for the study center to enter the patient identification Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 43 of 89 Version 4.0 26 Feb 2009 number and initials. MMC vials will be supplied to each study center as bulk drug supply, and will not be labeled in advance to a specific patient identification number. 9.1.2. Storage and Stability of MMC As noted in a representative U.S. package insert (see Appendix C), unreconstituted MMC should be stored at a controlled room temperature of 15ºC to 30ºC (59ºF to 86ºF), and is stable for the lot life indicated on t he package. Excessive heat (over 40ºC) should be avoided. All MMC supplies must be kept in a secure area with access limited to authorized clinical investigation personnel. When reconstituted for injection with sterile water to a concentration of 0.5 mg per mL, MMC is stable for 14 da ys refrigerated or 7 days at room temperature. Reconstituted solution should be protected from light. 9.1.3. Procedures for Proper Handling and Disposal of MMC As noted in a representative U.S. package insert (see Appendix C), procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published (see References 1-7 in Appendix C). There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Anyone exposed to MMC should be cautioned to avoid contact with the skin. Study patients should be instructed to wash hands and genitals after voiding intravesically administered MMC. Towels or washcloths used by study patients should be thoroughly washed after use. Vials and any unused portions of vials must be handled in a manner consistent with the safe management of non-infectious biohazard material. For accidental spills, wear protective gloves and avoid physical contact during removal. Use normal clean-up procedures for liquid spillage and wash thoroughly with water. 9.1.4. Preparation of MMC for Intravesical Instillation The reconstituted MMC for intravesical instillation will be aseptically prepared at the clinical study centers or designated pharmacies. For use in this clinical trial, 20 mL of sterile water will be added to one 40 mg vial of MMC, resulting in a concentration of 2 mg/mL. The reconstituted MMC can be shaken to dissolve. If the MMC does not dissolve immediately, it can be allowed to stand at room temperature until a solution is obtained. For this clinical trial, MMC should be reconstituted no more than 24 hours before intravesical administration and stored a room temperature. The reconstituted MMC will not be admixed with the Chemophase solution for instillation (see Section 9.2.3), but rather will be instilled following instillation of the Chemophase solution and the sterile saline. The reconstituted MMC will then be delivered to the catheter for intravesical instillation (see Section 9.3). Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 44 of 89 Version 4.0 26 Feb 2009 All MMC vials supplied for this study, both used and unused, must be retained for drug accountability. The patient ID number and initials, and date of preparation, should be written in ink on the vial label. See Section 12.5 regarding drug accountability. 9.2. Chemophase (rHuPH20) 9.2.1. Formulation and Supply of Chemophase The rHuPH20 active pharmaceutical ingredient (API) in Chemophase is a frozen solution at 1 mg/mL, pH 6.8, in 10 mM Hepes and 130 mM sodium chloride. The rHuPH20 drug substance will be supplied by Halozyme in 1.0 mL and 5.0 mL Type I glass vials w ith a Type I bromobutyl rubber serum stopper, bot h with a concentration of approximately 100,000 U/mL (see Section 9.2.3). Each vial will be labeled with the study protocol number and the statement “Caution: New Drug – Limited by Federal Law to Investigational Use.” The labels will designate a space for the study center to enter in ink the date the vial was first opened. Chemophase vials will be supplied to each study center as bulk drug supply, and will not be labeled in advance to a specific patient identification number. The Chemical Abstracts Index Name for rHuPH20 is 36-482-Hyaluronoglucosaminidase PH20 (human). The CAS Registry Number is [757971-58-7]. The USAN name is hyaluronidase (human recombinant). 9.2.2. Storage and Stability of Chemophase Chemophase must be stored frozen. The recommended storage condition for the Chemophase API solution is -20 ± 5º C. All Chemophase supplies must be kept in a secure area with access limited to authorized clinical investigation personnel. Vials of Chemophase must be thawed (see Section 9.2.3) prior to removal of Chemophase for dosing, but any remaining material in the vial will be immediately re- frozen at -20 ± 5º C. A given vial may be thawed, fluid withdrawn, and then frozen up to a total of five times, or over a maximum elapsed time of 12 months (or longer, as may be amended from time to time by the Sponsor based on additional stability data), whichever occurs first, after which the vial may not be used for any further dosing. 9.2.3. Preparation of Chemophase for Intravesical Instillation The vial labels will designate a space for the study center to record in ink the “date opened.” The solution of Chemophase for intravesical instillation will be aseptically prepared at the clinical study centers or designated pharmacies. For this clinical trial, Chemophase should be prepared no more than 24 hours before intravesical administration. In preparation for patient dosing, the Chemophase vial should be removed the freezer and allowed to thaw either in the refrigerator for at least several hours (typically overnight) or at room temperature for at least one hour but not more than 24 hours. Chemophase should Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 45 of 89 Version 4.0 26 Feb 2009 be protected from bright light and heat. Thaw only enough vials to prepare the required dose. After the vial is completely thawed, the volume of solution appropriate for the dose of Chemophase to which the patient is assigned will be drawn into a syringe. The size and graduation markings of the syringe that is used should be appropriate for measuring volumes to the nearest 0.1 mL. The specific activity of Chemophase is anticipated to range from 100,000 to 120,000 units/mL. The volume of Chemophase to be instilled is based on an average of 110,000 units/mL (see Table 9.2-A). As shown in Table 9.2-A, the total volume of Chemophase drawn from the vial also provides for up to 0.2 mL hold-up volume due to filtering through the syringe filter. After the solution is drawn from the vial, the syringe needle will be removed and exchanged for a 0.2 micron syringe filter. This syringe filter has a hold-up volume of 0.1 to 0.2 mL, which must be taken into account when withdrawing the dose to be dispensed. Next, the plunger on t he syringe is depressed and a small volume (approximately 0.1 mL) of the solution passed through the filter and discarded until the remaining volume of the solution in the syringe matches the exact volume for intravesical administration (e.g., for Cohort 1, a total of 0.4 mL is drawn into the syringe, the syringe needle replaced with the syringe filter, and the volume in the syringe is reduced to exactly 0.2 mL by expelling solution through the filter). After discarding the excess volume to reduce the remaining volume to the exact amount for intravesical instillation, the solution will then be passed through this filter as it is delivered into the catheter for intravesical instillation (see Section 9.3). The Chemophase solution for intravesical instillation will not be admixed with the reconstituted MMC for instillation (see Section 9.1.4), but rather will be instilled prior to instillation of the reconstituted MMC and before the instillation of the amount of sterile saline needed to follow the Chemophase to add up t o total of 8 mL (see Section 9.3). Table 9.2-A. Volume of Chemophase Withdrawn from Vial for Intravesical Administration Cohort Units of Chemophase for Instillation Volume of Chemophase Actual mL for Instillation Extra mL for Hold-up in Filter Total mL Drawn into Syringe 1 20,000 0.2 0.2 0.4 2 60,000 0.5 0.2 0.7 3 200,000 1.8 0.2 2.0 4 400,000 3.6 0.2 3.8 5 800,000 7.3 0.2 7.5 At the initial use of vial, the date that solution was first removed from the vial will be written in ink on the vial label and the vial immediately returned to the freezer. Each time the vial is thawed and solution removed, the date will be recorded. Note that the vials are not specific to an individual patient, and more than one patient can be dosed from the same vial. As noted in Section 9.2.2, a given vial may be thawed, fluid withdrawn, and Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 46 of 89 Version 4.0 26 Feb 2009 then frozen up to a total of five times, or over a maximum elapsed time of 10 months (or longer, as may be amended from time to time by the Sponsor based on additional stability data), which occurs first, after which the vial may not be used for any further dosing. The smallest number of vials necessary for a given intravesical instillation should be used. In general, the 1 mL-solution vials will be used for the lower doses (earlier cohorts) and the 5 mL-solution vials will be used for the higher doses (later cohorts). For example, for Cohorts 1 and 2, a 1 mL-solution vial w ill be used for the first, 0.2 or 0.6 mL volumes of instillation, respectively. The vial may be re-frozen and later thawed for continued use for subsequent dosing until the vial is empty. If there is insufficient volume in a given vial to complete a dose, the volume from that vial will be supplemented with volume from the next vial from the same lot number. Unless it is unavoidable in order to continue dosing of a patient without interruption, for any single instillation no patient should receive Chemophase study drug from more than one lot number 9.3. Dosing Schedule and Procedure for Intravesical Instillation of MMC with and without Chemophase . It is preferable to limit the number of lot numbers to which any given patient is exposed over the duration of that patient’s total exposure to Chemophase. For Cohorts 3, 4, and 5, the 5 mL-solution vials will be used in the same manner as the 1 mL-solution vials. For planning an adequate supply of study drug, note that it is not possible to extract the full 1.0 mL from a 1 mL- solution vial, or the full 5.0 mL from a 5 mL-solution vial. Note also that allowances should be made for the 0.1 to 0.2 mL hold-up volume lost due to the syringe filter (see Table 9.2-A). All Chemophase vials supplied for this study, both used and unused, must be retained for drug accountability. See Section 12.5 regarding drug accountability. The only dose of MMC used in this study is 40 mg in 20 mL of Sterile Water. As shown in Table 9.3-A, the initial intravesical instillation (Day 1, Week 1) for each patient in each cohort is MMC alone (without Chemophase). For Weeks 2 through 6, the patient will receive five additional, weekly, intravesical instillations, which will consist of both Chemophase and MMC, administered sequentially in the manner described below. The 12 patients treated at MTD will continue to receive combination therapy every three months until the end of Year 2 from Day 1 or until the time of documented tumor recurrence, whichever occurs first. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 47 of 89 Version 4.0 26 Feb 2009 Table 9.3-A. Dosing Schedule for MMC and Chemophase Cohort Week 1 (MMC Dose) Volume for Instillation Week 2 through Week 6 (1) Chemophase Dose (2) Sterile Saline (3) MMC Dose 1 40 mg/20 mL 20,000 units in 0.2 mL 7.8 mL 40 mg/20 mL 2 40 mg/20 mL 60,000 units in 0.5 mL 7.5 mL 40 mg/20 mL 3 40 mg/20 mL 200,000 units in 1.8 mL 6.2 mL 40 mg/20 mL 4 40 mg/20 mL 400,000 units in 3.6 mL 4.4 mL 40 mg/20 mL 5 40 mg/20 mL 800,000 units in 7.3 mL 0.7 mL 40 mg/20 mL 1. First step of intravesical administration. 2. Second step of intravesical administration. 3. Third step of intravesical administration. All study patients should refrain from drinking fluids for at least eight (8) hours before intravesical therapy, and also during intravesical therapy, except for sips of water needed to take medications, unless there is a medical contraindication to this eight-hour dehydration. Just prior to intravesical instillation, the patient should void completely to empty the bladder. Using sterile technique, a catheter will be inserted in the bladder and the bladder will be carefully emptied of any residual urine using the catheter. The volume of any residual urine will be recorded. If necessary to fully drain the bladder, the lower abdomen will be gently compressed and the patient may be rolled from side to side. After the bladder is fully drained of urine and the volume of urine measured, sequential instillation of study drugs will begin. The intravesical instillation of study drug is a three- step procedure in this study, as outlined below. The three sequential steps of instillation are presented in tabular format above, in Table 9.3-A. The intermediate step, instillation of sterile saline, has been incorporated in this clinical trial for the sole reason of having the overall volume of fluid administered held constant in all patients across all cohorts. The syringes with the Chemophase and saline and the reconstituted MMC should be prepared in advance of the actual catheterization, in order to allow for no interruption in the stepwise instillation. • First, the volume of prepared Chemophase solution (see Section 9.2.3) will be passed through the syringe filter and introduced into the sterile barrel of a syringe of at least 25 mL connected to the urinary catheter and allowed to enter the bladder by gravity flow. • Second, immediately following the Chemophase, the volume of sterile saline solution specified in Table 9.3-A will be introduced into the sterile barrel of the syringe connected to the urinary catheter and allowed to enter the bladder by gravity flow. • Third, immediately following the sterile saline, the prepared reconstituted 20 mL volume of MMC (see Section 9.1.3) will be shaken to mix the contents, the stopper removed from the vial, and the volume immediately poured from the vial into the sterile barrel of the syringe connected to the urinary catheter and allowed to enter the bladder by gravity flow. In order to assure that all the solutions have passed through the catheter and into the bladder, a small volume of air may be Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 48 of 89 Version 4.0 26 Feb 2009 gently pushed by s yringe into the catheter. The catheter is then withdrawn from the bladder. This procedure should ensure that all patients in all cohorts have received a total of 28 mL of intravesical volume at each dosing cycle. Aseptic, appropriate technique must be used during administration of intravesical Chemophase, sterile saline, and MMC to avoid introducing contaminants into the urinary tract or unduly traumatizing the urinary mucosa. After the intravesical instillation is completed, study patients will be instructed to lie on their abdomen for at least 15 minutes, after which the patient is intended to be ambulatory. Patients should retain the solution in their bladder, if possible, for a total of two (2) hours. If the solution cannot be retained in the bladder for the entire two hours, this will be noted on t he CRF along with the total bladder retention time and the reasons cited for a less than two-hour retention. During the intravesical procedure and afterwards, patients should be observed and questioned about adverse events. Two hours after intravesical instillation, patients w ill be instructed to empty the bladder into a urine collection container. The volume of urine voided will be measured and recorded in the CRF. A 5 mL aliquot of this urine will be frozen at -20°C and retained for possible future analysis. Patients should be instructed to carefully clean their hands and genitalia after voiding the intravesically administered MMC. Patients may then leave the clinic if no adverse events are reported or observed that require them to remain for observation or treatment. 10. ADVERSE EVENTS AND SAFETY MONITORING The safety parameters collected and monitored during this study include adverse events (AEs), laboratory determinations, physical examination and vital signs, 12-lead ECG, plasma concentration of MMC, and findings noted on cystoscopy. All AEs that occur during the study should be treated appropriately to protect and ensure the patient’s well-being. If such treatment constitutes a deviation from this protocol, Halozyme must be notified and the Investigator should comply with applicable Institutional Review Board (IRB)/Ethics Committee (EC) reporting requirements. If the patient is withdrawn from the study as a result of this deviation, the reason will be appropriately documented. 10.1. AE Definitions The following definitions of terms are guided by the International Conference on Harmonization and the U.S. Code of Federal Regulations [21 CFR 312.32, effective 6 April 1998] and are included herein. The terms "serious adverse event" and "adverse event," inserted in parentheses, are commonly used terminology. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 49 of 89 Version 4.0 26 Feb 2009 An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. Serious adverse drug experience • Is (serious adverse event, SAE) is any adverse drug experience (AE) occurring at any dose that results in any of the following outcomes: fatal or immediately life-threatening (life-threatening is defined as a medical event during which the patient is at immediate risk of death from the reaction as it occurred; it does not include an event that, had it occurred in a more serious form, might have caused death); • Requires hospitalization, or prolongs existing hospitalization . Any in-patient hospital admission, regardless of duration of hospital stay, will be considered as in-patient hos pitalization. Hospitalizations for procedures scheduled prior to enrollment into the study and emergency room visits do not constitute a serious AE. • Results in persistent or significant disability/incapacity ; • Results in a congenital anomaly or birth defect ; or • Is any other Important Medical Event. Important Medical Events that may not result in death, be life-threatening, or require hospitalization may be considered SAEs when, based upon appropriate medical judgment, they may jeopardize the patient or require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias, or convulsions that do not result in hospitalization of the patient, or the development of drug dependency or drug abuse. Life-threatening is any adverse drug experience (adverse event) that places the patient or subject, in the view of the Investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that, had it occurred in a more severe form, might have caused death. Associated with the use of the drug means that there is a reasonable possibility that the experience (adverse event) may have been caused by the drug. Unexpected adverse drug experience means any adverse drug experience (adverse event), the specificity or severity of which is not consistent with the current Investigator Brochure (IB). Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 50 of 89 Version 4.0 26 Feb 2009 10.2. Pre-Treatment-Emergent Adverse Events Halozyme considers adverse events (AEs) that occur between the time the patient signs the informed consent document for the study and the time when that patient is first exposed to study drug (MMC or Chemophase in this study) as “pre-treatment-emergent” events. All known pre-treatment-emergent AEs that are serious (see Section 10.1) should be reported to Halozyme. The reason for collection of serious pre-treatment-emergent AEs is to allow for an assessment of whether or not the SAE was causally associated with any protocol-related activities. Halozyme will not collect information on pre-treatment- emergent AEs that do not meet at least one accepted criterion for a serious classification under the most rigid and comprehensive of the applicable regulatory agency criteria for this study. Events occurring after first administration of study drug will be considered treatment-emergent AEs and will be captured on the AE CRF. 10.2. Laboratory Abnormalities as Adverse Events It is anticipated that many laboratory abnormalities observed during the course of a study will be encompassed under a reported adverse event (AE) describing a clinical syndrome (e.g., elevated BUN and creatinine in the setting of an AE of renal failure, or elevated SGOT/SGPT in the setting of an AE of hepatitis). In these cases (e.g., an AE of renal failure), the laboratory abnormality itself (e.g., elevated creatinine) does not need to be recorded as an AE. In the absence of a reported AE identifying a clinical syndrome that encompasses the observed laboratory abnormality, that isolated laboratory abnormality itself should be reported as an AE if it is judged by the Investigator to be clinically significant for that patient. For the purposes of this study, criteria defining a "clinically significant" laboratory abnormality are: a) Laboratory abnormality leads to a dose-limiting toxicity (e.g., judged to be associated with study drug administration and resulting in study drug dose reduction, suspension or discontinuation), or b) Laboratory abnormality results in any therapeutic intervention (i.e., concomitant medication or therapy), or c) Other laboratory abnormality judged by the Investigator to be of other particular clinical relevance. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 51 of 89 Version 4.0 26 Feb 2009 10.3. Classification of Adverse Events by Severity The Investigator must categorize the severity of each AE according to the following guidelines. The level of severity is guided by the National Cancer Institute (NCI) Common Terminology Criteria (CTC) for adverse events, which will be provided to each study center and is available on line at http://ctep.cancer.gov/reporting/ctc.html [12]. Mild: Grade 1 NCI Common Terminology Criteria AE; or if not found in the Common Terminology tables, an AE that is asymptomatic or barely noticeable to the patient; not interfering with patient’s daily activity performance or functioning; generally not requiring alteration or cessation of study drug administration; and/or ordinarily not needing therapeutic intervention. Moderate: Grade 2 NCI Common Terminology Criteria AE; or if not found in the Common Terminology tables, an AE of sufficient severity as to possibly make the patient moderately uncomfortable; possibly influencing the patient’s daily activity performance or functioning; generally not impairing the patient’s ability to continue in the study; and/or possibly needing therapeutic intervention. Severe: Grade 3 or 4 NCI Common Terminology Criteria AE; or if not found in the Common Terminology tables, an AE generally causing severe discomfort; significantly influencing the patient’s daily activity performance or functioning; generally requiring alteration or cessation of study drug administration; life- threatening; resulting in significant disability or incapacity; and/or generally requiring therapeutic intervention. 10.4. Classification of Adverse Events by Relationship to Study Drug Administration The relationship of each AE to the study drug administration will be assessed by the Investigator after careful consideration, and according to the following guidelines. Because there are two study drugs in this clinical trial (i.e., MMC and Chemophase), the Investigator will be expected to make his/her best assessment of the relationship of each event to each of the two study drugs. See Section 10.5 for information regarding the known toxicity profiles of MMC and Chemophase, which should guide the assessment of causality to each study drug. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 52 of 89 Version 4.0 26 Feb 2009 No, Not Re lated: This category is applicable to those AEs that are clearly due to extraneous causes (concurrent drugs, environment, etc.) and do not meet the criteria for drug relationship listed under UNLIKELY; POSSIBLY; PROBABLY; AND YES, RELATED. Unlikely Related: This category applies to those AEs that are judged to be unlikely to be related to the study drug administration. An AE may be considered to be PROBABLY NOT RELATED when it meets at least two (2) of the following criteria: a) It does not follow a reasonable temporal sequence from administration of the study drug. b) It could readily have been produced by the patient’s clinical state, environmental or toxic factors, or other modes of therapy administered to the patient. c) It does not follow a known or expected response pattern to the study drug. d) It does not reappear or worsen when the study drug is re-administered. Possibly Related: This category applies to those AEs that are judged to be perhaps related to the study drug administration. An AE may be considered POSSIBLY RELATED when it meets at least one (1) of the following criteria: a) It follows a reasonable temporal sequence from administration of the study drug. b) It could not readily have been produced by the patient’s clinical state, environmental or toxic factors, or other modes of therapy administered to the patient. c) It follows a known or expected response pattern to the study drug. Probably Related: This category applies to those AEs that are felt with a high degree of certainty to be related to the study drug administration. An AE may be considered PROBABLY RELATED if it meets at least two c) It disappears or decreases on cessation or reduction in study drug dose. There are exceptions when an AE does not disappear upon discontinuation of the drug, yet (2) of the following criteria: a) It follows a reasonable temporal sequence from administration of the study drug. b) It could not be reasonably explained by the known characteristics of the patient’s clinical state, environmental or toxic factors, or other modes of therapy administered to the patient. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 53 of 89 Version 4.0 26 Feb 2009 drug relatedness clearly exists (e.g., bone marrow depression, fixed drug eruptions, tardive dyskinesia, etc.). d) It follows a known or expected response pattern to the study drug. Yes, Related: This category applies to those AEs that are incontrovertibly related to study drug administration. An AE may be assigned to this category if it meets at least the first three 10.5. Known Toxicity Profiles of MMC and Chemophase (3) of the following criteria: a) It follows a reasonable temporal sequence from administration of the study drug. b) It could not be reasonably explained by the known characteristics of the patient’s clinical state, environmental or toxic factors, or other modes of therapy administered to the patient. c) It disappears or decreases on cessation or reduction in study drug dose. There are exceptions when an AE does not disappear upon discontinuation of the drug, yet drug relatedness clearly exists (e.g., bone marrow depression, fixed drug eruptions, tardive dyskinesia, etc.). d) It follows a known or expected response pattern to the study drug. e) It reappears or worsens when the study drug is re-administered. As noted in Section 10.4, the Investigator is expected to make his/her best assessment of the causal relationship of each adverse event to each 10.5.1. Known Toxicity Profile of MMC of the two study drugs (i.e., MMC and Chemophase) in this clinical trial. The information summarized below is intended to be only a guide to this assessment. The Investigator should base the assessment on all available information. The American Urologic Association (AUA) Bladder Cancer Guidelines Panel 1999 Report on the Management of Non-Muscular-Invasive Bladder Cancer provided a summary of probability estimates of treatment complications for MMC based on its review of the literature [3]. Complications were grouped by local bladder symptoms, systemic symptoms, and other, and have been excerpted below for Table 10.5-A. Of the 28 patients who had undergone TURBT and treated with MMC alone (who received a total of 788 intravesical instillations) in a randomized clinical trial, five (17.8%) had side effects, including four with cystitis and one with skin rash [10]. (Note: Of the 28 patients treated with MMC plus 200,000 units of bovine hyaluronidase [who received a total of 750 instillations], four [14.2%] had side effects, including three Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 54 of 89 Version 4.0 26 Feb 2009 with cystitis and one with skin rash. There was no significant alteration in white blood count during therapy.) In a separate publication, side effects of MMC plus 200,000 units of bovine hyaluronidase combination intravesical therapy were observed in a total of 14% (6/43) of patients, and consisted of bacterial cystitis (6.9%), chemocystitis (4.6%), and skin allergy (2.3%). No patients were withdrawn due to side effects [11]. Bladder fibrosis with a reduction in bladder capacity is an uncommon but known complication of generally long-term intravesical MMC therapy, the incidence of which appears to correlate directly with the cumulative MMC dose and correlate inversely with the time interval between a second tumor resection and the first MMC instillation [8]. Table 10.5-A. Probability Estimates of Treatment Complications from Intravesical MMC Treatment Complication Median Probability 95% CI G/P* LOCAL BLADDER SYMTPOMS Irritative Voiding Symptoms Dysuria 35% 30-41% 4/456 Frequency/Nocturia 42% 26-59% 3/420 Irritative symptoms 18% 12-26% 19/1596 Pain/Cramps 10% 6-14% 1/220 Other Local Symptoms Local side effects 5% 3-9% 2/296 Other side effects 2% 0.3-4% 1/148 Other Bladder contracture 5% 2-11% 2/234 Bacterial c ystitis 20% 17-23% 6/845 Hematuria 16% 7-28% 7/800 Incontinence 1% 0.4-4% 1/220 SYSTEMIC SYMPTOMS Flu-Like Arthralgia 9% 0.1-47% 2/278 Fever or Chills 3% 1-7% 5/686 Flu-like symptoms 20% 4-48% 3/498 Infectious Epid/Prost/Ureth infections 4% 2-9% 3/251 Hepatic changes 0.1% 0-1% 1/220 Pneumonia 0.2% 0-2% 1/148 Myelosuppression 2% 0.3-7% 2/102 Nausea/Vomiting 9% 1-26% 3/498 Skin Rash 13% 8-19% 14/992 Systemic Side Effects 3% 0.5-8% 2/296 OTHER Treatment Incomplete 9% 2-14% 7/683 Treatment Interruption 11% 8-16% 6/374 * G = Number of Groups/Treatment arms extracted; P = Number of Patients in those groups. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 55 of 89 Version 4.0 26 Feb 2009 10.5.2. Known Toxicity Profile of Chemophase Although there is an extensive body of knowledge establishing the clinical safety and tolerability of animal-derived hyaluronidases, there are no clinical data regarding the use of rHuPH20 administered intravesically. Except for the recently-initiated Phase I trial of a single administration of Chemophase and MMC, only one clinical trial has been conducted with rHuPH20 (except for trials of the ex vivo use of rHuPH20 to remove the cumulus matrix surrounding human oocytes for in vitro fertilization). This first exposure of rHuPH20 drug substance in humans was an investigation of the potential dermal sensitivity of an intradermal injection of Enhanze SC™ (rHuPH20 for injection) in 100 normal healthy volunteers and showed no s ignal of allergy or immunogenicity. Animal-derived hyaluronidase preparations have been the subject of multiple investigations and regulatory approvals in Europe, the U.S. and Asia, and collectively encompass over 50 years of use in humans. The 11 October 2000 package insert for Wydase (bovine hyaluronidase) lists hypersensitivity to hyaluronidase as a Contraindication. Under Adverse Events, it is stated that allergic reactions (urticaria, angioedema) are rare, and anaphylactic-like reactions following retrobulbar block or intravenous injections have occurred. The U.S. FDA has indicated that recently marketed bovine-derived preparations have a reported level of immediate hypersensitivity of less than 0.1%. In 1998, Baumgartner et al. published a review of the literature of animal-derived hyaluronidases (Permease 7500 IU or Neopermease 200,000 IU) used additively to cytostastic agents in neoplastic diseases in 420 patients in a series of pilot studies [13]. Hyaluronidase was well-tolerated by multiple routes of administration, including intramuscular, intravenous, intraperitoneal, intrapleural, intrathecal, and intravesical routes of administration. Allergic reactions were noted in 4.2% (3/72) of patients treated intramuscularly, consisting of local inflammation and pain in two patients and nausea, vomiting, and circulation disturbance in a third. Allergic reactions were noted in 10% of patients treated intravenously (except for a 20% rate in astrocytoma patients), all of which were reversible and easily manageable. Because rHuPH20 is up to 100-fold more pure than animal-derived products based on activity and contains human amino acid sequences rather than bovine, it is expected that most or all of the allergic and immunogenic problems associated with the animal-derived impurities will be avoided. A Phase I safety, tolerability, and PK single-administration clinical trial (HZ2-05-02) of a low dose (20,000 units) of Chemophase with 40 mg MMC administered intravesically in a targeted sample size of five evaluable patients who had undergone transurethral resection of bladder tumor (TURBT) for transitional cell bladder cancer Stage Ta , T1 or Tis (any grade), were free of known bladder cancer recurrence, and were being monitored for recurrence of superficial transitional cell bladder cancer was initiated in August 2005 and completed enrollment in March 2006. All five patients completed the study. There were no deaths, serious AEs, AEs judged to be possibly or more related to either study Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 56 of 89 Version 4.0 26 Feb 2009 drug, moderate or severe AEs, premature withdrawals, or dose-limiting toxicities. The only three AEs reported in the study were, by MedDRA Preferred Terms, Influenza, Urinary tract infection, and Acne. All plasma samples for MMC were below the lower limit of quantitation (10 ng/mL) and all plasma samples of PH20 were below the lower limit of quantitation (10 U/mL). 10.6. Reporting of Adverse Events For the purpose of this study, all 10.6.1. Reporting of Serious Adve rse Events AEs, regardless of seriousness, severity, expectedness, or relationship to the study drug (MMC or Chemophase in this study), will be collected if the date and time of onset of the AE was after the patient’s first exposure to either study drug and no later than 28 days after the last dose of study drug. There is no t ime limitation on the reporting of AEs that are treatment-emergent and assessed as reasonably associated with study drug (i.e., a drug-associated AE should be reported even if more than 28 days have passed since the last study drug treatment). Events that occur prior to first study drug administration will be considered pre- treatment-emergent because the time of onset preceded the first exposure to study drug (see Section 10.2), and these observations will be captured on the patient’s Medical History CRF. Events occurring after first administration of study drug will be considered treatment-emergent AEs and will be captured on the AE CRF. Note that AEs that may be known, expected toxicities caused by MMC (see Section 10.5.1) and occurring during the study must be reported as AEs on the AE CRF. Patients will be questioned and/or examined by the Investigator and his/her designee for evidence of AEs. The questioning of study patients with regard to the possible occurrence of AEs will be generalized such as, “How have you been feeling since your last visit?” Information gathering for AEs should generally not begin with direct solicitation from patients regarding the presence or absence of specific AEs. All serious AEs (SAEs) occurring with any patient participating in this clinical trial must be reported to Halozyme as described in Section 10.6.1. CONTACT THE HALOZYME-DESIGNATED MEDICAL MONITOR IMMEDIATELY (WITHIN 24 HOURS) FOR ANY • Reporter name and contact number, SERIOUS ADVERSE EVENT. The minimum required information for an initial report of an SAE is: • Protocol number, • Site and patient identification information, and • The SAE term with a brief summary of the event including the causality assessment, if possible. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 58 of 89 Version 4.0 26 Feb 2009 AE is judged to be related to the study drug administration. All such patients with AEs should be followed clinically and by the appropriate diagnostic evaluations. All AEs, regardless of severity, and whether or not ascribed to the study drug administration, will be recorded in the appropriate section of the CRF. 10.6.4. Reporting of Safety Information to the Institutional Review Board It is the responsibility of the Investigator to inform the study center’s Institutional Review Board (IRB)/Ethics Committee (EC) of all SAEs and other safety information in accordance with applicable IRB’s/EC’s requirements. At the completion or early termination of the study, a final report should be made to the IRB/EC by the Investigator within the applicable IRB/EC time frames. 10.7. Pregnancy A negative pregnancy test during screening for women of child- bearing potential and an agreement to use effective contraceptive methods during the treatment period of the study for men and women of child-bearing potential are be required for study eligibility. A pregnancy test will be repeated at Week 8 for women of child- bearing potential. Any pregnancy in a study patient must be immediately reported to the Investigator and in turn to Halozyme (see Section 10.6.1 for contact information). Pregnancy during the study period will be reported and followed until final resolution (i.e., delivery or early termination). Any birth defect or congenital anomaly will be reported to Halozyme immediately as an SAE. 10.8. Concomitant Medications and Procedures Any medication taken during the study, other than study drug (i.e., MMC and Chemophase), is regarded as concomitant medication. A history of current medications will be obtained from each patient during screening and recorded in the CRF. Patients must be queried regarding both prescription and over-the-counter medications that they take. Concomitant medications taken during the time period beginning 28 days prior to initial dosing, on Day 1/Week 1, through the Week 12 assessment will be collected for all patients, and through the last study drug treatment visit for the MTD patients who are continuing on study drug treatment after Week 12. Concomitant medications will be updated at each subsequent visit according to the Schedule of Events (see Section 2), including any medication taken to treat an AE. At each study visit, patients will be asked if there has been any change in the medications they have taken since their last study visit. Changes will be recorded on t he Concomitant Medications CRF. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 59 of 89 Version 4.0 26 Feb 2009 Recording of concomitant medications will include the name of the drug, dosage, route, frequency, date of treatment, and the clinical indication for which the medication was taken. Patients may receive medical care during the study including but not limited to antibiotics, analgesics, antipyretics, etc., when clinically indicated. Whenever possible, the patient should avoid starting any new medications during the treatment period of this study (including over-the-counter medications) unless the Investigator deems such medication medically necessary. A list of medications prohibited during the study is provided in Section 7.3 of this protocol. 11. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 11.1. Study Hypotheses This is a study to primarily assess the safety and tolerability of Chemophase administered intravesically with MMC. The primary objective is to determine the MTD and DLTs of escalating doses of Chemophase with MMC and establish the dose of Chemophase recommended for future studies. It is anticipated, based on previous human studies using intravesical bovine hyaluronidase along with MMC, that Chemophase will be well tolerated and will not appreciably increase the systemic absorption or toxicity of MMC. A secondary objective of this study is to observe patients for any preliminary evidence of anti-tumor activity of Chemophase and MMC when co-administered intravesically. Based on nonclinical data of rHuPH20 in various tumor cell models and on previous human studies using intravesical bovine hyaluronidase along with MMC, it is hypothesized that, compared to historical data of MMC monotherapy, Chemophase with MMC will reduce the risk of tumor recurrence. However, this early study of Chemophase in humans is neither designed nor powered to show statistical significance or otherwise confirm an anti-tumor effect of Chemophase. In 1995, a Southwest Oncology Group Study comparing BCG to MMC intravesical therapy (weekly for six weeks, then monthly for one year) found a median time to tumor recurrence or death from any cause of 22 months for the 186 patients treated with MMC 20 mg in 20 mL water [14]. In 2001, the International Mitomycin C Consortium published a randomized clinical trial of six weekly intravesical treatments showing the median time to recurrence for 119 patients in an optimized treatment arm (MMC 40 mg, PK manipulations to decrease urine volume, and urine alkalinization) was 29.1 months (95% CI 14.0 to 44.2 months) compared to 111 patients on standard, non-optimized therapy (MMC 20 mg) who had a median time to recurrence of 11.8 months (95% CI 7.2 to 16.4 months) [15]. Urine biomarkers for bladder cancer obtained at baseline and Week 8 (and beyond Week 8 for the MTD patients who are continuing on study drug treatment) will be assessed. The NMP22® BladderChek® Test biomarker is performed in clinic on a urine Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 60 of 89 Version 4.0 26 Feb 2009 specimen obtained between midnight and noon, and collected more than five days after cystoscopy/TURBT. The UroVysion test biomarker will be obtained in the clinic and sent to a central vendor lab for analysis. 11.2. Patient Data Sets for Analysis All patients randomized and receiving one or more doses of Chemophase will be included in the safety analysis data set. Any patient receiving MMC on study but not receiving Chemophase will be considered for safety, but assessed separately from patients receiving Chemophase. A modified “intent-to-treat” (ITT) analysis data set for anti-tumor effects includes all patients receiving one or more doses of Chemophase with MMC. Patients who enter the baseline screening period but are not treated with Chemophase plus MMC will not be included in this modified ITT analysis. A “per-protocol” analysis for anti-tumor effects will include all ITT patients who met the following criteria: • Satisfied the disease-defining Inclusion Criteria #1 and #2 (see Section 7.1), • Received at least four protocol-specified doses of Chemophase with MMC over an interval not exceeding 8 weeks, • Retained at least four intravesical instillations for at least 90 minutes, and • Were monitored to the time of tumor recurrence, or at least 5 years, whichever occurs first. A listing of all screen failures, with the reasons for failure, will be recorded on the patient screening log. A patient listing of screen failures and a tabulation of the reasons for screen failure will be prepared. 11.3. Endpoints and Statistical Analyses The primary endpoint in this study is the rate of toxicities observed with the combination of Chemophase and MMC. The primary statistical analysis w ill consist of point estimates and the 95% confidence intervals constructed around the point estimates. All safety data will be examined, such as AEs (including overall incidence by treatment group), physical examination findings and vital signs, laboratory data, plasma MMC concentration, and ECGs. Descriptive statistics will be used to summarize all safety variables. The MTD will be determined based on DLTs (see Sections 8.8 and 8.9). All AEs and toxicities will be recorded on the appropriate CRFs and reported according to severity and assessed relationship to the study medications. The NCI CTC grading of severity for AEs (CTCAE) Version 3 or higher [12] and the latest version of MedDRA will be used for reporting and medical coding of AEs. All AEs regardless of causality will be individually listed. The incidence of patients with AEs will be tabulated by MedDRA System Organ Class (SOC), Preferred Term, grade or severity, and also Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 61 of 89 Version 4.0 26 Feb 2009 summarized by study center. SAEs will also be listed and summarized separately. AEs will also be separated into localized bladder and systemic events. Based on the long-term follow-up monitoring, the data will be assessed for the median time to tumor recurrence and the two-year recurrence rate. For the purpose of this study, tumor recurrence is defined as a biopsy that histologically confirms the recurrence of bladder carcinoma. Recurrences will be characterized with regard to the number of tumors, TNM stage, and grading. Information on tumor progression will be summarized. The data collected on the urine biomarker, comparing baseline to post-baseline values, will be summarized. 11.4. Sample Size Considerations This is a Phase I-IIa multiple dose study of Chemophase in humans, and is neither designed nor powered for formal statistical comparisons. The study does not include a MMC-only control arm or other parallel control group. The sample size of 3 to 6 patients per dose cohort is standard for the determination of safety and tolerability in many initial clinical trials for oncology indications. The protocol intends a sample size of 12 evaluable patients treated at the MTD level, and it is believed that 12 patients will provide an adequate sample size to establish the tolerability of this dose regimen for the anticipated subsequent clinical trials and possibly provide a preliminary estimate of anti-tumor activity. 11.5. PK Analyses and Neutralizing Antibodies to rHuPH20 A secondary endpoint of this study is to assess the pharmacokinetics (PK) of intravesical administration of MMC alone (at Week 1) and in combination with Chemophase (subsequent weeks). Samples will be collected and assayed according to the schedule in Section 8, and according to Footnote 7 in the Schedule of Events in Section 2. Although samples will be collected for neutralizing antibodies (NABs) at Week 1 and Week 6, the Week 1 samples will be assayed only if the Week 6 sample shows evidence of NABs. 12. REGULATORY/ADMINISTRATIVE PROCEDURES AND DOCUMENTATION 12.1. Ethics This study will be conducted under a U.S. Investigational New Drug (IND) Application. All applicable U.S. regulations governing human subject protection must be followed. All ethical and regulatory requirements necessary to comply with the principals of Good Clinical Practice (GCP) for the conduct and monitoring of clinical investigations must be followed. To ensure ethical conduct of this clinical study, Investigators will be expected to adhere to basic principles provided from generally recognized guidelines such the Belmont Report and the International Ethical Guidelines for Biomedical Research Involving Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 62 of 89 Version 4.0 26 Feb 2009 Human Subjects. The study has been designed to involve the participation of representative patients affected by the disease under investigation. Participants must have provided written informed consent to document their voluntary participation in this study. Updated safety information will be provided to the Investigators, Institutional Review Boards (IRBs)/Ethics Committees (ECs) and patients as necessary in order that they may consider relevant and emerging information that could affect their willingness to continue participation in this study. 12.2. Institutional Review Board and Approval In accordance with 21 CFR Parts 50 and 56, the Investigator agrees to provide the appropriate Institutional Review Board (IRB)/Ethics Committee (EC) with all appropriate material, including a copy of the protocol, informed consent form (ICF), Investigator’s Brochure (IB), and any proposed advertisement for the study prior to the start of the study. The proposed informed consent form (ICF) and any proposed advertisement must also be agreed to by t he Sponsor (Halozyme). A copy of the IRB/EC approval letter of the protocol and the ICF must be supplied to Halozyme prior to consenting any patients for the study. A copy of the IRB/EC approval letter of any protocol amendments and any advertisements must be supplied to Halozyme prior to implementing these documents. The study may not begin screening or enrolling patients until the Investigator has obtained IRB/EC approval of the protocol and ICF and Halozyme has received a hardcopy documentation of each. The Investigator will supply to Halozyme a list of the names, professions, and affiliations of IRB/EC members to demonstrate compliance with membership requirements. If the Investigator or a subinvestigator is a routine voting member of the IRB/EC, Halozyme will be provided with a statement from the IRB/EC that the Investigator/subinvestigator did not and will not vote on the subject of this investigation. During the course of the study, the Investigator shall make timely and accurate reports to the IRB/EC on t he progress of the trial, at intervals not exceeding one year, as well as satisfying any other local IRB/EC regulations regarding reporting. Copies of all reports to and correspondence with and from the IRB/EC must be provided to Halozyme. Furthermore, at the completion or early termination of the study, a final report should be made to the IRB/EC by the Investigator within the applicable IRB/EC time frames. A copy of this report will be provided to Halozyme. Any significant changes or revisions in the study protocol or any changes that may alter patient risk must be approved by Halozyme (and may require FDA/other regulatory agency review and/or approval) and must be approved in writing by t he IRB/EC prior to implementation (see Section 12.7 for protocol amendments). The Investigator must also receive a written notice of approval from Halozyme prior to initiating the revised changes to the study protocol. A protocol change intended to eliminate an apparent immediate hazard may be implemented immediately, provided that Halozyme is immediately Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 63 of 89 Version 4.0 26 Feb 2009 notified and an amendment is subsequently provided by Halozyme and approved by t he IRB/EC. It is the Investigator's obligation to maintain an IRB/EC correspondence file, and to make this available for review by Halozyme or its designated representatives as part of the study monitoring process. 12.3. Informed Consent A copy of the proposed informed consent form (ICF) document must be submitted to Halozyme for review and comment prior Each patient (and/or legally authorized representative if the subject is a minor, mentally incompetent or physically incapacitated) found to be eligible for the study must have voluntarily provided written informed consent using the IRB/EC-approved ICF prior to screening procedures or enrollment in the study (i.e., before performing any protocol- dictated procedures that are not part of normal patient care). A copy of the signed and to submission to the reviewing IRB/EC. The ICF must be approved by t he IRB/EC and contain all elements required by all applicable federal, state, local, and institutional regulations or requirements prior to consenting a patient. Authorization to use or disclose Personal Health Information (PHI) in accordance with requirements of the Health Insurance Portability Act of 1996 (HIPAA) should be covered in the ICF or in a separate document to be signed by the patient. The proposed ICF must contain a full explanation of the purpose and nature of the study, a description of the procedures, the possible advantages, risks, alternate treatment options, and a statement of confidentiality of patient study records, a statement regarding voluntary compensation and availability of treatment in the case of injury, an explanation of whom to contact about the research, the patient’s rights, and notification that participation is voluntary and refusal will involve no penalty or loss of medical benefits. These requirements are in accordance with the U.S. Federal Regulations as detailed in the 21CFR50.25 and the Declaration of Helsinki. The ICF should also indicate by signature that the patient, or where appropriate, legal guardian/representative, permits access to relevant medical records by t he Sponsor (Halozyme) and/or the Sponsor's duly appointed agent and by representatives of the U.S. Food and Drug Administration (FDA) or other applicable regulatory agency and permits their data to be used in publications. The Investigator will be responsible for obtaining written informed consent from potential patients prior to any study specific screening and entry into the study. The research study will be completely explained to each prospective study patient. The Investigator or designee must explain that the patient is free to refuse to enter the study, and free to withdraw from it at any time for any reason. If new safety information becomes available and results in significant changes in the risk/benefit assessment, the ICF should be reviewed and updated if necessary. Under this circumstance, all patients (including those already being treated) should be informed of the new information, given a copy of the revised ICF, and be allowed to re-evaluate their consent to continue in the study. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 64 of 89 Version 4.0 26 Feb 2009 dated ICF document will be provided to the patient, and a copy will be maintained with the patient's CRFs, or in the study documentation. The original will be retained by the Investigator along with the CRFs. The ICF must be in a language that the patient can read and understand. 12.4. Laboratory Accreditation Any laboratory facility intended to be used for analysis of clinical laboratory samples required by this protocol must provide evidence of adequate licensure or accreditation. Reference values and/or normal ranges for the test results must be provided to Halozyme. Halozyme must be notified immediately in writing of any changes occurring in reference values during the course of the study. All local and central laboratories used in the study must have, at a minimum, the following. • College of American Pathologist (CAP) accreditation, and/or • Clinical Laboratory Improvement Amendments (CLIA) accreditation • Listing of laboratory normal reference values (for all protocol required tests) • Laboratory license • Curriculum vita of laboratory director may also be requested 12.5. Drug Accountability Upon receipt of study drug(s), the Investigator, pharmacist or qualified designee is responsible for taking an inventory of the study drug(s). A record of this inventory must be kept and all usage of study drugs must be documented. All vials of study drug, both used and unused, must be retained as discussed in Sections 9.1 and 9.2. The investigational drug (both MMC and Chemophase) is to be administered/ prescribed only by t he Principal Investigator or appropriately qualified physician subinvestigators named on the Form FDA 1572. Under no c ircumstances will the Investigator(s) allow the investigational drug to be used other than as directed by t his protocol. Although appropriate personnel may be designated to administer/dispense drug and maintain drug accountability records, the Principal Investigator is ultimately responsible for all drug accountability. The Investigator or their designee must maintain accurate records accounting for the receipt of the investigational drug supplies and for the disposition of the drug. Documentation of the disposition of the drug should consist of a dosing record including the identification of the person to whom the drug is dosed, the quantity and the date of dosing, and any unused drug. This record is in addition to any drug accountability information recorded on the CRFs. At study end, unused drug will be reconciled with dosing records. All unused investigational drug shall be returned to Halozyme upon request unless otherwise instructed. A copy of the reconciled drug inventory record will be provided to Halozyme or its designee, and the original will be retained at the site. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 65 of 89 Version 4.0 26 Feb 2009 12.6. Protocol Compliance and Protocol Deviations Except for a change that is intended to eliminate an apparent immediate hazard to a study patient, the protocol shall be conducted as specified. Any such change must be reported immediately to Halozyme and to the IRB/EC. From time to time, it is possible that Halozyme may prospectively authorize protocol deviations if the deviation is minor, and does not place patient at increased risk or the anticipated risk of potential benefit outweighs the anticipated risk of potential harm. All such protocol “waivers” must be provided in advance and in writing by Halozyme, and will be forwarded to the Investigator for filing with the patient’s study records. The Investigator must notify the IRB/EC of any and all protocol deviations according to the applicable IRB/EC policy. Written documentation of all protocol deviation must be kept in the study center file and provided to Halozyme. Examples of possible protocol deviations include, but are not limited to: • failure to obtain/maintain approval for research, • failure to obtain required informed consent, • failure to collect, report or file AE reports, • performance of an unapproved study procedure, • performance of research at an unapproved location, and • failure to file protocol modifications, and failure to adhere to an approved protocol. 12.7. Protocol Amendments If the protocol is revised, protocol amendments will be prepared and must be approved by Halozyme. All protocol amendments must be submitted to the IRB/EC for review and approval pr ior to implementation. However, as discussed in Section 12.2, immediate implementation of a protocol amendment may be necessary if the nature of the amendment concerns the safety of patients and is required to be implemented on an urgent basis to protect the safety of patients. Any such immediate implementation of protocol amendments must be agreed to in advance and in writing by Halozyme. Hard copy documentation of IRB/EC approval must be forwarded to Halozyme. If an amendment significantly alters the study design, increases potential risk to the subject or otherwise affects statements in the informed consent form (ICF), the ICF must be revised accordingly and submitted to the IRB/EC for review and approval (see Section 12.3). The approved ICF must be used to obtain informed consent from new patients prior to enrollment and must be used to obtain informed consent from patients already enrolled if they are potentially affected by t he amendment and wish to continue participation. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 66 of 89 Version 4.0 26 Feb 2009 12.8. Data Collection and Case Report Forms In accordance with 21 CFR 312.62, a case report form (CRF) must be completed for each patient enrolled in the study. CRFs are an integral part of the trial and subsequent reports. All data collected for each study patient will be recorded on CRFs provided or approved by Halozyme. CRFs need not be completed by the Investigator, but all entries in CRFs are the responsibility of the Investigator and entry of CRF data must be made under the supervision of the Investigator. CRF completion may be formally delegated to other study personnel. However, the Sponsor (Halozyme) must be informed in writing of the name of such persons and the scope of their authority. The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of all data reported in the CRFs and all required reports for each study patient. It is the obligation of the Investigator to review each page of the CRFs and to sign the designated and appropriate CRFs as the study's authority. The Investigator is also responsible for maintaining any source documentation related to the study, including, but not limited to, any operative reports, laboratory results, radiographic films, tracings, and computer discs, files or tapes. CRFs must be completed legibly, preferably with black ballpoint pen. A correction should be made by striking through the incorrect entry with a single line and entering the correct information adjacent to the incorrect entry. The correction must be initialed and dated by t he person making the correction. Erasure or the use of correction fluid or film is unacceptable. Entries to the CRFs should be made only in the spaces provided, and not in the margins. Information that cannot be accommodated by the spaces provided should be entered on the comments CRF page. For each study patient, the completed CRFs must be promptly reviewed, and required pages signed and dated by t he Investigator. The original copy of all CRFs will be reviewed and retrieved by the Study Monitor representing Halozyme. The Investigator must retain a copy of all CRFs. 12.9. Study Initiation, Monitoring and Closeout Visits and Reports Representatives of Halozyme, in conjunction with Study Monitor(s) representing Halozyme, will perform a number of on-site visits to the study center. Prior to commencement of the study, representatives of Halozyme will visit the study center to assure adequacy of facilities to conduct the protocol, and to discuss with the Investigator the general obligations regarding studies with investigational new drugs. This visit w ill be documented in a report. If the study center has participated in a clinical trial in conjunction with Halozyme within one year, this Pre-Study Qualification visit may be waived. Upon satisfactory receipt of all necessary documentation (including, but not limited to, an allowed IND, the FDA Form 1572, an executed Clinical Trials Agreement, and IRB/EC approval of the protocol and informed consent form), Halozyme or its designee Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 67 of 89 Version 4.0 26 Feb 2009 monitor(s) will arrange for all study material to be delivered to the study center and for the scheduling of a mutually convenient appointment for a Study Initiation visit. Patient entry must not begin until this initiation visit by Halozyme or its designee personnel has been made. At this meeting, all personnel expected to be involved in the conduct of the study should undergo an orientation to include review of the study protocol, instruction for CRF completion, and overall responsibilities including those for drug accountability and study file maintenance. This visit will be documented in a report. Throughout the course of the study, the Halozyme or its designee monitor(s) will make frequent contacts with the Investigator. Study Monitors representing Halozyme will visit study centers periodically throughout the trial for Routine Monitoring visits. The Study Monitor will review CRFs to verify that they are accurate, complete and verifiable from source documents. They will also verify the rights and well-being of the study patients are protected and that the study conduct is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirements. As part of the data review it is expected that source documents (e.g., hospital records, office records) will be made available for review by Halozyme or its designee monitor(s). The study and its monitors may also be similarly evaluated by auditors representing Halozyme. For these purposes, the Investigator will make CRFs, source documents and study files available when requested. A report will be generated for each monitoring visit. At fulfillment of patient enrollment, each Investigator will be notified in writing by Halozyme. The study will be terminated and the study center closed when all completed original CRFs have been collected, all data discrepancies resolved, and drug accountability has been reconciled. A Closeout visit will be scheduled for study centers that enrolled at least one patient, during which Halozyme or its representative will review all informed consents, CRFs, drug accountability records, and other study-related documents. Halozyme or its representative will hold a final meeting with the Investigator and study staff to explain procedures for record retention, publication policy, site audit notification, and financial disclosure. A final letter to the site will record the events of this closeout visit. Study-closure activities will be documented in a report. It will be the responsibility of the Investigator to notify the IRB/EC that the study has been completed (see Section 12.11). The Sponsor (Halozyme) has the right to terminate the study for non-adherence to protocol, unavailability of the Investigator or his or her study staff for Halozyme or its designee monitoring personnel, or for administrative reasons, at any time. In that event, Halozyme will notify each Investigator in writing that the study is to be discontinued. The Investigator will comply with the Halozyme’s written instructions for study discontinuation, which will include the following: • Date discontinuation will occur, • Rationale for discontinuation, • Instructions on how discontinuation is to be performed, • Instructions for patients participating in the study, and • Instructions for retention of study documents. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 68 of 89 Version 4.0 26 Feb 2009 In addition to monitoring by Halozyme or its designees, the study may be audited by representatives of the Food and Drug Administration (FDA), who will also be allowed access to study documents. The Investigator should immediately notify the Clinical Research Department at Halozyme of any proposed or scheduled audits with any regulatory authorities. 12.10. Study Documentation and Retention of Records All records of this clinical study must be retained by the Investigator, including but not limited to, the following. • Protocol and all protocol amendments • All signed versions of the Statement of Investigator, Form FDA 1572 • All drug accountability records • All IRB/EC approvals, correspondence and reports • Signed and dated informed consent forms for each patient • Completed CRFs for each patient • Copies of any other material distributed to patients • Any advertisements for this study • The Investigator’s final report to the IRB/EC • Source documents pertaining to the study, including, but not limited to, any operative reports, laboratory results, radiographic films, tracings, and computer discs, files or tapes The period of time these documents must be maintained is governed by U.S. law and, when applicable, non-U.S., regulations. Some countries require these documents to be maintained for 15 years or longer. All records are to be retained by the Investigator for a minimum of two (2) years after the FDA has approved the new drug application, or after the Sponsor (Halozyme) has notified the Investigator in writing that all investigations of the drug have been discontinued. However, because of international regulatory requirements, Halozyme may request retention for a longer period of time. Therefore, Halozyme or its designee will inform the Investigator when these documents may be destroyed. The Investigator must obtain written approval from the Halozyme prior to destruction of any records. The Investigator must advise Halozyme in writing if the records are to be moved to a location other than the Investigator’s archives. If the Investigator leaves the institution or study center, the records shall be transferred to an appropriate designee, at the study center, who assumes the responsibility for record retention. Notice of such transfer shall be documented in writing and provided to Halozyme. In the event of accidental loss or destruction of any study records, the Investigator will immediately notify Halozyme in writing. Halozyme or its designee must be notified in writing at least 30 days prior to the intended date of disposal of any study records related to this protocol. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 69 of 89 Version 4.0 26 Feb 2009 12.11. Investigator’s Final Report Shortly after completion of the Investigator’s participation in the study, the Investigator will submit a written report to Halozyme. This report may be a copy of the Investigator’s end-of-study report to their IRB/EC, which will include, but not be limited to; notification that the study has concluded, the number of patients enrolled/ treated, and the number of adverse and serious AEs that occurred during the study. The report to the IRB/EC will be consistent with the applicable IRB/EC regulations and time frames. 12.12. Financial Disclosure Each investigator is required to provide financial disclosure statements or certifications to Halozyme prior to study initiation. In accordance with 21 C FR 54, Investigators and all subinvestigators are required to disclose all financial interests in the Sponsor (Halozyme) in order to permit complete and accurate certification statements in an application for marketing authorization. This includes compensation affected by the outcome of a clinical study, significant equity interest in the Sponsor (Halozyme), and proprietary interest in the tested product. The investigators must promptly update this information if any relevant changes occur during the course of the investigation and over the period of one year following completion of the investigation (see 21 CFR 312.64(d)). 12.13 Disclosure of Data and Publication All information obtained as a result of this study or during the conduct of this study will be regarded as confidential. All unpublished information relating to this drug or to the operations of the Sponsor (Halozyme), including clinical indications, formula, methods of manufacture, and any other related scientific data provided to or developed by the Investigator, is confidential and shall remain the sole property of the Sponsor (Halozyme). The Investigator agrees to use the information for the purpose of carrying out this study and for no other purpose, unless prior written permission from the Sponsor (Halozyme) is obtained. The Sponsor has full ownership of the CRFs and database resulting from this study. Disclosures (i.e., any release of information to any third party not noted herein) of any not previously known to be public information and/or results of the investigation for publication or by oral or poster presentation shall not be made earlier than 45 days after submission of the proposed material to the Sponsor (Halozyme) for inspection, unless the Sponsor consents to earlier disclosure. Any proposed publication must be submitted to the at least 40 days prior to intended submission for publication. Publication or presentation of any study information, whether presented orally or in writing, may not be undertaken either during or after the study without Sponsor’s (Halozyme’s) express written approval. The Sponsor (Halozyme) may, for any reason, withhold approval for publication or presentation. If the Investigator is to be listed as an author of a publication prepared by t he Sponsor (Halozyme), the Investigator will be given 40 days for review of the manuscript prior to publication. The Investigator expressly agrees that no publication Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 70 of 89 Version 4.0 26 Feb 2009 of interim, non-final, data will occur without the written authorization of the Sponsor (Halozyme). The Investigator will take appropriate cognizance of the Sponsor’s (Halozyme’s) suggestions before disclosure for publication or presentation consistent with protection of the Sponsor's right to its confidential data. The Investigator agrees that results from this study may be used by the Sponsor (Halozyme) for purposes of domestic and international new drug registration, for publication, and to inform medical and pharmaceutical professionals. Regulatory authorities will be notified of the Investigator’s name, address, qualifications, and extent of involvement. 13. REFERENCES 1. Torti FM, Lum LL. The biology and treatment of superficial bladder cancer. J Clin Oncol 1984;2;505-531. 2. Draft FDA Requirements for Approval of Drugs to Treat Superficial Bladder Cancer, 19 December 1988. Draft guidance document later withdrawn by FDA. 3. Report on the management of non-muscular-invasive bladder cancer (Stages Ta, T1 and Tis). Bladder cancer guidelines panel, American Urological Association, Inc. 1999. 4. BCCancer Drug Manual, http://www.bccancer.bc.ca/HPI/DrugDatabase/DrugIndexPro/Mitomycin.htm 5. Novopharm product labeling for MMC, at www.rxmed.com 6. Reich SD, C linical pharmacology of mitomycin C. In: Carter S, Crooke ST, editors. Mitomycin C, current status and new developments. New York: Academic;1979;243-250. 7. Dalton JT, Wientjes MG, Badalament RA, Drago JR, Au JL-S. Pharmacokinetics of intravesical mitomycin C in superficial bladder cancer patients. Cancer Research 1991;51:5144-5152. 8. Eijsten A, Knonagel H, Hotz E, Brutsch HP, Hauri D. Reduced bladder capacity in patients receiving intravesical chemoprophylaxis with mitomycin C. Br J Urol 1990;66:386-388. 9. Maier U, Baumgartner G. Mitomycin C plasma levels after intravesical instillation with and without hyaluronidase. J Urol 1986;135:845-846. 10. Maier U, Baumgartner G. Metaphylactic effect of mitomycin C with and without hyaluronidase after transurethral resection of bladder cancer: Randomized trial. J Urol 1989;141:529-530. Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 71 of 89 Version 4.0 26 Feb 2009 11. Höbarth K, Maier U, Marberger M. Topical chemotherapy of superficial bladder cancer with mitomycin C and adjuvant hyaluronidase. Eur Urol 1992;21:206-210. 12. Common Terminology Criteria for Adverse Events (CTCAE), National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, http://ctep.cancer.gov/reporting/ctc.html. 13. Baumgartner G, Gomar-Höss Ch, Sakr L, Ulsperger E, Wogritsch Ch. The impact of extracellular matrix on the chemoresistance of solid tumors – experimental and clinical result of hyaluronidase as additive to cytostatic chemotherapy. Cancer Letter 1998;131:85-99. 14. Au JL-S, Badalament RA, Wientjes MG, Young DC, Warner JA, Venema PL, et al. Methods to improve efficacy of intravesical mitomycin C: Results of a randomized Phase III trial. J Nat Cancer Inst 2001;93(8):597-604. 15. Lamm DL, Blumenstein BA, Crawford ED, Crissman JD, Lowe BA, Smith JA, et al. Randomized intergroup comparison of bacillus Calmette-Guerin immunotherapy and mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of the bladder. Urol Oncol 1995;1:119-126. 14. APPENDICES Halozyme Therapeutics, Inc. Protocol HZ2-05-01 Appendix A. TNM Staging of Bladder Cancer TNM DEFINITIONS Primary tumor (T) • TX: Primary tumor cannot be assessed • T0: No evidence of primary tumor • Ta: Noninvasive papillary carcinoma • Tis: Carcinoma in situ: “flat tumor” • T1: Tumor invades subepithelial connective tissue • T2: Tumor invades muscle • pT2a: Tumor invades superficial muscle (inner half) • pT2b: Tumor invades deep muscle (outer half) • T3: Tumor invades perivesical tissue • pT3a: Microscopically • pT3b: Macroscopically (extravesical mass) • T4: Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, or abdominal wall • T4a: Tumor invades the prostate, uterus, vagina • T4b: Tumor invades the pelvic wall, abdominal wall (Note: The suffix “m” should be added to the appropriate T category to indicate multiple lesions. The suffix “is” may be added to any T to indicate the presence of associated carcinoma in situ.) Regional lymph nodes (N) • NX: Regional lymph nodes cannot be assessed • N0: No regional lymph node metastasis • N1: Metastasis in a single lymph node, 2 cm or less in greatest dimension • N2: Metastasis in a single lymph node, more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, none more than 5 cm in greatest dimension • N3: Metastasis in a lymph node, more than 5 cm in greatest dimension Distant metastasis (M) • MX: Distant metastasis cannot be assessed • M0: No distant metastasis • M1: Distant metastasis Acceptable stage for enrollment in this study. CONFIDENTIAL Page 72 of 89 Version 4.0 26 Feb 2009 Halozyme Therapeutics, Inc. Protocol HZ2-05-01 AJCC STAGE GROUPINGS Stage 0a • Ta, N0, M0 Stage 0is • Tis, N0, M0 Stage I • T1, N0, M0 Stage II • T2a, N0, M0 • T2b, N0, M0 Stage III • T3a, N0, M0 • T3b, N0, M0 • T4a, N0, M0 Stage IV • T4b, N0, M0 • Any T, N1, M0 • Any T, N2, M0 • Any T, N3, M0 • Any T, any N, M1 Acceptable stage for enrollment in this study. Urinary bladder. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002:335-340. CONFIDENTIAL Page 73 of 89 Version 4.0 26 Feb 2009 Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 75 of 89 Version 4.0 26 Feb 2009 Appendix C. United Stages Package Insert for Mitomycin INDICATIONS AND USAGE Mitomycin for Injection is not recommended as single-agent, primary therapy. It has been shown to be useful in the therapy of disseminated adenocarcinoma of the stomach or pancreas in proven combinations with other approved chemotherapeutic agents and as palliative treatment when other modalities have failed. Mitomycin is not recommended to replace appropriate surgery and/or radiotherapy. CONTRAINDICATIONS Mitomycin is contraindicated in patients who have demonstrated a hypersensitive or idiosyncratic reaction to it in the past. Mitomycin is contraindicated in patients with thrombocytopenia, coagulation disorder, or an increase in bleeding tendency due to other causes. WARNINGS Patients being treated with mitomycin must be observed carefully and frequently during and after therapy. The use of mitomycin results in a high incidence of bone marrow suppression, particularly thrombocytopenia and leukopenia. Therefore, the following studies should be obtained repeatedly during therapy and for at least 8 weeks following therapy: platelet count, white blood cell count, differential, and hemoglobin. The occurrence of a platelet count below 100,000/mm3 or a WBC below 4,000/mm3 or a progressive decline in either is an indication to withhold further therapy until blood counts have recovered above these levels. Patients should be advised of the potential toxicity of this drug, particularly bone marrow suppression. Deaths have been reported due to septicemia as a result of leukopenia due to the drug. Patients receiving mitomycin should be observed for evidence of renal toxicity. Mitomycin should not be given to patients with a serum creatinine greater than 1.7 mg percent. Usage in Pregnancy: Safe use of mitomycin in pregnant women has not been established. Teratological changes have been noted in animal studies. The effect of mitomycin on fertility is unknown. PRECAUTIONS Acute shortness of breath and severe bronchospasm have been reported following the administration of vinca alkaloids in patients who had previously or simultaneously received mitomycin. The onset of this acute respiratory distress occurred within minutes to hours after the vinca alkaloid injection. The total number of doses for each drug has varied considerably. Bronchodilators, steroids and/or oxygen have produced symptomatic relief. A few cases of adult respiratory distress syndrome have been reported in patients receiving mitomycin in combination with other chemotherapy and maintained at FIO2 concentrations greater than 50% perioperatively. Therefore, caution should be exercised using only enough oxygen to provide adequate arterial saturation since oxygen itself is toxic to the lungs. Careful attention should be paid to fluid balance and overhydration should be avoided. Bladder fibrosis/contraction has been reported with intravesical administration (not an approved route of administration), which in rare cases has required cystectomy. Nursing Mothers: It is not known if mitomycin is found in human milk. Because many drugs are found in milk, it is recommended that women receiving mitomycin not breast feed because of the potential for serious adverse reactions from mitomycin in nursing infants. Pediatric Use: Safety and effectiveness in pedriatric patients have not been established. ADVERSE REACTIONS Bone Marrow Toxicity: This was the most common and most serious toxicity, occurring in 605 of 937 patients (64.4%). Thrombocytopenia and/or leukopenia may occur anytime within 8 weeks after onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within 10 weeks. About 25% of the leukopenic or thrombocytopenic episodes did not recover. Mitomycin produces cumulative myelosuppression. Integument and Mucous Membrane Toxicity: This has occurred in approximately 4% of patients treated with mitomycin. Cellulitis at the injection site has been reported and is occasionally severe. Stomatitis and alopecia also occur frequently. Rashes are rarely reported. The most important dermatological problem with this drug, however, is the necrosis and consequent sloughing of tissue which results if the drug is extravasated during injection. Extravasation may occur with or without an accompanying stinging or burning sensation and even if there is adequate blood return when the injection needle is aspirated. There have been reports of delayed erythema and/or ulceration occurring either at or distant from the injection site, weeks to months after mitomycin, even when no obvious evidence of extravasation was observed during administration. Skin grafting has been required in some cases. Renal Toxicity: 2% of 1,281 patients demonstrated a statistically significant rise in creatinine. There appeared to be no correlation between total dose administered or duration of therapy and the degree of renal impairment. Pulmonary Toxicity: This has occurred infrequently but can be severe and may be life-threatening. Dyspnea with a nonproductive cough and radiographic evidence of pulmonary infiltrates may be indicative of mitomycin-induced pulmonary toxicity. If other etiologies are eliminated, mitomycin therapy should be discontinued. Steroids have been employed as treatment of this toxicity, but the therapeutic value has not been determined. A few cases of adult respiratory distress syndrome have been reported in patients receiving mitomycin in combination with other chemotherapy and maintained at FIO2 concentrations greater than 50% perioperatively. Hemolytic Uremic Syndrome (HUS): This serious complication of chemotherapy, consisting primarily of microangiopathic hemolytic anemia (hematocrit ≤25%), thrombocytopenia (≤100,000/mm3), and irreversible renal failure (serum creatinine ≥1.6 mg/dL) has been reported in patients receiving systemic mitomycin. Microangiopathic hemolysis with fragmented red blood cells on peripheral blood smears has occurred in 98% of patients with the syndrome. Other less frequent complications of the syndrome may include pulmonary edema (65%), neurologic abnormalities (16%), and hypertension. Exacerbation of the symptoms associated with HUS has been reported in some patients receiving blood product transfusions. A high mortality rate (52%) has been associated with this syndrome. The syndrome may occur at any time during systemic therapy with mitomycin as a single agent or in combination with other cytotoxic drugs. Less frequently, HUS has also been reported in patients receiving combinations of cytotoxic drugs not including mitomycin. Of 83 patients studied, 72 developed the syndrome at total doses exceeding 60 mg of mitomycin. Consequently, patients receiving ≥60 mg of mitomycin should be monitored closely for unexplained anemia with fragmented cells on peripheral blood smear, thrombocytopenia, and decreased renal function. The incidence of the syndrome has not been defined. Therapy for the syndrome is investigational. Cardiac Toxicity: Congestive heart failure, often treated effectively with diuretics and cardiac glycosides, has rarely been reported. Almost all patients who experienced this side effect had received prior doxorubicin therapy. Acute Side Effects Due to Mitomycin were fever, anorexia, nausea, and vomiting. They occurred in about 14% of 1,281 patients. Other: Headache, blurring of vision, confusion, drowsiness, syncope, fatigue, edema, thrombophlebitis, hematemesis, diarrhea, and pain. These did not appear to be dose related and were not unequivocally drug related. They may have been due to the primary or metastatic disease processes. Malaise and asthenia have been reported as part of postmarketing surveillance. Bladder fibrosis/contraction has been reported with intravesical administration (see PRECAUTIONS). DOSAGE AND ADMINISTRATION Mitomycin should be given intravenously only, using care to avoid extravasation of the compound. If extravasation occurs, cellulitis, ulceration, and slough may result. Each vial contains either mitomycin 5 mg and mannitol 10 mg, or mitomycin 20 mg and mannitol 40 mg, or mitomycin 40 mg and mannitol 80 mg. To administer, add Sterile Water for Injection, 10 mL 40 mL, or 80 mL, respectively. Shake to dissolve. If product does not dissolve immediately, allow to stand at room temperature until solution is obtained. After full hematological recovery (see guide to dosage adjustment) from any previous chemotherapy, the following dosage schedule may be used at 6- to 8-week intervals: 20 mg/m2 intravenously as a single dose via a functioning intravenous catheter. Because of cumulative myelosuppression, patients should be fully reevaluated after each course of mitomycin, and the dose reduced if the patient has experienced any toxicities. Doses greater than 20 mg/m2 have not been shown to be more effective and are more toxic than lower doses. The following schedule is suggested as a guide to dosage adjustment: No repeat dosage should be given until leukocyte count has returned to 4000/mm3 and platelet count to 100,000/mm3. When mitomycin is used in combination with other myelosuppressive agents, the doses should be adjusted accordingly. If the disease continues to progress after two courses of mitomycin, the drug should be stopped since chances of response are minimal. Stability 1. Unreconstituted mitomycin stored at controlled room temperature is stable for the lot life indicated on the package. Avoid excessive heat (over 40°C). 2. Reconstituted with Sterile Water for Injection to a concentration of 0.5 mg per mL, mitomycin is stable for 14 days refrigerated or 7 days at room temperature. Protect reconstituted solution from light. 3. Diluted in various IV fluids at room temperature, to a concentration of 20 to 40 micrograms per mL: Nadir After Prior Dose Percentage of Prior Dose Leukocytes/mm3 Platelets/mm3 To be Given >4000 >100,000 100% 3000–3999 75,000–99,999 100% 2000–2999 25,000–74,999 70% <2000 <25,000 50% Page 77 of 89 Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 78 of 88 Version 4.0 26 Feb 2009 Appendix D. Canadian Package Insert for Mitomycin Mitomycin CCO Formulary Revised 2004/2005 A DRUG NAME: MITOMYCIN SYNONYM(S): Mitomycin C, MMC COMMON TRADE NAME(S): Mutamycin® (Bristol), Mitomycin ( Mayne) (Novopharm) B MECHANISM OF ACTION AND PHARMACOKINETICS Mitomycin is a purple antibiotic isolated from Streptomyces caespitosus. Clinical trials were begun in the United States in the late 1960's. Mitomycin is activated in vivo to a bifunctional and trifunctional alkylating agent. Binding to DNA leads to cross-linking and inhibition of DNA synthesis and function. Mitomycin is cell cycle phase-nonspecific. Oral Absorption Erratic Detectable levels in kidney, muscles, heart, lungs, intestine and stomach, found in ascites Cross blood brain barrier? No Vd 16-56 L/m2 Distribution PPB No information found Prodrug activated in vivo, primary means of elimination is by hepatic metabolism Active metabolite(s) Yes Metabolism Inactive metabolite(s) Yes Excreted in urine, detected in bile and feces, biliary level may exceed plasma level Urine 10% excreted unchanged in urine t ½ α 8 minutes t ½ β 48 minutes Excretion Cl 201-801 mL/min/m2 C INDICATIONS AND STATUS Topical * Bladder cancer (superficial) Systemic * Gastric cancer (palliative) * Colorectal cancer (palliative) * Health Canada approved indication Other uses include: Breast cancer Cervical cancer Head and neck cancer Pancreatic cancer Biliary cancer Page 79 of 89 Mitomycin CCO Formulary Revised 2004/2005 D ADVERSE EFFECTS ORGAN SITE SIDE EFFECT ONSET Thromboembolism E Cardiac Cardiac failure (rare, with prior anthracyclines) E Headache E Ataxia Blurred vision Central nervous system Acute encephalopathy (rare) E D Alopecia E Blue bands in nails (rare) E Rash I Palmar erythema with desquamation E Dermatologic Radiation recall reaction (rare) I Extravasation hazard (refer to Appendix 2) VESICANT I E Nausea and vomiting I Diarrhea E Stomatitis E Gastrointestinal Anorexia E Hematologic Myelosuppression E Hypersensitivity Fever I Injection site Chemical phlebitis I Interstitial pneumonitis, ARDS E Acute respiratory symptoms especially with vinca’s Pulmonary Chronic fibrosis D Page 80 of 89 Mitomycin CCO Formulary Revised 2004/2005 D ADVERSE EFFECTS ORGAN SITE SIDE EFFECT ONSET Cystitis / fibrosis (with intravesical use, 25%) I Increased BUN Renal/metabolic Renal failure and hemolytic uremic syndrome (10%) D Reproductive Amenorrhea E Hypoglycaemia Other Fatigue Dose-limiting side effects are underlined. I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years) Myelosuppression is major dose limiting adverse effect, and may be cumulative. Onset is late at 3-4 weeks, with recovery by 8 – 10 weeks. Nausea and vomiting occur within 1-2 hours following administration. Vomiting usually subsides, but nausea may continue for 2-3 days. The tissue necrosis that happens with extravasation may happen days to weeks after the treatment. Patients must be observed for delayed reactions and prior injection sites carefully inspected. Soft tissue ulceration distal to the injection site following uneventful injection in a peripheral vein has been reported. Pulmonary toxicity consisting of dyspnea, non-productive cough has been reported with an incidence of 2.8- 12%. Approximately 40% of patients who develop pulmonary toxicity will die of progressive pulmonary dysfunction. Threshold dose associated with pulmonary toxicity appears to be 50-60 mg/m 2. Steroids may be of some benefit. Acute respiratory distress syndrome may occur with high FIO 2 concentrations or with combination chemotherapy. A syndrome of renal failure and microangiopathic hemolytic anemia (hemolytic-uremic syndrome) has been reported in 10% of patients. This syndrome appears to have a threshold of 50-60 mg/m 2 and usually appears after 6 months of therapy. Patients should be monitored for development of renal failure or hemolysis. The incidence of cardiotoxicity may be increased in patients receiving mitomycin in combination with doxorubicin or in patients who have had prior exposure to doxorubicin. No studies report cardiotoxicity in patients only receiving mitomycin. Genitourinary irritation following intravesical (bladder) administration includes dysuria, cystitis, nocturia, increased micturition and hematuria. Myelosuppression has not been noted with intravesical administration. Mitomycin has the potential to enhance radiation injury to tissues. While often called radiation recall reactions, the timing of the radiation may be before, concurrent with or even after the administration of the mitomycin. Recurrent injury to a previously radiated site may occur weeks to months following radiation. Page 81 of 89 Mitomycin CCO Formulary Revised 2004/2005 E DOSING Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of white blood cell count. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy. Patients should not be retreated until haematological recovery has occurred. Adults: Intravenous: q4-8w: 10-20 mg/m2 q6-8w: 2 mg/m2/day x 5 days, stop x 2 days, repeat x 1 Intravesical: q1w: 20-40 mg in 30-60 ml SWI x 8 weeks Dosage in myelosuppression: modify according to protocol by which patient is being treated; Lowest Value in Preceding Course Leucocytes Platelets % previous dose > 3000 > 75,000 100 2-3.99 X 103 25-74.99 X 103 70 < 2000 < 25,000 50 Dosage in renal failure: do not administer if creatinine > 150 µmol/L Dosage in hepatic failure: no adjustment required F ADMINISTRATION GUIDELINES (see Appendix 3a ) • Slow push through sidearm of free flowing IV (Normal Saline); Give 1.5mg/3mL per minute • Doses may be mixed in 50mL minibag (Normal Saline); Infuse through sidearm of free flowing IV over 10-30 minutes G SPECIAL PRECAUTIONS Mitomycin is classified as dangerous goods under the Transportation of Dangerous Goods Act, and must be declared as such for the purposes of transportation (substance is considered poisonous). Mitomycin is contraindicated in patients with thrombocytopenia, leukopenia, coagulation disorder, or an increased bleeding tendency due to other causes; with known hypersensitivity or an idiosyncratic reaction to it, or any component of its formulations. High FIO2 concentrations (anesthesia, oxygen therapy) should be avoided especially in patients with pulmonary toxicity. Mitomycin has been shown to be carcinogenic and teratogenic in animal studies and should not be used in pregnancy. Breast feeding is not recommended due to the potential secretion into breast milk. Page 82 of 89 Mitomycin CCO Formulary Revised 2004/2005 J REFERENCES Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA) Compendium of Pharmaceuticals and Specialties. 2004. Mutamycin®. Canadian Pharmacists Association. H INTERACTIONS AGENT EFFECT MECHANISM MANAGEMENT vinca alkaloids (vincristine, vinblastine, vindesine) acute bronchospasm unknown caution I RECOMMENDED CLINICAL MONITORING Recommended Clinical Monitoring Suggested Clinical Monitoring • Clinical exam, including pulmonary, neurological and local site toxicity • Baseline & periodic renal function tests (if failure suspected) • Baseline and regular CBC • Blood pressure at each visit • Baseline and regular liver function tests Page 83 of 89 Halozyme Therapeutics, Inc. Protocol HZ2-05-01 CONFIDENTIAL Page 84 of 88 Version 4.0 26 Feb 2009 Appendix E. United Kingdom Summary of Product Characteristics for Mitomycin 6. It has a possible role in combination with other cytotoxic drugs in colo-rectal cancer. 7. It shows a degree of activity as a single agent or part of combination therapy in cancer of the head and neck. 8. It shows a degree of activity as a single agent in cancer of the prostate. 9. It has a possible role in skin cancer. 10. It has a degree of activity in leukaemia and non-solid tumours. 11. It has a possible role in sarcomas. 12. It has been successfully used in combination with surgery, pre-operatively (oesophageal squamous cell carcinoma) and post-operatively (gastric cancer). 13. It has shown to be effective when used in combination with radiotherapy. 4.2 Posology and method of administration For parenteral use. Intravenously, the dose should be given with great care in order to avoid extravasation. The usual dose is in the range of 4 – 10mg (0.06-0.15mg/kg) given at 1 – 6 weekly intervals depending on whether other drugs are given in combination and on bone marrow recovery. In a number of combination schedules, the dose is 10mg/m2 of body surface area, the course being repeated at intervals for as long as required. A course ranging from 40-80mg (0.58 – 1.2mg/kg) is often required for a satisfactory response when used alone or in combination. A higher dosage course may be given when used alone or as part of a particular combination schedule and total cumulative doses exceeding 2mg/kg have been given. For administration into specific tissues, Mitomycin-C Kyowa can be given by the intra-arterial route directly into the tumours. Because of cumulative myelosuppression, patients should be fully re-evaluated after each course and the dose reduced if the patient has experienced any toxic effects. Doses greater than 0.6mg/kg have not been shown to be more effective and are more toxic than lower doses. Treatment of superficial bladder tumours : In the treatment of superficial bladder tumours the usual dose is 20-40mg dissolved in 20-40 of diluent, instilled into the bladder through a urethral catheter, weekly or three times a week for a total of 20 doses. The dose should be retained by the patient for a minimum of one hour. During this one-hour period the patient should be rotated every 15 minutes to ensure that the Mitomycin-C comes into contact with all areas of the bladder urthelium. When the bladder is emptied in the voiding process, care must be taken to ensure that no contamination occurs locally in the groin and genitalia areas. In the prevention of recurrent superficial bladder tumours, various doses have been used. These include 20mg in 20ml of diluent every two weeks and 40mg in 40ml of diluent monthly or three monthly. The dose is instilled into the bladder through a urethral catheter. 4.3 Contraindications Patients who have demonstrated a hypersensitive or idiosyncratic reaction to Mitomycin-C Kyowa in the past. Thrombocytopenia, coagulation disorders and increased bleeding tendency. Page 86 of 89 4.4 Special warnings and special precautions for use Mitomycin-C Kyowa should be administered under the supervision of a physician experienced in cytotoxic cancer chemotherapy. Local ulceration and cellulitis may be caused by tissue extravasation during intravenous injection and utmost care should be taken in administration. If extravasation occurs, it is recommended that the area is immediately infiltrated with sodium bicarbonate 8.4% solution, followed by an injection of 4mg dexamethasone. A systemic injection of 200mg of Vitamin B6 may be of some value in promoting the regrowth of tissues that have been damaged. Mitomycin-C Kyowa should not be allowed to come into contact with the skin. If it does, it should be washed several times with 8.4% sodium bicarbonate solution, followed by soap and water. Hand creams and emollients should not be used as they may assist the penetration of the drug into the epidermal tissue. In the event of contact with the eye, it should be rinsed several times with 8.4% sodium bicarbonate solution. It should then be observed for several days for evidence of corneal damage. If necessary, appropriate treatment should be instituted. 4.5 Interaction with other medicinal products and other forms of Interaction Not Known. 4.6 Pregnancy and lactation Mitomycin-C Kyowa should not normally be administrated to patients who are pregnant or to mothers who are breast-feeding. Teratological changes have been noted in animal studies. 4.7 Effects on ability to drive and use machines Generalised weakness and lethargy have been reported on rare occasions. If affected, patients should be advised not to drive or operate machinery. 4.8 Undesirable effects Thrombocytopenia and leucopenia resulting from myelosuppression, which is delayed and cumulative. Patients should be monitored closely during each course of treatment, paying particular attention to peripheral blood count including platelet count. No repeat dose should be given unless the leucocyte count is above 3.0 x 109/L or more and the platelet count is 90 x 109/L or more. The nadir is usually around four weeks after treatment and toxicity is usually cumulative, with increasing risk after each course of treatment. If disease progression continues after two courses of treatment, the drug should be stopped since the chances of response are minimal. Severe renal toxicity has occasionally been reported after treatment and renal function should be monitored before starting treatment and again after each course. Nausea and vomiting are sometimes experienced immediately after treatment, but these are usually mild and of short duration. Pulmonary toxicity and fever have been reported. Skin toxicity may occur in a small proportion of patients, with side effects such as alopecia (although this is less frequent and less severe than with certain other cytotoxic agents). Bleeding, rashes and mouth ulcers have been reported. General Page 87 of 89 weakness and lethargy have been reported on rare occasions. Other reported effects include anorexia, diarrhoea, stomatitis, interstitial pneumonitis, pulmonary fibrosis and microangiopathic haemolytic anaemia syndrome. 4.9 Overdose In the unlikely event of accidental overdosage then an increase in the more common side effects should be expected, such as fever, nausea, vomiting and myelosuppression. Appropriate supportive measures should be instituted. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Mitomycin-C Kyowa is an antitumour antibiotic that is activated in the tissues to an alkylating agent which disrupts deoxyribonucleic acid (DNA) in cancer cells by forming a complex with DNA and also acts by inhibiting division of cancer cells by interfering with the biosynthesis of DNA. 5.2 Pharmacokinetic properties In vivo Mitomycin-C Kyowa is rapidly cleared from the serum after intravenous administration. The time required to reduce the serum concentration by 50% after a 30mg bolus injection is 17 minutes. After injection of 30mg, 20mg or 10mg intravenously, the maximal serum concentrations were 2.4 mcg/ml, 1.7 mcg/ml and 0.52mcg/ml respectively. Clearance is effected primarily by metabolism in the liver, but metabolism occurs in other tissues as well. The rate of clearance is inversely proportional to the maximal serum concentration because, it is thought, of saturation of the degradative pathways. Approximately 10% of a dose of Mitomycin-C Kyowa is excreted unchanged in the urine. Since metabolic pathways are saturated at relatively low doses, the percentage dose excreted in the urine increases with increasing dose. In children, the excretion of intravenously administered Mitomycin-C Kyowa is similar to that in adults. 5.3 Preclinical safety data There are no preclinical data of relevance to the prescriber which are additional to that already included elsewhere in the SPC. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Sodium Chloride Ph.Eur. 6.2 Incompatibilities Page 88 of 89 Not known 6.3 Shelf life Four years from the date of manufacture. After reconstitution, the solution is stable for 24 hours when protected from light and stored in a cool place. Do not refrigerate. 6.4 Special precautions for storage None. 6.5 Nature and contents of container Mitomycin-C Kyowa consists of a blue/purple crystalline powder, contained within a colourless, type I or III glass vial with a rubber stopper and an aluminium seal. The vials are packaged into cardboard cartons containing 1, 5 or 10 vials. 6.6 Instructions for use and handling The contents of the vial should be reconstituted with Water for Injections or saline solution, at least 5 ml for the 2 mg vial, at least 10 ml for the 10 mg vial, at least 20 ml for the 20 mg vial, and at least 40 ml for the 40 mg vial. Administrative Data 7. MARKETING AUTHORISATION HOLDER Kyowa Hakko (UK) Ltd 258 Bath Road Slough Berkshire SL1 4DX 8. MARKETING AUTHORISATION NUMBER(S) PL12196/0001/0002/0003 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 26th November 1992 10. DATE OF REVISION OF THE TEXT July 2003 Page 89 of 89 SAP_001.pdf: Halozyme Therapeutics, Inc. Statistical Analysis Plan Protocol number: HZ2-05-01 January 11, 2008 C:\Users \Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 3 TABLE OF CONTENTS 1. INTRODUCTION .................................................................................................................. 4 2. OBJECTIVES ........................................................................................................................ 4 3. STUDY OVERVIEW ............................................................................................................ 4 4. GENERAL ANALYSIS CONSIDERATIONS ................................................................... 5 5. ANALYSIS SETS ................................................................................................................... 5 6. PATIENT DISPOSITION ..................................................................................................... 6 7. DEMOGRAPHIC AND BASELINE CHARACTERISTICS ............................................ 6 8. STUDY DRUG ADMINISTRATION .................................................................................. 6 9. PHARMACOKINETIC ANALYSES .................................................................................. 7 10 OTHER ANTI CANCER ANALYSES ................................................................................ 7 11. SAFETY ANALYSES ............................................................................................................ 7 11.1 ADVERSE EVENTS .......................................................................................................... 7 11.2 CLINICAL LABORATORY EVALUATION ......................................................................... 8 11.3 OTHER SAFETY ANALYSES ............................................................................................ 8 11.4 CONCOMITANT MEDICATIONS ....................................................................................... 9 12 LONG-TERM FOLLOW-UP ............................................................................................... 9 13. SAMPLE SIZE CALCULATION ........................................................................................ 9 APPENDIX A: LIST OF TABLES, FIGURES AND LISTINGS ........................................... 10 APPENDIX B: TABLE LAYOUTS .......................................................................................... 14 APPENDIX C: LISTING LAYOUTS ........................................................................................ 56 APPENDIX D: INTERNATIONALLY AGREED ORDER FOR SOC ............................... 104 Halozyme Therapeutics, Inc. Statistical Analysis Plan Protocol number: HZ2-05-01 January 11, 2008 C:\Users\ \Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 4 1. INTRODUCTION This document outlines the statistical methods to be implemented during the analyses of data collected within the scope of Halozyme Therapeutics, Inc. Protocol Number HZ2- 05-01 [A Phase I-IIa, Open-Label, Multiple Dose, Safety, Tolerability and Pharmacokinetic Study of Recombinant Human Hyaluronidase (Chemophase™) in Combination with Mitomycin in Patients with Non-Muscular-Invasive Bladder Cancer]. The purpose of this plan is to provide specific guidelines from which the analysis will proceed. Any deviations from these guidelines must be substantiated by sound statistical reasoning. 2. OBJECTIVES The primary objectives for this study are the following:  Determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of escalating doses of Chemophase in combination with mitomycin (Mitomycin, C, MMC) administered as weekly intravesical instillations for five weeks;  Establish the dose of Chemophase with MMC recommended for future studies. Secondary objectives for this study include:  Assess the pharmacokinetics of intravesical administration of MMC alone and in combination with intravesical administration of Chemophase;  For the patients treated at the MTD, assess the safety and tolerability of intravesical administration of MMC with Chemophase over up to 7 additional maintenance treatments every 3 months following the initial six weekly instillations;  Observe patients for any preliminary evidence of anti-tumor activity of MMC and Chemophase when combined. 3. STUDY OVERVIEW This is a Phase I-IIa, open-label, multicenter, dose-escalation, safety, tolerability, and pharmacokinetic study of intravesical treatment with combination of Chemophase and MMC. Patient may be considered for enrollment in this study if they have initial presentation or recurrence of Stage Ta, T1 or Tis, any grade, bladder cancer after TURBT. Groups of up to 6 patients will participate in each of the five individual dose cohorts in the dose escalation phase of the study. The amounts of Chemophase to be given for each of the five cohorts are as follows: 20,000 U, 60,000 U, 200,000 U, 400,000 U and 800,000 U. Once the maximum tolerated dose (MTD) has been established, 6 additional Halozyme Therapeutics, Inc. Statistical Analysis Plan Protocol number: HZ2-05-01 January 11, 2008 C:\Users \Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 5 evaluable patients will be enrolled at the MTD dose level. This will provide a total of 12 evaluable patients at MTD upon which to confirm safety and tolerability of the MTD regimen. In total, up to 36 evaluable patients will be enrolled. To reach this number, it is anticipated that no more than 44 patients will need to be enrolled. The MTD will be determined based on number of patients experiencing a dose-limiting toxicity (DLT) at a particular dose level. A patient will be considered to have experienced a DLT if any of the following occur:  Plasma MMC Concentration >= 100 ng/mL;  Adverse Event (AE) with a Common Toxicity Criteria (CTC) grade greater than or equal to 3;  New, treatment-emergent diagnosis of bladder fibrosis. For further details on MTD determination, refer to the protocol. Study patients will receive six weekly study treatments followed by post-treatment evaluations, at Weeks 8 and 12. In addition, the twelve patients receiving the MTD will continue to receive combination therapy every 3 months until the end of year 2 or until the time of documented tumor recurrence, whichever occurs first. Long-term follow-up information for those in the MTD cohort will be collected to help make a preliminary assessment of possible anti-tumor activity. 4. GENERAL ANALYSIS CONSIDERATIONS Statistical analyses will be reported using summary tables, figures, and data listings. No tests for statistical significance will be performed. All analyses and tabulations will be performed using SAS Version 8.2 on a PC platform. Continuous variables will be summarized with means, standard deviations, medians, minimums, and maximums. Categorical variables will be summarized by counts and by percentage of patients in corresponding categories. All raw data obtained from the case report forms as well as any derived data will be included in data listings. 5. ANALYSIS SETS The following patient population sets will be used for analyses:  The Safety Set will include all patients who received one or more doses of Chemophase. Any patient receiving MMC on study but not receiving Chemophase will be considered for safety, but assessed separately from patients receiving Chemophase for selected analysis;  The Intent-To-Treat (ITT) Set (for anti-tumor effects) will include all patients receiving one or more doses of Chemophase with MMC. It is recognized that this definition is a modification of the rigid definition of ITT; Halozyme Therapeutics, Inc. Statistical Analysis Plan Protocol number: HZ2-05-01 January 11, 2008 C:\Users\ \Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 6  The Per-Protocol Set will include all ITT patients who met the following criteria: o Satisfied disease-defining Inclusion Criteria #1 and #2; o Received at least 4 protocol-specified doses of Chemophase with MMC over an interval not exceeding 8 weeks; o Retained at least 4 intravesical instillations for at least 90 minutes; o Were monitored to the time of tumor recurrence, or at least 5 years, whichever occurs first. Anti-tumor analysis will be performed on the ITT and Per Protocol Sets. In the event all patients in the ITT Set are also in the Per Protocol Set, analysis will only be carried out on the ITT Set. Baseline and safety analysis will be performed on the Safety Set. Any patient who received MMC on study but not Chemophase will be considered for selected safety assessments; however, those patients will be assessed separately from patients receiving Chemophase. 6. PATIENT DISPOSITION Patient disposition information will be summarized for all patients. Summaries will include: the number of enrolled patients, the number of patients in each analysis set, the number of patients completing the study without premature withdrawal, and the reasons for not completing the study. 7. DEMOGRAPHIC AND BASELINE CHARACTERISTICS Demographic variables include: age, sex, ethnicity, and race. Other baseline characteristics include: Karnofsky performance status, medical history, urologic history and bladder cancer history. Patient history endpoints to be summarized include the years since initial bladder cancer diagnosis, total number of bladder cancer occurrences, estimated bladder capacity, total number of bladder tumor treatments, total number of bladder cancer surgeries, total number of previous cystoscopies with tumor detected and without tumor detected. When applicable, demographic and baseline characteristics will be summarized. 8. STUDY DRUG ADMINISTRATION For each visit during the study drug administration phase of the study other than Day 1, patients are expected to receive a pre-specified amount of Chemophase, MMC and sterile saline based on the cohort they are assigned to (on Day 1, patients will only receive MMC). Counts and percentages of those patients who receive the pre-specified dose of study drug as well as those who do not will be displayed by cohort and visit. Also summarized will be the instillation dwell time (end time of instillation minus post- instillation void time). Halozyme Therapeutics, Inc. Statistical Analysis Plan Protocol number: HZ2-05-01 January 11, 2008 C:\Users \Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 7 For amount of study drug and sterile saline to be administered for each cohort at each visit, refer to Table 9.3-A of the protocol. 9. PHARMACOKINETIC ANALYSES The plasma concentrations for MMC and plasma concentrations of rHuPH20 are part of the study design, but will not be summarized in tabular form as part of the analysis plan. Concentrations will be presented in listings. 10 OTHER ANTI CANCER ANALYSES Plasma determinations for rHuPH20 neutralizing antibodies are part of this study design, but will not be summarized in tabular form as part of this analysis plan. Plasma determinations for antibodies will be presented in listings. All patients completing the study will have a cystoscopy performed at the Week 12 visit. For those patients being treated at MTD, cystoscopies will be performed every three months through the end of Year 2 starting 3 months after the last study drug treatment, which is anticipated to be at Week 6. Endpoints to be collected include the cystoscopy result and the estimated bladder capacity. Summaries of these endpoints will be presented by cohort. Biomarker tests, consisting of NMP22 BladderChek tests and UroVysion tests, are to be conducted during Week 1 and Week 8 of the study. For those patients treated at MTD, these biomarker tests are also to be performed every 3 months, occurring 6 weeks before each every-three-month clinic visit. Results from these tests will be used to construct a shift table with possible results of positive, negative, no valid result and not done for the BladderChek test and negative, positive, equivocal, other and not done for the Urovysion test. 11. SAFETY ANALYSES All patients who received Chemophase will be included in the safety analyses. Patients who receive MMC, but not Chemophase, will be summarized separately for adverse events. Analysis will consist of point estimates and the 95% confidence interval constructed around the point estimates for the overall incidence of adverse events. 11.1 Adverse Events The adverse events considered are Treatment Emergent Adverse Events (TEAE) defined as those AEs that occurred after initial study drug dosing (first dose of MMC) and those existing AEs that worsened after initial study drug dosing. All listings and tabular summaries of AEs will be restricted to only TEAEs, except for a separate listing showing only those AEs that are pre-treatment-emergent, should any such AEs exist in the Halozyme Therapeutics, Inc. Statistical Analysis Plan Protocol number: HZ2-05-01 January 11, 2008 C:\Users \Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 8 database. Verbatim terms on case report forms will be mapped to preferred terms and system organ classes using the MedDRA dictionary (version 8.0, or a later version at the discretion of Synteract). If a patient has more than one adverse event mapped to the same preferred term, that adverse event will be reported only once in a given summary table using the highest severity and/or closest relationship to study medication. Patient incidence of adverse events will be displayed by system organ class (SOC) and preferred term. Adverse events will also be summarized by severity and relationship to each study drug (Chemophase, MMC) independently. Patient incidence of serious adverse events (including deaths) will also be displayed. Tabular summaries of AEs will list SOCs according to the internationally agreed order, and within each individual SOC the AEs will be listed in order of decreasing incidence. See Appendix D for the internationally agreed order for SOC. 11.2 Clinical Laboratory Evaluation Descriptive statistics of clinical laboratory assessment changes will be presented for baseline and each post baseline time point. In addition, shift tables will be presented to assess abnormal laboratory values over time. In constructing shift tables, baseline results will be compared to the most abnormal post baseline result. Laboratory parameters will be classified as low, normal, high and patient counts of shifts from baseline will be presented. The designation of clinical significance will be displayed. Listings will be provided for laboratory analyte values. Values outside of the normal range will be flagged as either high or low and the designation of clinical significance will be displayed. 11.3 Other Safety Analyses Complete physical examinations will occur at screening and Week 8. In addition, targeted physical examinations will take place through the study drug administration phase of the study. Shift tables will be created for each body system to show any abnormal result both pre- and post-study drug. Results for vital signs will be summarized by cohort for each visit. In addition, change from baseline will be presented. Information for 12-Lead ECG will be collected at screening and Week 8. A shift table of the results for the test will be displayed along with summary statistics of QT, QTc, Heart Rate, P-R Interval and QRS. The Karnofsky Performance Status will performed on each patient at each visit. Results will be shown by visit and cohort. Halozyme Therapeutics, Inc. Statistical Analysis Plan Protocol number: HZ2-05-01 January 11, 2008 C:\Users \Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 9 11.4 Concomitant Medications Concomitant medications taken during the time period beginning 28 days prior to initial dosing, on Day 1/Week 1, through the Week 12 assessment (and, for MTD patients continuing on study drug treatment, through the last study drug instillation) will be collected in this study. Concomitant medications will be linked to generic terms and ATC classes using the WHO dictionary, Version 4.3. Concomitant medication use will be presented in listings. 12 LONG-TERM FOLLOW-UP The twelve patients receiving the MTD will continue to receive combination therapy every 3 months until the end of Year 2 or until the time of documented tumor recurrence, whichever occurs first. During this time of extended, long-term, treatment information collected on patients will include vital signs, targeted physical examinations, cystoscopy and urine cytology, urine dipsticks, hematology results, study drug administration, AE collection, concomitant medications and NMP22 BladderChek and UroVysion biomarker tests. Results for endpoints collected will be summarized in similar manner as the regular dosing portion of the study, except results will be presented for only the MTD cohort. In addition, any patients reported to have tumor recurrences will be recorded. The data will be assessed to make Kaplan Meier estimates of time to tumor recurrence at 6, 12, 18 and 24 months as well as determine median time to tumor recurrence. All other information on tumor recurrences including number of tumors, TNM stage and grading will be shown in listings. 13. SAMPLE SIZE CALCULATION This is a Phase I-IIa multiple dose study of Chemophase, and is neither designed nor powered for formal statistical comparisons. Halozyme Therapeutics, Inc. Statistical Analysis Plan Protocol number: HZ2-05-01 January 11, 2008 C:\Users \Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 10 APPENDIX A: LIST OF TABLES, FIGURES AND LISTINGS List of Tables Table Number Table Description 1 Patient Disposition 2 Demographic Characteristics 3 Abnormal Medical History at Baseline (Safety) 4 Urologic History/ Bladder Cancer History 5 Bladder Treatments/ Surgeries/ Procedures 6 Study Drug Administration 7 Cystoscopy at Week 12 8.1 NMP22 BladderChek Test 8.2 UroVysion FISH Biomarker Test 9.1 Adverse Events by System Organ Class 9.2 Adverse Events by System Organ Class and Severity 9.3 Adverse Events by System Organ Class and Relationship to Chemophase 9.4 Adverse Events by System Organ Class and Relationship to MMC 9.5 Serious Adverse Events by System Organ Class 10 Clinical Laboratory Results 11 Shift Tables of Clinical Laboratory Results 12 Physical Examination 13 Vital Signs 14.1 Shift Table of 12-Lead ECG 14.2 12-Lead ECG 15 Karnofsky Performance Study 16 Long-Term Follow-Up- Vital Signs 17 Long-Term Follow-Up- Physical Examination 18 Long-Term Follow-Up- Cystoscopy 19 Long-Term Follow-Up- Hematology 20 Long-Term Follow-Up- Study Drug Administration 21 Long-Term Follow-Up- NMP22 BladderChek Biomarker Test 22 Long-Term Follow-Up- UroVysion Biomarker Test 23 Long-Term Follow-Up- Time to Tumor Recurrence from First Study Drug Administration (months) Halozyme Therapeutics, Inc. Statistical Analysis Plan Protocol number: HZ2-05-01 January 11, 2008 C:\Users \Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 11 List of Figures Figure Number Figure Description 1.1 Time to Tumor Recurrence from First Study Drug (ITT Set) 1.2 Time to Tumor Recurrence from First Study Drug (Per Protocol Set) (If needed) Halozyme Therapeutics, Inc. Statistical Analysis Plan Protocol number: HZ2-05-01 January 11, 2008 C:\Users \Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 12 List of Data Listings Listing Number Listing Description CRF Plate Number 1 Patient Disposition Derived 2 Inclusion Criteria 1, 2 3 Exclusion Criteria 3,4 4 Criteria Waiver 5 5 Demographics 6 6 Medical History 7 7 Urologic History / Bladder Cancer History 8 8 Previous Bladder Tumor Treatments 9 9 Previous Bladder Surgeries/Cystoscopies with Tumors Detected 10 10 Previous Bladder Cystoscopies without Tumors 11 11 Previous Bladder Fibrosis / Contracture 12 12 Previous Cystometrogram 12 13 Instillation of Chemophase and MMC 25,26 14 Blood Collection and Results for MMC, rHuPH20 and Neutralizing Antibodies (NAB) to rHuPH20 27 15 Urine Cytology 17 16 Cystoscopy 17 17 Urine Dipstick 23 18.1 NMP22 BladderChek Biomarker Test 24 18.2 UroVysion FISH Biomarker Test 31 19.1 Adverse Events (Treatment-Emergent) 97 19.2 Pre-Treatment-Emergent Adverse Events 97 20 Serious Adverse Events 97 21 Reference Range Lab Normals - Hematology 350 22 Reference Range Lab Normals - Chemistry 351,352 23 Reference Range Lab Normals - Urinalysis 353 24 Hematology Results 19 25 Chemistry Results 20,21 26 Urinalysis Results 22 27 Physical Examination 14,15 28 Vital Signs and Karnofsky Performance Status 13,16 29 12-Lead ECG 18 30 Pregnancy 18 31 Concomitant Medications 95 32 Procedures 96 33 Comments 98 34 Death Report 101 35 Tumor Recurrence 30 Halozyme Therapeutics, Inc. Statistical Analysis Plan Protocol number: HZ2-05-01 January 11, 2008 C:\Users \Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 13 36 Long-Term Follow-Up 28,29 37 Utility Database Panel for Dose-Limiting Toxicities (DLTs) Derived Halozyme Therapeutics, Inc. Statistical Analysis Plan Protocol number: HZ2-05-01 January 11, 2008 C:\Users \Desktop\For ClaritiDox\HZ2-05-01\HZ205-01_SAP_v4_11Jan2008_FINAL.doc 14 APPENDIX B: TABLE LAYOUTS 15 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 1 Patient Disposition All Patients 20,000 U 60,000 U 200,000 U 400,000 U 800,000 U Total Patients Enrolled [1] n n n n n n Received MMC Only n (%) n (%) n (%) n (%) n (%) n (%) Safety Set [2] n (%) n (%) n (%) n (%) n (%) n (%) ITT Set [3] n (%) n (%) n (%) n (%) n (%) n (%) Per Protocol Set [4] n (%) n (%) n (%) n (%) n (%) n (%) Completed Study Without Premature Withdrawal Yes n (%) n (%) n (%) n (%) n (%) n (%) No n (%) n (%) n (%) n (%) n (%) n (%) Reasons Patient Did Not Complete Study [5] Did not receive all expected instillations of study drug n (%) n (%) n (%) n (%) n (%) n (%) Protocol Violation n (%) n (%) n (%) n (%) n (%) n (%) Lost to Follow-up n (%) n (%) n (%) n (%) n (%) n (%) Adverse Event n (%) n (%) n (%) n (%) n (%) n (%) Non-compliance n (%) n (%) n (%) n (%) n (%) n (%) Patient Decision n (%) n (%) n (%) n (%) n (%) n (%) Investigator Decision n (%) n (%) n (%) n (%) n (%) n (%) Other n (%) n (%) n (%) n (%) n (%) n (%) Percentage based on number of patients enrolled. [1] Assigned to a treatment cohort. [2] Received at least one dose of Chemophase. [3] Received at least one dose of Chemophase with MMC. [4] Satisfied Inclusion Criteria 1 and 2; received at least 4 doses of Chemophase with MMC over an interval that did not exceed 8 weeks; retained at least 4 intravesical instillations for at least 90 minutes. Note: the criterion “monitored to the time of tumor recurrence, or at least 5 years, whichever occurs first” was not applied for the generation of this table. [5] Patient may have more than one reason for not completing study. path\t_program.sas date time 16 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 2.1 Demographic Characteristics Safety Set 20,000 U 60,000 U 200,000 U 400,000 U 800,000 U Total (N=) (N=) (N=) (N=) (N=) (N=) Age (years) [1] n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Sex Male n (%) n (%) n (%) n (%) n (%) n (%) Female n (%) n (%) n (%) n (%) n (%) n (%) Ethnicity Hispanic or Latino n (%) n (%) n (%) n (%) n (%) n (%) Not Hispanic or Latino n (%) n (%) n (%) n (%) n (%) n (%) Race White n (%) n (%) n (%) n (%) n (%) n (%) Black, of African Heritage n (%) n (%) n (%) n (%) n (%) n (%) Asian n (%) n (%) n (%) n (%) n (%) n (%) American Indian or Alaska Native n (%) n (%) n (%) n (%) n (%) n (%) Native Hawaiian or Other Pacific Islander n (%) n (%) n (%) n (%) n (%) n (%) Other n (%) n (%) n (%) n (%) n (%) n (%) Multiple Races Combination 1 n (%) n (%) n (%) n (%) n (%) n (%) Combination 2 n (%) n (%) n (%) n (%) n (%) n (%) [1] Age is calculated from the date of informed consent. path\t_program.sas date time Programmer Note Tables 2.2-2.3 will be for the ITT and Per Protocol Sets (if needed). 17 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 3 Abnormal Medical History at Baseline Safety Set 20,000 U 60,000 U 200,000 U 400,000 U 800,000 U Total Body System (N=) (N=) (N=) (N=) (N=) (N=) Respiratory n (%) n (%) n (%) n (%) n (%) n (%) Cardiovascular n (%) n (%) n (%) n (%) n (%) n (%) Gastrointestinal n (%) n (%) n (%) n (%) n (%) n (%) Hepatic n (%) n (%) n (%) n (%) n (%) n (%) Endocrine/Metabolic n (%) n (%) n (%) n (%) n (%) n (%) Central Nervous System n (%) n (%) n (%) n (%) n (%) n (%) Hematopoietic/Lymphatic n (%) n (%) n (%) n (%) n (%) n (%) Dermatological n (%) n (%) n (%) n (%) n (%) n (%) Musculoskeletal n (%) n (%) n (%) n (%) n (%) n (%) Genitourinary/Reproductive n (%) n (%) n (%) n (%) n (%) n (%) Psychiatric n (%) n (%) n (%) n (%) n (%) n (%) Alcohol/Drug Abuse n (%) n (%) n (%) n (%) n (%) n (%) Drug Allergy n (%) n (%) n (%) n (%) n (%) n (%) Non-Drug Allergy n (%) n (%) n (%) n (%) n (%) n (%) HEENT n (%) n (%) n (%) n (%) n (%) n (%) Other n (%) n (%) n (%) n (%) n (%) n (%) path\t_program.sas date time 18 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 4 Urologic History/ Bladder Cancer History Safety Set 20,000 U 60,000 U 200,000 U 400,000 U 800,000 U Total (N=) (N=) (N=) (N=) (N=) (N=) Years Since Initial Diagnosis [1] n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Total Number of Bladder Cancer Occurrences n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Most Recent Estimated Bladder Capacity (mL) n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx [1] Years Since Initial Diagnosis= (Informed Consent Date- Date of Initial Bladder Cancer Diagnosis + 1)/(365.25). path\t_program.sas date time Programmer Note: Years Since Initial Diagnosis is calculated as the difference in years between the Date of Initial Bladder Cancer Diagnosis (MHSTDT) and the Date of Informed Consent (IEDT). If only the year of Initial Bladder Cancer Diagnosis is reported then calculate the difference using only the years. 19 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 5 Bladder Treatments/ Surgeries/ Procedures Safety Set 20,000 U 60,000 U 200,000 U 400,000 U 800,000 U Total (N=) (N=) (N=) (N=) (N=) (N=) Total Number of Previous Bladder Tumor Treatments [1] n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Total Number of Previous Bladder Surgeries n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Total Number of Previous Cystoscopies With Tumors Detected n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Total Number of Previous Cystoscopies Without Tumors Detected n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx [1] Each “treatment” may include multiple cycles of the same treatment. path\t_program.sas date time 20 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 6 Study Drug Administration Safety Set 20,000 U 60,000 U 200,000 U 400,000 U 800,000 U Total Visit (N=) (N=) (N=) (N=) (N=) (N=) Week 1, Day 1 n n n n n n Dose of MMC Instilled 40 mg n (%) n (%) n (%) n (%) n (%) n (%) Other n (%) n (%) n (%) n (%) n (%) n (%) Volume of MMC Instilled 20 mL n (%) n (%) n (%) n (%) n (%) n (%) Other n (%) n (%) n (%) n (%) n (%) n (%) Dwell Time (min) [1] N n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx [1] Dwell Time= (Time of post-instillation voiding- end time of instillation) . path\t_program.sas date time Programmer Note Table will repeat for each day study drug is administered. 21 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 6 Study Drug Administration Safety Set 20,000 U 60,000 U 200,000 U 400,000 U 800,000 U Total Visit (N=) (N=) (N=) (N=) (N=) (N=) Week 2, Day 8 n n n n n n Volume of Chemophase Instilled Expected Volume n (%) n (%) n (%) n (%) n (%) n (%) Other n (%) n (%) n (%) n (%) n (%) n (%) Units of Chemophase Instilled Expected Units n (%) n (%) n (%) n (%) n (%) n (%) Other n (%) n (%) n (%) n (%) n (%) n (%) Volume of Saline Instilled Expected Volume n (%) n (%) n (%) n (%) n (%) n (%) Other n (%) n (%) n (%) n (%) n (%) n (%) Dose of MMC Instilled 40 mg n (%) n (%) n (%) n (%) n (%) n (%) Other n (%) n (%) n (%) n (%) n (%) n (%) Volume of MMC Instilled 20 mL n (%) n (%) n (%) n (%) n (%) n (%) Other n (%) n (%) n (%) n (%) n (%) n (%) Total Volume Instilled 28 mL n (%) n (%) n (%) n (%) n (%) n (%) Other n (%) n (%) n (%) n (%) n (%) n (%) Dwell Time (min) [1] N n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx [1] Dwell Time= (Time of post-instillation voiding- end time of instillation) . path\t_program.sas date time Programmer Note Table will repeat for each day study drug is administered. 22 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 7 Cystoscopy at Week 12 ITT Set 20,000 U 60,000 U 200,000 U 400,000 U 800,000 U Total (N=) (N=) (N=) (N=) (N=) (N=) Result n n n n n n Normal n (%) n (%) n (%) n (%) n (%) n (%) Abnormal, Not Clinically Significant n (%) n (%) n (%) n (%) n (%) n (%) Abnormal, Clinically Significant n (%) n (%) n (%) n (%) n (%) n (%) Estimated Bladder Capacity Volume n n n n n n n Mean (SD) xx.x (xx xx) xx.x (xx.xx) xx x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Absence of Tumor Recurrence Verified Yes n (%) n (%) n (%) n (%) n (%) n (%) No n (%) n (%) n (%) n (%) n (%) n (%) Not Applicable n (%) n (%) n (%) n (%) n (%) n (%) path\t_program.sas date time Programmer Note Table using ITT Set will be renumbered to 7.1 if analysis for Per Protocol Set is needed. Table number for Per Protocol Set will be 7.2. 23 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 8.1 NMP22 BladderChek Biomarker Test at Week 8 ITT Set Part 1 of 2 Baseline [1] 20,000 U (N=) 60,000 U (N=) 200,000 U (N=) 400,000 U (N=) 800,000 U (N=) Time Point Neg Pos Inv[2] ND[3] Neg Pos Inv[2] ND[3] Neg Pos Inv[2] ND[3] Neg Pos Inv[2] ND[3] Neg Pos Inv[2] ND[3] Week 8 n n n n n Negative n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Positive n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) No Valid Result (Invalid) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Not Done n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] Inv= No Valid Result (Invalid) [3] ND= Not Done If more than one test results is collected, the last repeated test is used. path\t_program.sas date time Programmer Note Table using ITT Set will be renumbered to 8.1.1 if analysis for Per Protocol Set is needed. Table number for Per Protocol Set will be 8.1.2. 24 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 8.1 NMP22 BladderChek Biomarker Test at Week 8 ITT Set Part 2 of 2 Baseline [1] Total (N=) Time Point Neg Pos Inv[2] ND[3] Week 8 n Negative n (%) n (%) n (%) n (%) Positive n (%) n (%) n (%) n (%) No Valid Result (Invalid) n (%) n (%) n (%) n (%) Not Done n (%) n (%) n (%) n (%) [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] Inv= No Valid Result (Invalid) [3] ND= Not Done If more than one test results is collected, the last repeated test is used. path\t_program.sas date time Programmer Note Table using ITT Set will be renumbered to 8.1.1 if analysis for Per Protocol Set is needed. Table number for Per Protocol Set will be 8.1.2. 25 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 8.2 UroVysion FISH Biomarker Test at Week 8 ITT Set Baseline [1] __20,000 U (N=)__ __60,000 U (N=)__ __200,000 U (N=)__ __400,000 U (N=)__ Time Point Neg Pos Eq[2] Oth[3] ND[4] Neg Pos Eq[2] Oth[3] ND[4] Neg Pos Eq[2] Oth[3] ND[4] Neg Pos Eq[2] Oth[3] ND[4] Week 8 n n n n Negative n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Positive n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Equivocal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Other n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Not Done n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] Eq= Equivocal [3] Oth= Other [4] ND= Not Done path\t_program.sas date time Programmer Note Table using ITT Set will be renumbered to 8.2.1 if analysis for Per Protocol Set is needed. Table number for Per Protocol Set will be 8.2.2. 26 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 8.2 UroVysion FISH Biomarker Test at Week 8 ITT Set Baseline [1] 800,000 U (N=) Total (N=) Time Point Neg Pos Eq[2] Oth[3] ND[4] Neg Pos Eq[2] Oth[3] ND[4] Week 8 n n Negative n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Positive n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Equivocal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Other n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Not Done n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] Eq= Equivocal [3] Oth= Other [4] ND= Not Done path\t_program.sas date time Programmer Note Table using ITT Set will be renumbered to 8.2.1 if analysis for Per Protocol Set is needed. Table number for Per Protocol Set will be 8.2.2. 27 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 9.1 Treatment Emergent Adverse Events by System Organ Class [1] Safety Set 20,000 U 60,000 U 200,000 U 400,000 U 800,000 U Total [2] Received Only MMC System Organ Class / Preferred Term (N=) (N=) (N=) (N=) (N=) (N=) (N=) Patients Experiencing at Least One Adverse Event n (%) n (%) n (%) n (%) n (%) n (%) n (%) 95% CI [3] (xx.x, xx.x) (xx.x, xx.x) (xx.x, xx.x) (xx.x, xx.x) (xx.x, xx.x) (xx x, xx x) (xx.x, xx.x) System Organ Class 1 n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 1 n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 2 n (%) n (%) n (%) n (%) n (%) n (%) n (%) . . System Organ Class 2 n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 1 n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 2 n (%) n (%) n (%) n (%) n (%) n (%) n (%) . . [1] At each level of summation (overall, system organ class, preferred term), patients reporting more than one adverse event are counted only once. [2] Total column does not consider patients that received only MMC. [3] 95% Confidence Interval based on a binomial distribution. path\t_program.sas date time 28 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 9.2 Treatment Emergent Adverse Events by System Organ Class and Severity [1] Safety Set Part 1 of 2 20,000 U (N=) 60,000 U (N=) 200,000 U (N=) 400,000 U (N=) 800,000 U (N=) System Organ Class / Preferred Term Mild Mod Sev Mild Mod Sev Mild Mod Sev Mild Mod Sev Mild Mod Sev Patients Experiencing at Least One Adverse Event n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) System Organ Class 1 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 1 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 2 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) . . System Organ Class 2 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 1 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 2 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) . . [1] At each level of summation (overall, system organ class, preferred term), patients reporting more than one adverse event are counted only once using the highest severity. path\t_program.sas date time 29 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 9.2 Treatment Emergent Adverse Events by System Organ Class and Severity [1] Safety Set Part 2 of 2 Total (N=) System Organ Class / Preferred Term Mild Mod Sev Patients Experiencing at Least One Adverse Event n (%) n (%) n (%) System Organ Class 1 n (%) n (%) n (%) Preferred Term 1 n (%) n (%) n (%) Preferred Term 2 n (%) n (%) n (%) . . System Organ Class 2 n (%) n (%) n (%) Preferred Term 1 n (%) n (%) n (%) Preferred Term 2 n (%) n (%) n (%) . . [1] At each level of summation (overall, system organ class, preferred term), patients reporting more than one adverse event are counted only once using the highest severity. path\t_program.sas date time 30 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 9.3 Treatment Emergent Adverse Events by System Organ Class and Relationship to Chemophase [1] Safety Set 20,000 U (N=) 60,000 U (N=) 200,000 U (N=) 400,000 U (N=) 800,000 U (N=) Total (N=) System Organ Class / Preferred Term Related [2] Not Rel [3] Related [2] Not Rel [3] Related [2] Not Rel [3] Related [2] Not Rel [3] Related [2] Not Rel [3] Related [2] Not Rel [3] Patients Experiencing at Least One Adverse Event n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) System Organ Class 1 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 1 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 2 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) . . System Organ Class 2 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 1 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 2 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) . . [1] At each level of summation (overall, system organ class, preferred term), patients reporting more than one adverse event are counted only once using the closest relationship to Chemophase. [2] Includes all events reported as “Possibly”, “Probably”, or “Related” relationship to Chemophase. [3] Includes all events reported as “Unlikely”, or “Not Related” relationship to Chemophase. path\t_program.sas date time 31 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 9.4 Treatment Emergent Adverse Events by System Organ Class and Relationship to MMC [1] Safety Set 20,000 U (N=) 60,000 U (N=) 200,000 U (N=) 400,000 U (N=) 800,000 U (N=) Total (N=) System Organ Class / Preferred Term Related [2] Not Rel [3] Related [2] Not Rel [3] Related [2] Not Rel [3] Related [2] Not Rel [3] Related [2] Not Rel [3] Related [2] Not Rel [3] Patients Experiencing at Least One Adverse Event n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) System Organ Class 1 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 1 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 2 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) . . System Organ Class 2 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 1 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 2 n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) . . [1] At each level of summation (overall, system organ class, preferred term), patients reporting more than one adverse event are counted only once using the closest relationship to MMC. [2] Includes all events reported as “Possibly”, “Probably”, or “Related” relationship to MMC. [3] Includes all events reported as “Unlikely”, or “Not Related” relationship to MMC. path\t_program.sas date time 32 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 9.5 Treatment Emergent Serious Adverse Events by System Organ Class [1] Safety Set 20,000 U 60,000 U 200,000 U 400,000 U 800,000 U Total System Organ Class / Preferred Term (N=) (N=) (N=) (N=) (N=) (N=) Patients Experiencing at Least One Adverse Event n (%) n (%) n (%) n (%) n (%) n (%) 95% CI (xx.x, xx.x) (xx.x, xx.x) (xx.x, xx.x) (xx.x, xx.x) (xx.x, xx.x) (xx.x, xx.x) System Organ Class 1 n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 1 n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 2 n (%) n (%) n (%) n (%) n (%) n (%) . . System Organ Class 2 n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 1 n (%) n (%) n (%) n (%) n (%) n (%) Preferred Term 2 n (%) n (%) n (%) n (%) n (%) n (%) . . [1] At each level of summation (overall, system organ class, preferred term), patients reporting more than one adverse event are counted only once. path\t_program.sas date time 33 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 10.1 Clinical Laboratory Results : Hematology Safety Set WBC (unit) 20,000 U (N=) 60,000 U (N=) 200,000 U (N=) 400,000 U (N=) 800,000 U (N=) Total (N=) Result Change [2] Result Change [2] Result Change [2] Result Change [2] Result Change [2] Result Change [2] Baseline [1] n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Above Normal n (%) n (%) n (%) n (%) n (%) n (%) Below Normal n (%) n (%) n (%) n (%) n (%) n (%) Week 2, Day 8 n n n n n n n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Above Normal n (%) n (%) n (%) n (%) n (%) n (%) Below Normal n (%) n (%) n (%) n (%) n (%) n (%) … … … … … … … … … … … … … … … … … … … … … … … … … … [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] Change= Change from Baseline path\t_program.sas date time Table will repeat for each analyte for each time point. Programmer note In most cases, baseline will be Week 1, Day 1. 34 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 10.2 Clinical Laboratory Results : Chemistry Safety Set Sodium (unit) 20,000 U (N=) 60,000 U (N=) 200,000 U (N=) 400,000 U (N=) 800,000 U (N=) Total (N=) Result Change [2] Result Change [2] Result Change [2] Result Change [2] Result Change [2] Result Change [2] Baseline [1] n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Above Normal n (%) n (%) n (%) n (%) n (%) n (%) Below Normal n (%) n (%) n (%) n (%) n (%) n (%) Week 2, Day 8 n n n n n n n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Above Normal n (%) n (%) n (%) n (%) n (%) n (%) Below Normal n (%) n (%) n (%) n (%) n (%) n (%) … … … … … … … … … … … … … … … … … … … … … … … … … … [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] Change= Change from Baseline path\t_program.sas date time Table will repeat for each analyte for each time point. Programmer note In most cases, baseline will be Week 1, Day 1. 35 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 10.3 Clinical Laboratory Results : Urinalysis Safety Set Specific Gravity 20,000 U (N=) 60,000 U (N=) 200,000 U (N=) 400,000 U (N=) 800,000 U (N=) Total (N=) Result Change [2] Result Change [2] Result Change [2] Result Change [2] Result Change [2] Result Change [2] Baseline [1] n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Above Normal n (%) n (%) n (%) n (%) n (%) n (%) Below Normal n (%) n (%) n (%) n (%) n (%) n (%) Week 2, Day 8 n n n n n n n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Above Normal n (%) n (%) n (%) n (%) n (%) n (%) Below Normal n (%) n (%) n (%) n (%) n (%) n (%) … … … … … … … … … … … … … … … … … … … … … … … … … … [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] Change= Change from Baseline path\t_program.sas date time Table will repeat for each analyte for each time point. Programmer note In most cases, baseline will be Week 1, Day 1. 36 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 11.1 Shift Tables of Clinical Laboratory Results : Hematology Safety Set Part 1 of 2 Baseline [1] 20,000 U (N=) 60,000 U (N=) 200,000 U (N=) 400,000 U (N=) 800,000 U (N=) Most Abnormal Post Baseline Result [2] High Normal Low High Normal Low High Normal Low High Normal Low High Normal Low WBC (unit) n n n n n High n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Normal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Low n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) ANC (unit) n n n n n High n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Normal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Low n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) RBC (unit) n n n n n High n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Normal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Low n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) … … [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] A patient will be assigned a “High” score for post baseline result if a patient has both a high and low post baseline result. path\t_program.sas date time Table will repeat for each analyte. Programmer note In most cases, baseline will be Week 1, Day 1. 37 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 11.1 Shift Tables of Clinical Laboratory Results : Hematology Safety Set Part 2 of 2 Baseline [1] Total (N=) Most Abnormal Post Baseline Result [2] High Normal Low WBC (unit) n High n (%) n (%) n (%) Normal n (%) n (%) n (%) Low n (%) n (%) n (%) ANC (unit) n High n (%) n (%) n (%) Normal n (%) n (%) n (%) Low n (%) n (%) n (%) RBC (unit) n High n (%) n (%) n (%) Normal n (%) n (%) n (%) Low n (%) n (%) n (%) … … [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] A patient will be assigned a “High” score for post baseline result if a patient has both a high and low post baseline result. path\t_program.sas date time Table will repeat for each analyte. Programmer note In most cases, baseline will be Week 1, Day 1. 38 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 11.2 Shift Tables of Clinical Laboratory Results : Chemistry Safety Set Part 1 of 2 Baseline [1] 20,000 U (N=) 60,000 U (N=) 200,000 U (N=) 400,000 U (N=) 800,000 U (N=) Most Abnormal Post Baseline Result [2] High Normal Low High Normal Low High Normal Low High Normal Low High Normal Low Sodium (unit) n n n n n High n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Normal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Low n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Potassium (unit) n n n n n High n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Normal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Low n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Chloride (unit) n n n n n High n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Normal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Low n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) … … [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] A patient will be assigned a “High” score for post baseline result if a patient has both a high and low post baseline result. path\t_program.sas date time Table will repeat for each analyte. Programmer note In most cases, baseline will be Week 1, Day 1. 39 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 11.2 Shift Tables of Clinical Laboratory Results : Chemistry Safety Set Part 2 of 2 Baseline [1] Total (N=) Most Abnormal Post Baseline Result [2] High Normal Low Sodium (unit) n High n (%) n (%) n (%) Normal n (%) n (%) n (%) Low n (%) n (%) n (%) Potassium (unit) n High n (%) n (%) n (%) Normal n (%) n (%) n (%) Low n (%) n (%) n (%) Chloride (unit) n High n (%) n (%) n (%) Normal n (%) n (%) n (%) Low n (%) n (%) n (%) … … [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] A patient will be assigned a “High” score for post baseline result if a patient has both a high and low post baseline result. path\t_program.sas date time Table will repeat for each analyte. Programmer note In most cases, baseline will be Week 1, Day 1. 40 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 11.3 Shift Tables of Clinical Laboratory Results : Urinalysis Safety Set Part 1 of 2 Baseline [1] 20,000 U (N=) 60,000 U (N=) 200,000 U (N=) 400,000 U (N=) 800,000 U (N=) Most Abnormal Post Baseline Result [2] High Normal Low High Normal Low High Normal Low High Normal Low High Normal Low Specific Gravity n n n n n High n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Normal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Low n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) pH n n n n n High n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Normal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Low n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] A patient will be assigned a “High” score for post baseline result if a patient has both a high and low post baseline result. path\t_program.sas date time Programmer note In most cases, baseline will be Week 1, Day 1. Also, only those analytes with numeric results will be considered. 41 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 11.3 Shift Tables of Clinical Laboratory Results : Urinalysis Safety Set Part 2 of 2 Baseline [1] Total (N=) Most Abnormal Post Baseline Result [2] High Normal Low Specific Gravity n High n (%) n (%) n (%) Normal n (%) n (%) n (%) Low n (%) n (%) n (%) pH n High n (%) n (%) n (%) Normal n (%) n (%) n (%) Low n (%) n (%) n (%) [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] A patient will be assigned a “High” score for post baseline result if a patient has both a high and low post baseline result. path\t_program.sas date time Programmer note In most cases, baseline will be Week 1, Day 1. Also, only those analytes with numeric results will be considered. 42 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 12 Physical Examination [1] Safety Set Pre-Study Drug 20,000 U (N=) 60,000 U (N=) 200,000 U (N=) 400,000 U (N=) 800,000 U (N=) Total (N=) Post-Study Drug Normal Abnormal Normal Abnormal Normal Abnormal Normal Abnormal Normal Abnormal Normal Abnormal Respiratory n n n n n n Normal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Abnormal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Cardiovascular n n n n n n Normal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Abnormal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Gastrointestinal n n n n n n Normal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Abnormal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) … … … … … … … … … … … … … [1] For both pre- and post baseline results, a patient is considered normal for body system unless a result of abnormal is reported for specified body system and time interval. path\t_program.sas date time 43 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 13 Vital Signs Safety Set Heart Rate (unit) 20,000 U (N=) 60,000 U (N=) 200,000 U (N=) 400,000 U (N=) 800,000 U (N=) Total (N=) Result Change [2] Result Change [2] Result Change [2] Result Change [2] Result Change [2] Result Change [2] Baseline [1] n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Week 2, Day 8 n n n n n n n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Week 3, Day 15 n n n n n n n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx … … … … … … … … … … … … … … … … … … … … … … … … … … [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] Change= Change from Baseline path\t_program.sas date time Table will repeat for each vital sign at each time point. Programmer note In most cases, baseline will be Week 1, Day 1. 44 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 14.1 Shift Table of 12-Lead ECG Safety Set Part 1 of 2 Screening 20,000 U (N=) 60,000 U (N=) 200,000 U (N=) 400,000 U (N=) 800,000 U (N=) Week 8, Day 50 Nor[1] Abn[2] ACS[3] Nor[1] Abn[2] ACS[3] Nor[1] Abn[2] ACS[3] Nor[1] Abn[2] ACS[3] Nor[1] Abn[2] ACS[3] n n n n n Normal n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Abnormal, not Clinically Significant n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Abnormal , Clinically Significant n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) [1] Nor= Normal [2] Abn= Abnormal, not Clinically Significant [3] ACS= Abnormal, Clinically Significant path\t_program.sas date time 45 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 14.1 Shift Table of 12-Lead ECG Safety Set Part 2 of 2 Screening Total (N=) Week 8, Day 50 Nor[1] Abn[2] ACS[3] n Normal n (%) n (%) n (%) Abnormal, not Clinically Significant n (%) n (%) n (%) Abnormal , Clinically Significant n (%) n (%) n (%) [1] Nor= Normal [2] Abn= Abnormal, not Clinically Significant [3] ACS= Abnormal, Clinically Significant path\t_program.sas date time 46 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 14.2 12-Lead ECG Safety Set 20,000 U (N=) 60,000 U (N=) 200,000 U (N=) 400,000 U (N=) 800,000 U (N=) Total (N=) Result Change [1] Result Change [1] Result Change [1] Result Change [1] Result Change [1] Result Change [1] QT (unit) Screening n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx Week 8, Day 50 n n n n n n n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx QTc (unit) Screening n n n n n n n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx … … … … … … … … … … … … … … … … … … … … … … … … … … [1] Change= Change from Baseline path\t_program.sas date time Table will repeat for each ECG parameter. 47 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 15 Karnofsky Performance Status Safety Set 20,000 U (N=) 60,000 U (N=) 200,000 U (N=) 400,000 U (N=) 800,000 U (N=) Total (N=) Result Change [2] Result Change [2] Result Change [2] Result Change [2] Result Change [2] Result Change [2] Baseline [1] n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx 100% n (%) n (%) n (%) n (%) n (%) n (%) 90% n (%) n (%) n (%) n (%) n (%) n (%) 80% n (%) n (%) n (%) n (%) n (%) n (%) 70% n (%) n (%) n (%) n (%) n (%) n (%) 60% n (%) n (%) n (%) n (%) n (%) n (%) 50% n (%) n (%) n (%) n (%) n (%) n (%) 40% n (%) n (%) n (%) n (%) n (%) n (%) 30% n (%) n (%) n (%) n (%) n (%) n (%) 20% n (%) n (%) n (%) n (%) n (%) n (%) 10% n (%) n (%) n (%) n (%) n (%) n (%) 0% n (%) n (%) n (%) n (%) n (%) n (%) Week 2, Day 8 n n n n n n n n n n n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx xx, xx 100% n (%) n (%) n (%) n (%) n (%) n (%) … … … … … … … … … … … … … … [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] Change= Change from Baseline path\t_program.sas date time Table will repeat for each available time point. Programmer note In most cases, baseline will be Week 1, Day 1. Categories may collapsed as requested by client. 48 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 16 Long-Term Follow-Up- Vital Signs Safety Set Heart Rate (unit) MTD Cohort (N=) Result Change [2] Baseline [1] n n Mean (SD) xx.x (xx.xx) Median xx.x Min, Max xx, xx Month 4 ½ n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x Min, Max xx, xx xx, xx Month 7 ½ n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x Min, Max xx, xx xx, xx … … … … … … [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] Change= Change from Baseline path\t_program.sas date time Table will repeat for each vital sign parameter for each long-term follow-up time point. Programmer note In most cases, baseline will be Week 1, Day 1 and should exactly match baseline expressed in table 13 (Vital Signs). 49 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 17 Long-Term Follow-Up- Targeted Physical Examination Safety Set Reported at least one instance of abnormality [1]: MTD Cohort (N=) Pre-Study Drug Respiratory n (%) Cardiovascular n (%) Gastrointestinal n (%) Hepatic n (%) … Post-Study Drug up to and including Week 12 Visit Respiratory n (%) Cardiovascular n (%) Gastrointestinal n (%) Hepatic n (%) … Post-Study Drug during Long-Term Follow-Up Starting with Month 6 until Study Discontinuation Respiratory n (%) Cardiovascular n (%) Gastrointestinal n (%) Hepatic n (%) … Patients reporting more than one abnormality for the same system will be only counted once per time period (pre-study drug/ post-study drug). path\t_program.sas date time Programmer note The first two endpoints should match up exactly with first two endpoints on table 12 (Physical Examination) 50 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 18 Long-Term Follow-Up- Cystoscopy ITT Set Month 4 ½ MTD Cohort (N=) Cystoscopy Result Normal n (%) Abnormal, Not Clinically Significant n (%) Abnormal, Clinically Significant n (%) Estimated Bladder Capacity Volume (mL) n n Mean (SD) xx.x (xx.xx) Median xx.x Min, Max xx, xx … path\t_program.sas date time Repeat table for each time point. 51 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 19 Long-Term Follow-Up- Hematology Safety Set WBC (unit) MTD Cohort (N=) Result Change [2] Baseline [1] n n Mean (SD) xx.x (xx.xx) Median xx.x Min, Max xx, xx Month 4 ½ n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x Min, Max xx, xx xx, xx Month 7 ½ n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x Min, Max xx, xx xx, xx … … … [1] Baseline defined as measurement taken most closely prior to first study drug administration. [2] Change= Change from Baseline path\t_program.sas date time Table will repeat for each analyte for each long-term follow-up time point. Programmer note In most cases, baseline will be Week 1, Day 1 and should exactly match baseline expressed in table 10.1 (Hematology Results). 52 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 20 Long-Term Follow-Up- Study Drug Administration Safety Set Visit MTD Cohort (N=) Month 4 ½ Chemophase Units Instilled- Mean (SD) xx.x (xx.xx) Volume Instilled- Mean (SD) xx.x (xx.xx) Sterile Saline Volume Instilled- Mean (SD) xx.x (xx.xx) MMC Dose Instilled- Mean (SD) xx.x (xx.xx) Volume Instilled- Mean (SD) xx.x (xx.xx) Total Volume Instilled- Mean (SD) xx.x (xx.xx) Any Interruptions or Adjustments Due to DLTs? Yes n (%) No n (%) Length of Time Patient Retain Solution in their Bladder 2 Hours n (%) >= 90 Minutes, < 2 Hours n (%) < 90 Minutes n (%) 5 mL Urine Sample Collected and Frozen? Yes n (%) No n (%) path\t_program.sas date time Table will repeat for each analyte for each long-term follow-up time point. 53 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 21 Long-Term Follow-Up- NMP22 BladderChek Biomarker Test Safety Set MTD Cohort (N=xx) Month 3 Negative n (%) Positive n (%) No Valid Result n (%) Not Done n (%) Month 6 Negative n (%) Positive n (%) No Valid Result n (%) Not Done n (%) … path\t_program.sas date time Table will repeat for each analyte for each long-term follow-up time point. 54 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 22 Long-Term Follow-Up- UroVysion FISH Biomarker Test Safety Set MTD Cohort (N=xx) Month 3 Negative n (%) Positive n (%) Equivocal n (%) Other n (%) Not Done n (%) Month 6 Negative n (%) Positive n (%) Equivocal n (%) Other n (%) Not Done n (%) … path\t_program.sas date time Table will repeat for each analyte for each long-term follow-up time point. 55 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Table 23 Long-Term Follow-Up- Time to Tumor Recurrence from First Study Drug Administration (Months) Safety Set Category, n (%) MTD Cohort (N=xx) Number Patients with Tumor Recurrence n Number Patients Censored n Quartiles (95% CI): 25th Percentile x.x (x.x, x.x) 50th Percentile (median) x.x (x.x, x,x) 75th Percentile x.x (x.x, x.x) Kaplan Meier Estimate (# at Risk) 6 Months 12 Months 18 Months 24 Months x.x (n) x.x (n) x.x (n) x.x (n) Range (Patients with Tumor Recurrence) xx, xx Range (All Patients) xx, xx path\t_program.sas date time 56 APPENDIX C: LISTING LAYOUTS 57 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 1 Patient Disposition (N=) Cohort X/ Chem Units Patient ID Received MMC Only? Safety Set [1] ITT Set [2] Per Protocol Set [3] Date of Study Discontinuation/ Study Termination Completed Study? Reason for Discontinuation [4] Date of Investigator’s Signature Name of Investigator [1] Received at least one dose of Chemophase. [2] Received at least one dose of Chemophase with MMC. [3] Satisfied Inclusion Criteria 1 and 2; received at least 4 doses of Chemophase with MMC over an interval that did not exceed 8 weeks; retained at least 4 intravesical instillations for at least 90 minutes. Note: the criterion “monitored to the time of tumor recurrence, or at least 5 years, whichever occurs first” was not applied for the generation of this table. [4] Reasons for discontinuation include: Did not receive all expected instillations of study drug. Protocol Violation, Lost to Follow-up, Adverse Event, Non-compliance, Patient Decision, Investigator Decision, Other. path\t_program.sas date time 58 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 2 Inclusion Criteria (N=) Cohort X/ Chem Units Patient ID Date Informed Consent Signed Inclusion Criteria 1a 1b 2 3 4 5 6 7 8 9 10 11 12 path\t_program.sas date time Programmer Note Inclusion criteria to be shown on separate page. 59 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 3 Exclusion Criteria (N=) Cohort X/ Chem Units Patient ID Date Informed Consent Signed Exclusion Criteria 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 path\t_program.sas date time Programmer Note Exclusion criteria to be shown on separate page. 60 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 4 Criteria Waiver (N=) Cohort X/ Chem Units Patient ID Patient Comply with All Entry Criteria? If No, Criteria Not Met Criteria Not Met Criteria Number Exemption Explanation Exemption Granted By Date of Exemption Inclusion/Exclusion path\t_program.sas date time 61 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 5 Demographics (N=) Cohort X/ Chem Units Patient ID Date of Birth Day 1 Dose Age on Day 1 Sex Ethnicity Race path\t_program.sas date time 62 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 6 Medical History (N=) Cohort X/ Chem Units Patient ID Mark if No Medical History Site / System Description Year of Diagnosis / Onset Ongoing path\t_program.sas date time 63 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 7 Urologic History / Bladder Cancer History Part 1 of 3 (Cancer Recurrences) (N=) Cohort X/ Chem Units Patient ID Bladder Cancer Date of Initial Diagnosis Date of Recurrences path\t_program.sas date time 64 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 7 Urologic History / Bladder Cancer History Part 2 of 3 (Estimation of Bladder Capacity) (N=) Cohort X/ Chem Units Patient ID Bladder Capacity Date of Estimation Method of Estimation Volume (mL) path\t_program.sas date time 65 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 7 Urologic History / Bladder Cancer History Part 3 of 3 (Bladder Symptoms) (N=) Cohort X/ Chem Units Patient ID Frequent Urination? Nighttime Urinations? Urinary Urgency? Urinary Incontinence? Use Pads? Yes/No Average Urinations/Day Yes/No Average Urinations/Night Yes/No Average Urinations/Week Yes/No Average Urinations/Week Yes/No Average Pads/Day path\t_program.sas date time 66 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 8 Previous Bladder Tumor Treatments (N=) Cohort X/ Chem Units Patient ID Medication / Treatment Start Date / Stop Date Dose / Units Route Toxicities path\t_program.sas date time 67 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 9 Previous Bladder Surgeries / Cystoscopies with Tumors Detected Part 1 of 2 (N=) Cohort X/ Chem Units Patient ID Mark if None Procedure Tumor # from CRF Date Type Tumor Size (mm) Histological Grading Location TNM Staging Surgery Cystoscopy path\t_program.sas date time 68 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 9 Previous Bladder Surgeries / Cystoscopies with Tumors Detected Part 2 of 2 (N=) Cohort X/ Chem Units Patient ID Mark if None Tumor # from CRF Biopsy Performed? If Yes, Biopsy Findings Gross Appearance of Tumor Depth of Involvement of Bladder Mucosa or Not Applicable path\t_program.sas date time 69 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 10 Previous Bladder Cystoscopies without Tumors (N=) Cohort X/ Chem Units Patient ID Mark if None Cystoscopy # from CRF Date of Procedure Abnormal Findings path\t_program.sas date time 70 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 11 Previous Bladder Fibrosis / Contracture (N=) Cohort X/ Chem Units Patient ID Mark if None Date Diagnosis Etiology path\t_program.sas date time 71 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 12 Previous Cystometrogram (N=) Cohort X/ Chem Units Patient ID Mark if None Test Date Result Test(s) Used If Abnormal, Specify Abnormality path\t_program.sas date time 72 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 13 Instillation of Chemophase and MMC Page 1 of 2 (N=) Refrain From Drinking Fluids? Pre-Instillation Instillation Post-Instillation Cohort X/ Chem Units Patient ID For >= 8 Hours Before Instillation During Instillation Fully Voided Before? Volume Obtained by Catheter (mL) Date Start Time End Time Elapsed Time (min) [1] Time of Voiding Dwell Time (min) [2] Voided Volume (mL) [1] Elapsed Time= End Time of Instillation – Start Time of Instillation [2] Dwell Time= Time of Voiding – End Time of Instillation path\t_program.sas date time 73 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 13 Instillation of Chemophase and MMC Page 2 of 2 (N=) Chemophase Instilled Saline Instilled MMC Instilled Cohort X/ Chem Units Patient ID Volume (mL) Units (U) Volume (mL) Volume (mL) Dose (mg) Total Volume Instilled (mL) Interrupt/ Adjust due to DLTs? If Yes, Specify Time Solution Retained [1] Post Drug Instillation Urine Sample Collected? [1] Possible responses for Time Solution Retained include: 2 Hours, 90 Minutes to <2 Hours, <90 Minutes path\t_program.sas date time 74 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 14 Blood Collection and Results for MMC, rHuPH20 and Neutralizing Antibodies (NAB) to rHuPH20 (N=) Collection Results Neutralizing Antibodies (NAB) to rHuPH20 Cohort X/ Chem Units Patient ID Visit # Mark if Not Done Date Drawn Scheduled Time Actual Time MMC (ng/mL) or Not Done rHuPH20 (U/mL) path\t_program.sas date time 75 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 15 Urine Cytology (N=) Cohort X/ Chem Units Patient ID Visit # Mark if Not Done Collection Date Diagnosis Microscopic Description path\t_program.sas date time 76 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 16 Cystoscopy (N=) Cohort X/ Chem Units Patient ID Visit # Mark if Not Done Cystoscopy Date Result If Abnormal, Specify Abnormality: Estimated Bladder Capacity (mL) Absence of Bladder Cancer Verified? path\t_program.sas date time 77 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 17 Urine Dipstick (N=) Cohort X/ Chem Units Patient ID Visit # Mark if Not Done Collection Date Collection Time Do Results Indicate Possible UTI? path\t_program.sas date time 78 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 18.1 NMP22 BladderChek Biomarker Test (N=) Cohort X/ Chem Units Patient ID Visit # Mark if Not Done Test Collection Date Collection Time Result If Invalid, Was Test Repeated? path\t_program.sas date time Programmer Note Test column will indicate whether test conducted is an initial test or a retest. 79 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 18.2 UroVysion FISH Biomarker Test (N=) Cohort X/ Chem Units Patient ID Visit # Mark if Not Done Test Collection Date Collection Time Result path\t_program.sas date time Programmer Note Test column will indicate whether test conducted is an initial test or a retest. 80 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 19.1 Adverse Events (Treatment-Emergent) (N=) Action Taken with: Relationship to: Cohort X/ Chem Units Patient ID Mark if None AE # Preferred Term/ Verbatim Term Start Date Stop Date Serious ? Severity (CTC) MMC Chemophase MMC Chemophase Other Action Outcome * Treatment-Emergent Adverse Events are defined as those adverse events that occurred after initial study drug dosing and those existing AE’s that worsened after initial study drug dosing. Adverse Events that occurred after the first dose of MMC but prior to first dose of Chemophase will be indicated with a “”. path\t_program.sas date time Programmer Note Abbreviations may be needed for some of the columns. If so, add a footnote to define the abbreviations. 81 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 19.2 Pre-Treatment-Emergent Adverse Events (N=) Action Taken with: Relationship to: Cohort X/ Chem Units Patient ID Mark if None AE # Preferred Term/ Verbatim Term Start Date Stop Date Serious ? Severity (CTC) MMC Chemophase MMC Chemophase Other Action Outcome Only Adverse Events that occurred between the time the patient signed the informed consent and prior to the first dose of MMC and Chemophase are included. path\t_program.sas date time Programmer Note Abbreviations may be needed for some of the columns. If so, add a footnote to define the abbreviations. 82 Page 1 of x Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 20 Serious Adverse Events (Treatment-Emergent) (N=) Action Taken with: Relationship to: Cohort X/ Chem Units Patient ID Mark if None AE # Preferred Term/ Verbatim Term Start Date Stop Date Serious ? Severity (CTC) MMC Chemophase MMC Chemophase Other Action Outcome * Treatment-Emergent Adverse Events are defined as those adverse events that occurred after initial study drug dosing and those existing AE’s that worsened after initial study drug dosing. Adverse Events that occurred prior to first dose of MMC but prior to first dose of Chemophase will be indicated with a “*”. path\t_program.sas date time Programmer Note Abbreviations may be needed for some of the columns. If so, add a footnote to define the abbreviations. 83 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 21 Reference Range Lab Normals – Hematology Age Lab (Both or Male) Lab (Female) Site ID Lab ID Date Effective Lab Test Low High Low High Low High Units path\t_program.sas date time Programmer Note Order the lab tests in the same order as on the CRF. 84 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 22 Reference Range Lab Normals – Chemistry Age Lab (Both or Male) Lab (Female) Site ID Date Effective Lab Test Low High Low High Low High Units COVANCE path\t_program.sas date time Programmer Note Order the lab tests in the same order as on the CRF. 85 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 23 Reference Range Lab Normals – Urinalysis Age Lab (Both or Male) Lab (Female) Site ID Test Code Lab Test Occu Seq Date Effective Low High Low High Low High Units COVANCE path\t_program.sas date time Programmer Note Order the lab tests in the same order as on the CRF. 86 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 24 Hematology Results (N=) Cohort X/ Chem Units Patient ID Lab Test Visit # Lab ID Mark if Not Done Collection Date Collection Time Result [1] Unit Abnormal, not CS Abnormal and CS CS = Clinically Significant. [1] H indicates a value above the normal range. L indicates a value below the normal range. path\t_program.sas date time Programmer Note Put an “H” next to results that are above the normal range. Put an “L” next to results that are below the normal range. Sort the lab tests in the same order as on the CRF. 87 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 25 Chemistry Results (N=) Cohort X/ Chem Units Patient ID Lab Test Visit # Lab ID Mark if Not Done Collection Date Collection Time Result [1] Unit Abnormal, not CS Abnormal and CS COVANCE CS = Clinically Significant. [1] H indicates a value above the normal range. L indicates a value below the normal range. path\t_program.sas date time Programmer Note Put an “H” next to results that are above the normal range. Put an “L” next to results that are below the normal range. Sort the lab tests in the same order as on the CRF. 88 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 26 Urinalysis Results (N=) Cohort X/ Chem Units Patient ID Lab ID Lab Test Visit # Lab ID Mark if Not Done Collection Date Collection Time Result [1] Unit Abnormal, not CS Abnormal and CS COVANCE CS = Clinically Significant. [1] H indicates a value above the normal range. L indicates a value below the normal range. path\t_program.sas date time Programmer Note Put an “H” next to results that are above the normal range. Put an “L” next to results that are below the normal range. Sort the lab tests in the same order as on the CRF. 89 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 27 Physical Examination (N=) Cohort X/ Chem Units Patient ID Visit # Mark if Not Done Exam Date New, Changed or Resolved Abnormality? PE # System Description of Abnormality Clinically Significant? path\t_program.sas date time Programmer Note For System’, add footnotes to explain abbreviations as needed. If Physical Exam was not done, put “Not Done” for Exam Date ’. Sort System by System code #. 90 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 28 Vital Signs and Karnofsky Performance Status (N=) Blood Pressure (mmHg) Temperature Weight Height Cohort X/ Chem Units Patient ID Visit # Mark if Not Done Date of Vital Collected Heart Rate (bpm) Respiration (breaths/min) Systolic Diastolic Result Unit Coll. Type Result Units Result Units Karnofsky Score Oral Aural path\t_program.sas date time Programmer Note If vitals were not done put “Not Done” for Date. 91 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 29 12-Lead ECG (N=) Cohort X/ Chem Units Patient ID Visit # Mark if Not Done ECG Date Result If Abnormal, CS, Specify: QT (msec) QTc (msec) HR (bpm) P-R Interval (msec) QRS (msec) path\t_program.sas date time 92 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 30 Pregnancy (N=) Cohort X/ Chem Units Patient ID Visit # Mark if Not Done Date Reason, If Not Done Result path\t_program.sas date time 93 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 31 Concomitant Medications (N=) Cohort X/ Chem Units Patient ID Mark if None Con Med # Medication Dose Unit Route Regimen Date of Day 1 Start Date Stop Date Indication Given for AE? If Yes, AE #s path\t_program.sas date time Programmer Note If there are no concomitant medications put “NONE” for Medication’. Add footnotes to explain abbreviations as needed. 94 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 32 Procedures (N=) Cohort X/ Chem Units Patient ID Mark if None Procedure # Procedure Date Findings / Results Related to AE? If Yes, AE #s path\t_program.sas date time Programmer Note If there are no procedures put “NONE” for Procedure’. 95 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 33 Comments (N=) Cohort X/ Chem Units Patient ID Mark if None Comment # Pertains to Visit Date CRF Page Comment path\t_program.sas date time Programmer Note If there are no comments put “NONE” for Comment #’. 96 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 34 Death Report (N=) Cohort X/ Chem Units Patient ID Date of Death Date Death Reported to Site Primary Cause Autopsy Performed? Comments Investigator Signed? Date of Signature path\t_program.sas date time 97 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 35 Tumor Recurrence (N=) Cohort X/ Chem Units Patient ID Mark if None Procedure Date Procedure Type Tumor Size (mm) Histopathological Grading Tumor Location TNM Staging Biopsy Performed? If Yes, Biopsy Findings Gross Appearance of Tumor Involvement of Bladder Mucosa, or NA path\t_program.sas date time 98 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 36 Long-Term Follow-Up Part 1 of 5 (N=) Bladder Cancer Treatments Cohort X/ Chem Units Patient ID Contact/ Visit Date Method of Contact Patient Status at Contact Source of Information Treatment Mark if None Start Date Stop Date Ongoing? path\t_program.sas date time 99 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 36 Long-Term Follow-Up Part 2 of 5 (N=) NMP22 BladderChek Test Cohort X/ Chem Units Patient ID Contact/ Visit Date Mark if None Collection Date/Time Result path\t_program.sas date time 100 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 36 Long-Term Follow-Up Part 3 of 5 (N=) UroVysion FISH Biomarker Test Cohort X/ Chem Units Patient ID Contact/ Visit Date Mark if None Collection Date/Time Result path\t_program.sas date time 101 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 36 Long-Term Follow-Up Part 4 of 5 (N=) Cystoscopy Urine Cytologies Bladder Biopsies Cohort X/ Chem Units Patient ID Contact/ Visit Date Mark if None Date Result If Abnormal, Specify Abnormality Mark if None Date Diagnosis Microscopic Description Mark if None Date Findings path\t_program.sas date time 102 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 36 Long-Term Follow-Up Part 5 of 5 (N=) Tumor Recurrence Cohort X/ Chem Units Patient ID Contact/ Visit Date Mark if None Date Confirmed Investigator Signed? path\t_program.sas date time 103 Halozyme Therapeutics, Inc. Protocol Number: HZ2-05-01 Listing 37 Utility Database Panel for Dose-Limiting Toxicities (DLTs) (N=) Cohort X/ Chem Units Patient ID Mark if No DLT Date Reported Adverse Event Considered to be DLT? If so, Name Adverse Event PK Lab Assessment of MMC Level Considered to be DLT? Treatment Emergent Bladder Fibrosis? Reason Given for Discontinuation on Termination Page Protocol defined DLTs are AEs with a CTC grade greater than or equal to 3, Plasma MMC Concentration >=100 ug/mL and Diagnosis of treatment-emergent bladder fibrosis. path\t_program.sas date time 104 APPENDIX D: INTERNATIONALLY AGREED ORDER FOR SOC Infections and infestations Neoplasms benign and malignant (including cysts and polyps) Blood and the lymphatic system disorders Immune system disorders Endocrine disorders Metabolism and nutrition disorders Psychiatric disorders Nervous system disorders Eye disorders Ear and labyrinth disorders Cardiac disorders Vascular disorders Respiratory, thoracic and mediastinal disorders Gastrointestinal disorders Hepato-biliary disorders Skin and subcutaneous tissue disorders Musculoskeletal, connective tissue and bone disorders Renal and urinary disorders Pregnancy, puerperium and perinatal conditions Reproductive system and breast disorders Congenital and familial/genetic disorders General disorders and administration site conditions Investigations Injury and poisoning Surgical and medical procedures Social circumstances This list is from an EMEA Guideline, ‘A Guideline on Summary of Product Characteristics’, October 2005.	5	arm 1: Participants will receive 40 milligrams (mg) MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 20,000 U Chemophase intravesically once weekly from Weeks 2 through 6. arm 2: Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 60,000 U Chemophase intravesically once weekly from Weeks 2 through 6. arm 3: Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 200,000 U Chemophase intravesically once weekly from Weeks 2 through 6. arm 4: Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 400,000 U Chemophase intravesically once weekly from Weeks 2 through 6. arm 5: Participants will receive 40 mg MMC intravesically on Day 1 of Week 1 followed by a combination of 40 mg MMC and 800,000 U Chemophase intravesically once weekly from Weeks 2 through 6.	[ 0, 0, 0, 0, 0 ]	2	[ 0, 0 ]	intervention 1: intravesical administration intervention 2: intravesical administration	intervention 1: Mitomycin C intervention 2: Chemophase	5	Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 La Mesa \| California \| United States \| -117.02308 \| 32.76783 Gainesville \| Florida \| United States \| -82.32483 \| 29.65163 New Port Richey \| Florida \| United States \| -82.71927 \| 28.24418 Tampa \| Florida \| United States \| -82.45843 \| 27.94752	27	0	0	0	NCT00318643	1COMPLETED	2009-08-11	2006-03-30	Halozyme Therapeutics	4INDUSTRY	true	true	false	https://cdn.clinicaltrials.gov/large-docs/43/NCT00318643/Prot_000.pdf https://cdn.clinicaltrials.gov/large-docs/43/NCT00318643/SAP_001.pdf	0	0	0	0	0	0
[ 0 ]	28	null	SEQUENTIAL	0TREATMENT	0NONE	false	0ALL	false	This study is designed to compare four currently used types of anesthesia used prior to intravitreal injection in order to evaluate the most effective method of anesthesia in reducing pain and discomfort associated with intravitreal injections.	Over the last several years intravitreal injection of pharmacologic agents has become a common procedure in ophthalmology. Injected agents include steroid, antibiotics, and most recently anti-VEGF agents. There are many methods of preparing a patient for intravitreal injection. While there are guidelines for infection prophylaxis, there is currently no standard of care or consensus on which method of anesthesia is most effective in reducing pain and discomfort associated with intravitreal injections. Patients who have received prior injections and are scheduled to continue regular injections will be randomized to utilize one of four types of anesthetic treatment for each of 4 treatment periods,so that each subject receives all four types of anesthesia over the course of the study. The order of the anesthetic treatment the subject will receive prior to each planned intravitreal injection during the study period will be different for each subject. This will decrease the effect of extraneous variables from influencing subjective pain scores. Following each procedure, patients will fill out an analog pain scale questionnaire, grading the discomfort of receiving both the anesthesia and the injection(on separate 0-10 scales). The anesthetic methods used will include: 1.) Drops of Proparacaine on the eye, 2.) Drops of Tetracaine on the eye, 3.) A cotton sponge (pledget) soaked with Lidocaine 4% placed over the conjunctiva and 4.)A subconjunctival injection with 2% Lidocaine. The subjects' number and type of visits, tests and treatments will be standard of care and will not be different due to the study. The total time for the treatment part of the study coincides with four injections (1 injection per month) or approximately 4 months and will be followed for up to 6 months.	Macular Degeneration	Macular Degeneration Intravitreal injections Eye anesthesia-Topical/subconjunctival Eye-surgical procedures Ophthalmologic anesthesia methods	null	1	arm 1: All Participants will be randomized to receive a unique sequence of one of the 4 anesthetic agents per month, prior to a standard of care monthly intravitreal injection (1 injection per month for a total of 4 months). At the end of study participation, each patient will have received each of the 4 anesthetic agents once prior to one of the 4 intravitreal injections (ex. Randomization to sequence: Proparacaine Ophthalmic drops used prior to Injection 1; Tetracaine Ophthalmic drops used prior to Injection 2; Lidocaine 4% sponge used prior to Injection 3; Lidocaine 2% injectable solution (subconjunctival) used prior to Injection 4).	[ 5 ]	4	[ 0, 0, 0, 0 ]	intervention 1: Drops of Proparacaine on the eye, administered as described in the package insert intervention 2: Drops of Tetracaine on the eye, administered as described in the package insert intervention 3: A cotton sponge(pledget)soaked with Lidocaine 4% placed over the conjunctiva intervention 4: A subconjunctival injection of Lidocaine 2%	intervention 1: Proparacaine Ophthalmic intervention 2: Tetracaine Ophthalmic intervention 3: Lidocaine 4% intervention 4: Lidocaine 2% Injectable Solution	3	Arlington \| Massachusetts \| United States \| -71.15644 \| 42.41537 Burlington \| Massachusetts \| United States \| -71.19561 \| 42.50482 Peabody \| Massachusetts \| United States \| -70.92866 \| 42.52787	24	0	0	0	NCT00769392	1COMPLETED	2009-08-12	2008-09-01	Lahey Clinic	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 3 ]	63	RANDOMIZED	SEQUENTIAL	0TREATMENT	2DOUBLE	false	0ALL	false	This study determined the maximum dose of LCI6999 with respect to effect on the ACTH-stimulated cortisol response in participants with hypertension.	null	Hypertension	Blood Pressure Hypertension Cortisol	null	5	arm 1: Participants received LCI699 0.5 mg, capsules, orally, once daily (QD), with or without food for up to 6 weeks. arm 2: Participants received LCI699 1.0 mg, capsules, orally, QD, with or without food for up to 6 weeks. arm 3: Participants received LCI699 1.0 mg, capsules, orally, twice daily (BID), with or without food for up to 6 weeks. arm 4: Participants received LCI699 2.0 mg, capsules, orally, QD, with or without food for up to 6 weeks. arm 5: Participants received LCI699-matching placebo, capsules, orally, QD or BID, with or without food for up to 6 weeks.	[ 0, 0, 0, 0, 2 ]	2	[ 0, 0 ]	intervention 1: LCI699-matching placebo oral capsules intervention 2: LCI699 oral capsules	intervention 1: LCI699-matching placebo intervention 2: LCI699	11	Beverly Hills \| California \| United States \| -118.40036 \| 34.07362 Buena Park \| California \| United States \| -117.99812 \| 33.86751 Harbor City \| California \| United States \| -118.29785 \| 33.79002 Long Beach \| California \| United States \| -118.18923 \| 33.76696 Littleton \| Colorado \| United States \| -105.01665 \| 39.61332 Asheville \| North Carolina \| United States \| -82.55402 \| 35.60095 Lenoir \| North Carolina \| United States \| -81.53898 \| 35.91402 Tipton \| Pennsylvania \| United States \| -78.29585 \| 40.6359 Carrollton \| Texas \| United States \| -96.89028 \| 32.95373 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Reykjavik \| SA \| Iceland \| -21.89541 \| 64.13548	63	0	0	0	NCT00817414	1COMPLETED	2009-08-12	2009-01-14	Novartis	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3 ]	115	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	This study will assess the long-term safety and tolerability of ACZ885 in patients with rheumatoid arthritis, as well as long-term efficacy, long-term preservation and/or improvement of joint structure and bone mineral density, and long term maintenance of health-related quality of life.	null	Rheumatoid Arthritis	Rheumatoid Arthritis Anti-interleukin-1 beta ACZ885	null	1	arm 1: Participants received one single dose of 600 mg canakinumab via intravenous infusion on Day 1 and thereafter every 6 weeks until completion of the 54-week treatment period.	[ 0 ]	1	[ 0 ]	intervention 1: Canakinumab	intervention 1: Canakinumab	51	Huntsville \| Alabama \| United States \| -86.58594 \| 34.7304 Tuscaloosa \| Alabama \| United States \| -87.56917 \| 33.20984 Paradise Valley \| Arizona \| United States \| -111.94265 \| 33.53115 Trumbull \| Connecticut \| United States \| -73.20067 \| 41.24287 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 South Miami \| Florida \| United States \| -80.29338 \| 25.7076 Tamarac \| Florida \| United States \| -80.24977 \| 26.21286 Rockford \| Illinois \| United States \| -89.094 \| 42.27113 Urbandale \| Indiana \| United States \| N/A \| N/A Richmond Heights \| Missouri \| United States \| -90.31956 \| 38.62866 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 Reno \| Nevada \| United States \| -119.8138 \| 39.52963 Tulsa \| Oklahoma \| United States \| -95.99277 \| 36.15398 Austin \| Texas \| United States \| -97.74306 \| 30.26715 Carrollton \| Texas \| United States \| -96.89028 \| 32.95373 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Fort Worth \| Texas \| United States \| -97.32085 \| 32.72541 Mesquite \| Texas \| United States \| -96.59916 \| 32.7668 Arlington \| Virginia \| United States \| -77.10428 \| 38.88101 Spokane \| Washington \| United States \| -117.42908 \| 47.65966 Antwerp \| N/A \| Belgium \| 4.40026 \| 51.22047 Diepenbeek \| N/A \| Belgium \| 5.41875 \| 50.90769 Liège \| N/A \| Belgium \| 5.56749 \| 50.63373 Berlin \| N/A \| Germany \| 13.41053 \| 52.52437 Hamburg \| N/A \| Germany \| 9.99302 \| 53.55073 Hanover \| N/A \| Germany \| 9.73322 \| 52.37052 Ratingen \| N/A \| Germany \| 6.84929 \| 51.29724 Sendenhorst \| N/A \| Germany \| 7.82996 \| 51.84303 Wiesbaden \| N/A \| Germany \| 8.24932 \| 50.08258 Arenzano \| GE \| Italy \| 8.68315 \| 44.40521 Valeggio sul Mincio \| VR \| Italy \| 10.73635 \| 45.35333 Genova \| N/A \| Italy \| 11.87211 \| 45.21604 Padua \| N/A \| Italy \| 11.88586 \| 45.40797 Leeuwarden \| N/A \| Netherlands \| 5.80859 \| 53.20139 Leiden \| N/A \| Netherlands \| 4.49306 \| 52.15833 Venlo \| N/A \| Netherlands \| 6.16806 \| 51.37 Moscow \| N/A \| Russia \| 37.61556 \| 55.75222 Yaroslavl \| N/A \| Russia \| 39.87368 \| 57.62987 Yekaterinburg \| N/A \| Russia \| 60.6122 \| 56.8519 Alicante \| N/A \| Spain \| -0.48149 \| 38.34517 Barcelona \| N/A \| Spain \| 2.15899 \| 41.38879 Bilbao \| N/A \| Spain \| -2.92528 \| 43.26271 Madrid \| N/A \| Spain \| -3.70256 \| 40.4165 Santiago de Compostela \| N/A \| Spain \| -8.54569 \| 42.88052 Seville \| N/A \| Spain \| -5.97317 \| 37.38283 Valencia \| N/A \| Spain \| -0.37966 \| 39.47391 Basel \| N/A \| Switzerland \| 7.57327 \| 47.55839 Zurich \| N/A \| Switzerland \| 8.55 \| 47.36667 Istanbul \| N/A \| Turkey (Türkiye) \| 28.94966 \| 41.01384 Izmir \| N/A \| Turkey (Türkiye) \| 27.13838 \| 38.41273 Sihhiye/Ankara \| N/A \| Turkey (Türkiye) \| N/A \| N/A	115	0	0	0	NCT00554606	1COMPLETED	2009-08-13	2007-10-11	Novartis	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3 ]	9	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	false	The purpose of this randomized, double-blinded study is to test the safety of GSK1265744 and how well it works on reducing the amount of HIV in the blood. It will also look at how people react to and how a human body uses GSK1265744. This study will compare the effects of GSK1265744 and placebo. The study will consist of 1 or 2 parts to look at doses of GSK1265744. About 8 people will take part in Part 1 of the study receiving dose A. If additional dosing information is needed after Part 1, about 6 people will take part in Part 2 of the study receiving dose B.	null	Infection, Human Immunodeficiency Virus	HIV naive Phase II integrase inhibitor GSK1265744 newly diagnosed pharmacokinetics AIDS integrase HIV Infections Treatment naive	null	3	arm 1: GSK1265744 30 mg arm 2: Placebo to match GSK1265744 arm 3: GSK1265744 5 mg	[ 0, 0, 0 ]	3	[ 0, 0, 0 ]	intervention 1: GSK1265744 30 mg intervention 2: Placebo to match GSK1265744 intervention 3: GSK1265744 5mg	intervention 1: GSK1265744 30mg intervention 2: Placebo intervention 3: GSK1265744 5mg	4	Fort Lauderdale \| Florida \| United States \| -80.14338 \| 26.12231 Orlando \| Florida \| United States \| -81.37924 \| 28.53834 Vero Beach \| Florida \| United States \| -80.39727 \| 27.63864 Charlotte \| North Carolina \| United States \| -80.84313 \| 35.22709	25	0	0	0	NCT00920426	1COMPLETED	2009-08-13	2009-06-09	ViiV Healthcare	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3 ]	54	RANDOMIZED	CROSSOVER	0TREATMENT	2DOUBLE	false	0ALL	false	This is a randomised, double-blind, placebo-controlled 4-period cross-over study to assess the efficacy and safety of repeat dose intranasal GSK1004723 (1000µg), oral GSK835726 (10mg) and cetirizine (10mg) in the environmental challenge chamber in subjects with seasonal allergic rhinitis.	null	Rhinitis, Allergic, Seasonal	Proof of concept	null	4	arm 1: 10mg oral dose arm 2: 1000mcg nasal spray solution arm 3: 10mg cetirizine as active comparator arm 4: placebo	[ 1, 1, 1, 2 ]	4	[ 0, 0, 0, 0 ]	intervention 1: GSK835726 10mg tablet intervention 2: GSK1004723 1000mcg nasal spray solution intervention 3: Cetirizine 10mg active comparator intervention 4: placebo to match actives	intervention 1: GSK835726 10mg intervention 2: GSK1004723 1000mcg intervention 3: Cetirizine 10mg intervention 4: placebo	1	Hanover \| Lower Saxony \| Germany \| 9.73322 \| 52.37052	211	0	0	0	NCT00972504	1COMPLETED	2009-08-14	2009-06-01	GlaxoSmithKline	4INDUSTRY	false	false	false	null	0	0	0	0	0	-0
[ 5 ]	290	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	To evaluate the percentage of subjects with clinical recurrence of UC at 6 months using MMX mesalamine once daily.	null	Ulcerative Colitis	ulcerative colitis compliance mesalamine clinical study clinical trial clinical research maintenance long term uc study uc trial uc research open label once a day once daily daily dosing simple oral	null	1	arm 1: None	[ 0 ]	1	[ 0 ]	intervention 1: MMX™ mesalamine 2.4g/day to 4.8g/day once-daily (QD) (two to four 1.2g tablets MMX™ mesalamine, dosed QD,respectively).	intervention 1: MMX Mesalamine	62	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Jonesboro \| Arkansas \| United States \| -90.70428 \| 35.8423 Long Beach \| California \| United States \| -118.18923 \| 33.76696 San Diego \| California \| United States \| -117.16472 \| 32.71571 San Diego \| California \| United States \| -117.16472 \| 32.71571 Englewood \| Colorado \| United States \| -104.98776 \| 39.64777 Greenwich \| Connecticut \| United States \| -73.62846 \| 41.02649 Hamden \| Connecticut \| United States \| -72.89677 \| 41.39593 New Haven \| Connecticut \| United States \| -72.92816 \| 41.30815 Washington D.C. \| District of Columbia \| United States \| -77.03637 \| 38.89511 Clearwater \| Florida \| United States \| -82.8001 \| 27.96585 Hollywood \| Florida \| United States \| -80.14949 \| 26.0112 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 New Smyrna Beach \| Florida \| United States \| -80.927 \| 29.02582 Palm Harbor \| Florida \| United States \| -82.76371 \| 28.07807 Decatur \| Georgia \| United States \| -84.29631 \| 33.77483 Macon \| Georgia \| United States \| -83.6324 \| 32.84069 Marietta \| Georgia \| United States \| -84.54993 \| 33.9526 Moline \| Illinois \| United States \| -90.51513 \| 41.5067 Peoria \| Illinois \| United States \| -89.58899 \| 40.69365 Rockford \| Illinois \| United States \| -89.094 \| 42.27113 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Davenport \| Iowa \| United States \| -90.57764 \| 41.52364 Iowa City \| Iowa \| United States \| -91.53017 \| 41.66113 Overland Park \| Kansas \| United States \| -94.67079 \| 38.98223 Shreveport \| Louisiana \| United States \| -93.75018 \| 32.52515 Annapolis \| Maryland \| United States \| -76.49184 \| 38.97859 Annapolis \| Maryland \| United States \| -76.49184 \| 38.97859 Laurel \| Maryland \| United States \| -76.84831 \| 39.09928 Troy \| Michigan \| United States \| -83.14993 \| 42.60559 Rochester \| Minnesota \| United States \| -92.4699 \| 44.02163 Mexico \| Missouri \| United States \| -91.88295 \| 39.16976 Bozeman \| Montana \| United States \| -111.03856 \| 45.67965 Manalapan \| New Jersey \| United States \| -74.39571 \| 40.25733 Bay Shore \| New York \| United States \| -73.24539 \| 40.7251 Long Island City \| New York \| United States \| -73.94875 \| 40.74482 Manhasset \| New York \| United States \| -73.69957 \| 40.79788 Mineola \| New York \| United States \| -73.64068 \| 40.74927 New Hyde Park \| New York \| United States \| -73.68791 \| 40.7351 New York \| New York \| United States \| -74.00597 \| 40.71427 Troy \| New York \| United States \| -73.69179 \| 42.72841 High Point \| North Carolina \| United States \| -80.00532 \| 35.95569 Jacksonville \| North Carolina \| United States \| -77.43024 \| 34.75405 Beachwood \| Ohio \| United States \| -81.50873 \| 41.4645 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Dayton \| Ohio \| United States \| -84.19161 \| 39.75895 Norman \| Oklahoma \| United States \| -97.43948 \| 35.22257 Sayre \| Pennsylvania \| United States \| -76.5155 \| 41.97896 Chattanooga \| Tennessee \| United States \| -85.30968 \| 35.04563 Germantown \| Tennessee \| United States \| -89.81009 \| 35.08676 Kingsport \| Tennessee \| United States \| -82.56182 \| 36.54843 Houston \| Texas \| United States \| -95.36327 \| 29.76328 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Chesapeake \| Virginia \| United States \| -76.27494 \| 36.81904 Christiansburg \| Virginia \| United States \| -80.40894 \| 37.12985 Spokane \| Washington \| United States \| -117.42908 \| 47.65966 Spokane \| Washington \| United States \| -117.42908 \| 47.65966 Milwaukee \| Wisconsin \| United States \| -87.90647 \| 43.0389 Milwaukee \| Wisconsin \| United States \| -87.90647 \| 43.0389 Waukesha \| Wisconsin \| United States \| -88.23148 \| 43.01168	345	0	0	0	NCT00446849	1COMPLETED	2009-08-17	2007-05-01	Shire	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 4 ]	346	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	This trial is a 52-week, open-label extension trial to investigate safety and to explore efficacy of Org 50081 (Esmirtazapine) in participants who completed Protocol 176001 (P05706) (NCT00482612) or 176002 (P05707) (NCT00506389). Participants who have completed Protocol P05706 or P05707, and are willing to continue treatment with Esmirtazapine, can participate in Protocol 176004 (P05708) after signing informed consent.	null	Insomnia	Fifty two weeks Open label extension	null	1	arm 1: One tablet of Esmirtazapine, 4.5 mg orally, daily for up to 52 weeks	[ 0 ]	1	[ 0 ]	intervention 1: One tablet daily	intervention 1: Org 50081	0	null	342	0	0	0	NCT00610675	1COMPLETED	2009-08-17	2006-12-07	Merck Sharp & Dohme LLC	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 4 ]	656	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	This study was designed to determine long-term safety of TREXIMET (sumatriptan/naproxen sodium) in adolescents for the acute treatment of migraine.	This study was designed to determine long-term safety of TREXIMET (sumatriptan/naproxen sodium) in adolescents (aged 12 to 17 years) for the acute treatment of migraine.	Migraine Disorders	Long-term Safety Migraine Adolescent Migraine Headache sumatriptan succinate naproxen sodium	null	1	arm 1: Combination Tablet of Treximet (sumatriptan/naproxen sodium)	[ 5 ]	1	[ 0 ]	intervention 1: Combination Tablet of Treximet(sumatriptan/naproxen sodium)	intervention 1: Combination Tablet of Treximet (sumatriptan/naproxen sodium)	77	Gilbert \| Arizona \| United States \| -111.78903 \| 33.35283 Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 Jonesboro \| Arkansas \| United States \| -90.70428 \| 35.8423 Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 Chico \| California \| United States \| -121.83748 \| 39.72849 Fair Oaks \| California \| United States \| -121.27217 \| 38.64463 Fresno \| California \| United States \| -119.77237 \| 36.74773 Fullerton \| California \| United States \| -117.92534 \| 33.87029 Huntington Beach \| California \| United States \| -117.99923 \| 33.6603 Irvine \| California \| United States \| -117.82311 \| 33.66946 La Jolla \| California \| United States \| -117.2742 \| 32.84727 Newport Beach \| California \| United States \| -117.92895 \| 33.61891 Northridge \| California \| United States \| -118.53675 \| 34.22834 Redondo Beach \| California \| United States \| -118.38841 \| 33.84918 Roseville \| California \| United States \| -121.28801 \| 38.75212 Sacramento \| California \| United States \| -121.4944 \| 38.58157 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Santa Monica \| California \| United States \| -118.49138 \| 34.01949 Walnut Creek \| California \| United States \| -122.06496 \| 37.90631 Aurora \| Colorado \| United States \| -104.83192 \| 39.72943 Colorado Springs \| Colorado \| United States \| -104.82136 \| 38.83388 East Hartford \| Connecticut \| United States \| -72.61203 \| 41.78232 Fairfield \| Connecticut \| United States \| -73.26373 \| 41.14121 Loxahatchee Groves \| Florida \| United States \| -80.27977 \| 26.68368 Naples \| Florida \| United States \| -81.79596 \| 26.14234 Pensacola \| Florida \| United States \| -87.21691 \| 30.42131 St. Petersburg \| Florida \| United States \| -82.67927 \| 27.77086 West Palm Beach \| Florida \| United States \| -80.05337 \| 26.71534 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Savannah \| Georgia \| United States \| -81.09983 \| 32.08354 Anderson \| Indiana \| United States \| -85.68025 \| 40.10532 Bardstown \| Kentucky \| United States \| -85.4669 \| 37.80923 Murray \| Kentucky \| United States \| -88.31476 \| 36.61033 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 Kalamazoo \| Michigan \| United States \| -85.58723 \| 42.29171 Paw Paw \| Michigan \| United States \| -85.89112 \| 42.21782 Protage \| Michigan \| United States \| N/A \| N/A Richland \| Michigan \| United States \| -85.45501 \| 42.37615 Plymouth \| Minnesota \| United States \| -93.45551 \| 45.01052 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 Henderson \| Nevada \| United States \| -114.98194 \| 36.0397 New Brunswick \| New Jersey \| United States \| -74.45182 \| 40.48622 Ridgewood \| New Jersey \| United States \| -74.11653 \| 40.97926 Vorhees \| New Jersey \| United States \| N/A \| N/A Albuquerque \| New Mexico \| United States \| -106.65114 \| 35.08449 Albany \| New York \| United States \| -73.75623 \| 42.65258 Amherst \| New York \| United States \| -78.79976 \| 42.97839 Endwell \| New York \| United States \| -76.02103 \| 42.11285 Mount Vernon \| New York \| United States \| -73.83708 \| 40.9126 New York \| New York \| United States \| -74.00597 \| 40.71427 Plainview \| New York \| United States \| -73.46735 \| 40.77649 Rochester \| New York \| United States \| -77.61556 \| 43.15478 Rochester \| New York \| United States \| -77.61556 \| 43.15478 Williamsville \| New York \| United States \| -78.73781 \| 42.96395 Raleigh \| North Carolina \| United States \| -78.63861 \| 35.7721 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Columbus \| Ohio \| United States \| -82.99879 \| 39.96118 Westerville \| Ohio \| United States \| -82.92907 \| 40.12617 Oklahoma City \| Oklahoma \| United States \| -97.51643 \| 35.46756 Eugene \| Oregon \| United States \| -123.08675 \| 44.05207 Medford \| Oregon \| United States \| -122.87559 \| 42.32652 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Greer \| South Carolina \| United States \| -82.22706 \| 34.93873 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Georgetown \| Texas \| United States \| -97.67723 \| 30.63269 Nassau Bay \| Texas \| United States \| -95.09104 \| 29.54468 Plano \| Texas \| United States \| -96.69889 \| 33.01984 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Charlottesville \| Virginia \| United States \| -78.47668 \| 38.02931 Norfolk \| Virginia \| United States \| -76.28522 \| 36.84681 Bremerton \| Washington \| United States \| -122.63264 \| 47.56732 Wenatchee \| Washington \| United States \| -120.31035 \| 47.42346	1,136	0	0	0	NCT00488514	1COMPLETED	2009-08-20	2007-07-13	GlaxoSmithKline	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 2 ]	18	NON_RANDOMIZED	SEQUENTIAL	0TREATMENT	0NONE	false	0ALL	true	The primary purpose of this trial is to determine the maximum tolerated dose (MTD), or the maximum acceptable dose (MAD) and evaluate the dose limiting toxicity (DLT) of oral suberoylanilide hydroxamic acid in participants with solid tumors.	null	Tumors	Solid tumors	null	4	arm 1: During Cycle 1, participants receive a single oral dose of vorinostat 100 mg on Day 1 in a fasted state, Day 3 in a fed state, and Day 19 in a fed state. On Days 5-18, participants receive vorinostat 100 mg twice daily, in the morning and evening. If participants do not match to the discontinuation criteria, they can continue the same dose level therapy during Cycle 2 and subsequent cycles. (Each cycle will be 26 days.) arm 2: During Cycle 1, participants receive a single oral dose of vorinostat 200 mg on Day 1 in a fasted state; on Day 3 in a fed state; and on Day 19 in a fed state. On Days 5-18, participants receive vorinostat 200 mg twice daily, in the morning and evening. If participants do not match to the discontinuation criteria, they can continue the same dose level therapy during Cycle 2 and subsequent cycles. (Each cycle will be 26 days.) arm 3: During Cycle 1, participants receive a single oral dose of vorinostat 400 mg on Day 1 in a fasted state; on Day 3 in a fed state; and on Day 19 in a fed state. On Days 5-18, participants receive a single oral dose of vorinostat 400 mg once-daily in the morning. If participants do not match to the discontinuation criteria, they can continue the same dose level therapy during Cycle 2 and subsequent cycles. (Each cycle will be 26 days.) arm 4: During Cycle 1, participants receive a single oral dose of vorinostat 500 mg on Day 1 in a fasted state; on Day 3 in a fed state; and on Day 19 in a fed state. On Days 5-18, participants receive a single oral dose of vorinostat 500 mg once-daily in the morning. If participants do not match to the discontinuation criteria, they can continue the same dose level therapy on the Cycle 2 and subsequent cycles.(Each cycle will be 26 days.)	[ 0, 0, 0, 0 ]	1	[ 0 ]	intervention 1: vorinostat 100 mg, 200 mg, 400 mg, or 500 mg single oral dose; once-daily or twice-daily administration	intervention 1: vorinostat	0	null	19	0	0	0	NCT00127127	1COMPLETED	2009-08-21	2005-06-10	Merck Sharp & Dohme LLC	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 2 ]	41	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	The primary objective of this study is to evaluate the safety and tolerability of SK\&F-105517-D in japanese patients with chronic heart failure.	null	Heart Failure, Congestive	carvedilol phosphate ß-blocker SK&F-105517-D Chronic heart failure(CHF)	null	2	arm 1: SK\&F-105517-D 10-80 mg/day arm 2: Carvedilol-IR 5-20 mg/day	[ 0, 5 ]	5	[ 0, 0, 0, 0, 0 ]	intervention 1: 1 capsule once a day intervention 2: 1 or 2 tablet(s) twice a day intervention 3: 1 capsule once a day intervention 4: 1 or 2 capsule(s) once a day intervention 5: 1 tablet twice a day	intervention 1: SK&F-105517-D 10 mg capsule intervention 2: Carvedilol-immediate release (IR) 2.5 mg tablet intervention 3: SK&F-105517-D 20 mg capsule intervention 4: SK&F-105517-D 40 mg capsule intervention 5: Carvedilol-IR 10 mg tablet	23	Chiba \| N/A \| Japan \| 140.11667 \| 35.6 Ehime \| N/A \| Japan \| N/A \| N/A Hiroshima \| N/A \| Japan \| 132.45 \| 34.4 Hokkaido \| N/A \| Japan \| N/A \| N/A Hokkaido \| N/A \| Japan \| N/A \| N/A Kanagawa \| N/A \| Japan \| 139.91667 \| 37.58333 Kanagawa \| N/A \| Japan \| 139.91667 \| 37.58333 Mie \| N/A \| Japan \| 131.58333 \| 32.96667 Nagano \| N/A \| Japan \| 138.18333 \| 36.65 Nagasaki \| N/A \| Japan \| 129.88333 \| 32.75 Osaka \| N/A \| Japan \| 135.50107 \| 34.69379 Ōita \| N/A \| Japan \| 131.6 \| 33.23333 Saga \| N/A \| Japan \| 130.3 \| 33.23333 Saitama \| N/A \| Japan \| 139.65657 \| 35.90807 Shizuoka \| N/A \| Japan \| 138.38333 \| 34.98333 Shizuoka \| N/A \| Japan \| 138.38333 \| 34.98333 Shizuoka \| N/A \| Japan \| 138.38333 \| 34.98333 Shizuoka \| N/A \| Japan \| 138.38333 \| 34.98333 Tokyo \| N/A \| Japan \| 139.69171 \| 35.6895 Tokyo \| N/A \| Japan \| 139.69171 \| 35.6895 Tokyo \| N/A \| Japan \| 139.69171 \| 35.6895 Tokyo \| N/A \| Japan \| 139.69171 \| 35.6895 Wakayama \| N/A \| Japan \| 135.16667 \| 34.23333	41	0	0	0	NCT00742508	1COMPLETED	2009-08-21	2008-08-28	GlaxoSmithKline	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3 ]	683	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	false	This study will test the safety and how effective telcagepant is when taken with ibuprofen or acetaminophen in participants with migraine with or without aura. The primary study hypothesis is that at least one drug combination is superior to telecagepant alone in the treatment of acute migraines.	null	Migraine		null	4	arm 1: Participants take two placebo tablets and two placebo capsules, orally, at onset of migraine arm 2: Participants take one telcagepant 280 mg tablet, one ibuprofen 400 mg tablet, and two placebo capsules, orally, at onset of migraine arm 3: Participants take one telcagepant 280 mg tablet, one placebo tablet, and two 500-mg APAP capsules, orally, at onset of migraine arm 4: Participants take one telcagepant 280 mg tablet, one placebo tablet, and two placebo capsules, orally, at onset of migraine	[ 2, 0, 0, 2 ]	4	[ 0, 0, 0, 0 ]	intervention 1: None intervention 2: None intervention 3: None intervention 4: None	intervention 1: placebo intervention 2: ibuprofen intervention 3: acetominophen intervention 4: telcagepant	0	null	563	0	0	0	NCT00758836	1COMPLETED	2009-08-24	2008-12-03	Merck Sharp & Dohme LLC	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3 ]	155	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	1FEMALE	false	This study is designed to see how elagolix works compared to placebo in women with endometriosis and to see the effect, if any, on bone mineral density.	This is a Phase II, multicenter, randomized, double-blind, placebo-controlled parallel-group study to assess the efficacy and safety of elagolix at two dose levels administered once daily for up to 6 months. Participants will be randomized (1:1:1) to one of the following treatment groups for the first 12 weeks of dosing: 150 mg elagolix once daily (QD); 250 mg elagolix QD or placebo QD. Following 12 weeks of dosing, participants will continue in the study for an additional 12 weeks; participants randomized to elagolix will continue to receive their assigned dose and participants randomized to placebo will be re-randomized to receive one of the two doses of elagolix for 12 weeks in a double-blind fashion. Six weeks after the last dose of study drug at the end of Week 24, a follow-up visit will be performed (end of Week 30).	Endometriosis, Pain	bone mineral density Pelvic Pain estradiol NBI-56418	null	3	arm 1: Participants received placebo tablets once a day for 12 weeks. At the end of 12 weeks participants were re-randomized to receive one of the two doses of elagolix (150 mg or 250 mg) QD for 12 weeks. arm 2: Participants received elagolix 150 mg tablets once a day for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 150 mg QD for an additional 12 weeks. arm 3: Participants received elagolix 250 mg tablets once a day for 12 weeks. At the end of 12 weeks participants continued to receive elagolix 250 mg for an additional 12 weeks.	[ 2, 0, 0 ]	2	[ 0, 0 ]	intervention 1: Elagolix tablets administered orally intervention 2: Placebo tablet administered orally	intervention 1: Elagolix intervention 2: placebo	0	null	193	0	0	0	NCT00619866	1COMPLETED	2009-08-28	2008-02-19	AbbVie	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 4 ]	326	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	null	This study will determine the relative efficacy and safety of up to 100 days Valcyte prophylaxis relative to up to 200 days Valcyte prophylaxis when given for the prevention of CMV disease in high-risk (D+/R-) kidney allograft recipients. The anticipated time on study treatment is 3-12 months and the target sample size is 100-500 individuals.	null	Cytomegalovirus Infections		null	2	arm 1: Valganciclovir for up to 100 days post kidney transplant arm 2: Valganciclovir for up to 200 days post kidney transplant	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: 900 mg orally daily for up to 100 days intervention 2: 900 mg orally daily for up to 200 days	intervention 1: Valganciclovir intervention 2: Valganciclovir	80	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 San Diego \| California \| United States \| -117.16472 \| 32.71571 San Francisco \| California \| United States \| -122.41942 \| 37.77493 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 Minneapolis \| Minnesota \| United States \| -93.26384 \| 44.97997 Hackensack \| New Jersey \| United States \| -74.04347 \| 40.88593 Livingston \| New Jersey \| United States \| -74.31487 \| 40.79593 New Brunswick \| New Jersey \| United States \| -74.45182 \| 40.48622 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Seattle \| Washington \| United States \| -122.33207 \| 47.60621 Camperdown \| New South Wales \| Australia \| 151.17642 \| -33.88965 Clayton \| Victoria \| Australia \| 145.11667 \| -37.91667 Parkville \| Victoria \| Australia \| 144.95 \| -37.78333 Brussels \| N/A \| Belgium \| 4.34878 \| 50.85045 Ghent \| N/A \| Belgium \| 3.71667 \| 51.05 Leuven \| N/A \| Belgium \| 4.70093 \| 50.87959 Porto Alegre \| Rio Grande do Sul \| Brazil \| -51.23019 \| -30.03283 Porto Alegre \| Rio Grande do Sul \| Brazil \| -51.23019 \| -30.03283 Campinas \| São Paulo \| Brazil \| -47.06083 \| -22.90556 São Paulo \| São Paulo \| Brazil \| -46.63611 \| -23.5475 São Paulo \| São Paulo \| Brazil \| -46.63611 \| -23.5475 Edmonton \| Alberta \| Canada \| -113.46871 \| 53.55014 Hamilton \| Ontario \| Canada \| -79.84963 \| 43.25011 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Bordeaux \| N/A \| France \| -0.5805 \| 44.84044 Grenoble \| N/A \| France \| 5.71479 \| 45.17869 Montpellier \| N/A \| France \| 3.87635 \| 43.61093 Nantes \| N/A \| France \| -1.55336 \| 47.21725 Paris \| N/A \| France \| 2.3488 \| 48.85341 Strasbourg \| N/A \| France \| 7.74553 \| 48.58392 Toulouse \| N/A \| France \| 1.44367 \| 43.60426 Tours \| N/A \| France \| 0.70398 \| 47.39484 Vandœuvre-lès-Nancy \| N/A \| France \| 6.17114 \| 48.66115 Berlin \| N/A \| Germany \| 13.41053 \| 52.52437 Berlin \| N/A \| Germany \| 13.41053 \| 52.52437 Erlangen \| N/A \| Germany \| 11.00783 \| 49.59099 Frankfurt \| N/A \| Germany \| 10.53333 \| 49.68333 Hanover \| N/A \| Germany \| 9.73322 \| 52.37052 Lübeck \| N/A \| Germany \| 10.68729 \| 53.86893 Regensburg \| N/A \| Germany \| 12.10161 \| 49.01513 Bari \| Apulia \| Italy \| 16.86982 \| 41.12066 Rome \| Lazio \| Italy \| 12.51133 \| 41.89193 Milan \| Lombardy \| Italy \| 9.18951 \| 45.46427 Padua \| Veneto \| Italy \| 11.88586 \| 45.40797 Auckland \| N/A \| New Zealand \| 174.76349 \| -36.84853 Krakow \| N/A \| Poland \| 19.93658 \| 50.06143 Warsaw \| N/A \| Poland \| 21.01178 \| 52.22977 Wroclaw \| N/A \| Poland \| 17.03333 \| 51.1 Bucharest \| N/A \| Romania \| 26.10626 \| 44.43225 Cluj-Napoca \| N/A \| Romania \| 23.6 \| 46.76667 L'Hospitalet de Llobregat \| Barcelona \| Spain \| 2.10028 \| 41.35967 Barakaldo \| Vizcaya \| Spain \| -2.98813 \| 43.29639 Barcelona \| N/A \| Spain \| 2.15899 \| 41.38879 Madrid \| N/A \| Spain \| -3.70256 \| 40.4165 Madrid \| N/A \| Spain \| -3.70256 \| 40.4165 Valencia \| N/A \| Spain \| -0.37966 \| 39.47391 Antrim \| N/A \| United Kingdom \| -6.211 \| 54.7175 Birmingham \| N/A \| United Kingdom \| -1.89983 \| 52.48142 Bristol \| N/A \| United Kingdom \| -2.59665 \| 51.45523 Glasgow \| N/A \| United Kingdom \| -4.25763 \| 55.86515 Liverpool \| N/A \| United Kingdom \| -2.97794 \| 53.41058 London \| N/A \| United Kingdom \| -0.12574 \| 51.50853 Manchester \| N/A \| United Kingdom \| -2.23743 \| 53.48095 Newcastle upon Tyne \| N/A \| United Kingdom \| -1.61396 \| 54.97328 Nottingham \| N/A \| United Kingdom \| -1.15047 \| 52.9536 Oxford \| N/A \| United Kingdom \| -1.25596 \| 51.75222	320	1	0.003125	1	NCT00294515	1COMPLETED	2009-08-31	2006-03-31	Hoffmann-La Roche	4INDUSTRY	false	false	false	null	0	0	0	0	1	0.000552
[ 3 ]	732	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	false	This is a study to evaluate the safety, efficacy, and tolerability of cariprazine (RGH-188) relative to placebo in adult patients (18-60 years of age) with acute exacerbation of schizophrenia.	null	Schizophrenia		null	5	arm 1: Participants received placebo orally once a day for 6 weeks. arm 2: Participants received cariprazine 1.5 mg orally once a day for 6 weeks. arm 3: Participants received cariprazine 3.0 mg orally once a day for 6 weeks. arm 4: Participants received cariprazine 4.5 mg orally once a day for 6 weeks. arm 5: Participants received risperidone 4.0 mg orally once a day for 6 weeks.	[ 2, 0, 0, 0, 1 ]	3	[ 0, 0, 0 ]	intervention 1: Placebo was supplied in capsules. intervention 2: Cariprazine was supplied in capsules intervention 3: Risperidone was supplied in capsules	intervention 1: Placebo intervention 2: Cariprazine intervention 3: Risperidone	65	Costa Mesa \| California \| United States \| -117.91867 \| 33.64113 Long Beach \| California \| United States \| -118.18923 \| 33.76696 Oceanside \| California \| United States \| -117.37948 \| 33.19587 Paramount \| California \| United States \| -118.15979 \| 33.88946 Riverside \| California \| United States \| -117.39616 \| 33.95335 Washington D.C. \| District of Columbia \| United States \| -77.03637 \| 38.89511 Bradenton \| Florida \| United States \| -82.57482 \| 27.49893 Kissimmee \| Florida \| United States \| -81.41667 \| 28.30468 Lake Charles \| Louisiana \| United States \| -93.2044 \| 30.21309 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Flowood \| Mississippi \| United States \| -90.13898 \| 32.30959 Bridgeton \| Missouri \| United States \| -90.41151 \| 38.767 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Charleston \| South Carolina \| United States \| -79.93275 \| 32.77632 Memphis \| Tennessee \| United States \| -90.04898 \| 35.14953 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Irving \| Texas \| United States \| -96.94889 \| 32.81402 Vijaywada \| ANDH PRAD \| India \| N/A \| N/A Visakhapatnam \| Andh Prad \| India \| 83.20161 \| 17.68009 Ahmedabad \| Gujarat \| India \| 72.58727 \| 23.02579 Ahmedabad \| Gujarat \| India \| 72.58727 \| 23.02579 Bangalore \| Karna \| India \| 77.59369 \| 12.97194 Bangalore \| Karna \| India \| 77.59369 \| 12.97194 Mangalore \| Karna \| India \| 74.85603 \| 12.91723 Mangalore \| Karna \| India \| 74.85603 \| 12.91723 Manipal \| Karna \| India \| 74.78333 \| 13.35 Mysore \| Karna \| India \| 76.63925 \| 12.29791 Pune \| Mahara \| India \| 73.85535 \| 18.51957 Jaipur \| Rajasthan \| India \| 75.78781 \| 26.91962 Chennai \| Tamil Nadu \| India \| 80.27847 \| 13.08784 Chennai \| Tamil Nadu \| India \| 80.27847 \| 13.08784 Tirupati \| Tamil Nadu \| India \| N/A \| N/A Kanpur \| Uttar Prad \| India \| 80.34975 \| 26.46523 Johor Bahru \| Johor \| Malaysia \| 103.7578 \| 1.4655 Kota Bharu \| Kelantan \| Malaysia \| 102.24333 \| 6.12361 Lembah Pantai \| Kuala Lumpur \| Malaysia \| N/A \| N/A Ipoh \| Perak \| Malaysia \| 101.0829 \| 4.5841 Ulu Kinta \| Perak \| Malaysia \| 101.21667 \| 4.66667 Arkhangelsk \| N/A \| Russia \| 40.55291 \| 64.54717 Gatchina \| N/A \| Russia \| 30.12833 \| 59.57639 Kazan' \| N/A \| Russia \| 49.12214 \| 55.78874 Moscow \| N/A \| Russia \| 37.61556 \| 55.75222 Moscow \| N/A \| Russia \| 37.61556 \| 55.75222 Moscow \| N/A \| Russia \| 37.61556 \| 55.75222 Nizhny Novgorod \| N/A \| Russia \| 44.00205 \| 56.32867 Saint Petersburg \| N/A \| Russia \| 30.31413 \| 59.93863 Saint Petersburg \| N/A \| Russia \| 30.31413 \| 59.93863 Saint Petersburg \| N/A \| Russia \| 30.31413 \| 59.93863 Saint Petersburg \| N/A \| Russia \| 30.31413 \| 59.93863 Saint Petersburg \| N/A \| Russia \| 30.31413 \| 59.93863 Saint Petersburg \| N/A \| Russia \| 30.31413 \| 59.93863 Saint Petersburg \| N/A \| Russia \| 30.31413 \| 59.93863 Samara \| N/A \| Russia \| 50.15 \| 53.20007 Dnipropetrovsk \| Dnipropetrovsk Oblast \| Ukraine \| 35.04066 \| 48.46664 Donetsk \| Donetsk Oblast \| Ukraine \| 37.80224 \| 48.023 Kharkiv \| Kharkivs’ka Oblast’ \| Ukraine \| 36.25475 \| 49.98177 Hlevakha \| Kyiv Oblast \| Ukraine \| 30.32706 \| 50.27423 Kyiv \| Kyiv Oblast \| Ukraine \| N/A \| N/A Kyiv \| Kyiv Oblast \| Ukraine \| N/A \| N/A Odesa \| Odesa Oblast \| Ukraine \| 30.74383 \| 46.48572 Ternopil \| Ternopil Oblast \| Ukraine \| 25.59067 \| 49.55404 Chernihiv \| N/A \| Ukraine \| 31.28656 \| 51.50541 Kherson, Vil. Stepanivka \| N/A \| Ukraine \| 32.61458 \| 46.63695 Kiev \| N/A \| Ukraine \| 30.5238 \| 50.45466	729	0	0	0	NCT00694707	1COMPLETED	2009-08-31	2008-06-30	Forest Laboratories	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3 ]	18	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	1FEMALE	true	ZPE-201 Extension of treatment	This is an extension of the phase II, three-arm, parallel design, dose-ranging, placebo-controlled, randomized, double-blind, multicenter study in which placebo or one (1) of two (2) dose levels of Proellex® was administered once-daily for four (4) months.	Endometriosis	Endometriosis Pelvic pain Oral progesterone blocker	null	1	arm 1: 25 mg Proellex®	[ 0 ]	1	[ 0 ]	intervention 1: one (1) 25 mg capsule daily	intervention 1: Proellex®	8	Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 San Diego \| California \| United States \| -117.16472 \| 32.71571 San Ramon \| California \| United States \| -121.97802 \| 37.77993 West Palm Beach \| Florida \| United States \| -80.05337 \| 26.71534 Cary \| North Carolina \| United States \| -78.78112 \| 35.79154 Miamisburg \| Ohio \| United States \| -84.28661 \| 39.64284 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412	18	0	0	0	NCT00958412	6TERMINATED	2009-08-31	2009-02-28	Repros Therapeutics Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3 ]	3,000	RANDOMIZED	PARALLEL	1PREVENTION	2DOUBLE	true	0ALL	true	This study will test the safety and efficacy of an investigational Human Immunodeficiency Virus (HIV) vaccine. Efficacy will be measured by either prevention of HIV infection or control of HIV viral load in subjects who become HIV infected. On September 18, 2007 the Protocol V520-023 DSMB (Data \& Safety Monitoring Board) reviewed data from a planned interim analysis. These data demonstrated that the investigational vaccine candidate was not effective, and all vaccinations in the study were halted. Participants were encouraged to continue to come to the clinic for scheduled visits and ongoing risk reduction counseling since the vaccine was not effective.	No further treatment was given in V520-023, however participants were followed. V520-023 protocol ended earlier than originally planned per protocol and participants (HIV infected and uninfected) had the option of participating in an observational long term follow up protocol called V520-030/HVTN 504, which served as an extension of V520-023 and would continue through the end of 2009.	AIDS HIV Infections		null	2	arm 1: Participants randomized to receive three 1.0-ml intramuscular (IM) injections of Merck Trivalent Adenovirus Serotype 5 HIV-1 gag/pol/nef (MRKAd5 HIV-1 gag/pol/nef) Vaccine at a dose of 1.5x10\^10 adenovirus genomes (Ad vg) per dose at Day 1, Week 4, and Week 26. arm 2: Participants randomized to receive three 1.0-ml intramuscular (IM) injections of placebo to MRKAd5 HIV-1 gag/pol/nef at Day 1, Week 4, and Week 26.	[ 0, 2 ]	2	[ 2, 0 ]	intervention 1: Trivalent MRKAd5 HIV-1 gag/pol/nef (1.5x10\^10 adenovirus genomes \[ad-vg\]/dose). This dose is equivalent to 3x10\^10 vp/dose used in study V520-016. intervention 2: Placebo to Trivalent MRKAd5 HIV-1 gag/pol/nef in three 1 mL doses at Day 1, Week 4, and Week 26 administered intramuscularly.	intervention 1: Trivalent MRKAd5 HIV-1 gag/pol/nef (1.5x10^10 ad-vg/dose) intervention 2: Comparator: placebo	0	null	2,979	1	0.000336	0	NCT00095576	6TERMINATED	2009-09-01	2004-11-01	Merck Sharp & Dohme LLC	4INDUSTRY	false	false	false	null	0	0	0	0	1	0.000059
[ 4 ]	382	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	true	In the proposed study 450 veterans with a primary diagnosis of schizophrenia who had at least one psychiatric hospitalization for schizophrenia in the previous 2 years would be randomly assigned at 16 VA medical centers to long-acting injectable risperidone or doctor's choice of oral antipsychotic medication (i.e., excluding other long-acting injectable medications, but not specifying any particular oral agents or dosages). Recruitment would take 27 months to complete, and the study would continue for a third year to allow 9 months of follow-up for the last patient recruited. All patients would be treated from the time of entry up to the end of the three-year study period. Follow-up assessments would continue quarterly. Treatments would not be blinded since giving placebo injections to the comparison group would interfere with the goal of comparing the acceptability of two different methods of medication administration. However, end points will be blindly rated.	The purpose of the study is to assess the effectiveness of long-acting injectable risperidone on psychiatric inpatient hospitalization, schizophrenia symptoms, quality of life, medication adherence, side effects, and health care costs. Objectives: Primary: To evaluate the impact of long-acting intramuscular (IM) risperidone on risk of inpatient psychiatric hospitalization in comparison to standard oral antipsychotic treatment in a randomized controlled trial to be conducted with 450 veterans diagnosed with schizophrenia or schizoaffective disorder at 16 VA medical centers over three years. Secondary: To evaluate adherence, health benefits, and costs of long-acting IM risperidone as compared to standard oral antipsychotic treatment as measured by: a) symptom reduction over 12 months, b) time to all-cause medication discontinuation, c) quality of life, d) VA and non-VA health service use and related costs, e) medication side effects, f) violent behavior, g) use of concomitant medication, and h) the incremental cost-effectiveness ratio.	Schizoaffective Disorder Schizophrenia		null	2	arm 1: long-acting injectable risperidone arm 2: oral antipsychotic medication	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: long-acting injectable risperidone intervention 2: doctor's choice (excluding other long-acting injectable medications but not specifying any particular oral agents or dosages)	intervention 1: IM risperidone intervention 2: oral antipsychotic medication	19	Tuscaloosa \| Alabama \| United States \| -87.56917 \| 33.20984 Long Beach \| California \| United States \| -118.18923 \| 33.76696 Palo Alto \| California \| United States \| -122.14302 \| 37.44188 West Haven \| Connecticut \| United States \| -72.94705 \| 41.27065 Miami \| Florida \| United States \| -80.19366 \| 25.77427 Augusta \| Georgia \| United States \| -81.97484 \| 33.47097 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Detroit \| Michigan \| United States \| -83.04575 \| 42.33143 Minneapolis \| Minnesota \| United States \| -93.26384 \| 44.97997 Kansas City \| Missouri \| United States \| -94.57857 \| 39.09973 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 Albuquerque \| New Mexico \| United States \| -106.65114 \| 35.08449 New York \| New York \| United States \| -74.00597 \| 40.71427 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Waco \| Texas \| United States \| -97.14667 \| 31.54933 Seattle \| Washington \| United States \| -122.33207 \| 47.60621	369	1	0.00271	1	NCT00132314	1COMPLETED	2009-09-01	2006-09-01	US Department of Veterans Affairs	1FED	false	false	false	null	1	0	0	0	0	0.000479
[ 3 ]	524	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	null	This study was conducted to assess the safety and tolerability of Abatacept combined with Methotrexate in participants with active rheumatoid arthritis (RA). The secondary objectives were to assess efficacy, pharmacodynamic marker activity, and immunogenicity of Abatacept combined with Methotrexate.	All participants who completed the 12-month double-blind study period were eligible to continue in the open-label study. Participants received placebo, Abatacept 2 mg/kg, or Abatacept 10 mg/kg in the double-blind study. Participants receiving placebo in the double-blind study were switched 1:1 to continued treatment with placebo or Abatacept 2 mg/kg. Participants receiving Abatacept 2 mg/kg or Abatacept 10 mg/kg continued at the double-blind study dosage. After results from the double-blind period became available, all participants were switched to a weight-tiered 10 mg/kg dose of Abatacept. Open label study design: Single group assignment, Single arm, Open label,	Rheumatoid Arthritis		null	4	arm 1: None arm 2: None arm 3: None arm 4: None	[ 0, 0, 0, 0 ]	4	[ 0, 0, 0, 0 ]	intervention 1: IV, 10 mg/Kg, monthly, for the duration of the trial intervention 2: Intravenous (IV) infusion, 2 mg/kg, infused intravenously for approximately 30 min, infusions on Days 1, 15, 30 and monthly thereafter for 12 months intervention 3: Intravenous (IV) infusion, 10 mg/kg, infused intravenously for approximately 30 min, infusions on Days 1, 15, 30 and monthly thereafter for 12 months intervention 4: Intravenous (IV) infusion, 0 mg/kg, infused intravenously for approximately 30 min, infusions on Days 1, 15, 30 and monthly thereafter for 12 months	intervention 1: Abatacept (BMS-188667) intervention 2: Abatacept (BMS-188667) intervention 3: Abatacept (BMS-188667) intervention 4: Placebo	57	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Huntsville \| Alabama \| United States \| -86.58594 \| 34.7304 Long Beach \| California \| United States \| -118.18923 \| 33.76696 Highlands Ranch \| Colorado \| United States \| -104.96943 \| 39.55388 Largo \| Florida \| United States \| -82.78842 \| 27.90979 Titusville \| Florida \| United States \| -80.80755 \| 28.61222 West Palm Beach \| Florida \| United States \| -80.05337 \| 26.71534 Rome \| Georgia \| United States \| -85.16467 \| 34.25704 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Wichita \| Kansas \| United States \| -97.33754 \| 37.69224 Cumberland \| Maryland \| United States \| -78.76252 \| 39.65287 Springfield \| Massachusetts \| United States \| -72.58981 \| 42.10148 Worcester \| Massachusetts \| United States \| -71.80229 \| 42.26259 Duluth \| Minnesota \| United States \| -92.10658 \| 46.78327 Lincoln \| Nebraska \| United States \| -96.66696 \| 40.8 Albuquerque \| New Mexico \| United States \| -106.65114 \| 35.08449 Los Alamos \| New Mexico \| United States \| -106.30697 \| 35.88808 Albany \| New York \| United States \| -73.75623 \| 42.65258 Binghamton \| New York \| United States \| -75.91797 \| 42.09869 The Bronx \| New York \| United States \| -73.86641 \| 40.84985 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Duncansville \| Pennsylvania \| United States \| -78.4339 \| 40.42341 Sellersville \| Pennsylvania \| United States \| -75.3049 \| 40.35399 Amarillo \| Texas \| United States \| -101.8313 \| 35.222 Austin \| Texas \| United States \| -97.74306 \| 30.26715 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Buenos Aries \| Buenos Aries \| Argentina \| N/A \| N/A Quilmes \| Burenos Aires \| Argentina \| -58.25454 \| -34.72065 Adelaide \| South Australia \| Australia \| 138.59863 \| -34.92866 Malvern \| Victoria \| Australia \| 145.02811 \| -37.86259 Perth \| Western Australia \| Australia \| 115.8614 \| -31.95224 Antwerp \| N/A \| Belgium \| 4.40026 \| 51.22047 Brussels \| N/A \| Belgium \| 4.34878 \| 50.85045 Ghent \| N/A \| Belgium \| 3.71667 \| 51.05 Leuven \| N/A \| Belgium \| 4.70093 \| 50.87959 Mons \| N/A \| Belgium \| 3.95229 \| 50.45413 Edmonton \| Alberta \| Canada \| -113.46871 \| 53.55014 Ottawa \| Ontario \| Canada \| -75.69812 \| 45.41117 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Sherbrooke \| Quebec \| Canada \| -71.89908 \| 45.40008 Ste-Foy \| Quebec \| Canada \| N/A \| N/A St. John's \| N/A \| Canada \| -52.70931 \| 47.56494 Montpellier \| Cedex \| France \| 3.87635 \| 43.61093 Strasbourg \| Cedex \| France \| 7.74553 \| 48.58392 Paris \| N/A \| France \| 2.3488 \| 48.85341 Berlin \| N/A \| Germany \| 13.41053 \| 52.52437 Freiburg im Breisgau \| N/A \| Germany \| 7.85222 \| 47.9959 Jena \| N/A \| Germany \| 11.5899 \| 50.92878 Cork \| Cork \| Ireland \| -8.47061 \| 51.89797 Nijmegen \| N/A \| Netherlands \| 5.85278 \| 51.8425 Muckleneuk \| Gauteng \| South Africa \| N/A \| N/A Cape Town \| Western Cape \| South Africa \| 18.42322 \| -33.92584 Cambridge \| Cambridgeshire \| United Kingdom \| 0.11667 \| 52.2 Manchester \| Greater Manchester \| United Kingdom \| -2.23743 \| 53.48095 Maidstone \| Kent \| United Kingdom \| 0.51667 \| 51.26667 Leeds \| Yorkshire \| United Kingdom \| -1.54785 \| 53.79648	558	1	0.001792	1	NCT00162266	1COMPLETED	2009-09-01	2000-10-01	Bristol-Myers Squibb	4INDUSTRY	false	false	false	null	0	0	0	0	1	0.000316
[ 4 ]	524	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	To compare the health outcome of patients with schizophrenia, who are at risk for relapse, when treated with a long acting injection form of olanzapine versus treatment with oral olanzapine.	null	Schizophrenia		null	2	arm 1: Olanzapine pamoate depot arm 2: Oral olanzapine	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: 10 milligrams (mg), oral tablets, once daily for 4 weeks followed by 5-20 mg flexible dosing, oral tablets, once daily, for 100 weeks, for a total treatment duration of 104 weeks. intervention 2: 405 milligrams (mg), intramuscular injection, followed 4 weeks later by 150-405 mg flexible dosing, intramuscular injection, every 4 weeks thereafter for 96 weeks, for a total treatment duration of 104 weeks.	intervention 1: olanzapine intervention 2: olanzapine pamoate depot	49	Escondido \| California \| United States \| -117.08642 \| 33.11921 National City \| California \| United States \| -117.0992 \| 32.67811 Orange \| California \| United States \| -117.85311 \| 33.78779 San Diego \| California \| United States \| -117.16472 \| 32.71571 Washington D.C. \| District of Columbia \| United States \| -77.03637 \| 38.89511 Honolulu \| Hawaii \| United States \| -157.85833 \| 21.30694 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Cedarhurst \| New York \| United States \| -73.7243 \| 40.62288 Staten Island \| New York \| United States \| -74.13986 \| 40.56233 Canton \| Ohio \| United States \| -81.37845 \| 40.79895 Allentown \| Pennsylvania \| United States \| -75.49018 \| 40.60843 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 West Chester \| Pennsylvania \| United States \| -75.60804 \| 39.96097 Banfield \| N/A \| Argentina \| -58.39365 \| -34.74563 Buenos Aires \| N/A \| Argentina \| -58.37723 \| -34.61315 Mendoza \| N/A \| Argentina \| -68.84582 \| -32.88946 Pelotas \| N/A \| Brazil \| -52.34101 \| -31.76997 Rio de Janeiro \| N/A \| Brazil \| -43.18223 \| -22.90642 São Paulo \| N/A \| Brazil \| -46.63611 \| -23.5475 Calgary \| Alberta \| Canada \| -114.08529 \| 51.05011 Winnipeg \| Manitoba \| Canada \| -97.14704 \| 49.8844 Burlington \| Ontario \| Canada \| -79.83713 \| 43.38621 Chatham \| Ontario \| Canada \| -82.18494 \| 42.41224 Greater Sudbury \| Ontario \| Canada \| -80.99001 \| 46.49 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Dijon \| N/A \| France \| 5.01667 \| 47.31667 Dole \| N/A \| France \| 5.48966 \| 47.09225 La Seyne-sur-Mer \| N/A \| France \| 5.87816 \| 43.10322 Limoges \| N/A \| France \| 1.24759 \| 45.83362 Strasbourg \| N/A \| France \| 7.74553 \| 48.58392 Toulon \| N/A \| France \| 5.92836 \| 43.12442 Chaïdári \| N/A \| Greece \| 23.66597 \| 38.01135 Haidari, Athens \| N/A \| Greece \| 23.72784 \| 37.98376 Thessaloniki \| N/A \| Greece \| 22.93086 \| 40.64361 Tripoli \| N/A \| Greece \| 22.37944 \| 37.50889 Lisbon \| N/A \| Portugal \| -9.1498 \| 38.72509 Cabo Rojo \| N/A \| Puerto Rico \| -67.14573 \| 18.08663 Caguas \| N/A \| Puerto Rico \| -66.0485 \| 18.23412 Mayagüez \| N/A \| Puerto Rico \| -67.13962 \| 18.20107 Rio Piedras \| N/A \| Puerto Rico \| -66.04989 \| 18.39745 Bucharest \| N/A \| Romania \| 26.10626 \| 44.43225 Iași \| N/A \| Romania \| 27.6 \| 47.16667 Târgu Mureş \| N/A \| Romania \| 24.55747 \| 46.54245 Bratislava \| N/A \| Slovakia \| 17.10674 \| 48.14816 Alzira \| N/A \| Spain \| -0.43333 \| 39.15 Barcelona \| N/A \| Spain \| 2.15899 \| 41.38879 Hua-Lian County \| N/A \| Taiwan \| N/A \| N/A Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306 Taoyuan \| N/A \| Taiwan \| 121.29696 \| 24.99368	524	2	0.003817	1	NCT00320489	1COMPLETED	2009-09-01	2006-04-01	Eli Lilly and Company	4INDUSTRY	false	false	false	null	1	0	1	0	0	0.001047
[ 4 ]	25,086	RANDOMIZED	FACTORIAL	0TREATMENT	4QUADRUPLE	false	0ALL	true	The purpose of this study is to evaluate whether a higher dosage of clopidogrel with aspirin (two doses) will decrease the risk of ischemic complications (cardiac death (CV death), myocardial infarction (MI), stroke) after a percutaneous coronary intervention (PCI).	null	Acute Coronary Disease Angina Unstable	platelet aggregation inhibitors acute coronary disease percutaneous coronary	null	4	arm 1: None arm 2: None arm 3: None arm 4: None	[ 0, 0, 1, 1 ]	2	[ 0, 0 ]	intervention 1: oral administration intervention 2: oral administration	intervention 1: Clopidogrel intervention 2: acetylsalicyclic acid (ASA)	38	Bridgewater \| New Jersey \| United States \| -74.64815 \| 40.60079 Buenos Aires \| N/A \| Argentina \| -58.37723 \| -34.61315 Macquarie Park \| N/A \| Australia \| 151.12757 \| -33.78105 Vienna \| N/A \| Austria \| 16.37208 \| 48.20849 Diegem \| N/A \| Belgium \| 4.43354 \| 50.89727 São Paulo \| N/A \| Brazil \| -46.63611 \| -23.5475 Sofia \| N/A \| Bulgaria \| 23.32415 \| 42.69751 Laval \| N/A \| Canada \| -73.692 \| 45.56995 Santiago \| N/A \| Chile \| -70.64827 \| -33.45694 Beijing \| N/A \| China \| 116.39723 \| 39.9075 Zagreb \| N/A \| Croatia \| 15.97798 \| 45.81444 Prague \| N/A \| Czechia \| 14.42076 \| 50.08804 Tallinn \| N/A \| Estonia \| 24.75353 \| 59.43696 Helsinki \| N/A \| Finland \| 24.93545 \| 60.16952 Paris \| N/A \| France \| 2.3488 \| 48.85341 Berlin \| N/A \| Germany \| 13.41053 \| 52.52437 Athens \| N/A \| Greece \| 23.72784 \| 37.98376 Mumbai \| N/A \| India \| 72.88261 \| 19.07283 Dublin \| N/A \| Ireland \| -6.24889 \| 53.33306 Netanya \| N/A \| Israel \| 34.85992 \| 32.33291 Milan \| N/A \| Italy \| 12.59836 \| 42.78235 Riga \| N/A \| Latvia \| 24.10589 \| 56.946 Vilnius \| N/A \| Lithuania \| 25.2798 \| 54.68916 Kuala Lumpur \| N/A \| Malaysia \| 101.68653 \| 3.1412 Mexico \| N/A \| Mexico \| -98.43784 \| 18.88011 Gouda \| N/A \| Netherlands \| 4.70833 \| 52.01667 Warsaw \| N/A \| Poland \| 21.01178 \| 52.22977 Bucharest \| N/A \| Romania \| 26.10626 \| 44.43225 Moscow \| N/A \| Russia \| 37.61556 \| 55.75222 Singapore \| N/A \| Singapore \| 103.85007 \| 1.28967 Brastislava \| N/A \| Slovakia \| N/A \| N/A Midrand \| N/A \| South Africa \| 28.118 \| -25.976 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Madrid \| N/A \| Spain \| -3.70256 \| 40.4165 Bromma \| N/A \| Sweden \| 17.94 \| 59.34 Geneva \| N/A \| Switzerland \| 6.14569 \| 46.20222 Istanbul \| N/A \| Turkey (Türkiye) \| 28.94966 \| 41.01384 Guildford \| Surrey \| United Kingdom \| -0.57427 \| 51.23536	25,086	1	0.00004	0	NCT00335452	1COMPLETED	2009-09-01	2006-06-01	Sanofi	4INDUSTRY	false	false	false	null	0	0	0	0	1	0.000007
[ 4 ]	755	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	2MALE	null	This is a randomized, open-label, multi-center study comparing the safety and efficacy of XRP6258 plus prednisone to mitoxantrone plus prednisone in the treatment of hormone refractory metastatic prostate cancer previously treated with a Taxotere®-containing regimen. The primary objective is overall survival. Secondary objectives include progression free survival, overall response rate, prostate-specific antigen (PSA) response/progression, pain response/progression, overall safety, and pharmacokinetics. Patients will be treated until disease progression, death, unacceptable toxicity, or for a maximum of 10 cycles. Patients will have long-term follow-up for a maximum of up to 2 years.	null	Neoplasms Prostatic Neoplasms	Cancer Prostate	null	2	arm 1: Mitoxantrone + Prednisone arm 2: Cabazitaxel + Prednisone	[ 1, 0 ]	3	[ 0, 0, 0 ]	intervention 1: 25 mg/m\^2 administered by intravenous (IV) route over 1 hour on day 1 of each 21-day cycle intervention 2: 12 mg/m\^2 administered by intravenous (IV) route over 15-30 minutes on day 1 of each 21-day cycle intervention 3: 10 mg daily administered by oral route	intervention 1: cabazitaxel (XRP6258) (RPR116258) intervention 2: mitoxantrone intervention 3: prednisone	26	Bridgewater \| New Jersey \| United States \| -74.64815 \| 40.60079 Buenos Aires \| N/A \| Argentina \| -58.37723 \| -34.61315 Diegem \| N/A \| Belgium \| 4.43354 \| 50.89727 São Paulo \| N/A \| Brazil \| -46.63611 \| -23.5475 Laval \| Quebec \| Canada \| -73.692 \| 45.56995 Santiago \| N/A \| Chile \| -70.64827 \| -33.45694 Prague \| N/A \| Czechia \| 14.42076 \| 50.08804 Hørsholm \| N/A \| Denmark \| 12.50111 \| 55.88098 Helsinki \| N/A \| Finland \| 24.93545 \| 60.16952 Paris \| N/A \| France \| 2.3488 \| 48.85341 Berlin \| N/A \| Germany \| 13.41053 \| 52.52437 Budapest \| N/A \| Hungary \| 19.04045 \| 47.49835 Mumbai \| N/A \| India \| 72.88261 \| 19.07283 Milan \| N/A \| Italy \| 12.59836 \| 42.78235 Mexico \| N/A \| Mexico \| -98.43784 \| 18.88011 Gouda \| N/A \| Netherlands \| 4.70833 \| 52.01667 Moscow \| N/A \| Russia \| 37.61556 \| 55.75222 Singapore \| N/A \| Singapore \| 103.85007 \| 1.28967 Bratislava \| N/A \| Slovakia \| 17.10674 \| 48.14816 Midrand \| N/A \| South Africa \| 28.118 \| -25.976 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Barcelona \| N/A \| Spain \| 2.15899 \| 41.38879 Bromma \| N/A \| Sweden \| 17.94 \| 59.34 Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306 Istanbul \| N/A \| Turkey (Türkiye) \| 28.94966 \| 41.01384 Guildford \| Surrey \| United Kingdom \| -0.57427 \| 51.23536	742	1	0.001348	1	NCT00417079	1COMPLETED	2009-09-01	2007-01-01	Sanofi	4INDUSTRY	false	false	false	null	1	0	0	0	0	0.000238
[ 4 ]	5,407	RANDOMIZED	PARALLEL	1PREVENTION	2DOUBLE	false	0ALL	true	The purpose of this study is to learn whether apixaban can prevent the blood clots in the leg (deep vein thrombosis) and lung (pulmonary embolism) that sometimes occur after hip replacement surgery and to learn how apixaban compares with enoxaparin in preventing these clots. The safety of apixaban will also be studied	null	Deep Vein Thrombosis Pulmonary Embolism	Prevention of deep vein thrombosis and pulmonary embolism after total hip replacement surgery	null	2	arm 1: Participants received apixaban, 2.5 mg twice daily (BID), as oral tablets, and matching enoxaparin-placebo injection once daily (QD) arm 2: Participants received enoxaparin, 40 mg QD subcutaneously, and matching apixaban-placebo tablets BID	[ 1, 0 ]	4	[ 0, 0, 0, 0 ]	intervention 1: Subcutaneous, 40 mg, once daily, 5 weeks intervention 2: Oral tablets, 2.5 mg, twice daily, 5weeks intervention 3: Administered as injection intervention 4: Administered as oral tablets	intervention 1: Enoxaparin intervention 2: Apixaban intervention 3: Enoxaparin-matching placebo intervention 4: Apixaban-matching placebo	143	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 Sacramento \| California \| United States \| -121.4944 \| 38.58157 Aurora \| Colorado \| United States \| -104.83192 \| 39.72943 Denver \| Colorado \| United States \| -104.9847 \| 39.73915 Denver \| Colorado \| United States \| -104.9847 \| 39.73915 Brandon \| Florida \| United States \| -82.28592 \| 27.9378 Clearwater \| Florida \| United States \| -82.8001 \| 27.96585 Fort Lauderdale \| Florida \| United States \| -80.14338 \| 26.12231 Tamarac \| Florida \| United States \| -80.24977 \| 26.21286 Decatur \| Georgia \| United States \| -84.29631 \| 33.77483 Boise \| Idaho \| United States \| -116.20345 \| 43.6135 Meridian \| Idaho \| United States \| -116.39151 \| 43.61211 Altoona \| Pennsylvania \| United States \| -78.39474 \| 40.51868 Lubbock \| Texas \| United States \| -101.85517 \| 33.57786 Lubbock \| Texas \| United States \| -101.85517 \| 33.57786 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Capital Federal \| Buenos Aires \| Argentina \| N/A \| N/A Capital Federal \| Buenos Aires \| Argentina \| N/A \| N/A Capital Federal \| Buenos Aires \| Argentina \| N/A \| N/A Ciudad de Buenos Aires \| Buenos Aires \| Argentina \| N/A \| N/A Coronel Suárez \| Buenos Aires \| Argentina \| -61.93294 \| -37.45859 Monte Grande \| Buenos Aires \| Argentina \| -58.46592 \| -34.8194 Camperdown \| New South Wales \| Australia \| 151.17642 \| -33.88965 Kogarah \| New South Wales \| Australia \| 151.13564 \| -33.9681 Lismore \| New South Wales \| Australia \| 153.2773 \| -28.81354 Southport \| Queensland \| Australia \| 153.39796 \| -27.96724 Bedford Park \| South Australia \| Australia \| 138.56815 \| -35.02204 Box Hill \| Victoria \| Australia \| 145.12545 \| -37.81887 Malvern \| Victoria \| Australia \| 145.02811 \| -37.86259 Windsor \| Victoria \| Australia \| 144.99241 \| -37.85344 Perth \| Western Australia \| Australia \| 115.8614 \| -31.95224 Antwerp \| N/A \| Belgium \| 4.40026 \| 51.22047 Brasschaat \| N/A \| Belgium \| 4.49182 \| 51.2912 Genk \| N/A \| Belgium \| 5.50082 \| 50.965 Hasselt \| N/A \| Belgium \| 5.33781 \| 50.93106 Leuven \| N/A \| Belgium \| 4.70093 \| 50.87959 Edmonton \| Alberta \| Canada \| -113.46871 \| 53.55014 Ajax \| Ontario \| Canada \| -79.03288 \| 43.85012 Cambridge \| Ontario \| Canada \| -80.31269 \| 43.3601 Chatham \| Ontario \| Canada \| -82.18494 \| 42.41224 Guelph \| Ontario \| Canada \| -80.25599 \| 43.54594 Newmarket \| Ontario \| Canada \| -79.46631 \| 44.05011 Oshawa \| Ontario \| Canada \| -78.84957 \| 43.90012 Sarnia \| Ontario \| Canada \| -82.40407 \| 42.97866 Scarborough Village \| Ontario \| Canada \| -79.22124 \| 43.73899 St. Catharines \| Ontario \| Canada \| -79.24267 \| 43.17126 Stratford \| Ontario \| Canada \| -80.94972 \| 43.36679 Waterloo \| Ontario \| Canada \| -80.51639 \| 43.4668 Windsor \| Ontario \| Canada \| -83.01654 \| 42.30008 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Québec \| Quebec \| Canada \| -71.21454 \| 46.81228 Beijing \| Beijing Municipality \| China \| 116.39723 \| 39.9075 Beijing \| Beijing Municipality \| China \| 116.39723 \| 39.9075 Guangzhou \| Guangdong \| China \| 113.25 \| 23.11667 Qingdao \| Shandong \| China \| 120.38042 \| 36.06488 Shanghai \| Shanghai Municipality \| China \| 121.45806 \| 31.22222 Shanghai \| Shanghai Municipality \| China \| 121.45806 \| 31.22222 Shanghai \| Shanghai Municipality \| China \| 121.45806 \| 31.22222 Amager \| N/A \| Denmark \| 12.59033 \| 55.61404 Frederiksberg \| N/A \| Denmark \| 12.53463 \| 55.67938 Herlev \| N/A \| Denmark \| 12.43998 \| 55.72366 Hvidovre \| N/A \| Denmark \| 12.47708 \| 55.64297 Hørsholm \| N/A \| Denmark \| 12.50111 \| 55.88098 København NV \| N/A \| Denmark \| 12.52343 \| 55.71258 Silkeborg \| N/A \| Denmark \| 9.54508 \| 56.1697 Nice \| N/A \| France \| 7.26608 \| 43.70313 Paris \| N/A \| France \| 2.3488 \| 48.85341 Paris \| N/A \| France \| 2.3488 \| 48.85341 Paris \| N/A \| France \| 2.3488 \| 48.85341 Saint-Etienne \| N/A \| France \| 4.39 \| 45.43389 Saint-Saulve \| N/A \| France \| 3.55612 \| 50.37141 Frankfurt \| N/A \| Germany \| 10.53333 \| 49.68333 Frankfurt am Main \| N/A \| Germany \| 8.68417 \| 50.11552 Rheinfelden \| N/A \| Germany \| 7.78715 \| 47.56013 Budapest \| N/A \| Hungary \| 19.04045 \| 47.49835 Kecskemét \| N/A \| Hungary \| 19.69128 \| 46.90618 Szeged \| N/A \| Hungary \| 20.14824 \| 46.253 Szolnok \| N/A \| Hungary \| 20.2 \| 47.18333 Ahmedabad \| Gujarat \| India \| 72.58727 \| 23.02579 Ludhiana \| Punjab \| India \| 75.85379 \| 30.91204 Lucknow \| Uttar Prsdesh \| India \| 80.92313 \| 26.83928 Bangalore \| N/A \| India \| 77.59369 \| 12.97194 Mangalore \| N/A \| India \| 74.85603 \| 12.91723 Beersheba \| N/A \| Israel \| 34.7913 \| 31.25181 Haifa \| N/A \| Israel \| 34.99928 \| 32.81303 Holon \| N/A \| Israel \| 34.77918 \| 32.01034 Kfar Saba \| N/A \| Israel \| 34.90694 \| 32.175 Ẕerifin \| N/A \| Israel \| 34.84852 \| 31.95731 Aguascalientes \| Aguascalientes \| Mexico \| -102.2843 \| 21.88262 Chihuahua City \| Chihuahua \| Mexico \| -106.08889 \| 28.63528 Tijuana \| Estado de Baja California \| Mexico \| -117.00371 \| 32.5027 Guadalajara \| Jalisco \| Mexico \| -103.34749 \| 20.67738 Mexico City \| Mexico City \| Mexico \| -99.12766 \| 19.42847 Mexico City \| Mexico City \| Mexico \| -99.12766 \| 19.42847 Monterrey \| Nuevo León \| Mexico \| -100.31721 \| 25.68435 Ciudad Madero \| Tamaulipas \| Mexico \| -97.83665 \| 22.2475 Gjettum \| N/A \| Norway \| 10.52911 \| 59.90607 Kongsvinger \| N/A \| Norway \| 11.99772 \| 60.19049 Lillehammer \| N/A \| Norway \| 10.46628 \| 61.11514 Tynset \| N/A \| Norway \| 10.78241 \| 62.27594 Tønsberg \| N/A \| Norway \| 10.40762 \| 59.26754 Gdansk \| N/A \| Poland \| 18.64912 \| 54.35227 Lodz \| N/A \| Poland \| 19.47395 \| 51.77058 Szczecin \| N/A \| Poland \| 14.55302 \| 53.42894 Warsaw \| N/A \| Poland \| 21.01178 \| 52.22977 Warsaw \| N/A \| Poland \| 21.01178 \| 52.22977 Wroclaw \| N/A \| Poland \| 17.03333 \| 51.1 Bucharest \| N/A \| Romania \| 26.10626 \| 44.43225 Cluj-Napoca \| N/A \| Romania \| 23.6 \| 46.76667 Chelyabinsk \| N/A \| Russia \| 61.42915 \| 55.15402 Kazan' \| N/A \| Russia \| 49.12214 \| 55.78874 Moscow \| N/A \| Russia \| 37.61556 \| 55.75222 Moscow \| N/A \| Russia \| 37.61556 \| 55.75222 Moscow \| N/A \| Russia \| 37.61556 \| 55.75222 Moscow \| N/A \| Russia \| 37.61556 \| 55.75222 Saint Petersburg \| N/A \| Russia \| 30.31413 \| 59.93863 Saint Petersburg \| N/A \| Russia \| 30.31413 \| 59.93863 Saint Petersburg \| N/A \| Russia \| 30.31413 \| 59.93863 Saint Petersburg \| N/A \| Russia \| 30.31413 \| 59.93863 Saint Petersburg \| N/A \| Russia \| 30.31413 \| 59.93863 Saint Petersburg \| N/A \| Russia \| 30.31413 \| 59.93863 Samara \| N/A \| Russia \| 50.15 \| 53.20007 Yaroslavl \| N/A \| Russia \| 39.87368 \| 57.62987 Badalona-Barcelone \| N/A \| Spain \| N/A \| N/A Barcelona \| N/A \| Spain \| 2.15899 \| 41.38879 Barcelona \| N/A \| Spain \| 2.15899 \| 41.38879 Barcelona \| N/A \| Spain \| 2.15899 \| 41.38879 Barcelona \| N/A \| Spain \| 2.15899 \| 41.38879 Gothenburg \| N/A \| Sweden \| 11.96679 \| 57.70716 Stockholm \| N/A \| Sweden \| 18.06871 \| 59.32938 Cherkassy \| N/A \| Ukraine \| 32.05738 \| 49.44452 Chernivtsy \| N/A \| Ukraine \| N/A \| N/A Dnipropetrovsk \| N/A \| Ukraine \| 35.04066 \| 48.46664 Ivano-Frankivsk \| N/A \| Ukraine \| 24.71248 \| 48.92312 Kyiv \| N/A \| Ukraine \| 30.5238 \| 50.45466 Kyiv \| N/A \| Ukraine \| 30.5238 \| 50.45466 Sevastopol \| N/A \| Ukraine \| 33.52134 \| 44.60795 London \| Greater London \| United Kingdom \| -0.12574 \| 51.50853 Wigan \| Lancashire \| United Kingdom \| -2.63706 \| 53.54296 Epsom \| Surrey \| United Kingdom \| -0.27011 \| 51.3305	5,332	11	0.002063	1	NCT00423319	1COMPLETED	2009-09-01	2007-03-01	Bristol-Myers Squibb	4INDUSTRY	false	false	false	null	0	1	0	0	10	0.001152
[ 4 ]	129	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	null	To evaluate the tolerability of a new formulation of rebif and Betaseron in subjects with relapsing-remitting multiple sclerosis (RRMS) by comparing the mean change in injection site pain scores from pre-injection to 30 minutes post therapy administration.	null	Relapsing Remitting Multiple Sclerosis (RRMS)		null	2	arm 1: interferon beta-1a arm 2: interferon beta-1b	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: New Formulation of rebif- 44 mcg, SC (sub-cutaneous) thrice weekly (tiw) injection. intervention 2: Betaseron - 250 mcg, SC (sub-cutaneous) every other day injection.	intervention 1: New Formulation of rebif - human interferon beta-1a intervention 2: Interferon beta -1b	1	Rockland \| Massachusetts \| United States \| -70.91616 \| 42.13066	129	2	0.015504	1	NCT00428584	1COMPLETED	2009-09-01	2006-12-01	EMD Serono	4INDUSTRY	false	false	false	null	2	0	0	0	0	0.004262
[ 5 ]	201	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	null	The primary objective of this study is to evaluate efficacy, arterial stiffness measured by Pulse Wave Velocity (PWV) of Losartan potassium group compared to Carvedilol group after 24 weeks of treatment in patients with the essential hypertension.	null	Hypertension		null	2	arm 1: Losartan or Losartan/HCTZ arm 2: Carvedilol or Carvedilol/HCTZ	[ 0, 1 ]	4	[ 0, 0, 0, 0 ]	intervention 1: Once daily , Cozaar® (losartan) 50 mg, Cozaar® (losartan) 100 mg, Cozaar Plus®-pro Tab. (losartan 100 mg/ hydrochlorothiazide 12.5 mg) or Cozaar Plus®-F Tab. (losartan 100 mg / hydrochlorothiazide 25 mg), 24 weeks (Patients who have failed in blood pressure control, increase the study medication dose step by step according to the titration plan) intervention 2: Once daily, Dilatrend Tab® (carvedilol) 12.5 mg, Dilatrend Tab® (carvedilol) 25 mg, Dilatrend Tab® (carvedilol) 25 mg plus half Dichlozid Tab® (hydrochlorothiazide 25 mg) or Dilatrend Tab® (carvedilol) 25 mg plus full Dichlozid Tab® (hydrochlorothiazide 25 mg), 24 weeks (Patients who have failed in blood pressure control, increase the study medication dose step by step according to the titration plan) intervention 3: Once daily , Cozaar® (losartan) 50 mg, Cozaar® (losartan) 100 mg, Cozaar Plus®-pro Tab. (losartan 100 mg/ hydrochlorothiazide 12.5 mg) or Cozaar Plus®-F Tab. (losartan 100 mg / hydrochlorothiazide 25 mg), 24 weeks (Patients who have failed in blood pressure control, increase the study medication dose step by step according to the titration plan) intervention 4: Once daily, Dilatrend Tab® (carvedilol) 12.5 mg, Dilatrend Tab® (carvedilol) 25 mg, Dilatrend Tab® (carvedilol) 25 mg plus half Dichlozid Tab® (hydrochlorothiazide 25 mg) or Dilatrend Tab® (carvedilol) 25 mg plus full Dichlozid Tab® (hydrochlorothiazide 25 mg), 24 weeks (Patients who have failed in blood pressure control, increase the study medication dose step by step according to the titration plan)	intervention 1: losartan potassium intervention 2: Comparator: carvedilol intervention 3: Comparator: losartan (+) hydrochlorothiazide (HCTZ) intervention 4: Comparator: carvedilol (+) hydrochlorothiazide	0	null	201	6	0.029851	1	NCT00496834	1COMPLETED	2009-09-01	2008-02-01	Organon and Co	4INDUSTRY	false	false	false	null	0	0	0	0	6	0.013751
[ 4 ]	439	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	0ALL	true	This purpose of this study is to determine the efficacy and safety of a grass sublingual (under-the-tongue) tablet.	This is a multicenter, double-blind, randomized, placebo-controlled, parallel-group study in participants 18 to 65 years of age, of either sex, and of any race with a history of grass pollen induced rhinoconjunctivitis with or without asthma. While receiving treatment, participants will receive either grass sublingual tablet or placebo. Open-label rescue medications for the hinoconjunctivitis and asthma symptoms will be provided. Participants will visit the study site for at least 12 visits. A total of 10 allergic symptoms, 6 rhinoconjunctivitis and 4 lung symptoms, will be recorded daily on an electronic diary by the participant. The start and end of the grass pollen season (GPS) was determined based on the regional grass pollen count, and lasted up to 162 days. For each region, the GPS is defined as the first day of 3 consecutive recorded days with a grass pollen count of ≥ 10 grains/m\^3, to the last day of the last occurrence of 3 consecutive recorded days with a grass pollen count ≥ 10 grains/m\^3, inclusively.	Rhinoconjunctivitis Rhinitis Conjunctivitis Allergy	rhinoconjunctivitis rhinitis conjunctivitis allergy allergen immunotherapy	null	2	arm 1: Matching Placebo arm 2: None	[ 2, 0 ]	9	[ 0, 2, 0, 0, 0, 0, 0, 0, 0 ]	intervention 1: Placebo sublingual tablet intervention 2: SCH 697243 (2800 Bioequivalent Allergen Units \[BAU\] of Phleum pratense extract, containing approximately 15 mcg Phl p 5), administered sublingually once daily. intervention 3: Loratadine 10 mg RediTabs tablets were dosed orally once daily as rescue medication among participants with a total symptom score ≥ 4 during the GPS. intervention 4: Olopatadine hydrochloride 0.1% ophthalmic solution was administered intraocularly at a dose of 1 drop in each affected eye twice daily as rescue medication for rhinoconjunctivitis, as needed. intervention 5: Mometasone furoate monohydrate nasal spray 50 mcg was admininstered intranasally at a dose of 2 sprays in each nostril once daily as rescue medication for rhinoconjunctivitis, as needed. intervention 6: Prednisone 5 mg tablets were administered orally at a dose of 1 mg/kg/day (maximum 50 mg/day) on Day 1 and 0.5 mg/kg/day (maximum 25 mg/day) on Days 2, 3, 5 and 7 as rescue medication for rhinoconjunctivitis among participants with a total symptom score of ≥ 4 despite treatment with loratadine and mometasone furoate nasal spray. intervention 7: Albuterol sulfate inhalation aerosol 108 mcg/inhalation was administed via inhalation at a dose of 2 inhalations every 4 to 6 hours, as needed, as rescue medication for asthma. intervention 8: Fluticasone propionate inhalation aerosol 44 mcg/inhalation was administered via inhalation at a dose of two inhalations twice daily, to a maximum dose of 10 inhalations twice daily, as rescue medication for asthma among participants utilizing four or more albuterol sulfate inhalations/day for 2 days for nocturnal asthma or shortness of breath. intervention 9: Prednisone 5 mg tablets were administered orally at a dose of 1 mg/kg/day (maximum 50 mg/day) on Day 1 and 0.5 mg/kg/day (maximum 25 mg/day) on Days 2, 3, 5 and 7 as rescue medication for asthma at the discretion of the investigator for the treatment of asthma exacerbation.	intervention 1: Placebo intervention 2: SCH 697243 intervention 3: Loratadine 10 mg Rescue Treatment intervention 4: Olopatadine 0.1% Rescue Treatment intervention 5: Mometasone 50 mcg Rescue Treatment intervention 6: Prednisone 5 mg Rescue Treatment intervention 7: Albuterol sulfate 108 mcg intervention 8: Fluticasone propionate 44 mcg intervention 9: Prednisone 5 mg	0	null	439	1	0.002278	1	NCT00562159	1COMPLETED	2009-09-01	2007-11-01	ALK-Abelló A/S	4INDUSTRY	false	false	false	null	0	0	0	1	0	0.000402
[ 4 ]	326	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	true	Objectives of the study are to evaluate the safety, tolerability, and efficacy of two different doses of AVP-923 (capsules containing either 30 mg of dextromethorphan hydrobromide and 10 mg of quinidine sulfate \[AVP-923-30\] or 20 mg of dextromethorphan hydrobromide and 10 mg of quinidine sulfate \[AVP-923-20\]) when compared to placebo, for the treatment of PBA in a population of patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS) over a 12-week period. An additional objective is to determine the pharmacokinetic parameters of the two different doses of AVP-923 in a subset of the study population. Pseudobulbar Affect (PBA) is a condition characterized by involuntary, sudden and frequent episodes of laughing and/or crying out of proportion or incongruous to the underlying emotion of happiness or sadness Other terms used to describe this condition include emotional lability, emotionalism, emotional incontinence, emotional discontrol, excessive emotionalism, and pathological laughing and crying. The outbursts can occur spontaneously or in response to provocative stimuli such as questions or events. A body of evidence suggests that PBA can be modulated through pharmacologic intervention. Dextromethorphan (DM) is a low-affinity uncompetitive antagonist of the N-Methyl-D-aspartate (NMDA) receptor, reducing the level of excitatory activity. DM also acts at the phencyclidine-binding site, which is part of the NMDA receptor complex. DM is a sigma receptor agonist, suppressing the release of excitatory neurotransmitters. Quinidine (Q) is a known potent inhibitor of cytochrome P450 2D6 (CYP2D6), that decreases the metabolism of dextromethorphan and helps to achieve sustained and therapeutic levels of this drug.	null	Pseudobulbar Affect (PBA)	Amyotrophic Lateral Sclerosis (Lou Gehrig's disease, ALS) Multiple Sclerosis (MS)	null	3	arm 1: AVP-923-30/10 Capsules (30 mg dextromethorphan/10 mg quinidine)administered once daily for 1 week and then twice daily for 11 weeks arm 2: AVP-923-20/10 Capsules (20 mg dextromethorphan/10 mg quinidine)administered once daily for 1 week and then twice daily for 11 weeks arm 3: Placebo Capsules once daily for 1 week and then twice daily for an additional 11 weeks	[ 0, 0, 2 ]	3	[ 0, 0, 0 ]	intervention 1: Dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) capsules (AVP-923 capsules), containing DM 20 mg/ Q 10 mg, taken once daily for 1 week and then twice daily for 11 consecutive weeks to complete a 12-week period intervention 2: Dextromethorphan hydrobromide (DM) and quinidine sulfate (Q) capsules (AVP-923 capsules), containing DM 30 mg/ Q 10 mg taken once daily for 1 week and then twice daily for 11 consecutive weeks to complete a 12-week period intervention 3: Placebo capsules (identical in appearance to AVP-923 capsules being studied in this trial), taken once daily for 1 week and then twice daily for 11 consecutive weeks to complete a 12-week period	intervention 1: dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg intervention 2: dextromethorphan hydrobromide 30 mg and quinidine sulfate 10 mg intervention 3: Placebo	62	Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 Scottsdale \| Arizona \| United States \| -111.89903 \| 33.50921 Anaheim \| California \| United States \| -117.9145 \| 33.83529 Irvine \| California \| United States \| -117.82311 \| 33.66946 La Jolla \| California \| United States \| -117.2742 \| 32.84727 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 San Francisco \| California \| United States \| -122.41942 \| 37.77493 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Aurora \| Colorado \| United States \| -104.83192 \| 39.72943 Fort Lauderdale \| Florida \| United States \| -80.14338 \| 26.12231 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 Miami \| Florida \| United States \| -80.19366 \| 25.77427 St. Petersburg \| Florida \| United States \| -82.67927 \| 27.77086 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Decatur \| Georgia \| United States \| -84.29631 \| 33.77483 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Northbrook \| Illinois \| United States \| -87.82895 \| 42.12753 Lexington \| Kentucky \| United States \| -84.47772 \| 37.98869 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Springfield \| Massachusetts \| United States \| -72.58981 \| 42.10148 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 Detroit \| Michigan \| United States \| -83.04575 \| 42.33143 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Great Falls \| Montana \| United States \| -111.30081 \| 47.50024 Lincoln \| Nebraska \| United States \| -96.66696 \| 40.8 Las Vegas \| Nevada \| United States \| -115.13722 \| 36.17497 Albany \| New York \| United States \| -73.75623 \| 42.65258 Buffalo \| New York \| United States \| -78.87837 \| 42.88645 New York \| New York \| United States \| -74.00597 \| 40.71427 New York \| New York \| United States \| -74.00597 \| 40.71427 Charlotte \| North Carolina \| United States \| -80.84313 \| 35.22709 Durham \| North Carolina \| United States \| -78.89862 \| 35.99403 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Columbus \| Ohio \| United States \| -82.99879 \| 39.96118 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Lubbock \| Texas \| United States \| -101.85517 \| 33.57786 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Burlington \| Vermont \| United States \| -73.21207 \| 44.47588 Morgantown \| West Virginia \| United States \| -79.9559 \| 39.62953 Madison \| Wisconsin \| United States \| -89.40123 \| 43.07305 Buenos Aires \| Buenos Aires F.D. \| Argentina \| -58.37723 \| -34.61315 Buenos Aires \| Buenos Aires F.D. \| Argentina \| -58.37723 \| -34.61315 Buenos Aires \| Buenos Aires F.D. \| Argentina \| -58.37723 \| -34.61315 Buenos Aires \| Buenos Aires F.D. \| Argentina \| -58.37723 \| -34.61315 Buenos Aires \| Buenos Aires F.D. \| Argentina \| -58.37723 \| -34.61315 Buenos Aires \| Buenos Aires F.D. \| Argentina \| -58.37723 \| -34.61315 Buenos Aires \| Buenos Aires F.D. \| Argentina \| -58.37723 \| -34.61315 Buenos Aires \| Buenos Aires F.D. \| Argentina \| -58.37723 \| -34.61315 Córdoba \| Córdoba Province \| Argentina \| -64.18853 \| -31.40648 Godoy Cruz \| Mendoza Province \| Argentina \| -68.84428 \| -32.92533 Rosario \| Santa Fe Province \| Argentina \| -60.63932 \| -32.94682 Belo Horizonte \| M G \| Brazil \| -43.93778 \| -19.92083 Curitiba \| Paraná \| Brazil \| -49.27306 \| -25.42778 Recife \| Pernambuco \| Brazil \| -34.88111 \| -8.05389 Rio de Janeiro \| Rio de Janeiro \| Brazil \| -43.18223 \| -22.90642 Porto Alegre \| Rio Grande do Sul \| Brazil \| -51.23019 \| -30.03283 São Paulo \| São Paulo \| Brazil \| -46.63611 \| -23.5475	579	1	0.001727	1	NCT00573443	1COMPLETED	2009-09-01	2007-12-01	Avanir Pharmaceuticals	4INDUSTRY	false	false	false	null	0	0	0	0	1	0.000305
[ 2 ]	45	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	null	The study will compare the effects of prednisone vs placebo on synovial blood flow and overall DAS (disease activity score) in patients with rheumatoid arthritis.	null	Rheumatoid Arthritis		null	4	arm 1: Prednisone 15 mg tablets once daily for 15 days arm 2: Prednisone 15 mg placebo tablets once daily for 15 days arm 3: Prednisone 7.5 mg over-encapsulated tablets once daily for 15 days As per adaptive dose-ranging design, this arm was added to the study because a difference between prednisone 15 mg and placebo was demonstrated during interim analysis. arm 4: Prednisone 7.5 mg placebo over-encapsulated tablets once daily for 15 days As per adaptive dose-ranging design, this arm was added to the study because a difference between prednisone 15 mg and placebo was demonstrated during interim analysis.	[ 0, 2, 0, 2 ]	4	[ 0, 0, 0, 0 ]	intervention 1: Prednisone 15 mg tablets once daily for 15 days. intervention 2: Prednisone placebo tablets once daily for 15 days. intervention 3: Prednisone 7.5 mg over-encapsulated tablets once daily for 15 days intervention 4: Prednisone 7.5 mg placebo over-encapsulated tablets once daily for 15 days	intervention 1: Prednisone 15 mg intervention 2: Placebo Tablets intervention 3: Prednisone 7.5 mg intervention 4: Placebo Over-Encapsulated Tablets	0	null	45	1	0.022222	1	NCT00746512	1COMPLETED	2009-09-01	2008-09-01	Merck Sharp & Dohme LLC	4INDUSTRY	false	false	false	null	1	0	0	0	0	0.003934
[ 3 ]	222	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	true	To assess the effect of two doses of Apixaban (2.5 mg BID and 5 mg BID) versus Warfarin on the composite endpoint of major and clinically relevant non-major bleeding during the treatment period.	null	Atrial Fibrillation		null	3	arm 1: None arm 2: None arm 3: None	[ 0, 0, 1 ]	3	[ 0, 0, 0 ]	intervention 1: Apixaban 5 mg tablet BID for 12 weeks intervention 2: Apixaban 2.5 mg tablet BID for 12 weeks intervention 3: At each visit, the subject to take appropriate Warfarin tablet (on investigator's order) once a day every morning for 12 weeks	intervention 1: Apixaban intervention 2: Apixaban intervention 3: Warfarin sodium	18	Nagoya \| Aichi-ken \| Japan \| 136.90641 \| 35.18147 Seto \| Aichi-ken \| Japan \| 137.1 \| 35.23333 Touon \| Ehime \| Japan \| N/A \| N/A Fukuoka \| Fukuoka \| Japan \| 130.41667 \| 33.6 Kitakyushu \| Fukuoka \| Japan \| 130.85034 \| 33.85181 Ōgaki \| Gifu \| Japan \| 136.61667 \| 35.35 Isesaki \| Gunma \| Japan \| 139.2 \| 36.31667 Shibukawa \| Gunma \| Japan \| 139.0 \| 36.48333 Sapporo \| Hokkaido \| Japan \| 141.35 \| 43.06667 Higashiibaraki-gunn Ibarakimachi \| Ibaraki \| Japan \| N/A \| N/A Zentsujichó \| Kagawa-ken \| Japan \| 133.77791 \| 34.22699 Kawasaki \| Kanagawa \| Japan \| 139.71722 \| 35.52056 Kumamoto \| Kumamoto \| Japan \| 130.69181 \| 32.80589 Tsu \| Mie-ken \| Japan \| 136.51667 \| 34.73333 Minato-ku \| Tokyo \| Japan \| N/A \| N/A Shinagawa-ku \| Tokyo \| Japan \| N/A \| N/A Shinjuku-ku \| Tokyo \| Japan \| N/A \| N/A Iwakuni \| Yamaguchi \| Japan \| 132.22 \| 34.16297	218	3	0.013761	1	NCT00787150	1COMPLETED	2009-09-01	2008-06-01	Pfizer	4INDUSTRY	false	false	false	null	2	0	0	0	1	0.004691
[ 4 ]	193	RANDOMIZED	PARALLEL	1PREVENTION	2DOUBLE	false	0ALL	true	The purpose of this study is to determine if hydroxyurea therapy is effective in the prevention of chronic end organ damage in pediatric patients with sickle cell anemia.	BACKGROUND: In 1995, the Multicenter Study of Hydroxyurea (MSH) demonstrated that hydroxyurea is effective in decreasing the frequency of painful crises, hospitalizations for crises, acute chest syndrome, and blood transfusions by 50%. The recently completed phase II study of hydroxyurea in children (PED HUG) demonstrated that children have a response to hydroxyurea similar to that seen in adults in terms of increasing fetal hemoglobin levels and total hemoglobin, and decreasing complications associated with sickle cell anemia. In addition, this study demonstrated that the drug does not adversely affect growth and development between the ages of 5 and 15. A recently completed pilot study of hydroxyurea given to children between the ages of 6 months and 24 months demonstrated that the drug is tolerated well by small infant, and that the fetal hemoglobin switch can be forced to remain in the "on position" by hydroxyurea administration. A Special Emphasis Panel (SEP) met on April 12, 1996 to review the results of the MSH trial and the progress to date of the PED HUG study. The SEP recommended that NHLBI undertake the BABY HUG trial. DESIGN NARRATIVE: BABY HUG is a randomized, double-blind, placebo-controlled study to determine if hydroxyurea can prevent the onset of chronic end organ damage in young children with sickle cell anemia. Approximately 200 children with sickle cell disease will be recruited to receive either hydroxyurea or placebo. The children will be screened at study entry for signs of abnormal brain, kidney, pulmonary, and splenic function, and developmental milestones. They will then be randomly assigned to receive either hydroxyurea or placebo and followed yearly to assess chronic end organ damage of the major organ systems. The primary endpoint will be a 50% reduction in rates of damage to the major organs with surrogate markers of organ function during follow-up in Phase II of the trial.	Hematologic Diseases Anemia, Sickle Cell	Blood Diseases Sickle Cell Anemia	Prot_SAP_000.pdf: _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/B-CoverPageOnly.wpd — 8/09 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL BABY HUG PROTOCOL August 2009 . Prepared by: Clinical Trials & Surveys Corp. 10065 Red Run Blvd., Suite 250 Owings Mills, Maryland 21117 NOTICE: The contents of this document are confidential and are not to be cited or discussed except with individuals to whom it has been distributed. _________________________________________________________________________________________________________ SLC/F:/BABY_HUG/BHUG Protocol/August-09/B-TOC.wpd — 8/09 Page TOC-1 of TOC-8 PROTOCOL TABLE OF CONTENTS CHAPTER PAGE Preface P1 1 BACKGROUND AND STUDY RATIONALE 1.1 Overview of Sickle Cell Anemia 1-1 1.2 Chronic Organ Damage in Sickle Cell Anemia 1-2 1.2.1 Spleen 1-2 1.2.2 Kidneys 1-2 1.2.3 Brain 1-3 1.2.4 Lungs 1-4 1.3 Sickle Cell Anemia and Fetal Hemoglobin 1-4 1.3.1 Fetal Hemoglobin 1-4 1.3.2 Physiologic Decline of HbF 1-5 1.4 Efficacy of Hydroxyurea in Sickle Cell Anemia 1-6 1.4.1 Induction of HbF 1-6 1.4.2 Hydroxyurea for Adults with SCA 1-7 1.4.3 Hydroxyurea for Children with SCA 1-7 1.4.4 Hydroxyurea for Very Young Children with SCA 1-8 1.5 Toxicities of Hydroxyurea Therapy 1-9 1.5.1 Organ Damage 1-9 1.5.2 Neurodevelopmental Effects 1-10 1.5.3 Mutagenic and Carcinogenic Potential 1-11 1.5.4 Acquired DNA Mutations in Association with Hydroxyurea Therapy 1-12 Table 1 Acquired DNA Mutations 1.6 Summary 1-13 Figure 1-1 HbF Parameters 1-15 2 OBJECTIVES AND DESIGN OF THE TRIAL 2.1 Introduction 2-1 2.2 Specific Aims 2-2 2.3 Design of the Trial 2-3 2.3.1 Overview of the Trial 2-3 2.3.2 The Feasibility and Safety Pilot Study 2-4 PROTOCOL TABLE OF CONTENTS (CONTINUED) CHAPTER PAGE _________________________________________________________________________________________________________ SLC/F:/BABY_HUG/BHUG Protocol/August-09/B-TOC.wpd — 8/09 Page TOC-2 of TOC-8 2.4 Endpoints 2-7 2.5 Safety Monitoring 2-8 Figure 2-1 Projected Enrollment, Maintenance of Assigned Study Treatment 2-10 3 PATIENT ELIGIBILITY, RECRUITMENT, ORIENTATION, AND INFORMED CONSENT 3.1 Introduction 3-1 3.2 Inclusion and Exclusion Criteria 3-2 3.2.1 Inclusion Criteria 3-2 3.2.2 Exclusion Criteria for Pilot and Main Study 3-3 3.3 Recruitment 3-4 3.4 Parent/Guardian Orientation 3-5 3.5 Baseline Assessment 3-6 3.6 Informed Consent 3-7 3.7 Patient/Family Advocates 3-7 Exhibit 3-1 Qualifications and Responsibilities of Patient/Family Advocate 3-9 4 STUDY ENDPOINTS 4.1 Introduction 4-1 4.2 Primary Endpoints 4-2 4.2.1 Spleen Scintigraphy 4-2 Table 4-1 Power for Ordinal Spleen Endpoint as a Function of Improvement Rates 4-6 Table 4-2 Power for Ordinal Spleen Endpoint as a Function of Improvement Rates 4-7 4.3 Secondary and Safety Endpoints 4-8 4.3.1 Central Nervous System 4-8 4.3.2 Spleen 4-9 4.3.3 Kidney Function and Bladder Control 4-10 4.3.4 Abdominal Sonogram 4-11 4.3.5 Pulmonary 4-11 4.3.6 Anthropometry 4-12 4.3.7 Chromosome Analysis 4-12 PROTOCOL TABLE OF CONTENTS (CONTINUED) CHAPTER PAGE _________________________________________________________________________________________________________ SLC/F:/BABY_HUG/BHUG Protocol/August-09/B-TOC.wpd — 8/09 Page TOC-3 of TOC-8 4.3.8 Acquired DNA Mutations 4-12 4.3.9 Immune Function 4-13 4.3.10 Clinical Events 4-13 Table 4-3 Complication Frequencies in Infants with Hb SS 4-14 4.3.11 Transcranial Doppler Measurements 4-15 4.4 Statistical Considerations in Design and Study Size 4-17 4.4.1 Feasibility and Safety Pilot Study 4-17 4.4.2 Primary Treatment Comparison (Full Phase III Trial) 4-17 4.4.3 Spleen Endpoint 4-19 Table 4-4 Power Tables for Treatment Crossover 4-22 Tables 4-5 and 4-6 removed with DTPA 4.4.4 Data Analysis 4-23 4.4.4.1 Introduction 4-23 4.4.4.2 Regression Analyses and Adjustment 4-25 4.4.4.3 Missing Data - Prevention and Analysis 4-26 4.4.5 Interim Monitoring 4-27 Table 4-7 P-Values for Interim Analyses 4-27 4.4.6 Safety Related Outcomes 4-30 4.4.7 Pharmacokinetics of Hydroxyurea (HU) 4-32 Table 4-8 Definition of Adverse Events and Classification and Reporting of Adverse Events 4-34 Figure 4-1 Absolute Effect Size Two Sample Proportions 4-35 Figure 4-2 Overlay of the Entry and Exit PK Studies on the DTPA Procedure 4-36 Figure 4-3 HU Concentrations in Infants 4-37 5 RANDOMIZATION AND ENROLLMENT OF PATIENTS 5.1 Eligibility Assessment 5-1 5.2 Randomization and Treatment Allocation 5-1 5.2.1 Treatment Allocation 5-2 PROTOCOL TABLE OF CONTENTS (CONTINUED) CHAPTER PAGE _________________________________________________________________________________________________________ SLC/F:/BABY_HUG/BHUG Protocol/August-09/B-TOC.wpd — 8/09 Page TOC-4 of TOC-8 6 STUDY TREATMENTS 6.1 Overview 6-1 6.2 Dose Titration 6-3 6.2.1 Hydroxyurea 6-3 6.2.2 Placebo 6-3 6.3 Treatment Preparation 6-4 6.4 Definitions of Toxicity 6-5 6.5 Monitoring for Toxicity 6-6 6.6 Blinding 6-7 6.6.1 Emergency Unblinding 6-9 6.6.2 Treatment Interruptions 6-10 6.7 Assessment of Compliance 6-10 6.8 Missed Visits and Drop-Outs 6-11 6.9 Duration of Study Treatment 6-11 Table 6-1 BABY HUG Dose Titration Algorithm 6-12 7 LABORATORIES AND SPECIMENS 7.1 Introduction 7-1 7.2 Hematology and Biochemistry Core Laboratory 7-1 7.3 Local (Clinical Center) Hematology Laboratories 7-1 7.3.1 Monitoring for Toxicity 7-1 7.3.2 Blinding 7-2 7.3.3 Emergency Unblinding 7-3 7.3.4 Alert System 7-3 7.4 Cytogenetics Core Laboratory 7-5 7.5 Immunology Core Laboratory 7-5 7.6 Mutation Analysis/DNA Core Laboratory 7-5 7.7 Pitted Cell Core Laboratory 7-5 7.8 TCD Core Laboratory 7-5 7.9 Biomarkers Core Laboratory 7-6 7.10 HU Assay Core Laboratory 7-6 PROTOCOL TABLE OF CONTENTS (CONTINUED) CHAPTER PAGE _________________________________________________________________________________________________________ SLC/F:/BABY_HUG/BHUG Protocol/August-09/B-TOC.wpd — 8/09 Page TOC-5 of TOC-8 7.11 NHLBI Specimen Repository 7-6 Table 7-1 Laboratory Determinations 7-7 Table 7-2 BABY HUG Laboratory Data Alert and Monitoring Levels 7-9 8 GUIDELINES FOR STANDARD CLINICAL CARE 8.1 Introduction 8-1 8.2 Immunizations 8-1 8.3 Prophylactic Medications 8-3 8.4 Parent Education 8-4 9 SPECIAL STUDIES AND READING GROUPS 9.1 Introduction 9-1 9.2 Pitted Cell Counts 9-1 9.3 Cytogenetics (Karyotype and Chromosome Breakage Analyses) 9-1 9.4 VDJ/DNA Mutation Studies 9-1 9.5 Liver-Spleen Scans 9-2 9.6 Abdominal Ultrasound 9-3 9.7 Hydroxyurea Assay 9-3 9.8 Immune Function Studies 9-3 9.9 Clinical Events 9-4 9.10 Transcranial Doppler (TCD) 9-4 9.11 Cystatin C 9-4 10 FOLLOW-UP PROCEDURES 10.1 Introduction 10-1 10.2 Follow-Up Visits 10-1 10.2.1 Real Time Complete Blood Counts 10-2 10.2.2 Ascertainment of Specified Events and Possible Adverse Effects in Patients 10-3 10.2.3 BABY HUG Adverse Event Reporting 10-4 10.2.3.1 Introduction 10-4 10.2.3.2 DBDR Adverse Event Coverage 10-6 10.2.3.3 Elevated Adverse Event Rate Detection 10-6 10.2.3.4 Interim Reports 10-7 PROTOCOL TABLE OF CONTENTS (CONTINUED) CHAPTER PAGE _________________________________________________________________________________________________________ SLC/F:/BABY_HUG/BHUG Protocol/August-09/B-TOC.wpd — 8/09 Page TOC-6 of TOC-8 10.2.3.5 Analysis of Death or Stroke 10-9 10.2.3.6 Analysis of Growth and Development 10-10 10.2.3.7 Analysis of Acute Chest Syndrome, Splenic Sequestration and Serious, Unexpected Adverse Events 10-11 10.2.3.8 Alert and Monitoring Levels 10-11 Table 10-1 BABY HUG Laboratory Data Alert and Monitoring Levels 10-13 10.2.4 Adverse Event Management 10-15 10.2.5 Laboratory Specimen and Data Collection 10-19 10.3 Patient Compliance and Management 10-19 10.4 Long-Term Follow-Up 10-21 10.4.1 Introduction 10-21 10.4.2 Follow-Up Data Collection 10-22 10.4.3 Follow-Up Procedures 10-22 10.5 Debriefing Contacts 10-22 11 CLOSE-OUT PROCEDURES 11.1 Overview 11-1 11.2 Duration of Randomized, Blinded Study Treatment 11-1 11.3 Debriefing Contacts 11-2 11.4 Final Study Data and Dissemination of Results 11-2 12 CONDUCT OF THE TRIAL 12.1 Overview 12-1 12.2 Timeline 12-1 12.3 Planning and Study Design 12-2 12.4 Training, Certification and Start-Up 12-2 12.5 Data Editing and Management 12-4 12.5.1 Introduction 12-4 12.5.2 Receipt and Inventory 12-4 12.5.3 Expected Receipt of Forms 12-5 12.6 Monitoring Progress and Performance 12-7 12.7 Routine Reporting 12-13 PROTOCOL TABLE OF CONTENTS (CONTINUED) CHAPTER PAGE _________________________________________________________________________________________________________ SLC/F:/BABY_HUG/BHUG Protocol/August-09/B-TOC.wpd — 8/09 Page TOC-7 of TOC-8 12.8 Safety and Patient Monitoring 12-13 12.9 Protocol Violations 12-14 12.10 IRB Approval 12-15 13 ORGANIZATIONAL STRUCTURE AND PARTICIPATING UNITS 13.1 Introduction 13-1 13.2 Participating Units 13-1 13.2.1 Operations Committee 13-1 13.2.2 Clinical Centers 13-2 13.2.3 Study Coordinator Committee 13-2 13.2.4 Core Laboratories 13-3 13.2.5 Pharmacy Distribution Center and Investigational Pharmacies 13-3 13.2.6 National Heart, Lung, and Blood Institute 13-3 13.2.7 Medical Coordinating Center 13-4 13.2.8 National Institute of Child Health and Human Development 13-5 13.3 Study Administration 13-5 13.3.1 Study Chairman and Vice-Chairman 13-5 13.3.2 Steering Committee 13-5 13.3.3 Data and Safety Monitoring Board 13-5 13.3.4 Endpoints Evaluation 13-7 Exhibit 13-1 Organizational Chart 13-8 Exhibit 13-2 Participating Clinical Centers 13-9 14 POLICY MATTERS 14.1 Introduction 14-1 14.2 Quality Assurance 14-1 14.3 Changes in Principal Investigators 14-2 14.4 Types of BABY HUG Research 14-3 14.4.1 Endpoint Studies 14-3 14.4.2 Data Bank Studies 14-4 14.4.3 Ancillary Studies 14-4 PROTOCOL TABLE OF CONTENTS (CONTINUED) CHAPTER PAGE _________________________________________________________________________________________________________ SLC/F:/BABY_HUG/BHUG Protocol/August-09/B-TOC.wpd — 8/09 Page TOC-8 of TOC-8 14.5 Clinical Center Access to BABY HUG Data Files at the End of the Study 14-4 14.6 Publication 14-5 14.7 Conflict-of-Interest 14-5 LITERATURE CITED R-1 APPENDIX A Detailed Schedule of Visits and Total Amount of Blood A-1 APPENDIX B List of Tests and Diagnostic Procedures B-1 (for Parent Information) APPENDIX C Central Laboratories and Facilities C-1 APPENDIX D Study Timeline D-1 APPENDIX E Anthropometric Measurement Procedures E-1 Figure E-1 Standing Scale E-7 Figure E-2 Length E-8 Figure E-3 Head Circumference E-9 APPENDIX F Clinical Event Definitions F-1 _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/BHUG-Preface.wpd — 8/09 Page P1 of P2 PREFACE TO THE BABY HUG PROTOCOL Decades of observational data have documented that sickle cell anemia (SCA) is a devastating medical disorder. Over 50,000 affected persons in the United States have inherited SCA, and the vast majority of them are African-American. To date, there have been few therapeutic options for persons with SCA. Bone marrow transplantation, which can provide a cure for individuals with a matched sibling donor, and chronic blood transfusions to prevent cerebrovascular disease are possible therapeutic options that are not appropriate or available for all patients. No other treatment has yet been demonstrated to prevent the chronic end organ damage seen in this disorder. SCA is characterized by acute complications and chronic organ damage that cause lifelong morbidity and early mortality. Acute events result from erythrocyte sickling and vaso-occlusion, and begin early in life with dactylitis, other painful events, and acute chest syndrome. Chronic organ damage from sickling is more insidious but also begins early in life as fetal hemoglobin (HbF) levels begin to decline. During the first two years of life, sickling begins to damage the spleen, rendering the child susceptible to overwhelming infection. The kidney also is affected in infancy and manifests abnormality first as increased glomerular filtration, followed by proteinuria in older children and finally renal failure in young adults. Other organs (e.g., brain, liver, and lungs) are also affected by chronic sickling, but damage that begins in infancy typically does not become manifest until an older age. The anti-neoplastic agent hydroxyurea has emerged recently as an oral medication that can increase fetal hemoglobin (HbF) production and thereby reduce intracellular sickling. Hematological benefits of hydroxyurea therapy include higher HbF values, higher hemoglobin concentration, and less hemolysis. The clinical efficacy of hydroxyurea therapy in reducing acute events (crisis, acute chest syndrome, hospitalizations, rate of transfusions) in severely affected adults with SCA was demonstrated in a randomized clinical trial -- the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) -- long-term follow-up suggests that hydroxyurea therapy may be associated with reduced mortality as well. The short-term safety of hydroxyurea therapy has been demonstrated in school-aged children (HUGKIDS) and infants and very young children (HUSOFT) with SCA, but its clinical efficacy has not been proven in this younger age group. Importantly, the effects of hydroxyurea on chronic end organ damage in SCA have not been investigated, although children in HUSOFT had the suggestion of reduced splenic dysfunction compared to historical controls, and their observed increases in glomerular filtration rate with age were inversely correlated with the amount of HbF. With these encouraging results, the challenge now is to determine the appropriate and optimal use of hydroxyurea therapy for children with SCA. Several important questions must be addressed, and the proposed answers must be sensitive to the history of medical investigation involving African-Americans. Highest priority must be given to patient protection and to assuring that patients’ families make their decisions regarding participation in BABY HUG freely, with confidence and trust in the choices offered. Conversely, however, it would be unethical to allow hydroxyurea to be used indiscriminately in this vulnerable patient population without demonstrated benefit in a randomized clinical trial. A recent survey by the American Society of Pediatric Hematology/Oncology noted that 30% of pediatric hematologists already use hydroxyurea in children under age 5 years, and some already use it as early as age 1 year of life. It is essential, therefore, to design and conduct a formal randomized clinical trial to ensure that hydroxyurea will be used appropriately in young children with SCA. The following are three critical study design questions with proposed answers: _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/BHUG-Preface.wpd — 8/09 Page P2 of P2 1. What is the best age range in which to consider hydroxyurea therapy for the prevention of chronic organ damage? The pathophysiology of sickling in SCA begins during the first year of life, and organ damage to the spleen and kidney clearly begins before 2 years of age. The onset of damage appears to be associated with the decline in Hb F levels that begins at 6 months of age. Since the onset of disease begins in infancy, the first year or two of life is the appropriate age range to study. In BABY HUG, enrollment will begin at 9 months of life and continue through age 17 months. 2. Should hydroxyurea be reserved only for patients with severe disease, or might less severely affected infants benefit as well? Even though only a subset of infants with SCA will manifest acute clinical sickling complications during the first two years of life, chronic (subclinical) sickling occurs in all patients. Treatment that is limited to severely affected infants might not address the capacity of hydroxyurea to prevent organ damage. Conversely, the exclusion of well- appearing infants would be inappropriate since they might be denied beneficial therapy. Functional asplenia is recognized as a poor prognostic sign, hence the prevention of splenic damage is a worthwhile goal for all infants. In BABY HUG, very young children with SCA will be randomly assigned to either hydroxyurea or placebo therapy. 3. Can hydroxyurea help prevent the chronic end organ damage in sickle cell disease that begins early in life? This question will be addressed directly in BABY HUG. The spleen and the kidneys are the organs commonly affected early in childhood; hence these organs will be the primary study endpoints. Summary. Based on the known pathophysiology of SCA, previous data from studies using hydroxyurea in infants and children, and careful consideration of sociological and ethical factors, we propose that hydroxyurea should be tested in a formal randomized clinical trial for the prevention of chronic organ damage in infants with SCA. We propose a randomized double-blinded placebo-controlled trial to prevent damage to the spleen and kidney, since these organs are the first to be affected early in life. We propose to determine if we can enroll children with SCA who are between 9 and 17 months of age, to prevent chronic damage to the spleen and kidneys. With proper precautions to ensure safety of all participants, we believe that this is the optimal trial design that allows equipoise, ethical patient protection, and the opportunity to determine the true efficacy of hydroxyurea in preventing chronic organ damage in children with SCA. ____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-1.wpd — 8/09 Page 1-1 of 1-15 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) PROTOCOL CHAPTER 1 BACKGROUND AND STUDY RATIONALE 1.1 OVERVIEW OF SICKLE CELL ANEMIA The term Sickle Cell Disease (SCD) refers to a group of genetic hematological disorders characterized by the predominance of sickle hemoglobin (HbS). SCD is one of the most common inherited diseases in the United States, affecting approximately 1 in 375 African-American live births. Currently it is estimated that there are over 75,000 persons in the United States with SCD. A single inherited amino acid substitution in beta globin results in the formation of HbS (containing beta-globin S instead of beta-globin A). HbS undergoes polymerization in the deoxygenated state, leading to deformation of the cellular membrane and alteration of cellular physiology. Sickle Cell Anemia (SCA) is characterized by homozygous state for HbS and represents the majority of SCD patients. Clinical manifestations of SCA result primarily from hemolytic anemia and the effects of intravascular sickling, including both acute tissue hypoxia and chronic organ damage. Patients with SCD commonly develop acute vaso-occlusive events due to sickling of erythrocytes within the capillaries and small venules. Acute vaso-occlusive sickling events can manifest in many ways, including painful crisis, priapism, splenic sequestration, acute chest syndrome, or stroke. Over a period of years, patients with SCA develop organ damage from repeated acute and chronic sickling events. The primary organs that are affected chronically by sickling include the spleen, kidneys, brain, and lungs. Data gathered during the Cooperative Study of Sickle Cell Disease (CSSCD) demonstrate clearly that chronic organ damage is a major cause of morbidity and mortality for patients with SCA. ____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-1.wpd — 8/09 Page 1-2 of 1-15 1.2 CHRONIC ORGAN DAMAGE IN SICKLE CELL ANEMIA 1.2.1 Spleen Of all internal organs affected by chronic sickling, the spleen is the one damaged most severely early in life. The slow circulation within the spleen provides an ideal milieu for sickling, which leads to tissue hypoxia and organ infarction. In most children with sickle cell anemia, the spleen is non-functional by the age of 2 years (Pearson et al, 1979). This acquired state of functional asplenia (Diamond, 1969) leads to a susceptibility to infection by encapsulated bacteria (Zarkowsky et al, 1986; Gill et al, 1995; Kabins and Lerner, 1970; Pearson, 1977). Splenic damage can be identified by the absence of radioactive tracer uptake, or the presence of increased numbers of pitted erythrocytes (Pearson et al, 1979; Rogers et al, 1982; Pearson et al, 1985; Fatunde and Scott, 1986). Transfusion therapy has been associated with a “reversal” of splenic hypofunction (Buchanan et al, 1989; Barrios et al, 1993), suggesting that splenic damage may be reversible during the first few years of life. Similarly, bone marrow transplantation in children with SCD may be able to correct splenic dysfunction (Ferster et al, 1993). Splenic regeneration may also occur with hydroxyurea (HU) therapy in patients with SCA (Claster and Vichinsky, 1996). 1.2.2 Kidneys The term “sickle nephropathy” refers to the constellation of chronic renal damage that occurs in patients with SCA. For decades, it has been known that defects in renal tubular function, specifically in acidification (Oster et al, 1976) and concentrating ability (Francis and Worthen, 1968) begin early in childhood, along with papillary necrosis (Eknoyan et al, 1982). More recently, sickle nephropathy has been characterized by proteinuria, occasionally with urinary protein loss in the range of the nephrotic syndrome (Tejani et al, 1985). The prognosis of nephrotic syndrome is poor, with chronic azotemia and acute renal failure occurring frequently (Bakir et al, 1987). The estimated prevalence of proteinuria in SCA is about 6% for children (Wigfall et al, 2000) and 25% for adults (Falk et al, 1992). Focal and segmental glomerulosclerosis and mesangial proliferation ____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-1.wpd — 8/09 Page 1-3 of 1-15 have been described histologically, and probably result from glomerular hyperfiltration (Tejani et al, 1985). An elevated glomerular filtration rate (GFR) is a common feature in patients with sickle nephropathy that begins very early in life (Allon et al, 1988), and may portend later severe renal damage. Therapy to reduce glomerular capillary hypertension significantly can reduce urinary protein excretion in adults with SCA (Falk et al, 1992). Renal damage from chronic sickling is a significant cause of morbidity and mortality; in the CSSCD, 18% of deaths in adults with SCA occurred secondary to overt organ failure, primarily renal (Platt et al, 1994). 1.2.3 Brain The CSSCD has collected prospective data on chronic organ damage to the brain in over 300 children with SCD. Using brain magnetic resonance imaging (MRI), 22% of children age 6-12 years had infarction/ischemia and/or atrophy, including 13% who had no history of a clinical CVA (Leong et al, 1997). The lesions in these latter children are referred to as “silent infarcts” that reflect subclinical organ damage to the brain. Most of the lesions were present at entry into the study (age 6 years). More recently, 39 infants with SCA, 7 - 48 months of age, were found to have an 11% prevalence of brain abnormalities on MRI (Wang et al, 1998). Organ damage to the brain in SCD is often associated with changes in the large intracranial arteries, most commonly stenosis within the distal internal carotid artery (ICA) and proximal middle cerebral artery (MCA). Abnormal cerebral blood flow can be identified in some children by magnetic resonance angiography (MRA), while transcranial doppler (TCD) has been shown to identify children with an increased risk of developing stroke. An abnormal time averaged maximum TCD velocity (>200 cm/sec) in the distal ICA or proximal MCA is associated with a high risk of stroke (Adams et al, 1992). In the Stroke Prevention (STOP) Trial, children with SCA and an abnormal TCD who received monthly blood transfusions had significantly fewer strokes than children who were simply observed (Adams et al, 1998). ____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-1.wpd — 8/09 Page 1-4 of 1-15 Taken together, these data suggest that chronic organ damage to the brain from sickling begins early in life. Moreover, therapeutic intervention may help prevent the development of organ damage to the brain. Even in the absence of overt neurological disease, SCA puts some children at risk for neuropsychological sequelae including lowered intellectual functioning, academic skills deficits, impaired fine-motor functioning, and attentional deficits (Bonner et al, 1999). 1.2.4 Lungs The lungs are also frequent target organs in patients with SCA. Episodes of acute chest syndrome (ACS, with intrapulmonary sickling) can result in obstructive lung disease with reactive airways (Leong et al, 1997). However, repeated organ damage from ACS and chronic sickling in the lungs most frequently leads to a restrictive pattern of lung disease with diminished lung compliance (Bowen et al, 1991). Recent studies using pulmonary function tests (PFTs) have suggested that abnormal lung function in SCA may begin in early infancy (Koumbourlis et al, 1997). 1.3 SICKLE CELL ANEMIA AND FETAL HEMOGLOBIN 1.3.1 Fetal Hemoglobin There is great clinical heterogeneity observed in SCD, even for patients with an identical hemoglobin phenotype (Platt et al, 1991; Powars, 1991; Seward et al, 1993; Steinberg et al, 1995). This clinical variation is partly explained by differences in the hemoglobin concentration, mean cellular hemoglobin concentration, proportion of dense cells, erythrocyte rheology, % adhesive cells, presence of alpha-thalassemia, and the beta-globin haplotype (Platt et al, 1994; Platt et al, 1991; Steinberg et al, 1984; Baum et al, 1987; Powars, 1991; Phillips et al,1991; Embury and Steinberg, 1994). The amount of fetal hemoglobin (% HbF) is perhaps the most important parameter influencing clinical severity in SCA (Charache, 1990). Normal adults have <1% HbF (Wood, 1993), while patients with SCA have 1-20% HbF (Serjeant, 1975). Patients with hereditary persistence of fetal hemoglobin (HPFH) can have fetal hemoglobin (HbF) levels that reach 30-40% (Wood et al, 1975). Higher % HbF is associated with decreased clinical severity and fewer painful events, ____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-1.wpd — 8/09 Page 1-5 of 1-15 transfusions, and hospitalizations in sickle cell anemia (Platt et al, 1991; Rucknagel et al, 1987; Odenheimer et al, 1987). A threshold of 10-20% HbF has been postulated, above which patients experience fewer clinical events (Powars et al, 1984). The % HbF also predicts early mortality in patients with SCD (Platt et al, 1994; Leikin et al, 1989). Except in the case of HPFH, HbF is not found in all erythrocytes, but rather is located in a subset known as HbF-containing cells or “F cells” (Dover et al, 1978; Boyer et al, 1975). In normal adults, the percentage of F cells ranges from 0.5% to 7%, while in patients with SCA, the % F cells has a much broader range (Wood et al, 1975; Dover et al, 1978). Because F cells have a decreased tendency toward sickle formation, they survive preferentially in the peripheral blood of patients with SCA (Dover et al, 1978). The number of F cells, therefore, may be of equal or greater importance than the absolute amount of HbF in influencing the clinical severity of an affected individual with SCA. F cells can be quantitated accurately by several methods, including immunological staining of HbF by monoclonal antibodies, followed by enumeration by visual methods (Horiuchi et al, 1995) or flow cytometry (Dover and Boyer, 1987; Campbell et al, 1999; Marcus et al, 1997). 1.3.2 Physiologic Decline of HbF Fetal hemoglobin (HbF), the predominant hemoglobin produced in utero, comprises approximately 80-90% of the total hemoglobin at birth. In normal persons, the % HbF declines to adult levels during the first year of life (Wood, 1993). For patients with SCA, this physiologic decline occurs more slowly, and the HbF nadir may not be reached until age 5 years (Mason et al, 1982; Brown et al, 1994). Clinical events from SCA rarely occur in the first 6 months of life, due primarily to high HbF levels. Events occur during the first two years of life, however, including splenic hypofunction (Pearson et al, 1979; Rogers et al, 1982), pneumococcal sepsis (Zarkowsky et al, 1986), splenic sequestration (Topley et al, 1981), dactylitis (Gill et al, 1995), and acute chest syndrome (Gill et al, 1995). These observations suggest that maintaining high HbF levels might prevent acute and chronic sickling damage. ____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-1.wpd — 8/09 Page 1-6 of 1-15 The physiologic decline in % HbF and % F cells in a cohort of infants homozygous for HbSS between birth and 24 months of age was recently investigated (Marcus and Ware, 1999). The % HbF was measured by 2-minute alkali denaturation and % F cells by flow cytometry (Marcus et al, 1997). The amount of HbF per F cell was calculated using the formula: (mean corpuscular hemoglobin) x (% HbF) ] / (% F cells). Over this period of time, the HbF parameters declined in an exponential fashion (Figure 1-1). At 24 months of age, the average % HbF was 14.6 ± 7.3% and the % F cells was 64.7 ± 16.9%. The average amount of HbF per F cell fell below 15 pg/cell by age 12 months, confirming data from a previous study (Maier-Redelsperger et al, 1994). Previous in vitro studies have suggested a threshold value of 15 pg HbF per F cell, below which sickling occurs (Sunshine et al, 1979; Poillon et al, 1993). These data demonstrate clearly that HbF parameters decline significantly during the first 1-2 years of life, below levels sufficient to inhibit sickling. These results support the concept of early pharmacologic intervention for very young children with SCA, with the intention to increase HbF parameters to levels that inhibit in vivo sickling. 1.4 EFFICACY OF HYDROXYUREA IN SICKLE CELL ANEMIA 1.4.1 Induction of HbF The pharmacologic enhancement of HbF can be achieved using a variety of agents including cytotoxic drugs (e.g. 5-azacytidine, hydroxyurea), hematopoietic growth factors (e.g. erythropoietin), and short chain fatty acids (e.g. butyrate and derivatives). Each of these therapeutic agents has been shown to have efficacy for increasing the % HbF in patients with sickle cell anemia (Goldberg et al, 1990; Charache et al, 1992; Perrine et al, 1993; Dover et al, 1994; Charache et al, 1995). However, side-effects and toxicities vary considerably and no direct comparisons of efficacy have been reported. Hydroxyurea is a prototypic therapeutic agent due to its efficacy, ease of administration, and modest toxicity profile. ____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-1.wpd — 8/09 Page 1-7 of 1-15 1.4.2 Hydroxyurea For Adults With SCA Hydroxyurea has been tested in adults with sickle cell anemia, and in most patients will increase both the absolute amount of HbF as well as the number of F cells (Goldberg et al, 1990; Charache et al, 1992). Charache and co-workers (Charache et al, 1992) reported a mean increase in HbF of 11% in a Phase I/II study of adults receiving daily HU treatment. In the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) Phase III clinical trial (Charache et al, 1995), adult patients were randomized prospectively either to daily HU or placebo. The study results demonstrated that HU therapy led to a significant reduction in the annual number of painful events, episodes of acute chest syndrome, and erythrocyte transfusions (Charache et al, 1995). The mean increase in % HbF was 8.6%, although the range of HbF responses was substantial and some patients did not respond, possibly due to either non-compliance or exhaustion of marrow reserves (Steinberg et al, 1995). Even when compliance was assured, approximately 20% of adults with SCA did not respond to HU therapy (Rodgers et al, 1990). The primary toxicity of HU therapy was dose- dependent and reversible bone marrow suppression (Charache et al, 1992; Charache et al, 1995). 1.4.3 Hydroxyurea For Children With SCA After the Phase I/II adult HU trial was completed, several anecdotal reports suggested that HU therapy might be beneficial for children with SCA (Jayabose et al, 1996; Scott et al, 1996; Ferster et al, 1996; de Montalembert et al,1997). To determine the safety and efficacy of HU therapy for children, investigators from seven institutions administered HU therapy to a total of 84 school- aged children with SCA in an NHLBI-sponsored Phase I/II clinical protocol (HUG-KIDS). HUG-KIDS provided convincing evidence that HU therapy is associated with improved hematological parameters in this younger patient population, including increased % HbF and % F cells (Kinney et al, 1999). The toxicity profile of HU was mild and included primarily reversible myelosuppression. Clinical efficacy was not a stated goal of this Phase I/II study, but it was clear that the pediatric patients with SCA had a less severe acute clinical course while on HU therapy. Based on these encouraging results in older children, it is reasonable to consider HU therapy for very young children ____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-1.wpd — 8/09 Page 1-8 of 1-15 with sickle cell anemia, to allow therapeutic intervention before in vivo sickling leads to acute clinical events and chronic organ damage. 1.4.4 Hydroxyurea For Very Young Children With SCA A recent report provided short-term data regarding HU therapy for young children with SCA. Eight children, age 2-5 years, received HU with evidence of both hematological and clinical efficacy, and with minimal toxicity (Hoppe et al, 2000). To determine the feasibility of HU therapy for very young children with SCD, a Phase I/II pilot trial (HUSOFT) was recently performed. Children between age 6-24 months were eligible for enrollment from four institutions, including Duke University Medical Center, St. Jude Children’s Research Hospital, University of Texas Southwestern Medical Center, and Medical College of Wisconsin. A total of 21 completed two years of therapy at 20 mg/kg/day. All patients then on study desired to continue treatment for an additional two years at 25 and 30 mg/kg/day. Laboratory studies and physical examinations were performed every four weeks. Patients were closely monitored for toxicities, especially of the blood counts and growth parameters, and for compliance. Routine testing of the complete blood count, %HbF and %F cells were used to document hematological efficacy in before-after comparisons and compared to untreated children with sickle cell anemia. Additional studies included brain MRI/MRA, neurodevelopmental testing, and liver-spleen scans. Hematological toxicities in HUSOFT were well- tolerated, and laboratory efficacy was demonstrated (Wang et al, 2001). Recently, follow-up of the majority of patients from the HUSOFT study who were continued on hydroxyurea treatment for an additional 2-4 years, showed that these patients tolerate prolonged hydroxyurea therapy with sustained hematologic benefits, fewer acute chest syndrome events, improved growth, and possibly preserved organ junction (Hankins et al, 2005). Preliminary results of clinical efficacy in HUSOFT relate to the potential prevention of chronic organ damage, specifically the possibility that hydroxyurea can help preserve splenic and renal function in some infants with SCA (Wang et al, 2001). Splenic function, as evidenced by uptake of radioactive tracer, was present in eight of 17 HUSOFT children (47%) after two years on study. This ____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-1.wpd — 8/09 Page 1-9 of 1-15 compares favorably with data from CSSCD (Pearson et al, 1985) that document elevated pitted cell counts (consistent with functional asplenia) in >80% of children with SCA at the same median age of 39 months. Renal function was assessed primarily by GFR estimation, calculated using the formula [(height) x k] divided by (creatinine), as described by Schwartz (Schwartz et al, 1987). The estimated GFR is normal (100 ± 20 ml/min) in infants with SCA during the first 6-12 months of life, but quickly rises to 150 ml/min by age 2-4 years and >200 ml/min by age 6-10 years (Wigfall et al, 2000; Kinney et al, 1999; Russell Ware, unpublished observations). Analysis of HUSOFT data reveal that the estimated GFR was 121 ± 20 ml/min/1.73 m2 at study entry (median age 15 months, n=28) and 162 ± 43 ml/min/1.73 m2 at study exit (Franca Barton and Russell Ware, unpublished observations). The absolute change in GFR was strongly associated with change in %HbF (Pearson coefficient -0.60, p=0.004), suggesting that preservation of HbF can help prevent the elevation of GFR observed over time in untreated children with sickle cell anemia. Recently two groups of investigators have presented evidence that hydroxyurea therapy in children is associated with lower TCD velocities (Zimmerman et al, 2002; Bernaudin et al, 2001). 1.5 TOXICITIES OF HYDROXYUREA THERAPY 1.5.1 Organ Damage The short-term toxicities of HU for patients with SCA have been carefully studied in two large Phase I/II trials. In the safety trial for adults with SCA (Charache et al, 1992), the only observed short-term toxicity was bone marrow depression. Neutropenia was most common (76%), followed by reticulocytopenia (22%), anemia (4%), and thrombocytopenia (1%). The myelosuppression was typically mild, dose-dependent, and reversible. In the safety trial (HUG-KIDS) for children with SCA (Kinney et al, 1999), laboratory toxicity occurred at approximately 8% of the clinic visits. Neutropenia was the most common hematological toxicity (63%), followed by reticulocytopenia (19%), anemia (13%), and thrombocytopenia (4%). Hepatic toxicity (>2-fold increase in ALT levels) was observed at only 0.3% of clinic visits, and was not associated with HU dose or additional medications. No episodes of renal toxicity were noted, nor other significant clinical adverse events during this ____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-1.wpd — 8/09 Page 1-10 of 1-15 pediatric HU safety trial. Growth (assessed by height and weight) and development (menarche, puberty) also were not adversely affected by HU therapy (Kinney et al, 1999). 1.5.2 Neurodevelopmental Effects There are limited data in children with SCA regarding the effects of HU therapy on neuropsychological development. Previous small studies of HU therapy for children with SCA did not report any obvious neurodevelopmental decline. Similarly, the Phase I/II HUG-KIDS pediatric safety trial did not specifically test for neurodevelopmental progress, although no obvious declines in neurocognitive function were noted (Kinney et al, 1999). In the HUSOFT infant pilot trial, a subset of patients had full neurodevelopmental testing both at study entry (median score = 93) and at study exit (median score = 89). These values were not statistically different by t-test or Wilcoxon rank sum test (Wang et al, 2001). A recent abstract has suggested that HU therapy is associated with improvement in neurodevelopmental scores (Bernaudin et al, 1999). Animal data suggest, however, that HU therapy can be toxic for the developing brain. Almost thirty years ago, prenatal treatment with HU was found to cause substantial postnatal effects on rats: perinatal mortality was increased (Fritz and Hess, 1980), weight gain was inhibited (Butcher et al, 1973; Adlard and Dobbing, 1975), locomotor activity was reduced (Fritz and Hess, 1980; Butcher et al, 1973), and maze learning was impaired (Butcher et al, 1973; Adlard and Dobbing, 1975). Given early in gestation, HU therapy also can be embryolethal or have embryotoxic effects on the eyes, face, brain, heart, and limbs (Aliverti et al, 1980). Neuronal cells such as the dorsal root ganglia may be especially susceptible to impairment of DNA synthesis by HU (Theisen, 1979). A recent abstract suggests that post-natal HU therapy also impairs weight gain, organ size, and brain development of rats (Horiuchi et al, 1998). It must be emphasized that all of these studies used doses of HU up to 1000-2000 mg/kg/day. No studies have documented embryotoxicity or severe neurodevelopmental toxicity using pharmacologic HU doses (20-40 mg/kg/day). Also, effects of HU exposure may be considerably different in rats than in primates (Wilson et al, 1975). Differences in HU plasma levels, half-life clearance, and tissue penetration exist; previous studies suggest that the ____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-1.wpd — 8/09 Page 1-11 of 1-15 effects on rodents do not accurately reflect the effects of HU in primates (Wilson et al, 1975). Taken together, the available laboratory and clinical data neither establish nor exclude the possibility that pharmacologic HU doses in early childhood are related to any marked neurodevelopmental toxicity for the human brain, although very high doses of HU could be. 1.5.3 Mutagenic And Carcinogenic Potential Although the short-term toxicities of HU are typically well-tolerated, the long-term risks associated with HU therapy are unclear. Specifically, the risk of developing leukemia or other malignancies following HU exposure has not been determined. Hydroxyurea has been shown experimentally to have clastogenic (Gebhart, 1981; Oppenheimer and Fishbein, 1965), teratogenic (Murphy and Chaube, 1964; Aliverti et al, 1980) and in some settings mutagenic effects (Ziegler- Skylakakis et al, 1985), but its potential as a carcinogen at therapeutic doses has not been established. Since HU is a potent inhibitor of ribonucleotide reductase and reduces intracellular dNTP pools, HU interferes not only with DNA synthesis but also with DNA repair mechanisms (Snyder, 1984). In vitro, DNA damage that develops either spontaneously or from environmental mutagens cannot be fully repaired in the presence of HU, leading to the accumulation of somatic mutations and chromosomal damage (Li and Kaminskas, 1987). These laboratory observations provide a plausible biochemical mechanism by which in vivo HU therapy could lead to somatic DNA mutations and eventual carcinogenesis. The carcinogenic potential of HU therapy has been investigated most carefully in patients with myeloproliferative disorders (MPD). The Polycythemia Vera Study Group (PVSG) reported a 5.9% incidence of acute leukemia in 51 adults with PV treated with HU (Fruchtman et al, 1994; Landaw, 1986) compared to 1.5% of historical counterparts who received phlebotomy alone (p=0.12). Reports of acute leukemia in adults with MPD treated with HU alone (Sedlacek et al, 1986; Lofvenberg et al, 1990; Holcombe et al, 1991; Weinfeld et al, 1994; Furgeson et al, 1996) have added concern regarding the long-term leukemogenic potential of HU therapy in this clinical setting. Recently, large studies have provided some evidence that long-term HU therapy for patients with ____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-1.wpd — 8/09 Page 1-12 of 1-15 MPD is associated with an increased risk of developing acute leukemia (Najean et al, 1997a; Sterkers et al, 1998; Najean et al, 1997b). Taken together, these data suggest that hydroxyurea therapy may have a mutagenic and carcinogenic potential for patients with MPD, especially with long-term usage. The carcinogenic potential of HU therapy is not evident in the setting of other hematological diseases. Sixty-four patients with erythrocytosis secondary to cyanotic congenital heart disease were treated with HU (mean 5.6 years) and had no cases of secondary malignancy (Triadou et al, 1994). In the United States, some adults with SCA have received HU therapy for over 10 years; no cases of secondary leukemia from the MSH trial have been observed (Steinberg et al, 1999). However, anecdotes of malignancy or myelodysplasia in patients with SCA on hydroxyurea therapy have been reported. These cases need to be evaluated in light of the incidence of cancer in the African-American population in general, and specifically in patients with SCD. The incidence of cancer among African-American children in the US is about 11 new cases per 100,000 children per year (Gurney et al, 1995), of which one-third are leukemia or lymphoma. The incidence among African-American children under age four years, however, is at least 15 cases per 100,000 children per year (Gurney et al, 1995), due primarily to leukemia, neuroblastoma, and Wilms’ tumor (Miller et al, 1993). In the setting of SCA, the incidence of malignancy is not known. The CSSCD identified 1 child with Wilms’ tumor in the original study period and 14 subsequent cases of cancer were reported in children and adults with SCD (Dianne Gallagher and Duane Bonds, unpublished observations). In a large retrospective survey performed by members of the International Association of Sickle Cell Nurses and Physician Assistants (IASCNAPA), a total of 41 cases of cancer were reported in patients with sickle cell anemia. These cases included children and adults of all ages, and a wide variety of cancer types were reported (Schultz et al, 1999). 1.5.4 Acquired DNA Mutations In Association With Hydroxyurea Therapy The inhibitory effects of HU on DNA repair mechanisms could lead to an accumulation of acquired DNA mutations that eventually could result in malignant transformation. Two in vitro ____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-1.wpd — 8/09 Page 1-13 of 1-15 assays of DNA damage can measure the mutagenic effects of in vitro and in vivo hydroxyurea exposure: the hypoxanthine phosphoribosyltransferase (HPRT) assay that measures the frequency of mutations at the selectable hprt gene locus (Albertini et al, 1982; O’Neill et al, 1987), and the VDJ gene locus assays that detect “illegitimate” interlocus recombination events between the T-cell receptor V( and J$ gene loci within chromosome 7 (Stern et al, 1989; Lipkowitz et al, 1992). Using these two quantitative assays, the mutagenic effects of in vitro and in vivo hydroxyurea exposure were measured (Hanft et al, 2000). In vivo HU exposure was not associated with more DNA mutations in adults with SCD or myeloproliferative disorders (MPD), but was associated with a suggestively higher numbers of VDJ events in children with SCD (Table 1). These results suggest that the mutagenic potential of HU exposure is low, and serial studies should be performed in young SCD patients on HU therapy. Patient Population # patients Mean Age (years) Median HU exposure HPRT Mf (x 10-6) VDJ events (per :g DNA) Adults with MPD 27 Low HU exposure 15 57 ± 17 0 months 37.3 ± 37.6 1.06 ± 0.73 Prolonged HU exposure 12 62 ± 16 11 years 41.1 ± 29.3 0.64 ± 0.29 Adults with SCD 30 No HU exposure 15 27 ± 12 0 months 19.1 ± 19.1 1.07 ± 0.38 Short HU exposure 15 29 ± 9 24 months 16.7 ± 10.9 1.14 ± 0.38 Children with SCD 38 No HU exposure 21 11 ± 3 0 months 11.5 ± 18.7 1.06 ± 0.45 Shorter HU exposure 17 11 ± 3 7 months 11.2 ± 6.7 1.58 ± 0.87 Longer HU exposure 17 13 ± 3 30 months 9.2 ± 7.8 1.82 ± 1.20 Normal Controls 32 43 ± 15 0 months 25.8 ± 24.8 1.04 ± 0.38 Table 1. Patient characteristics and quantitation of acquired DNA mutations after in vivo hydroxyurea exposure. Patient and control PBMC were tested for DNA mutations in both the HPRT and VDJ assays. The 27 adults with MPD, with either low or prolonged HU exposure, had no significant differences in hprt- Mf or number of VDJ recombination events. Adults with SCD also had no significant differences, according to HU exposure. Children with SCD and HU exposure had more VDJ events compared to those with no HU exposure, P=0.04 by ANOVA (Hanft, 2000). 1.6 SUMMARY Decades of observational data, including landmark studies from the CSSCD, have documented that sickle cell anemia is a severe, debilitating hematological disorder. The morbidity and mortality of SCA arise from both acute vaso-occlusive events and chronic organ damage. Protection from HbF is typically lost in infancy and early childhood, with the physiologic decline of HbF. Accordingly, ____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-1.wpd — 8/09 Page 1-14 of 1-15 therapy designed to prevent chronic organ damage in SCA should be considered early in life. Hydroxyurea has emerged as an exciting therapeutic agent for patients with SCA, due to its ease of oral administration, modest toxicity profile, laboratory efficacy with increased %HbF, and clinical efficacy for acute vaso-occlusive events. The efficacy of HU in preventing chronic organ damage has not been tested, but data from the pilot HUSOFT trial suggest that HU may help prevent damage to the spleen and kidneys compared to expectations from the CSSCD and nonrandomized groups (Wang et al, 2001; Hankins et al, 2005) not given HU. Finally, hematological and neurodevelopmental toxicities from HU in infants and young children with SCA appear to be mild or absent. Taken together, the available data make a compelling case for the proposed Phase III trial of hydroxyurea in very young children (9 through 17 months of age) with SCA, designed to prevent chronic organ damage. ____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-1.wpd — 8/09 Page 1-15 of 1-15 BABY HUG Protocol Figure1-1 Figure 1.1. Measurement of HbF parameters in infants with HbSS over the first 24 months of life (Marcus and Ware, 1999). The top panel illustrates the exponential decline in % HbF as a function of age. At 12 months, the average HbF (mean ± 1SD) is 24.5 ± 5.0 %, and at 24 months is 14.6 ± 7.3 %. The lower panel plots the calculated value of HbF per F cell versus age, showing a exponential decrease to below 15 pg/cell at age 12 months and below 10 pg/cell by age 24 months, below the threshold of HbF per cell that inhibits in vitro sickling (Sunshine et al, 1979; Poillon et al, 1993). ______________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-2.wpd — 8/09 Page 2-1 of 2-10 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) PROTOCOL CHAPTER 2 OBJECTIVES AND DESIGN OF THE TRIAL 2.1 INTRODUCTION Hydroxyurea (HU) has demonstrated laboratory and clinical efficacy for adults with sickle cell anemia (SCA). In this patient population, several studies have demonstrated that HU increases the hemoglobin concentration, mean corpuscular volume, and fetal hemoglobin (HbF) parameters including %HbF and % F cells. Toxicities are mild and primarily include transient and reversible neutropenia. In the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) clinical trial, which was an NHLBI-sponsored randomized, double-blinded, placebo-controlled trial in adults with SCA, HU reduced the number of acute vaso-occlusive episodes such as painful events and acute chest syndromes, transfusions, and hospitalizations (Charache et al, 1995). Pediatric patients with SCA also benefit from HU therapy. A Phase I/II trial (HUG-KIDS) involving 84 children who were 5-15 years old concluded that HU was well tolerated by pediatric patients with SCA, and the laboratory effects were similar to those observed in adults (Kinney et al, 1999). Several smaller studies have further suggested that HU has clinical efficacy in this younger age group (Hoppe et al, 2000; Bernaudin et al, 1999), and reduces the number of acute vaso-occlusive events. A pilot trial involving infants and very young children with SCA (HUSOFT) has provided preliminary data demonstrating that HU is well-tolerated in this very young age group, with laboratory effects similar to those for older children (Wang et al, 2001; Hankins et al, 2005). Although HU therapy has emerged as an exciting and efficacious therapeutic agent for patients with SCA, important issues remain regarding its use, especially for children less than 2 years old. Perhaps the most important issue is whether or not HU therapy can prevent chronic organ damage secondary to vaso-occlusive sickling. HUSOFT data are suggestive, but not conclusive, regarding the potential for hydroxyurea to prevent chronic organ damage, specifically ______________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-2.wpd — 8/09 Page 2-2 of 2-10 in the spleen and kidney. Ideally, HU therapy to prevent organ damage would begin early in life, before repeated sickling events begin to damage the spleen, brain, kidneys, and lungs. Another important issue regarding HU therapy relates to its mechanism of action, e.g., whether or not HbF parameters mediate the prevention of chronic organ damage. Finally, there are questions about the long-term safety of HU administration for young patients with SCA, including its effects on growth and development, as well as its mutagenic and carcinogenic potential. At this time, however, there are limited data regarding the toxicities, effects on growth and development, and occurrence of adverse events in this very young age group (9-17 months). Moreover, the accurate and reproducible quantitative measurements of splenic and renal function have not been fully validated. For these reasons, a Feasibility and Safety Pilot Study has been performed to (1) determine the feasibility of the protocol design, (2) provide additional safety and toxicity data, and (3) validate the proposed methods of evaluating splenic and renal function. 2.2 SPECIFIC AIMS The primary aim of this trial is: 1. To determine whether daily oral hydroxyurea can reduce by $50% chronic organ damage that develops in young children with sickle cell anemia. Secondary objectives of this trial include: 1. To determine the relationship between fetal hemoglobin (HbF) levels and chronic organ damage in young children with sickle cell anemia; 2. To investigate the safety of HU for young children with sickle cell anemia regarding a. physical growth and development, b. neuropsychological development, c. immunological responses, and d. mutagenic effects on DNA. ______________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-2.wpd — 8/09 Page 2-3 of 2-10 2.3 DESIGN OF THE TRIAL 2.3.1 Overview of the Trial This NHLBI- and NICHD-sponsored Phase III therapeutic trial will be a randomized, placebo-controlled double-blinded study and will involve 14 Clinical Centers, a Medical Coordinating Center, and eight core laboratories within the United States. The Phase III study will include 200 children with sickle cell anemia (SCA) aged 9-17 months. A Feasibility and Safety Pilot Study has enrolled 40 children from 12 to 17 months of age. Each child was randomly assigned to either hydroxyurea or placebo and will receive study treatment for no more than two years (see Figure 2- 1). Selected data from all 40 children in the Feasibility and Safety Pilot Study have been presented to the DSMB and a decision has been made regarding reopening recruitment for the full study. After the children’s treatment period has ended, they will remain in study follow-up to determine whether or not there are untoward effects of discontinuing study treatment. After study treatment ends, renewed consent will be requested for continued follow-up clinic visits for up to five years after the end of study treatment. The target dose of hydroxyurea will be 20 mg/kg/day in liquid formulation or equivalent volumes of placebo. A Medical Coordinating Center and Pharmacy Distribution Center will ensure that patients and investigators are blinded to the treatment assignments of individual patients. A battery of laboratory tests and special studies will be performed at entry and exit. Clinical events (including death, acute chest syndrome, and stroke) and other outcomes will be classified by a central evaluation panel, blind to treatment assigned and under the direction of the Medical Coordinating Center. Interim results will be monitored by an NHLBI-appointed Data and Safety Monitoring Board according to statistical plans outlined in the Protocol (Chapter 4) and elaborated in a separate document prior to the start of recruitment. Long-term follow-up in an observational study after study treatment is terminated in BABY HUG is anticipated so that children enrolled in ______________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-2.wpd — 8/09 Page 2-4 of 2-10 BABY HUG will be observed for growth and safety outcomes for at least five years, if resources for the follow-up can be obtained. 2.3.2 The Feasibility and Safety Pilot Study The 40 children enrolled in the Feasibility and Safety Pilot Study will be on study treatment for two years. The DSMB authorized immediately continuing recruitment for the remaining 160 children in the full Phase III BABY HUG Clinical Trial. The anticipated recruitment and follow-up periods are presented in Figure 2-1. The Primary Aims of the Feasibility and Safety Pilot Study were: 1. To determine the feasibility of BABY HUG in terms of recruitment, follow-up, adherence to study treatment, and compliance with the study schedule of procedures; 2. To assess hydroxyurea toxicity, effect on growth and development, and occurrence of severe/unexpected adverse events; 3. To establish the distribution and inter-observer and intra-observer variability of spleen function based on dual, independent readings of liver-spleen scans; 4. To evaluate the validity and variability of glomerular filtration rate (GFR) as estimated by serum creatinine and height (the Schwartz formula) compared with a “gold standard” such as DTPA clearance; and, 5. To assess some pharmacokinetic parameters of hydroxyurea in the BABY HUG age group. At study entry, plasma specimens for pharmacokinetics were collected from the blood collected as part of the radionuclide (DTPA) study (at 1, 2 and 4 hours following radionuclide injection), in addition to plasma specimens collected at time 0 and 8 hours from the start of the test. After counting radioactivity in the plasma for the renal function study, the plasma from each specimen was saved, frozen (-70° C) for at least a month (well after all radiation decays) and shipped on dry ice for pharmacokinetic evaluations. The 8-hour specimen was collected after the ______________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-2.wpd — 8/09 Page 2-5 of 2-10 DTPA study and was handled similarly to the other four specimens. Measurements of hydroxyurea levels were made on specimens from all 40 children in a commercial laboratory recommended by the manufacturer for regulatory purposes. Children assigned to placebo were also tested for DTPA according to the same schedule; their plasma was prepared and shipped for HU determination just as the HU-assigned specimens. The DSMB Chair, Executive Secretary of DSMB, the NHLBI Project Officer and the Steering Committee reviewed monthly and semi-annual Feasibility and Safety Pilot Study reports including information on: 1. Recruitment: Expected vs. Actual (overall), and reasons for ineligibility 2. Patients screened, eligible and randomized 3. Patient characteristics at baseline (overall) a. Age, race and gender b. Spleen function (scan reading) c. Spleen and kidney size (by ultrasound evaluation) d. Pitted cell counts e. Schwartz equation GFR estimates f. DTPA clearance for GFR quantitation g. Urine concentrating ability h. CBC i. Presence of gallstones j. Blood chemistries k. Microalbuminuria l. Transcutaneous O2% saturation m. Physical examinations n. Neurological examination and neuropsychological tests ______________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-2.wpd — 8/09 Page 2-6 of 2-10 o. Height, weight, head circumference p. Transcranial doppler (TCD) measurements (supported by grant funds independent of BABY HUG contracts) 4. Blood count toxicities 5. Dose adjustments 6. Intra- and Inter-observer agreement of liver-spleen scan readings 7. GFR estimated from the Schwartz equation versus measured by DTPA 8. Immunological impairment 9. Safety assessments and adverse events a. Height, weight and head circumference b. Neurological examination and neuropsychological development c. Unexpected and serious adverse events: counts and percentages. Individual cases were summarized also for immediate review by the DSMB Chair, the Executive Secretary of the DSMB, and the NHLBI Project Officer. Based on individual patient and group safety monitoring reviews, the Executive Secretary of the DSMB, the NHLBI Project Officer and/or DSMB Chair could recommend full DSMB review or individual treatment interruptions. All individuals whose treatment was interrupted continued to be monitored. There were monthly reviews of accumulating data. If height, weight, or Bayley scores were worse among children assigned to HU than children assigned to placebo through the early months (at least three) of randomized study treatment, the DSMB could have recommended to the NHLBI that the full Phase III trial not proceed in children less than 18 months of age. If serious adverse events (e.g., death, stroke, or splenic sequestration) were more frequent among children assigned to HU than among children assigned to placebo, to a greater degree than could be expected by chance, the DSMB could have recommended to the NHLBI that the study be discontinued. If spleen function according to liver-spleen scan readings ______________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-2.wpd — 8/09 Page 2-7 of 2-10 was absent at entry for more than 40% of the children enrolled, the DSMB could have recommended to the NHLBI to re-design the primary outcome or other features of the study design (e.g., eligibility criteria) as necessary. See Chapter 4 for detailed study stopping rules. 2.4 ENDPOINTS 1. The primary endpoints are chronic organ damage to the spleen and kidney. a. Spleen -- organ damage will be defined as decrease or loss of radionuclide 99mTc uptake (relative to the liver) at 2 years from baseline; and, b. Kidney -- Deleted as of May 29, 2009. 2. Secondary endpoints for this study include the following: a. Spleen -- pitted cell count, size as measured by ultrasound; b. Kidney--urine specific gravity, osmolality, urinalysis including microalbuminuria, size as measured by ultrasound; c. Lung -- oxygen saturation (percutaneous monitor); d. Hepatobiliary – cholelithiasis (ultrasound evaluation), serum bilirubin (direct); e. Hematology and Chemistry -- hemoglobin F, serum bilirubin (indirect); f. Clinical events -- e.g., hospitalization, pain, splenic sequestration, splenomegaly, and acute chest syndrome occurrence; and, g. Transcranial doppler – time averaged maximum flow velocity in the distal internal carotid/proximal middle cerebral arteries. 3. Safety endpoints include the following: a. Death, stroke, TIA, splenic sequestration, prolonged hospitalization (greater than 7 days), life threatening events, acute chest syndrome, ICU admissions; b. Growth -- weight, height, head circumference; c. Brain -- neurodevelopmental testing, neurological examination; ______________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-2.wpd — 8/09 Page 2-8 of 2-10 d. Mutagenesis -- VDJ recombination events (first 140 patients), chromosomal karyotype and breakage studies; e. Hematology and Chemistry -- hemoglobin, platelets, liver function, etc.; and f. Immune System -- antibody response to immunizations, T-cell counts and antigen-specific responses. 2.5 SAFETY MONITORING 1. Individual patients will be monitored according to routine hematology and biochemistry parameters (see Section 6.5). Patients will have treatment interruptions if any of the following occur: a. a “toxicity” level, as defined in Chapter 10; b. the DSMB confirms a central review recommendation that a decline across two major percentile lines, or drop below the 1.5th percentile on age-specific standard growth curves based on confirmed measurements in height, or weight or head circumference growth warrants a treatment interruption (central reviewers for this aspect of the study are two physicians who are not seeing patients and are not associated with any of the Clinical Centers); c. Bayley standardized Mental score that falls to < 70 (confirmed on repeat evaluation within three months); or d. clinical stroke, or failure of head circumference to increase according to normal growth curves. Treatment will not be terminated unless a toxicity condition persists or therapy that contraindicates study treatment – such as chronic transfusion – is initiated, to allow the determination of primary, secondary and safety endpoints in that patient. Children whose treatment is terminated, whether assigned to hydroxyurea or placebo will complete as much follow-up in BABY HUG as possible (e.g., all primary endpoint assessments and growth and development assessments will be expected). ______________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-2.wpd — 8/09 Page 2-9 of 2-10 2. Group comparisons between hydroxyurea-assigned patients and placebo-assigned patients will be included in semi-annual reviews of the data by the Data and Safety Monitoring Board (see Section 4.4). These reviews will include all secondary and safety endpoints defined in the study. Safety comparisons and inferences based on them will be discussed by the DSMB as data accrue in the study. 3. Monitoring for unanticipated adverse clinical effects will be done using adverse event (AE) forms that will be submitted to the Medical Coordinating Center (MCC) and tabulated based on the affected organ system. A central review group (consisting of two pediatric hematologists with expertise in sickle cell disease and without association with the Clinical Centers) will designate each event as serious or non-serious. Each suspected serious AE (SAE) will be reported to the MCC within 24 hours of the event. MCC staff will immediately review the material and forward it to the central review group. If the central review group finds that an event is serious, MCC staff will send the information to the NHLBI and NICHD Project Officers for review. The NHLBI Project Officer will forward the information to the FDA. The Clinical Centers will report the occurrence of serious AEs that occur at their institution according to the requirements of their local IRB. Further plans for adverse event detection and assessment are in Sections 4.3, 4.4 and Chapter 8. Figure 2-1 Projected Enrollment, Maintenance of Assigned Study Treatment (Gray Areas) and Follow-up to Common Termination N N 200 160 120 80 40 0 15 24 31 39 55 Months of Study INTERIM MONITORING LOOKS FOR EFFICACY: 1 2 3 4 (Final) (# on HU / # on PLBO) (20/20) (40/40) (60/60) (80/80) (100/100) BABY HUG Projected Enrollment, Maintenance of Assigned Study Treatment (Gray Areas) and Follow-Up Light gray: Feasibility and Safety Pilot Study (N=40 children are enrolled over 15 months and each maintained on assigned study treatment for 24 months) Dark gray: Remainder of Phase III Clinical Trial cohort (N=160 additional children are enrolled over 16 months and each maintained on assigned study treatment for 24 months) Follow-up may continue for up to 5 years or longer after the end of study treatment. 12/21/05 2-10 _____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-3.wpd — 8/09 Page 3-1 of 3-9 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) PROTOCOL CHAPTER 3 PATIENT ELIGIBILITY, RECRUITMENT, ORIENTATION, AND INFORMED CONSENT 3.1 INTRODUCTION The primary objective of this study is to determine whether hydroxyurea administration can prevent organ damage commonly found in young children with sickle cell anemia. This will be accomplished by the administration of hydroxyurea or placebo to a group of very young children with sickle cell anemia (or sickle beta zero thalassemia) at an age before extensive organ damage has usually occurred. Patients will be randomly assigned to receive either hydroxyurea or placebo. Investigators and patients/parents will be blinded to treatment assignments. Parents (or guardians) of the first forty patients enrolled were informed that they were participating in a Feasibility and Safety Pilot Study -- randomized, placebo-controlled, and double- blind -- testing oral hydroxyurea for the prevention of primary end organ damage (spleen and kidney) in children with sickle cell anemia 12 through 17 months of age at entry. The DSMB has authorized additional recruitment after the Feasibility and Safety Pilot Study without an interim wait. All families will be informed that their renewed agreement will be sought at the end of treatment for five years or up to ten years of follow-up clinical visits. Primary aims of the Feasibility and Safety Pilot Study are outlined in Section 2.3. The end-organ damage found in sickle cell anemia is not uniform in time of onset or distribution across organs. While all organs and systems may ultimately be affected, the timing and severity of organ damage is variable. For example, damage to the spleen and brain is known to begin early in life, while that affecting the bones and eyes occurs later. An additional 160 patients from 9 months through 17 months of age will be enrolled, before the frequency of extensive organ damage is high. However, even at that young age, some children will already have early evidence of disease-specific organ damage. _____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-3.wpd — 8/09 Page 3-2 of 3-9 Care will be taken to avoid coercion of this vulnerable population of parents of children with sickle cell anemia. Many of these parents will be young, some single heads of households, some limited in English language skills, and some may have highly constrained financial resources. Patient/Family advocates have been identified at each Clinical Center to advise families independently of any discussions with study investigators or health care providers (see Exhibit 3-1). The services of these advocates will be supported from study resources. Documentation of thorough review of the study and consent form with a Patient/Family Advocate will be required of each family enrolling a child in BABY HUG. The consent form will be appropriately worded and available in translation as needed at individual Clinical Centers. Clinical Center Principal Investigators and staff will be sensitive to the need to diminish the burdens of the study on patients and families without compromising safety; funds will be provided to families for the purpose of removing barriers to participation rather than being inducements for enrolling dependent children to provide experimental observations. 3.2 INCLUSION AND EXCLUSION CRITERIA 3.2.1 Inclusion Criteria • Children with majority fetal and sickle (FS or SF) hemoglobin pattern confirmed centrally by electrophoresis, who are 9 through 17 months of age, and whose parents have provided written informed consent can be eligible for BABY HUG. Patient screening may begin at 7 months of age. • For the Feasibility and Safety Pilot Study, eligible children were enrolled between 12 and 17 months (up to 18 months) of age. The age range of organ damage onset is usually between six and 23 months of age. Children less than nine months of age will be excluded from BABY HUG due to potential toxicity concerns; nine to twelve-month old children were excluded until a final safety analysis (April, 2005) was performed on the 12-17 month old children enrolled in the Feasibility and Safety Pilot Study; enrollment of 18-23 month old children will not be allowed in BABY HUG. _____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-3.wpd — 8/09 Page 3-3 of 3-9 • Parents or guardians must provide informed consent for the Feasibility and Safety Pilot Study for the first 40 children and for the main study for the subsequent 160 children enrolled. 3.2.2 Exclusion Criteria for Pilot and Main Study • Chronic transfusion therapy. • Malignancy. • Less than 5th (10th percentile for the pilot study) percentile height, weight or head circumference for age. • Severe developmental delay (e.g., cerebral palsy or other mental retardation; Grade III/IV intraventricular hemorrhage). • Stroke with neurological deficit. • Surgical splenectomy. • Participation in other clinical intervention trials. • Probable or known diagnosis of Hemoglobin S-Hereditary Persistence of Fetal Hemoglobin. • Known hemoglobin S-beta plus thalassemia (hemoglobin A present). • Any condition or chronic illness, which in the opinion of the Principal Investigator makes participation unadvised or unsafe. • Inability or unwillingness to complete baseline (pre-enrollment) studies, including blood or urine specimen collection, liver-spleen scan, abdominal sonogram, neurological examination, neuropsychological testing or transcranial Doppler ultrasound (interpretable study not required, but confirmed velocity >200 cm/sec results in ineligibility). • Previous or current treatment with HU or another anti-sickling drug. • The following exclusion criteria are transient; patients can be re-evaluated for eligibility: (Children must be declared eligible and randomized by 18 months of age.) - Hemoglobin less than 6.0 gm/dL. - Reticulocyte count less than 80,000/cu mm if hemoglobin is less than 9 gm/dL. _____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-3.wpd — 8/09 Page 3-4 of 3-9 - Neutrophil count less than 2,000/cu mm. - Platelet count less than 130,000/cu mm. - Blood transfusion in the previous 2 months unless HbA less than 10%. - ALT greater than twice upper limit of normal. - Ferritin less than 10 ng/ml. - Serum creatinine > twice upper limit of normal for age. - Bayley standardized Mental score below 70. 3.3 RECRUITMENT The 14 BABY HUG Clinical Centers will have an active recruitment phase designed to enroll patients into the BABY HUG study. Each Clinical Center will draw upon its own patient rosters for potential patients, as well as additional local patients who fall within its catchment area. Patients who are not normally followed at a Clinical Center will still be eligible for enrollment. Publicity for the sickle cell community and physicians concerning the BABY HUG study will occur at each Clinical Center according to local needs and will be at the discretion of the Principal Investigator with appropriate Institutional Review Board, NICHD and National Heart, Lung, and Blood Institute approval. The BABY HUG study will have a quarterly newsletter for patient families which may also be used for recruitment. Potentially eligible children will be identified by the Clinical Center staff. It is anticipated that most eligible children will be known to the Clinical Centers through referrals after identification through newborn screening programs. All potential study patients’ families will be referred to independent, Patient/Family advocates who are not otherwise involved in BABY HUG or in providing health care to these children or their families (see Section 3.7). Parents (or guardians) will receive information on BABY HUG after they have been provided education about sickle cell anemia. Chart review and initial visits will be used to exclude children who would not be eligible for BABY HUG. _____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-3.wpd — 8/09 Page 3-5 of 3-9 For the Feasibility and Safety Pilot Study, children began to be evaluated for eligibility as early as 10 months of age in anticipation that they would qualify for the study in two months. No child was randomized prior to his/her first birthday. For the main study, children may begin to be evaluated for eligibility as early as 7 months of age, with randomization occurring no earlier than 9 months of age. 3.4 PARENT/GUARDIAN ORIENTATION The experience with hydroxyurea will be presented, including evidence of clinical benefit in adults and apparent safety in children above one year of age. Known risks will be described in detail along with the fact that relatively little is known about drug effects in this age group. A list of the known and possible risks (including possible malignancy or growth retardation which are not definitely known to be risks of HU) will be provided to families. The Protocol and related issues will be discussed in detail and a copy of the consent form provided to the parents or guardians to consider at home. Parents (or guardians) will be given a list of baseline evaluations that must be completed prior to study entry (see Appendix B), and an explanation that children who do not complete the baseline evaluations cannot enroll in BABY HUG. They will then be provided with a list of procedures that will be required after they enroll their child in BABY HUG (see Appendix B). Explanations of these procedures will include the risk of radiation exposure associated with the radionuclide kidney function test and the liver-spleen scan. Finally, parents (or guardians) will meet with assigned independent Patient/Family advocates to discuss making a decision whether or not to enroll their child in BABY HUG. Parents (or guardians) will be informed that their child’s participation in BABY HUG and their child’s treatment, which will be made known to them at the end of the last-enrolled child’s treatment in the study (along with study conclusions), should be noted in their child’s medical record. This information should be provided by the parents (or guardians) to all doctors taking care of their child. At the start of each child’s long-term follow-up, the parents (or guardians) will be contacted for _____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-3.wpd — 8/09 Page 3-6 of 3-9 permission to examine their children for up to five to ten years to learn about any long term effects the study treatment may have. Parents (or guardians) who express interest in BABY HUG will be advised of the importance of adherence with study visits and procedures. Evidence of compliance with clinic visits and of compliance with standard care for sickle cell anemia such as prophylactic penicillin administration (see Section 8.3) will be documented in BABY HUG. Study personnel will use this information to estimate the family’s likelihood of complying with study requirements. 3.5 BASELINE ASSESSMENT The children of those parents who express interest in participation will undergo the pre- enrollment studies listed in this section. Children who are unable to complete baseline evaluations will not be enrolled in BABY HUG. After obtaining informed consent (see attachment to this chapter) from the parent or guardian, baseline studies will be performed before randomization and enrollment. Baseline assessment includes: • Directed history and physical examination (including neurological evaluation) • Hemoglobin electrophoresis • Complete blood count and other baseline blood determinations • Urinalysis, including urine concentrating ability • Anthropometry: Height, weight and head circumference • Neuropsychological evaluation and parent questionnaire • Liver-spleen scan • Abdominal sonogram (for gallstones, spleen size and kidney size) • Transcranial doppler measurements (interpretable study not required, but confirmed velocity >200 cm/sec results in ineligibility) Renal DTPA clearance studies will be evaluated after the first dose of medication is given (i.e., after randomization) for all children enrolling in BABY HUG. _____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-3.wpd — 8/09 Page 3-7 of 3-9 Children whose hemoglobin electrophoresis does not document an FS or SF pattern will not be eligible for BABY HUG. Any serious medical problems unrelated to sickle cell anemia, for example, leukemia or cerebral palsy or mental retardation, identified in the course of pre-enrollment evaluations (e.g., history and physical examination, complete blood counts, neuropsychological evaluations) will result in referral for appropriate medical care and ineligibility for BABY HUG. 3.6 INFORMED CONSENT Individual Clinical Center consent forms will be prepared based on a model informed consent approved by the Data and Safety Monitoring Board. Recruitment brochures (including the BABY HUG study quarterly newsletter) or advertisements, consent forms and the Protocol will be submitted for approval by local Institutional Review Boards. Each final consent form will be reviewed by a member of the BABY HUG Data and Safety Monitoring Board (See Section 13.3) to ensure all appropriate issues are addressed. Patient/Family advocates have been identified at each Clinical Center to advise families independently of any discussions they have with study investigators or health care providers. The Clinical Center Principal Investigator will obtain the consent from each family. If both parents are reasonably available and responsible for the child, they will both be asked for signed, informed consent. Copies of the signed consent form will be given to the parents (or guardians) and placed on the child’s medical record. The original will be maintained in study files by the Principal Investigator. 3.7 PATIENT/FAMILY ADVOCATES Each BABY HUG Clinical Center will develop a plan to have a third party person (Patient/Family advocate) involved in the consent process to eliminate any coercion, in particular because of the vulnerable study population. Some BABY HUG Clinical Center Institutional Review Boards employ a full time staff to function in this capacity. The Patient/Family advocate role focuses on ensuring that systems are in place and working effectively to minimize research-related _____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-3.wpd — 8/09 Page 3-8 of 3-9 risks experienced by patients and families, addressing concerns or complaints that arise from treatment or research, and facilitating resolution of substantive issues that could have negative impacts on patient/family understanding of and participation in research (see Exhibit 3-1). The Patient/Family advocate acts as an impartial advocate to ensure that patients/families are treated fairly and equitably, are directed to appropriate resources within the institution for resolution of non- clinical, operational problems and are assisted in their communication with all Clinical Center staff. The Patient/Family advocate is responsible for appropriately collaborating with all internal and external resources required to bring closure to the issues presented. Meeting(s) with the Patient/Family advocate will be documented for each child enrolling in BABY HUG. _____________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-3.wpd — 8/09 Page 3-9 of 3-9 Exhibit 3-1 Qualifications and Responsibilities of Patient/Family Advocate Each BABY HUG Clinical Center will develop a plan to provide a Patient/Family advocate (ombudsman) for patients and families in the BABY HUG study. The following are minimal general requirements for this position. Each BABY HUG institution must devise their own proposal within these guidelines. Each proposal then must be approved by the BABY HUG DSMB. 1. Qualifications a. Familiarity with clinical trials/informed consent b. Familiarity with bio-ethics concepts c. Complete NIH acceptable human subjects training d. Independence from BABY HUG investigators 2. Responsibilities and Activities a. Ensure that patients/families are treated fairly and equitably b. Assist families in communication of concerns, complaints, or questions that arise from participation in the study c. Facilitate resolution of substantive issues that impact participation in research d. Direct patients/families to appropriate resources within the institution e. Meet potential BABY HUG subjects/families prior to enrollment, to review the study and address concerns f. Ensure understanding of the risks and benefits of the study g. Ensure that the patient’s family understands the randomization process and that the subject may receive a placebo h. Clarify patients’/family’s rights and responsibilities i. Monitor the informed consent process j. Maintain availability and contact with families during the course of the trial _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-1 of 4-37 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) PROTOCOL CHAPTER 4 STUDY ENDPOINTS 4.1 INTRODUCTION The primary objective of Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) is to determine the safety and effectiveness of hydroxyurea (HU) in the prevention of chronic end organ injury occurring among sickle cell anemia patients who are 9 through 17 months of age at the time of study entry. A Feasibility and Safety Pilot Study initiated BABY HUG recruitment with 40 patients 12 through 17 months of age to (1) determine the feasibility of the protocol design, (2) provide additional safety and toxicity data, and (3) validate the proposed methods of quantitating splenic and renal function. This initial group was studied intensively and monitored closely. The DSMB has recommended that 160 additional participants be enrolled in BABY HUG for a total of 200 patients in the full Phase III trial. The primary analysis in the full study will compare the frequency of worsening of spleen function (from normal to decreased or absent, or from decreased to absent) as measured by splenic uptake on a technetium -99m sulfur colloid liver-spleen scan at two years of follow-up after study entry in patients randomly assigned to treatment with hydroxyurea versus those assigned to placebo. Data monitoring analyses are scheduled every six months from the start of enrollment in the study. The analysis of the primary study outcomes of the full Phase III trial will be conducted on an "intention to treat" basis, with two-sided statistical tests comparing the outcome between groups of patients defined at study entry by random assignment to the hydroxyurea and placebo groups. Blinding of outcomes in the primary analysis is protected by use of placebo, standardized methods for performance of spleen scintigraphy studies in nuclear medicine departments not otherwise involved in the BABY HUG, and blinded central reading of spleen scans by nuclear medicine specialists not otherwise involved in BABY HUG. There will be more than 90% power to detect a _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-2 of 4-37 50% reduction in the incidence of categorical worsening of spleen function, if 60% or more of patients assigned to placebo experience categorical worsening of spleen function (80% are expected to experience this effect by 3 to 4 years of age). A more detailed presentation of anticipated analyses is provided in Sections 4.4 through 4.7. 4.2 PRIMARY ENDPOINTS 4.2.1 Spleen Scintigraphy The spleen is damaged early in life in a large percentage of children with sickle cell anemia or sickle beta zero thalassemia. The consequences of splenic injury -- episodes of splenic sequestration and invasive pneumococcal infection -- are clinically significant and quantifiable. These clinical events will not form the spleen endpoint per se, but will be evaluated along with other clinical events during the course of the study. Nearly 40 years ago it was recognized that young children with sickle cell anemia were at high risk of bacteremia with encapsulated organisms, and that the consequence of those invasive infections was often fatal septicemia. This susceptibility was attributed to splenic dysfunction, and indeed many of these young children had Howell-Jolly bodies on their peripheral blood smears; however, on clinical examination these patients also often had palpable, enlarged spleens. Thus the concept of functional asplenia, in which a palpable, enlarged spleen did not function normally, was developed or invoked to explain the clinical observation in children with sickle cell disease (Pearson et al, 1969). The standard procedure used to detect functional asplenia is the 99mTc sulfur-colloid liver-spleen scan. Liver-spleen scans are available in all participating BABY HUG institutions and their performance in each center is well standardized. Pediatric hematologists are aware that spleen function declines with age in infants and toddlers with sickle cell anemia; however, there are no good data on the cross sectional frequency or rate of loss of splenic uptake of 99mTc sulfur colloid at a given age in young patients with sickle cell anemia. The Cooperative Study of Sickle Cell Disease (CSSCD), a National Heart, Lung, and Blood Institute (NHLBI) - sponsored observational study that has been responsible for documenting the _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-3 of 4-37 clinical course of sickle cell disease in the U.S., examined pitted cell counts and liver-spleen scans in a cross-sectional cohort of 8 to 13 month old patients. Pearson (Pearson et al, 1985) reported that by 8 to 13 months of age, 23% of infants with HbSS had absent and 8% had decreased splenic uptake of 99mTc sulfur-colloid on liver-spleen scan indicating functional asplenia. Decreased or absent visualization of the spleen on liver-spleen scan correlated with a pitted cell count over 3.5% in this group of young children with sickle cell disease. Spleen function will be assessed by uptake of 99mTc sulfur colloid on liver-spleen scan before initiation of treatment and 2 years later. The results of each of the two scans will be categorized as normal, functional but abnormal, or not functional by a panel of nuclear medicine specialists blinded to treatment assignment. In HUSOFT, the intra-observer agreement on re-reading scans was over 90% (33/36 scan readings) (Rogers, unpublished observations). The difference between the HU and placebo groups in the proportion of patients worsening in spleen function over the study period will be tested. The CSSCD further examined spleen function by serial performance of pitted cell counts. Their data indicated that by one year of age pitted cell count values over 3.5%, which are associated with absent visualization on liver-spleen scan, occurred in 28% of SCA patients, by 18 months 44%, by 24 months 58%, by 36 months 78%, and by 48 months 89% of SCA patients. They concluded that the average age of onset of a pitted cell count greater than 2% but less than 3.5%, i.e., impaired spleen function, was 13 months and could be as early as 5 months (Pearson et al, 1985). Thus, up to one-third of enrolled children could be unassessable for worsening of spleen function (will have absent spleen function at entry). At entry into the HUSOFT pilot trial, liver-spleen scans showed absent uptake in 24% of patients at entry (mean age 15 months). After 2 years on HU (mean age 39 months) 47% of the scans were interpreted as demonstrating absent uptake (functional asplenia). Since the CSSCD pitted cell count data suggest that functional asplenia should have been present in 34% of patients _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-4 of 4-37 at entry and 80% at exit, HUSOFT suggests a possible spleen protection benefit compared to untreated patients (Pearson et al, 1985; Wang et al, 2001; Hankins et al, 2005). Therapy with hydroxyurea, however, may alter the ability of the pitted cell count to accurately reflect spleen function. A longer red cell life span (which may be expected to occur when fetal hemoglobin rises and intravascular hemolysis decreases during hydroxyurea therapy) will likely increase the pitted cell counts. Elevated levels of fetal hemoglobin may increase the rate of endocytosis, and thereby also increase the pitted cell counts. Conversely, preservation of spleen function while on HU therapy could maintain low pitted cell counts. Restoration of splenic function on HU therapy, analogous to the effect observed on chronic transfusion therapy, would be expected to decrease the pitted cell counts (Sills et al, 1988; Lane et al, 1996). The entry and exit 99mTc sulfur colloid liver-spleen scans will be individually read by a panel of three radiologists not involved in the acquisition of the images. Scans will be categorized as showing normal, decreased, or absent spleen function, and then will be compared for change. In the unlikely event of an apparent increase in splenic uptake of sulfur colloid, splenic function will be counted as stable. The proportion of patients whose paired scans demonstrate a decline in splenic function will be compared in the HU versus placebo groups. Statistical power to detect differences that are 50% (relative) or greater in the incidence of worsening of spleen function should be good to excellent, in view of the fact that over 80% of children with sickle cell anemia would be expected to lose splenic function completely by the end of the treatment period (Pearson, 1988). Scintigraphic assessment of splenic function is one of the two primary endpoints of BABY HUG. In a recent publication (Santos et al, 2002) on splenic function in older children (none in the BABY HUG age range) treated with hydroxyurea for sickle cell anemia, semi-quantitative analyses using spleen/liver ratios were conducted. However, only two of 21 (9.5%) patients in this before- after comparison showed large degrees of improvement, and one showed a large degree of deterioration. Small differences that were interpreted as improvement could be random noise. In HUSOFT, only one of 17 (5.9%) patients (most in the BABY HUG age range) had improved spleen _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-5 of 4-37 function in a before-after assessment of hydroxyurea therapy. To evaluate the potential for splenic function improvement in BABY HUG, a blinded review of spleen function will be made in the BABY HUG study. Tables 4-1 and 4-2 show the power to detect a difference between categories of a trichotomous endpoint for varying levels of treatment and placebo patient improvement rates (in increments of 0.05) that are possible given the placebo incidence rate; the calculations in Table 4-1 assume a placebo incidence rate of worsening spleen function of 80/100 patients (see Section 4.4.3) over the course of two years whereas Table 4-2 is based on 60/100 (see Section 4.4.1.5). The boldface line in each table denotes the power “break-even” point between the dichotomous endpoint (assuming 20% of the patients have no spleen function at study entry and thus cannot worsen) and the ordinal endpoint. For example, in the current study design with a dichotomous endpoint, we have 96.8% power to detect a difference between the two categories (assuming a placebo incidence rate of 0.60 and 80 patients in each group). Thus, the boldface line in Table 4-2 is drawn along the 96.8% power continuum. For all treatment/placebo improvement rate combinations to the left of the line, the dichotomous endpoint will provide greater power; for all combinations to the right of the line, the ordinal endpoint will provide greater power. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-6 of 4-37 Table 4-1 Power for Ordinal Spleen Endpoint as a Function of Improvement Rates Placebo Incidence of Worsening Spleen Function = 0.80 Treatment Incidence of Worsening Spleen Function = 0.40 Alpha =0.04 N=100 in each group Y = Treatment “Improvement” Rate .05 .10 .15 .20 .25 .30 X = Placebo “Improvement” rate .05 99.5 99.6 99.8 99.8 99.9 99.9 .10 98.7 99.1 99.3 99.5 99.7 99.8 .15 96.7 97.7 98.3 98.7 99.1 99.3 Power (%) Where X and Y are splenic function improvement rates with the following constraints: Splenic Function Improvement Stable Worsen Placebo X (1-0.8) - X 0.8 Treatment Y (1-0.4) - Y 0.4 _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-7 of 4-37 Table 4-2 Power for Ordinal Spleen Endpoint as a Function of Improvement Rates Placebo Incidence of Worsening Spleen Function = 0.60 Treatment Incidence of Worsening Spleen Function = 0.30 Alpha = 0.04 N= 100 in each group Y = Treatment “Improvement” Rate .05 .10 .15 .20 .25 .30 .35 .40 .45 .50 .55 .60 .65 .05 92.3 95.2 97.2 98.5 99.2 99.6 99.8 99.9 100 100 100 100 100 X = .10 84.3 89.5 93.3 95.9 97.7 98.7 99.3 99.7 99.8 99.9 100 100 100 Placebo .15 72.3 79.9 86.0 90.8 93.9 96.3 97.9 98.9 99.4 99.7 99.9 99.9 100 “Improvement” Rate .20 56.0 65.4 73.9 81.2 87.1 91.6 94.7 96.9 98.3 99.1 99.5 99.8 99.9 .25 39.5 49.2 58.9 68.1 76.2 82.5 88.6 92.3 95.5 97.2 98.5 99.2 99.6 .30 24.0 32.2 41.4 51.1 60.8 69.8 77.7 84.3 89.5 93.3 95.9 97.7 98.7 .35 12.6 19.0 25.5 34.0 44.3 54.0 63.6 72.3 79.9 86.0 90.4 94.2 96.3 Power (%) Where X and Y are splenic function improvement rates with the following constraints: Splenic Function Improvement Stable Worse Placebo X (1-0.6) - X 0.6 Treatment Y (1-0.3) - Y 0.3 _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-8 of 4-37 Both tables indicate that, in general, high rates of splenic function improvement are needed before the ordinal endpoint provides greater power than the dichotomous endpoint. Both endpoint types have high power (> 99%) when the placebo improvement rate is low and the placebo incidence rate is high. However, in general, an ordinal endpoint for BABY HUG would have less power than a dichotomous endpoint unless at least 20% of patients have improved spleen function. At the end of the Feasibility and Safety Pilot Study, it was determined that the spleen endpoint will be kept dichotomous as currently described in the Protocol. The ordinal spleen endpoint will be included as a secondary outcome. Kidney - Glomerular Filtration Rate (GFR) This endpoint has been removed as of May 29, 2009. 4.3 SECONDARY AND SAFETY ENDPOINTS 4.3.1 Central Nervous System In addition to potential HU toxicity or protection of brain development, CNS infarction may occur during this study period and this will affect outcome. In the CSSCD, at the time of first CNS evaluation (around 6 years of age), 5% of children with HbSS disease had experienced a clinical CVA (Armstrong et al, 1996; Moser et al, 1996). Other CSSCD findings related to stroke suggest that the first clinical CVA may occur by 2-3 years of age (Ohene-Frempong, 1991). Evaluation of neurodevelopmental functioning will help determine whether HU (a) increases developmental risk, either through an increase in the occurrence of CNS infarction or some other pathophysiologic process (e.g., vascular formation and function, metabolic activity, hypoxia; Brown et al, 1993), (b) decreases infarction risk, or c) has no effect on CNS development. These evaluations are particularly sensitive to a child’s neurodevelopmental course during the first years of life. They make comparisons based on normative motor (gross motor and fine motor) and language and verbal skill development during the first 3.5 years of life, and these discriminate between children with disease progression and those with no disease progression (Gay et al, 1995). _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-9 of 4-37 Neurological examinations and neuropsychologic evaluations with Bayley and Vineland tests will be performed annually, and compared between treatment groups as part of early and ongoing monitoring as well as for the 2-year outcome. Head circumference measurements will be performed quarterly and compared to a normal black population (Pivnick et al, 1999). 4.3.2 Spleen 99mTc sulfur-colloid liver-spleen scans provide significant information about spleen function but, since they involve radionuclide exposure, cannot be repeated frequently. During the process of aging, the red cell membrane forms vacuoles, which appear on the surface of the cell as “pits” under Nomarski optics. Pitted or pocked red cells are removed from the circulation by splenic macrophages. Thus the percentage of red cells with pits increases as splenic function declines (Pearson et al, 1985). Pearson reported that pit counts >3.5% correlated with nonvisualization of the spleen on liver-spleen scan (Pearson et al, 1969). Thus, serial pitted cell counts can theoretically serve as a surrogate for liver-spleen scan determinations of splenic function in the most patients with sickle cell anemia. However the cumulative effect of hydroxyurea therapy on pitted cell counts is not known. Pitted cell counts are performed as follows: One drop of EDTA anticoagulated fresh venous blood is fixed in 0.5 ml of isotonic 1% buffered glutaraldehyde. One thousand cells are counted under Nomarski differential interference contrast microscopy and scored for percentage of pitted cells by an experienced technologist. The test should be performed in a laboratory with demonstrated long term interest and expertise in order to assure that the numerical values at the end of the study can be compared to those at the start. Entry, exit and interim pitted cell counts will be compared. Statistical models will be used to compare entry and exit values and test for trends. In this manner we may be able to validate the use of the pitted cell count, which is less invasive than the liver-spleen scan, to assess splenic function during hydroxyurea therapy. The proportion of patients in the HU treatment group compared to the placebo treated group with pitted cell counts above predetermined thresholds will _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-10 of 4-37 be a secondary outcome measure in BABY HUG. 4.3.3 Kidney Function and Bladder Control Proteinuria occurs in 6.2% of children with sickle cell anemia, and the rate increases with age (Wigfall et al, 2000). Microalbuminuria is an early marker of other nephropathies, and occurs in 26.5% of children with sickle cell anemia (Darnidharka et al, 1998); however, it was not detected in children under 7 years of age in the only reported study in children. Ultrasound imaging of the kidneys often reveals increased size and echogenicity (Miller, unpublished observations). Normal kidneys increase from approximately 6 to 8 cm in length over the first 4 years of life; in infants with a single functioning kidney, hypertrophy results in a length of 10 cm by the age of 3-4 yr. (Laufer and Griscom, 1971). Not only is renal failure a significant problem in adults with sickle cell anemia, the problem of enuresis and/or nocturia is nearly ubiquitous in children with sickle cell anemia, and is embarrassing and inconvenient. The CSSCD documented nocturia in 58% of 6 year-olds, and enuresis in 58% (75% of males). Forty-one percent of males remained enuretic at age 12 years. In comparison, 75% of normal children have nocturnal bladder control by 4 years of age (Rudolph and Kamei, 1998). Treatment of enuresis is often ineffective. Enuresis is related to loss of ability to concentrate urine. Enrolled patients’ urine concentration will be evaluated by measuring urine and serum osmolality, after overnight and early AM withholding of water at baseline (prior to random treatment assignment) and at the end of study treatment (e.g., this could be incidentally accomplished when the children are NPO for abdominal sonogram studies). Urine and sera will be shipped to the Hematology and Biochemistry Core Laboratory for measurement of the urine osmolality (mOsml/kg water), and serum osmolality and creatinine (LaPorte-Wijsman and Struyker- Boudier, 1967). Specific gravity will be measured locally at the Clinical Center on routine urinanalysis. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-11 of 4-37 4.3.4 Abdominal Sonogram Although hepatomegaly commonly occurs in infants and young children with sickle cell anemia and some patients have total indirect bilirubin levels in excess of that attributable solely to hemolysis (recently attributed to mutations of the glucuronosyl transferase gene), hepatic dysfunction, as detected by direct hyperbilirubinemia, elevation of liver specific enzymes (ALT), hypoalbuminemia, or coagulopathy, is rare; in fact if it occurs, other causes must be carefully sought. However, as with most chronic hemolytic disorders, cholelithiasis is common in sickle cell anemia. Bilirubinate pigment stones have recently been estimated to occur in 14% of children by age 10 years. However, an early study using only radiography found gallstones in 17% of children under the age of ten (Schubert, 1986; Stephens and Scott, 1980). Only about 50% of pigment stones are radio-opaque, suggesting that there may have been a much higher incidence of stones in this early series. While often stones are asymptomatic, cholecystectomy is nonetheless a common elective surgical procedure in individuals with sickle cell anemia and sometimes must be performed urgently (Vichinsky et al, 1995). Common duct obstruction is a common and morbid complication of cholelithiasis. Cholelithiasis is best diagnosed by ultrasonography (Sarnaik et al, 1980). Hydroxyurea therapy, by increasing total and fetal hemoglobin and reducing hemolysis, might reduce the incidence of gallstones. Abdominal ultrasonography techniques will visualize the kidneys and right upper quadrant, and sonograms can be read centrally with attention to presence or absence of gallstones or sludge, the presence or absence of gall bladder thickening or duct dilation, renal volume and echogenicity, liver enlargement and spleen volume and size. 4.3.5 Pulmonary The pulmonary system is adversely affected by SCA, in particular because of the phenomenon of the acute chest syndrome (ACS). There is evidence that the development of chronic lung disease in adults with SCA is associated with recurrent episodes of ACS (Santoli et al, 1998). Several methods have been used to assess pulmonary function in patients with SCA, _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-12 of 4-37 including transcutaneous pulse-oximetry. The progression of pulmonary dysfunction in SCA may be assessed with pulse oximetry, which measures hemoglobin oxygen saturation transcutaneously. Although there are some methodologic problems with its use in sickle cell anemia due to abnormal hemoglobin oxygen half-saturation (P-50) in HbSS patients, this non-invasive, inexpensive technique has been the most widely studied method in SCA. In a study of 108 children with SCA, those with histories of ACS had lower saturations (mean = 94%) than those without a history of ACS (mean = 98%) (Rackoff et al, 1993). Oxygen saturation by pulse oximetry will be measured at entry and every three months. 4.3.6 Anthropometry Standing or sitting weight will be measured at every clinic visit (see Appendix E). Recumbent length (standing height after 18 months of age) and head circumference (see Appendix E) will be obtained quarterly. These measurements will be checked for quality with longitudinal data analysis methods and compared between treatment groups using t-tests and longitudinal data analysis. 4.3.7 Chromosome Analysis Karyotype and chromosome breakage studies will be performed to determine whether or not hydroxyurea is clastogenic in children. Hydroxyurea has been clastogenic in onion root tips and alters mouse testicular kinetics and sperm chromosome structure, but it is not certain whether hydroxyurea is clastogenic in humans (Evenson and Jost, 1993). 4.3.8 Acquired DNA Mutations Mutation events will be evaluated centrally in a defined DNA model to determine whether or not hydroxyurea is mutagenic. The mutagenicity of hydroxyurea is controversial. Mutation analyses will be performed for illegitimate T cell receptor (VDJ) recombinations in the Mutation Analysis Core Laboratory at St. Jude Children’s Research Hospital. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-13 of 4-37 4.3.9 Immune Function Because hydroxyurea has the capacity both to suppress immune response and to alter spleen function, it is of interest to observe directly the effect of hydroxyurea on antibody formation and on immune cell populations. To this purpose, specific antibody titers and opsonization assays before and after measles-mumps-rubella (MMR) immunization and conjugate pneumococcal immunization will be compared between the treatment groups. Also, T-cell subpopulations will be evaluated by flow cytometry. 4.3.10 Clinical Events All patients will be monitored for the occurrence and severity of clinical events. These will be identified through the use of standardized history questions administered at each clinical encounter. At each visit, parents will be asked to describe any illnesses experienced since the last visit. If illness is reported, a directed history will be obtained to allow its characterization. All events will be reported utilizing standardized definitions (See Appendix F) on an Events Form. Documentation (discharge summaries, clinic/emergency department records, local laboratory values or radiology reports) for all fatal or life threatening events will be collected by Clinical Center staff for review. Events of interest include bacteremia with known pathogens, meningitis, splenic sequestration, acute chest syndrome, stroke or transient ischemic attacks, osteomyelitis, all hospital admissions and any event for which the patient receives a transfusion. Selected events and supporting documentation collected by Clinical Center staff will be reviewed centrally by two pediatric hematologists who are not involved in the BABY HUG Clinical Center. Pain (Platt et al, 1991) and acute chest syndrome (Castro et al, 1994) are the most frequent complications of sickle cell disease and most frequent causes of hospitalization. In addition to causing substantial morbidity, both have been associated with early death (Platt et al, 1994), and acute chest syndrome has been associated both with chronic sickle cell lung disease (Powars et al, 1988), a major cause of morbidity in adults, and also with increased risk of infarctive stroke (Ohene-Frempong et al, 1998). One of the earliest clinical manifestations of sickle cell disease, _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-14 of 4-37 dactylitis, is associated with adverse clinical outcomes later in childhood in the Jamaican cohort (Stevens et al, 1981), and recently early onset of dactylitis was associated with an increased risk of death, stroke, or recurrent pain and acute chest syndrome later in childhood in the Cooperative Study of Sickle Cell Disease (Miller et al, 2000). The Multicenter Hydroxyurea Study (MSH) was stopped early due to significant reduction in these major sickle cell complications (Charache et al, 1995). Several single institution pediatric trials have suggested that similar beneficial clinical effects will be seen in children treated with hydroxyurea (Ferster et al, 1996; Jayabose et al, 1996; Maier-Redelsperger et al, 1999; Olivieri and Vichinsky, 1998; Scott et al, 1996). In the newborn cohort, comprised of infants enrolled to the CSSCD prior to six months of age, frequencies of complications in infants with Hb SS per 100 patient-years of observation were reported (Gill et al, 1995). Table 4-3 summarizes the frequencies. Table 4-3 Complication Frequencies in Infants with Hb SS Per 100 patient-years of observation CSSCD AGE PAIN EVENT ACUTE CHEST < 6 mos 2.9 6.8 6-12 mos 9.5 16.4 1 yr 24.0 26.8 2 yr 38.3 26.3 3 yr 42.4 34.2 4 yr 49.6 25.5 In comparison, event rates among the HUSOFT children, who were treated with hydroxyurea starting at six to twenty four months of age and followed for up to two years were 17/100 patient years for pain events and 15/100 patient years for acute chest syndrome occurrences. These data suggest that hydroxyurea may have clinical efficacy in these very young children. While the acute chest syndrome in children may be different than that seen in adults (Castro et al, 1994; Golden et al, 1998; Vichinsky et al, 1997), with children having more infectious causes, _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-15 of 4-37 it is clear that, at least in older children with sickle cell disease, chronic transfusion substantially reduces the frequency of this complication in the pediatric population. Both in a retrospective review by Oakland Children’s Hospital (Styles and Vichinsky, 1994) and in a prospective analysis of the patients enrolled in the Stroke Prevention in Sickle Cell Anemia (STOP) (Miller et al, 2001) there were reductions in acute chest syndrome with transfusion. Hydroxyurea therapy may similarly reduce frequency of these events in BABY HUG. Since the primary concern of the BABY HUG investigators is the prevention of organ damage, the study will not be terminated for any demonstrated advantage of hydroxyurea over placebo in terms of the occurrence of clinical events. If these expectations are proven incorrect, and hydroxyurea is associated with a demonstrably increased frequency of death, stroke, acute chest syndrome or consequential splenic sequestration events, the study would be terminated. Events to be centrally reviewed include all Serious Adverse Events (e.g., death, events that are life-threatening, events that cause or prolong hospitalization greater than 7 days, splenic sequestration crisis, acute chest syndrome, stroke, transient ischemic attacks, ICU admissions and any AE that is related to study treatment and unexpected). Other clinical occurrences will be denoted as having occurred or not occurred on clinic visit reports. There is adequate statistical power in BABY HUG to detect 50% differences between treatment groups at alpha = 0.01 if the event rates are in the range expected from the CSSCD and the study is completed with 200 patients. The BABY HUG investigators do not plan for early termination based on clinical events other than demonstrated inferiority of hydroxyurea for the outcomes death, stroke or splenic sequestration. 4.3.11 Transcranial Doppler Measurements In children between the ages of 2 and 16 years, an abnormal TCD velocity (200 cm/sec or more) in the proximal middle cerebral artery or distal internal carotid artery has been found to predict a high risk of stroke. In the STOP study, a randomized trial in which chronic transfusion was compared with observation in patients with abnormal TCD velocities, a greater than 90% reduction _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-16 of 4-37 in stroke risk was associated with transfusion (Adams et al, 1998). More recently, Zimmerman and Ware (Zimmerman et al, 2002) have presented evidence that hydroxyurea treatment in school-aged children is associated with a lower TCD velocity, in part related to improved hemoglobin levels. In addition, Bowman and Adams (Bowman et al, 2002) have recently presented information indicating that TCD measurements can be performed in very young children with sickle cell disease, ages 2- 21 months (mean 11 mo.); 23 of these 27 children were able to have TCD studies performed and in 22 of those 23, meaningful results were obtained (although only 7 had complete studies). The mean TCD velocity was 109 cm/sec., substantially lower than in school-aged children. Studies from the French group led by Bernaudin (Bernaudin et al, 2001) have also shown a lowering of TCD velocity in children (age 3-18 years) when treated with hydroxyurea. These data raise the possibility that infants who are randomized to hydroxyurea in the BABY HUG trial may have a lower TCD velocity compared to the control group receiving placebo. If TCD velocity is considered a surrogate marker for stroke risk in this population, velocities may provide a continuous variable which can be used as an endpoint of hydroxyurea efficacy. There are, however, a number of unanswered questions: Are the lower velocities seen in infants with sickle cell disease likely to be modulated by hydroxyurea? Are the effects, if any, mediated by changes in hemoglobin level and other red cell properties? Does a lowering of TCD within the normal range (for example, from 150 to 130 cm/sec) actually result in a reduced stroke risk? At this time, these questions cannot be fully addressed and, therefore, TCD would not be likely to be useful for addressing the primary objective of BABY HUG: Does hydroxyurea prevent organ damage? However, the potential for TCD measurements to provide relevant data on the risk of CNS events in this population warrants inclusion of these studies as a secondary endpoint for evaluating prevention of organ damage by hydroxyurea. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-17 of 4-37 4.4 STATISTICAL CONSIDERATIONS IN DESIGN AND STUDY SIZE 4.4.1 Feasibility and Safety Pilot Study The Feasibility and Safety Pilot Study has been completed and these sections have been removed for the sake of Protocol continuity. The relevant modifications, based on information from the Feasibility and Safety Pilot Study, have been incorporated into this Protocol revision. 4.4.2 Primary Treatment Comparison (Full Phase III Trial) Most of the studies conducted in BABY HUG will compare the effect of treatment with hydroxyurea (HU) to treatment with placebo (PLBO). This study will be conducted with one primary endpoint: worsening of spleen function from normal to decreased or absent, or from decreased to absent on uptake of technetium sulfur colloid. The primary analysis in the full Phase III trial will be done using an intention-to-treat principle. Patients randomly assigned to a treatment will be analyzed according to the assigned treatment, irrespective of whether the treatment was actually given. The spleen endpoint will be tested at an overall alpha = 0.04. An interim monitoring plan is proposed for each of these endpoints. The interim monitoring plan will be constructed such that the experiment-wise error rate of the study is preserved at the specified overall alpha levels (0.04 for spleen). The monitoring plan will reserve most of the alpha level for the final comparison. The shape of the rejection regions will follow a Haybittle (Haybittle, 1971) type plan with consistent, wide bounds set for the interim analyses and a bound for the final analysis approximately equal to the critical value that would be used if there were no interim monitoring. Actual allocation of alpha will be done using the spending functions of Lan and DeMets (Lan and DeMets, 1983). The BABY HUG investigators considered using a single primary endpoint for this study and developing composite scores of different endpoints. Five different organs were considered: the brain, lung, spleen, liver, and kidney. The rationale follows: Primary endpoints based on neurological and neuro-imaging evaluations were excluded because the incidence of central nervous system injury is too infrequent (e.g., stroke less than 1 _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-18 of 4-37 per 100 children per year) for a study of 200 very young children. Also, central nervous system outcomes will be monitored for safety as are continuous measures of brain function (e.g.,neuropsychological tests and head circumference). Differences in transcranial doppler (TCD) velocities have not yet been confirmed as clinically important below 170 cm/sec and have not been shown to be clinically useful in children less than two years old. All of these assessments are of interest as secondary endpoints. The lung was excluded since there are no reproducibly good pulmonary function tests over this age range; spirometry is hard to obtain on infants and pulse-oximetry lacks the variability necessary to be considered as a primary endpoint (e.g., infants do not vary much from 94-98% under normal circumstances). Liver damage that could be detected using standard measures is rare in untransfused very young children. The incidence of gallstones in very young children is expected to be low. As described fully in Chapter 1, spleen function deteriorates rapidly in the absence of treatment, and treatment with HU may have a substantial effect on this endpoint over a two-year period. Spleen function on 99mTc sulfur colloid liver-spleen scan can be characterized as normal, decreased or absent. This evaluation of the spleen is categorical in nature. Categorical endpoints generally require greater sample sizes than continuous measures to detect clinically meaningful differences. DTPA GFR was originally a primary endpoint for this study but its measurement was discontinued as of May 29, 2009. The features common to power evaluations for this endpoint are the critical values used to determine the alpha level and power. We have designated these values as Z" and Z$ respectively. ”N” is the number of children in each treatment group necessary for this study. We have presented the formulas for study size calculations, but each of these formulas can be algebraically rearranged to provide corresponding power calculations. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-20 of 4-37 is the average of p1 and p2, = 1- and N = study size (each group). The overall alpha level p q p of this comparison will be alpha = 0.04 (two-tailed). We will test the null hypothesis: HO: p1 = p2 versus the alternative: HA: p1 …p2. There are four planned interim reviews of this endpoint by the DSMB over the course of the study. Allowing for sequential tests of the endpoint, nominal values of Z = 3.5 will be used for interim looks, the final comparison will be performed at a nominal alpha level of 0.0394 (Z" =2.06). It is assumed that the rate of worsening function of the spleen will be at least 80% in the PLBO group. Figure 4-1 presents the power to detect 50% reductions in the spleen endpoint event rate as a function of a range of anticipated placebo event rates for categorically worse or absent spleen function by the end of the study, and of a range of possible sample sizes from 20 to 100 per group. A review of this figure shows that the proposed study will have adequate power (80% or more) to detect 50% reductions in the rate of absent spleen function in the HU group, provided that the sample size is 70 or more in each of the treatment arms. Even with 20% of the initial study population classified as having absent spleen function, the realized sample size of 160 infants (80 in each group) will have more than 90% power to detect a 50% reduction in the incidence of the endpoint as a result of the administration of HU, if the PLBO group incidence of this endpoint is 60% or more. With 30% of the initial study population classified as having absent spleen function, the realized sample size of 140 infants (70 in each group) will have more than 80% power to detect a 50% reduction in the incidence of the endpoint as a result of the administration of HU. Based on CSSCD data, by 48 months of age, at least 80% of patients assigned to placebo are expected to have absent spleen function. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-21 of 4-37 The power to detect a 50% reduction in worsening of spleen function for the current study design is shown graphically in Figure 4-1 for five placebo incidence (of worsening) rates. In the presence of treatment crossover, both the placebo and treatment incidence rates are adjusted (the placebo rates decrease and the treatment rates increase), and the power to detect a difference is calculated based on these adjusted incidence rates. Table 4.4 shows the reductions in power resulting from crossovers (children assigned to hydroxyurea who discontinue taking the treatment or children assigned to placebo who take hydroxyurea) according to four levels of treatment and placebo crossover rates (0.05, 0.10, 0.15, 0.20), two levels of placebo (0.80 and 0.60) and treatment initial incidence rates, two levels of sample size and alpha=0.04. The adjusted rates are the initial incidence of worsening rates adjusted for the specified crossover rate and are shown in the table in parentheses under the crossover rates. The sample sizes used assume either 20% or 30% of the initial study population are classified as having absent spleen function, resulting in N=80 and N=70 (in each group), respectively. The first two sub-tables in Table 4-4 show that for a placebo incidence rate of 80% for worsening of spleen function (dichotomous outcome) and low crossover rates (i.e., 10% or less), the study has at least 97% power to detect a difference between the treatment and placebo. This level of crossover presents no threat to the integrity of BABY HUG. The last two sub-tables show that for an incidence rate of 60% for the placebo combined with low noncompliance rates, the study has at least 80% power to detect a difference. Thirty percent crossover will be a threat to study integrity. The BABY HUG investigators will do everything possible to prevent treatment crossovers. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-22 of 4-37 Table 4-4 Power Tables for Treatment Crossover Alpha = .04 Treatment crossover rate (adjusted incidence rate) 0.05 (0.42) 0.10 (0.44) 0.15 (0.46) 0.20 (0.48) Placebo crossover rate (adjusted incidence rate) .05 (0.78) 0.997 0.994 0.987 0.976 Placebo incidence rate = 0.80 Treatment incidence rate = 0.40 Power (100% compliance) = 1.00 N=80 in each group 0.10 (0.76) 0.993 0.986 0.973 0.952 0.15 (0.74) 0.985 0.971 0.948 0.914 0.20 (0.72) 0.969 0.945 0.909 0.859 Treatment crossover rate (adjusted incidence rate) 0.05 (0.42) 0.10 (0.44) 0.15 (0.46) 0.20 (0.48) Placebo crossover rate (adjusted incidence rate) .05 (0.78) 0.993 0.986 0.975 0.956 Placebo incidence rate = 0.80 Treatment incidence rate = 0.40 Power (100% compliance) = 0.999 N=70 in each group 0.10 (0.76) 0.985 0.972 0.952 0.922 0.15 (0.74) 0.970 0.949 0.917 0.873 0.20 (0.72) 0.946 0.913 0.867 0.808 _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-23 of 4-37 Treatment crossover rate (adjusted incidence rate) 0.05 (0.315) 0.10 (0.33) 0.15 (0.345) 0.20 (0.36) Placebo crossover rate (adjusted incidence rate) .05 (0.585) 0.924 0.890 0.846 0.793 Placebo incidence rate = 0.60 Treatment incidence rate = 0.30 Power (100% compliance = 0.968 N=80 in each group 0.10 (0.57) 0.892 0.848 0.795 0.733 0.15 (0.555) 0.851 0.798 0.736 0.666 0.20 (0.54) 0.801 0.739 0.669 0.594 Treatment crossover rate (adjusted incidence rate) 0.05 (0.315) 0.10 (0.33) 0.15 (0.345) 0.20 (0.36) Placebo crossover rate (adjusted incidence rate) .05 (0.585) 0.885 0.843 0.793 0.735 Placebo incidence rate = 0.60 Treatment incidence rate = 0.30 Power (100% compliance) = 0.944 N=70 in each group 0.10 (0.57) 0.846 0.795 0.737 0.673 0.15 (0.555) 0.798 0.740 0.675 0.605 0.20 (0.54) 0.743 0.678 0.608 0.535 Analysis of GFR This endpoint evaluation was discontinued on May 29, 2009. 4.4.4 Data Analysis 4.4.4.1 Introduction Primary analyses for BABY HUG will focus on estimating treatment effects on the designated primary endpoint: loss of spleen function. Assessment of treatment differences will be based on pooling data across all participating Clinical Centers using all patients entered. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-24 of 4-37 Secondary analyses will develop statistical models to determine associations and relationships between dependent variables, risk factors and the treatment variable. Analysis of binary endpoints will be accomplished using contingency table analysis. Significance of results will be assessed with the Chi-square test uncorrected for continuity or Fisher’s exact test. If necessary, contingency table analyses will be adjusted for confounding variables using logistic regression. For continuous variables, comparisons of groups will be accomplished using Student’s t test or the Wilcoxon rank sum test depending on the distributional properties of the data. Stratified designs will be analyzed using regression methods with the strata represented as randomized blocks for the analysis. Analysis of continuous and categorical endpoints that are measured repeatedly over time, such as serial neuropsychological tests, weight, height, etc. will use longitudinal data analysis models (Laird and Ware, 1982; Schlucter, 1992; Liang and Zeger, 1986; Andersen and Gill, 1982). Estimation in these models can be in terms of point and interval estimates or trends (i.e., slopes of growth curves) over time. The comparison between two treatments of time to event endpoints will be evaluated using the log-rank statistic. We will use the LIFETEST procedure in SAS to perform the test. The cumulative distributions of this outcome will be estimated using the methods of Kaplan and Meier (Kaplan and Meier, 1958). Multivariate adjustments to this comparison will also be made using the PHREG procedure for SAS to accomplish Cox proportional hazards models analyses (Cox, 1972). Non-proportionality of the hazards will be investigated by plotting log[-log(S(t))], in which S(t) is the survival function, for important stratifying variables such as age and gender. Should the above functions be non-parallel (and/or cross) for any of the specified variables (p < 0.01), the primary analysis will be stratified by those variables. Cox proportional hazards models will be stratified for variables that demonstrate non-proportional hazards (crossing or non-crossing). Once determined, we will include these variables as stratification variables in the Cox regression. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-25 of 4-37 Analyses for the regressors will be summarized across the strata. Patients who are lost to follow-up before the end of the follow-up interval will be censored at the time of their last visit. 4.4.4.2 Regression Analyses and Adjustment We will adjust study results for potential confounding factors in secondary analyses. The most important of these analyses may test whether the distributions of the primary and secondary endpoints differ by the age of enrollment of the infant. For these evaluations, we will divide the infant population into those who are less than 15 months of age at the time of enrollment and those who are 15 months of age or more at the time of enrollment. Tests of interaction will be performed to determine if treatment effects are different in these two groups of infants. We plan to use regression methods to evaluate the significance of the hypothesized interactions. This will be done by multiplying an indicator variable for the birth cohort (1 = less than 15 months, 0 = 15 months or older) times treatment (1 = HU, 0 = PLBO) and evaluating the beta coefficient associated with this variable. If significant (p < 0.01), we will report that treatment effects differed according to the age of enrollment. Interaction tests such as these are low in power to detect specified alternatives (half the efficiency of a main effects comparison). Additional analyses will be required to support the discovery of a proposed interaction, as a large number of interaction tests will be performed and some, by chance, will be found to be significant. The addition of confounding variables generally improves the operating characteristics of analyses of the main effect, but given the small sample size, the number of confounding variables will be small in any secondary analysis. Given the small sample size proposed for this analysis, it may be necessary to limit the number of confounders in any one analysis to five or ten. We will use step-wise regression methods to isolate and include the most important confounding variables in the regression model. We will use SAS procedures to perform adjusted analyses, PROC GLM to perform randomized block analysis of variance, PHGLM to perform stratified and standard Cox proportional hazards analyses, PROC GENMOD and MIXED to perform longitudinal data analyses, and PROC _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-26 of 4-37 LOGISTIC to perform unconditional logistic regression. The standard output from these procedures provide point estimates for the regression coefficients, standard error estimates and confidence intervals. The results of these analyses are printed into computer files so that they can be directly inserted in progress reports using PROC REPORT. In some instances, the procedures in SAS will not suffice since SAS procedures usually do not include methods to incorporate information about missing data, nor do they include complex models specifically designed to relate a biological process with the risk of disease progression. We will use PROC IML and PROC NLIN to program the required models if necessary. 4.4.4.3 Missing Data - Prevention and Analysis BABY HUG will use the methods of Probstfield (Shumaker et al, 1990; Probstfield et al, 1986) for improving adherence with follow-up. A key feature of this approach is the management of parents who show signs of dropping out of the study. Senior level clinical staff will contact these families in an effort to improve compliance with the next visit. This action conveys a sense of how important the child is to the study and can increase the parent’s compliance with future follow-up visits. For those patients who are already missing visits, the Principal Investigator of a Clinical Center can contact the parents to assure that they continue with the follow-up visits. As part of the conversation, the Principal Investigator can negotiate with the parents (or guardians) on the parts of the study they are willing to complete. By prioritizing the components of the Protocol, a mutually acceptable follow-up procedure can be established for the patient. We will generally use the methods of Rubin (Little and Rubin, 1987) to impute missing data from patients’ records with complete data to complete the records for patients with missing data. This method has been accepted by the U.S. Food and Drug Administration (FDA) as a legitimate method for correcting for missing data. We will also use analyses involving rank statistics in which patients who die or have bad clinical events are given the worst rank for other dependent variables. We have successfully used this technique in the analysis of the MSH (McMahon et al, 1992; McMahon et al, 1997). For categorical data, or time to event data, the composite endpoint of death _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-27 of 4-37 or the event (such as occurrence of acute chest syndrome) can be used. 4.4.5 Interim Monitoring During the course of this study, the BABY HUG Data and Safety Monitoring Board (DSMB) will carry out interim data analyses to monitor the study for evidence of beneficial and adverse treatment effects. The DSMB will review reports on study performance including recruitment, protocol violations, complications of treatment, patients lost to follow-up, submission of forms, quality of laboratory and forms data submitted, monthly during the Feasibility and Safety Pilot Study and semiannually (months 6, 12, 18, 24, 36, 42 and 48) from the start of Feasibility and Safety Pilot Study enrollment. The study will also be monitored for efficacy with respect to the two co-primary endpoints and for adverse events. Below we present the proposed interim monitoring plan for efficacy for the BABY HUG study. This plan will call for five primary endpoint analyses (four interim analyses and one final analysis) during the course of the study. The first interim analysis will be conducted with data collected on children enrolled in the Feasibility and Safety Pilot Study. Extreme evidence (nominal alpha = 0.0005, Z = 3.5) of treatment differences will be required in the interim analyses to demonstrate the efficacy of the proposed intervention for either endpoint. The use of these extreme Z values will allow for final nominal alpha levels for each co-primary endpoint to be just under the specified alpha level for the study (nominal alpha = 0.0394, Z = 2.06 for spleen function. Table 4-7 shows the nominal alpha levels expected to be used during the course of the study. TABLE 4-7 P-Values for Interim Analyses Month of Study Type of Report p-value (Spleen) 27 Interim 0.0005 33 Interim 0.0005 39 Interim 0.0005 45 Interim 0.0005 51 Final analysis 0.0394 _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-28 of 4-37 If appropriate, the DSMB may recommend revising the interim analysis schedule by altering the proposed number and/or dates of the interim analysis; the method of Lan and DeMets (Reboussin et al, 1992; Lan and DeMets, 1983) will be used to determine the actual “spending” of the alpha over the course of the study. The interim analysis reports for the DSMB will include, but are not limited to comparisons by treatment group for: 1. Primary endpoint; Spleen – worsening of function on scintigraphy 2. Secondary endpoints; Clinical Events (See Appendix F) Laboratory Evaluation 3. Adverse events; Serious Adverse Events (See Table 4.8) Splenic Sequestration Abnormal Neurological Tests Abnormal Neuro-development Evaluation Abnormal CBC Abnormal Chemistry 4. Distributions of baseline characteristics; Gender Age at Entry Initial Spleen and Kidney Function Initial Transcranial Doppler Measurements Initial Neuropsychosocial Testing Level _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-29 of 4-37 5. Clinical Center Performance; Recruitment Completeness of Follow-up Submission of Forms Quality of Forms Data Distribution of Specimens to Core Laboratories Drop Out Rate. Monitoring Safety and Adverse Events The DSMB Chair, Executive Secretary of DSMB, and NHLBI and NICHD Project Officers will review monthly reports including: 1. Recruitment: Expected vs. Actual 2. Patients screened, eligible and randomized 3. Patient characteristics at baseline A. Age, race and gender B. Spleen function C. Spleen size D. Pitted cell counts E. Schwartz equation GFR estimates F. Urine concentrating ability G. CBC H. Presence of gallstones I. Blood chemistries J. Microalbuminuria K. O2 saturation L. Physical examinations _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-30 of 4-37 M. Neurological examination and neuropsychological development N. Height, weight, head circumference O. Transcranial doppler (TCD) measurements 4. Blood count toxicities 5. Dose adjustments 6. Intra- and Inter-observer agreement liver-spleen scans 7. Immunological impairment 8. Safety assessments and adverse events A. Height, weight, head circumference B. Neurological examination and neuropsychological development C. Unexpected and serious adverse events: update tallies, rates and individual summaries (case reports) for immediate review by DSMB Chair, Executive Secretary of DSMB and Project Officer 4.4.6 Safety Related Outcomes Adverse event (AE) forms will be submitted to the MCC and tabulated based on the affected organ system according to standardized monitoring procedures (e.g., the National Cancer Institute Cancer Therapy Evaluation Program Adverse Event Expedited Reporting System). Table 4-8 defines adverse events and specifies classification and reporting considerations. The timing of the AE report will depend upon the nature of the AE. If the AE is serious, Clinical Center staff will be instructed to report the AE to the MCC within 24 hours of the event. MCC staff will immediately review the material and forward it to the central review group. If the central review group finds that an event is serious, MCC staff will attach the treatment assignment to the report, and send the information to the DSMB Chair, Executive Secretary of DSMB and the NHLBI and NICHD Project Officers for review. This AE will be tabulated with the other AEs that have been reported for the study and a systematic review will be made to determine if one treatment has more _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-31 of 4-37 reports of serious AEs than the other treatment. The occurrence of serious AEs will be reported to the FDA promptly after the Executive Secretary of the DSMB and the Project Officer review. The Clinical Center will report the occurrence of serious AEs that occur at their institution according to the requirements of their local IRB. Other AEs will be collected and tabulated by treatment group on a monthly basis. A critical value corresponding to p = 0.05 will be used for each AE evaluation (except for the events discussed earlier). The approach here will be to err on the side of detecting a trend early rather than protecting alpha. Depending upon the evidence accumulated and severity of the events, it will be the responsibility of the DSMB Chair, Executive Secretary of DSMB and the Project Officer to decide whether a full meeting of the DSMB is necessary to discuss the results and make recommendations, whether a conference call is necessary, or whether the report warrants no further action. The MCC staff plan to send a written notification to the DSMB Chair, Executive Secretary of DSMB and the Project Officer for each severe complication and if any severe complication is found six times in one treatment group without a single occurrence in the other treatment group. If six complications have been observed, all in one of the treatment groups, the alpha level of rejecting the null hypothesis of no treatment effect on the appearance of the adverse event is less than 0.05 and suggests that the risk of this complication in one group is not equal to the risk of complication in the other group. The alpha level of rejecting the null hypothesis of no treatment effect is obtained by using a binomial approximation for the log-rank statistic. If complications occur in both treatment groups, a 95% confidence interval for the difference between proportions for the assigned study treatments will be used to compare the occurrence of symptoms which are potential adverse effects of treatment, such as a neurological deficit. If the confidence interval for the difference in these proportions does not cover zero, the Project Officer will be notified promptly. The Executive Secretary of DSMB and the Project Officer in consultation _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-32 of 4-37 with the DSMB Chair will then recommend whether there should be an emergency meeting (or conference call of the DSMB) to determine the appropriate actions for this trial. 4.4.7 Pharmacokinetics of Hydroxyurea (HU) NOTICE: Exit PK Studies are not being collected as of May 29, 2009. Full pharmacokinetic (PK) studies of hydroxyurea will be performed on all children (both HU and placebo) at entry and exit, at the times that the DTPA measurements for GFR are made. The results of PK analyses from the Feasibility and Safety Pilot Study suggest that the time frame for sample selection should be changed from 0,1,2,4,and 8 hours to 30,90, and 210 minutes. These informative times of blood collection for the PK studies will coincide exactly with blood collection times for the DTPA measurement without any further requirements for additional blood by administering the daily dose of study treatment 30 minutes after the DTPA procedure is started. Figure 4-2 shows an overlay of the collection schedule for these two PK and DTPA studies. Standard blood collections for the DTPA study were collected at 1,2, and 4 hours after the DTPA procedure was initiated. By lagging the administration of the study treatment, the blood collections will yield PK data points at 30, 90, and 210 minutes. Based on data from the Feasibility and Safety Pilot Study, trivial residual HU concentrations are predicted to persist from a previous dose, thus collecting a pre-dose concentration adds little information, and these three post-dose blood collections will allow estimation of the PK curve for each infant. In addition, the collection times will allow the measurements to bracket the expected peak concentration for an infant as shown in the PK concentrations curve for the first 22 infants studied in the BABY HUG Feasibility and Safety Pilot Study (Figure 4-3). The collection of entry and exit PK specimens in this fashion imparts minimal risk and discomfort to the child. A third PK study will be done approximately one month (at the week 004 visit) after each child begins taking study treatment. Blood specimens will be collected at only two time points for this third study as it does not coincide with a DTPA procedure. The time points for collection will be 30 and 90 minutes after the daily dose of study treatment is administered. The collection of specimens _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-33 of 4-37 at these two time points after one month of study treatment administration will allow the study investigators to confirm that first dose HU pharmacokinetics predict HU exposure with chronic administration. The collection of these two additional data points represents a minimal risk assessment since only one extra venipuncture is required. All of the data from the HU assays will be analyzed using population pharmacokinetic models. A one-compartment open model with first order elimination will be utilized. First order absorption, with and without lag times, will be evaluated as well as other input functions justified by the data. The data will be modeled recognizing the two stages of a non-linear hierarchical model. The first stage introduces the structural model (e.g., the one compartment open model), the population parameters, individual effects, and within-patient variation. The second stage of the model recognizes that variation between patients in pharmacokinetic parameters exists, and will attempt to determine covariates that may identify different pharmacokinetic subpopulations. The collection of these data will support the New Drug Application to the FDA for package insert specifications about the metabolism of the liquid formulation of hydroxyurea for use in infants with sickle cell disease. Table 4-8 Definition of Adverse Events and Classification and Reporting of Adverse Events A serious adverse event is any one of the following. 1. Death 2. Life-threatening events 3. Prolonged hospitalization (greater than 7 days) 4. Splenic sequestration crisis 5. Stroke, TIA 6. Acute chest syndrome 7. ICU admissions _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-34 of 4-37 8. Any AE related to study treatment and unexpected. Serious Adverse Events that are sickle cell related have been added to the list, as defined by the FDA. Item #3 has been modified from the FDA definition given that frequent hospitalizations occur as a consequence of having sickle cell anemia without being enrolled in a clinical trial. In addition, a centralized over-ride system (the central review group) will be carried out by individuals with knowledge about the treatment assignments. These individuals will review adverse events that are not thought to be serious in the eyes of the blinded investigators and make a decision about whether an adverse event is “serious” and reportable to the FDA. The two central review individuals will be the NHLBI Project Officer and MCC Medical Consultant. Either of these individuals will have the ability to elevate an adverse event being reported to the MCC to the “serious” category. Adverse events and serious adverse events will be listed individually and according to body system, will be designated according to severity (mild, moderate, severe, life-threatening, or fatal), will be designated according to likelihood of relation to study treatment (not related, possibly, probably or definitely related), will be classified according to action taken (none, treatment stopped or interrupted, specific treatment instituted) and according to outcome (recovery without change in previous condition, some impairment, significant impairment, or death). _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-35 of 4-37 Figure 4-1 _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-36 of 4-37 Initiate DTPA Study 0 60 120 180 240 Administer Study Treatment Draw Blood Draw Blood Draw Blood 30 Figure 4-2 Overlay of the Entry and Exit PK Studies on the DTPA Procedure NOTICE: Exit PK studies were discontinued as of May 29, 2009. Time (minutes) _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-4.wpd — 8/09 Page 4-37 of 4-37 Figure 4-3 _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-5 — 8/09 Page 5-1 of 5-2 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) PROTOCOL CHAPTER 5 RANDOMIZATION AND ENROLLMENT OF PATIENTS 5.1 ELIGIBILITY ASSESSMENT Potential patients are identified by the Clinical Center Principal Investigators and coordinators. Patients’ parents or guardians will complete orientation and provide informed consent, and patients will complete the pre-enrollment assessment period and procedures. All pre- enrollment forms must be received at the Medical Coordinating Center (MCC) where eligibility will be assessed based on data submitted. Patients who meet all eligibility criteria in a Clinical Center enrolling BABY HUG patients will be able to enroll in the study. Patients who are not eligible may be re-evaluated as long as the enrollment period is still open and baseline evaluations can be completed before the close of the enrollment period. Exclusion criteria, which could change and allow re-evaluation for eligibility, include: age less than 9 months for the main study (12 months for the Feasibility and Safety Pilot Study); transfusion within two months of enrollment unless HbA < 10%; abnormal liver function or renal function tests; Bayley Mental Scale standardized score <70; low hemoglobin, reticulocyte or neutrophil count. 5.2 RANDOMIZATION AND TREATMENT ALLOCATION MCC staff will prepare a unique randomization schedule for each BABY HUG Clinical Center. Each randomization schedule will be known only to a small group of people at the MCC. Individual treatment assignments will be available to selected MCC staff only on a "need-to-know" basis. Clinical Center investigators forced by urgent circumstances to unblind an individual patient's treatment will be required to follow procedures and provide documentation as set out in Section 6.6.1. _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-5 — 8/09 Page 5-2 of 5-2 MCC staff will use an automated telephone response system (ATRS) to randomly assign treatments to patients enrolling at a Clinical Center in sequence according to the randomization schedule for that Clinical Center. Each treatment assignment will specify a kit number for a kit that contains either hydroxyurea or placebo. Treatment group allocations will be stratified according to Clinical Center to ensure balance of numbers to each treatment arm within each Clinical Center. A standard procedure for stratified, blocked randomization will be used. 5.2.1 Treatment Allocation The MCC will identify eligible patients on a daily basis throughout the enrollment period. The MCC will provide a continual report of pending requirements for patients still in eligibility assessment. After the child’s parents or guardians have provided written informed consent, the child’s baseline evaluations are completed and the child has been declared eligible, the Clinical Center staff may use the MCC automated telephone response system (ATRS) to enroll a child and to obtain a study treatment kit assignment. The MCC will send the Pharmacy Distribution Center directions to maintain the supply of study treatments for this patient at the Clinical Center pharmacy. For each eligible patient the ATRS will issue to the Clinical Center a confirmation of enrollment into the study, including the BABY HUG Patient Identification Number and Alphabetic Code. Clinical Center staff will return to the MCC the form confirming the date the patient starts study treatment. _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-6 — 8/09 Page 6-1 of 6-12 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) PROTOCOL CHAPTER 6 STUDY TREATMENTS 6.1 OVERVIEW For children enrolled in BABY HUG and assigned to study treatment, treatment will begin at a fixed dose of 20 mg/kg/day, and remain at this dose unless repeated or prolonged toxicity is encountered, in which case the dose will be reduced to a lower stable dose. The goal for dose adjustment is given in Table 6-1. Patients will be maintained at 20 mg/kg/day or the lower stable dose for the duration of the 2-year period on blinded study treatment. The NHLBI has submitted an investigational new drug (IND) application to the U.S. Food and Drug Administration (FDA) for use of hydroxyurea in BABY HUG (IND #67,289). Administration and monitoring of treatment in BABY HUG will follow all accountability and reporting requirements of the FDA. Hydroxyurea will be formulated as a liquid preparation (100 mg/ml). Parents will be advised to administer treatment at approximately the same time each day (e.g. each morning or each evening before bedtime) to assist with compliance. All study medications (hydroxyurea and placebo) will be distributed by the Pharmacy Distribution Center in bottles of powder to the Clinical Centers. Each child’s treatment supply will be formulated by the appropriate Clinical Center before the patient’s scheduled visit. Before each scheduled clinic visit, the Medical Coordinating Center will recommend a dose for the upcoming 2- or 4-week therapy period, and transmit this information electronically to the Clinical Center Principal Investigator and coordinator. On the day of the clinic visit (Day 1), the child will be weighed, examined, and monitored for toxicity. At each 2- or 4-week visit, the used bottle will be collected, and the family will be given a new bottle with an appropriately marked oral syringe. The instructions will be to continue therapy using the new bottle, unless they receive a phone call _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-6 — 8/09 Page 6-2 of 6-12 to stop administering treatment. If a treatment had been stopped in the previous 2- or 4-week period, a new bottle of study medication will be dispensed. The family will be instructed to start administering the study medication with the possibility that a phone call for a stop order may be issued within three days. Blood specimens for routine study visits will be sent to the local Clinical Center laboratory for CBC determinations. Within one day of collecting the blood or by 9:00 a.m. of the following morning, the Primary Endpoint person will review local laboratory results for alert and toxicity values and data-enter the CBC values into the Internet Data Entry System. The MCC will also analyze the local CBC results. If the specimen is unusable (e.g. clotted), Clinical Center staff will be given an opportunity to collect a second hematology blood specimen. However, the second hematology specimen must be collected within 48 hours of the first specimen. By Day 3, the Medical Coordinating Center will send out a recommendation for stopping or continuing study medication for the next 2- or 4-week period based on review of all blood counts received, study medication prescription history, toxicities and adverse reactions. The Clinical Center physician verifies that the recommendations and prescriptions are consistent on Day 3. When indicated, Clinical Center staff will notify families to “STOP” using the study treatment (if it is currently being administered). Failure to contact families to “STOP” using study treatment can jeopardize patient safety (see section 12.9). If appropriate efforts are made to contact a family with a “STOP” order, but the family is not contacted, the Clinical Center Principal Investigator will provide the Operations Committee with a written explanation of the reason contact could not be established and a plan to avoid inability to contact this patient in the future. If a family cannot be contacted for two “STOP” orders, the patient’s treatment will be interrupted until the Operations Committee assesses that it can be safely restarted (see Section 6.6.2). Every six months at designated visits which must occur on a Monday - Thursday, blood will also be sent to the Hematology and Biochemistry Core Laboratory by overnight courier, and arrive there early on Day 2. Within six hours of receipt of the blood, the Hematology and Biochemistry _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-6 — 8/09 Page 6-3 of 6-12 Core Laboratory will transmit hematology and biochemistry results to the Medical Coordinating Center. No toxicities will be determined from the Core Laboratory results. However, the MCC will analyze the results for alerts and notify the Clinical Center PEP of any alerts. 6.2 DOSE TITRATION 6.2.1 Hydroxyurea The plan for dose reduction and toxicity monitoring in BABY HUG (Table 6-1) is based on data obtained from HUSOFT (Wang et al, 2001). The starting dose of hydroxyurea will be 20 mg/kg (once a day, orally). If toxicity occurs (e.g., neutropenia), treatment will be stopped and blood counts will be checked every two weeks until they return to non-toxic values. Transient toxicity will not cause a dose reduction, but prolonged or repeated toxicity will. Following a toxic blood count, treatment will be discontinued for 14 days. If counts recover, treatment will be resumed at the previous dose. If the toxicity persists, treatment will continue to be held for an additional 14 days and treatment will resume at a daily dose 2.5 mg/kg lower than the previous dose once the toxicity is resolved. If that dose does not cause toxicity for eight weeks, an attempt will be made to increase the daily dose by 2.5 mg/kg; if toxicity occurs, the lower dose will be assigned as the stable dose. If transient toxicity occurs more than twice at the same dose within a 12-week period, treatment will resume at a dose 2.5 mg/kg lower than the previous dose and continue for the duration of study. If blood counts reach the toxic range while on an established stable dose, treatment will be stopped until toxicity resolves and then treatment will resume with the previously established stable dose; repeated toxicity in a 12-week period will reduce the stable dose by 2.5 mg/kg for the remainder of the study. An outline of the dose titration algorithm is presented in Table 6-1. 6.2.2 Placebo Patients assigned to placebo will be given identically-appearing bottles containing placebo powder and the same flavoring as the HU-containing bottles. The placebo-containing bottles will be labeled identically to the HU-containing bottles. The Medical Coordinating Center will devise _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-6 — 8/09 Page 6-4 of 6-12 schedules of treatment stops and dose reductions and escalations for placebo patients based on the experience of bone marrow suppression, recovery, dose reduction and dose escalations seen in the open-label HUSOFT patients. Enough individual plans will be devised so that each of the children assigned to placebo in each Clinical Center will follow a different course of stops and dose changes that would just as readily occur in a child assigned to hydroxyurea. The goal of the plans is that the distribution of the final dose achieved among the placebo assigned patients will be similar to the final dose distribution among those assigned to hydroxyurea, and that the same proportion of children have treatment stops. This type of plan was implemented in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) (Handy et al, 1996). 6.3 TREATMENT PREPARATION An independent manufacturing facility will prepare and send bottles containing powdered hydroxyurea or placebo to the Pharmacy Distribution Center, which will forward these bottles, grouped as individual treatment kits, to each Clinical Center (Investigational) Pharmacy. Bottles for each patient will be reconstituted with water and simple syrup by each Clinical Center (Investigational) Pharmacy to formulate the medications into liquid preparations. Hydroxyurea powder and flavoring will be dissolved in water and simple syrup to achieve a final volume of 120 ml with a final concentration of 100 mg/ml. Placebo will be dissolved in an identically appearing and flavored solution. Each Clinical Center (Investigational) Pharmacy will bottle the liquid formulation in a child-proof container, label it with the subject's study acrostic/number, study ID number and instructions (including the "Investigational New Drug" warning, "BABY HUG Hydroxyurea Study for Sickle Cell Anemia", a prescription number, and the "emergency call" telephone number of the Principal Investigator). Inventory records for hydroxyurea and placebo will be kept by Pharmacy Distribution Center staff, and the Medical Coordinating Center will keep inventories of kit numbers used. _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-6 — 8/09 Page 6-5 of 6-12 Several days before a patient’s four-week visit, the Medical Coordinating Center staff will generate a prescription recommendation for the patient to be reviewed by a physician or physician consultant at the MCC with a synopsis of recent blood counts. The MCC physician will check all prescription recommendations, and the MCC will notify each Clinical Center of the official prescription. The Clinical Center (Investigational) Pharmacy will generate a label that includes the patient’s dose for the next month with instructions on how to take the liquid. All verified prescriptions will be prepared by the Clinical Center (Investigational) Pharmacy, the bottles will be labeled appropriately, and the study treatment given to the family on the day of the patient’s clinic visit. The Clinical Center (Investigational) Pharmacy will prepare a 35-day supply of the liquid formulation, and dispense it to each patient with the appropriate dose marked on the label and on syringes. 6.4 DEFINITIONS OF TOXICITY The most common toxicity observed in preliminary studies has been transient and reversible bone marrow depression. Hydroxyurea has only rarely been reported to be the cause of fever, skin rash, nausea, vomiting or hair loss. Such manifestations will be investigated locally and will be reported to the Food and Drug Administration (FDA) as adverse reactions if other etiologies are not apparent. Toxic bone marrow depression is defined as an absolute neutrophil count < 1250/cu mm, absolute reticulocyte count < 80,000/cu mm (if the hemoglobin concentration is below 7 gm/dL), platelet count < 80,000/cu mm, a hemoglobin concentration < 6.0 gm/dL, or >20% fall in hemoglobin concentration from the 3-month rolling average. The following occurrences will also be defined as toxicity: unexplained gastrointestinal disturbance, or unexplained rash or hair loss. Toxicity levels are used for adjustment of study treatment dose and are distinct from alert levels which are used for clinical management of the child (see section 7.2.4 and Table 7-3). _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-6 — 8/09 Page 6-6 of 6-12 6.5 MONITORING FOR TOXICITY Patients will be seen at the Clinical Centers and will have blood sampled every two weeks until a stable dose is reached, then every four weeks thereafter. A few infants will be seen in peripheral clinics that are visited by the clinic director every four weeks. Blood specimens for routine study visits can be collected any day of the week provided blood is not also scheduled for collection and shipment to the Hematology and Biochemistry Core Laboratory, which must occur on a Monday - Thursday. If a patient misses the clinic visit, and the visit can be rescheduled within the extended visit window, the Clinical Center staff should complete the clinic visit (and blood collection) within the extended window. If a patient misses a visit that cannot be rescheduled during the extended window, the family will be advised to complete the available study medication (interrupting daily doses when the treatment runs out) and return in two weeks. One pediatric tube of blood (0.5 ml) in EDTA will be obtained for a blood count including hemoglobin concentration, white blood cell count, platelet count, absolute reticulocyte count (ARC) and absolute neutrophil count (ANC). The local laboratory will perform automated (manual if automated is invalidated) CBC counts and the Primary Endpoint Person (PEP) will data enter them into the BABY HUG database via the Internet Data Entry System within one day of collecting the blood or by 9:00 a.m. the following day. An additional EDTA purple-top tube (0.5 ml) for hematology and a red-top tube (1.0 ml) for serum chemistries will be collected every six months (see Table 7.1) and sent to the Hematology and Biochemistry Core Laboratory. The Hematology and Biochemistry Core Laboratory will perform blood counts and chemistries, and transmit results to the Medical Coordinating Center within six hours of receipt of the sample. No toxicities will be determined from the Core Laboratory results. The PEP will review the local results to determine if a toxicity is present in the data. If there is a toxicity, the PEP will notify the Clinical Center staff of the need for a stop order. If there is not a toxicity, the PEP will open a previously delivered notice from the MCC that will instruct whether _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-6 — 8/09 Page 6-7 of 6-12 the PEP is to report a sham toxicity for the visit. Once reported, all other aspects of the reporting mechanism will be done in the same manner as if the toxicity is real (e.g., a meeting with ancillary staff, etc. to perpetuate the notion that the report is in fact a real toxicity). In addition to the PEP review of the local laboratory results, the Medical Coordinating Center will scan the in-coming local laboratory reports for "toxic" results. If the specimen is unusable (e.g. clotted) the Clinical Center staff will be given an opportunity to collect a second blood specimen. However, the second specimen must be collected within 48 hours of the first specimen. If there are no local laboratory results, the Medical Coordinating Center will notify the Clinical Center of the need for a stop order. After MCC staff issue/confirm a stop order, they will notify the Clinical Center coordinator, who will call the family and give the order to stop treatment if it has not already been done. The clinic coordinator and thus the family will be told to "stop treatment", without use of the word "toxicity." The coordinator will inquire concerning the child’s health (e.g., regarding fever, lassitude, weakness). Parents (guardians) of any child whose condition is worrisome will be asked to bring in the child for an examination to rule out complications with potentially severe consequences such as parvovirus B-19 infection or splenic sequestration (see Section 8.4). Patient families will be notified of stop orders within 48 hours of the clinic visit. The child must then return for two week visits until the toxicity is resolved. Medical Coordinating Center staff will provide the Clinical Centers with stop orders for placebo patients, in a similar manner as patients with toxicity due to HU. If the MCC physician(s) and other Medical Coordinating Center staff disagree on the toxicity evaluation, any stop orders, and/or the dose recommendation for the next therapy period, the laboratory results and treatment recommendation will be referred to the Study Chairman for immediate action. 6.6 BLINDING In the Clinical Centers, the patients, their families, Clinical Center Principal Investigators, coordinators, and other study staff will be blinded to treatment assignments. The central event or _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-6 — 8/09 Page 6-8 of 6-12 image reviewers will not be able to link study treatment assignments to individual event reports or other outcome data. Pharmacy Distribution Center staff and Medical Coordinating Center staff will have access to individual subject treatment assignment and current dose on a "need-to-know" basis. The Medical Coordinating Center will maintain records of each child’s treatment assignment and current dose. Plans have been made to prevent toxicity monitoring from resulting in unblinding of patients’ assigned study treatments. Despite these precautions, if the Clinical Center Principal Investigator thinks he/she inadvertently has become unblinded, contact with the child and his/her family and clinical site staff must be carefully managed to avoid any comments regarding unblinding. The person who has the most patient contact, usually the coordinator, must be absolutely excluded from any contact with laboratory data. The Primary Endpoint Person (PEP), who monitors the local CBC evaluations for toxicity, will have access to informative data about treatment assignment and must not share that information with the Principal Investigator or coordinator. In addition, the child’s 3- month rolling average hemoglobin concentration will be provided by the MCC to the Clinical Center PEP every month for use with standard medical practice guidelines (see Chapter 8) as needed locally. The Clinical Center Principal Investigators have agreed to avoid seeking information that may unblind them with regard to individual treatment assignments, especially laboratory results. Clinic coordinators will conduct follow-up visits and process and maintain files of study documents. Study documents that contain potentially unblinding information or baseline characteristics on individual patients (e.g., local lab reports, liver/spleen scan results, GFR results) will be maintained by the PEP. Although not preferred, Clinical Center Principal Investigators may be the primary care providers for BABY HUG children, and will be aware of the need to maintain blinding under normal circumstances and maintain the child on study drug even during hospitalization. Discussion among _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-6 — 8/09 Page 6-9 of 6-12 Clinical Center staff or with families regarding a child’s treatment assignment is inappropriate. Clinical Center coordinators must avoid any information that may unblind them. 6.6.1 Emergency Unblinding Every family will be given an identification card describing the child’s participation in the BABY HUG study, listing emergency study telephone numbers (e.g., the Clinical Center Principal Investigator’s telephone number and the Central Study Emergency Contact’s telephone number). The Central Study Emergency Contact’s telephone will be answered by a pediatric sickle cell anemia consultant to the Medical Coordinating Center at all times. If BABY HUG children become ill, treating physicians will be urged to call the Clinical Center Principal Investigator before altering the child's study regimen. In an emergency, family members will be instructed to call a telephone number that will be manned by a pediatric sickle cell anemia consultant to the Medical Coordinating Center 24 hours a day. Arrangements will be made so that the child’s medication can be disclosed to the Clinical Center Principal Investigator after consultation between the Clinical Center Principal Investigator and the pediatric sickle cell anemia consultant to the Medical Coordinating Center. Reasons for unblinding are limited and are based on clinical grounds. Unblinding must be initiated by the Clinical Center Principal Investigator. Reasons for unblinding include overdose of the study medication, accidental ingestion of the study medication by another person, development of infection or bleeding that could be due to reduced white blood cell or platelet counts and for which management might be changed if the nature of the study drug were known. Examples of clinical situations when information on study treatment could be useful include severe thrombocytopenia calling for a decision to use prednisone versus platelet transfusion or severe neutropenia calling for a decision on choice of antibiotics. If a child's therapy is unblinded, the Clinical Center Principal Investigator or staff member who unblinded the treatment must send a report to the Medical Coordinating Center. _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-6 — 8/09 Page 6-10 of 6-12 Each Clinical Center will assign another non-BABY HUG hematologist and nurse practitioner to be available for acute care visits. The study coordinator will have the most contact with patients and families and will be excluded from contact with laboratory data collected during acute events. The Primary Endpoint Person will, however, have access to a patient’s 3-month rolling average hemoglobin value every month, which will be provided by the MCC for use in evaluation of anemia. Unblinding will occur only after consultations between the Clinical Center PI and an external, Consultant Pediatric Study Hematologist. Unblinding events will be discussed by the Operations Committee and often will result in discontinuing study treatments. However, all patients, including those whose treatments have been unblinded, will continue to be followed in BABY HUG for safety outcomes and clinical outcomes not already declared at the time of unblinding. Since analysis will be conducted according to the principle of Intention to Treat and unblinding is expected to occur infrequently, the impact of unblinding is anticipated to be less than that of possible crossovers (see Sections 4.4.3 and 4.4.4). 6.6.2 Treatment Interruptions There may be instances related to medical conditions (e.g., acute, intercurrent illnesses such as an infection) or other reasons (e.g., study medication is lost by the family or “STOP” orders cannot be delivered) when it may be advisable to interrupt study therapy without unblinding. Interruptions for medical conditions should be allowed only with consultation of the Clinical Center Principal Investigator. The Clinical Center Principal Investigator is responsible for notifying the Medical Coordinating Center of treatment interruptions. These notifications are important because they may in turn have an influence on dose titration. 6.7 ASSESSMENT OF COMPLIANCE Study treatment will be measured at each regular follow-up visit. If the volume of study treatment remaining in the bottle is not consistent with the prescribed dosing plan, staff will inquire about any difficulties that may have occurred. The importance of compliance will be emphasized _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-6 — 8/09 Page 6-11 of 6-12 for all patients. Even if patients are repeatedly considered to be non-compliant, they will continue to be followed and will continue to receive their study reimbursements (i.e., travel/telephone allowances). 6.8 MISSED VISITS AND DROP-OUTS Each regularly scheduled clinic visit missed by a patient will be reported to the Medical Coordinating Center. Families who do not wish to continue attending clinic visits in the BABY HUG study will continue to be telephoned by the Clinical Center coordinator to ascertain the medical condition, any identifiable events and vital status. Attempts will be made to obtain semi-annual and annual evaluations for all study participants. 6.9 DURATION OF STUDY TREATMENT The goal of the study treatment plans will be to maintain patients on the assigned study treatment until the end of the 24-month period and on the maximum non-toxic dose (up to 20 mg/kg/day) of study treatment for at least 18 months of the two-year trial period. _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-6 — 8/09 Page 6-12 of 6-12 TABLE 6-1 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) DOSE TITRATION ALGORITHM Goal: To treat at 20 mg/kg/day or a lower, stable dose, defined as the highest dose maintained for eight weeks without observed blood count toxicity; and to maintain the patient at stable dose thereafter. Titration Phase (visits every 2 weeks): 1. Begin hydroxyurea at a dose of 20 mg/kg/day. 2. Continue treatment and monitor for toxicity. 3. If toxicity develops: a. A stop order is issued, and the patient will have repeat blood counts performed every 14 days until toxicity resolves. b. If the toxicity resolves at 14 days, then the study drug will resume at the pre-toxic dose. If the toxicity requires more than 14 days to resolve, then the daily dose will be lowered by 2.5 mg/kg. A patient must take a prescribed dose before a lower subsequent dose will be prescribed (i.e., toxicities that require more than 14 days to resolve will have the dose reduced 2.5 mg/kg from the last dose that was actually administered to the patient). c. As long as the patient does not become toxic over the subsequent eight-week period on the lower dose, the daily dose will be increased by 2.5 mg/kg not to exceed 20 mg/kg/day. d. If a patient becomes toxic at any given dose twice in a 12-week period, no further increases will be made. The highest dose that does not produce toxicity for an eight-week period is designated the stable dose. 4. No patient will receive more than 20 mg/kg/day. Stable Dose Phase (visits every 4 weeks): 1. If the patient becomes toxic after the stable dose is established, a stop order is issued and the study drug is stopped. When the toxicity resolves, the study drug will be resumed at the pre- toxic stable dose. If toxicity recurs within a 12-week period, the stable dose will be lowered by 2.5 mg/kg. _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-7 — 8/09 Page 7-1 of 7-9 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) PROTOCOL CHAPTER 7 LABORATORIES AND SPECIMENS 7.1 INTRODUCTION Eight Core Laboratories (a Hematology and Biochemistry Core, an Immunology Core, a Mutation Analysis/DNA Core, a Pitted Cell Core, a TCD Core, a Biomarkers Core, an HU Assay Core and a Cytogenetics Core) and an NHLBI Specimen Repository will be utilized for processing of BABY HUG study specimens, collected at the times specified in Table 7-1. In addition, the Clinical Center local hematology laboratories will process specimens collected at every study visit. 7.2 HEMATOLOGY AND BIOCHEMISTRY CORE LABORATORY The Hematology and Biochemistry Core Laboratory will provide standardized hematology and routine blood chemistry results which will be used to monitor for alerts and for analysis of effects of HU on these parameters. The Hematology and Biochemistry Core Laboratory will assay specimens according to the schedule in Table 7-1. If the specimen is deemed untestable, insufficient quantity, or missing, the Clinical Center should continue to re-draw for up to two more subsequent study visits. Blood samples will be collected and sent to the Hematology and Biochemistry Core Laboratory from Monday to Thursday by overnight express carrier so that they arrive within 24 hours. Blood counts and chemistry assays will be performed, reports generated, and results transmitted to the MCC within 6 hours of receipt. 7.3 LOCAL (CLINICAL CENTER) HEMATOLOGY LABORATORIES 7.3.1 Monitoring for Toxicity The major toxicity of HU is bone marrow depression which will be detected by complete blood count (CBC with white blood cell differential). HU has rarely been reported to be the cause of clinical manifestations such as fever, rash, nausea, vomiting or hair loss. Since HU is excreted _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-7 — 8/09 Page 7-2 of 7-9 in the urine, renal function will be monitored closely based on BUN and creatinine results. Clinical manifestations and toxicity will be investigated locally and will be reported to the FDA as adverse reactions if other etiologies are not apparent. Toxic bone marrow depression and other organ toxicities in BABY HUG are defined in Section 6.4. The MCC staff will screen incoming local CBC reports for “toxic” results. If toxic values are noted on the local CBC reports, the MCC will issue a stop order to the Clinical Center. Clinical Center will notify the patient’s parent(s) and tell them to stop treatment without the use of the word “toxicity”. The MCC will notify the Clinical Center of placebo patients whose treatments are to stop in the same manner as HU patients. Stop orders will be used for all placebo patients whose laboratory results are “spontaneously” (i.e., without hydroxyurea treatment) at levels that would be considered “toxic” with hydroxyurea therapy. The parent(s) will be notified of the stop order within 48 hours of a clinic visit. The remaining study drug must be returned at the next clinic visit. Doses for placebo patients and HU patients will be adjusted in similar manners. The MCC staff will receive and edit incoming local CBC reports, and compare them to previous reports for the patient. MCC staff will check for discrepancies between the central computer reviews and the stop orders. 7.3.2 Blinding In the Clinical Centers, the patients’ families, Principal Investigators, coordinators, and other study staff will be blinded to treatment assignments. On the Central Event Adjudication Panels and in the Core Laboratories, staff will not be able to link study treatment assignments to specimens, event reports or other outcome evaluations. The staff of the MCC will have access to individual patient treatment assignment codes and current dose on a “need to know” basis. The MCC will maintain records of each patient’s drug assignment and current dose. The Clinical Center Principal Investigators will assert their intention to avoid seeking information that may unblind them with regard to individual patient’s treatment assignments, especially laboratory parameters. The Primary Endpoint Person (PEP) will monitor the local CBC evaluations for toxicity and thus have access to potentially unblinding information. The Clinical _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-7 — 8/09 Page 7-3 of 7-9 Center coordinator will conduct follow-up patient visits and will be the primary contact person for the patient and families. She/he will maintain files of study documents and must be rigidly excluded from any contact with laboratory data, including data which may be collected on hospitalizations or outpatient visits. For these purposes it is preferred (but not required) that physicians and nurse practitioners outside BABY HUG manage the primary care and laboratory data during these events. The Clinical Center Principal Investigators and coordinators will be responsible for maintaining their blinded status and maintaining the patient on study drug during hospitalizations, if appropriate. 7.3.3 Emergency Unblinding Each patient’s family will be given an identification card describing the patient’s participation in BABY HUG, listing emergency study telephone numbers (the Study Chairman, and the Clinical Center Principal Investigator’s telephone numbers). If a BABY HUG patient becomes ill, parents will be instructed to show this identification card to the child’s treating physician. The card will recommend to treating physicians that they contact the Clinical Center Principal Investigator before altering the patient’s study regimen. The MCC will be allowed to disclose the patient’s treatment assignment only in cases of emergencies, such as accidental drug ingestion or in cases of severe cytopenias associated with severe infections or bleeding where therapeutic options may be dependent on identification of the study treatment assignment. 7.3.4 Alert System The Primary Endpoint Person (PEP) will review the local CBC results to determine if an alert is present in the data. In addition, the Hematology and Biochemistry Core Laboratory data and local CBC data will be used by the MCC to monitor electronically for values exceeding alert levels (Table 7-2). Local CBC results will override Core Laboratory results. If an alert level is detected, the Clinical Centers will use the following guidelines for responding to notification of an alert. _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-7 — 8/09 Page 7-4 of 7-9 Every time a value exceeds the alert level: 1. The PEP will handle the alert in a straightforward manner when possible, or, more likely, contact a Hematologist/Sickle Cell Specialist who is not directly connected with the BABY HUG Trial. 2. When indicated, the PEP and the Hematologist will develop a plan for a clinical response to the alert value. (For example: If the patient were severely neutropenic and febrile, the patient would be hospitalized for antibiotic treatment; if the patient had > 20% decrease in hemoglobin level, the patient would be hospitalized and/or transfused; if the patient met criteria for a splenic sequestration, the patient would be hospitalized and/or transfused; etc.) 3. In the event that no non-BABY HUG Hematologist was available, the PEP would need to contact the BABY HUG PI and discuss a course of action. In doing so, the PEP would provide the PI only with “need to know” laboratory information. In most cases this will not create an unblinding problem because, for example: severe neutropenia may more likely be related to an acute viral infection rather than HU toxicity; worse anemia might be caused by an aplastic crisis or splenic sequestration rather than HU; splenic sequestration might or might not be related to HU, etc. In most situations, CBC values would not readily distinguish between treatment with hydroxyurea or placebo, although it is important that the MCV should not be revealed to the PI or BABY HUG Study Coordinators. 4. In the ensuing management of the child, the bulk of the decision-making should be carried out by the non-BABY HUG Hematologist and the PEP. 5. The alert values for increased hematologic blood counts would not necessarily warrant any immediate reaction by a clinician. _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-7 — 8/09 Page 7-5 of 7-9 7.4 CYTOGENETICS CORE LABORATORY Freshly collected blood will be shipped overnight to the Cytogenetics Core Laboratory for culture of cells to assess karyotype and perform a chromosome breakage analysis. 7.5 IMMUNOLOGY CORE LABORATORY Blood specimens before and after critical immunizations (e.g., Measles-Mumps-Rubella, or pneumococcal polysaccharide vaccine) will be shipped by overnight courier to the Immunology Core Laboratory for evaluation of antibody and cellular immune response. 7.6 MUTATION ANALYSIS/DNA CORE LABORATORY Blood specimens will be shipped to the Mutation Analysis Core Laboratory at St. Jude Children’s Research Hospital for the assessment of VDJ and other mutations and DNA extraction. All DNA samples will subsequently be sent to the NHLBI repository. Leftover patient serum from the Biochemistry specimen will be shipped from the Biochemistry Core Laboratory to the DNA Core Laboratory for Cystatin C testing. 7.7 PITTED CELL CORE LABORATORY Every six months one drop of blood will be preserved in gluteraldehyde for each child enrolled in BABY HUG. These specimens will be stored and refrigerated locally, and shipped in batches to the Pitted Cell Core Laboratory. 7.8 TCD CORE LABORATORY A TCD Core Laboratory supported by funds from a separately awarded grant will be responsible for the performance and central evaluation of TCD studies at entry, at 12 months on study treatment and at the end of follow-up for each child enrolled in BABY HUG. The Principal Investigator of a child who has a “conditional” TCD will be contacted by the MCC medical consultant to decide the frequency of follow-up. Any requested follow-up TCDs will be paid with BABY HUG funds and will be performed according to BABY HUG Protocol. Standard of care is to perform routine TCD screening beginning at 2 years of age (approximately at 12 months on study treatment for BABY HUG). _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-7 — 8/09 Page 7-6 of 7-9 7.9 BIOMARKERS CORE LABORATORY A Biomarkers Core Laboratory supported by funds from a separately awarded grant will be responsible for central evaluation of circulating levels of selected biomarkers in blood specimens collected at study entry, 2 months after entry, six months after entry and at study exit. 7.10 HU ASSAY CORE LABORATORY NOTICE: Exit HU assays were discontinued as of May 29, 2009. Plasma specimens from the DTPA evaluations of GFR at treatment initiation for the children enrolled in the Feasibility and Safety Pilot Study were stored and later shipped in a batch to the HU Assay Laboratory for assessment of circulating hydroxyurea levels. Additionally, all incoming patients will have entry and exit pharmacokinetic (PK) studies (on plasma specimens from the DTPA evaluations of GFR), all patients currently enrolled in the study will have exit PK studies (on plasma specimens from the DTPA evaluations of GFR), and all incoming patients will have PK studies at approximately one month on study treatment. These plasma specimens will be frozen and stored locally and shipped in batches to the HU Assay Core Laboratory. 7.11 NHLBI SPECIMEN REPOSITORY The Hematology and Biochemistry Core Laboratory will conserve residual plasma, serum, and cell pellets for shipment to the NHLBI Specimen Repository where they will be kept in a bank of samples for the purpose of ancillary studies approved by the Steering Committee. At the end of the study, a limited amount of data will be provided to be linked to the specimens (e.g., whether they come from a male or female child) and, following appropriate IRB review, the specimens will be available for use, if consent was given at the time of their collection, without any link to the individual from whom the specimen(s) were obtained. _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-7 — 8/09 Page 7-7 of 7-9 TABLE 7-1 LABORATORY DETERMINATIONS STUDY SCHEDULE BLOOD VOLUME Hematology (Local-L and Central-C) 0.5 ml (L), 0.5 ml (C) Hemoglobin q 2-4 weeks (L), q6 mos (C) Packed Cell Volume (PCV) q 2-4 weeks (L), q6 mos (C) Red Cell Count (RBC) q 2-4 weeks (L), q6 mos (C) White Cell Count (WCC) q 2-4 weeks (L), q6 mos (C) Absolute Neutrophil Count (ANC) q 2-4 weeks (L), q6 mos (C) Reticulocyte Absolute Count (RAC) q 2-4 weeks (L), q6 mos (C) Platelet Count q 2-4 weeks (L), q6 mos (C) Mean Corpuscular Volume (MCV) q 2-4 weeks (L), q6 mos (C) Mean Corpuscular Hb Conc (MCHC) q 2-4 weeks (L), q6 mos (C) F-cells q 6 months (C) Fetal Hemoglobin Concentration q 6 months (C) Blood Chemistry 1.0 ml Electrolytes, Calcium, Phosphorous and Magnesium q 6 months Urea nitrogen q 6 months Serum alanine aminotransferase (ALT) q 6 months Total Bilirubin q 6 months Direct Bilirubin q 6 months Ferritin q 6 months Serum creatinine (HPLC) q 6 months RBC pitted cell count q 6 months 0.1 ml DNA Analysis 3.0 ml VDJ events 0, 24 months Genetic modifiers 0 months Alpha gene number 0 months Alleles (S/beta0/beta+/alpha) 0 months Other (banked sample) 0 months Cystatin C 0, 24 months 0.1 ml (chemistry serum remainder) Cytogenetics 0, 24 months 4.0 ml Immunology Pneumococcal antibody titers and Opsonophagocytic activity entry, 24 months of age, 25 months of age (or after Pneumovax), and exit 3.0 ml MMR titers 13 months of age (or after MMR), 24 months of age, and exit 1.2 ml T-cell counts entry, 24 months of age, and exit 0.5 ml Biomarkers entry, 8 weeks, 24 weeks, exit 1.5 ml _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-7 — 8/09 Page 7-8 of 7-9 Approximate Phlebotomy Volumes: Baseline: 13.1 ml (includes cytogenetics/mutation and T cell/biomarkers) First Treatment: 11.0 ml (includes GFR assessment) q2-4 weeks: 0.5 ml q6 months: 2.0 ml Exit (patients 1-140): 17.0 ml (collected over 1 month prior to exit) Exit (patients 141-200): 15.0 ml (collected over 1 month prior to exit) An additional 17.1 ml of blood is required for immunology studies, collected at intervals appropriate for the child’s age, immunization status, and other blood specimen collection, and 3.0 ml for biomarker studies calculated as 1.5 ml at 8 weeks and 24 weeks following study entry. _________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG PROTOCOL/August-09/CHAP-7 — 8/09 Page 7-9 of 7-9 Table 7-2 BABY HUG LABORATORY DATA ALERT AND MONITORING LEVELS Alert Levelsa Changeb Study Low High WBC 50K Hemoglobin 6.0 13.3x2FVs - 20%c Platelet Count 80K 1M Neutrophil Count 1.25 30K Reticulocyte Count 80Kd -- Creatinine -- 1.0 +100%e Total bilirubin -- 10 ALT -- 150 NOTE: Low alerts must be less than those listed in the table; high alerts must be greater than those listed in the table. a Alert levels which should be evaluated for clinical monitoring of the patient. FV = Follow-Up Visits. b Loss or gain (sign indicates direction), in % change. c Hemoglobin 20% decrease from three-month running average. d If Hb<7.0gm/dl. e Creatinine level at least twice baseline and greater than 1.0. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-8.wpd — 8/09 Page 8-1 of 8-10 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) PROTOCOL CHAPTER 8 GUIDELINES FOR STANDARD CLINICAL CARE 8.1 INTRODUCTION The basic principles of supportive care for the infants with sickle cell anemia enrolled in the BABY HUG trial are based upon the recommendations found in several publications (Mountain States Regional Genetic Services Network, 2000; Council of Regional Networks for Genetic Services (CORN), 2000; Ohene-Frempong, 2001; US Department of Health and Human Services, Public Health Service, 1993). Supportive care should be similar whether the patient is receiving hydroxyurea or placebo. For the ease of clinicians involved with participants, all patients should be treated as if they were receiving hydroxyurea. The cooperation of all medical staff involved in the clinical care of study patients will be solicited to enhance patient adherence to the BABY HUG Protocol and avoid compromise of blinding of treatment assignments. Common clinical events are addressed in specific sections below. At no time should the performance of the study Protocol be allowed to compromise the elements of good clinical care of BABY HUG participants. 8.2 IMMUNIZATIONS All routine pediatric immunizations should be given as per standard clinical recommendations, including vaccination against diphtheria, pertussis, tetanus, polio, measles, mumps, hepatitis B, rubella and Haemophilus influenzae type b. Immunizations against hepatitis A and varicella may be given if indicated and commonly available locally. These vaccines should be provided through usual local pediatric primary care mechanisms if possible. Any and all vaccines may be withheld for medical indications (e.g., allergy or history of prior reaction) or parental preference. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-8.wpd — 8/09 Page 8-2 of 8-10 All participants should receive all recommended doses of pneumococcal vaccine according to the following schedule. A history of vaccination with pneumococcal conjugate vaccine (Prevnar or PCV7), including date(s) given, must be documented by the BABY HUG Clinical Center and reported to the Medical Coordinating Center for each infant enrolled. Patients deficient in PCV7 immunizations at study entry should be brought up to date by the Clinical Center as soon as possible. Bacteremia and meningitis with S. pneumoniae will be monitored closely as clinical events in BABY HUG. Further, the antibody response to pneumococcal vaccination will be measured in the study. The total number of doses required is dependent upon the age of the patient when the first dose is given even if the interval between doses is longer than intended. Adequate series of vaccinations are indicated in the table below. Pneumococcal Conjugate Vaccine Series (Prevnar or PCV7) Age at first dose (mos) Primary Series Additional Dose** 2-6 3 doses, 2 months apart* 1 dose at 12-15 months 7-11 2 doses, 2 months apart* 1 dose at 12-15 months 12-23 2 doses, 2 months apart more than 24 months 1 dose Pneumococcal polysaccharide vaccine (pneumovax or PV23) Age at first dose (mos) Primary Series Additional Dose** less than or equal to 24 months 1 dose 1 dose at 60 months * For children vaccinated before 1 year the minimum interval between doses is 4 weeks. *Additional dose should be 8 or more weeks after the primary series has been completed. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-8.wpd — 8/09 Page 8-3 of 8-10 Measles, Mumps, and Rubella vaccine (MMR): one dose of the vaccine should be documented as given between 12 and 15 months of age and then repeated between 4 and 6 years of age. The immunologic response to this vaccine will be assessed to document the ability of patients receiving either hydroxyurea or placebo to respond to these antigens. Thus, the date of this immunization must be recorded for each patient by the Clinical Center and reported to the Medical Coordinating Center. Parents will be encouraged, and assisted by the BABY HUG Clinical Center as necessary, to obtain this vaccine as early in the scheduled vaccine interval as possible. Influenza vaccine: the annual flu vaccine is encouraged for all infants 6 months of age or older. The first year this is administered this should be given as two 0.25 ml doses, with a minimum of four weeks between doses. Each subsequent flu season, one dose is given. A single dose of 0.25 ml is given to patients from 6 to 35 months of age and 0.5 ml to patients over 36 months of age. 8.3 PROPHYLACTIC MEDICATIONS Twice daily prophylactic penicillin will be prescribed from first medical contact. This should have already been initiated prior to enrollment in BABY HUG. The doses are from birth to 35 months of age - 125mg po BID – and over 36 months of age - 250 mg po BID. Either the liquid formulation, which must be kept refrigerated and refilled every 2 weeks, or tablets may be used (Mountain States Regional Genetic Services Network, 2000; American Academy of Pediatrics, 2000). Erythromycin estolate 250 mg po BID may be used for penicillin allergic patients (Mountain States Regional Genetic Services Network, 2000; Council of Regional Networks for Genetic Services (CORN), 2000; Ohene-Frempong, 2001; US Department of Health and Human Services, Public Health Service, 1993). Reminders about the need for this prophylactic agent should be offered at each clinical contact. Folic Acid supplementation will not be required for patients on BABY HUG. It may be prescribed at parental or Clinical Center preference. It is very unlikely that infants enrolled on this study will be deficient in folate. The majority will either still be drinking or just have been weaned _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-8.wpd — 8/09 Page 8-4 of 8-10 from high folic acid containing infant formula. The widespread fortification of a variety of foods with folic acid and the generally adequate diets of young patients with sickle cell anemia should prevent folate deficiency. Supplemental iron will be prescribed only for documented iron deficiency or bleeding or similar reasons. Adequacy of iron stores will be documented at study entry and every six months and supplemented as necessary. 8.4 PARENT EDUCATION All parental and caregiver education routinely offered to families of patients with sickle cell anemia should be provided to BABY HUG participants. However, in order to standardize some aspects of care the following suggestions are offered for each Clinical Center to review with BABY HUG families at quarterly visits : Fever: The temperature should be measured if the child feels hot. Families should be advised to have a thermometer at home and taught how to accurately use it. They should be instructed to seek medical attention for any temperature over 101.50F regardless of route (oral, axillary or rectal) measured. The parent or caregiver should be cautioned against use of antipyretics unless recommended by treating physicians. They are encouraged to seek medical attention for all febrile episodes. The medical response to a reported history of fever should include a complete blood count, blood culture, and an empiric dose of parenteral antibiotics (usually ceftriaxone) effective against encapsulated organisms. Admission or outpatient management will be at local option (Mountain States Regional Genetic Services Network, 2000; Council of Regional Networks for Genetic Services (CORN), 2000). Neutropenia: A complete blood count with differential white blood cell count should be performed at the Clinical Center or site of care with each febrile event. If the absolute neutrophil count (ANC) on the local blood count is below 1,000/uL, the child should be admitted to the hospital for observation and parenteral antibiotics. BABY HUG study medication should be stopped and the Medical Coordinating Center notified. If the ANC on the local blood count exceeds 1,250/uL _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-8.wpd — 8/09 Page 8-5 of 8-10 prior to hospital discharge, BABY HUG study medication should be resumed at the same dose as on admission. If on hospital discharge the ANC on the local blood count is still below 1,250/uL, the patient and family should be instructed not to resume treatment until a local scheduled blood specimen shows a count of 1,250/µL or greater. If the absolute neutrophil count on local blood count is between 1,000/uL and 1,250/uL during evaluation for a febrile event, the BABY HUG study medication should be stopped. The patient may be treated as an outpatient or admitted at local option. If admitted, BABY HUG study treatments will be stopped as above. If managed as an outpatient, the patient should remain off BABY HUG study medication until a local scheduled blood count is performed and the count is 1,250/µL or greater. Hospitalization: The BABY HUG study medication should be continued during all clinically indicated hospitalizations unless the ANC of a BABY HUG participant is found to be below 1,250/uL. Then the study medication should be stopped and the Medical Coordinating Center notified. Study treatment should be resumed at the same dose when the ANC on the local blood count exceeds 1,250/uL. If the patient is otherwise able to be discharged to outpatient management before the ANC recovers, the patient and family should be instructed not to resume treatment until the next scheduled local blood specimen can be reviewed. The Clinical Center Principal Investigator and Nurse Coordinator will not review the local blood counts for mean corpuscular volume (MCV) or other parameters that may compromise blinding of the patient’s study medication assignment. Positive Cultures: The blood culture (plus cerebrospinal fluid -- CSF -- or urine cultures if performed) obtained at all febrile encounters will be monitored by each Clinical Center. Positive cultures from normally sterile sites will be managed according to Clinical Center preference and reported to the Medical Coordinating Center. The organism should be identified; if possible, and antibiotic sensitivities obtained. The serotype of Streptococcus pneumoniae isolates from sterile sites for patients on this trial should be obtained if possible. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-8.wpd — 8/09 Page 8-6 of 8-10 Varicella: The family should be instructed to contact the Clinical Center for suspected varicella infection. If the child is febrile, management should be as above. If fever does not exceed 101.50 F, no extra CBC is required. BABY HUG study medication should be stopped for all episodes of varicella and the Medical Coordinating Center notified. BABY HUG medication should be resumed at the same dose when all lesions are crusted over. Acyclovir may be prescribed at Clinical Center discretion. Tuberculosis: Surveillance for exposure to tuberculosis is standard in many pediatric clinic populations. If a patient receiving BABY HUG study medication is incidentally found to have a positive tuberculosis skin test (PPD), a repeat PPD and chest radiograph should be done per standard practice. If the chest radiograph and physical examination show no signs of active tuberculosis, the child should be treated as appropriate and the study medication continued once the PPD treatment is no longer a risk for continuation of the study treatment. If the chest radiograph is positive or there is evidence of active infection with tuberculosis, the child’s situation should be discussed with the Operations Committee. Transfusion Therapy: The use of blood products as therapy for a clinical event will be at the option of the Clinical Center. The red cell products selected should be matched for Rh (CcDEe) and Kell if possible. Similarly leukofiltration of all cellular blood components should be considered, if available. Chronic transfusion therapy for any indication, an option that would remove the patient from study treatment, should be discussed with the Operations Committee prior to implementation. Steady State Hematologic Values: Many clinical decisions in the young patient with sickle cell anemia are based upon steady state hemoglobin levels. Obtaining such data on patients in BABY HUG Clinical Centers could undermine blinding of treatment assignments. The Medical Coordinating Center will provide the unblinded Primary Endpoint Person at each Clinical Center 3- month rolling averages of steady state hemoglobin measurements monthly. Steady state is defined by intervals when the patient is not having a febrile, acute chest syndrome, aplastic crisis or splenic _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-8.wpd — 8/09 Page 8-7 of 8-10 sequestration event. MCV and white cell or neutrophil counts will not be included with the information on hemoglobin level. Spleen and Splenic Sequestration: Parents and caregivers should be instructed in techniques of spleen palpation at each clinical visit and asked to feel for the child’s spleen daily. A newly palpable spleen or one more than 2 cm larger than previously noted should be reported immediately to the Clinical Center, and the patient should have a CBC and be examined by a physician or nurse practitioner knowledgeable about sickle cell anemia. The span of the spleen below the costal margin in the midclavicular and anterior axillary lines should be carefully measured and recorded (in centimeters) at each clinical visit. Splenic sequestration and splenomegaly as defined in Appendix F will be recorded on the appropriate study form as outlined in the Manual of Operations. The management of splenic enlargement (admission, close outpatient follow-up or transfusion) will be at the discretion of the Principal Investigator at each Clinical Center, but the following guidelines should be used whenever appropriate/possible. On initial evaluation: 1. Vital signs at presentation and q1-2 hours initially; 2. Careful physical examination with assessment of pallor, measurement of spleen size, presence of gallop, liver size; repeat examination q1-2 hours initially; 3. Labs including CBC, WBC differential, reticulocytes STAT. Type and crossmatch for packed red blood cells (PRBCs); 4. If hypovolemic or with cardiovascular compromise, emergent infusion of intravenous fluids (IVF) or PRBC to restore blood volume and maintain normal blood pressure. If normovolemic, start IVF at 1x maintenance. 5. Admission unless stable over 4-8 hour period; close follow-up. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-8.wpd — 8/09 Page 8-8 of 8-10 On admission: 1. Monitor heart rate (HR), respiratory rate (RR), pulse oximetry q2 hours until stable, then q4h; 2. Repeat CBC studies q4-12 hours; 3. Maintain IVF at 1x maintenance; 4. If febrile obtain blood culture and begin antibiotics, e.g. cefuroxime 50 mg/kg IV every 8 hours; 5. Transfuse for evidence of hypotension, cardiovascular (CV) compromise, enlarging tender spleen with 10-15 cc/kg over 4 hours. If no CV compromise, transfuse if Hgb <5 gm/dL for stable splenomegaly regardless of reticulocyte count; if Hgb> 5gm/dL transfuse at Principal Investigator discretion. Goal of transfusion is Hgb about 8 gm/dL, (splenic unloading of trapped RBC may cause an "overshoot phenomenon"); 6. Supplemental oxygen until condition is stable (or acute episode resolves); 7. Other clinical interventions, including antipyretics and analgesics, at Principal Investigator discretion. After the initial splenic sequestration event, the child will be monitored every 2 weeks. The decision to continue PRBC transfusions and/or proceed to splenectomy, will be at the discretion of the Principal Investigator. However, the number of children undergoing splenectomy according to local indications will be tabulated in each treatment group. Chronic transfusion therapy or splenectomy, options that would remove the patient from study treatment or scintographic evaluation of the primary (spleen) endpoint, should be discussed with the Operations Committee prior to implementation. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-8.wpd — 8/09 Page 8-9 of 8-10 Episodes of splenomegaly, splenic sequestration and associated measures will be tabulated and compared according to HU and placebo group assignment. If an excess of sequestration events is found in the HU group, the DSMB may consider stopping the trial. Renal: Parents and caregivers will be educated about the importance of the kidneys in children with sickle cell disease, and reminded that the kidneys are special organs tested in the BABY HUG trial. Infants should remain adequately hydrated at all times, as dehydration is detrimental and could be injurious to the kidneys. Treatment that has potential risk to the kidneys, such as prolonged use of aminoglycosides or high-dose non-steroidal anti-inflammatory drugs, should be avoided. Frequent urinary tract infections and hematuria will be documented during the BABY HUG trial, as these findings may reflect or cause renal damage. Painful Events (vaso-occlusive or dactylitis): Parents and caregivers will be educated about dactylitis and painful events as part of their education about sickle cell disease. They will be taught to push fluids and use ibuprofen and/or acetaminophen with codeine at home. Small supplies of both analgesics should be prescribed for home use at routine clinical visits. They and caregivers will be educated about dactylitis and painful events as part of their education about sickle cell disease. The definition of a painful event is an event lasting two hours or more without obvious cause requiring the use of one or more doses of non-steroidal or narcotic pain medication. Events treated as an outpatient (including emergency room) or requiring admission will be reported at the next Clinical Center contact and included in data entered. Events requiring admission will be reported to the Medical Coordinating Center on appropriate form, and supporting documents collected for central review. Acute Chest Syndrome, Aplastic Crisis, Priapism: All events meeting defined criteria will be reported to the Medical Coordinating Center on Event Report Forms. Clinical management, including the need for simple or exchange transfusion will be at the option of each Clinical Center. Chronic transfusion therapy, an option that would remove the patient from study treatment, should be discussed with the Operations Committee prior to implementation. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-8.wpd — 8/09 Page 8-10 of 8-10 Parents will be educated about signs of acute chest syndrome (fever, respiratory symptoms) and aplastic crisis (pallor, decreased energy) at regular clinic visits and asked to seek medical attention should they occur. Parents of male children will be taught about priapism, a prolonged painful erection of the penis, and asked to seek medical attention, if the episode persists beyond two hours. Briefer episodes of priapism will be recorded at the next clinic visit. Neurologic Events: Families will be taught standardized definitions of TIA, stroke and other neurologic events and reminded at each clinical contact to call the Clinical Center immediately if the child is not able to move arms or legs (unrelated to pain), has facial drooping or dysarthria. Each Clinical Center will promptly evaluate such patients. The minimum evaluation must include documentation of complete neurologic examination, preferably by a neurologist. If the neurologist suspects stroke or TIA clinically, neuroimaging including MRI/MRA must be done. If a stroke is confirmed, acute management will be at the preference of the Clinical Center. Transfusion timing and technique (exchange or simple) will be at Clinical Center preference. Chronic transfusion therapy, an option that would remove the patient from study treatment, should be discussed with the Operations Committee prior to implementation. If transcranial Doppler (TCD) screening is part of an individual Clinical Center’s standard care, such testing should be offered to patients enrolled in BABY HUG as per usual practice. TCD screening is not yet universally available or standardized for children less than two years of age. If screening is performed and values are persistently abnormally elevated in children over 2 years of age, the parents should be offered chronic transfusion therapy for the child in accordance with standard practice at each Clinical Center. Patients for whom chronic transfusion therapy is considered should be discussed in advance with the Operations Committee. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-9.wpd — 8/09 Page 9-1 of 9-4 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) PROTOCOL CHAPTER 9 SPECIAL STUDIES AND READING GROUPS 9.1 INTRODUCTION Special studies and event reports that will be centrally evaluated by individuals blind to treatment assignment and independent of the BABY HUG Clinical Centers include liver-spleen scans, pitted cell counts, karyotype and chromosome breakage studies, VDJ mutation studies, immunological function studies, clinical events, and serum Cystatin C levels. 9.2 PITTED CELL COUNTS Pitted cell counts will be done in a single laboratory, the Pitted Cell Core Laboratory. Tubes containing the glutaraldehyde buffer and directions for specimen collection will be provided to the Clinical Centers by the Pitted Cell Core Laboratory. Pitted cell counts from specimens collected at baseline, six, twelve, and eighteen months, and 24 months will be compared between treatment groups. If the proportion of patients in the HU treatment group who have pitted cell count values above a predetermined level (e.g., 3.5 or 7-10%) decreases in relation to the placebo group, this finding will be interpreted as secondary outcome evidence of prevention by HU of injury to the spleen. 9.3 CYTOGENETICS (KARYOTYPE AND CHROMOSOME BREAKAGE ANALYSES) Fresh blood specimens will be analyzed for karyotype and chromosome breakage at baseline and 24 months in a cytogenetics laboratory. White blood cells will be taken from fresh specimens shipped on wet ice, overnight to the cytogenetics laboratory, cultured for 48 hours and prepared with colchicine for morphologic study of the karyotype and chromosomes. 9.4 VDJ/DNA MUTATION STUDIES Genomic DNA will be isolated using a standard commercially available kit (Puregene DNA Isolation Kit, Gentra Systems Inc.). The purified DNA will be quantitated using a spectrophotometer _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-9.wpd — 8/09 Page 9-2 of 9-4 and used directly in the VDJ mutation assay. Leftover DNA will be frozen at -70°C and used for future studies assuming proper IRB authorization and patient consent is in place. The overall goal of the VDJ studies is the investigation and quantification of the mutagenic and carcinogenic risks of HU therapy for very young children with SCD enrolled in the BABY HUG study. To accomplish this goal, we will analyze peripheral blood for the presence of changes in chromosomal integrity that indicate unrepaired genetic damage. The specific aims of the VDJ mutation study are: to quantitate the frequency of “illegitimate” VDJ recombination events that occur between the T cell receptor gamma (TCR-gamma) and beta (TCR-beta) gene loci located on chromosome 7; and to compare the frequency of VDJ mutational events among patients assigned to hydroxyurea as compared with the placebo group, using serial measurements for both groups. Quantitations of Howell-Jolly bodies will also be performed. For each of the patients, a small aliquot of RBC will be fixed in ice-cold methanol and frozen at -85°C according to a previously published protocol. This sample will be shipped frozen to Litron Laboratories, Inc. in Rochester, NY and analyzed by flow cytometry for quantitation of Howell-Jolly bodies (micronuclei) in both immature and mature erythrocytes. 9.5 LIVER-SPLEEN SCANS Tc99m sulfur colloid liver-spleen scans will be performed according to standard techniques. Results will be assessed at the end of the study by a panel of 3 pediatric radiologists unaware of the treatment assignment of the patient. Two readers will be given copies of the entry and exit Tc99m sulfur colloid liver-spleen scans and asked to score each scan as splenic uptake “normal” (80-100% of liver uptake), decreased (splenic uptake 20-79% of liver uptake) or absent (splenic uptake 0-19% of liver uptake). In case of disagreement between the two readers, a third reader on the panel will evaluate the scan, and the final evaluation will be that of the majority. The proportion of patients in each treatment group classified by spleen function (normal, decreased, or absent) and the proportion of entry and exit scan pairs demonstrating a decline (from one category _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-9.wpd — 8/09 Page 9-3 of 9-4 to another) in splenic function will be compared in the HU vs placebo treated groups. Paired scans that demonstrate an improvement in uptake will be scored as not demonstrating a decline. 9.6 ABDOMINAL ULTRASOUND A central reader with specialty expertise in pediatric ultrasound studies will advise the BABY HUG investigators on performance standards for abdominal ultrasound studies and image preparation. These images will be read centrally, blind to treatment assignment for assessment for gallstones, kidney size, spleen size and liver enlargement. 9.7 HYDROXYUREA ASSAY Quantitative assays of hydroxyurea will be performed on selected bottles of study treatments at the end of manufacturing after reconstitution. Also, plasma levels of hydroxyurea will be assessed at the time of first dose, approximately one month after the first dose, and upon exit from the study. 9.8 IMMUNE FUNCTION STUDIES To determine the effects of hydroxyurea treatment on antibody responses to standard vaccines administered before and during hydroxyurea therapy, baseline pneumococcal antibody level (in response to pneumococcal conjugate vaccine administered at two, four and six months of age -- prior to study entry) and after 23-valent pneumococcal polysaccharide vaccine (given at 24 months of age) will be measured. Antibody levels for measles, mumps and rubella (vaccine given at 12 - 15 months of age) before and after immunization will be measured for those enrolled prior to vaccination. To determine the effects of hydroxyurea treatment on T cell maturation and T cell responses to a vaccine administered during hydroxyurea therapy, we will measure peripheral blood naïve (CD45RA) and memory (CD45RO) CD4 and CD8 cells at entry and 12 and 24 months thereafter. To determine the effects of hydroxyurea treatment on serum opsonophagocytic function, we will measure opsonophagocytic activity against pneumococci at study entry, after the 24-month of age pneumococcal immunization, and at the end of treatment (24 months on study treatment). _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-9.wpd — 8/09 Page 9-4 of 9-4 Measurement of relative contributions of complement and antibody to opsonophagocytic activity will be accomplished by comparing the activity of fresh versus heat-treated sera. 9.9 CLINICAL EVENTS Description of Clinical Events will be based on Clinical Event Forms submitted to the MCC where they will be classified by independent pediatric hematologists or neurologists. Independent review for adjudication by a third physician will be performed in the case of disagreement. Definitions of clinical events will be based on CSSCD, HUSOFT and other published experience with pediatric sickle cell anemia and provided in a separate classification criteria document. 9.10 TRANSCRANIAL DOPPLER (TCD) Transcranial Doppler studies will be performed by trained technicians from a Central Laboratory located in the Medical College of Georgia (MCG), Augusta, Georgia, or by local Clinical Center examiners trained and certified by the MCG technicians. The Central Laboratory will perform standardized readings of the studies (supported by grant funding independent of the BABY HUG contracts). 9.11 CYSTATIN C Leftover serum from the biochemistry treatment initiation and exit specimens sent to the Biochemistry Core Laboratory will be shipped to the DNA/VDJ Core Laboratory for determining Cystatin C levels. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-1 of 10-22 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) PROTOCOL CHAPTER 10 FOLLOW-UP PROCEDURES 10.1 INTRODUCTION Patients will be followed every two weeks for at least eight weeks after study treatment initiation. Subsequent visits will be every 4 weeks unless toxicity occurs. The total follow-up is a minimum of 24 months. During the period of study treatment at each monthly visit, a medical review will be conducted to determine any adverse or acute events and adherence to study medication. Medical history and adherence forms will be completed. At each of these regularly scheduled visits, a complete blood count will be assessed locally by a physician who is not otherwise affiliated with BABY HUG, and who will keep this information confidential except as needed for urgent patient management on the day of the visit. All adverse events in a patient will be reported on the appropriate form accompanied by appropriate documentation from the medical record. Appendix A shows an ideal schedule of patient visits and data collection. A patient’s actual schedule will depend on his/her toxicities. 10.2 FOLLOW-UP VISITS The BABY HUG Clinical Center staff will perform all study visit examinations. Study patients will be evaluated in accordance with good clinical practice. The Medical Coordinating Center (MCC) will be responsible for organizing and transmitting data from clinical laboratory studies outlined in the Protocol and for endpoint adjudication. Under the direction of the MCC, a Pharmacy Distribution Center (PDC) will distribute hydroxyurea and placebo to Clinical Centers where dose adjustments will be prescribed based on information from the MCC. At the monthly visits, medical reviews will be conducted, and measurements of weight (height and head circumference every three months), ascertainment of possible adverse events, major procedures, and current therapies (including hydroxyurea outside of study treatment) will be recorded. Blood specimens for CBCs will be collected and analyzed locally. Other blood specimens will be collected and prepared for _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-2 of 10-22 shipment to the Core Laboratory every six months or at study entry/exit. Each patient’s current address and telephone number will be updated and maintained in the Clinical Center files. Although not mandatory, each Clinical Center is encouraged to set aside a specific day of the week for BABY HUG clinic visits, preferably early in the week to allow dose adjustments before the weekend. In addition, a specified clinic day may help to increase adherence to the Protocol. 10.2.1 Real Time Complete Blood Counts 1. Each Clinical Center will designate the person (a hematologist, or nurse practitioner or physician’s assistant qualified to perform this task relative to the regulations of the state health regulations, who has no other BABY HUG responsibility) who will monitor each child's blood work that is performed locally at each clinic visit. 2. The Primary Endpoint Person (PEP) will data enter the CBCs into the BABY HUG database vis the Internet Data Entry System within one day of collecting the specimen or by 9:00 a.m. of the following morning. 3. The PEP will keep the local laboratory results in a locked file with no access by BABY HUG staff. 4. The MCC will check the local lab data for violating BABY HUG toxicity and/or alert levels and will send the appropriate messages to the PEP. 5. The designee, if in his/her clinical judgment, believes a toxicity and/or alert level has been crossed, will contact the Clinical Center Principal Investigator to notify of the toxicity and/or alert and to arrange for appropriate emergency clinical care. If the absolute neutrophil count (ANC) on the local blood count is below 1250/uL or the Hgb <6.0 g/dl or the Hgb has dropped 20% or more from the three-month rolling average or the platelet count is <80,000 mm3, study treatment should be stopped and the child should be clinically evaluated to determine if intervention is required. BABY HUG study medication should be stopped and the Medical Coordinating Center notified. If the ANC on the local blood count exceeds 1,250/uL prior to hospital discharge, BABY HUG study medication should be resumed at the same dose as on admission. If on hospital discharge the ANC on the local blood count is still below 1,250/uL, the patient and family should _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-3 of 10-22 be instructed not to resume treatment until a scheduled local blood specimen is above 1,250/uL and reviewed in the Medical Coordinating Center. If the absolute neutrophil count on local blood count is between 1,000/uL and 1,250/uL during evaluation for a febrile event, the BABY HUG study medication should be stopped. The patient may be treated as an outpatient or admitted at local option. If admitted, BABY HUG study treatments will be stopped as above. If managed as an outpatient, the patient should remain off BABY HUG study medication until a scheduled blood count is performed locally and reviewed in the Medical Coordinating Center. 10.2.2 Ascertainment of Specified Events and Possible Adverse Effects in Patients At each visit, parents will be queried regarding recent medical events or procedures. Events will be documented to ascertain the nature of the event, including special treatment(s) and their indication(s). Reportable events and hospitalizations will be recorded on event forms and followed up by the BABY HUG PEP, who will review hospital charts, medical records and office visit records. These forms will be forwarded to the MCC and maintained in a locked file by the PEP. The event report forms and documentation will identify the occurrence of death, stroke with neurologic deficit, splenic sequestration, dactylitis, pain, acute chest syndrome, priapism, splenomegaly, biliary obstruction, hepatopathy, hepatic sequestration, pancreatitis, fever >101.5° F (38.5° C), acute renal failure, permanent renal failure, sepsis, severe neutropenia, aplastic crisis, acute osteomyelitis, transient ischemic attack and hospitalizations for sickle cell related events. If any study patient dies, efforts will be made to obtain complete post-mortem information. Discharge summaries and narratives of the fatal events will be sent with study forms to the MCC. All reportable events, whether treated on an out-patient or in-patient basis, will be reviewed by the Central Review Group (the NHLBI Project Director and the MCC Medical Consultant). Adverse treatment effects will be reported to the U.S. Food and Drug Administration (FDA). _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-4 of 10-22 10.2.3 BABY HUG Adverse Event Reporting 10.2.3.1 Introduction The safety of interventions and treatments associated with this protocol will be under continual review by the MCC, NHLBI, NICHD and DSMB. Accrual, efficacy and safety data will be monitored by all four groups. Accrual and safety data will be reviewed annually by each center’s Institutional Review Board (IRB). Prior to implementation of this study, the Protocol and the proposed patient consent forms will be reviewed and approved by the properly constituted Institutional Review Board (IRB) operating according to the 45 CFR 46 code of federal regulations. This committee will also approve all amendments to the Protocol or informed consent, and conduct continuing annual review so long as BABY HUG is open to accrual or follow-up of subjects. The NHLBI Data and Safety Monitoring Board will review the Protocol at 6 month intervals. A progress report showing results according to treatment assignment will be forwarded to the DSMB at these times and their recommendations will be expeditiously implemented. The DSMB members will be provided with monthly reports documenting each child’s growth, development and progress in BABY HUG. The DSMB may recommend early termination of the study for considerations of safety or efficacy. Monitoring for unanticipated adverse clinical effects will be done using event forms. The Clinical Center staff will determine the degree of severity (mild to fatal). Event forms will be submitted to the Medical Coordinating Center (MCC) and tabulated based on the affected organ system. Each serious AE (SAE) will be reported to the MCC within 24 hours of the event; supporting information will be required from the Clinical Center. MCC staff and the central review group will immediately review the report to determine if the event is serious. If so, MCC staff will send the information to the NHLBI and NICHD Project Officers and the FDA for review. The occurrence of serious AEs will be reported to the Clinical Center IRBs within 24 hours of NHLBI review. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-5 of 10-22 A serious adverse event is any of the following. 1. death 2. a life-threatening event 3. prolonged hospitalization (greater than 7 days) 4. splenic sequestration crisis 5. stroke, TIA 6. acute chest syndrome 7. an ICU admission 8. Any AE that is related to study treatment and unexpected Certain Serious Adverse Events that are sickle cell related have been added to the list, as defined by the FDA. Item #3 has been modified from the FDA definition given that frequent hospitalizations occur as a consequence of having sickle cell anemia without being enrolled in a clinical trial. Any serious adverse events (as defined by the FDA) which are not included in the above list, will be summarized and reported semi-annually. The Clinical Centers will be required to provide supporting information using a MedWatch Form 3500A for the events in the above list. In addition to this reporting mechanism, a centralized over-ride system will be carried out by individuals with knowledge about the treatment assignments. These individuals will review adverse events that are not thought to be serious in the eyes of the blinded investigators and make decisions about whether an adverse event is “serious” and reportable to the FDA. The two central review individuals will be the NHLBI Project Officer and MCC Medical Consultant. Either of these individuals will have the ability to elevate an adverse event being reported to the MCC to the “serious” category which will precipitate the collection of the required information for the MedWatch Form 3500A and a subsequent report to the FDA. Adverse events and serious adverse events will be listed individually and according to body system, designated according to severity (mild, moderate, severe, life-threatening, or fatal), and likelihood of relation to study treatment (not related, possibly, probably or definitely related), and _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-6 of 10-22 classified according to action taken (none, treatment stopped or interrupted, specific treatment instituted) and outcome (recovery without change in previous condition, some impairment, significant impairment, or death). 10.2.3.2 DBDR Adverse Event Coverage NHLBI Division of Blood Diseases and Resources (DBDR) staff will examine all adverse event reports from BABY HUG in real time and discuss with the BABY HUG Operations Committee appropriate clinical management. NHLBI - DBDR will hold emergency meetings to review adverse event reports as they occur. These DBDR staff will alternate night and week-end coverage via cell- phone so that the BABY HUG MCC will have access to a DBDR staff person at all times to discuss the management of adverse events in BABY HUG subjects. 10.2.3.3 Elevated Adverse Event Rate Detection Events to be centrally reviewed include all serious adverse events (e.g., death or events that are life-threatening, or events that cause or prolong hospitalization), splenic sequestration crisis, acute chest syndrome, stroke, transient ischemic attacks and ICU admissions. Other clinical occurrences will be denoted as having occurred or not occurred on clinic visit reports. There is adequate statistical power in BABY HUG to detect 50% differences between treatment groups at alpha = 0.01 if the event rates are in the range expected from the Cooperative Study of Sickle Cell Disease (CSSCD) and the study is completed with 200 patients. The BABY HUG investigators do not plan for early termination based on clinical events other than demonstrated inferiority of hydroxyurea for the outcomes death, stroke or splenic sequestration. The most important clinical events other than death and stroke are acute chest syndrome (ACS) and splenic sequestration (defined in Appendix F). Each child will be clinically evaluated repeatedly to determine if he/she has had acute chest syndrome, splenic sequestration or a serious, unexpected adverse event in the course of the study period. The proportion of very young children experiencing these adverse events will be compared according to assigned treatment. A one-sided test-based confidence interval (alpha = 0.005) will be used to determine if very young _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-7 of 10-22 children treated with HU have significantly higher frequencies than very young children treated with placebo. If the test-based, one-sided confidence interval does not cover zero, the Steering Committee proposes that the DSMB will consider all relevant information for the study and will recommend that the clinical trial not continue and HU not be recommended as a treatment for very young children. 10.2.3.4 Interim Reports Adverse events used to evaluate the safety of the BABY HUG regimen will be collected to include any unfavorable and unintended signs (including abnormal laboratory findings), symptoms or diseases (i.e. incidence of stroke, renal failure, regimen related toxicities, or infectious complications), which either occur during the study, having been absent at baseline or if present at baseline, appear to worsen and are determined to be possibly, probably or definitely related to this investigational treatment. Although the size of the Feasibility and Safety Pilot Study was chosen to allow the BABY HUG investigators to evaluate several administrative issues of the overall study design, it will be important to monitor the study in an ongoing fashion with respect to performance criteria and the occurrence of adverse events. For analyses other than those discussed above, we will protect our findings against finding spurious associations due to the large number of repeated tests of significance that will be performed. To do this, we propose to use monitoring bounds (for HU versus control comparisons) of 0.01 rather than 0.05 for the safety and adverse event evaluations listed below. We propose the following monitoring. Monitoring Safety and Adverse Events The DSMB Chair, Executive Secretary of DSMB, and NHLBI and NICHD Project Officers will review monthly reports including: 1. Recruitment: Expected vs. Actual 2. Patients screened, eligible and randomized 3. Patient characteristics at baseline _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-8 of 10-22 A. Age, race and gender B. Spleen function C. Spleen size D. Pitted cell counts E. Schwartz equation GFR estimates F. DTPA GFR was discontinued as of May 29, 2009. G. Urine concentrating ability H. CBC I. Presence of gallstones J. Blood chemistries K. Microalbuminuria L. O2 saturation M. Physical examinations N. Neurological examination and neuropsychological development O. Height, weight, head circumference P. Transcranial doppler (TCD) measurements 4. Blood count toxicities 5. Dose adjustments 6. Intra- and Inter-observer agreement liver-spleen scans 7. DTPA GFR was discontinued as of May 29, 2009. 8. Immunological Impairment 9. Safety assessments and adverse events A. Height, weight, head circumference B. Neurological examination and neuropsychological development _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-9 of 10-22 C. Unexpected and serious adverse events: update tallies, rates and individual summaries (case reports) for immediate review by the Executive Secretary of the DSMB, DSMB Chair, and NHLBI and NICHD Project Officers Individual Patient and Group Safety Monitoring a. In consultation with the Project Officer, the Executive Secretary of DSMB, and the DSMB chair may recommend full DSMB review or individual treatment interruptions. b. All individuals whose treatment is interrupted or stopped will continue to be monitored. 10.2.3.5 Analysis of Death or Stroke Death and clinically manifest stroke represent the most adverse outcomes that can occur within this study, and it will be important to determine if HU treatment results in an excess number of these types of events. These two outcomes will be evaluated separately from each other. One- sided test-based confidence intervals (alpha = 0.05) will be used to determine if very young children treated with HU have a significantly higher frequency of either outcome than very young children treated with placebo. If the 95% one-sided confidence interval for either stroke or death does not cover 0, it will be recommended that the trial not proceed and that HU not be used as a treatment for very young children. Clinical Centers will be expected to report to the Medical Coordinating Center the occurrence of death or stroke within 24 hours of learning about the event. The Medical Coordinating Center will prepare a report immediately with the information at hand for the NHLBI and NICHD Project Officers, Executive Secretary of DSMB and the DSMB Chair. Within 10 days, the Medical Coordinating Center staff will provide an updated report for the NHLBI and NICHD Project Officers, DSMB Executive Secretary, and for the DSMB Chair. Each case will be reviewed individually with the DSMB. The NHLBI Project Officer and DSMB Executive Secretary will file reports on each death or stroke with the U.S. Food and Drug Administration (FDA) under the study IND. If the p-value for an association of death or of stroke with hydroxyurea is between 0.05 and _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-10 of 10-22 0.20 after any occurrence, the members of the DSMB will review all death or stroke reports in BABY HUG in aggregate and with other study data to consider whether or not there is a concern that should be addressed with a Protocol revision or study termination. 10.2.3.6 Analysis of Growth and Development We will analyze each child’s weight (monthly), height (quarterly), head circumference (quarterly) and growth velocity (monthly). We will measure their neurodevelopment (Bayley, Vineland) annually. Height, weight and head circumference growth will be analyzed using actual measurements and percentiles standardized to the CSSCD population of children with HbSS for height and weight, and to a normal black American population for head circumference (Pivnick et al, 1999). Average scores for the two treatment groups will be compared to test: HO: :2 > :1 versus the alternative: HA: :2 < :1, where :2 is the mean of measurements or percentiles for children assigned to HU and :1 is the mean of measurements or percentiles for children assigned to placebo. Each test will be a t-test performed on the estimates of height, weight and head circumference calculated for each child. It is proposed that DSMB members review individual growth and height for possible clinical indications of adverse effects of HU on height and weight if the mean in HU-treated very young children is between 1 and 2 standard deviations (SD) below the mean for placebo-treated very young children and to stop the study if the mean of HU-treated very young children is more than 2 SDs below placebo treated very young children. For review, DSMB members will be provided with the growth curves of each child printed on paper with percentiles from the CSSCD and specifying treatment assignment, and a graph of the average growth velocity over three month intervals according to time from study entry and treatment. Growth will be analyzed with cubic models (mixed model analysis of variance to incorporate child-specific random effects, and in treatment group comparisons to account for _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-11 of 10-22 correlation of serial measurements) fit to each child. Growth velocity will be estimated with the first derivative with respect to time of the cubic models. Curves will be plotted as each child’s percentiles for growth over time also. Neuro-development questionnaires will be administered annually. For the evaluation of this endpoint, we will compare the one-year cognitive function between toddlers treated with HU and toddlers treated with placebo. If a test-based, one-sided 99% confidence interval of the difference in mean Bayley score at one-year does not cover zero, it will be recommended that the trial not continue and that HU not be used as a treatment for very young children. 10.2.3.7 Analysis of Acute Chest Syndrome, Splenic Sequestration and Serious, Unexpected Adverse Events The most important clinical events other than death and stroke are acute chest syndrome (ACS) and splenic sequestration (as defined in Appendix F). Each very young child will be clinically evaluated repeatedly to determine if he/she has had acute chest syndrome, splenic sequestration or a serious, unexpected adverse event in the course of the two-year follow-up period. The proportion of very young children experiencing these adverse events will be compared according to assigned treatment. A one-sided test-based confidence interval (alpha = 0.005) will be used to determine if very young children treated with HU have significantly higher frequencies than very young children treated with placebo. If the test-based, one-sided confidence interval does not cover zero, the Steering Committee proposes that the DSMB will consider all relevant information for the study and recommend that the clinical trial not continue and HU not be recommended as a treatment for very young children. 10.2.3.8 Alert and Monitoring Levels The local Primary Endpoint person will review the local CBC results to determine if an alert is present in the data. In addition, the Hematology and Biochemistry Core Laboratory data and the local CBC data will be used by the MCC to monitor electronically for values exceeding alert levels. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-12 of 10-22 Alert laboratory values (Table 10-1) are indicators to the MCC and the Center staff that the patient requires clinical follow-up and are distinct from toxicity values (Section 6.4). The laboratory alerts are intended as possible indicators of adverse events such as splenic sequestration, aplastic crises, renal insufficiency, etc requiring treatment interruptions and further clinical evaluations or interventions by the Center staff. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-13 of 10-22 Table 10-1 BABY HUG LABORATORY DATA ALERT AND MONITORING LEVELS Alert Levelsa Changeb Study Low High WBC 50K Hemoglobin 6.0 13.3x2FVs - 20%c Platelet Count 80K 1M Neutrophil Count 1.25 30K Reticulocyte Count 80Kd -- Creatinine -- 1.0 100%e Total bilirubin -- 10 ALT -- 150 NOTE: Low alerts must be less than those listed in the table; high alerts must be greater than those listed in the table. a Alert levels which should be evaluated for clinical monitoring of the patient. FV = Follow-Up Visits. b Loss or gain (sign indicates direction), in % change. c Hemoglobin 20% decrease from three-month running average. d If Hb<7.0gm/dl. e Creatinine level at least twice from baseline and greater than 1.0. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-14 of 10-22 If an alert level is detected, the Clinical Center will use the following guidelines for responding to notification of an alert. 1. The PEP will handle the alert in a straightforward manner when possible, or, more likely, contact a Hematologist/Sickle Cell Specialist who is not directly connected with the BABY HUG Trial. 2. When indicated, the PEP and the Hematologist will develop a plan for a clinical response to the alert value. (For example: If the patient were severely neutropenic and febrile, the patient would be hospitalized for antibiotic treatment; if the patient had > 20% decrease in hemoglobin level, the patient would be hospitalized and/or transfused; if the patient met criteria for a splenic sequestration, the patient would be hospitalized and/or transfused; etc.) 3. In the event that no non-BABY HUG Hematologist was available, the PEP would need to contact the BABY HUG PI and discuss a course of action. In doing so, the PEP would provide the PI only with “need to know” laboratory information. In most cases this would not create an unblinding problem because, for example: severe neutropenia may more likely be related to an acute viral infection rather than HU toxicity; worse anemia might be caused by an aplastic crisis or splenic sequestration rather than HU; splenic sequestration might or might not be related HU, etc. In most situations, CBC values would not readily distinguish between treatment with hydroxyurea or placebo, although it is important that the MCV should not be revealed to the PI or BABY HUG Study Coordinators. 4. In the ensuing management of the child, the bulk of the decision-making will be carried out by the non-BABY HUG Hematologist and the PEP. 5. The alert values for increased hematologic blood counts will not necessarily warrant any immediate reaction by a clinician. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-15 of 10-22 10.2.4 Adverse Event Management Spleen and Splenic Sequestration: Parents and caregivers should be instructed in techniques of spleen palpation at each clinical visit and asked to feel for the child’s spleen daily. A newly palpable spleen or one more than 2 cm larger than previously noted should be reported immediately to the Clinical Center, and the patient should have a CBC and be examined by a physician or nurse practitioner knowledgeable about sickle cell anemia. In order to assure the availability of steady state hemoglobin level information, the Medical Coordinating Center will provide each Primary Endpoint Person with a three-month rolling average of each patient’s hemoglobin measurements. The span of the spleen below the costal margin in the midclavicular and anterior axillary lines should be carefully measured and recorded (in centimeters) at each clinical visit. Splenic sequestration and splenomegaly as defined in Appendix F will be recorded on the appropriate study form as outlined in the Manual of Operations. The management of splenic enlargement (admission, close outpatient follow-up or transfusion) will be at the discretion of a non BABY HUG hematologist or unblinded physician at each Clinical Center, but the following guidelines should be used whenever appropriate/possible. On initial evaluation: 1. Vital signs at presentation and q1-2 hours initially; 2. Careful physical examination with assessment of pallor, measurement of spleen size, presence of gallop, liver size; repeat examination q1-2 hours initially; 3. Labs including CBC, WBC differential, reticulocytes STAT. Type and crossmatch for packed red blood cells (PRBCs); 4. If hypovolemic or with cardiovascular compromise, emergent infusion of intravenous fluids (IVF) or PRBC to restore blood volume and maintain normal blood pressure. If normovolemic, start IVF at 1x maintenance. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-16 of 10-22 5. Admission unless stable over 4-8 hour period; close follow-up. On admission: 1. Monitor heart rate (HR), respiratory rate (RR), pulse oximetry q2 hours until stable, then q4h; 2. Repeat CBC studies q4-12 hours; 3. Maintain IVF at 1x maintenance; 4. If febrile obtain blood culture and begin antibiotics, e.g. cefuroxime 50 mg/kg IV every 8 hours; 5. Transfuse for evidence of hypotension, cardiovascular (CV) compromise, enlarging tender spleen with 10-15 cc/kg over 4 hours. If no CV compromise, transfuse if Hgb <5 gm/dL for stable splenomegaly regardless of reticulocyte count; if Hgb> 5gm/dL transfuse at Principal Investigator discretion. Goal of transfusion is Hgb about 8 gm/dL, (splenic unloading of trapped RBC may cause an "overshoot phenomenon"); 6. Supplemental oxygen until condition is stable (or acute episode resolves); 7. Other clinical interventions, including antipyretics and analgesics, at Principal Investigator discretion. After the initial splenic sequestration event, the child will be monitored every 2 weeks. The decision to continue PRBC transfusions and/or proceed to splenectomy, will be at the discretion of the Principal Investigator. However, the number of children undergoing splenectomy according to local indications will be tabulated in each treatment group. Chronic transfusion therapy or splenectomy, options that would remove the patient from study treatment or scintographic evaluation of the primary (spleen) endpoint, should be discussed with the Operations Committee prior to implementation. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-17 of 10-22 Episodes of splenomegaly, splenic sequestration and associated measures will be tabulated and compared according to HU and placebo group assignment. If an excess of sequestration events is found in the HU group, the DSMB may consider stopping the trial. Renal: Parents and caregivers will be educated about the importance of the kidney in children with sickle cell disease, and reminded that the kidney is one of the special organs tested in the BABY HUG trial. Infants should remain adequately hydrated at all times, as dehydration is detrimental and could be injurious to the kidney. Medications that have potential risk to the kidney such as prolonged use of aminoglycosides or high-dose non-steroidal anti-inflammatory drugs, should be avoided. Frequent urinary tract infections and hematuria will be documented during the BABY HUG trials, as these findings may reflect or cause renal damage. Painful Events (vaso-occlusive or dactylitis): Parents and caregivers will be educated about dactylitis and painful events as part of their education about sickle cell disease. They will be taught to push fluids and use ibuprofen and/or acetaminophen with codeine at home. Small supplies of both analgesics should be prescribed for home use at routine clinical visits. They and caregivers will be educated about dactylitis and painful events as part of their education about sickle cell disease. The definition of a painful event is an event lasting two hours or more without obvious cause requiring the use of one or more doses of non-steroidal or narcotic pain medication. Events treated as an outpatient (including emergency room) or requiring admission will be reported at the next Clinical Center contact and included in data entered. Events requiring admission will be reported to the Medical Coordinating Center on appropriate form, and supporting documents collected for central review. Acute Chest Syndrome, Aplastic Crisis, Priapism: All events meeting defined criteria will be reported to the Medical Coordinating Center on Event Report Forms. Clinical management, including the need for simple or exchange transfusion will be at option of each Clinical Center. Chronic transfusion therapy, an option that would remove the patient from study treatment, should be discussed with the Operations Committee prior to implementation. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-18 of 10-22 Parents will be educated about signs of acute chest syndrome (fever, respiratory symptoms) and aplastic crisis (pallor, decreased energy) at regular clinic visits and asked to seek medical attention should they occur. Parents of male children will be taught about priapism, a prolonged painful erection of the penis, and asked to seek medical attention, if the episode persists beyond two hours. Briefer episodes of priapism will be recorded at the next clinic visit. Neurologic Events: Families will be taught standardized definitions of TIA, stroke and other neurologic events and reminded at each clinical contact to call the Clinical Center immediately if the child is not able to move arms or legs (unrelated to pain), has facial drooping or dysarthria. Each Clinical Center will promptly evaluate such patients. The minimum evaluation must include documentation of complete neurologic examination, preferably by a neurologist. If the neurologist suspects stroke or TIA clinically, neuroimaging including MRI/MRA must be done. If a stroke is confirmed, acute management will be at the preference of the Clinical Center. Transfusion timing and technique (exchange or simple) will be at Clinical Center preference. Chronic transfusion therapy, an option that would remove the patient from study treatment, should be discussed with the Operations Committee prior to implementation. If transcranial Doppler (TCD) screening is part of an individual Clinical Center’s standard care, such testing should be offered to patients enrolled in BABY HUG as per usual practice. TCD screening is not yet universally available or standardized for children less than two years of age. If screening is performed and values are persistently elevated in children over 2 years of age, the parents should be offered chronic transfusion therapy for the child in accordance with standard practice at each Clinical Center. Patients for whom chronic transfusion therapy is considered should be discussed in advance with the Operations Committee. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-19 of 10-22 10.2.5 Laboratory Specimen and Data Collection Blood specimens will be collected at designated follow-up visits by the Clinical Center staff. A finger/heel stick or venipuncture may be performed for routine hematology evaluations. The blood specimens will be analyzed locally (and every six months specimens will be shipped to the Hematology and Biochemistry Core Laboratory by overnight courier). Results of blood counts and other blood studies performed locally used to monitor for hydroxyurea toxicity (bone marrow depression) will be available within 24 hours of collection. Every six months, blood will be sent for evaluation of liver function (ALT and bilirubin) and for renal function (BUN/Creatinine). The MCC will obtain blood test results from the local laboratories daily and will review the studies to determine the dose recommendation for hydroxyurea or placebo. Dosage adjustments or temporary treatment stops will be performed for patients assigned to placebo so that patients and Clinical Center staff will be blind to treatment assignments. The Pharmacy Distribution Center (PDC) will ship hydroxyurea and placebo supplies to the Clinic Center for each patient on a regular basis. No patient can receive a new drug prescription until a blood specimen has been analyzed locally. Blood specimen containers and mailers will be provided by the Hematology and Biochemistry Core Laboratory. The MCC will notify Clinical Centers within 48 hours of receipt of blood count to issue directions to stop study treatment (either hydroxyurea or placebo). It will be the responsibility of the Clinical Center to notify patients of stop orders. 10.3 PATIENT COMPLIANCE AND MANAGEMENT The major obstacle to successfully completing follow-up procedures in BABY HUG will be ensuring adherence with the study protocol, and in particular, study visits. The major responsibility for this task rests with each Clinical Center. MCC staff will assist the Clinical Center staff with schedules for follow-up, identification of patients whose follow-up is interrupted, and notification of outstanding forms/data. If a patient misses three consecutive appointments, this patient will be considered inactive in the study, and study treatment will be temporarily stopped. The patient will become active again and resume study treatments only if the Clinical Center Principal Investigator _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-20 of 10-22 can explain the missed visits and provide a plan for more complete participation in the future. Extra effort will be made to increase Protocol adherence for any patient who misses four or more visits (not consecutive) in a six-month period. Strategies to increase contact with BABY HUG patients may include: 1. providing comprehensive care for management of the complications of sickle cell anemia, including hydroxyurea therapy; 2. maintaining availability through telephone contact with the patients’ parents; 3. promoting accessible, positive contact with the Patient/Family advocate at any time during the study (see Section 3.1 and Exhibit 3-1); 4. maintaining up-to-date, accessible records of BABY HUG patient enrollees and locator information including home address, telephone numbers; 5. fostering supportive relationship with BABY HUG families; 6. providing transportation reimbursement and meal vouchers ($30.00 per visit); and 7. providing assistance with telephone service ($30.00 per month) or providing pager system access for families. If a patient leaves the study early (before 24 months of treatment) for any reason, every attempt should be made to secure the exit studies at that time. The studies in order of priority are Tc99m sulfur colloid liver-spleen scan, blood specimen collection (for pitted cell count, and fetal hemoglobin determination), and abdominal ultrasound. If the patient plans to move to an area served by another BABY HUG Clinical Center, the family should be offered the opportunity to transfer care to the other Clinical Center. If they accept, the child will not need to become inactive in the study. Subsequent follow-up and evaluations will be at the new Clinical Center and reimbursement will be transferred to the new Clinical Center. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-21 of 10-22 10.4 LONG-TERM FOLLOW-UP 10.4.1 Introduction At the end of the study treatment each family will be asked to agree to return for long-term follow-up visits. If NHLBI and NICHD cannot fund this long-term follow-up, the investigators plan to follow their subjects at the respective clinical sites for at least ten years. Hydroxyurea therapy is part of the accepted management of adults, adolescents and school age children with severe courses from their sickle cell disease. Two limited studies observed no additional toxicity from the use of hydroxyurea by children from 6 months to 5 years of age for periods up to 4 years. However, large numbers of persons with sickle cell disease of any age have not been followed for long periods of time (decades) after initiation of hydroxyurea therapy. Although a survival advantage has been suggested for severely involved adult patients who took hydroxyurea in the MSH, it is unclear if the same benefit will occur in children, particularly those prescribed the medication before the onset of a severe clinical course. Further, children must continue to grow and develop toward adulthood. Problems from early use of hydroxyurea might only become evident years after the completion of study treatment in BABY HUG. Thus, very young children with sickle cell anemia must be carefully assessed longitudinally for all potential toxicities, including oncogenic potential of this drug, to accurately determine the risks of hydroxyurea use. If benefit is demonstrated from early hydroxyurea therapy, it will be important to determine how long that benefit continues. Thus, clinical ascertainment and structured evaluation should be a part of the long term follow-up of this unique group of patients. Clinical care after the two-year study treatment might or might not include use of hydroxyurea regardless of initial random treatment assignment. An additional five to ten years of follow-up will provide important information to physicians and parents of very young children with sickle cell anemia, with the goal to follow these subjects for 5 to 10 years after the end of their participation in the randomized clinical trial if their parents and the subjects are willing. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-10.wpd — 8/09 Page 10-22 of 10-22 10.4.2 Follow-Up Data Collection Data will be collected for all BABY HUG patients whose families agree to continue in follow- up. A separate protocol and consent form will be developed for long-term follow-up. Consent will be obtained after the end of treatment (the full, planned two-year course or earlier termination) in BABY HUG. If NHLBI and NICHD cannot fund this long-term follow-up, the investigators plan to follow their subjects at the respective clinical sites for at least ten years. All families would be encouraged to participate in this portion of the study. Participating families will remain in follow-up even if they decline specific follow-up evaluations. 10.4.3 Follow-Up Procedures Standardized data collection forms will be submitted by the BABY HUG follow-up coordinators at the times specified using the BABY HUG Internet data collection system. Even if families decline to participate in specific follow-up testing or move from the area, the coordinator will attempt to contact the family at intervals indicated to obtain information on clinical events (major events and unusual events), growth, height, weight and head circumference, vital status and use of hydroxyurea. With the family’s consent, this will include information from other health care providers. 10.5 DEBRIEFING CONTACTS After final BABY HUG treatment data have been collected and final reports on treatment results prepared for presentation or submitted for publication, each patient’s family will be scheduled for a debriefing contact. The families will be informed of their individual treatments, the primary results of BABY HUG and the recommendations of the investigators. At the end of long- term follow-up, the families will be informed of the results of long-term follow-up and any reconsideration of the recommendations of the investigators. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-11.wpd — 8/09 Page 11-1 of 11-3 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) PROTOCOL CHAPTER 11 CLOSE-OUT PROCEDURES 11.1 OVERVIEW Assuming no early stop of the study for reason of either efficacy or safety, at 24 months of randomized study treatment for each patient, individual patients will have study treatment discontinued and their families will be asked to agree to return for visits for the duration of BABY HUG to allow collection of information on each child’s growth, health and well-being up to five years. After the last patient enrolled has completed 24 months of randomized treatment, all patients’ families (i.e., Feasibility and Safety Pilot Study and all other patients’ families) will be given information on their children’s assigned treatments and on the findings of the study, as will be determined by the Steering Committee, the Data and Safety Monitoring Board, the National Heart, Lung, and Blood Institute and the NICHD. 11.2 DURATION OF RANDOMIZED, BLINDED STUDY TREATMENT Patients will be followed on randomly assigned study treatment for 24 months. At 24 months, patients’ randomized, blinded study treatment will be discontinued. Patients will continue being monitored for major medical events (see Section 10.2.1) through their regular pediatric hematology care provider, who is expected to be in the BABY HUG Clinical Center, affiliated with the BABY HUG Clinical Center, or by previous agreement the child’s regular pediatrician. If the patient changes primary provider, Clinical Center staff will maintain contact with the family and if necessary through the family with the new primary provider. The discontinuation of study treatment at 24 months on study and the need to maintain contact up to the common termination will be explained to the parents at the time that informed consent is obtained at study entry. The explanation will be repeated in the course of the study and at the individual patient’s 24-month visit. Contact with the family will be maintained to assure that monitoring for medical events will continue, and that the family can return for final close-out when study results will be made available. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-11.wpd — 8/09 Page 11-2 of 11-3 Patients’ families and physicians will not be unblinded at the 24-month end of treatment visit. Neither blinded study treatment nor open-label hydroxyurea will be provided by BABY HUG for enrolled patients after 24 months. An assessment of the use of hydroxyurea for sickle cell anemia in this age group will await final study results and a review of those results by the BABY HUG Data and Safety Monitoring Board, Steering Committee, the NICHD and the National Heart, Lung, and Blood Institute (NHLBI). Labelling for use of hydroxyurea in this age group will depend on the determination of the US Food and Drug Administration (FDA) if a supplemental New Drug Application (NDA) is submitted. 11.3 DEBRIEFING CONTACTS There will be two debriefing contacts. After final BABY HUG treatment data have been collected and final reports on treatment results prepared for presentation or submitted for publication, each patient’s family will be scheduled for a debriefing contact. The families will be informed of their individual treatments, the primary results of BABY HUG and the recommendations of the investigators. In a second debriefing contact at the end of long-term follow-up, the families will be informed of the results of long-term follow-up and any reconsideration of the recommendation of the investigators. 11.4 FINAL STUDY DATA AND DISSEMINATION OF RESULTS Data processing and analysis of final study data will proceed on a “time-of-the-essence” basis. The Data and Safety Monitoring Board will review the final data (see Section 4.4.4) including the specified analysis for efficacy and safety at a planned final meeting. A final, consensus recommendation from the DSMB, Steering Committee, NICHD and NHLBI will be shared first with the study patients’ families (at which time they will also be informed of their assigned treatments). This recommendation will be made public as soon as possible thereafter. Submission of final BABY HUG data to the FDA will proceed under the terms of the Investigational New Drug (IND) application filed by the NHLBI at the start of BABY HUG. In the event that HU is found to be safe and efficacious for infants and very young children with sickle cell _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-11.wpd — 8/09 Page 11-3 of 11-3 anemia, study investigators, the NICHD and the NHLBI will support a submission to the FDA for labeling for this new indication. In the event HU is not found to be safe and efficacious, established procedures for submission of the study data in a final IND report to the FDA will be followed in an orderly fashion. The data closure upon which the determination of HU’s safety and efficacy, if any, is made will form the basis of the final consensus recommendation and informing patients’ families of the results. A final data closure, based on cleaned and complete data reporting, will be available for the submission to the FDA, final archival and databank studies. Clinical Centers will implement the following procedures for finalization of study data. All queries for data clean-up including resolution of forms/procedures expected but not completed, as determined by the MCC, will be addressed within two months of the last patient visit. Clinical Centers will be responsible for archiving records that document reported events and specified outcomes. The MCC will archive all electronic study data. Data from the Core Laboratories, Endpoints Evaluation Committees and medical records serve as the definitive sources for patient outcomes in the study. Archival of central source data, including Core Laboratory results, will be consistent with requirements for a study conducted under an Investigational New Drug (IND) Exemption and sponsored by the National Heart, Lung, and Blood Institute (NHLBI). Storage of frozen and preserved specimens will be maintained according to the requirements of NHLBI subcontracts. The MCC will archive study data in accordance with FDA guidance and National Heart, Lung, and Blood Institute requirements. Public data files will be made available according to National Heart, Lung, and Blood Institute policy. The NHLBI will finalize the disposition of the IND report(s) according to their agreement with the FDA under the IND. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-1 of 12-16 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) PROTOCOL CHAPTER 12 CONDUCT OF THE TRIAL 12.1 OVERVIEW BABY HUG is a randomized, double blind clinical trial. Study procedures will be designed and implemented so as to optimize data capture and assure the highest level of quality for the scientific goals of the study while minimizing inconvenience to patients and inefficiencies in the performance of the study. Appropriate mechanisms will be implemented to maintain the study on schedule, provide tools and aids to Clinical Centers and other participating units in the performance of their activities on behalf of the study and ultimately arrive at a study data set that will provide the answers to the study primary objectives and key questions. Patient safety is the overriding concern, while maintaining the integrity of the study, and consideration of the family’s efforts in their child’s participation. Appropriate checks and monitoring systems will be implemented so that no study patient or his/her family experience any untoward outcome or unnecessary difficulty. 12.2 TIMELINE The study timeline is presented in Appendix D. Planning and study design, development of the Protocol and Manual of Operations are scheduled for September 2000 through August 2003, including review of the Protocol and model Informed Consent Form by the Data and Safety Monitoring Board and the participating Institutional Review Boards (IRB). Meetings of the Steering Committee and Data and Safety Monitoring Board are scheduled throughout the first year to meet these goals. Recruitment and enrollment for the Feasibility and Safety Pilot Study began in the fall of 2003. In January 2005, the DSMB authorized immediate continuation of recruitment following the Feasibility and Safety Pilot Study with a goal of 200 patients total. Follow-up will continue through 2008. Patients will be taken off study treatment as they complete two years of randomized _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-2 of 12-16 treatment, but will continue to be followed through 2008. Final study data will be collected and cleaned for the next two months, and main study results will be prepared as rapidly as possible for review first with the DSMB, then with the investigators, then with the patients, and then with the public. 12.3 PLANNING AND STUDY DESIGN The Steering Committee will meet regularly during the first six months of the planning and design period (first year) to write the Protocol and Consent Form. These will be presented to the NHLBI-appointed Data and Safety Monitoring Board. Following suggestions for revisions, the Protocol and Consent Forms will be submitted to individual IRBs for approval. Model consent forms will in many instances need to be modified to include local IRB requirements. Individual institutions’ informed consent forms will be reviewed by the Chairman of the DSMB to assure that they conform to the model consent form and they do not allow policies or practices which may be incompatible with BABY HUG. 12.4 TRAINING, CERTIFICATION AND START-UP After the Protocol and Model Informed Consent Form are approved by the DSMB and the Protocol and individual institutional consent forms are approved by the local IRBs, the study will be ready to begin data collection. A Manual of Operations will be written to give specific performance directions. Training of Clinical Center staff in procedures of data collection and study procedures will be conducted by Medical Coordinating Center staff (MCC). Training will include: • completion of study forms • data entry over the Internet • maintenance of study patient data files • completion of data cleaning procedures including response to edit queries • collection, labeling and processing of central laboratory specimens • patient orientation and information _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-3 of 12-16 • obtaining informed consent • conducting eligibility assessment • the use of the Automated Telephone Randomization System (ATRS) • retrieving initial and continuing prescription recommendations as transmitted over the Internet and coordinated with the Clinical Center (Investigational) Pharmacy to dispense study treatments to the patients • conduct of clinic visits including assessment of patient compliance. Clinical Center staff who will complete study forms or otherwise provide study data will be certified after successful completion of the training in these areas. Each will receive a unique certification number that will be entered on every study form completed, along with a signature and date of data collection. This certification number identifies the individual who is responsible for the accuracy and completeness of the data collected. Clinical staff who will be conducting special evaluations will be trained in BABY HUG data collection procedures. Standardized methods for data collection for special evaluations (e.g., neurological examinations or neuropsychological evaluations) have been set by specialists designated by the Steering Committee. Clinical staff will be STE certified and given study certification numbers that will identify the evaluations for which they are responsible. Members of adjudication panels have been given detailed instructions on the adjudication process and have completed several sample cases designed to test the adjudication process. The MCC prepared these cases in collaboration with designated specialists (e.g., for radionuclide scanning). Clinical Center Principal Investigators and coordinators must attend at least one training session and successfully complete the certification process, which will include satisfactory completion of practice procedures and data collection with patients. Training is conducted and certification is issued by the Medical Coordinating Center staff after review with the Study Chairman, Vice-Chairman and Project Officer. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-4 of 12-16 12.5 DATA EDITING AND MANAGEMENT 12.5.1 Introduction The Medical Coordinating Center serves BABY HUG as the repository of all forms, documents and minutes. Clinical Centers will use the Medical Coordinating Center Internet Data Entry System to send to the Medical Coordinating Center data in electronic format from the original of each BABY HUG form, which will be completed and kept in a manner acceptable for regulatory purposes in Clinical Center files. All BABY HUG data collection forms and transmittal lists for blood specimens and other materials (e.g., images) shipped in the course of BABY HUG data collection will be sent to the Medical Coordinating Center via Internet Data Entry. Medical Coordinating Center staff will monitor the arrival of data and transmittal lists to identify form and procedure delinquencies based on appointment schedules and anticipated study forms. Medical Coordinating Center staff will monitor Core Laboratory specimen receipt dates for specimen delinquencies based on appointment schedules, expected specimen collection, and reports of specimens received in the Core Laboratories. 12.5.2 Receipt and Inventory Medical Coordinating Center staff will receive, log in and store all Internet Data Entry transmissions. Clinical Centers should send specimens directly to the Core Laboratories with Internet Data Entry of transmittal lists to the Medical Coordinating Center. Data from the Clinical Centers will be automatically linked to the date of receipt. Transmittal lists are compared with data received from the Clinical Center and data transmitted from the Core Laboratories. Any discrepancies between crucial patient identifiers (e.g., name code, ID number or date of study entry/follow-up visit) that Medical Coordinating Center staff find will be brought to the Clinical Center’s attention immediately by e-mail. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-5 of 12-16 12.5.3 Expected Receipt of Forms The expected dates for receipt at the Medical Coordinating Center of the BABY HUG patients' form data will be: one week after each visit for eligibility screening data; one week after their study entry visit for Treatment Initiation Forms; two days after clinic visit for Core Laboratory Reports and Missing Specimen Lists; two weeks for Follow-Up Visit Forms or Missed Visit Forms; two weeks for Clinical Event Report Forms; and one week for Imaging Study Forms. Data not sent to the Medical Coordinating Center or specimens not sent to the Core Laboratory within two weeks of the expected date will be denoted as delinquent. Guidance to assist the questioner in obtaining the information (QxQs) for each of the forms is posted on the Website for ease of use by the Clinical Center staff. Practice with data entry and discussion of the fine points of data entry for neuropsychological evaluations have made clear to the Clinical Center staff the extent of effort necessary for intelligent, single entry of the BABY HUG data. The Internet Data Entry System has been developed to accommodate timely data entry and preliminary edit at the time of data entry so that the time critical information necessary to keep the BABY HUG patients on study treatments and adequately monitored for safety is available. Print back capability for Clinical Center verification and sign off as index document is provided by the Internet Data Entry system. The system allows for data entry at a rate of 3600 characters per hour (most people key at this rate easily). At this rate, 200 binary (or single field) variables can be entered in three minutes. The regular follow-up visit form (Form 31), has 131 keystrokes to the form and takes approximately 1.5 minutes to key. The items entered from a form are registered in the central data base immediately after entering the data. Critical forms such as the Form 31 must be entered on a more timely basis than other forms. In the event of a Clinical Center burden management problem the MCC recommends that a two-tiered system for data entry be established. Critical forms such as the Form 31 will be entered first and lower priority forms will be entered when more time is available for the coordinator (or when another designated data entry person is available) to enter the lower priority forms. To cover for the possibility that BABY HUG Clinical _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-6 of 12-16 Center staff are unable to transmit time critical information because of equipment failure (e. g. , the server at the Medical Coordinating Center or the server at the Clinical Center is down), a dedicated fax line in the BABY HUG Coordinating area has been established. This fax line is used for BABY HUG transmissions only. Clinical Center staff will fax their completed, time critical forms to the Medical Coordinating Center where they will be processed electronically, or if need be, manually to maintain the processing of time critical information. Information that is not time critical (e.g., annual neurology exams) can be keyed by Clinical Center staff when full functionality is restored. BABY HUG Clinical Centers that participate in the Children’s Oncology Group (COG) already have experience with Internet data entry and note that this backup plan offers a level of security and assurance that is not available in other studies that delay Clinical Center data transmissions until all systems are functioning and data processing staff are available following any interruptions. In the event of national emergencies (e.g., concerted attack on the Internet, communication systems or air transportation), contingency plans will be written so that whatever communications and specimen transportation systems that can be used will be. In the short term if fax lines are working, all critical information may be sent by fax to the Medical Coordinating Center for data entry. Disruptions of specimen transportation may require short term stop-orders interrupting individual study habits for brief periods until central safety monitoring can be reestablished. Long term disruptions will have to be addressed with reconsideration of design. Long term failure of Internet data entry will also be addressed with negotiated design changes such as installation of distributed systems in the Clinical Centers or central data entry of forms transmitted to the Medical Coordinating Center by the fastest available method (e.g., fax or courier). In the event that certain other aspects of data entry are found to be highly burdensome to the coordinators, they will be discussed on the coordinators’ bi-monthly conference calls and their concerns presented to the Operations Committee and as appropriate to the Steering Committee and addressed by the Medical Coordinating Center and other members of the Steering Committee. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-7 of 12-16 12.6 MONITORING PROGRESS AND PERFORMANCE a. Clinical Centers Clinical Centers will be monitored individually and in the aggregate for unexplained lag in recruitment, missed visits, missed blood specimen collection, missed scheduled procedures, missing expected forms, agreement between treatment dose recommended and dose dispensed, study treatment not accounted for, medical events required to be reported, and routine adverse events. Weekly lists of expected visits, blood specimens, and scheduled procedures, will be posted on the web site for each enrolled patient. Forms and procedures expected but not reported within three days and treatment status not reported within one day will be noted on the website and added to a cumulative delinquency report. Some delinquencies may be corrected at a later date. Other delinquent information may not be recoverable after the critical time period has elapsed. Unrecoverable delinquent data will be counted in summary reports as Protocol deviations for the time-critical aspect. For instance, if a stop order is issued but is not reported as having been implemented for three days, the database will show the day it was reported implemented, but the time-lag will remain on record as a minor Protocol deviation. Certain events such as adverse events and stop orders not implemented will not be allowed to continue unresolved. The Study Chairman will be notified within 48 hours of a stop order not implemented or serious adverse event(s). 1. Eligibility Status regarding eligibility criteria will be entered into the database for all consented patients. Their progress will be posted daily on the web site until they either are disqualified or are fully qualified. If they have a reversible eligibility disqualification, this will be noted. Aggregate reports will be generated weekly throughout recruitment showing, according to Clinical Center, the numbers of patients who are eligible, those disqualified and why, those qualified, those randomized and enrolled, and those in follow-up. Steering Committee members will monitor these accruing _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-8 of 12-16 reports and make recommendations to improve performance where needed or recommend changes in procedures. 2. Follow-Up Clinic Visits At every follow-up visit, the form will require a report of specific events (see Chapter 4) and any unusual conditions or occurrences (write-in). The Clinical Center investigator will be required to review this and provide an assessment of whether an adverse event has occurred. Since this is an IND monitored study, the usual definitions of adverse event may be implemented, such as the occurrence of death or a life-threatening condition or an event that causes or prolongs hospitalization. 3. Study Treatments Monitoring study treatments will be one of the most important activities of the study. Study forms will require complete accounting of study treatments to verify that each patient received his/her correct bottle with the correct dose, and that treatment was administered daily. If scheduled, blood specimens must be collected for a patient to continue taking prescribed study treatment. If blood results (CBCs) do not arrive from the local laboratory at the Medical Coordinating Center when expected, a stop-treatment order will be issued immediately and automatically. At every study visit treatments are expected to be returned, and they will be assessed for compliance by measurement of residual treatment returned. Treatment errors will be reported to the Study Chairman immediately and will be counted cumulatively, if they represent major Protocol violations. Study policies regarding remedial action on repeated treatment regimen violations will be implemented. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-9 of 12-16 4. Monitoring the Clinical Centers Medical Coordinating Center staff will produce recruitment reports weekly during the recruitment phase from the data entered from forms submitted for each entered patient. A sufficiently low recruitment performance will be responded to by a site visit from the Study Chairman or Vice-Chairman, Medical Coordinating Center staff, and NHLBI and NICHD staff. Failure to improve performance after such a site visit may result in an end to support for recruitment in a Clinical Center. On a bi-weekly basis, the Operations Committee (Study Chairman, Vice-Chairman, Medical Coordinating Center staff, Coordinator representatives, Steering Committee representatives and NHLBI and NICHD staff) meet by conference call to review recruitment goals and Protocol violations reported for each Clinical Center. Protocol exceptions for eligible patients will be considered by the Operations Committee and may be granted as long as study integrity is not compromised. If the committee arrives at a recommendation to grant an exception to the Protocol, the local IRB will be notified and the exception will be conducted in accord with the local IRB’s Standard Operating Procedures. Clinical Centers will be notified of minor violations with suggestions for remedial action. Major violations will result in a site visit by the Study Chairman or Vice-Chairman, Medical Coordinating Center staff and an NHLBI and NICHD staff member. At each scheduled Steering Committee meeting, a report of progress toward accomplishment of study goals will be presented, both for BABY HUG as a whole and for individual Clinical Centers. These reports will include certification status, number of eligible patients identified, number of patients enrolled of those identified, completeness of scheduled visit data collection, completeness of specimen collection, completeness of clinical event reporting, adherence to Protocol and results of actions taken to improve compliance. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-10 of 12-16 5. Site Visits Clinical Centers will be visited during the study to assure quality of data collection. Medical Coordinating Center staff will generate computer printouts of form data for comparison to Clinical Center form copies and to actual patient charts. If a Clinical Center is under consideration for being discontinued from treatment of patients in BABY HUG, the Study Chairman or Vice-Chairman, Medical Coordinating Center staff and NHLBI and NICHD Project Officers will visit the Clinical Center and provide a site visit report to the Data and Safety Monitoring Board (DSMB) for recommendation on final action. Clinical Centers with the greatest difficulty in meeting proposed goals for recruitment may also be site visited, and recommendations for improvement made, with a report to the DSMB. b. Central Facilities The MCC will monitor routinely receipt of expected reports from the Core Laboratories and treatments shipped from the Pharmacy Distribution Center. Any expected blood result that is not received will be tracked by MCC staff by telephone with the Clinical Center and the Core Laboratory. Because many courier shipments can be traced on the Internet, there should be a rapid resolution to any questions about shipments lost in transit. Quality assurance programs will be established to monitor the results from the Core Laboratories. In addition, the Core Laboratories will be chosen for their high level internal quality assurance programs. Hematology and Biochemistry Core Laboratory values will be monitored both for range and for consistency with the child’s laboratory measurement history. Values that are deemed “alert” values will be discussed immediately between MCC staff and Hematology and Biochemistry Core Laboratory staff. If the value is confirmed, the alert process will be implemented. Table 7-3 shows the lab alert values. Treatments dispensed by the Clinical Center (Investigational) Pharmacies will be checked for agreement with the treatment kit number assigned to the child, as well as the recommended prescription. The Clinical Center Principal Investigator will be notified immediately of any _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-11 of 12-16 discrepancies. Confirmed discrepancies will be tallied cumulatively. Pharmacies accruing unacceptable numbers of discrepancies will be reported to the Study Chairman for immediate action. c. Endpoint Evaluation Committees Members of endpoint evaluation committees will receive appropriate guidelines for the purpose of performing study assessments. They will first adjudicate sample cases. During the conduct of the study, various methods of quality assurance will be implemented including masked duplicate case reviews, both within-reviewer (reader) and between-reviewers (readers). Results of these reviews will be tabulated according to Clinical Center and reviewer. Between and within reviewer agreement rates will be available to the DSMB. The schedule of the reviews or readings of adverse event reports and images will be monitored and reported routinely to the Steering Committee. Reviewers or readers who fall behind in their assigned study work will be contacted by the Study Chairman and MCC Principal Investigator to assess the situation and propose a plan of action. Repeated failure to perform may result in replacement of a reviewer (reader). d. Medical Coordinating Center 1. Randomization The randomization schedule will be devised to assure the appropriate blocking and balance of treatment groups for clinically important clinical patient characteristics and within each Clinical Center. Two schedules will be devised for use: one for Clinical Center staff to practice using the ATRS, and one that will be the final study randomization schedule. The final schedule will also be analyzed to assure that balance is achieved by age and Clinical Centers, and that there are no unusual sequential runs of treatment assignments within any Clinical Center. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-12 of 12-16 2. Laboratory Results, Prescription Recommendations and Record of Treatments MCC staff will develop computer programs to take into account each patient’s baseline laboratory values, new laboratory data and recent laboratory values. These programs will identify extreme outliers for possible safety alerts (see Table 7-3), and will be used to assess whether changes from baseline or recent results are unusual. Outlier results will be verified and reviewed if necessary with the Study Chairman. Extreme values that constitute an adverse event will be managed according to specified procedures. Abnormal values that do not exceed levels will be used in formulating treatment recommendations. The system will follow the dose adjustment Protocol (see Chapter 6) to make the appropriate dose recommendation for the next 2- or 4-week period. Dose recommendations will be reviewed along with the attending laboratory results by the designated medical staff at the MCC. Confirmed treatment recommendations will be forwarded to the Clinical Center electronically (e-mail or Website). All occurrences of misreported laboratory results will be cumulated and reported, as well as all alert values, and routine dose changes. MCC staff will review accruing information about reported toxicities and their resolution and consequent dose adjustments to see if the frequency of adjustments is reasonable or if patients are being stopped too frequently. Tabulations of how much of the time patients are not maintained on assigned treatment will also be reviewed. Placebo stops and adjustments will be compared for similarity to the hydroxyurea group to help maintain the blind. 3. Data entry and database quality assurance Because data entry will be from the remote sites, data quality assurance will derive from site visits that will include complete audits of the data against the medical record. Periodically copies of original forms may be requested from Clinical Centers for independent data entry and comparison in the Medical Coordinating Center to check the quality of Clinical Center data entry. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-13 of 12-16 12.7 ROUTINE REPORTING Routine reports for the Steering Committee will be prepared on: eligibility and enrollment, by Clinical Center and overall; recruitment expected versus actual; study forms and specimens, expected and received; unusable results, alert values, values requiring verification, values modified, values deleted, and stop orders issued on the basis of unavailable results; treatment adjustments, dispensing, return of and compliance with study treatments; special studies expected and performed or not performed; endpoints evaluation; committee performance (e.g., case reports and images reviewed and cases pending); and adverse events by Clinical Center and overall. 12.8 SAFETY AND PATIENT MONITORING a. Central Review of Laboratory Results A Medical Coordinating Center physician will confirm all toxicities and alert values and review individual cases and tabulations of toxicities and alert values. b. Adverse Events Any adverse event, regardless of attribution to study treatment or sickle cell disease will be reported to the Medical Coordinating Center. Any event meeting the definition of a serious adverse event will be reported to the DSMB Chair, Executive Secretary of DSMB, the NHLBI and NICHD Project Officers and to the FDA. The Clinical Centers will report all occurrences of serious adverse events that occur at their institution according to their local IRB requirements. c. Data and Safety Monitoring Reports and Meetings The DSMB will meet regularly to review cumulative study data. In addition to the routine performance reports, they will review data according to the assigned groups. Interim review of the primary and secondary endpoint data with statistical testing will be presented according to the interim monitoring plan (see Section 4.4.5). All cases of adverse events and laboratory alert values will be reviewed in detail. The DSMB will make recommendations to the NHLBI and NICHD regarding recruitment goals, study performance, and patient safety. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-14 of 12-16 d. Unblinding In the event of an emergency that the Clinical Center Principal Investigator or that a local treating physician considers knowledge of the BABY HUG patient’s treatment assignment is necessary for determining patient management, the Principal Investigator or treating physician will telephone the BABY HUG Study Chairman to discuss the need for unblinding. The Study Chairman will be able to use the Automated Telephone Response System (ATRS) to obtain unblinding information 24 hours/day as necessary. 12.9 PROTOCOL VIOLATIONS Staff of Clinical Centers, Core Laboratories, Endpoint Evaluation Committee members, Medical Coordinating Center personnel and any other personnel who implement the study Protocol, manage patients on behalf of the study, report, manage or analyze study data share in responsibility for patient safety and the scientific integrity of BABY HUG. With the assistance of oversight provided by the NHLBI and NICHD through the Data and Safety Monitoring Board and the local Institutional Review Boards (IRBs), all matters of Protocol implementation and data reporting will subject to review. Procedures for monitoring of scientific integrity and quality assurance in multicenter trials have been promulgated by the Society for Clinical Trials (Knatterud et al, 1998). Violations of the Protocol will be investigated promptly to maintain patient safety. The steps to prevent Major Protocol Violations or reporting of incorrect data are: training and certification, site visits, audits, statistical checks, edit checks, and careful follow-up of any abnormalities that may result in clinic-wide treatment stop and suspension of randomization. Data collection by non-certified personnel will be prevented by training and certification (including education that misuse of certification number is a scientific integrity issue), detected by review of study forms all of which require signature, certification number and date, and if found, acted upon by clinic-wide audit; deletion of data found erroneous; and requirement of assurances and a plan from the Clinical Center Principal Investigator to keep the problem(s) from recurring. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-15 of 12-16 Failure to provide a Patient/Family advocate will be prevented by training and certification, detected by review of initial and follow-up Patient/Family advocate forms, site visits, and data audit, and acted upon with clinic-wide treatment stop and suspension of randomization. Requesting enrollment (randomization) for a child who does not meet eligibility criteria will be prevented by training and certification, detected on checking eligibility data collection forms, and acted upon with suspension of randomized study treatment and randomization. Requesting enrollment (randomization) for a child on whom informed consent has not been obtained, or whom the Patient/Family advocate has not found the family in agreement will be prevented by training and certification, detected on site visit, and acted upon with suspension of randomized study treatment and randomization. Failure to act to implement a treatment stop order within 72 hours will be prevented by training and certification, detected by review of study treatment data collection forms and Patient/Family advocate follow-up and acted upon with suspension of randomized study treatment and randomization. Failure to report a serious adverse event (Section 10.2.3) within 24 hours of learning of event will be prevented by training and certification, detected on review of study treatment data collection forms and Patient/Family advocate follow-up, and acted upon with suspension of randomized study treatment and randomization. 12.10 IRB APPROVAL Clinical Centers will submit the BABY HUG Protocol and the Informed Consent Form as modified for use to the Local Institutional Review Boards (IRBs) for initial review before any patient can be screened for BABY HUG. Clinical Centers will submit local updates to the IRB for annual review, Protocol amendments and study-wide reports such as DSMB recommendations and any other information that may be requested by the IRB. Clinical Centers will comply with local IRB requirements regarding reporting serious adverse events, whether or not related to study treatment. Clinical Centers will provide the Medical Coordinating Center with documentation of approval from _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-12.wpd — 8/09 Page 12-16 of 12-16 the IRB. The approved local consent form will be sent to the NHLBI and submitted to the DSMB Chair for review to assure that it conforms to the requirements for protection of human subjects. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-13.wpd — 8/09 Page 13-1 of 13-9 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) PROTOCOL CHAPTER 13 ORGANIZATIONAL STRUCTURE AND PARTICIPATING UNITS 13.1 INTRODUCTION The Pediatric Hydroxyurea Clinical Trial (BABY HUG) will be conducted in 14 Clinical Centers, a Medical Coordinating Center and central units. The Clinical Center staff will be trained in accordance with the procedures set out in the study Manual of Operations. The objective is to standardize all study procedures carried out in the Clinical Centers and at the operational central units. Study monitoring will be carried out by the Data and Safety Monitoring Board (DSMB), Steering Committee and Operations Committee. Monitoring will include adherence to protocol, achievement of recruitment goals, patient safety and efficacy of treatment. Outcome reviewers in the specialties of neurology, neuroradiology, neuropsychology, nuclear medicine and pediatric hematology will evaluate imaging studies and reports of possible outcome events as members of an Endpoints Evaluation Committee to ascertain selected components of the primary and secondary study endpoints. The Steering Committee will review and approve or disapprove Operations Committee recommendations on proposals for secondary analyses and ancillary studies. An organizational chart for BABY HUG is presented in Exhibit 13-1. 13.2 PARTICIPATING UNITS 13.2.1 Operations Committee The Operations Committee will comprise the Study Chairman, the Vice-Chairman, the Principal Investigator of the Medical Coordinating Center, the NHLBI and NICHD Project Officers, two Clinical Center Principal Investigators (rotating every six months), the Coordinator Chair and two Clinical Center Coordinators (by election) and, ex officio, the directors of the Pharmacy _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-13.wpd — 8/09 Page 13-2 of 13-9 Distribution Center and of the Core Laboratories, and the Medical Coordinating Center Deputy Director. The Operations Committee will maintain close ties with the Clinical Centers. The Operations Committee will provide technical and scientific guidance in developing the Protocol and Manual of Operations, study forms, Clinical Center procedures, quality control systems, study treatment titration and distribution procedures, and laboratory specimens preparation and processing. The Operations Committee will implement study procedures to address major or minor protocol violations. The Operations Committee will help prepare agendas and contents of reports for Data and Safety Monitoring Board and Steering Committee meetings. In addition, the Operations Committee receives and reviews all scientific proposals for use of study data, including ancillary studies. Their considerations in evaluating proposals will include scientific merit, feasibility and resource availability, including statistical, computing and technical support. No ancillary study will be approved which interferes with the conduct of the overall study or is not approved by the Steering Committee and Data and Safety Monitoring Board. 13.2.2 Clinical Centers The collaborating centers are funded by contracts from the NHLBI. At a minimum, each will have a Principal Investigator and a coordinator. Exhibit 13-2 lists the Clinical Centers identified at the start-up of the study. A final recruitment report specifying the number of patients enrolled by each certified Clinical Center will be distributed after the end of enrollment. 13.2.3 Study Coordinator Committee One BABY HUG study coordinator (Coordinator Chair) will be selected to have responsibility for organizing all the BABY HUG study coordinators into the Study Coordinators Committee - SCC. This person’s responsibility will include: 1. foster enthusiasm for the BABY HUG project; 2. act as a liaison between the Steering Committee and the SCC; _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-13.wpd — 8/09 Page 13-3 of 13-9 3. coordinate regular SCC conference calls; and 4. organize SCC meeting agenda and SCC project reports. The SCC’s responsibility will include: 1. development of coordinator writing projects; 2. attending Steering Committee meetings; and 3. participating in SCC conference calls to a. report enrollment progress, b. collaborate on enrollment successes/problems, c. discuss adherence strategies, d. team build, and e. develop writing plans. 13.2.4 Core Laboratories The Core Laboratories have responsibility for receiving blood samples from the Clinical Centers and performing specimen analyses as required for monitoring effects of hydroxyurea. Effects on blood counts will be used to titrate study drug dosages. In addition, the Core Laboratories will perform other analyses such as analyses for fetal hemoglobin and chromosome breakage. 13.2.5 Pharmacy Distribution Center and Investigational Pharmacies The study treatments (hydroxyurea and placebo) for BABY HUG will be distributed to Clinical Center Investigational Pharmacies by the Pharmacy Distribution Center. Clinical Center Investigational Pharmacies will maintain records of all patient prescriptions and dosages dispensed for each patient visit. 13.2.6 National Heart, Lung, and Blood Institute The National Heart, Lung, and Blood Institute (NHLBI) staff -- Office of Blood Diseases Program (Division of Blood Disease and Resources) and Office of Biostatistics Research (Division of Epidemiology and Clinical Applications) will participate with study investigators and key study personnel in all phases of the study. A member of the Blood Diseases Program (Division of Blood Diseases and Resources) will serve as a voting member on the Steering Committee, and other _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-13.wpd — 8/09 Page 13-4 of 13-9 study committees as appropriate. NHLBI staff on the Steering Committee will participate throughout the phases of Protocol development, recruitment, follow-up, data analysis and interpretation. The NHLBI staff will address issues concerning recruitment, treatment, follow-up, quality control, and adherence to Protocol to assist the study investigators in assessing potential problems affecting the study and potential changes in the Protocol. They will provide direction in the management of the contracts which fund the study, and assistance in developing solutions to major problems such as insufficient participant enrollment. A Data and Safety Monitoring Board has been appointed by the NHLBI to provide overall monitoring of the study. 13.2.7 Medical Coordinating Center The Medical Coordinating Center staff will include the Principal Investigator/Medical Coordinating Center Director, Project Manager/Deputy Director, statistician(s), computer programmer(s) and coordinator(s). Medical Coordinating Center staff for BABY HUG will provide expertise in the areas of study design, quality control, data processing and data analysis. Medical Coordinating Center staff will provide biostatistical and epidemiological advice for the overall conduct of BABY HUG; collaborate with the BABY HUG investigators in all phases of the study including planning, participant recruitment and follow-up, development and maintenance of a data management system for BABY HUG, preparing required statistical analyses; generate Core Laboratory work lists, report forms, blood specimen transmittal lists, and progress reports; and, assist in the preparation of manuscripts for publication. Medical Coordinating Center staff will undertake the primary responsibility for the collection, processing, storage and analysis of the study data, as well as cooperating with the Operations Committee to ascertain that the provisions of the Protocol are carried out by each Clinical Center. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-13.wpd — 8/09 Page 13-5 of 13-9 13.2.8 National Institute of Child Health and Human Development A Memo of Understanding between the NHLBI and NICHD will allow the NICHD to perform pharmacokinetic (PK) studies under the Best Pharmaceuticals for Children Act (BPCA) to support a submission to the FDA for labeling of hydroxyurea for infants and very young children with sickle cell disease. Premier Research Group will be the NICHD’s coordinating center and will assist in the design of PK studies and perform data quality control. 13.3 STUDY ADMINISTRATION 13.3.1 Study Chairman and Vice-Chairman The Study Chairman and Vice-Chairman have been elected by the Steering Committee. The Study Chairman is Chairman of the Operations Committee and Steering Committee. The Study Chairman is responsible for overall conduct of the study and adherence to the study time table (see Appendix D). The Vice-Chairman acts in place of the Study Chairman in case of the Study Chairman’s unavailability. Consultants to the Medical Coordinating Center will be available 24 hours a day for emergency unblinding of assigned study medication. 13.3.2 Steering Committee The Study Chairman will preside over the Steering Committee which will consist of the Principal Investigators from each Clinical Center and the Medical Coordinating Center, the NHLBI and NICHD Project Officers and (ex officio) directors of the central units. This committee will be responsible for overseeing the writing of main papers as directed by the DSMB and as approved by the NHLBI. 13.3.3 Data and Safety Monitoring Board The Data and Safety Monitoring Board (DSMB) has been appointed by the NHLBI. DSMB voting members include experts in sickle cell anemia, the clinical use of hydroxyurea, biostatistics and bioethics, who are not connected with the study, and ex officio (non-voting) members -- the Study Chairman and the Medical Coordinating Center Principal Investigator -- and representatives of the NHLBI and NICHD who will attend meetings to present information and receive recommenda- _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-13.wpd — 8/09 Page 13-6 of 13-9 tions. The DSMB reviewed the initial study Protocol and will approve all changes made to it during the course of the study, review Data and Safety Monitoring Reports, and make recommendations on major Protocol changes and/or early release of study results. The Operations Committee will report any unexpected or unusual findings to the DSMB which may be convened ad hoc for a special review of BABY HUG any time circumstances so warrant. The DSMB will meet at least yearly, to review the annual BABY HUG report. It will review safety as the trial progresses, will evaluate treatment efficacy at pre-specified interim time points for possible early termination of the study, and will review any proposals to discontinue treatment of patients in a Clinical Center because of non-adherence to the Protocol. DSMB meetings begin with an Executive Session at which summary notes are taken by a representative of the NHLBI. Other BABY HUG Steering Committee members do not participate in the Executive Session. The Study Chairman, Vice-Chairman, Medical Coordinating Center Principal Investigator and invited BABY HUG investigators join the DSMB for other parts of the agenda until the presentation of study outcome data. The BABY HUG Clinical Center investigators are excused for the study outcome presentation and discussion. Medical Coordinating Center staff take summary notes of the DSMB meeting from the end of the Executive Session through the presentation of study outcomes and discussion. At the end of the presentation of study outcomes and discussion, the Medical Coordinating Center staff are excused for the DSMB to meet in a second Executive Session. The NHLBI representative is responsible for recording summary notes of the second Executive Session and the recommendations of the DSMB. At the end of the second Executive Session, the BABY HUG investigators rejoin the DSMB for a preliminary review of DSMB recommendations. The NHLBI Executive Secretary of DSMB provides the summary notes and recommendations of the DSMB, in an expeditious and timely manner, to the Medical Coordinating Center. The Medical Coordinating Center communicates these recommendations to the BABY HUG Steering Committee. At the next DSMB meeting, the DSMB votes to accept (or revise) the summary notes recording transactions of the meeting and recommendations. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-13.wpd — 8/09 Page 13-7 of 13-9 13.3.4 Endpoints Evaluation Forms, images and records received from the Clinical Centers will be reviewed on a regular basis by committees consisting of experienced clinicians who are familiar with the area of special study evaluations (i.e., liver-spleen scans, MRI, neuropsychological tests and clinical events) and with the spectrum of illness in sickle cell anemia and who have no other connection with this study. They will receive materials for review from and return classifications of reports or other information to the Medical Coordinating Center for incorporation into the study database. Exhibit 13-1 Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) ORGANIZATIONAL CHART NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT Zhaoxia Ren, M.D., Ph.D., Project Officer Anne Zajicek, Pharm.D, M.D. NATIONAL HEART, LUNG, AND BLOOD INSTITUTE Jonathan Goldsmith, M.D., Project Officer Myron Waclawiw, Ph.D., Statistician Henry Chang, M.D. Executive Secretary of the Data and Safety Monitoring Board DATA AND SAFETY MONITORING BOARD Paul Swerdlow, M.D. (Chair) Kenneth Bridges, M.D. Gary Cutter, Ph.D. Carlton Haywood, Jr., M.A. Larry Muenz, Ph.D. Alexis Thompson, M.D. Joann Bodurtha, M.D., M.P.H. OPERATIONS COMMITTEE Winfred Wang, M.D. (Chair) Russell Ware, M.D., Ph.D. (Vice Chair) Two Clinical Center PIs Coordinator Chair Two Clinical Center Coordinators Jonathan Goldsmith, M.D. Zhaoxia Ren, M.D., Ph.D. Bruce Thompson, Ph.D. Beatrice Files, M.D. PREMIER RESEARCH GROUP Frank Norton, Ph.D., Project Mgr. MEDICAL COORDINATING CENTER (MCC) Bruce Thompson, Ph.D., PI Beatrice Files, M.D., Medical Consultant Michael Jeng, M.D., Medical Consultant CLINICAL CENTERS Exhibit 13-2 STEERING COMMITTEE PI’s of 14 Clinical Centers NHLBI Project Officer NICHD Project Officer MCC PI STUDY COORDINATOR COMMITTEE ENDPOINTS EVALUATION COMMITTEES MRI/MRA - Steven Pavlakis, M.D. Kathleen Helton, M.D. Robert McKinstry, M.D. Neurological - Rebecca Ichord, M.D. Clinical Events - Millicent Sutton, M.D. - Thomas Kinney, M.D. - Howard Pearson, M.D. Liver-Spleen - Eglal (Gila) Shalaby-Rana, M.D. - Michael Gelfand, M.D. - Barry Shulkin, M.D. Abdominal Ultrasound - Beth McCarville, M.D. Psychometric - Daniel Armstrong, Ph.D. HEMATOLOGY AND BIOCHEMISTRY CORE LABORATORY PHARMACY DISTRIBUTION CENTER OTHER CORE LABORATORIES ________________________________________________________________________________________________________________________________________________________ SLC:/BABY-HUG/BHUG Protocol/August-09/CHAP-13.wpd — 8/09 Page 13-8 of 13-9 _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-13.wpd — 8/09 Page 13-9 of 13-9 Exhibit 13-2 PARTICIPATING CLINICAL CENTERS CLINICAL CENTERS Children’s Research Institute, Lori Luchtman-Jones, M.D. - 01 (Washington, DC) Duke University Medical Center, Courtney Thornburg, M.D. - 02 (Durham, NC) Howard University College of Medicine, Sohail Rana, M.D. - 03 (Washington, DC) Johns Hopkins University School of Medicine, James F. Casella, M.D. - 04 (Baltimore, MD) Medical University of South Carolina, Ram Kalpatthi, M.D. - 05 (Charleston, SC) St. Jude Children’s Research Hospital, Winfred C. Wang, M.D. - 06 (Memphis, TN) State University of New York - Brooklyn (SUNY), Scott T. Miller, M.D. - 07 (Brooklyn, NY) University of Miami School of Medicine, Julio Barredo, M.D. - 08 (Miami, FL) University of Mississippi Medical Center, Rathi V. Iyer, M.D. - 09 (Jackson, Mississippi) University of Texas Southwestern Medical Center, Zora R. Rogers, M.D. - 10 (Dallas, TX) University of Alabama, Birmingham, Thomas Howard, M.D. - 11 (Birmingham, AL) Drexel University, Frank Shafer, M.D. (Interim) [Norma Lerner, M.D. (Starting mid-September 2009)] - 12 (Philadelphia, PA) Emory University School of Medicine/CHOA, R. Clark Brown, M.D. - 13 (Atlanta, GA) Wayne State University, Ingrid Sarnaik, M.D. - 14 (Detroit, MI) MEDICAL COORDINATING CENTER Clinical Trials & Surveys, Corp. (Baltimore, MD) Bruce W. Thompson, Ph.D., Principal Investigator PROJECT OFFICE Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute (Bethesda, MD) Jonathan Goldsmith, M.D., Project Officer Myron Waclawiw, Ph.D., Statistician Henry Chang, M.D., Executive Secretary of the Data and Safety Monitoring Board _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-14.wpd — 8/09 Page 14-1 of 14-6 PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL (BABY HUG) PROTOCOL CHAPTER 14 POLICY MATTERS 14.1 INTRODUCTION Procedural guidelines are established to ensure that all investigators adhere to the protocol, to facilitate optimum use of data generated by the study, and to ensure optimal use of the resources of the Central Units and Medical Coordinating Center (for quality control in the study see Section 10.4). 14.2 QUALITY ASSURANCE Members of the Steering Committee will create a list of major and minor protocol violations. Major violations are those which endanger patients, such as repetitive failure to obtain scheduled blood counts or failure to discontinue therapy promptly when so advised. Minor violations are those which impede the progress of the study, such as not filing reports in timely fashion (form delinquencies) and excessive delays in supplying materials (e.g, scans, other images or event reports) for central review. Also, the Steering Committee will consider exceptions to the Protocol and advise the Operations Committee of its decision. After the first major violation, a clinic will be asked to submit a proposal outlining how recurrence will be prevented. After a second major violation, clinics will not be allowed to recruit more patients, but will be able to follow those already recruited. After three major violations the Clinical Center may no longer be supplied with study drug. Prior to suspension of study treatments at a Clinical Center, the Study Chairman or Vice-Chairman, Medical Coordinating Center Principal Investigator and NHLBI and NICHD Project Officers will visit the Clinical Center and provide a site visit report to the Data and Safety Monitoring Board (DSMB) for recommendation on final action. Clinical Centers with the greatest difficulty in meeting their proposed goals for recruitment will also be site visited, and recommendations for improvement made to them, with a report to the DSMB. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-14.wpd — 8/09 Page 14-2 of 14-6 (Clinical Centers which are not having problems with performance will also be visited at least once during the study, to assure quality of data produced). The Data and Safety Monitoring Board (DSMB) will be made aware of all major violations, and will consider discontinuing study treatment at the Clinical Center after a third violation. The Medical Coordinating Center will document minor violations in performance reports, as well as notifying the Clinical Centers of them. Repeated minor violations which are not corrected will result in reports to the Data and Safety Monitoring Board (DSMB), the NICHD and the National Heart, Lung, and Blood Institute (NHLBI). 14.3 CHANGES IN PRINCIPAL INVESTIGATORS Over the seven year course of the trial, it is expected that changes in Principal Investigators (PIs) will occur in some of the Clinical Centers. These changes may be necessitated by movement of the Principal Investigators to another institution, illness, retirement, or change in responsibility within the same institution. When a change in PI occurs, the viability of the Clinical Center as a BABY HUG participant could become problematic. In this situation, retention of the established/experienced nurse coordinator may help ensure that the Clinical Center can continue to function effectively. When such a change occurs, it is understood that the contractual arrangement between the NHLBI and the Clinical Center will be reviewed and possibly altered. However, because of the profound influence that such a change may have on the remaining Clinical Centers in the conduct of BABY HUG, the members of the Steering Committee and/or the Operations Committee should have the opportunity to discuss and provide input into the decisions that are made. As noted in Section 14.2, problems in the performance of a Clinical Center will be discussed by the Operations Committee. The Clinical Centers and/or their representatives, the Medical Coordinating Center, and the NHLBI and NICHD Project Offices should all participate in any decisions which involve turnover of Principal Investigators and/or Clinical Centers. _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-14.wpd — 8/09 Page 14-3 of 14-6 14.4 TYPES OF BABY HUG RESEARCH BABY HUG research and the resulting presentation and publications may be grouped into the following study categories. 1. Endpoint studies; 2. Data bank studies; 3. Ancillary studies. The Steering Committee will exercise responsibility for all endpoint, data bank, and ancillary studies, and for all publications and presentations evolving from BABY HUG research, through the Scientific Affairs and Publications Committee. BABY HUG investigators have agreed that all BABY HUG research is collaborative in nature. No investigator will publish BABY HUG data from any one Clinical Center or group of Clinical Centers without the written approval of the Publication Committee, the NICHD and the NHLBI. Investigators at all BABY HUG sites, including the Medical Coordinating Center and the NHLBI and NICHD Program Offices, have equal status with regard to developing protocols, participating in such studies as are approved and collaborating in the development and publication of research papers based on BABY HUG material. The procedures in this section for endpoint, data bank, and ancillary studies, and for publication of BABY HUG research results are similar to those used in other cooperative clinical trials. These procedures are intended to protect the interests of all investigators and patients in the trial, namely, to assure that study data conform to the requirements of study design, are accurately presented, authorship is appropriately acknowledged, and the text of all publications is well written with proper attention to the protection of patient privacy. All BABY HUG presentations are subject to review and approval by the NHLBI and NICHD. 14.4.1 Endpoint Studies An endpoint study is a study pertaining to the fundamental goals of the project (e.g., the evaluation of the efficacy of hydroxyurea in the prevention of chronic end organ damage) or which _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-14.wpd — 8/09 Page 14-4 of 14-6 involves data, such as treatment assignment, differences in hospitalization by treatment assignment, or mortality rates, which cannot be released prior to the end of the study. These studies will summarize the findings of BABY HUG, based on the entire study population, and will be written at the conclusion of follow-up or data collection. 14.4.2 Data Bank Studies A data bank study is a study which uses data routinely collected on patients when they are screened for or enrolled in BABY HUG and analyzes these data to answer some scientific question. Data used in this research are not directly related to the fundamental goals of the study. 14.4.3 Ancillary Studies An ancillary study is a study which uses supplementary data collected on patients who are screened for or enrolled in BABY HUG, over and above the data collection required by the BABY HUG Protocol. Such studies are usually restricted to consideration of a specific test technique or involve only supplemental data collected on some or all BABY HUG patients. Approval and participation in ancillary studies are considered by the Steering Committee, the NICHD and National Heart, Lung, and Blood Institute (NHLBI) with the advice of independent review committees (the Data and Safety Monitoring Board or the Protocol Review Committee). Proposals for ancillary studies are submitted to the Medical Coordinating Center which distributes them to the Steering Committee for scientific review and Clinical Center Principal Investigator consideration with regard to feasibility and interest in participation in the ancillary study in each Clinical Center. Steering Committee members reply to a ballot distributed by the Medical Coordinating Center indicating their approval or disapproval of the ancillary study, the priority they would accord the ancillary study and whether or not their Clinical Center would participate in the ancillary study. Approval requires a majority vote. 14.5 CLINICAL CENTER ACCESS TO BABY HUG DATA FILES AT THE END OF THE STUDY At the end of the study, Medical Coordinating Center staff will produce a well documented data tape containing a refined (and reduced) set of the BABY HUG data for the purpose of analysis Bristol-Myers Squibb, Par Pharmaceuticals _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-14.wpd — 8/09 Page 14-5 of 14-6 by the BABY HUG investigators and eventual release to the public domain in accordance with NHLBI policy. Clinical Center directors may analyze the data on this data tape in their own centers, but prior to submission of articles for publication must submit the analyses proposed for publication to the Medical Coordinating Center, where they will be reviewed and computations replicated. Clinical Center directors who perform their own analyses are responsible for obtaining all support necessary for the data bank or ancillary study outside of regular study resources. The Medical Coordinating Center will be the center of study analysis activities as long as the BABY HUG investigators continue in their collaborative efforts. 14.6 PUBLICATION The design and the main results manuscripts will list all Principal Investigators and all members of the manuscript writing committees in the authorship. The authors of other publications stemming from the study will be those who actually write the document (the writing committee), plus the group as a whole (“Doe J, Roe K, and the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) investigators), with all investigators and coordinators listed in the appendix at the end of the paper or reference made to a publication listing all investigators. Study manuscripts may only be submitted for publication for main endpoint studies and approved data bank and ancillary studies. All manuscripts related to study patients must be reviewed and approved by the Publication Committee. The Publication Committee will implement day-to-day policy on publications and authorship in accordance with the directions of the Steering Committee. 14.7 CONFLICT-OF-INTEREST BABY HUG investigators and their immediate family will not buy, sell, or hold stock options in any of the companies* providing medication (or making competing products) under study from the time the recruitment of patients for the trial begins until funding for the study in the investigator’s unit ends and the results are made public; or from the time the recruitment of patients for the trial _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/CHAP-14.wpd — 8/09 Page 14-6 of 14-6 begins until the investigator’s active and personal involvement in the study or the involvement of the institution conducting the study (or both) ends. Each investigator will agree not to serve as a paid consultant to the companies during these same periods. The guidelines will also apply to the investigator’s spouse and dependents. The Medical Coordinating Center will hold and update annually conflict-of-interest statements from each investigator. Certain other activities are not viewed as constituting prohibited conflicts-of-interest but must be reported annually to the Medical Coordinating Center: the participation of investigators in education activities supported by the companies (permitted only if no honorarium is paid to the investigator); the participation of investigators in other research projects supported by the companies; and, occasional scientific consulting to the companies on issues not related to the products in the trial and for which there is no financial payment or other compensation. The BABY HUG conflict-of-interest policy will incorporate the NHLBI and U.S. Food and Drug Administration (FDA) policies on conflict-of-interest for investigators. The BABY HUG investigators will not accept any restraint on freedom of publication. SLC/F:/BABY-HUG/BHUG ProtocolAugust-09/References.wpd — 8/09 Page R-1 of R-14 LITERATURE CITED Adams R.J., McKie V.C., Nichols, F.T., Carl, E.M., Zhang, D.L., McKie K., Figueroa, R., Litaker, M., Thompson, W., and Hess, D.C. (1992). The use of transcranial ultrasonography to predict stroke in sickle cell disease. New Eng J Med. 326. 605-10. Adams R.J., McKie V.C., Hsu L., Files B., Vichinsky, E., Pegelow C., Abboud M., Gallagher, D. Kutlar A., Nichols F.T., Bonds D.R., Brambilla D., Woods G., Olivieri N., Driscoll C., Miller S., Wang W., Hurlet A., Scher C., Berman B., Carl E.M., Jones A.M., Roach E.S., Wright E., Zimmerman R.A. and Waclawiw, M. (1998). 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Appendix A Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) Medical Coordinating Center Detailed Schedule of Visits and Total Amount of Blood _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/Appendix A.wpd — 8/09 Page A-1 of A-3 Introduction Over the course of the two-year BABY HUG Clinical Trial, patients will each have a total volume of approximately 77.6 ml of blood collected for evaluations, including 17.1 ml for immunology studies. The largest volume will be obtained in the pre-randomization evaluation period and the first 4 weeks on study treatment, during which time approximately 29.6 ml will be collected. Efforts are made to work with the smallest volumes of specimens possible. For example, Schwartz GFR specimens will be aliquotted from specimens already prepared for other evaluations. Using a conservative estimate of a 12 month old infant entering the study with an initial weight of 8 kg, this amount will constitute approximately 3.7 ml/kg over an 8-week period. This amount is within the guidelines for maximum volume of phlebotomy (3-7 ml/kg per 8 week period), which have been utilized by the St. Jude Children's Research Hospital and Duke University Medical Center Institutional Review Boards (IRBs). The maximum amount obtained at a single blood draw will be approximately 8 ml; this will not exceed the guideline of 1 ml/kg (Duke University Medical Center IRB) in an 8 kg infant and will not produce significant cardiovascular stress. Older children with sickle cell disease have tolerated phlebotomy of 5-10 ml/kg every 2 to 4 weeks (Ware et al., 1999). During the other time periods in the course of the BABY HUG Clinical Trial, blood sampling volumes will be considerably less. __________________________________________________________________________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/Appendix A.wpd — 8/09 Page A-2 of A-3 APPENDIX A. Schedule and Volume of Blood and Urine Collection and Schedule of Special Studies Note: This is an ideal schedule with no toxicities and stable dose reached after eight weeks. BLOOD SAMPLE COLLECTION (All volumes in ml) URINE SPECIAL STUDIES WEEKS Heme & HbF (Local & Central) Chem† Electro phor. Pitted cells Cyto- genet VDJ/HJB/ DNA O2 Satur. Cystatin C^ Urinalysis/ Urine Concentr (ml) Liver- spleen scan Anthropo metry H-height W-weight C-head cir Abdominal Sono Neuropsych/ NQ DTPA* Clearance (ml) GFR Schwartz (ml) HU Assay Immun ology‡ (ml) TCD Screening 1.0* 1.0 1.0 0.1 4.0 3.0 Y 5.0 Y H, W, C Y Y 3.5 Y Treatment Initiation 1.0* 1.0 Y W 9.0 Y Y Titration Schedule - Visits every two weeks until stable dose reached. 2 0.5 W 4 0.5 W 4.0 6 0.5 W 1.2 8 0.5 W Stable Dose Schedule - Schedule shifts to every four weeks from here until Exit unless otherwise noted 12 - 3 MO 0.5 Y H, W, C 16 0.5 W 20 0.5 W 24 - 6 MO 1.0* 1.0 0.1 Y H, W, C Y 28 0.5 W 32 0.5 W 36 0.5 W 40 - 9 MO 0.5 Y H, W, C 44 0.5 W 48 0.5 W 3.0 52 -12MO 1.0* 1.0 0.1 Y H, W, C Y Y 1.2 Y 56 0.5 W 0.5 60 0.5 W 3.0 64 -15MO 0.5 Y H, W, C BLOOD SAMPLE COLLECTION (All volumes in ml) URINE SPECIAL STUDIES WEEKS Heme & HbF (Local & Central) Chem† Electro phor. Pitted cells Cyto- genet VDJ/HJB/ DNA O2 Satur. Cystatin C^ Urinalysis/ Urine Concentr (ml) Liver- spleen scan Anthropo metry H-height W-weight C-head cir Abdominal Sono Neuropsych/ NQ DTPA* Clearance (ml) GFR Schwartz (ml) HU Assay Immun ology‡ (ml) TCD __________________________________________________________________________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/Appendix A.wpd — 8/09 Page A-3 of A-3 68 0.5 W 72 0.5 W 76-18MO 1.0* 1.0 0.1 Y H, W, C Y 80 0.5 W 84 0.5 W 88 0.5 W 92-21MO 0.5 Y H, W, C 96 0.5 W 100 0.5 W 104-24MO 1.0* 1.0 0.1 4.0 3.0 Y Y 5.0 Y H, W, C Y Y 9.0 Y Y 4.7 Y HbF will be assessed on aliquots from blood collected at these times. Baseline includes two measurements, one during qualifying visits and one at the start of study treatment. †Ferritin, electrolyte and magnesium levels will be measured every six months from an aliquot of the chemistry specimen. vCystatin C will be assessed on leftover serum collected for biochemistry. ‡Immunology studies will require 22.0% of total blood volume collected (77.6 ml) over 2 years. DTPA discontinued on May 29, 2009. Appendix B Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) Medical Coordinating Center List of Tests and Diagnostic Procedures (for Parent Information) SLC\F:/BABY-HUG/BHUG Protocol/August-09/Appendix B.wpd — 8/09 Page B1 of B1 APPENDIX B. Tests and Diagnostic Procedures (For Parent Information) • The doctor and nurse will examine your child and ask you questions about his/her health. • Blood specimen collection usually with a lancet to the skin but for some tests with a needle in a vein: the blood and genetic material (DNA ) will be obtained. • Urine concentrating ability and urinalysis You will be asked to give your child nothing by mouth overnight. Urine collection will be done by applying a bag and watching the child for several hours. • Your child will be measured for height, weight and head size. • Oxygen saturation will be measured with a wrap around baby’s finger or toe for 1-2 minutes. • Neurological Evaluation A pediatric neurologist will examine your child and ask him/her to perform various tasks, as appropriate to age. • Psychodevelopmental evaluation (Bayley and Vineland) A specialty nurse working under the supervision of a licensed psychologist will ask your child to do a number of age appropriate tasks. Also, you, the parents will be asked a series of questions about your child in an interview. • Liver-spleen scan Your child will be given a dose of radioactive tracer by vein. He/she will lay down on a table beneath a camera that takes detailed pictures of the abdomen to determine the location and size of vital organs. • Abdominal sonogram An ultrasound machine will be passed over your child’s stomach area and pictures of liver, spleen, and kidneys will be made. • Transcranial doppler An ultrasound machine will be passed over your child’s neck and head, and calculations of blood flow speed in the blood vessels that lead to the brain will be made. Appendix C Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) Medical Coordinating Center Central Laboratories and Facilities __________________________________________________________________________________________________________ SLC/BABY-HUG/BHUG Protocol/August-09/Appendix C.wpd — 8/09 Page C-1 of C-1 Central Laboratories and Facilities Hematology and Biochemistry Core Laboratory Medical College of Georgia Research Institute Abdullah Kutlar, M.D. Cytogenetics Core Laboratory Medical College of Georgia Research Institute K.L. Satya-Prakash, Ph.D. Pitted Cell Count Core Laboratory Children’s Medical Center of Dallas Zora Rogers, M.D. DNA/VDJ Mutations Core Laboratory (and Cystatin C testing) St. Jude Children’s Research Hospital Russell Ware, M.D., Ph.D. TCD Core Laboratory Medical College of Georgia Robert Adams, M.D. Immunology Core Laboratory The Johns Hopkins University School of Medicine James Casella, M.D., and Howard Lederman, M.D. Biomarkers Core Laboratory Thomas Jefferson University Medical Center Marie Stuart, M.D. Pharmacy Distribution Center (PDC) HHS Supply Service Center Michael Soler HU Assay Core Laboratory MDS Pharma Appendix D Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) Medical Coordinating Center Study Timeline _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/Appendix D.wpd — 8/09 Page D-1 of D-2 Appendix D STUDY TIMELINE Phase I: Planning 2000 Sep Steering Committee Meeting 1 - Protocol development Oct Steering Committee Meeting 2 - Protocol development Dec Steering Committee Meeting 3 - Protocol development 2001 Jan Steering Committee Meeting 4 - Protocol development Apr Data and Safety Monitoring Board (DSMB) Meeting 1 DSMB Conference Call 1 Protocol revision recommendations to Steering Committee Jun DSMB Meeting 2 Protocol revision recommendations to Steering Committee Jul Steering Committee Meeting 5 - Further protocol revisions as necessary Aug Special Review Panel Steering Committee Meeting 6 - Final Protocol recommendations Sep Forms and data collection instruments development begins Manual of Operations development begins Oct Protocol submitted to Clinical Center IRBs for review Dec Steering Committee and Nurse Coordinators Meeting - Forms Review 2002 Jan Analysis Plan submitted to NHLBI Mar Forms and data collection instruments completed and posted to the Web Site May Revised Analysis Plan submitted for DSMB Review July Data collection design and database design completed ATRS System developed and tested Steering Committee Meeting and Training Session DSMB Conference Call requesting Protocol Review Committee to convene Sep Steering Committee Luncheon Meeting Nov Protocol Review Committee Conference Call Dec Steering Committee Luncheon Meeting 2003 Mar Investigational New Drug (IND) application submitted to US FDA Central Units subcontracts negotiated IRB reviews back from Clinical Centers Phase II: Recruitment and Follow-Up 2003 May Training Session Aug Steering Committee Meeting 2004 Jun DSMB Meeting 3 Sep Steering Committee Meeting 2005 Jan DSMB Meeting 4 Apr DSMB Meeting 5 (Analyses of Feasibility and Safety Pilot Study final) Apr Steering Committee Meeting Jun DSMB Meeting 6 Sep Steering Committee Meeting Nov DSMB Meeting 7 2006 Apr Steering Committee Meeting Jun DSMB Meeting 8 Sep Steering Committee Meeting Nov DSMB Meeting 9 _________________________________________________________________________________________________________ SLC/F:/BABY-HUG/BHUG Protocol/August-09/Appendix D.wpd — 8/09 Page D-2 of D-2 2007 Apr Steering Committee Meeting Jun DSMB Meeting 10 Sep Steering Committee Meeting Nov DSMB Meeting 11 2008 Apr Steering Committee Meeting Jun DSMB Meeting 12 Sep Steering Committee Meeting Nov DSMB Meeting 13 Appendix E Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) Medical Coordinating Center ANTHROPOMETRIC MEASUREMENT PROCEDURES _____________________________________________________________________________________________________________ SLC:/BABY-HUG/BHUG Protocol/August-09-Word/Appendix E.wpd — 8/09 Page E-1 of E-9 Appendix E Anthropometric Measurement Procedures BACKGROUND Since BABY HUG is a longitudinal study and growth velocity data will be collected, it is important that all measures be made as accurately as possible. Accuracy and standardized procedures are also necessary in multicenter studies to make sure that data from one center are comparable to data from other centers. In BABY HUG data will be gathered on date of birth, birth weight, and gestational age. Gestational age is estimated from of the number of weeks between the mother’s record (recollection) of the onset of her last menstrual period and the child’s birth. In clinic anthropometric measures of weight, length, and head circumference will also be taken. Weight should be recorded in kilograms to the nearest 0.1 kg (100 grams). Length and head circumference should be recorded to the nearest 0.1 cm. GENERAL PROCEDURES Anthropometric measurements should be taken by BABY HUG personnel specifically trained and certified to perform these measurements. If possible, the same examiner(s) should measure participants throughout the study period. Whenever possible, measurements should be taken by a team of two observers. One observer takes the measurements while the other observer records. The observer taking the measurements calls out the results to the recorder. The recorder repeats the results and then calls out the name of the next measurement. The observer keeps the measuring instrument in place until the recorder repeats the number. The recorder checks the examinee’s position during the procedure. All of the measurements – weight, length, and head circumference – are made once before repeating them a second time in the same sequence by the same observer. A third measurement is made by the same observer only if the second measurement differs from the first by the specified amounts. _____________________________________________________________________________________________________________ SLC:/BABY-HUG/BHUG Protocol/August-09-Word/Appendix E.wpd — 8/09 Page E-2 of E-9 It is important that the measurements be made in pleasant, warm, and quiet surroundings. If blood specimens are taken, they should be drawn after anthropometric data have been obtained. Each center will use the same apparatus for all measurements. Weight The weight measurement is critical to assessing growth velocity. Thus, weight must be measured accurately. Following is a description of instruments and methods used for weighing infants. There is general agreement that weight should be measured using a beam scale with movable weights or a well calibrated electronic scale, and that a pan scale is needed for measurements made during infancy. Weight is best measured with the subject nude, which is practical during infancy. At older ages, nude measurements may not be possible. If nude measurements are not feasible, standardized light clothing, for example, a disposable paper gown, should be worn in preference to “light indoor clothing.” There are diurnal variations in weight of about 1 kg in children and 2 kg in adults. Therefore, making a note of the time of day at which measurements are made is desirable. Usually it is not practical to measure at a fixed time, but a narrow range may be achievable. Materials and Methods Pan Balance • A pan-type balance (scale) accurate to ± 10 grams (preferably to ±1 g) is needed for children under 12 months old. It may be a beam balance or a modern electronic recording balance. • The balance should be checked for accuracy just prior to use by adjustment of zero weight on the balance beam and weekly by verifying standard (National Bureau of Standards - NBS) weights of 2 and 4 kg. At least yearly, the balance should be _____________________________________________________________________________________________________________ SLC:/BABY-HUG/BHUG Protocol/August-09-Word/Appendix E.wpd — 8/09 Page E-3 of E-9 inspected and adjusted if necessary by a qualified representative of the manufacturer. • The child is weighed nude. Because a pan balance may be uncomfortable, a pad can be placed on the pan. The pad is weighed, and this weight is recorded and subtracted from the total weight (infant + pad). Alternatively, the balance is adjusted to zero with the pad in place. Whichever procedure is used, it should be practiced consistently throughout the study. • The child must be relatively quiet and still during the weighing. • The child is weighed to at least the nearest 100 grams. • The first weight is recorded on the BABY HUG Anthropometry Form. The child is then weighed again, and this measurement is also recorded. If the two measurements (made to the nearest 0.1 kg) differ by more than 200 grams (0.2 kg), a third weighing is made and recorded. Individuals making the weighings should sign the data form and record their certification numbers. Standing Scale A subject able to stand without support is weighed using a leveled platform scale with a beam and moveable weights (see Appendix E Figure 1). The beam on the scale must be graduated so that it can be read from both sides and the scale positioned so that the measurer can stand behind the beam, facing the subject, and can move the beam weights without reaching around the subject. The movable tare is arranged so that a screwdriver is needed to shift it. The subject stands still over the center of the platform with the body weight evenly distributed between both feet. At older ages, children object to being weighed in the nude, and light indoor clothing such as a disposable paper gown can be worn but not shoes, long trousers, or a sweater. Standardized clothing, for example, a disposable paper gown should be the same at every weighing. The weight of this clothing is not subtracted from the observed weight when the recommended reference data are used. Weight is recorded to the nearest 100 g. Weight is _____________________________________________________________________________________________________________ SLC:/BABY-HUG/BHUG Protocol/August-09-Word/Appendix E.wpd — 8/09 Page E-4 of E-9 measured and recorded twice. If the two measurements disagree by more than 100 g, a third measurement is made and recorded (see Appendix E Figure 1). Length Linear growth of children is assessed by measuring length. Recumbent length should be used up to 18 months of age and standing height after 18 months of age. Of the anthropometric data, recumbent length may be the most difficult to obtain accurately. Examiners should practice measuring infants and verify their ability to measure recumbent length accurately. Materials and Methods • A recumbent length measuring board with fixed headboard and movable footboard that are perpendicular to a table surface is required. The measuring scale must be along the length of the board. The scale should be in centimeters with 0.1 cm divisions. • The board should be regularly checked that the scale is in place and that the footboard is functioning properly with minimum play around a horizontal or vertical axis. • Two measurers are needed to obtain satisfactory measurements. One measurer holds the child’s head in a plane that allows the child to look upward in a line joining the left tragus and the lowest point of the inferior margin of the left orbit: line of sight (13). Slight traction is applied to bring the top of the child’s head to the headboard. The other measurer holds the child’s feet with toes pointed upward and brings the footboard gently against the child’s feet. Press knees to straighten legs, i.e., they should be fully extended to avoid under-estimating length. Once the child is in place, the measurer holding the head may observe that the head is no longer touching the headboard. The footboard should not be brought forward. Instead, the head should be brought gently but firmly back to the headboard. This is appropriate, _____________________________________________________________________________________________________________ SLC:/BABY-HUG/BHUG Protocol/August-09-Word/Appendix E.wpd — 8/09 Page E-5 of E-9 because the child should be stretched slightly to give an accurate measurement (see Appendix E Figure 2). • The child’s recumbent length is measured to the nearest 0.1 cm. • The recumbent length measurement in cm and the data are recorded on the appropriate data form. • The measurement should be repeated and value recorded. If the two measurements do not agree within 0.5 cm, the recumbent length should be measured a third time. The two measurers may change positions for the third measurement. Head Circumference Materials and Methods • Head circumference is measured with a flexible narrow non-stretchable tape. Steel and fiberglass tapes are satisfactory. Disposable paper tapes can also be used. • If the same tape is used repeatedly, it should be checked periodically against a steel centimeter reference tape. • Head circumferences are measured in young children while lying still. In measuring the older child, it is preferable for the child to be on the mother’s lap. • The tape is placed firmly around the head above the supraorbital ridges (right above the brows). While holding the tape in place with the index or middle finger of one hand, the tape is passed over the occipital prominence (bump) at the back of the head with the other hand and the maximum circumference is noted. • The tape should be pulled snugly around the head compressing the hair (see Appendix E Figure 3). The tape must be kept in the same plane on left and right sides of the head. The measurement should be recorded to the nearest 0.1 cm. • If the child has a hairstyle that may interfere with the tape’s proper position and cannot be easily undone (e.g., “Corn rows”), the best circumference measures _____________________________________________________________________________________________________________ SLC:/BABY-HUG/BHUG Protocol/August-09-Word/Appendix E.wpd — 8/09 Page E-6 of E-9 possible should be taken and the presence of such a hair style should be noted on the Anthropometry Form. TRAINING AND CERTIFICATION Problems with different observers over time occur and thus it is important to keep the number of observers to a minimum and ensure continued training and certification over time. Inter- observer variability and errors related to lack of skills can introduce major errors in the data. A goal will be to have an individual certified as a trainer at each Clinical Center so that individuals subsequently joining the staff can be trained on site, certified, and recertified. Training and certification will be on site at all BABY HUG Clinical Centers and carried out by the master trainer. The certification procedures trains the measurers at each site in the techniques and process of taking the actual measurements covered in this manual. During this procedure recording methods, equipment calibration and potential sources of error will be demonstrated. Recertification will be required every year after the original certification. This will be carried out by each center’s designated trainer or by the Study’s master trainer. The designated trainer will be certified as having demonstrable measurement skills and knowledge of the methodology, including recording, for avoidance of errors. _____________________________________________________________________________________________________________ SLC:/BABY-HUG/BHUG Protocol/August-09-Word/Appendix E.wpd — 8/09 Page E-7 of E-9 Appendix E Figure 1 _____________________________________________________________________________________________________________ SLC:/BABY-HUG/BHUG Protocol/August-09-Word/Appendix E.wpd — 8/09 Page E-8 of E-9 Appendix E Figure 2 _____________________________________________________________________________________________________________ SLC:/BABY-HUG/BHUG Protocol/August-09-Word/Appendix E.wpd — 8/09 Page E-9 of E-9 Appendix E Figure 3 Appendix F Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) Medical Coordinating Center Clinical Event Definitions SLC/F:/BABY-HUG/BHUG Protocol/August-09/Appendix F.wpd — 8/09 Page F-1 of F-6 Appendix F: Clinical Event Definitions Introduction In BABY HUG, clinical event definitions will be applied for consistency with other important NHLBI-sponsored clinical studies of sickle cell anemia such as the Clinical Study of Sickle Cell Disease (CSSCD) and the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH). Definitions Anemia: A reduction of hemoglobin level by at least 30% from the steady-state level OR a reduction by at least 20% accompanied by an acute increase in spleen size. Acute anemic events should be classified into one of the following categories. 1. Splenic sequestration crisis: The event is characterized by an increase in spleen size and firmness, reduction of hemoglobin level by at least 20% and may include drop in platelet or white counts. Splenic sequestration is defined in BABY HUG by the findings of a palpable, large spleen with hemoglobin less than 5 gm/dL for nonfatal occurrences. 2. Aplastic Crisis: This event is characterized by a substantial decrease in reticulocyte count to below 1.5 % before or concurrent with a reduction in hemoglobin level to a level greater than 30% below the steady-state level. Characteristically results from acute infection with parvovirus B19. Check the patient’s parvovirus IgM titer; usually it should be positive. 3. Other anemia: Reduction of hemoglobin because of blood loss, transfusion reaction or hyper-hemolysis will be classified as an other anemia. A hyper-hemolytic episode is characterized by normal or increased reticulocyte counts and nucleated red cell count during an episode of falling hemoglobin associated with an increase in indirect bilirubin level over the usual value. The latter finding is important to allow discrimination from a recovering aplastic crisis. SLC/F:/BABY-HUG/BHUG Protocol/August-09/Appendix F.wpd — 8/09 Page F-2 of F-6 Aplastic Crisis: See Anemia. Arthritis (septic): See Infection (other). Aseptic Necrosis: Presentation in the age range of patients in BABY HUG would be unusual. Patients encounter pain in their hip or shoulder, often of a different character than their usual crisis pain. The pain persists indefinitely, long after the expected duration of crisis pain. Early radiographic findings are subepiphyseal lucency and widening of the joint space. Late changes include flattening of the epiphysis and sclerosis with fragmentation. Bacteremia: Febrile illness with blood culture positive for bacteria. Organism must be specified. Cerebrovascular Accident (CVA): Acute neurologic syndrome secondary to occlusion of an artery or hemorrhage with resultant ischemic and neurologic symptoms and signs. 1. Stroke, hemorrhagic: Injury to brain tissue resulting from disturbance of blood supply to the brain due to hemorrhage. The area of the hemorrhage should also be reported (e.g., subarachnoid, subdural, intracerebral, aneurysm). 2. Stroke, infarctive: Injury to brain tissue consistent with occlusion of vessel(s) by thrombus or embolus which results in neurologic abnormalities on physical examination that persist beyond 24 hours. 3. Transient Ischemic Attack (TIA): Temporary interference with blood supply to the brain. The symptoms include neurologic signs that clear within 24 hours (48 hours if basilar system is involved). After the attack, no evidence of residual neurologic damage remains on physical examination. Chest Syndrome: Also known as acute chest syndrome (ACS). A clinical syndrome that includes at least 3 of the following symptoms: chest pain, temperature elevation over 38.5oC/101.5oF , tachypnea, wheezing or cough. A new pulmonary infiltrate must be present on x-ray involving at least one complete lung segment to be consistent with alveolar consolidation instead of atelectasis. Cholangitis: See Right Upper Quadrant Syndrome Cholecystitis: See Right Upper Quadrant Syndrome SLC/F:/BABY-HUG/BHUG Protocol/August-09/Appendix F.wpd — 8/09 Page F-3 of F-6 Cholelithiasis: See Right Upper Quadrant Syndrome CVA: See Cerebrovascular Accident Dactylitis: Pain and tenderness with or without swelling in hands and/or feet. Also known as Hand- foot syndrome. Fever without Focus: Elevation of temperature greater than 38.5oC/101.5oF (regardless of route, oral, axillary or rectal) not associated with a positive culture from any source or with any other special event. Will be characterized as an event managed with blood culture (no growth) and empiric parenteral antibiotics or by parental history (no blood culture, no empirical parenteral antibiotics). Gastroenteritis: See Infection, Gastroenteritis Hand-Foot Syndrome: See Dactylitis. Hematuria: Blood in the urine (greater than 5 red blood cells per high power field), usually suggested by history, confirmed by urinalysis. Hepatitis: See Right Upper Quadrant Syndrome Infection (other): Inflammation, caused by a pathogenic agent, which may or may not be accompanied by a fever. Sepsis, meningitis, osteomyelitis, hepatitis and urinary tract infections are NOT INCLUDED in this category since they are categorized elsewhere. If encountered, the type of infection, site, and organism if known should be specified. 1. Abscess/Cellulitis: Infection of skin or deeper tissues. 2. Gastroenteritis: Inflammation of the stomach and intestinal tract. Signs include nausea, vomiting and diarrhea lasting at least 8 hours. 3. Lymphadenitis/Lymphangitis: Infection in regional lymph nodes or channels draining the primary site of infection. 4. Mastoiditis: Infection of the mastoid bone. 5. Orbital Cellulitis: Infection of the orbit and tissues posterior to the eye. SLC/F:/BABY-HUG/BHUG Protocol/August-09/Appendix F.wpd — 8/09 Page F-4 of F-6 6. Otitis Media: Infection of the middle ear associated with ear pain and erythema of eardrum, bulging or decreased mobility of eardrum with loss of landmarks. 7. Periorbital or Preseptal Cellulitis: Infection of the eyelids causing erythema and swelling. 8. Pharyngitis: Pain in the pharynx associated with redness of pharyngeal and tonsillar mucosa with or without exudates. Indicate if streptococcal culture positive. 9. Septic Arthritis: Bacterial infection of a joint. The causative agent should be listed if known. 10. Upper Respiratory Infections (URI): An imprecise term for almost any kind of infectious process involving the nasal passages, pharynx and bronchi. Often called a “cold.” 11. Varicella Infection: Clinical syndrome of skin lesions, fever associated with varicella zoster virus infection. Liver Sequestration: See Right Upper Quadrant Event 5. Liver Sequestration. Mastoiditis: See Infection (other). Meningitis: Inflammation of the membranes of the spinal cord or brain usually caused by and infectious agent, as demonstrated by lumbar puncture abnormalities and culture. The causative agent should be listed if known. Orbital Cellulitis: See infection (other) Osteomyelitis: Bacterial infection of bone requiring long-term antibiotics. The causative agent should be listed if known. Other Event Not Specified: Includes any event that is not included in the list of the events specified on this form. Painful events: Pain in the extremities, back, abdomen, chest or head for which no other explanation can be found and which is not classified as one of the other special events. The pain shall have lasted for at least 2 hours and for which medication either narcotic or non steroidal, antiflammatory agent is taken. In a young child, pain or tenderness on palpation will be considered appropriate evidence of event. SLC/F:/BABY-HUG/BHUG Protocol/August-09/Appendix F.wpd — 8/09 Page F-5 of F-6 Pancreatitis: See Right Upper Quadrant Event 6. Pancreatitis. Pneumonia: See Chest Syndrome. Priapism: A painful erection of the penis lasting for more than 2 hours. Proteinuria: Presence of 1+ protein or more on urinalysis. Renal Complications (not specified): A renal condition not categorized as hematuria, urinary tract infection, proteinuria or renal insufficiency. The type of complication should be sought and specified. Renal Insufficiency: At least a two-fold increase in serum creatinine to a level greater than or equal to 1.0 mg/dl. Right Upper Quadrant (RUQ) Event: Defined as any two of the following; pain only in the right upper quadrant of the abdomen, twofold increase in total bilirubin over baseline to a level exceeding the upper limit of normal, two centimeter increase in liver size over baseline or twofold increase in ALT over baseline to a level exceeding the upper limit of normal. 1. Cholangitis: Inflammation of the bile ducts. Diagnosis is usually made by abdominal ultrasound. 2. Cholecystitis: Inflammatory condition of the gallbladder causing RUQ pain that may or may not be associated with gallstones. Diagnosis is usually made by abdominal ultrasound. 3. Cholelithiasis: Formation or presence of calculi or bile stones in the gallbladder or common bile duct, with minimal or no symptoms. 4. Hepatitis: An inflammation of the liver. The causative agent if known, should be specified. 5. Liver Sequestration/Intrahepatic Sequestration: Jaundice and pain in the liver not due to gallstones. May include intrahepatic sickling crisis. 6. Pancreatitis: Inflammation of the pancreas. May be related to medication, infection or gallstone blockage of the Ampulla of Vater. SLC/F:/BABY-HUG/BHUG Protocol/August-09/Appendix F.wpd — 8/09 Page F-6 of F-6 Seizure: A paroxysmal disorder of cerebral function characterized by sudden, transient attack of altered consciousness, motor activity or sensory phenomena. The type of seizure (e.g., petit mal, psychomotor, grand mal) and etiology if known should be specified. Sepsis: Severe febrile illness with unstable vital signs or shock associated with positive blood culture. Organism must be specified. Positive blood culture in stable patients reported as bacteremia. Splenic Sequestration: See anemia. Splenomegaly: without acute sequestration: Spleen is palpable in abdomen with stable hemoglobin (within 1 gm/dl of baseline), and platelet counts > 100,000/cu mm. Surgery: Any operative procedure will be listed. Transient Ischemic Attack (TIA): See Cerebrovascular Accident (CVA). Transfusion: The provision of red blood cells to correct anemia. The reason for the transfusion should also be specified. Simple or Exchange transfusion should be specified. Upper Respiratory Infection (URI): See Infection (other). Urinary Tract Infection: A clinical event which may or may not be associated with fever and symptoms which is associated with a positive urine culture. ICF_001.pdf:	2	arm 1: Participants will receive hydroxyurea. arm 2: Participants will receive placebo.	[ 1, 2 ]	2	[ 0, 0 ]	intervention 1: Participants will receive hydroxyurea. intervention 2: Participants will receive placebo.	intervention 1: Hydroxyurea intervention 2: Placebo	14	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Washington D.C. \| District of Columbia \| United States \| -77.03637 \| 38.89511 Washington D.C. \| District of Columbia \| United States \| -77.03637 \| 38.89511 Miami \| Florida \| United States \| -80.19366 \| 25.77427 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Detroit \| Michigan \| United States \| -83.04575 \| 42.33143 Jackson \| Mississippi \| United States \| -90.18481 \| 32.29876 Brooklyn \| New York \| United States \| -73.94958 \| 40.6501 Durham \| North Carolina \| United States \| -78.89862 \| 35.99403 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Charleston \| South Carolina \| United States \| -79.93275 \| 32.77632 Memphis \| Tennessee \| United States \| -90.04898 \| 35.14953 Dallas \| Texas \| United States \| -96.80667 \| 32.78306	193	0	0	0	NCT00006400	1COMPLETED	2009-09-01	2000-08-01	National Heart, Lung, and Blood Institute (NHLBI)	0NIH	true	true	true	https://cdn.clinicaltrials.gov/large-docs/00/NCT00006400/Prot_SAP_000.pdf https://cdn.clinicaltrials.gov/large-docs/00/NCT00006400/ICF_001.pdf	0	0	0	0	0	0
[ 4 ]	738	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	null	The purpose of this clinical research study is to determine whether abatacept treatment on a background of Disease Modifying Antirheumatic Drugs (DMARDs) will relieve the symptoms of rheumatoid arthritis (RA) in participants who are currently receiving anti-tumor necrosis factor (TNF) therapy for at least 3 months and are not responding or have taken anti-TNF therapy in the last 3 months and did not respond. The safety of treatment with abatacept will also be evaluated. This study also has a 4.5-year long-term extension beginning 6 months after the start of the study.	null	Rheumatoid Arthritis		null	3	arm 1: Short Term Portion of Study arm 2: Short Term Portion of Study arm 3: Long Term Portion of Study: All participants receive Active Drug	[ 1, 2, 1 ]	3	[ 0, 0, 0 ]	intervention 1: Vials, intravenous (IV), \~10mg/kg abatacept, One every 2 weeks for first month then every 4 weeks thereafter, 6 months. intervention 2: Vials, IV, 0mg, One every 2 weeks for first month then every 4 weeks thereafter, 6 months. intervention 3: Vials, IV, \~10mg/kg abatacept, every 4 weeks, 5.5 years	intervention 1: Abatacept intervention 2: Placebo intervention 3: Abatacept	42	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Mobile \| Alabama \| United States \| -88.04305 \| 30.69436 Paradise Valley \| Arizona \| United States \| -111.94265 \| 33.53115 La Jolla \| California \| United States \| -117.2742 \| 32.84727 Long Beach \| California \| United States \| -118.18923 \| 33.76696 Palo Alto \| California \| United States \| -122.14302 \| 37.44188 Rancho Mirage \| California \| United States \| -116.41279 \| 33.73974 Denver \| Colorado \| United States \| -104.9847 \| 39.73915 Englewood \| Colorado \| United States \| -104.98776 \| 39.64777 Bridgeport \| Connecticut \| United States \| -73.18945 \| 41.17923 Hamden \| Connecticut \| United States \| -72.89677 \| 41.39593 Clearwater \| Florida \| United States \| -82.8001 \| 27.96585 Fort Lauderdale \| Florida \| United States \| -80.14338 \| 26.12231 Largo \| Florida \| United States \| -82.78842 \| 27.90979 Palm Harbor \| Florida \| United States \| -82.76371 \| 28.07807 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 Rome \| Georgia \| United States \| -85.16467 \| 34.25704 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Wichita \| Kansas \| United States \| -97.33754 \| 37.69224 New Orleans \| Louisiana \| United States \| -90.07507 \| 29.95465 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Springfield \| Massachusetts \| United States \| -72.58981 \| 42.10148 Lincoln \| Nebraska \| United States \| -96.66696 \| 40.8 New Brunswick \| New Jersey \| United States \| -74.45182 \| 40.48622 Albany \| New York \| United States \| -73.75623 \| 42.65258 Syracuse \| New York \| United States \| -76.14742 \| 43.04812 Charlotte \| North Carolina \| United States \| -80.84313 \| 35.22709 Hickory \| North Carolina \| United States \| -81.3412 \| 35.73319 Bismarck \| North Dakota \| United States \| -100.78374 \| 46.80833 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Oklahoma City \| Oklahoma \| United States \| -97.51643 \| 35.46756 Eugene \| Oregon \| United States \| -123.08675 \| 44.05207 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Duncansville \| Pennsylvania \| United States \| -78.4339 \| 40.42341 Norristown \| Pennsylvania \| United States \| -75.3399 \| 40.1215 Sellersville \| Pennsylvania \| United States \| -75.3049 \| 40.35399 Willow Grove \| Pennsylvania \| United States \| -75.11573 \| 40.144 Charleston \| South Carolina \| United States \| -79.93275 \| 32.77632 Austin \| Texas \| United States \| -97.74306 \| 30.26715 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Vancouver \| Washington \| United States \| -122.66149 \| 45.63873 Milwaukee \| Wisconsin \| United States \| -87.90647 \| 43.0389	708	0	0	0	NCT00048581	1COMPLETED	2009-09-01	2002-12-01	Bristol-Myers Squibb	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 4 ]	247	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	0ALL	true	The purpose of this study is to determine if therapy with pioglitazone or vitamin E will lead to an improvement in liver histology in non-diabetic adult patients with non-alcoholic steatohepatitis (NASH).	The purpose of this study is to determine if therapy with pioglitazone or vitamin E will lead to an improvement in liver histology in non-diabetic adult patients with non-alcoholic steatohepatitis (NASH).	Liver Diseases	Non alcoholic steatohepatitis Steatohepatitis	null	3	arm 1: Pioglitazone arm 2: Vitamin E arm 3: Placebo Pioglitazone or Placebo Vitamin E	[ 1, 1, 2 ]	3	[ 0, 7, 0 ]	intervention 1: 30 mg daily intervention 2: 800 IU daily intervention 3: Daily	intervention 1: Pioglitazone intervention 2: Vitamin E intervention 3: Matching placebo	8	San Diego \| California \| United States \| -117.16472 \| 32.71571 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Durham \| North Carolina \| United States \| -78.89862 \| 35.99403 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Richmond \| Virginia \| United States \| -77.46026 \| 37.55376 Seattle \| Washington \| United States \| -122.33207 \| 47.60621	247	0	0	0	NCT00063622	1COMPLETED	2009-09-01	2005-01-01	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	0NIH	false	false	false	null	0	0	0	0	0	-0
[ 3 ]	21	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	OVERVIEW Essential tremor (ET) is a common movement disorder affecting 0.4% of the general population and up to 14% of people 65 years and older. Response to medications such as beta blockers and primidone may be of benefit, but are often accompanied by intolerable side effects. Response to ethanol, on the other hand, has a roughly 80% chance of significant tremor reduction, though daily use of this as a treatment has potentially serious medical, social, and legal consequences. The leading hypothesis for ET pathophysiology is an unmasking of spontaneous oscillations originating in neurons of the inferior olive. Both ethanol and 1-octanol have been shown to reduce these spontaneous oscillations in an animal model of ET; however, 1-octanol does this at a dose much lower than that leading to intoxication, suggesting in may be useful in the treatment of essential tremor. Our initial studies with 1-octanol have shown it to be safe at dosages up to 64mg/kg without signs of intoxication, while at the same time showing benefit. OBJECTIVE We plan to evaluate the efficacy of different 1-octanol formulations in humans based on accelerometry and spirography. We will also evaluate drug and metabolite bioavailabilities using a high performance liquid chromatography (HPLC) detection method from plasma and urine samples. STUDY POPULATION We will study adult subjects with ethanol-responsive Essential Tremor (ET). DESIGN This study is designed as a two-phase unblinded inpatient study of adults with ET receiving weight-adjusted oral dosages of 2 different formulations of 1-octanol in a crossover fashion. Phase I of the study is designed to develop an octanol detection assay using HPLC. Four subjects will receive daily escalating dosages (1-32 mg/kg) of a single 1-octanol formulation followed by a crossover trial of both formulations at a dosage of 64 mg/kg. Phase II will study 20 subjects receiving one of the two formulations at 64 mg/kg on inpatient day 1 followed by a 24 hour period of close monitoring. The second formulation will be given on day 3 and the patient will again undergo close monitoring for 24 hours. OUTCOME MEASURES The primary outcome measures for the study will be efficacy based on tremor ratings from accelerometry and spirography. Secondary outcome measures will be the determination of bioavailability, pharmacodynamic and pharmacokinetic profiles of octanol #61864 and octanol #68751 and their metabolites.	OVERVIEW Essential tremor (ET) is a common movement disorder affecting 0.4% of the general population and up to 14% of people 65 years and older. Response to medications such as beta blockers and primidone may be of benefit, but are often accompanied by intolerable side effects. Response to ethanol, on the other hand, has a roughly 80% chance of significant tremor reduction, though daily use of this as a treatment has potentially serious medical, social, and legal consequences. The leading hypothesis for ET pathophysiology is an unmasking of spontaneous oscillations originating in neurons of the inferior olive. Both ethanol and 1-octanol have been shown to reduce these spontaneous oscillations in an animal model of ET; however, 1-octanol does this at a dose much lower than that leading to intoxication, suggesting it may be useful in the treatment of essential tremor. Our initial studies with 1-octanol have shown it to be safe at dosages up to 64mg/kg without signs of intoxication, while at the same time showing benefit. OBJECTIVE We plan to evaluate the efficacy of different 1-octanol formulations in humans based on accelerometry and spirography. We will also evaluate drug and metabolite bioavailabilities using a high performance liquid chromatography (HPLC) detection method from plasma and urine samples. STUDY POPULATION We will study adult subjects with ethanol-responsive Essential Tremor (ET). DESIGN This study is designed as a two-phase unblinded inpatient study of adults with ET receiving weight-adjusted oral dosages of 2 different formulations of 1-octanol in a crossover fashion. Phase I of the study is designed to develop an octanol detection assay using HPLC. Four subjects will receive daily escalating dosages (1-32 mg/kg) of a single 1-octanol formulation followed by a crossover trial of both formulations at a dosage of 64 mg/kg. Phase II will study 20 subjects receiving one of the two formulations at 64 mg/kg on inpatient day 1 followed by a 24 hour period of close monitoring. The second formulation will be given on day 3 and the patient will again undergo close monitoring for 24 hours. OUTCOME MEASURES The primary outcome measures for the study will be efficacy based on tremor ratings from accelerometry and spirography. Secondary outcome measures will be the determination of bioavailability, pharmacodynamic and pharmacokinetic profiles of octanol #61864 and octanol #68751 and their metabolites. Addendum: Based on the results of the assays for all subjects who participated in Part 1 and 2 of this protocol, we would like to conduct an exploratory study (Part 3) consisting of two subjects receiving a dose of 128mg/kg of 1-octanol. This is meant to primarily explore the plasma concentration of 1-octanol, while also providing valuable information regarding the safety and efficacy at this higher dose. The remainder of the experimental design will be maintained, with exception of additional safety precautions which will be discussed in the protocol and consent.	Essential Tremor	Ethanol Alcohol Responsive Movement Disorder Gas Chromatography Bioavailability Pharmacokinetics Essential Tremor	null	0	null	null	1	[ 0 ]	intervention 1: 1-Octanol is an long-chain alcohol with potential therapeutic benefits in treating alcohol-responsive tremors based on unknown mechanisms. The intervention consisted of either 1) 1-octanol adsorbed to microcrystalline cellulose, NF (Avicel PH 102, FMC Corp., Philadelphia, PA), and fine particle silica (Sipernat 50S, Evonik Degussa Corp., Parsippany, NJ) and encapsulated in 50 mg and 250 mg dosages; or 2) a soft-gel capsule containing 1-octanol embedded in soybean oil at 50 mg and 800 mg dosages (Best Formulations Inc, City of Industry, CA).	intervention 1: 1-Octanol	1	Bethesda \| Maryland \| United States \| -77.10026 \| 38.98067	15	0	0	0	NCT00102596	1COMPLETED	2009-09-01	2005-01-01	National Institute of Neurological Disorders and Stroke (NINDS)	0NIH	false	false	false	null	0	0	0	0	0	0
[ 3 ]	108	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	0ALL	true	The purpose of this study is to determine whether gabapentin is efficacious as an analgesic for chronic low back pain.	Chronic low back pain (CLBP) is a major health problem for the VA, affecting up to 15% of all veterans. Nationally, its medical and disability costs exceed $50 billion annually. Despite its impact, relatively little research evaluates treatment for CLBP. Wide variation in patterns of care suggests uncertainty over effective therapy. Most chronic back cases are not surgical candidates. The mainstays of medical treatment have been non-steroidal anti-inflammatory drugs (NSAIDs), muscle relaxants, opioids, and antidepressants. Non-steroidal drugs and muscle relaxants are effective for acute but not for chronic back pain. Opioids may provide analgesia but safety limits their use. Tricyclic antidepressants provide modest pain relief, separate from effects on depression. But it is clear additional research is needed to develop more effective pharmacotherapy. One approach favored by many authorities is determining if agents effective for one type of chronic pain syndrome (e.g., diabetic neuropathy) can be generalized to other syndromes, like chronic back pain. Another is to identify effective drug combinations, based on selecting drugs with differing therapeutic mechanisms. This research is a program of rigorous randomized clinical trials testing the efficacy of antidepressants for analgesia in chronic back pain. Because chronic pain is a complex disorder, the program features a multidisciplinary research team, involving specialists in psychiatry, orthopedic surgery, psychology, anesthesiology, clinical pharmacology, and biomathematics. The research has both pragmatic and explanatory aims. Our strategy has been to test antidepressants with differing, and selective properties in an attempt to isolate therapeutic mechanisms. Thus, we began with trials using selective norepinephrine reuptake inhibitors, and selective serotonin reuptake inhibitors (SSRIs), rather than those with dual noradrenergic and serotonergic effects (e.g., amitriptyline, imipramine). To ensure applicability of results, we have used rigorous diagnostic procedures to identify patients with chronic back pain due to degenerative disk disease. To enhance generalizability we recruit primary care patients rather than tertiary pain clinic samples. Patients without major depression are studied to examine analgesia separate from antidepressant effects. Secondary outcomes address function and life quality. We have conducted three controlled trials using identical recruitment and assessment methodology. The first, comparing a noradrenergic antidepressant (nortriptyline) with placebo, indicated that the noradrenergic agent provided clinically relevant analgesia. The second was a head-to-head comparison of a selective noradrenergic agent (maprotiline) with a selective serotonin reuptake inhibitor (SSRI, paroxetine). The noradrenergic agent outperformed the SSRI, which was equivalent to placebo. To clarify these results we explored whether efficacy might be evident only at specific drug concentrations. Therefore, the third study, has a prospective concentration design comparing the most potent and selective noradrenergic antidepressant (desipramine) to the standard SSRI, fluoxetine. Subjects were randomized to placebo or predetermined concentration windows reflecting low, medium, and high exposure to study drugs and followed for 12 weeks. Interim analysis suggests that low concentration desipramine outperforms placebo (p\<0.05). It is also superior to mid-concentration and high exposure desipramine--as well as all exposure levels of the SSRI, which are equivalent to placebo. In sum, all three studies supported noradrenergic analgesia in CLBP, and the two studies that evaluated SSRIs failed to find analgesia. This suggests noradrenergic activity, perhaps within a therapeutic window, may be primarily responsible for back pain analgesia. These findings have led us away from studies proposing combining noradrenergic and serotonergic agents. An alternative approach which builds on these data, but first employs another class of agents, seems reasonable. This strategy is to assess if gabapentin, a calcium channel blocker agent with demonstrated efficacy in neuropathic pain, can be extended to chronic back pain. We conducted a double-blind, randomized assignment, 12-week, placebo controlled clinical trial of the efficacy of gabapentin. Non-depressed chronic low back pain patients (N = 130) will be randomized to placebo or high dose gabapentin (3600 mg/day or maximum tolerable dose). Analysis was by intent to treat. The primary efficacy assessment is mean pain intensity (Descriptor Differential Scale, DDS) at exit. Secondary outcomes are function and life quality (Oswestry Disability Index, Short Form-36, Quality of Well-Being Scale). Safety evaluation includes rating adverse events (Scandinavian Society of Psychopharmacology Committee on Clinical Investiagations Side Effects Rating Scale, UKU), standardized physical examination, and clinical laboratory testing. Results could provide explanatory insight into mechanisms of back pain, and address the pragmatic clinical need by primary care providers and others for effective therapy.	Chronic Low Back Pain	analgesia antidepressant agents back pain pain	null	2	arm 1: Gabapentin 300 mg orally three times daily up to a maximum of 1200 mg orally three times daily for 12 weeks arm 2: Inert placebo capsules identical in size and shape to the experimental capsules, one to three capsules taken orally three times daily for 12 weeks	[ 0, 3 ]	2	[ 0, 0 ]	intervention 1: Gabapentin 300m on Day 1, with daily or weekly increase to 3600 mg (maximum) by mouth by Week 5 of the 12-week trial intervention 2: Inactive placebo capsule, one capsule on Day 1 with daily or weekly increase to 9 capsules daily by Week 5 of the 12-week trial	intervention 1: gabapentin intervention 2: Inert placebo	1	San Diego \| California \| United States \| -117.16472 \| 32.71571	108	0	0	0	NCT00108550	1COMPLETED	2009-09-01	2004-10-01	US Department of Veterans Affairs	1FED	false	false	false	null	0	0	0	0	0	0
[ 3 ]	226	NON_RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	null	This phase II trial is studying how well giving bevacizumab together with combination chemotherapy works in treating patients who have undergone surgery for breast cancer that has spread to the lymph nodes. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with more than one chemotherapy drug (combination chemotherapy), may be a better way to block tumor growth.	PRIMARY OBJECTIVES: I. To determine the incidence of clinically apparent cardiac dysfunction in patients with lymph node positive breast cancer treated with bevacizumab and dose dense doxorubicin/cyclophosphamide followed by paclitaxel (ddAC \> T). SECONDARY OBJECTIVES: I. To evaluate changes in LVEF during treatment. II. To evaluate non-cardiac toxicity. OUTLINE: This is a non-randomized, multicenter study. Patients are sequentially assigned to 1 of 2 treatment arms. Arm A: Patients receive doxorubicin IV, cyclophosphamide IV over 20-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Patients also receive filgrastim (G-CSF) subcutaneously (SQ) on days 2-11 or pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients then receive paclitaxel IV over 3 hours and bevacizumab IV over 30-90 minutes on day 1. Patients also receive G-CSF or pegfilgrastim as above. Treatment with paclitaxel, bevacizumab, and G-CSF or pegfilgrastim repeats every 14 days for 4 courses. Patients then receive bevacizumab alone every 14 days for up to 18 courses. Arm B: Patients receive doxorubicin, cyclophosphamide, and G-CSF or pegfilgrastim as in group I. Patients then receive paclitaxel, bevacizumab, and G-CSF or pegfilgrastim as in group I. Patients then receive bevacizumab alone every 14 days for up to 22 courses. Treatment in both groups continues in the absence of disease recurrence or unacceptable toxicity. Patients who require radiotherapy (post-lumpectomy) or who plan radiotherapy at the discretion of the investigator (post-mastectomy) undergo radiotherapy beginning within 6 weeks after the completion of chemotherapy. Premenopausal patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive disease receive oral tamoxifen once daily for 5 years beginning at the time of radiotherapy or within 6 weeks after the completion of chemotherapy. Postmenopausal patients with ER and/or PR positive disease receive an aromatase inhibitor (e.g., anastrozole, letrozole, or exemestane) or tamoxifen followed by an aromatase inhibitor once daily for up to 10 years. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for up to 3 years from study entry. ACCRUAL: A total of 226 patients (104 on arm A and 122 on arm B) were accrued for this study.	Male Breast Cancer Stage II Breast Cancer Stage IIIA Breast Cancer Stage IIIB Breast Cancer		null	2	arm 1: See detailed description. arm 2: See detailed description.	[ 0, 1 ]	9	[ 0, 0, 2, 0, 2, 2, 4, 0, 0 ]	intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given SC intervention 6: Given SC intervention 7: Undergo radiation therapy intervention 8: Given orally intervention 9: Receive aromatase inhibition therapy	intervention 1: doxorubicin hydrochloride intervention 2: cyclophosphamide intervention 3: bevacizumab intervention 4: paclitaxel intervention 5: filgrastim intervention 6: pegfilgrastim intervention 7: radiation therapy intervention 8: tamoxifen citrate intervention 9: aromatase inhibition therapy	1	Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843	223	0	0	0	NCT00119262	1COMPLETED	2009-09-01	2005-10-01	National Cancer Institute (NCI)	0NIH	false	false	false	null	0	0	0	0	0	0
[ 5 ]	110	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	The overall objective of the study was to describe the long-term effectiveness and safety of etanercept in patients with psoriatic arthritis in a Canadian clinical practice setting.	null	Psoriatic Arthritis	Psoriatic Arthritis PsA Commercial product American College of Rheumatology ACR/PASI	null	1	arm 1: Open-label etanercept administered by subcutaneous injection at a dose of 50 mg/week for 24 months.	[ 5 ]	1	[ 0 ]	intervention 1: Administered according to the product monograph by subcutaneous (SC) injection	intervention 1: Etanercept	0	null	110	0	0	0	NCT00127842	1COMPLETED	2009-09-01	2005-08-01	Amgen	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 4 ]	364	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	true	The purpose of this study is to determine whether an alternative drug, (rifampin) given daily, is better at treating tuberculosis (TB) and more tolerable than the usual drug treatment, isoniazid (INH). Study participants will include 972, TB infected, San Francisco Jail inmates, aged 18 or older. One group of volunteers will take INH two times a week for 9 months, and the other group will take rifampin daily for 4 months. Medication will be administered in jail and at the San Francisco TB Clinic if the volunteer is released from jail prior to completing the study. Participants will be seen daily for 4 months (rifampin group), and 2 times a week for 9 months (INH group) for directly observed therapy. Study procedures will include 5 symptom review visits and blood samples for lab testing. Follow-up will continue for each subject for five years after enrollment into the study.	The purpose of this project is to evaluate the effect of two accepted regimens for treating latent tuberculosis infection (LTBI) in jail. Tuberculosis (TB) in incarcerated populations continues to be a serious problem, due to the large proportion of persons who are at high risk of both having latent tuberculosis infection (LTBI) and developing active disease. Completion of treatment of LTBI, while an important component of overall TB control efforts, has not been successful in jails. This is primarily because inmates are frequently released before finishing a 6-9 month course of standard therapy, and have low rates of completing therapy in the community. This study proposes to look at toxicity and adherence for this 4-month regimen compared to the nine-month regimen of to isoniazid (INH), and to examine costs, both cost of delivered care and the cost of TB disease prevented, with examination of reasons for completion or noncompletion of therapy. Short-course therapies for LTBI may address this problem but they are more expensive and have not been studied adequately to answer questions about side effects, completion rates, and overall cost. The investigators propose a randomized trial to test the effects of a short course therapy, rifampin (600 mg orally) given daily for 4 months, as compared to (INH) (900 mg orally) given twice weekly for 9 months. Both regimens are listed by the Centers for Disease Control and Prevention (CDC) and the American Thoracic Society as acceptable treatments for persons with LTBI. The study participants will include 972 San Francisco Jail inmates, 18 years and older, enrolled over a 28-month period, for a sample of 486 in each study group. Subjects, followed in jail and after release, will be followed to test three hypotheses: the null hypothesis of a difference in toxicity of rifampin as compared to INH within a 95% confidence interval of (.4-1.87) and no difference by study group in adherence and in cost-effectiveness. A secondary aim is to describe reasons for completion or noncompletion of therapy. Toxicity is defined as complications leading to stopping drug. Adherence is defined as completion of care, or 120 doses taken within 6 months for the rifampin group and 76 doses of INH taken within 12 months for the INH group. Cost effectiveness will be calculated as the total cost of care (nursing, medical, laboratory, as well as facility costs), and measured against costs of TB cases prevented. All treatments will be administered by directly observed therapy (DOT) in jail, and by DOT after release at the San Francisco TB Clinic. Counseling on adherence (going to the TB Clinic if released before completing therapy) and on possible side effects will be given to all study subjects at enrollment and during follow-up clinic visits. All subjects will be routinely evaluated by study personnel every two weeks for the first 6 weeks, and thereafter to detect possible drug toxicity including hepatitis, peripheral neuropathy, arthralgias, rash, memory loss, and other clinical symptoms. All patients will undergo laboratory assessment at regular intervals according to a schedule which compares study group participation and the usual care in the jail. All blood test results, and new symptoms or changes in symptoms found at follow-up, will be added to the jail medical record. A final interview will be done with subjects at the time that they have completed or not completed this course of therapy for LTBI, to determine reasons (barriers and enablers). Follow-up will continue for each subject for five years after enrollment into the study, to measure study endpoint (completion of care, taken off drugs for toxicity or loss to follow-up) and to measure subsequent treatment for LTBI or development of active TB by record review.	Tuberculosis	LTBI, tuberculosis, rifampin, isoniazid, prisoners	null	2	arm 1: isoniazid (INH) (900 mg orally) given twice weekly for 9 months arm 2: rifampin (600 mg orally) given daily for 4 months	[ 1, 1 ]	2	[ 0, 0 ]	intervention 1: Isoniazid 900 mg twice weekly intervention 2: Rifampin 600mg once per day	intervention 1: Isoniazid intervention 2: Rifampin	1	San Francisco \| California \| United States \| -122.41942 \| 37.77493	364	0	0	0	NCT00128206	1COMPLETED	2009-09-01	2004-11-01	University of California, San Francisco	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 4 ]	321	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	To see if Disease Free Survival (DFS) is improved when complete surgical resection of liver metastases (R0) is followed by chemotherapy with CPT-11 and 5-FU/FA as FOLFIRI regimen, compared to 5-FU/FA alone.	null	Colorectal Neoplasms Liver Neoplasms		null	2	arm 1: None arm 2: None	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: irinotecan 180 mg/m2 folinic acid 400 mg/m2 (DL) followed by 5 FU bolus 400 mg/m2 5 FU continuous infusion (2400 mg/m2 over 46 hours) every 2 weeks intervention 2: folinic acid 400 mg/m2(DL) followed by bolus 5 FU 400mg/m2 5 FU continuous infusion (2400 mg/m2 over 46 hours) every 2 weeks	intervention 1: Irinotecan + 5 FU + folinic acid intervention 2: Folinic Acid + 5 FU	66	Ghent \| N/A \| Belgium \| 3.71667 \| 51.05 Roeselare \| N/A \| Belgium \| 3.12269 \| 50.94653 Copenhagen \| N/A \| Denmark \| 12.56553 \| 55.67594 Herlev \| N/A \| Denmark \| 12.43998 \| 55.72366 Odense \| N/A \| Denmark \| 10.38831 \| 55.39594 Amiens \| N/A \| France \| 2.3 \| 49.9 Avignon \| N/A \| France \| 4.80892 \| 43.94834 Boulogne-Billancourt \| N/A \| France \| 2.24128 \| 48.83545 Clermont-Ferand Cedex 1 \| N/A \| France \| N/A \| N/A Colmar \| N/A \| France \| 7.35584 \| 48.08078 Grenoble \| N/A \| France \| 5.71479 \| 45.17869 Marseille \| N/A \| France \| 5.38107 \| 43.29695 Marseille \| N/A \| France \| 5.38107 \| 43.29695 Marseille \| N/A \| France \| 5.38107 \| 43.29695 Montpellier \| N/A \| France \| 3.87635 \| 43.61093 Montpellier \| N/A \| France \| 3.87635 \| 43.61093 Nice \| N/A \| France \| 7.26608 \| 43.70313 Nîmes \| N/A \| France \| 4.35788 \| 43.83665 Rennes \| N/A \| France \| -1.67429 \| 48.11198 Strasbourg \| N/A \| France \| 7.74553 \| 48.58392 Toulouse \| N/A \| France \| 1.44367 \| 43.60426 Cottbus \| N/A \| Germany \| 14.32888 \| 51.75769 Dessau \| N/A \| Germany \| 12.24555 \| 51.83864 Erlangen \| N/A \| Germany \| 11.00783 \| 49.59099 Hamburg \| N/A \| Germany \| 9.99302 \| 53.55073 Leipzig \| N/A \| Germany \| 12.37129 \| 51.33962 Magdeburg \| N/A \| Germany \| 11.62916 \| 52.12773 Magdeburg \| N/A \| Germany \| 11.62916 \| 52.12773 Mainz \| N/A \| Germany \| 8.2791 \| 49.98419 Oldenburg \| N/A \| Germany \| 8.21467 \| 53.14118 Regensburg \| N/A \| Germany \| 12.10161 \| 49.01513 Tübingen \| N/A \| Germany \| 9.05222 \| 48.52266 Hong Kong \| N/A \| Hong Kong \| 114.17469 \| 22.27832 Haifa \| N/A \| Israel \| 34.99928 \| 32.81303 Petah Tikva \| N/A \| Israel \| 34.88747 \| 32.08707 Rehovot \| N/A \| Israel \| 34.81199 \| 31.89421 Tel Aviv \| N/A \| Israel \| 34.78057 \| 32.08088 Tel Litwinsky \| N/A \| Israel \| 34.84588 \| 32.05096 Carpi \| Modena \| Italy \| 10.8777 \| 44.78237 Brescia \| N/A \| Italy \| 10.21472 \| 45.53558 Latisana, UD \| N/A \| Italy \| 13.00618 \| 45.76859 Padua \| N/A \| Italy \| 11.88586 \| 45.40797 Parma \| N/A \| Italy \| 10.32618 \| 44.79935 Piacenza \| N/A \| Italy \| 9.69342 \| 45.05242 Reggio Emilia \| N/A \| Italy \| 10.63125 \| 44.69825 Rozzano (Mi) \| N/A \| Italy \| 9.1559 \| 45.38193 Porto \| N/A \| Portugal \| -8.61099 \| 41.14961 Panorama \| Cape Town \| South Africa \| 31.89113 \| -28.75383 Daegu \| N/A \| South Korea \| 128.59111 \| 35.87028 Goyang \| N/A \| South Korea \| 127.19731 \| 36.21689 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Barcelona \| Barcelona \| Spain \| 2.15899 \| 41.38879 L'Hospitalet de Llobregat \| Barcelona \| Spain \| 2.10028 \| 41.35967 Santander \| Cantabria \| Spain \| -3.80444 \| 43.46472 Madrid \| Madrid \| Spain \| -3.70256 \| 40.4165 Seville \| Sevilla \| Spain \| -5.97317 \| 37.38283 Gothenburg \| N/A \| Sweden \| 11.96679 \| 57.70716 Bern \| N/A \| Switzerland \| 7.44744 \| 46.94809 Taoyuan District \| N/A \| Taiwan \| 121.3187 \| 24.9896 Donetsk \| Ukraine \| Ukraine \| 37.80224 \| 48.023 Kiev \| N/A \| Ukraine \| 30.5238 \| 50.45466 London \| N/A \| United Kingdom \| -0.12574 \| 51.50853 Southampton \| N/A \| United Kingdom \| -1.40428 \| 50.90395 Surrey \| N/A \| United Kingdom \| N/A \| N/A	306	0	0	0	NCT00143403	1COMPLETED	2009-09-01	2001-12-01	Pfizer	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 0 ]	24	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	true	The purpose of this study is to see if a medication called prazosin is useful in the treatment of agitation and aggression in persons with Alzheimer's disease (AD) and other types of dementia in late life.	Although the occurrence of disruptive agitation behaviors likely are influenced by environmental/ interpersonal factors, it is also likely that behaviorally relevant neurobiologic abnormalities lower the threshold for the expression of such behavior in Alzheimer's disease. Because of the success prazosin has had in the treatment of Posttraumatic Stress Disorder, it is thought that it could be used similarly with disruptive agitation. Originally designed to evaluate Alzheimer's disease patients in nursing homes, the study now includes outpatients. It is a 9-week placebo-controlled trial.	Alzheimer Disease Psychomotor Agitation	double-blind treatment prazosin	null	2	arm 1: None arm 2: None	[ 1, 2 ]	2	[ 0, 0 ]	intervention 1: Participants taking prazosin. Prazosin was administered as 1 or 2 mg capsules. Doses were initiated at 1 mg at bedtime. Titration based on tolerability was conducted up to a dose of 2 mg in the morning plus 4mg at bedtime. Duration was 8 weeks. intervention 2: Placebo is an inert substance used as a standard comparator in clinical pharmacologic trials. Duration is 8 weeks.	intervention 1: prazosin intervention 2: placebo (inert substance)	1	Seattle \| Washington \| United States \| -122.33207 \| 47.60621	24	0	0	0	NCT00161473	1COMPLETED	2009-09-01	2001-01-01	University of Washington	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 3 ]	29	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	0ALL	false	The purpose of this study is to find out if omalizumab is effective in treating non-allergic asthma. The US Food and Drug Administration has approved the use of omalizumab to treat moderate to severe allergic asthma.	Asthma is a chronic inflammatory disease of the lower airways. The inflammatory process is associated with changes in airway hyperresponsiveness (irritability), and airflow limitations caused by bronchoconstriction, edema, and mucous plugging. Mast cells, basophils, eosinophils, activated T-lymphocytes, macrophages, neutrophils, and airway epithelial cells all play a role in this inflammatory process by releasing mediators directly responsible for local inflammation and by releasing mediators that encourage a further influx of inflammatory cells (Expert Panel Report 2, 1997). These cells and their products eventually produce a state of chronic allergic inflammation leading to increased vascular leakage, mucous secretion, smooth muscle hyperresponsiveness, and nerve activation. Clinically, this process is characterized by intermittent shortness of breath, wheezing, coughing, and chest tightness. Although most asthmatics are atopic (allergic), non-atopic asthmatics exist and can develop equally severe disease. Non-allergic asthmatics have a trend towards higher than normal levels of the allergic antibody (IgE) though obviously they lack skin test specificity. When examining skin test reactivity and serum IgE as independent variables for asthma risk, there was a stronger association with serum IgE elevation than skin test reactivity. In fact, serum IgE tended to be high in asthmatics regardless of skin test reactivity. Omalizumab (Xolair®) is a recombinant humanized monoclonal antibody that binds specifically to the (FceRI) binding site on human IgE. The binding of omalizumab inhibits the ability of IgE to bind to basophils or mast cells. Omalizumab recently received FDA approval for the treatment of moderate to severe persistent allergic asthma in pediatric (12 years of age and above) and adult patients. The addition of omalizumab to standard asthma therapies has been found to reduce asthma exacerbations and decrease both inhaled corticosteroid dose and rescue medication use. (Busse, 2001). In a phase III double blinded placebo controlled trial involving 525 severe allergic asthmatics, omalizumab treated patients had fewer exacerbations during both a steroid stable phase and steroid reduction phase than did placebo controls (Busse, 2001). The median reduction in steroid dose during reduction phase was 75% and 50% in the omalizumab and placebo groups respectively. In a similarly designed steroid reduction study involving 6 to 12 year-old moderate to severe allergic asthmatics, steroid reduction was possible in 100% of treated patient verses 66.7% of placebo treated patients (Milgrom, 2001). Other steroid reduction studies have had similar results (Buhl 2002, Soler 2001). Omalizumab has also been shown to improve quality of life in allergic asthmatics as measured by the Asthma Quality of Life Questionnaire (AQLQ). In adults, AQLQ demonstrated greater improvement at 16, 28 and 52 weeks in omalizumab treated patients than in placebo treated (Finn 2003). Similarly in pediatric populations, AQLQ improvement reached statistical significance in omalizumab treated patients (Lemanske 2002). Omalizumab has shown itself to be a promising new therapy for the treatment of moderate to severe allergic asthma. It is currently not indicated for patients with non-allergic asthma. The objective of this study will be to define the effects of omalizumab on cell surface FceRI expression and serum IgE of non-allergic asthmatics.	Asthma	asthma	null	2	arm 1: water injection arm 2: Other Names: Xolair 150-375 milligrams administered by subcutaneous injection every 2-4 weeks depending on body weight and serum IgE.	[ 2, 0 ]	2	[ 0, 10 ]	intervention 1: 150-375 milligrams administered by subcutaneous injection every 2-4 weeks depending on body weight and serum IgE. intervention 2: 150-375 milligrams depending on body weight and serum IgE.	intervention 1: omalizumab intervention 2: Placebo	1	Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038	29	0	0	0	NCT00162773	6TERMINATED	2009-09-01	2005-04-01	Johns Hopkins University	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 5 ]	220	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	true	0ALL	true	This study will determine the effectiveness of combining escitalopram, venlafaxine, or duloxetine with donepezil, a medication used in Alzheimer's disease, in improving memory, concentration, attention, and problem solving abilities, and reducing the risk of depressive relapse in older individuals with depression.	The purpose of this research study is to learn if combining an antidepressant medication (escitalopram, venlafaxine, or duloxetine) with a medication used in Alzheimer's Disease (donepezil), in elderly patients age 65 and older with major depression, will help to 1) improve and/or maintain memory, concentration, attention, and problem solving abilities such as ability to balance a checkbook, pay bills, use the telephone, and 2) reduce the risk of depressive symptoms from returning. Study participation will last up to two years. We aim to investigate pharmacologic strategies for improving and stabilizing cognitive functioning in late-life depression and minimizing progression of cognitive and associated functional impairment. Cognitive impairment in late-life depression has not been adequately addressed in previous intervention research, is a core feature of the illness, contributes markedly to disability and impaired quality of life, and is an overlooked but potentially critical target of intervention. Data from the MTLD II study suggest that treating depression does not normalize cognitive functions and may not prevent their progression. We will test a pharmacologic strategy involving the cholinesterase inhibitor donepezil, in combination with maintenance antidepressant pharmacotherapy (escitalopram, venlafaxine, or duloxetine), to improve and to maintain cognitive functioning and functional competence in elderly patients with major depression. We hypothesize that maintenance antidepressant pharmacotherapy combined with donepezil will be superior to maintenance antidepressant pharmacotherapy combined with placebo/clinical management in (1) improving cognitive performance; and (2) slowing progression of cognitive impairment and decline in functional competence. We plan to recruit 200 patients aged 65 and above in current episodes of major depression. Those who respond to antidepressant pharmacotherapy with citalopram, venlafaxine, or duloxetine will then be randomly assigned on a double-blind basis to one of two 24-month treatments: 1)antidepressant pharmacotherapy plus donepezil/clinical management; or 2)antidepressant pharmacotherapy plus placebo/clinical management. For information on related studies, please follow these links: http://clinicaltrials.gov/show/NCT00000377 http://clinicaltrials.gov/show/NCT00178100	Depression Dementia	Depression Dementia Alzheimer's Disease Cognitive Donepezil Memory Function Elderly Late-Life	null	2	arm 1: escitalopram plus donepezil (DNP)in the experimental maintenance phase of the study. For subjects failing to respond to escitalopram during the initial open phase of acute treatment we allowed the use of duloxetine or venlafaxine to bring about remission and establish eligibility for randomized assignment to maintenance treatment with augmentation donepezil. Participants remained on the same antidepressant medication and dosage throughout the 2 year maintenance phase of the study. In the event of a recurrence of major depression during maintenance treatment, dosages of antidepressant medication were raised, or the antidepressant was switched to venlafaxine or duloxetine. For subjects failing to respond to escitalopram during the initial open phase of acute treatment, we allowed the use of duloxetine to bring about remission and establish eligibility for randomized assignment to maintenance treatment with augmentation placebo. arm 2: escitalopram plus placebo (PBO) in the experimental maintenance phase of the study. For subjects failing to respond to escitalopram during the initial open phase of acute treatment, we allowed the use of duloxetine or venlafaxine to bring about remission and establish eligibility for randomized assignment to maintenance treatment with augmentation placebo. Participants remained on the same antidepressant medication and dosage throughout the 2 year maintenance phase of the study. In the event of a recurrence of major depression during maintenance treatment, dosages of antidepressant medication were raised, or the antidepressant was switched to venlafaxine or duloxetine. For subjects failing to respond to escitalopram during the initial open phase of acute treatment, we allowed the use of venlafaxine or duloxetine to bring about remission and establish eligibility for randomized assignment to maintenance treatment with augmentation placebo.	[ 0, 2 ]	5	[ 0, 0, 0, 0, 0 ]	intervention 1: Escitalopram, 10mg to 20mg daily. intervention 2: Donepezil, 5mg to 10mg daily. intervention 3: Venlafaxine, 150mg to 300mg daily. intervention 4: None intervention 5: None	intervention 1: Escitalopram intervention 2: Donepezil intervention 3: Venlafaxine intervention 4: Placebo intervention 5: Duloxetine	1	Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062	130	0	0	0	NCT00177671	1COMPLETED	2009-09-01	2003-12-01	University of Pittsburgh	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 5 ]	268	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	true	This study will assess the effectiveness of venlafaxine XR, randomized to either venlafaxine XR or placebo in preventing the relapse of generalized anxiety disorder after 6 months of treatment versus 12 months of treatment.	Generalized anxiety disorder (GAD) is a highly prevalent, chronic psychiatric disorder. Despite the fact that GAD frequently demands prolonged treatment with medication, very little is known about the benefits of long-term treatment. GAD is characterized by 6 months or more of exaggerated worry and tension that is unfounded or much more severe than the normal anxiety most people experience. People with GAD are unable to relax and often suffer from insomnia. Venlafaxine XR, a drug used to treat depression, has been shown to be effective in the short-term treatment of GAD. However, its benefits over a course of more than 8 weeks have not been assessed. This study will evaluate the effectiveness of venlafaxine XR in treating GAD on a long-term basis and preventing the relapse of GAD after 6 months of treatment versus 12 months of treatment. Participants in this double-blind study will first receive 6 months of open-label treatment with venlafaxine XR. Upon completion of this initial phase, participants will be randomly assigned to either continue on venlafaxine XR or begin taking placebo. After 12 months, participants taking venlafaxine XR will be randomly assigned to continue on the drug or switch to placebo. Participants will have 22 study visits over at least 18 months. Follow-up visits will occur 24 months after enrollment. Relapse of GAD will be assessed with the Hamilton Anxiety Scale and Global Severity and Improvement Scale. A variety of methods, including questionnaires and standardized scales, will be used to assess secondary outcomes.	Anxiety Disorders	Generalized Anxiety Disorder Chronic Mediation Treatment Double-Blind Placebo Controlled Venlafaxine XR Relapse	null	6	arm 1: 6-month randomized phase of Venlafaxine XR at a flexible dose of 75 - 225 mg/d arm 2: 6-month randomized, double-blind phase of Venlafaxine XR at a flexible dose of 75 - 225 mg/d occurring between months 6 - 12 of the study arm 3: 6-month randomized, double blind phase of placebo occurring between months 6 - 12 of the study arm 4: 6-month randomized, double blind phase of Venlafaxine XR at a flexible dose of 75 - 225 mg/d occurring between months 13 - 19 of the study arm 5: 6-month randomized, double blind phase of placebo occurring between months 13 - 19 of the study arm 6: 6-month randomized, double blind phase of placebo occurring between months 13 - 19 of the study	[ 1, 1, 2, 1, 2, 2 ]	2	[ 0, 0 ]	intervention 1: Six month intervention of Venlafaxine XR treatment with flexible range of 75 to 225 mg/d intervention 2: six month intervention with placebo drug	intervention 1: Venlafaxine XR intervention 2: Placebo	1	Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238	268	0	0	0	NCT00183274	1COMPLETED	2009-09-01	2004-01-01	University of Pennsylvania	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 4 ]	64	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	true	Data have suggested that consensus interferon (CIFN) has greater antiviral activity in vitro compared with interferon alfa-2a or alfa-2b. Several clinical studies also suggest that CIFN has greater antiviral activity in patients with genotype 1 hepatitis C infection, particularly if given as a daily injection. These data indicate that the use of a regimen of daily CIFN and ribavirin will lead to greater virologic response rates compared with pegylated interferon alfa-2b and ribavirin in patients with genotype 1 infection, with comparable adverse events. Emerging data indicate that HCV genotype 1 patients with a delayed virologic response to initial therapy may benefit from an extended duration of therapy. Therefore, the goals of this pilot study are to determine the tolerability and efficacy of daily CIFN plus ribavirin when given for 52 weeks or an extended duration of therapy. The target population will consist of "difficult-to-treat" patients, defined as having the following characteristics: genotype 1, a North American patient population, predominantly male gender, and no specific exclusions for pre-existing psychiatric or substance abuse co-morbidities.	Current treatment for hepatitis C is a pegylated interferon alfa plus ribavirin. This treatment is inadequate for patients with HCV genotype 1, since the majority of patients do not respond (termed non-responders) or respond but relapse (termed relapsers) following termination of these treatments. Data from the Veterans Health Administration (VHA) Hepatitis C Registry and community hospitals indicate that the large majority of patients identified with hepatitis C have characteristics associated with a poor treatment response and remain untreated at this time. Data have suggested that consensus interferon (CIFN, CIFN or interferon alfacon-1) has greater antiviral activity in vitro compared with interferon alfa-2a or alfa-2b. Preliminary data indicate that more patients with genotype 1 can respond to CIFN and ribavirin than current standard treatments, due to the fact that approximately 25% of patients who are nonresponders to pegylated interferon and ribavirin may have a sustained response to a regimen of daily CIFN and ribavirin. Furthermore, difficult to treat patients may benefit from a longer duration of therapy than the standard 48 week regimen based on when an initial virologic response to therapy occurs. Aims: To determine the safety and efficacy of (A) daily CIFN (15 mcg/d sq) and ribavirin (1-1.2 gm/d PO) given for 52 weeks, vs (B) daily CIFN (15 mcg/d sq) and ribavirin (1-1.2 gm/d PO) given for 52 to 72 weeks for treatment-naïve patients with hepatitis C genotype 1, with treatment duration based on the virologic response during the initial 24 weeks. Methods: Patients who meet eligibility criteria will be stratified by race and randomized to one of two treatment arms, and all patients will have viral kinetics measured by quantitative PCR at weeks 4,8,12,16,20 and 24. Patients in treatment arm A will follow "standard" stopping rules, i.e., if there is not a 2-log drop in viremia by 12 weeks the treatment will be discontinued, otherwise they will all receive 52 weeks of treatment if they also are qualitative PCR negative by week 24. In treatment arm B the patients will be monitored monthly until they have a virologic response (defined as \>2 log drop in viral levels from baseline) by quantitative PCR for up to 24 weeks. Once they have a virologic response by quantitative PCR their treatment will be continued for an additional 48 weeks. In both groups, treatment will be stopped if the patients do not become negative for HCV RNA by qualitative PCR by 24 weeks on therapy. A total of 192 patients at up to 10-20 sites will be recruited. The primary endpoint would be the number who achieve a sustained virologic response; secondary endpoints are the percentage of patients who complete therapy, have significant adverse events, and the relationship of early virologic response at each 4 week period between 4 and 24 weeks and those who achieve a sustained virologic response. Sample size determination: To detect an absolute difference of 20% or more in sustained virologic response between treatment arms A and B; the Log-rank test is performed at the alpha level of .05 and the test is maintained at least 80 percent statistical power; it is estimated that a total of 96 patients in each treatment arm will be required. Analysis: Univariate and multivariate analysis will be used to determine factors associated with final endpoints. Subgroup analyses will be done based on time to early virologic response and duration of therapy each stratification. The primary and secondary endpoints will be determined on an intention-to-treat basis starting with all patients that receive at least one dose of study medications. The primary and secondary endpoints will also be determined in a per-protocol analysis on those patients who take 80% of the prescribed CIFN and 80% of the prescribed ribavirin for 80% of the time. Significance: The current initial treatment of pegylated interferon alfa and ribavirin for patients with hepatitis C who are genotype 1 and have other "difficult-to-treat" characteristics is inadequate. The results of this trial are needed to demonstrate the safety and efficacy of two regimens of daily CIFN and ribavirin. Since the large majority of hepatitis C patients in VA and other community hospitals fall into this category, the results of this trial may influence the potential treatments recommended for these patients.	Chronic Hepatitis C	Hepatitis C interferon alfa ribavirin interferon alfacon-1 antiviral therapy	null	2	arm 1: Daily CIFN (15 mcg/day SQ) and RBV (1-1.2 g/d PO) given 52 weeks (group A) arm 2: CIFN (15 mcg/day SQ) and RBV (1-1.2 g/d PO) given for 52-72 weeks (from time of viral response +48 weeks) (group B)	[ 1, 0 ]	2	[ 0, 0 ]	intervention 1: CIFN (15 mcg/day SQ) and RBV (1-1.2 g/d PO) given for either 52 weeks (group A, n = 33) or 52-72 weeks (from time of viral response +48 weeks) (group B) intervention 2: CIFN (15 mcg/day SQ) and RBV (1-1.2 g/d PO) given for either 52 weeks (group A, n = 33) or 52-72 weeks (from time of viral response +48 weeks) (group B)	intervention 1: consensus interferon (Interferon Alfacon-1) and ribavirin intervention 2: Consensus Interferon alfa (CIFN) and ribavirin	0	null	64	0	0	0	NCT00211692	1COMPLETED	2009-09-01	2005-07-01	Minneapolis Veterans Affairs Medical Center	1FED	false	false	false	null	0	0	0	0	0	0
[ 3 ]	18	NON_RANDOMIZED	SINGLE_GROUP	null	0NONE	false	0ALL	true	The purpose of this study is to examine the effect of imatinib on dermatofibrosarcoma protuberan tumors.	null	Dermatofibrosarcoma Protuberans	newly diagnosed or recurrent	null	1	arm 1: None	[ 5 ]	1	[ 0 ]	intervention 1: 400 mg orally twice a day for 10 - 14 days	intervention 1: imatinib mesylate	4	Tampa \| Florida \| United States \| -82.45843 \| 27.94752 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Houston \| Texas \| United States \| -95.36327 \| 29.76328	18	0	0	0	NCT00243191	1COMPLETED	2009-09-01	2006-05-01	Sarcoma Alliance for Research through Collaboration	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 3 ]	112	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	true	The purpose of this study is to determine which of 3 different doses of tenecteplase (TNK) is better for treating stroke patients and if TNK offers an advantage over currently available treatment with tissue plasminogen activator (tPA).	Stroke is the third leading cause of death and a leading cause of adult disability in the United States and worldwide. To date, the only scientifically-proven and FDA-approved treatment for acute stroke is the clot-busting drug, tissue plasminogen activator (tPA). A newer clot-busting drug, tenecteplase (TNK), has chemical properties that make it a potentially safer and more effective drug for treating stroke. Preliminary testing of TNK in patients with acute stroke has been encouraging enough to warrant further testing. This study, TNK-S2B, will compare three different doses of TNK with standard tPA treatment in patients with acute stroke. Patients will be chosen randomly to receive either TNK or tPA. Neither the patient nor his/her doctor will know which medication the patient received until the study is completely finished. The first part of the study will look at results of treatment in the first 24 hours to select the best dose of TNK to carry forward into a more detailed comparison with standard tPA treatment. After at least 100-150 pairs of the best dose of TNK and tPA patients have been enrolled, entry into the study will pause, and the outcomes at 3 months after stroke will be compared to see if the results of TNK treatment are sufficiently promising as an improvement over standard treatment to justify expanding the study to find a definitive answer. The study, which will be conducted in at least 8 large medical centers, is expected to last about 3 years.	Stroke	stroke tenecteplase TNK ischemic tissue plasminogen activator tPA	null	2	arm 1: tenecteplase arm 2: tissue plasminogen activator, tPA	[ 1, 1 ]	2	[ 0, 0 ]	intervention 1: This study will compare 3 different doses of tenecteplase to tPA. intervention 2: To date, tissue plasminogen activator (tPA) is the only scientifically-proven and FDA-approved treatment for acute stroke.	intervention 1: tenecteplase intervention 2: tissue plasminogen activator, tPA	9	San Diego \| California \| United States \| -117.16472 \| 32.71571 Englewood \| Colorado \| United States \| -104.98776 \| 39.64777 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 New Hyde Park \| New York \| United States \| -73.68791 \| 40.7351 New York \| New York \| United States \| -74.00597 \| 40.71427 New York \| New York \| United States \| -74.00597 \| 40.71427 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Charlottesville \| Virginia \| United States \| -78.47668 \| 38.02931	112	0	0	0	NCT00252239	6TERMINATED	2009-09-01	2005-11-01	University of Virginia	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 3 ]	48	RANDOMIZED	PARALLEL	0TREATMENT	1SINGLE	false	1FEMALE	false	The purpose of this study is to determine the effects of Plavix and aspirin in women with metastatic breast cancer.	null	Breast Neoplasms	Breast Cancer Metastatic Platelet	null	2	arm 1: Patients will receive a 300 mg loading dose of Plavix on day 1, followed by 75 mg/day, and aspirin 81 mg per day starting day 1. Treatment will be continued until the treating physician elects to resume systemic therapy for the treatment of breast cancer or until unacceptable toxicity is observed. A pill diary will be collected monthly to monitor patients' compliance with the medication regimen. arm 2: Observation by treating physician	[ 0, 4 ]	2	[ 0, 0 ]	intervention 1: None intervention 2: None	intervention 1: Plavix intervention 2: Aspirin	1	St Louis \| Missouri \| United States \| -90.19789 \| 38.62727	48	0	0	0	NCT00263211	6TERMINATED	2009-09-01	2006-01-01	Washington University School of Medicine	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 3, 4 ]	26	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	false	The purpose of this study is to explore the potential benefit of the medication, pentoxifylline, for the treatment of NASH.	This is an investigational study looking at subjects who have been diagnosed with nonalcoholic steatohepatitis (NASH) or 'fatty liver disease'. There is currently no FDA approved available treatment for NASH. The purpose of this study is to explore the potential benefit of the medication, pentoxifylline, for the treatment of NASH. The effectiveness of this drug will be determined by taking blood samples and a liver biopsy. To determine if there is any effect of the medication, two-thirds of the patients participating in the study will receive pentoxifylline and one-third will receive placebo (sugar pill). Thus, an individual's chance of receiving the drug is 67%. In addition to receiving a study drug (placebo or pentoxifylline) the subjects will be encouraged to achieve modest weight loss (\~1-2 lbs/week) via low-fat diet and exercise. The drug (Pentoxifylline) being studied is not approved for use in people who have NASH. Pentoxifylline is considered experimental in this study. Pentoxifylline has been safely used for the treatment of other medical conditions such as alcohol related liver disease and poor circulation. Pentoxifylline is a pill which is taken three times a day.	Nonalcoholic Steatohepatitis Liver Diseases	Fatty Liver Disease Liver NASH Nonalcoholic Steatohepatitis Nonalcoholic Fatty Liver Disease (NAFLD) Pentoxifylline	null	2	arm 1: 400mg PO TID arm 2: 1 pill PO TID	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: 400mg PO TID intervention 2: 1 pill PO TID	intervention 1: Pentoxifylline intervention 2: Placebo	1	Chicago \| Illinois \| United States \| -87.65005 \| 41.85003	26	0	0	0	NCT00267670	1COMPLETED	2009-09-01	2005-03-01	Northwestern University	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 4 ]	64	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	null	The purpose of this study is to evaluate the efficacy and safety of zonisamide for anti-epilepsy drugs (AEDs) treated subjects with refractory simple partial, complex partial or partial with secondary generalized seizures.	null	Epilepsy	Epilepsy seizures	null	2	arm 1: tablet arm 2: tablet	[ 1, 1 ]	2	[ 0, 0 ]	intervention 1: Tablet once or twice daily orally for 16 weeks intervention 2: Tablet once daily orally for 16 weeks	intervention 1: Zonisamide intervention 2: Lamotrigine	8	Changhua \| Taiwan \| China \| 118.61765 \| 29.90718 Kaohsiung \| Taiwan \| China \| N/A \| N/A Linkou \| Taiwan \| China \| 130.27332 \| 45.2762 Taichun \| Taiwan \| China \| N/A \| N/A Tainan \| Taiwan \| China \| 120.26944 \| 32.76205 Taipei \| Taiwan \| China \| N/A \| N/A Taipei \| Taiwan \| China \| N/A \| N/A Taipei \| Taiwan \| China \| N/A \| N/A	64	0	0	0	NCT00292461	1COMPLETED	2009-09-01	2006-03-01	Eisai Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 2, 3 ]	70	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	This is a phase 1/2 open-label, dose-escalation study investigating single-agent therapy with VELCADE in patients with previously treated systemic AL-amyloidosis who require further treatment.	null	Amyloidosis		null	1	arm 1: VELCADE	[ 0 ]	1	[ 0 ]	intervention 1: Once weekly at: 0.7, 1.0, 1.3 or 1.6 mg/m2 Or Twice-weekly at: 0.7, 1.0, or 1.3 mg/m2	intervention 1: VELCADE	4	Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 New York \| New York \| United States \| -74.00597 \| 40.71427	70	0	0	0	NCT00298766	1COMPLETED	2009-09-01	2005-06-01	Millennium Pharmaceuticals, Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3 ]	54	RANDOMIZED	CROSSOVER	0TREATMENT	2DOUBLE	false	0ALL	true	Lay Language Summary: High cholesterol levels are common in persons with HIV infection. However, conventional cholesterol-lowering medications may have harmful side effects when given to HIV-infected persons. Therefore, we plan to evaluate the safety and effectiveness of policosanol, a dietary supplement derived from sugar cane that has cholesterol-lowering properties, to lower cholesterol levels in persons with HIV infection. We hypothesize that policosanol will lower levels of LDL cholesterol ("bad" cholesterol) and raise levels of HDL cholesterol ("good" cholesterol).	As per Brief Summary	Dyslipidemia HIV Infections	HIV lipids dyslipidemia policosanol treatment experienced	null	2	arm 1: 20 mg daily of policosanol arm 2: 20 mg of microcrystalline cellulose daily	[ 0, 2 ]	2	[ 0, 7 ]	intervention 1: 20 mg of policosanol in capsular form daily intervention 2: Two capsules of 10 mg of microcrystalline cellulose daily	intervention 1: Policosanol intervention 2: Placebo	1	Chicago \| Illinois \| United States \| -87.65005 \| 41.85003	0	0	0	0	NCT00312923	1COMPLETED	2009-09-01	2005-09-01	Rush University Medical Center	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 4 ]	374	RANDOMIZED	PARALLEL	1PREVENTION	3TRIPLE	true	0ALL	true	The purpose of this study is to see whether giving acetaminophen (the medicine in Tylenol) for routine infant vaccinations is helpful in preventing fever or other symptoms.	Post-vaccination fever occurs in up to 40% of infants receiving routinely recommended childhood vaccinations. Although serious events are rare, post-vaccination fever causes discomfort for the child, can lead to medical utilization, can rarely result in febrile seizure, and can cause a working parent to miss time from their job to care for a febrile infant who cannot attend day care. The benefits of acetaminophen prophylaxis for infants receiving current vaccinations, in terms of reduction of discomfort for the child, improvement of quality-of-life indicators for the parent, or reduction of medical utilization, have not been measured. This randomized, blinded, placebo-controlled trial will assess the efficacy of prophylaxis with acetaminophen in prevention of fever following routine childhood immunizations.	Fever	Acetaminophen Vaccination Immunization	null	2	arm 1: Children were randomized 1:1 to receive up to five doses of acetaminophen (10-15mg per kg) or placebo following routine vaccinations. arm 2: Children were randomized 1:1 to receive up to five doses of acetaminophen (10-15mg per kg) or placebo following routine vaccinations.	[ 1, 2 ]	2	[ 0, 10 ]	intervention 1: Children were randomized 1:1 to receive up to five doses of acetaminophen (10-15mg per kg) or placebo following routine vaccinations. intervention 2: Children were randomized 1:1 to receive up to five doses of acetaminophen (10-15mg per kg) or placebo following routine vaccinations.	intervention 1: Acetaminophen intervention 2: placebo	1	Seattle \| Washington \| United States \| -122.33207 \| 47.60621	352	0	0	0	NCT00325819	1COMPLETED	2009-09-01	2006-05-01	Kaiser Permanente	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 0 ]	3	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	To explore the hypothesis that the use of Lopinavir/ritonavir will be associated with improved CD4 immune reconstitution in volunteers who fail to demonstrate a significant CD4 cell increase (while on their first antiretroviral treatment regimen) despite sustained viral suppression by a non-Lopinavir/ritonavir-containing regimen	This is an open-labeled, non-randomized exploratory trial in selected volunteers who meet the stated enrollment criteria. This study will assess the impact of Lopinavir/ritonavir on CD4 immune reconstitution. All volunteers must have been on antiretroviral therapy with sustained viral load suppression of \< 400 copies/mL for at least 24 months (or, HIV-1 RNA \< 400 copies/mL for 12 months, during which HIV-1 RNA was \< 50 copies/mL for 6 months prior to screen). Despite induction of viral suppression, all volunteers must have demonstrated limited post-antiretroviral CD4 increase. Lopinavir/ritonavir will be substituted for one of the 3 ARV drugs in the current (baseline) antiretroviral treatment regimen. Lopinavir/ritonavir will be substituted for any of the following: 3rd NRTI, an NNRTI, a PI or a boosted PI, while the nucleoside backbone will remain the same. If the subject is currently on a three-drug nucleoside/nucleotide plus a 4th anchor drug such as a NRTI, NNRTI, PI or boosted PI regimen, the triple nucleoside will remain constant and only the anchor drug is to be substituted with Lopinavir/ritonavir. Patients on 2 NRTIs with an NNRTI and a PI combination will not be allowed in the study. Patients will be evaluated frequently, to include physical examination, assessment for the development of AIDS-defining conditions, hematology, chemistry, lipid profile, CD4 CD8 cell counts, plasma HIV-1 RNA ultrasensitive, and assessment of adverse events. If HIV-1 RNA becomes detectable, this will be repeated for confirmation with 2 weeks. HIV genotyping and phenotyping will be performed on patients who demonstrate repetitive plasma viral load levels of \> 1,000 copies/mL. An assessment of memory and naïve T cell response to antiretroviral regimen change will be performed in this study. Dose and dose selection Lopinavir/ritonavir is also approved for once a day dosing. The dose of lopinavir/ritonavir (Kaletra) for this study will be 400/100mg. BID or 800/200mg. qd. New tablet formulation no longer requires that lopinavir/ritonavir be taken with food. We will give the volunteer the option for once a day dosing or BID dosing of Kaletra. However, those switching from an NNRTI to Kaletra will initially be placed on BID dosing of Kaletra, and allowed to switch to once-a-day dosing of Kaletra after 4 weeks on study drug.	HIV		null	1	arm 1: lopinavir/ritonavir (Kaletra)400/100mg tablets by mouth twice a day for 48 weeks.	[ 0 ]	1	[ 0 ]	intervention 1: Dosing of Kaletra will be per package insert and BID with food. A three-drug standard of care antiretroviral regimen will be used in this study. Subjects will enter the study already on an effective, virally-suppressive treatment regimen. One of these drugs will be substituted for Lopinavir/ritonavir (Kaletra®). However, the nucleoside/nucleotide backbone drugs that the subject is already on will remain the same.	intervention 1: Lopinavir/Ritonavir	1	Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038	3	0	0	0	NCT00344487	6TERMINATED	2009-09-01	2005-12-01	University of Maryland, Baltimore	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 5 ]	155	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	This 36-month open-label study of adefovir dipivoxil investigates the clinical benefits of the therapy in chronic hepatitis B patients with advanced fibrosis or cirrhosis confirmed with biopsy. Primary endpoint is histological improvement defined as a decrease of Ishak Fibrosis Score by one point or more from baseline at Month 36 of adefovir dipivoxil treatment. Approximately 150 patients will be recruited in study centres in the Asia Pacific area. The patients are offered 36 months of open label adefovir dipivoxil treatment, with assessments every three months, after which there is a 6-month post study treatment follow-up prior to study completion. After the 36 months of study treatment, it is likely that the patient will benefit from continued treatment with adefovir dipivoxil. If this is the case in the investigators clinical judgement, the investigator should ensure that a routine prescription is available in a timely manner, and that no unnecessary interruption in treatment occurs.	null	Hepatitis B, Chronic Cirrhosis Fibrosis Chronic Hepatitis B	Cirrhosis Advanced Fibrosis Chronic Hepatitis B Adefovir Dipivoxil	null	1	arm 1: 10mg once daily in patients with CHB related advanced fibrosis/cirrhosis.	[ 5 ]	1	[ 0 ]	intervention 1: 10mg once daily	intervention 1: adefovir dipivoxil	12	Pokfulam \| N/A \| Hong Kong \| N/A \| N/A Singapore \| N/A \| Singapore \| 103.85007 \| 1.28967 Daegu \| N/A \| South Korea \| 128.59111 \| 35.87028 Pusan \| N/A \| South Korea \| 128.3681 \| 36.3809 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Sungnam-City \| N/A \| South Korea \| N/A \| N/A Kaohsiung City \| N/A \| Taiwan \| 120.31333 \| 22.61626 Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306 Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306 Ho Chi Minh City \| N/A \| Vietnam \| 106.62965 \| 10.82302	155	0	0	0	NCT00347009	1COMPLETED	2009-09-01	2005-05-01	GlaxoSmithKline	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 4 ]	643	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	true	The purpose of this study is to assess the clinical effectiveness and safety of golimumab intravenous (IV) infusions every 12 weeks with or without Methotrexate (MTX), compared with MTX alone, in patients with active rheumatoid arthritis (RA) despite concurrent MTX treatment. In addition, the safety of subcutaneous (SC) golimumab injections following transition from IV golimumab infusions will also be evaluated.	This is a Phase III, double blind (neither investigator nor participant knows the treatment received), placebo-controlled (an inactive substance that is compared with the study medication to test whether the study medication has a real effect in clinical study), multicenter, 5-arm (treatment groups) study of golimumab at 2 doses (given with or without MTX over a period of 30 minutes) for at least 48 weeks in patients with active RA despite concurrent MTX therapy. The study consists of a treatment period of golimumab IV infusions (IV Period) which ranges from 48 weeks to approximately 140 weeks, assuming an enrollment period of approximately 92 weeks, and a long-term optional extension period (Extension Study) in which golimumab SC injections will be given for 24 weeks. The end of study will be the time the last participant completes the Week E-40 visit (Extension Study) for safety follow-up assessments. For the IV Period, participants will be randomly assigned to 1 of the 5 treatment groups in a 1:1:1:1:1 ratio (approximately 125 patients per group). At Week 16 and Week 24, joint assessment results will be used to allow participants to enter early escape and dose regimen adjustment, respectively, in a blinded fashion. Treatment will be unblinded after the 48-week database lock and participants will be given the option to participate in the Extension Study and receive SC injections of 50mg golimumab (with or without MTX) every 4 weeks for an additional 24 weeks. Safety will be monitored throughout the study. The entire study duration (IV Period plus Extension Study) for each participant will range from 88 weeks up to 192 weeks, assuming an enrollment period of approximately 92 weeks.	Rheumatoid Arthritis	Rheumatoid arthritis Golimumab Methotrexate Tumor Necrosis Factor-alpha Immunology	null	5	arm 1: Intravenous (IV) infusions of 2mg/kg golimumab at Week 0 and every 12 weeks thereafter with early escape (an additional 2mg/kg IV infusion of golimumab) and dose regimen adjustment (switch to 4mg/kg IV golimumab), depending on joint assessment results, at Week 16 and 24, respectively. The duration of the combined IV treatment period (initial treatment plus early escape and/or dose regimen adjustment) will be a minimum of 48 weeks. The IV treatment period will be followed by the option of subcutaneous (SC) injections of 50mg golimumab every 4 weeks for a further 24 weeks (Extension Study). In addition, patients will receive methotrexate (MTX) at the same dose as that before study entry arm 2: IV infusions of 2mg/kg golimumab at Week 0 and every 12 weeks thereafter with early escape (addition of MTX) and dose regimen adjustment (addition of MTX or switch to 4mg/kg IV golimumab), depending on joint assessment results, at Week 16 and 24, respectively. The duration of the combined IV treatment period (initial treatment plus early escape and/or dose regimen adjustment) will be a minimum of 48 weeks. The IV treatment period will be followed by the option of SC injections of 50mg golimumab every 4 weeks for a further 24 weeks (Extension Study). In addition, patients will receive placebo (sham MTX) capsules arm 3: IV infusions of 4mg/kg golimumab at Week 0 and every 12 weeks thereafter for a minimum of 48 weeks followed by the option of SC injections of 50mg golimumab every 4 weeks for a further 24 weeks (Extension Study). In addition, patients will receive MTX at the same dose as that before study entry. arm 4: IV infusions of 4mg/kg golimumab at Week 0 and every 12 weeks thereafter with early escape (addition of MTX) and dose regimen adjustment (addition of MTX), depending on joint assessment results, at Week 16 and 24, respectively. The duration of the combined IV treatment period (initial treatment plus early escape and/or dose regimen adjustment) will be a minimum of 48 weeks. The IV treatment period will be followed by the option of SC injections of 50mg golimumab every 4 weeks for a further 24 weeks (Extension Study). In addition, patients will receive placebo (sham MTX) capsules. arm 5: IV infusions of placebo at Week 0 and Week 12 with early escape (switch to 4mg/kg IV golimumab) and dose regimen adjustment (switch to 4mg/kg IV golimumab), depending on joint assessment results, at Week 16 and 24, respectively. The duration of the combined IV treatment period (placebo plus golimumab) will be a minimum of 48 weeks. The IV treatment period will be followed by the option of SC injections of 50mg golimumab every 4 weeks for a further 24 weeks (Extension Study). In addition patients will receive MTX at the same dose as that before study entry. Participants still receiving placebo injections at Week 48 are not eligible to enter the Extension Study.	[ 0, 0, 0, 0, 2 ]	3	[ 0, 0, 0 ]	intervention 1: 2mg/kg or 4mg/kg will be administered as an IV infusion over 30 minutes intervention 2: Active MTX capsules, filled with microcrystalline cellulose (Avicel PH 102) and a 2.5 mg MTX tablet, will be administered at the same dose as before the study entry. intervention 3: Placebo solution will be administered through IV infusion in Group V and oral placebo capsules (sham MTX) filled with microcrystalline cellulose (Avicel PH 102) will be administered in Group II and IV.	intervention 1: Golimumab intervention 2: Methotrexate intervention 3: Placebo	72	Peoria \| Arizona \| United States \| -112.23738 \| 33.5806 Aventura \| Florida \| United States \| -80.13921 \| 25.95648 Orlando \| Florida \| United States \| -81.37924 \| 28.53834 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Lincoln \| Nebraska \| United States \| -96.66696 \| 40.8 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 Voorhees Township \| New Jersey \| United States \| -74.49062 \| 40.4795 Albany \| New York \| United States \| -73.75623 \| 42.65258 Roslyn \| New York \| United States \| -73.65096 \| 40.79982 Charlotte \| North Carolina \| United States \| -80.84313 \| 35.22709 Oklahoma City \| Oklahoma \| United States \| -97.51643 \| 35.46756 Duncansville \| Pennsylvania \| United States \| -78.4339 \| 40.42341 Norristown \| Pennsylvania \| United States \| -75.3399 \| 40.1215 West Reading \| Pennsylvania \| United States \| -75.94743 \| 40.3337 Willow Grove \| Pennsylvania \| United States \| -75.11573 \| 40.144 Amarillo \| Texas \| United States \| -101.8313 \| 35.222 Fort Worth \| Texas \| United States \| -97.32085 \| 32.72541 Lubbock \| Texas \| United States \| -101.85517 \| 33.57786 Spokane \| Washington \| United States \| -117.42908 \| 47.65966 Buenos Aires \| N/A \| Argentina \| -58.37723 \| -34.61315 Córdoba \| N/A \| Argentina \| -64.18853 \| -31.40648 Rosario \| N/A \| Argentina \| -60.63932 \| -32.94682 San Juan \| N/A \| Argentina \| -68.52568 \| -31.53726 San Miguel de Tucumán \| N/A \| Argentina \| -65.21051 \| -26.81601 Santa Fe \| N/A \| Argentina \| -60.70868 \| -31.64881 Fitzroy \| N/A \| Australia \| 144.97833 \| -37.79839 Heidelberg \| N/A \| Australia \| 145.06667 \| -37.75 Maroochydore \| N/A \| Australia \| 153.09953 \| -26.66008 Melbourne \| N/A \| Australia \| 144.96332 \| -37.814 Perth \| N/A \| Australia \| 115.8614 \| -31.95224 Woodville \| N/A \| Australia \| 138.54291 \| -34.877 Barranquilla \| N/A \| Colombia \| -74.78132 \| 10.96854 Bogotá \| N/A \| Colombia \| -74.08175 \| 4.60971 Bucaramanga \| N/A \| Colombia \| -73.11895 \| 7.125 Floridablanca \| N/A \| Colombia \| -73.08644 \| 7.06222 Erlangen \| N/A \| Germany \| 11.00783 \| 49.59099 Hamburg \| N/A \| Germany \| 9.99302 \| 53.55073 Magdeburg \| N/A \| Germany \| 11.62916 \| 52.12773 München \| N/A \| Germany \| 13.31243 \| 51.60698 Budapest \| N/A \| Hungary \| 19.04045 \| 47.49835 Szolnok \| N/A \| Hungary \| 20.2 \| 47.18333 Daugavpils \| N/A \| Latvia \| 26.53333 \| 55.88333 Riga \| N/A \| Latvia \| 24.10589 \| 56.946 Kaunas \| N/A \| Lithuania \| 23.90961 \| 54.90272 Klaipėda \| N/A \| Lithuania \| 21.13912 \| 55.7068 Šiauliai \| N/A \| Lithuania \| 23.31667 \| 55.93333 Vilnius \| N/A \| Lithuania \| 25.2798 \| 54.68916 Ipoh \| N/A \| Malaysia \| 101.0829 \| 4.5841 Kuching \| N/A \| Malaysia \| 110.33333 \| 1.55 Precinct 7 \| N/A \| Malaysia \| N/A \| N/A Selangor Darul Ehasan \| N/A \| Malaysia \| N/A \| N/A Msd06 Gwardiamangia \| N/A \| Malta \| N/A \| N/A Colonia del Valle \| N/A \| Mexico \| -99.16204 \| 19.38611 Guadalajara \| N/A \| Mexico \| -103.34749 \| 20.67738 Guadalajara Jalisco \| N/A \| Mexico \| N/A \| N/A Monterrey \| N/A \| Mexico \| -100.31721 \| 25.68435 Christchurch \| N/A \| New Zealand \| 172.63333 \| -43.53333 Dunedin \| N/A \| New Zealand \| 170.50361 \| -45.87416 Rotorua \| N/A \| New Zealand \| 176.24516 \| -38.13874 Takapuna Auckland \| N/A \| New Zealand \| N/A \| N/A Timaru \| N/A \| New Zealand \| 171.25364 \| -44.39672 Lima \| N/A \| Peru \| -77.02824 \| -12.04318 Bialystok \| N/A \| Poland \| 23.16433 \| 53.13333 Elblag \| N/A \| Poland \| 19.40884 \| 54.1522 Krakow \| N/A \| Poland \| 19.93658 \| 50.06143 Warsaw \| N/A \| Poland \| 21.01178 \| 52.22977 Włoszczowa \| N/A \| Poland \| 19.96593 \| 50.85256 Kiev \| N/A \| Ukraine \| 30.5238 \| 50.45466 Kyiv \| N/A \| Ukraine \| 30.5238 \| 50.45466 Symferpol \| N/A \| Ukraine \| N/A \| N/A Zhaporizhzhya \| N/A \| Ukraine \| N/A \| N/A	1,438	0	0	0	NCT00361335	1COMPLETED	2009-09-01	2006-09-01	Centocor, Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 5 ]	688	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	false	This study will evaluate the longer-term glycemic effect of two medicines approved for initial treatment of type 2 diabetes. The study consists of a 2 week screening period (2 study visits), followed by an 80 week double-blind treatment period (11 study visits). Also, a sub-study was included to look at changes in bone mineral density (BMD) at the lumbar spine.	This was a phase IV, randomized, double-blind, global, multi-centre study. The study consisted of a 2 week screening period followed by an 80 week double-blind treatment period. Subjects who met all eligibility requirements were randomized in a 1:1 ratio, stratified by country, gender (male and female) and pre-screening HbA1c (≤9% or\>9) either to MET or AVM. When the substudy was added, a new randomization was created for the participating centers. Those subjects in the bone sub-study were stratified by country, gender (male, premenopausal female, and postmenopausal female), pre-screening HbA1c (i.e., ≤9%; \>9%), and either to MET or AVM. At randomization, Visit 3 (Week 0), subjects were initiated at Dose Level 1. Treatment with AVM was initiated at a dose of 4 mg/500 mg and titrated up to a maximum total daily dose of AVM 8 mg/2000 mg. Treatment with MET therapy was initiated at a dose of 500 mg and titrated up to a maximum daily dose of 2000mg.	Diabetes Mellitus, Type 2	Fasting Plasma Glucose Dual energy X ray absorptiometry (DXA) Drug-naive Type 2 diabetes mellitus Bone Mineral Density Hyperglycemia HbA1c	null	2	arm 1: MET began at a total daily dose of 500 mg and could be increased up to a maximum dose of MET 2000 mg. The dose level was to be increased unless a tolerability issue existed at the current dose level. arm 2: AVM began at a total daily dose of 4 mg/500 mg and could be increased up to a maximum dose of AVM 8 mg/2000 mg	[ 2, 1 ]	8	[ 0, 0, 0, 0, 0, 0, 0, 0 ]	intervention 1: One 2 mg/ 500 mg capsule will be taken in the AM with the morning meal Two 2 mg/ 500 mg capsules will be taken in the PM with the evening meal intervention 2: One 2 mg/500 mg capsule will be taken in the AM with the morning meal. One 2 mg/500 mg capsule will be taken in the PM with the evening meal. intervention 3: one placebo capsule will be taken in the AM with the morning meal one 2 mg/ 500 mg capsule will be taken in the PM with the evening meal. intervention 4: Two 2 mg/ 500 mg capsules will be taken in the AM with the morning meal. Two 2 mg/ 500 mg capsules will be taken in the PM with the evening meal. intervention 5: One placebo capsule will be taken in the AM with the morning meal. One 500 mg capsule will be taken in the PM with the evening meal. intervention 6: One 500 mg capsule will be taken in the AM with the morning meal. One 500 mg capsule will be taken in the PM with the evening meal. intervention 7: One 500 mg capsule will be taken in the AM with the morning meal. Two 500 mg capsules will be taken in the PM with the evening meal. intervention 8: Two 500 mg capsule will be taken in the AM with the morning meal. Two 500 mg capsule will be taken in the PM with the evening meal.	intervention 1: Avandamet 6 mg/1500 mg (ttd) intervention 2: Avandamet 4 mg/1000 mg (ttd) intervention 3: Avandamet 2 mg/500 mg (ttd) intervention 4: Avandamet 8 mg/ 2000 mg (ttd) intervention 5: Metformin 500 mg (ttd) intervention 6: Metformin 1000 mg (ttd) intervention 7: Metformin 1500 mg (ttd) intervention 8: Metformin 2000 mg (ttd)	116	Tuscaloosa \| Alabama \| United States \| -87.56917 \| 33.20984 Gilbert \| Arizona \| United States \| -111.78903 \| 33.35283 Glendale \| Arizona \| United States \| -112.18599 \| 33.53865 Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 Alhambra \| California \| United States \| -118.12701 \| 34.09529 Artesia \| California \| United States \| -118.08312 \| 33.86585 Greenbrae \| California \| United States \| -122.5247 \| 37.94854 Roseville \| California \| United States \| -121.28801 \| 38.75212 Sacramento \| California \| United States \| -121.4944 \| 38.58157 Wheat Ridge \| Colorado \| United States \| -105.07721 \| 39.7661 Hialeah \| Florida \| United States \| -80.27811 \| 25.8576 Ocala \| Florida \| United States \| -82.14009 \| 29.1872 Kahului \| Hawaii \| United States \| -156.47432 \| 20.88953 Peoria \| Illinois \| United States \| -89.58899 \| 40.69365 Avon \| Indiana \| United States \| -86.39972 \| 39.76282 Evansville \| Indiana \| United States \| -87.55585 \| 37.97476 Evansville \| Indiana \| United States \| -87.55585 \| 37.97476 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Waterloo \| Iowa \| United States \| -92.34296 \| 42.49276 Slidell \| Louisiana \| United States \| -89.78117 \| 30.27519 Sunset \| Louisiana \| United States \| -92.06845 \| 30.41131 Elkridge \| Maryland \| United States \| -76.71358 \| 39.21261 Chaska \| Minnesota \| United States \| -93.60218 \| 44.78941 Minneapolis \| Minnesota \| United States \| -93.26384 \| 44.97997 City of Saint Peters \| Missouri \| United States \| -90.62651 \| 38.80033 Excelsior Springs \| Missouri \| United States \| -94.22606 \| 39.33917 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Billings \| Montana \| United States \| -108.50069 \| 45.78329 Las Vegas \| Nevada \| United States \| -115.13722 \| 36.17497 Pahrump \| Nevada \| United States \| -115.98391 \| 36.20829 Hamilton \| New Jersey \| United States \| -74.08125 \| 40.20706 Albuquerque \| New Mexico \| United States \| -106.65114 \| 35.08449 East Syracuse \| New York \| United States \| -76.07853 \| 43.06534 Flushing \| New York \| United States \| -73.81736 \| 40.76538 Kingston \| New York \| United States \| -73.99736 \| 41.92704 Huntersville \| North Carolina \| United States \| -80.84285 \| 35.41069 Canal Fulton \| Ohio \| United States \| -81.59762 \| 40.88978 Canton \| Ohio \| United States \| -81.37845 \| 40.79895 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Columbus \| Ohio \| United States \| -82.99879 \| 39.96118 Kettering \| Ohio \| United States \| -84.16883 \| 39.6895 Mogadore \| Ohio \| United States \| -81.39789 \| 41.04645 Wandsworth \| Ohio \| United States \| N/A \| N/A Oregon City \| Oregon \| United States \| -122.60676 \| 45.35734 Beaver \| Pennsylvania \| United States \| -80.30478 \| 40.69534 Clairton \| Pennsylvania \| United States \| -79.88171 \| 40.29229 Coatsville \| Pennsylvania \| United States \| N/A \| N/A Erie \| Pennsylvania \| United States \| -80.08506 \| 42.12922 Sewickley \| Pennsylvania \| United States \| -80.1845 \| 40.53646 West Chester \| Pennsylvania \| United States \| -75.60804 \| 39.96097 Clinton \| South Carolina \| United States \| -81.88066 \| 34.47263 Columbia \| South Carolina \| United States \| -81.03481 \| 34.00071 Pelzer \| South Carolina \| United States \| -82.45596 \| 34.64234 Kingsport \| Tennessee \| United States \| -82.56182 \| 36.54843 Corpus Christi \| Texas \| United States \| -97.39638 \| 27.80058 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Georgetown \| Texas \| United States \| -97.67723 \| 30.63269 South Burlington \| Vermont \| United States \| -73.17096 \| 44.46699 Burke \| Virginia \| United States \| -77.27165 \| 38.79345 Manassas \| Virginia \| United States \| -77.47527 \| 38.75095 Salem \| Virginia \| United States \| -80.05476 \| 37.29347 Gig Harbor \| Washington \| United States \| -122.58013 \| 47.32926 Graham \| Washington \| United States \| -122.29428 \| 47.05288 Olympia \| Washington \| United States \| -122.90169 \| 47.04491 Tacoma \| Washington \| United States \| -122.44429 \| 47.25288 Vancouver \| Washington \| United States \| -122.66149 \| 45.63873 Wenatchee \| Washington \| United States \| -120.31035 \| 47.42346 Wauwatosa \| Wisconsin \| United States \| -88.00759 \| 43.04946 Buenos Aires \| Buenos Aires \| Argentina \| N/A \| N/A Buenos Aries \| Buenos Aires \| Argentina \| N/A \| N/A Capital Federal \| Buenos Aires \| Argentina \| N/A \| N/A Ciudad Autonoma de Buenos Aires \| Buenos Aires \| Argentina \| N/A \| N/A Ciudad Autonoma de Buenos Aires \| Buenos Aires \| Argentina \| N/A \| N/A Córdoba \| Córdoba Province \| Argentina \| -64.18853 \| -31.40648 Mendoza \| Mendoza Province \| Argentina \| -68.84582 \| -32.88946 Buenos Aires \| N/A \| Argentina \| -58.37723 \| -34.61315 Fortaleza \| Ceará \| Brazil \| -38.54306 \| -3.71722 Goiânia \| Goiás \| Brazil \| -49.25389 \| -16.67861 Porto Alegre \| Rio Grande do Sul \| Brazil \| -51.23019 \| -30.03283 Campinas \| São Paulo \| Brazil \| -47.06083 \| -22.90556 São Paulo \| São Paulo \| Brazil \| -46.63611 \| -23.5475 Brasília \| N/A \| Brazil \| -47.92972 \| -15.77972 Coquitlam \| British Columbia \| Canada \| -122.78217 \| 49.2846 Bathurst \| New Brunswick \| Canada \| -65.65112 \| 47.61814 Bay Roberts \| Newfoundland and Labrador \| Canada \| -53.26478 \| 47.59989 St. John's \| Newfoundland and Labrador \| Canada \| -52.70931 \| 47.56494 Brampton \| Ontario \| Canada \| -79.76633 \| 43.68341 Smiths Falls \| Ontario \| Canada \| -76.02333 \| 44.90452 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Gatineau \| Quebec \| Canada \| -75.70164 \| 45.47723 Sherbrooke \| Quebec \| Canada \| -71.89908 \| 45.40008 Tijuana \| Baja California Norte \| Mexico \| -117.00371 \| 32.5027 Durango \| Durango \| Mexico \| -104.65756 \| 24.02032 Pachuca \| Hidalgo \| Mexico \| -98.73329 \| 20.11697 Monterrey \| Nuevo León \| Mexico \| -100.31721 \| 25.68435 Karachi \| N/A \| Pakistan \| 67.0104 \| 24.8608 Lahore \| N/A \| Pakistan \| 74.35071 \| 31.558 Cebu City \| N/A \| Philippines \| 123.89071 \| 10.31672 Manila \| N/A \| Philippines \| 120.9822 \| 14.6042 Manila \| N/A \| Philippines \| 120.9822 \| 14.6042 Marikina City \| N/A \| Philippines \| 121.1133 \| 14.6481 Quezon City \| N/A \| Philippines \| 121.0509 \| 14.6488 Gwangju \| N/A \| South Korea \| 126.91556 \| 35.15472 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Suwon, Kyonggi-do \| N/A \| South Korea \| 127.00889 \| 37.29111 Uijeongbu-si, Kyonggi-do \| N/A \| South Korea \| 127.0474 \| 37.7415 Changhua \| N/A \| Taiwan \| 120.5512 \| 24.0692 Kaohsiung City \| N/A \| Taiwan \| 120.31333 \| 22.61626 Taichung \| N/A \| Taiwan \| 120.6839 \| 24.1469 Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306 Taoyuan Hsien \| N/A \| Taiwan \| N/A \| N/A	678	0	0	0	NCT00386100	1COMPLETED	2009-09-01	2006-10-01	GlaxoSmithKline	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 4 ]	161	RANDOMIZED	PARALLEL	1PREVENTION	4QUADRUPLE	false	1FEMALE	false	The primary purpose of the protocol is to evaluate the sensitivity of 3D-pQCT (3D-Peripheral Quantitative Computed Tomography) technology to detect minute changes in bone microarchitecture.	The 3D-pQCT equipment allows the evaluation of changes occurring within the bone at "microarchitecture" level, without the need for invasive bone biopsies. The primary objective is to evaluate the sensitivity of the technology to detect a difference between those treated with risedronate 35mg OAW (once a week) or placebo. Early phase postmenopausal women with osteopenia have been chosen because they have a more rapid and higher level of bone loss during the first few years of the menopause.	Osteopenia		null	2	arm 1: Placebo dose arm 2: 35 mg risedronate, orally, once weekly	[ 2, 0 ]	2	[ 0, 0 ]	intervention 1: oral weekly for one year intervention 2: 35 mg risedronate, once a week for one year	intervention 1: Placebo comparator intervention 2: risedronate	9	Buenos Aires \| Buenos Aires \| Argentina \| N/A \| N/A Heidelberg \| Victoria \| Australia \| 145.06667 \| -37.75 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Lyon \| Lyon \| France \| 4.84671 \| 45.74846 Saint-Etienne \| Saint-Etienne \| France \| 4.39 \| 45.43389 Toulouse \| Toulouse \| France \| 1.44367 \| 43.60426 Berlin \| State of Berlin \| Germany \| 13.41053 \| 52.52437 Geneva \| Canton of Geneva \| Switzerland \| 6.14569 \| 46.20222 Cambridge \| Cambridge \| United Kingdom \| 0.11667 \| 52.2	159	0	0	0	NCT00386360	1COMPLETED	2009-09-01	2006-04-01	Warner Chilcott	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 5 ]	31	RANDOMIZED	FACTORIAL	0TREATMENT	3TRIPLE	false	0ALL	true	The primary objective of this study is to examine the efficacy of topiramate in combination with olanzapine for the prevention of weight gain in youth with bipolar disorder. The secondary objective is to examine the tolerability of topiramate in combination with olanzapine for the prevention of weight gain in youth with bipolar disorder.	After consent and screening, patients will be initiated on 5mg or 10mg per day of olanzapine. Olanzapine doses will be titrated to 10-20 mg of olanzapine over one week, to a maximum of 20mg by day 21. Patients will also receive either topiramate (25mg bid titrated over 18 days to 150 mg bid. with flexibility to titrate to 200mg bid) or matched placebo. Topiramate will be initiated at a dose of 25 mg bid and will be increased by 25 mg bid every three days as tolerated. Patients will be evaluated by a blinded (to treatment status and adverse events) rater.	Bipolar Disorder Weight Gain	Bipolar Disorder Weight Gain	null	2	arm 1: Patients' initial dose of topiramate 25mg bid, which was titrated over 18 days to 150 mg bid (with flexibility to titrate to 200mg bid) as tolerated. arm 2: Sugar pill	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: Oral topiramate 300-400mg/day for 12 weeks intervention 2: Matched placebo to Experimental arm	intervention 1: Topiramate intervention 2: Placebo	1	Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711	30	0	0	0	NCT00394095	1COMPLETED	2009-09-01	2006-12-01	University of Cincinnati	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 3 ]	3	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	RATIONALE: Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of abnormal cells, either by killing the cells or by stopping them from dividing. Colony-stimulating factors, such as darbepoetin alfa and G-CSF, may increase the number of red blood cells and white blood cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of chemotherapy. Giving azacitidine together with darbepoetin alfa and G-CSF may be an effective treatment for myelodysplastic syndromes. PURPOSE: This clinical trial is studying how well giving azacitidine together with darbepoetin alfa and G-CSF works in treating patients with myelodysplastic syndromes.	OBJECTIVES: Primary * Determine the hematological response rate in patients with myelodysplastic syndromes treated with azacitidine, darbepoetin alfa, and filgrastim (G-CSF). Secondary * Determine the time to leukemia progression, survival, and changes in apoptotic index of bone marrow in patients treated with this regimen. OUTLINE: This is an open-label, nonrandomized study. * Initial therapy (courses 1 and 2): Patients receive azacitidine subcutaneously (SC) or intra-venous (IV) on days 1-5 (week 1) and darbepoetin alfa\* SC on day 8 (week 2). Treatment repeats every 28 days for 2 courses. Patients undergo bone marrow aspirate and biopsy to assess response. Patients with a major hematological improvement OR with grade 3-4 hematological toxicities during the first 2 courses of therapy AND/OR ≥ 50% reduction in bone marrow cellularity compared to baseline proceed to optimization therapy A. Patients not meeting any of the above criteria proceed to optimization therapy B. Patients with disease progression are removed from study. * Optimization therapy A (courses 3-8): Patients receive azacitidine SC or IV on days 1-5 (week 1), darbepoetin alfa\\ SC on day 8 (week 2), and filgrastim (G-CSF) SC 3 times weekly in weeks 2-4. * Optimization therapy B (courses 3-8): Patients receive a higher dose of azacitidine on days 1-5 (week 1), darbepoetin alfa\\ SC on day 8 (week 2), and G-CSF 3 times weekly in weeks 2-4. In both optimization therapy A and B, treatment repeats every 28 days for 6 courses. Patients with any degree of hematological improvement after initial therapy and optimization therapy proceed to maintenance therapy. * Maintenance therapy (course 9 and all subsequent courses): Patients receive azacitidine on days 1-5 (week 1). Only patients with anemia (hemoglobin \< 12 g/dL) and/or neutropenia (absolute neutrophil count \< 1,500/mm ³) at the start of any given course during maintenance therapy receive darbepoetin alfa\\ SC beginning on day 8 (week 2) and continuing once every 21 days and G-CSF SC 3 times weekly beginning in week 2. Courses repeat every 28-56 days (determined by the treating physician) in the absence of disease progression or unacceptable toxicity. Bone marrow samples are obtained at baseline and after the completion of course 2 of study treatment for apoptosis analysis, flow cytometry, and gene expression profiles of p53 and p21 by immunohistochemistry. Peripheral blood samples are obtained periodically and analyzed for hemoglobin F quantitation. NOTE: \Administered only if the patient is anemic (hemoglobin \< 12 g/dL). NOTE: \\*Darbepoetin alfa is held if hemoglobin \> 12 g/dL on day 1 of a given cycle.	Leukemia Myelodysplastic Syndromes	de novo myelodysplastic syndromes refractory anemia with ringed sideroblasts refractory anemia with excess blasts refractory anemia refractory cytopenia with multilineage dysplasia chronic myelomonocytic leukemia secondary myelodysplastic syndromes childhood myelodysplastic syndromes	null	1	arm 1: Combination of Azacitadine andHematopoietic Growth Factors	[ 0 ]	1	[ 0 ]	intervention 1: Combination of Azacitadine and Hematopoietic Growth Factors	intervention 1: Azacitadine and Hematopoietic Growth Factors	1	Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986	3	0	0	0	NCT00398047	6TERMINATED	2009-09-01	2006-09-01	Wake Forest University Health Sciences	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 3 ]	14	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	This is a Phase II study designed to test the efficacy of chemotherapy with docetaxel, cisplatinum (cisplatin) and 5-fluorouracil in patients with squamous cell carcinoma of the oral cavity to determine what effects these agents may have on cancer cells.	This is a Phase II study designed to test the efficacy of chemotherapy with docetaxel, cisplatinum, and 5-fluorouracil in patients with squamous cell carcinoma of the oral cavity to determine what effects these agents may have on cancer cells. Approximately 60 patients will take part at multi-sites with potentially 20 patients participating at the Emory Winship Cancer Institute in Atlanta, Georgia.	Squamous Cell Carcinoma Oral Cancer	Squamous Cell Carcinoma of the Oral Cavity	null	1	arm 1: Participants with squamous cell carcinoma receiving chemotherapy with docetaxel, cisplatinum, and 5-fluorouracil.	[ 0 ]	3	[ 0, 0, 0 ]	intervention 1: Docetaxel 75 mg/m2, intravenous infusion over 1 hour, mixed with normal saline per institutional standard, day 1 and then every 3 weeks. intervention 2: Cisplatin 100 mg/m2, intravenous infusion over 30 minutes to 3 hours, day 1 and then every 3 weeks. intervention 3: 5-fluorouracil 1000 mg/m2/day, 24 hour continuous infusion over 4 days, every 3 weeks.	intervention 1: Docetaxel intervention 2: Cisplatin intervention 3: 5-fluorouracil	1	Atlanta \| Georgia \| United States \| -84.38798 \| 33.749	14	0	0	0	NCT00400205	6TERMINATED	2009-09-01	2006-08-01	Emory University	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 3 ]	11	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	The purpose of this research study is to test the safety and effectiveness of VELCADE® in the treatment of acute graft-versus-host disease (GVHD) that has not responded to steroids or has worsened when the steroid dose was decreased. VELCADE® is a drug that inhibits certain immune reactions that happen when lymphocytes encounter foreign substances. We are doing this research to determine if VELCADE® may be useful in treating GVHD.	Graft-versus-host disease (GVHD) is a serious complication after bone marrow transplantation from another donor. GVHD is caused by certain cells called lymphocytes. Normally these cells make immune reactions that help protect the body from foreign substances that cause infection. Here, these cells attack the normal tissues of the body as if they were foreign substances. This interferes with the normal function of vital organs and results in their damage. In GVHD these cells attack the skin, liver and bowel. GVHD also increases the chances of infection. VELCADE® is a drug that inhibits certain immune reactions that happen when lymphocytes encounter foreign substances. We are doing this research to determine if VELCADE® may be useful in treating GVHD. VELCADE® is approved by the Food and Drug Administration (FDA) for the treatment of multiple myeloma in patients who have received at least two prior therapies and have demonstrated disease progression on their last therapy. Its effectiveness is also being tested in other cancers. The dose of the drug being used in this research study is the same as what is used for the treatment of multiple myeloma. It has not been approved by the FDA for use in GVHD. Therefore, using VELCADE® for GVHD is experimental in this research study.	Graft-versus-Host Disease	Graft-versus-Host Disease bortezomib	null	1	arm 1: To determine if bortezomib (VELCADE®) will successfully inhibit T-cell responses in clinically acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT).	[ 0 ]	1	[ 0 ]	intervention 1: Bortezomib at 1.3 mg/m2/dose given twice weekly for two weeks followed by a 10-day rest period. If patients have a complete response, they will receive additional cycles of bortezomib.	intervention 1: Bortezomib	1	Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238	11	0	0	0	NCT00408928	1COMPLETED	2009-09-01	2005-11-01	Sidney Kimmel Cancer Center at Thomas Jefferson University	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 0 ]	40	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	true	This study will investigate whether etanercept will result in improved inflammatory indices, glucose tolerance and endothelial function in patients with the metabolic syndrome.	Metabolic syndrome is an increasingly prevalent disorder associated with elevated risks of type II DM (diabetes mellitus) and cardiovascular morbidity and mortality. A subclinical inflammatory state is thought to contribute to the pathophysiology of metabolic syndrome, insulin resistance, and coronary artery disease (CAD). Tumor Necrosis Factor (TNF) -alpha is an inflammatory cytokine that is increased in a spectrum of inflammatory diseases as well as in insulin resistance. TNF-alpha antagonists are clinically effective in the inflammation of arthritides, and have recently been shown by our group to decrease inflammatory cardiovascular risk markers in metabolic syndrome. Data suggests that adiponectin, a recently discovered adipocytokine that may protect against the development of insulin resistance and atherosclerosis, may be downregulated by TNF-alpha. In addition, population based studies have shown that those with the highest levels of TNF-alpha have an increased relative risk of cardiovascular morbidity while rheumatoid arthritis patients treated with TNF-alpha blockade appear protected from cardiovascular disease. We will perform a 6-month study in which we will administer etanercept, a TNF-alpha receptor fusion protein, to subjects with metabolic syndrome to investigate its effect on surrogate markers of cardiovascular disease, including inflammatory markers, adiponectin and glucose tolerance and endothelial function. The results of the proposed study will have broad implications regarding the physiological role of TNF-alpha on the inflammatory cascade, cardiovascular indices and endothelial function.	Metabolic Syndrome	Inflammation Visceral adiposity TNF Adiponectin glucose tolerance endothelial function metabolic syndrome	null	2	arm 1: None arm 2: None	[ 2, 1 ]	2	[ 0, 0 ]	intervention 1: 50 mg one syringe sc 2X per week for three months followed by 50 mg one syringe sc 1X per week for three months intervention 2: 50 mg one syringe sc 2x per week for three months followed by 50 mg one syringe sc 1X per week for three months	intervention 1: Etanercept intervention 2: Placebo	1	Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843	40	0	0	0	NCT00413400	1COMPLETED	2009-09-01	2006-12-01	Massachusetts General Hospital	7OTHER	false	false	false	null	0	0	0	0	0	0
[ 4 ]	228	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	0ALL	false	The primary objective of this study is to assess the efficacy of two doses of Keppra XR compared with a historical control as the placebo, in the monotherapy treatment of partial onset seizures.	null	Epilepsy	Keppra XR conversion to monotherapy partial seizures	null	2	arm 1: 1000 mg/day once daily for 18 weeks (administered as two levetiracetam XR tablets and two placebo tablets once daily) arm 2: 2000 mg/day once daily for 18 weeks (administered as four levetiracetam XR tablets once daily)	[ 0, 0 ]	2	[ 0, 0 ]	intervention 1: Administered as two 500 mg tablets (1000 mg) and two placebo tablets once daily for 18 weeks intervention 2: Administered as four 500 mg tablets (2000 mg) once daily for 18 weeks	intervention 1: Keppra XR intervention 2: Keppra XR	45	Dothan \| Alabama \| United States \| -85.39049 \| 31.22323 Northport \| Alabama \| United States \| -87.57723 \| 33.22901 Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 Bakersfield \| California \| United States \| -119.01871 \| 35.37329 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 Loxahatchee Groves \| Florida \| United States \| -80.27977 \| 26.68368 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Suwanee \| Georgia \| United States \| -84.0713 \| 34.05149 Winfield \| Illinois \| United States \| -88.1609 \| 41.8617 Witchita \| Kansas \| United States \| N/A \| N/A Shreveport \| Louisiana \| United States \| -93.75018 \| 32.52515 Bethesda \| Maryland \| United States \| -77.10026 \| 38.98067 Detroit \| Michigan \| United States \| -83.04575 \| 42.33143 Camden \| New Jersey \| United States \| -75.11962 \| 39.92595 New Brunswick \| New Jersey \| United States \| -74.45182 \| 40.48622 Buffalo \| New York \| United States \| -78.87837 \| 42.88645 Cedarhurst \| New York \| United States \| -73.7243 \| 40.62288 Toledo \| Ohio \| United States \| -83.55521 \| 41.66394 Tulsa \| Oklahoma \| United States \| -95.99277 \| 36.15398 Bend \| Oregon \| United States \| -121.31531 \| 44.05817 Monaca \| Pennsylvania \| United States \| -80.27145 \| 40.68729 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Beaufort \| South Carolina \| United States \| -80.66993 \| 32.4317 Monterrey \| Nuevo León \| Mexico \| -100.31721 \| 25.68435 Aguascalientes \| N/A \| Mexico \| -102.2843 \| 21.88262 Distrio Federal \| N/A \| Mexico \| N/A \| N/A Guadalajara \| N/A \| Mexico \| -103.34749 \| 20.67738 Guadalajara Jalisco \| N/A \| Mexico \| N/A \| N/A Mexico City \| N/A \| Mexico \| -99.12766 \| 19.42847 Monterrey \| N/A \| Mexico \| -100.31721 \| 25.68435 Bialystok \| N/A \| Poland \| 23.16433 \| 53.13333 Gdansk \| N/A \| Poland \| 18.64912 \| 54.35227 Katowice \| N/A \| Poland \| 19.02754 \| 50.25841 Lodz \| N/A \| Poland \| 19.47395 \| 51.77058 Lublin \| N/A \| Poland \| 22.56667 \| 51.25 Poznan \| N/A \| Poland \| 16.92993 \| 52.40692 Szczecin \| N/A \| Poland \| 14.55302 \| 53.42894 Warsaw \| N/A \| Poland \| 21.01178 \| 52.22977 Kalingrad \| N/A \| Russia \| N/A \| N/A Kazan' \| N/A \| Russia \| 49.12214 \| 55.78874 Moscow \| N/A \| Russia \| 37.61556 \| 55.75222 Saint Petersburg \| N/A \| Russia \| 30.31413 \| 59.93863 Samara \| N/A \| Russia \| 50.15 \| 53.20007 Yaroslavl \| N/A \| Russia \| 39.87368 \| 57.62987	228	0	0	0	NCT00419094	1COMPLETED	2009-09-01	2007-08-01	UCB Pharma	4INDUSTRY	false	false	false	null	0	0	0	0	0	0
[ 3 ]	21	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	false	Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by progressive deterioration in the function of the pancreatic beta-cells, which are the cells that produce and secrete insulin (the hormone primarily responsible for the handling of glucose in the body). The investigators propose a double-blind, randomized controlled pilot study comparing the effect of sitagliptin (a novel anti-diabetic drug with beta-cell protective potential) versus placebo, on the preservation of beta-cell function over one year in patients with T2DM on metformin, the first-line agent for the treatment of T2DM (ie. the study groups will be (i) sitagliptin and metformin versus (ii) placebo and metformin). This study may demonstrate an important beta-cell protective capacity of sitagliptin. Hypothesis: In patients with T2DM on metformin, treatment with the DPP-IV inhibitor sitagliptin will preserve pancreatic beta-cell function.	Medications currently used in the treatment of T2DM have not been shown to modify the progressive decline in beta-cell function that occurs over time. Recent evidence, however, suggests that a new class of anti-diabetic medications, called dipeptidyl peptidase-IV (DPP-IV) inhibitors, may be able to protect beta cells and hence alter the natural history of T2DM. We thus wish to study the effect of sitagliptin (a DPP-IV inhibitor) on the preservation of beta-cell function in patients with T2DM randomized to either (i) sitagliptin and metformin or (ii) placebo and metformin.	Type 2 Diabetes Mellitus	Type 2 diabetes beta-cell function sitagliptin intensive insulin therapy	null	2	arm 1: Sitagliptin 100mg once a day (od) by mouth (po) arm 2: Placebo once a day (od) by mouth (po)	[ 0, 2 ]	3	[ 0, 0, 0 ]	intervention 1: sitagliptin 100 mg once a day intervention 2: placebo once a day intervention 3: metformin 1000 mg twice a day (bid) by mouth (po)	intervention 1: Sitagliptin intervention 2: Placebo intervention 3: metformin	1	Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643	21	0	0	0	NCT00420511	1COMPLETED	2009-09-01	2007-01-01	Samuel Lunenfeld Research Institute, Mount Sinai Hospital	7OTHER	false	false	false	null	0	0	0	0	0	0

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