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_Drug administration error int64	METADATA_count_Incorrect dose administered int64	METADATA_count_Intentional overdose int64	METADATA_count_Medication error int64	METADATA_count_Multiple drug overdose intentional int64	METADATA_count_Overdose int64	METADATA_count_Underdose int64	METADATA_wilson_lower_bound float32
[ 4 ]	269	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	0ALL	false	This Phase III study is designed to assess the efficacy and safety of PEP005 Gel, 0.015% when applied to an area of skin containing 4-8 AK lesions on the face or scalp.	null	Actinic Keratosis	Peplin Actinic keratosis PEP005	null	2	arm 1: PEP005 gel, 0.015% applied once daily for three consecutive days arm 2: Vehicle gel applied once daily for three consecutive days	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: 0.015%, three day treatment intervention 2: Vehicle gel, three day treatment	intervention 1: PEP005 Gel intervention 2: Vehicle gel	21	Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Oceanside \| California \| United States \| -117.37948 \| 33.19587 San Diego \| California \| United States \| -117.16472 \| 32.71571 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Miami \| Florida \| United States \| -80.19366 \| 25.77427 Alpharetta \| Georgia \| United States \| -84.29409 \| 34.07538 Newnan \| Georgia \| United States \| -84.79966 \| 33.38067 Buffalo Grove \| Illinois \| United States \| -87.95979 \| 42.15141 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Owensboro \| Kentucky \| United States \| -87.11333 \| 37.77422 Fort Gratiot \| Michigan \| United States \| N/A \| N/A Fridley \| Minnesota \| United States \| -93.26328 \| 45.08608 Raleigh \| North Carolina \| United States \| -78.63861 \| 35.7721 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 College Station \| Texas \| United States \| -96.33441 \| 30.62798 Tyler \| Texas \| United States \| -95.30106 \| 32.35126 Webster \| Texas \| United States \| -95.11826 \| 29.53773 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Norfolk \| Virginia \| United States \| -76.28522 \| 36.84681 Kogarah \| New South Wales \| Australia \| 151.13564 \| -33.9681 Kogarah \| New South Wales \| Australia \| 151.13564 \| -33.9681	267	0	0	0	NCT00916006	1COMPLETED	2009-09-01	2009-06-01	Peplin	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	506	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) 60 mg\~120 mg 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, Losartan-controlled, Parallel Group Comparison Dose Titration Clinical Study to Evaluate the Antihypertensive Efficacy and Safety of Fimasartan (BR-A-657•K) 60mg\~120mg in Patients with Mild to Moderate Essential Hypertension. Approximately 480 patients will be enrolled over 12 months in 24 centers nationwide. After 2 weeks of placebo run-in period, all subjects will be randomized into one of the following 2 groups. Subjects will take test/control drug for 12 weeks of treatment period. And Extensin study have 12 weeks in treatment period. If subjects take any antihypertensive medications before screening, the subjects will have 1 week of wash-out period. If the hypertension is not controlled well, there is a possibility of dose titration. Group I : Fimasartan group. Group II : Losartan group	Hypertension	Hypertension Losartan	null	2	arm 1: Losartan group arm 2: Fimasartan 60mg, 120mg	[ 1, 1 ]	2	[ 0, 0 ]	intervention 1: Fimasartan 60 \~ 120mg/po take one tablets once a day intervention 2: Losartan 50 mg \~ 100 mg/po, take one tablets once a day	intervention 1: Fimasartan intervention 2: Losartan (Control)	0	null	505	0	0	0	NCT00922480	1COMPLETED	2009-09-01	2008-12-01	Boryung Pharmaceutical Co., Ltd	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 0 ]	47	RANDOMIZED	CROSSOVER	null	2DOUBLE	false	0ALL	false	The safety and tolerability of two new artificial tears will be compared to a currently-available artificial tear in subjects with dry eye. Each subject will receive all three products in a randomly assigned order. The subject will use one product at a time for a duration of one week before switching to the next assigned product.	null	Dry Eye Syndrome		null	3	arm 1: Formulation 1: Carboxymethylcellulose Sodium, Glycerin and Polysorbate 80, based artificial tear arm 2: Formulation 2: Carboxymethylcellulose Sodium, Glycerin and Polysorbate 80, based artificial tear arm 3: Glycerin and Polysorbate 80 based artificial tear	[ 0, 0, 1 ]	3	[ 0, 0, 0 ]	intervention 1: 1 to 2 drops into each eye three times per day intervention 2: 1 to 2 drops into each eye three times per day intervention 3: 1 to 2 drops into each eye three times per day	intervention 1: Formulation 1: Carboxymethylcellulose Sodium, Glycerin and Polysorbate 80, based artificial tear intervention 2: Formulation 2: Carboxymethylcellulose Sodium, Glycerin and Polysorbate 80, based artificial tear intervention 3: Glycerin and Polysorbate 80 based artificial tear	1	San Diego \| California \| United States \| -117.16472 \| 32.71571	141	0	0	0	NCT00932477	1COMPLETED	2009-09-01	2009-08-01	Allergan	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 0 ]	115	RANDOMIZED	CROSSOVER	0TREATMENT	0NONE	true	1FEMALE	false	The purpose of this study is to compare the Vipon tampon with ibuprofen in relieving pain in women with dysmenorrhea. Subjects completed a total of 4 treatment intervals; each subject was randomized to use the VIPON as their treatment for two intervals and Ibuprofen as their treatment for two intervals.	Pain caused by dysmenorrhea can range from mild to severe. At least 50% of all menstruating women experience appreciable pain at some time during their menstruation. An estimated 600 million work hours are lost annually to this affliction with an average loss of time of two or more workdays per year per female employee. Treatment of dysmenorrhea may include either non-pharmacological or pharmacological measures. Pharmacological treatments include oral contraceptives to treat hormonal imbalances, over-the-counter analgesics or non-steroidal anti-inflammatory drugs. The Vipon is a tampon with a small motor unit within, which produces vibratory stimulation. This study aims to provide information on the safety and efficacy of the Vipon in a randomized controlled clinical trial.	Dysmenorrhea	Dysmenorrhea	null	2	arm 1: None arm 2: None	[ 0, 1 ]	2	[ 1, 0 ]	intervention 1: The Vipon is a tampon with a small motor unit within, which produces vibratory stimulation, used during menstruation to provide pain relief for women with dysmenorrhea. intervention 2: 400 mg daily	intervention 1: Vipon intervention 2: Ibuprofen	2	Kansas City \| Missouri \| United States \| -94.57857 \| 39.09973 Kansas City \| Missouri \| United States \| -94.57857 \| 39.09973	102	0	0	0	NCT00951561	1COMPLETED	2009-09-01	2006-11-01	Another Way Products	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	78	RANDOMIZED	CROSSOVER	7BASIC_SCIENCE	4QUADRUPLE	true	0ALL	false	The purpose of this study is to compare the subjective and objective effects of Oxymorphone ER (Opana ER) versus Oxycodone CR (Oxycontin).	null	Healthy	Opioid Recreational Oxymorphone Oxycodone Extended Release Healthy NonDependent Recreational Opioid Users	null	5	arm 1: 15mg arm 2: 30mg arm 3: None arm 4: 30mg arm 5: 60mg	[ 0, 1, 2, 0, 1 ]	4	[ 0, 0, 0, 0 ]	intervention 1: 15mg or 30mg intervention 2: 30mg or 60mg intervention 3: The placebo was a sugar pill. intervention 4: 8 mg	intervention 1: Oxymorphone ER intervention 2: Oxycodone CR intervention 3: Placebo intervention 4: Hydromorphone	1	Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643	193	0	0	0	NCT00955110	1COMPLETED	2009-09-01	2009-06-01	Endo Pharmaceuticals	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 0 ]	12	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	Atopic keratoconjunctivitis (AKC) is a rare type of ocular allergy that is often associated with eczema. Over time, the complications from this disease process lead to loss of vision due to continual scarring of the corneal surface. The pathophysiology of AKC has not been fully elucidated, and the triggers are still unknown. Corticosteroids are very effective in controlling the acute symptoms of AKC. However, two thirds of patients managed with a combination of oral antihistamine, topical mast cell stabilizer, and intermittent topical steroid regimen eventually developed significant keratopathy and vision loss. Additionally, there are many side effects of corticosteroids, including local immunosuppression, cataract formation, and increased risk of glaucoma. Cyclosporin A is an immunomodulator that specifically inhibits T lymphocytes by blocking the expression of the interleukin-2 receptor. It also blocks the release of inflammatory mediators from mast cells and eosinophils. Cyclosporin has no known side effects except for burning upon instillation, and safe to use over long-term . The investigators have demonstrated that a 0.05% ophthalmic emulsion of cyclosporine has been shown to be effective at improving the ocular signs and symptoms of AKC over short-term. However, the long-term efficacy of cyclosporine A in slowing the natural history of AKC and possible steroid sparing effects have not been assessed. The investigators hypothesize that cyclosporine A can be used as a mainstay treatment of AKC to control signs and symptoms over a long period of time and also prevent the progression of this disease.	Atopic keratoconjunctivitis (AKC) is a rare type of ocular allergy that is often associated with eczema. Over time, the complications from this disease process lead to loss of vision due to continual scarring of the corneal surface. The pathophysiology of AKC has not been fully elucidated, and the triggers are still unknown. Corticosteroids are very effective in controlling the acute symptoms of AKC. However, two thirds of patients managed with a combination of oral antihistamine, topical mast cell stabilizer, and intermittent topical steroid regimen eventually developed significant keratopathy and vision loss. Additionally, there are many side effects of corticosteroids, including local immunosuppression, cataract formation, and increased risk of glaucoma. Cyclosporin A is an immunomodulator that specifically inhibits T lymphocytes by blocking the expression of the interleukin-2 receptor. It also blocks the release of inflammatory mediators from mast cells and eosinophils. Cyclosporin has no known side effects except for burning upon instillation, and safe to use over long-term . The investigators have demonstrated that a 0.05% ophthalmic emulsion of cyclosporine has been shown to be effective at improving the ocular signs and symptoms of AKC over short-term. However, the long-term efficacy of cyclosporine A in slowing the natural history of AKC and possible steroid sparing effects have not been assessed. The investigators hypothesize that cyclosporine A can be used as a mainstay treatment of AKC to control signs and symptoms over a long period of time and also prevent the progression of this disease.	Atopic Keratoconjunctivitis	Atopic Keratoconjunctivitis Restasis Cyclosporine	null	1	arm 1: cyclosporine 0.05% ophthalmic eye drops will be used starting with 1 drop in both eyes 6 times daily for first month, followed by 1 drop in both eyes 4 times daily for the following month, then will be adjusted by clinician as needed for appropriate disease control	[ 0 ]	1	[ 0 ]	intervention 1: Cyclosporine 0.05% ophthalmic solution, 1 drop 6 times in both eyes daily for first month, then 1 drop 4 times in both eyes daily for next month, then dosage was adjusted based on clinical disease by investigator.	intervention 1: Cyclosporin 0.05% ophthalmic	1	Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038	12	0	0	0	NCT00987467	1COMPLETED	2009-09-01	2007-08-01	Johns Hopkins University	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 2 ]	12	NON_RANDOMIZED	CROSSOVER	0TREATMENT	0NONE	false	0ALL	null	The purpose of this study is to investigate whether ketoconazole, taken orally, influences the level of eribulin in the blood when the two drugs are given at the same time. The study will enroll patients with solid tumors whose cancer became worse even after standard treatment, or for whom there is no standard treatment available. The study will also investigate whether eribulin given together with ketoconazole is safe (has few side-effects) and is effective against cancer.	null	Cancer	Cancer solid tumors	null	2	arm 1: None arm 2: None	[ 0, 0 ]	2	[ 0, 0 ]	intervention 1: Group 1 Cycle 1 (28 days): Eribulin IV 1.4 mg/m\^2 alone on Day 1, then eribulin IV 0.7 mg/m\^2 plus oral ketoconazole 200 mg on Day 15 and oral ketoconazole 200 mg alone on Day 16. Subsequently, subjects were able to receive eribulin 1.4 mg/m\^2 on Days 1 and 8 every 21 days. intervention 2: Group 2 Cycle 1 (28 days): Eribulin IV 0.7 mg/m\^2 plus oral ketoconazole 200 mg on Day 1, then oral ketoconazole 200 mg alone on Day 2 and eribulin IV 1.4 mg/m\^2 alone on Day 15. Subsequently, subjects were able to receive eribulin 1.4 mg/m\^2 on Days 1 and 8 every 21 days.	intervention 1: Eribulin alone intervention 2: Eribulin plus Ketoconazole	1	Amsterdam \| North Holland \| Netherlands \| 4.88969 \| 52.37403	22	0	0	0	NCT01000376	1COMPLETED	2009-09-01	2009-02-01	Eisai Limited	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	36	RANDOMIZED	PARALLEL	0TREATMENT	1SINGLE	true	0ALL	false	This is a single-blind (blinded expert grader) study that will enroll 25-30 healthy volunteers without facial acne. On 1 side of the face, the subject will apply 1 of the 2 test products, clindamycin and benzoyl peroxide 5% or clindamycin phosphate and benzoyl peroxide 2.5% and the other 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 5%) or clindamycin and benzoyl peroxide 2.5%) and the other 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 (screened 3 days prior to randomization) who qualify will be entered into a 2-week treatment phase. The once-daily applications for the clindamycin and benzoyl peroxide 5%and clindamycin phosphate and benzoyl peroxide 2.5%) will be supervised at the site, Monday through Friday of each week. 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 in terms of erythema and dryness on each week day (excluding Saturdays and Sundays) during the study before study product is applied. Instruments will be used to measure transepidermal water loss (TEWL) to assess skin moisture in order to evaluate product mildness. Instrumentation measurements of skin surface conductance will be utilized to evaluate product performance in terms of level of skin hydration. Subjects will complete questionnaires and all adverse events will be recorded.	Acne Vulgaris	Healthy volunteers	null	2	arm 1: Once-daily applications, to the randomized side of the face either left or right, of clindamycin and benzoyl peroxide (BPO) 5% gel. arm 2: Once Daily application of clindamycin phosphate and benzoyl peroxide (BPO) 2.5% gel.	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: Once-daily applications, to the randomized side of the face either left or right, of clindamycin and benzoyl peroxide (BPO) 5% gel. intervention 2: Once daily application of clindamycin phosphate and benzoyl peroxide (BPO) 2.5% gel	intervention 1: Clindamycin and BPO 5% gel intervention 2: Clindamycin phosphate and benzoyl peroxide 2.5% gel.	1	Broomall \| Pennsylvania \| United States \| -75.35658 \| 39.9815	36	0	0	0	NCT01015638	1COMPLETED	2009-09-01	2009-08-01	Stiefel, a GSK Company	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	150	RANDOMIZED	PARALLEL	4SUPPORTIVE_CARE	0NONE	false	0ALL	false	The goal of this clinical research study is to compare the effectiveness of 3 drug schedules in preventing chemotherapy-related nausea and/or vomiting in patients with acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (MDS).	Chemotherapy-related nausea and vomiting is a frequent problem among patients with leukemia that can lead to further medical problems, such as malnutrition, dehydration, electrolyte imbalance, and a lower quality of life. Cytarabine, one of the drugs that is used to treat AML and high-risk MDS, is known to cause nausea and/or vomiting, so all patients that receive chemotherapy with cytarabine also need to receive medication to prevent these side effects. One standard-of-care drug to treat chemotherapy-related nausea and vomiting is called Ondansetron. Palonosetron is a new drug similar to Ondansetron that is designed to stay longer in the bloodstream. Researchers want to find out if palonosetron can prevent nausea and vomiting better than ondansetron. Women who are able to have children must have a negative blood or urine pregnancy test before starting treatment. If you are still eligible to take part in this study, you will be randomly assigned (as in the roll of the dice) to one of 3 treatment groups. Participants in the first group will be given Ondansetron as an intravenous (IV--through a needle in your vein) continuous infusion, from 30 minutes before your chemotherapy treatment until 12 hours after chemotherapy ends. This is considered the standard of care. Participants assigned to the second treatment group will be given palonosetron once a day by IV injection for 5 days. Each dose will be given over a period of 30 seconds, 30 minutes before your chemotherapy treatment. Participants assigned to the third treatment group will be given palonosetron once a day by IV injection, on Days 1, 3, and 5 of chemotherapy treatment. Each dose will be given over a period of 30 seconds, 30 minutes before your chemotherapy treatment. No matter what group you are assigned to, you will receive extra medication for nausea and/or vomiting as needed. You will be asked to fill out a study diary daily for 7 days, and it should take you no longer than 10 minutes to complete. The diary will be used to record the number of episodes of nausea and/or vomiting you experience during this study, as well as to record any need for extra medications, and to help researchers learn which of the 2 drugs helps the best to improve participants' quality of life (such as sleep, daily activities, and your ability to think and reason). You will be taken off study if intolerable side effects occur. This is an investigational study. The Food and Drug Administration (FDA) has approved palonosetron and Ondansetron for the prevention of chemotherapy-related nausea and vomiting, and both drugs are commercially available. Up to 150 participants will take part in this study. All will be enrolled at UT MD Anderson Cancer Center.	Acute Myelogenous Leukemia Chemotherapy-induced Nausea and Vomiting	Nausea Vomiting CINV Leukemia High-risk Myelodysplastic syndrome AML Hematologic malignancies Hematologic Disorder Continuous multi-day chemotherapy High-dose cytarabine Palonosetron Aloxi Ondansetron Zofran	null	3	arm 1: Standard of care, Ondansetron 8 mg IV as bolus followed by 24 mg IV from 30 minutes before chemotherapy until 12 hours after chemotherapy ends. arm 2: Palonosetron once a day 0.25 mg IV injection for 5 days, given over 30 seconds, 30 minutes before chemotherapy treatment. arm 3: Palonosetron once a day 0.25 mg IV injection on Days 1, 3, and 5 of chemotherapy treatment, given over 30 seconds, 30 minutes before chemotherapy treatment.	[ 1, 0, 0 ]	2	[ 0, 0 ]	intervention 1: 8 mg IV as bolus followed by 24 mg IV from 30 minutes before chemotherapy until 12 hours after chemotherapy ends. intervention 2: Palonosetron Group 1: 0.25 mg IV bolus over 30 seconds daily for 5 days, 30 minutes before cytarabine chemotherapy. Palonosetron Group 2: 0.25 mg IV bolus over 30 seconds on Days 1, 3, and 5 of cytarabine chemotherapy, 30 minutes before chemotherapy.	intervention 1: Ondansetron intervention 2: Palonosetron	1	Houston \| Texas \| United States \| -95.36327 \| 29.76328	150	0	0	0	NCT01031498	1COMPLETED	2009-09-01	2005-09-01	M.D. Anderson Cancer Center	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3, 4 ]	32	NA	SINGLE_GROUP	0TREATMENT	0NONE	true	0ALL	false	The goal of this proposal is to explore the potential effectiveness of varenicline to treat tobacco dependence among recovering alcoholic smokers who, as a group, are at high risk for tobacco-caused morbidity and mortality. In this open-label phase II clinical trial, we are proposing to enroll 32 recovering alcoholic smokers who are motivated to stop smoking. After the initial up titration of varenicline in week 1, all 32 subjects will receive a total of 2 mg/day of varenicline for 12 weeks. In addition to receiving varenicline, all subjects will receive brief behavioral counseling and our standard intervention at each visit during participation in the study.	This is an open-label, phase II clinical trial. All subjects will be screened for study eligibility after providing informed consent. During the clinic screen visit the subjects are informed of the study, the study informed consent is signed by the subject and staff member, a series of screening tests are conducted and screening criteria are reviewed. Once enrolled in study, the subject will return for a face to face clinic visit weekly for the first 4 weeks (visits 3-6) and then biweekly for the last 8 weeks(visits 7-10). Target quit day is the day after visit 3 (week 1 visit). During the first week varenicline will be started at a dose of 0.5 mg once daily for days 1-3; then 0.5 mg twice daily for days 4-7. Target quit date is set at day 8. Varenicline is then continued for weeks 2-12 at a dose of 1 mg twice daily. Subjects will return weekly for 4 weeks then bi-weekly for the remaining 8 weeks. The study end-date will be Week 12, which is also the end-of-treatment date.	Tobacco Abstinence	Tobacco Dependence Smoking Tobacco Cessation	null	1	arm 1: Everyone on study will receive Varenicline daily for 12 weeks	[ 5 ]	1	[ 0 ]	intervention 1: During the first week varenicline will be started at a dose of 0.5 mg once daily for days 1-3; then 0.5 mg twice daily for days 4-7. Target quit date is set at day 8. Varenicline is then continued for weeks 2-12 at a dose of 1 mg twice daily.	intervention 1: Varenicline	1	Rochester \| Minnesota \| United States \| -92.4699 \| 44.02163	32	0	0	0	NCT01092702	1COMPLETED	2009-09-01	2008-04-01	Mayo Clinic	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	34	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	To document the short term \& long term effect of treatment with Nasonex (mometasone furoate nasal spray) in moderate to severe adenoids hypertrophy (which cause \> 50% obstruction of the posterior choanae).	null	Adenoids		null	1	arm 1: None	[ 0 ]	1	[ 0 ]	intervention 1: One spray (50 mcg per spray) in each nostril once daily (100 mcg daily) for 3 months	intervention 1: mometasone furoate nasal spray	0	null	34	0	0	0	NCT01098071	1COMPLETED	2009-09-01	2008-08-01	Organon and Co	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 0 ]	31	RANDOMIZED	CROSSOVER	9OTHER	2DOUBLE	false	0ALL	null	Conventional pain efficacy measures such as Visual Analogue Scores (VAS) are often unable to detect treatment efficacy in small-scale clinical trials. Combining conventional pain efficacy measures with quantitative sensory testing (QST) may provide more sensitive and informative outcome measures in clinical trials.	Methodology to assess reproducibility and sensitivity of quantitative sensory testing	Neuropathic Pain	Methodology Quantitative Sensory Testing Neuropathies Pain Pregabalin	null	2	arm 1: None arm 2: None	[ 1, 2 ]	2	[ 0, 0 ]	intervention 1: Dose titration according to following regimen: 75mg BID for 3 days; 150mg for 4 days; 225mg BID for 4 days; 300mg BID for 17 days. Dose reduced for renally impaired patients intervention 2: BID dosing for 28 days	intervention 1: Pregabalin intervention 2: Placebo	5	Vienna \| N/A \| Austria \| 16.37208 \| 48.20849 Brussels \| N/A \| Belgium \| 4.34878 \| 50.85045 Boulogne-Billancourt \| N/A \| France \| 2.24128 \| 48.83545 Liverpool \| N/A \| United Kingdom \| -2.97794 \| 53.41058 London \| N/A \| United Kingdom \| -0.12574 \| 51.50853	58	0	0	0	NCT01117766	1COMPLETED	2009-09-01	2006-12-01	Pfizer	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	40	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	At the conclusion of study AZA PH GL 2003 CL 001 (NCT00071799), eligible participants could be enrolled in an optional extension phase in order to continue treatment with azacitidine until it became commercially available; the continued treatment was for ethical and safety reasons only and not to provide additional efficacy data.	At the conclusion of study AZA PH GL 2003 CL 001 (NCT00071799), eligible participants could be enrolled in an optional extension phase in order to continue treatment with azacitidine until it became commercially available; the continued treatment was for ethical and safety reasons only and not to provide additional efficacy data. During the extension phase, participants were treated based on 28-day cycles and monitored for hematologic, nonhematologic, and renal toxicities. Recommended monitoring procedures included complete blood count with differential and platelets at least once each cycle prior to dosing and as needed, bone marrow biopsy and aspirate as clinically indicated, and additional tests or more frequent monitoring at the investigator's discretion based on the patient's clinical status. The azacitidine dose could be modified for toxicities. Laboratory data were not collected during the extension phase.	Myelodysplastic Syndromes	Myelodysplastic Syndromes MDS	null	1	arm 1: Azacitidine (study drug) plus best supportive care.	[ 0 ]	1	[ 0 ]	intervention 1: Azacitidine was injected subcutaneously (SC) for 7 days. The 7-day dosing was repeated every 28 days with dose adjustments allowed. The initial dose during the primary study was 75mg/m\^2/day.	intervention 1: Azacitidine	22	East Melbourne \| Victoria \| Australia \| 144.9879 \| -37.81667 Herston \| N/A \| Australia \| 153.01852 \| -27.44453 Perth \| N/A \| Australia \| 115.8614 \| -31.95224 Woolloongabba \| N/A \| Australia \| 153.03655 \| -27.48855 Plovdiv \| N/A \| Bulgaria \| 24.75 \| 42.15 Aulnay-sous-Bois \| N/A \| France \| 2.49402 \| 48.93814 Berlin \| N/A \| Germany \| 13.41053 \| 52.52437 Düsseldorf \| N/A \| Germany \| 6.77616 \| 51.22172 Essen \| N/A \| Germany \| 7.01228 \| 51.45657 Kiel \| N/A \| Germany \| 10.13489 \| 54.32133 Heraklio \| Crete \| Greece \| N/A \| N/A Haidari \| N/A \| Greece \| N/A \| N/A Budapest \| N/A \| Hungary \| 19.04045 \| 47.49835 Bologna \| N/A \| Italy \| 11.33875 \| 44.49381 Florence \| N/A \| Italy \| 11.24626 \| 43.77925 Genova \| N/A \| Italy \| 11.87211 \| 45.21604 Rome \| N/A \| Italy \| 12.51133 \| 41.89193 Nijmegen \| N/A \| Netherlands \| 5.85278 \| 51.8425 Lodz \| N/A \| Poland \| 19.47395 \| 51.77058 Avda Campanar \| N/A \| Spain \| N/A \| N/A León \| N/A \| Spain \| -5.57032 \| 42.60003 London \| N/A \| United Kingdom \| -0.12574 \| 51.50853	40	0	0	0	NCT01186939	1COMPLETED	2009-09-01	2007-04-01	Celgene	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	678	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	false	The objective is to assess the efficacy and tolerability of a combination of 400 mg ibuprofen plus 1000 mg acetaminophen, 200 mg ibuprofen plus 500 mg acetaminophen compared with Nurofen Plus® and Panadeine® Extra.	RB has developed a fixed-dose combination of ibuprofen and acetaminophen (paracetamol). Since the pharmacological actions of ibuprofen and acetaminophen (paracetamol) differ in their site and mode of action, the combination would be expected to be more effective than either active alone, given that pain is multi-factorial with different mediators. The purpose of this study was to compare the efficacy and tolerability of ibuprofen/acetaminophen (paracetamol) combination with leading market analgesics. The efficacy and tolerability was assessed in terms of total analgesic effect, peak analgesic effect, onset and duration of action and the subject's overall assessment of the study medication.	Post-operative Pain	Dental pain Ibuprofen Acetaminophen Nurofen Plus® Panadeine® Extra Paracetamol	null	5	arm 1: One tablet of ibuprofen 200 mg plus acetaminophen 500 mg and one placebo tablet arm 2: Two tablets of ibuprofen 200 mg plus acetaminophen 500 mg arm 3: Two tablets ibuprofen 200mg plus codeine 12.8mg (Nurofen Plus®) arm 4: Two tablets acetaminophen 500 mg plus codeine 15 mg (Panadeine® Extra) arm 5: Two placebo tablets	[ 0, 0, 1, 1, 2 ]	5	[ 0, 0, 0, 0, 0 ]	intervention 1: One tablet of ibuprofen 200 mg plus acetaminophen 500 mg and one placebo tablet, single dose taken orally with 300 ml water intervention 2: Two tablets of ibuprofen 200 mg plus acetaminophen 500 mg, single dose taken orally with 300 ml water intervention 3: Two tablets ibuprofen 200mg plus codeine 12.8mg (Nurofen Plus®), single dose taken orally with 300 ml water intervention 4: Two tablets acetaminophen 500 mg plus codeine 15 mg (Panadeine® Extra), single dose taken orally with 300 ml water intervention 5: Two placebo tablets, single dose taken orally with 300 ml water	intervention 1: Ibuprofen/acetaminophen intervention 2: Ibuprofen/acetaminophen (higher dose) intervention 3: Nurofen Plus® intervention 4: Panadeine® Extra intervention 5: Placebo	1	Austin \| Texas \| United States \| -97.74306 \| 30.26715	678	0	0	0	NCT01229449	1COMPLETED	2009-09-01	2009-01-01	Reckitt Benckiser LLC	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	504	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	null	The purpose of the study is to evaluate the safety of epoetin alfa in patients with cancer who have chemotherapy-related anemia.	Epoetin alfa is an agent similar to a hormone produced in the kidney (ie, erythropoietin) that functions to increase the amount of red blood cells made in the bone marrow. This is a randomized (study drug assigned by chance), open-label (patients and their doctors will know the identity of study drug administered), safety study of 2 dosing regimens (doses and schedules) of epoetin alfa administered to patients with cancer who have chemotherapy-related anemia. Anemia is a lack of red blood cells that can result in symptoms of weakness, shortness of breath, fatigue, tiredness, and decreased activity. The primary outcome measure in the study is the number of patients in each treatment group with at least 1 clinically relevant and objectively confirmed (adjudicated) thrombovascular event (TVE) reviewed by an independent adjudication committee from Day 1 (baseline or the day of the first dose) through Week 16. An external review of relevant clinical data and medical imaging studies by an Adjudication Committee will be performed in a blinded fashion for confirmation of TVEs. The Adjudication Committee will confirm TVEs by reviewing all images (X-ray, Computed tomography \[CT\] scan, ultrasound, Magnetic Resonance Imaging \[MRI\] scan, etc) and other diagnostic procedures auch as coagulation tests or electrocardiograms in combination with a clinical patient profile as described for each specific type of TVE. Only TVEs that are determined by the Adjudication Committee to be clinically relevant and objectively confirmed will be counted in the analysis for the primary endpoint. Approximately 500 patients, who have cancer, are receiving chemotherapy, and are anemic, will take part in the study. Patients will participate in the study for up to 32 weeks (this includes a 2-week screening period to determine eligibility for the study, a 26-week treatment period, and a 4-week follow-up period to have end-of-study assessments \[tests\] performed). The length of participation in the study depends on the length of time the patient is receiving chemotherapy and epoetin alfa; patients in the study may receive up to a maximum of 26 weeks of treatment with epoetin alfa. Patients will be randomly assigned (assigned by chance like flipping a coin) to 1 of 2 treatment groups (Epoetin Alfa QW or Epoetin Alfa TIW). Patients assigned to the Epoetin Alfa QW Group will receive epoetin alfa at an initial dosage of 450 IU/kg once a week and patients assigned to Epoetin Alfa TIW Group will receive epoetin alfa 150 IU/kg 3 times a week by subcutaneous (underneath the skin) injection. Injections will be given preferably on Monday for patients in the Epoetin Alfa QW Group and on Mondays, Wednesdays, and Fridays for patients in the Epoetin Alfa TIW Group. During the study, patients will visit the study center weekly to have a blood sample collected to measure the amount of hemoglobin (red blood cells) in the blood. Depending on the hemoglobin level, the dose of epoetin alfa may be increased or decreased. Regardless of treatment group, if anemia does not improve in patients after 4 weeks of treatment, the dose of epoetin alfa will be increased to 300 IU/kg 3 times a week. If anemia does not improve after 4 weeks at the increased dose level of epoetin alfa (300 IU/kg 3 times a week), treatment with epoetin alfa will be stopped. In addition, during the study, patients may also receive treatment with iron supplements if the level of iron in the blood is low. During the study, safety will be monitored by evaluating adverse events and findings from clinical laboratory tests, 12-lead electrocardiograms (ECGs), blood pressure measurements, and physical examinations. Patients will receive epoetin alfa at an initial dose of 450 IU/kg once a week or 150 IU/kg 3 times a week by subcutaneous injection, preferably in the abdomen, for up to 4 weeks after the last dose of chemotherapy for a maximum of 26 weeks. Injections for Epoetin Alfa QW Group will be at the study center and for Epoetin TIW Group, the 1st weekly injection will be at the study center and the 2nd and 3rd weekly injections will be at the study center or at home by self-administration.	Anemia Neoplasms	Epoetin alfa (EPREX, ERYPO)	null	2	arm 1: Epoetin alfa 450 IU/kg once a week (QW) 450 IU/kg once a week (QW) by subcutaneous injection preferably in the abdomen for up to 4 weeks after the last dose of chemotherapy for a maximum of 26 weeks arm 2: Epoetin alfa 150 IU/kg 3 times a week (TIW) 150 IU/kg 3 times a week (TIW) by subcutaneous injection preferably in the abdomen for up to 4 weeks after the last dose of chemotherapy for a maximum of 26 weeks.	[ 0, 0 ]	4	[ 0, 0, 0, 0 ]	intervention 1: 450 IU/kg once a week by subcutaneous injection preferably in the abdomen for up to 4 weeks after the last dose of chemotherapy for a maximum of 26 weeks. intervention 2: 150 IU/kg 3 times a week by subcutaneous injection preferably in the abdomen for up to 4 weeks after the last dose of chemotherapy for a maximum of 26 weeks. intervention 3: 450 IU/kg once a week (QW) by subcutaneous injection preferably in the abdomen for up to 4 weeks after the last dose of chemotherapy for a maximum of 26 weeks intervention 4: 150 IU/kg 3 times a week (TIW) by subcutaneous injection preferably in the abdomen for up to 4 weeks after the last dose of chemotherapy for a maximum of 26 weeks.	intervention 1: Epoetin alfa 450 IU/kg once a week intervention 2: Epoetin alfa 150 IU/kg 3 times a week intervention 3: Epoetin alfa 450 IU/kg once a week (QW) intervention 4: Epoetin alfa 150 IU/kg 3 times a week (TIW)	0	null	504	0	0	0	NCT01394991	1COMPLETED	2009-09-01	2006-01-01	Johnson & Johnson Pharmaceutical Research & Development, L.L.C.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 2 ]	28	RANDOMIZED	CROSSOVER	null	0NONE	true	2MALE	false	The drug investigated in this study is Rivaroxaban, a novel, once-daily, oral anticoagulant for the prevention (prophylaxis) of deep vein thrombosis (DVT) which may lead to a pulmonary embolism (PE) in people undergoing knee or hip replacement surgery. The purpose of this study is to establish bioequivalence of 2 immediate-release tablet treatments with Rivaroxaban: 2\5 mg tablets and 1\10 mg tablet will be given to healthy volunteers under fasting conditions; they will be administered as single oral doses in 2 periods. Both periods will be separated by a 7-day washout phase. Thus, the bioequivalence represents the primary study objective. As a secondary objective, this treatment will be assessed in terms of safety and tolerability. Bioequivalence will be evaluated and verified on the basis of pharmacokinetic data. Blood samples of the volunteers will be taken at specific points in time; these samples will be analyzed using various statistical methods to establish pharmacokinetic characteristics required to compare the 2 treatments. The planned treatments with Rivaroxaban will be considered bioequivalent if specific criteria defined in the study protocol are met. The study will be conducted in one center in Germany. 28 subjects meeting the inclusion criteria will participate. They will be treated according to a single-dose, randomized, 2-way cross-over, non-placebo-controlled design.	null	Therapeutic Equivalency	Bioequivalence	null	2	arm 1: Single oral dose of rivaroxaban administered under fasting conditions 2\5 mg tablet in first intervention period and 1\10 mg tablet in second intervention period (after washout period) arm 2: Single oral dose of rivaroxaban administered under fasting conditions 1\10 mg tablet in first intervention period and 2\5 mg tablet in second intervention period (after washout period)	[ 0, 0 ]	2	[ 0, 0 ]	intervention 1: Single oral dose of rivaroxaban administered under fasting conditions 2\5 mg tablet in first intervention period and 1\10 mg tablet in second intervention period (after washout period) intervention 2: Single oral dose of rivaroxaban administered under fasting conditions 1\10 mg tablet in first intervention period and 2\5 mg tablet in second intervention period (after washout period)	intervention 1: Rivaroxaban (Xarelto, BAY59-7939) intervention 2: Rivaroxaban (Xarelto, BAY59-7939)	1	Mönchengladbach \| North Rhine-Westphalia \| Germany \| 6.44172 \| 51.18539	54	0	0	0	NCT01436526	1COMPLETED	2009-09-01	2009-08-01	Bayer	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	405	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	The purpose of this study is to evaluate the effectiveness of paliperidone extended-release (ER; designed to slowly release a drug in the body over an extended period of time) tablets in participants with schizophrenia (psychiatric disorder with symptoms of emotional instability, detachment from reality, often with delusions \[a false belief held in the face of strong differing evidence, especially as a symptom of psychiatric disorder\] and hallucinations \[imagining things\], and withdrawal into the self) who were not satisfied with other prior antipsychotics (agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect; olanzapine, quetiapine and risperidone) they had been taking. The safety and tolerability of paliperidone ER tablets will also be assessed.	This is an open label (all people know the identity of the intervention), prospective (study following participants forward in time), non-randomized (the study drug is not assigned by chance, participants may choose which group they want to be in, or they may be assigned to the groups by the researchers), single-arm (getting one dose of medicine) and multi-center (when more than one hospital or medical school team work on a medical research study) study designed to determine the efficacy, tolerability and safety of flexible dosage of paliperidone ER tablets in treatment of participants with schizophrenia not satisfied with other prior antipsychotics. The duration of the study will be 12 weeks. All participants will be given paliperidone ER 3 milligram (mg) or 6 mg or 9 mg or 12 mg oral (by mouth) tablets depending on Investigator's discretion once daily for 12 weeks; initial dose for paliperidone ER will be 6 mg/day. The primary objective will be to evaluate the efficacy of treatment with paliperidone ER using Positive and Negative Symptom Scale (PANSS) total scores. Participants safety and tolerability will be monitored throughout the study.	Schizophrenia	Schizophrenia Paliperidone extended-release tablets	null	1	arm 1: None	[ 0 ]	1	[ 0 ]	intervention 1: Paliperidone Extended Release (ER) 3 milligram (mg) or 6 mg or 9 mg or 12 mg oral (by mouth) tablets depending on Investigator's discretion once daily for 12 weeks.	intervention 1: Paliperidone ER	0	null	403	0	0	0	NCT01541371	1COMPLETED	2009-09-01	2008-07-01	Xian-Janssen Pharmaceutical Ltd.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	12	NON_RANDOMIZED	PARALLEL	0TREATMENT	0NONE	true	0ALL	null	An open label, parallel-group study to determine multiple dose pharmacokinetics of LCZ696 and its metabolites in subjects with severe renal impairment compared to matched healthy subjects with normal renal function	null	Pharmacokinetics Renal Impaired Healthy Volunteer	LCZ696 pharmacokinetics	null	2	arm 1: once daily administration of 400 mg LCZ696 for 5 days arm 2: once daily administration of 400 mg LCZ696 for 5 days	[ 0, 0 ]	2	[ 0, 0 ]	intervention 1: None intervention 2: once daily administration of 400 mg LCZ696 for 5 days	intervention 1: LCZ696A intervention 2: LCZ696A	3	Neuss \| N/A \| Germany \| 6.68504 \| 51.19807 Moscow \| N/A \| Russia \| 37.61556 \| 55.75222 Belgrade \| N/A \| Serbia \| 20.46513 \| 44.80401	12	0	0	0	NCT01569828	1COMPLETED	2009-09-01	2009-03-01	Novartis Pharmaceuticals	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	40	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	true	This study compares treatment of Neonatal Abstinence Syndrome (NAS) with two different drugs for the difference in the length of treatment. This is a randomized, open-label comparison of phenobarbital and methadone versus phenobarbital and diluted deodorized tincture of opium (dDTO) where phenobarbital is the initial drug used to stabilize neonatal withdrawal.	a.Procedures: NAS scoring is currently done on infants meeting the inclusion criteria \[IDD 29:070\]. NAS scores are initially done every 2 hours for 24 hours and then every 4 hours when awake or before feeding for the duration of observation or treatment. i. NAS scores may indicate more than withdrawal. Conditions such as colic, reflux, or baseline irritability may influence the baseline scores. Decisions made based on the NAS scores should take into account these factors and the baseline for the infant. b.Emergence of symptom, dosing, and initiation of treatment: Withdrawal is defined as at least 2 NAS scores \>8 or 1 NAS score \>12. Once withdrawal has emerged, the infant will be given: i. Phenobarbital 20 to 30 mg/kg to load divided in up to 3 doses over 24 hours and maintenance phenobarbital should be started at 2.5 mg/kg/dose administered Q 12h, 12 hours after the loading dose is ended. NAS scoring is continued and if scores remain \<8 for a minimum of 5 days after starting phenobarbital, the infant is eligible for discharge. ii. If after phenobarbital treatment has been started, at least 2 NAS scores \>8 or 1 NAS score \>12, then a phenobarbital level will be drawn and a mini-load calculated to reach a level of 30 mg/dl. If withdrawal is not controlled or re-emerges after the mini-load dose, the infant will be randomized to one of the two arms of the study - methadone or dDTO. iii. Twins will be randomized together to the same arm. iv. Randomization will be stratified into mothers on narcotic treatment \>3 months and those not in treatment or \<3 months. Randomization will be done in blocks of 10 for each stratum. v. For both drugs, the neonatal preparation will be used. vi. The following is a dosing guide for methadone: 1. The neonatal concentration is 1 mg/ml of methadone. It is administered orally every 12 hours - standardized eventually to 0900 and 2100. 2. For the first 24 hours, doses will be prescribed every 6 hours for 4 doses, using a sliding scale in response to the last NAS score: NAS Score Methadone dose 8-11 0.05 mg/kg/dose 12-15 0.1 mg/kg/dose \>16 0.15 mg/kg/dose 3. Maximum loading dose of methadone will be 0.15 mg/kg/dose Q 6 hour 4. After the first 24 hours of treatment, the total methadone dose will be summed and that dose divided into two doses, given 12 hours apart. Subsequently, PRN doses of 0.05 mg/kg/dose may be given every 6 hours for scores \>8 X 2 and added to the next 24 hour's doses, divided every 12 hours, until NAS scores are consistently \<8 for 48 hours. 5. If at any point the maximum dose of methadone is reached and withdrawal is not controlled, then in the opinion of two neonatologists the patient can be crossed-over to the dDTO arm. vii. The following is a dosing guide for dDTO: 1. The neonatal concentration is 1:24 dilution for a concentration of 0.4%, equivalent to 0.4 mg/ml of morphine. It is administered orally every 4 hours - standardized eventually to 0400, 0800, 1200, 1600, 2000, 0000. 2. The starting dose is determined by using a sliding scale in response to the last NAS score before starting: NAS Score dDTO dose 8-11 0.1 mg/kg/day 12-15 0.15 mg/kg/day \>16 0.2 mg/kg/day For next day, the maintenance dose will return to the previous dose and given in 6 divided doses given Q 4 hours. iv. For either methadone or dDTO, dosing will be held at this level and weaning will be resumed when the infant has NAS scores \<8 for 48 hours. e. Holding of doses: Methadone or dDTO will be held for poor feeding, respiratory depression, or somnolence at any time in the protocol. f. Behavioral assessment: Behavioral assessment will be done by two methods. The first by actigraphy and the second by NINS, both during the second week of weaning. The latter will be done prior to a scheduled phenobarbital dose. g. Formula: A 24 kcal/ounce formula should be fed initially using either standard formula or by adding breast milk fortifier. During the weaning period, when weight gain is \>30 grams/day for at least 2 days, formula will be changed to 20 kcal/ounce and weight gain monitored. If not sustained, then formula should be changed back to 24 kcal/ounce.	Neonatal Abstinence Syndrome	Neonatal Abstinence Syndrome Methadone Diluted Deodorized Tincture of Opium dDTO Phenobarbital	null	2	arm 1: The following is a dosing guide for methadone: 1. The neonatal concentration is 1 mg/ml of methadone. It is administered orally every 12 hours. 2. For the first 24 hours, doses will be prescribed every 6 hours using a sliding scale in response to the last NAS score: NAS Score Methadone dose 8-11 0.05 mg/kg/dose 12-15 0.1 mg/kg/dose ≥16 0.15 mg/kg/dose 3. Maximum dose of methadone will be 0.15 mg/kg/dose. 4. After the first 24 hours of treatment, the total methadone dose will be summed and that dose divided into two doses, given 12 hours apart. For the following 24 hours, additional doses may be given every 6 hours as needed and added to the next 24 hour's doses divided every 12 hours, until NAS scores are consistently \<8 for 48 hours. 5. If at any pointthe maximum dose of methadone is reached and withdrawal is not controlled, then in the opinion of two neonatologists the patient can be crossed-over to the dDTO arm. arm 2: The following is a dosing guide for dDTO: 1. The neonatal concentration is 1:24 dilution for a concentration of 0.4%, equivalent to 0.4 mg/ml of morphine. It is administered orally every 4 hours. 2. The starting dose will be determined using a sliding scale in response to the last NAS score before starting. NAS Score Starting dDTO dose 8-11 0.4 mg/kg/day 12-15 0.6 mg/kg/day ≥16 0.8 mg/kg/day 3. The maximum dose of DTO will be 0.8 mg/kg/day. 4. After the first 24 hours of treatment, if the NAS scores are still ≥8, the dose will be increased to the next level. 5. If at any point the maximum dose of methadone is reached and withdrawal is not controlled, then in the opinion of two neonatologists the patient can be crossed-over to the methadone arm.	[ 1, 1 ]	2	[ 0, 0 ]	intervention 1: Concentration is 1mg/mL administered every 12 hours given on sliding scale in response to last NAS score. intervention 2: Concentration is 1:24 dilution for a concentration of 0.4%	intervention 1: Methadone intervention 2: Diluted Deodorized Tincture of Opium	1	Bangor \| Maine \| United States \| -68.77265 \| 44.79884	40	0	0	0	NCT01723722	1COMPLETED	2009-09-01	2007-01-01	Eastern Maine Medical Center	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 2, 3 ]	69	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	1FEMALE	null	This study will define an optimal chemotherapy dose regimen of Myocet in combination with paclitaxel and intravenous Herceptin and will evaluate the efficacy and safety of this dose regimen in patients with metastatic or locally advanced breast cancer and HER2 overexpression. The anticipated time on study treatment is 3-12 months.	null	Breast Cancer		null	2	arm 1: Participants received an initial loading dose of trastuzumab 4 milligrams per kilogram (mg/kg), intravenously (IV), over 1.5 hours during Week 1, followed by 2 mg/kg, IV, over 30 minutes once per week from Week 2 to Week 52 or until disease progression. Participants also received myocet, 40 mg/ square meter (m\^2), IV, every 3 weeks, from Week 1; if no dose limiting toxicity (DLT) was observed in greater than or equal to (≥) two-thirds (2/3) of cohort for 2 treatment cycles, the dose was increased to 50 mg/m\^2, IV, and continued for 6 cycles. Participants also received paclitaxel 60 mg/ m\^2, IV, once per week, from Week 19; if no DLT was observed in ≥ 2/3 of cohort for 2 treatment cycles, the dose was increased to 70 mg/m\^2, IV, and subsequently 80 mg/m\^2, IV, and continued until disease progression. arm 2: Participants received an initial loading dose of trastuzumab 4 mg/kg, IV, over 1.5 hours during Week 1, followed by 2 mg/kg, IV, over 30 minutes once per week from Week 2 to Week 52 or until disease progression. Participants also received myocet, 50 mg/m\^2, IV, every 3 weeks, from Week 1 for 6 cycles. Participants also received paclitaxel 80 mg/m\^2, IV, once per week, from Week 19 until disease progression.	[ 0, 0 ]	3	[ 0, 0, 0 ]	intervention 1: Initial loading does of 4 mg/kg IV, followed by 2 mg/kg IV weekly, until disease progression intervention 2: 60 mg/m\^2 IV weekly; dose increased to 70 mg/m\^2, and subsequently 80 mg/m\^2, after 2 treatment cycles with no evidence of DLT until disease progression intervention 3: 40 mg/m\^2 IV weekly; dose increased to 50 mg/m\^2 IV after 2 treatment cycles with no evidence of DLT for 6 cycles	intervention 1: trastuzumab intervention 2: paclitaxel intervention 3: Myocet	1	Madrid \| N/A \| Spain \| -3.70256 \| 40.4165	69	0	0	0	NCT02015676	1COMPLETED	2009-09-01	2001-07-01	Hoffmann-La Roche	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	165	RANDOMIZED	CROSSOVER	0TREATMENT	2DOUBLE	false	0ALL	true	The purpose of this study is to evaluate the safety and efficacy of telcagepant in the treatment of acute migraine in participants with stable vascular disease. Acetaminophen/paracetamol (APAP) will be used as an active comparator in this study. The primary hypothesis of this study is that telcagepant 300 mg is superior to placebo.	null	Migraine Disorders Heart Disease Cerebrovascular Accident TIA (Transient Ischemic Attack) Vascular Diseases Peripheral Vascular Diseases		null	2	arm 1: Participants receive up to 12 doses of telcagepant (280 mg tablet/capsule 300 mg), orally, and placebo to acetaminophen/paracetamol (APAP) (2- 500 mg dry filled capsules), orally, for up to 12 migraine attacks in Period 1 (6 weeks). Participants receive APAP and placebo to telcagepant for up to 12 doses, for up to 12 migraine attacks in Period 2 (6 weeks). The participant may take a blinded optional second dose of study medication or their own rescue medication if 2 hours after initial treatment, the participant still has a moderate or severe migraine headache or if the headache has returned. arm 2: Participants receive 1 dose of placebo to APAP and placebo to telcagepant for the first migraine attack and then up to 11 doses of APAP and placebo to telcagepant for up to 11 migraine attacks in Period 1 (6 weeks). Participants receive up to 12 doses of telcagepant and placebo to APAP for up to 12 migraine attacks in Period 2 (6 weeks). The participant may take a blinded optional second dose of study medication or their own rescue medication if 2 hours after initial treatment, the participant still has a moderate or severe migraine headache or if the headache has returned.	[ 0, 0 ]	4	[ 0, 0, 0, 0 ]	intervention 1: Telcagepant (MK-0974) (300 mg soft gel capsules or 280 mg tablets) intervention 2: Acetaminophen/Paracetamol (500 mg X 2 dosage units) intervention 3: Placebo 300 mg soft gel capsules or placebo 280 mg tablet. intervention 4: Placebo to acetaminophen/paracetamol (500 mg X 2 dosage units)	intervention 1: Telcagepant intervention 2: Acetaminophen/Paracetamol intervention 3: Placebo to Telcagepant intervention 4: Placebo to Acetaminophen/Paracetamol	0	null	184	0	0	0	NCT00662818	1COMPLETED	2009-09-02	2008-03-17	Merck Sharp & Dohme LLC	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	10	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	to assess the effect of treatment with Sitagliptin (MK0431) on HbA1c (Hemoglobin A1c) and the safety and tolerability of Sitagliptin.	null	Diabetes Mellitus Non-insulin-dependent		null	1	arm 1: sitagliptin	[ 0 ]	1	[ 0 ]	intervention 1: Sitagliptin, 100 mg, 1 Tablet, once a day, for 18 weeks	intervention 1: sitagliptin	0	null	0	0	0	0	NCT00832624	6TERMINATED	2009-09-02	2008-11-26	Merck Sharp & Dohme LLC	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	194	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	false	This was a 2-part study of dexpramipexole in patients with ALS. Part 1 was a randomized, placebo-controlled, multi-center study to evaluate the safety, tolerability, and clinical effects of oral administration of 3 dosage levels of dexpramipexole vs. placebo for 12 weeks. Part 2 was a randomized, double-blind, 2-arm, parallel group, extension study evaluating the safety, tolerability, and clinical effects of oral administration of 2 dosage levels of dexpramipexole for up to 72 weeks.	This study was a two-part, multicenter, double-blind study in subjects with ALS to evaluate the safety and tolerability of dexpramipexole treatment, as well as the preliminary effects on measures of clinical function and mortality of dexpramipexole treatment. In part 1, 102 subjects with ALS were randomized at 20 US sites to receive placebo, dexpramipexole at 50 mg/day; dexpramipexole at 150 mg/day; or dexpramipexole at 300 mg/day for 12 weeks. Participants who completed Part 1 were eligible to enroll into Part 2. Part 2 was a randomized, double-blind, 2-arm, parallel-group, extension study evaluating the longer-term safety, tolerability, and clinical effects of oral administration of 2 dosage levels of dexpramipexole. In part 2, following a 4-week, placebo washout, continuing subjects received dexpramipexole at 50 mg/day or 300 mg/day as double-blind treatment for up to 72 additional weeks (Part 2 duration was up to a total of 76 weeks, including the 4 week placebo portion).	Amyotrophic Lateral Sclerosis	ALS Amyotrophic Lateral Sclerosis Lou Gehrig Lou Gehrig's Lou Gehrig's disease Motor Neuron Disease Nervous System Diseases KNS-760704 BIIB050	null	3	arm 1: During Part 1, subjects received twice daily doses of dexpramipexole (50 mg/day, 150 mg/day, or 300 mg/day) or matching placebo for approximately 12 weeks. arm 2: At the beginning of Part 2, subjects received twice daily doses of placebo for approximately 4 weeks. arm 3: Following the Part 2 placebo washout, subjects received dexpramipexole (50 mg/day or 300 mg/day), subjects received twice daily doses of placebo for up to 18 months.	[ 2, 0, 0 ]	4	[ 0, 0, 0, 0 ]	intervention 1: Placebo: 2 tablets taken orally twice daily intervention 2: Dexpramipexole: 2 x 12.5 mg tablets taken orally twice daily intervention 3: Dexpramipexole: 2 x 37.5 mg tablets taken orally twice daily intervention 4: Dexpramipexole: 2 x 75 mg tablets taken orally twice daily	intervention 1: Placebo intervention 2: Dexpramipexole 50 mg/day intervention 3: Dexpramipexole 150 mg/day intervention 4: Dexpramipexole 300 mg/day	21	Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Aurora \| Colorado \| United States \| -104.83192 \| 39.72943 Miami \| Florida \| United States \| -80.19366 \| 25.77427 Kansas City \| Kansas \| United States \| -94.62746 \| 39.11417 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Lincoln \| Nebraska \| United States \| -96.66696 \| 40.8 New York \| New York \| United States \| -74.00597 \| 40.71427 Syracuse \| New York \| United States \| -76.14742 \| 43.04812 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Hershey \| Pennsylvania \| United States \| -76.65025 \| 40.28592 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Charlottesville \| Virginia \| United States \| -78.47668 \| 38.02931 Seattle \| Washington \| United States \| -122.33207 \| 47.60621	291	0	0	0	NCT00647296	1COMPLETED	2009-09-04	2008-04-09	Knopp Biosciences	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	829	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	null	Ulcerative colitis is a disease of the large bowel (colon) and rectum in which the lining of the bowel becomes red and swollen. Over time, patients with this disease may experience acute episodes of diarrhea, rectal bleeding and abdominal pain followed by periods of time without disease symptoms. 5-ASA drugs are a standard treatment for ulcerative colitis. Mesalazine is an experimental drug designed to gradually release 5-ASA into the areas of large bowel associated with ulcerative colitis. This study will test the safety and efficacy of mesalazine in keeping ulcerative colitis in remission.	null	Ulcerative Colitis		null	2	arm 1: Mesalazine arm 2: None	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: 2.4 g/day Once Daily (QD) intervention 2: 1.6g/day administered 800 mg Twice Daily (BID)	intervention 1: SPD476 intervention 2: Asacol	142	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Bristol \| Connecticut \| United States \| -72.94927 \| 41.67176 Washington D.C. \| District of Columbia \| United States \| -77.03637 \| 38.89511 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 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Moline \| Illinois \| United States \| -90.51513 \| 41.5067 Davenport \| Iowa \| United States \| -90.57764 \| 41.52364 Metairie \| Louisiana \| United States \| -90.15285 \| 29.98409 Rochester \| Minnesota \| United States \| -92.4699 \| 44.02163 Mexico \| Missouri \| United States \| -91.88295 \| 39.16976 Lake Success \| New York \| United States \| -73.71763 \| 40.77066 Chattanooga \| Tennessee \| United States \| -85.30968 \| 35.04563 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Capital Federal \| Buenos Aires \| Argentina \| N/A \| N/A Ciudad de Buenos Aires \| N/A \| Argentina \| N/A \| N/A Mendoza \| N/A \| Argentina \| -68.84582 \| -32.88946 Bankstown \| New South Wales \| Australia \| 151.03333 \| -33.91667 Concord \| New South Wales \| Australia \| 151.10381 \| -33.84722 Adelaide \| South Australia \| Australia \| 138.59863 \| -34.92866 Box Hill \| Victoria \| Australia \| 145.12545 \| -37.81887 Fitzroy \| Victoria \| Australia \| 144.97833 \| -37.79839 Fremantle \| Western Australia \| Australia \| 115.74557 \| -32.05632 Bonheiden \| N/A \| Belgium \| 4.54714 \| 51.02261 Genk \| N/A \| Belgium \| 5.50082 \| 50.965 Roeselare \| N/A \| Belgium \| 3.12269 \| 50.94653 Castelo \| N/A \| Brazil \| -41.18472 \| -20.60361 Porto Alegre \| N/A \| Brazil \| -51.23019 \| -30.03283 Rio de Janeiro \| N/A \| Brazil \| -43.18223 \| -22.90642 Salvador \| N/A \| Brazil \| -38.49096 \| -12.97563 São Paulo \| N/A \| Brazil \| -46.63611 \| -23.5475 São Paulo \| N/A \| Brazil \| -46.63611 \| -23.5475 Calgary \| Alberta \| Canada \| -114.08529 \| 51.05011 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Québec \| Quebec \| Canada \| -71.21454 \| 46.81228 Edmonton \| N/A \| Canada \| -113.46871 \| 53.55014 Santiago \| N/A \| Chile \| -70.64827 \| -33.45694 Santiago \| N/A \| Chile \| -70.64827 \| -33.45694 Santiago \| N/A \| Chile \| -70.64827 \| -33.45694 Santiago \| N/A \| Chile \| -70.64827 \| -33.45694 Pilsen \| N/A \| Czechia \| 13.37759 \| 49.74747 Prague \| N/A \| Czechia \| 14.42076 \| 50.08804 Prague \| N/A \| Czechia \| 14.42076 \| 50.08804 Prague \| N/A \| Czechia \| 14.42076 \| 50.08804 Prague \| N/A \| Czechia \| 14.42076 \| 50.08804 Prague \| N/A \| Czechia \| 14.42076 \| 50.08804 Příbram \| N/A \| Czechia \| 14.01043 \| 49.68988 Tábor \| N/A \| Czechia \| 14.6578 \| 49.41441 Ústí nad Labem \| N/A \| Czechia \| 14.03227 \| 50.6607 Copenhagen NV \| N/A \| Denmark \| N/A \| N/A Hvidovre \| N/A \| Denmark \| 12.47708 \| 55.64297 Køge \| N/A \| Denmark \| 12.18214 \| 55.45802 Grenoble \| N/A \| France \| 5.71479 \| 45.17869 Nice \| N/A \| France \| 7.26608 \| 43.70313 Pessac \| N/A \| France \| -0.6324 \| 44.80565 Freiburg im Breisgau \| N/A \| Germany \| 7.85222 \| 47.9959 Homburg \| N/A \| Germany \| 7.33867 \| 49.32637 Wiesbaden \| N/A \| Germany \| 8.24932 \| 50.08258 Budapest \| N/A \| Hungary \| 19.04045 \| 47.49835 Budapest \| N/A \| Hungary \| 19.04045 \| 47.49835 Debrecen \| N/A \| Hungary \| 21.62444 \| 47.53167 Eger \| N/A \| Hungary \| 20.37329 \| 47.90265 Gyula \| N/A \| Hungary \| 21.28333 \| 46.65 Kochi \| Kerala \| India \| 76.26022 \| 9.93988 Chennai \| N/A \| India \| 80.27847 \| 13.08784 Hyderabaad \| N/A \| India \| N/A \| N/A Jaipur \| N/A \| India \| 75.78781 \| 26.91962 Lucknow \| N/A \| India \| 80.92313 \| 26.83928 Ludhiana \| N/A \| India \| 75.85379 \| 30.91204 Mumbai \| N/A \| India \| 72.88261 \| 19.07283 New Delhi \| N/A \| India \| 77.2148 \| 28.62137 Trivandrum \| N/A \| India \| 76.94924 \| 8.4855 La Paz \| Baja California Sur \| Mexico \| -110.31316 \| 24.14231 Guadalajara \| N/A \| Mexico \| -103.34749 \| 20.67738 La Paz \| N/A \| Mexico \| -110.31316 \| 24.14231 Mexico City \| N/A \| Mexico \| -99.12766 \| 19.42847 Mexico City \| N/A \| Mexico \| -99.12766 \| 19.42847 Torreón \| N/A \| Mexico \| -103.41898 \| 25.54389 Sittard \| N/A \| Netherlands \| 5.86944 \| 50.99833 Zwolle \| N/A \| Netherlands \| 6.09444 \| 52.5125 Auckland \| N/A \| New Zealand \| 174.76349 \| -36.84853 Hamilton \| N/A \| New Zealand \| 175.28333 \| -37.78333 Tauranga \| N/A \| New Zealand \| 176.16667 \| -37.68611 Wellington \| N/A \| New Zealand \| 174.77557 \| -41.28664 Lima \| N/A \| Peru \| -77.02824 \| -12.04318 Lima \| N/A \| Peru \| -77.02824 \| -12.04318 Lima \| N/A \| Peru \| -77.02824 \| -12.04318 Lima \| N/A \| Peru \| -77.02824 \| -12.04318 Bialystok \| N/A \| Poland \| 23.16433 \| 53.13333 Lodz \| N/A \| Poland \| 19.47395 \| 51.77058 Szczecin \| N/A \| Poland \| 14.55302 \| 53.42894 Torun \| N/A \| Poland \| 18.59814 \| 53.01375 Warsaw \| N/A \| Poland \| 21.01178 \| 52.22977 Braga \| N/A \| Portugal \| -8.42005 \| 41.55032 Lisbon \| N/A \| Portugal \| -9.1498 \| 38.72509 Porto \| N/A \| Portugal \| -8.61099 \| 41.14961 Bucharest \| N/A \| Romania \| 26.10626 \| 44.43225 Bucharest \| N/A \| Romania \| 26.10626 \| 44.43225 Cluj-Napoca \| N/A \| Romania \| 23.6 \| 46.76667 Constanța \| N/A \| Romania \| 28.63432 \| 44.18073 Iași \| N/A \| Romania \| 27.6 \| 47.16667 Târgu Mureş \| N/A \| Romania \| 24.55747 \| 46.54245 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 Singapore \| N/A \| Singapore \| 103.85007 \| 1.28967 Singapore \| N/A \| Singapore \| 103.85007 \| 1.28967 Singapore \| N/A \| Singapore \| 103.85007 \| 1.28967 Bellville \| Western Cape \| South Africa \| 18.62847 \| -33.90022 Observatory \| Western Cape \| South Africa \| 18.46787 \| -33.93613 Cape Town \| N/A \| South Africa \| 18.42322 \| -33.92584 Durban \| N/A \| South Africa \| 31.0292 \| -29.8579 Durban \| N/A \| South Africa \| 31.0292 \| -29.8579 Johannesburg \| N/A \| South Africa \| 28.04363 \| -26.20227 Port Elizabeth \| N/A \| South Africa \| 25.61494 \| -33.96109 Somerset West \| N/A \| South Africa \| 18.82113 \| -34.08401 Anyang-si \| N/A \| South Korea \| 126.92694 \| 37.3925 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 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Badalona \| N/A \| Spain \| 2.24741 \| 41.45004 Córdoba \| N/A \| Spain \| -4.77275 \| 37.89155 Madrid \| N/A \| Spain \| -3.70256 \| 40.4165 Valencia \| N/A \| Spain \| -0.37966 \| 39.47391 Gothenburg \| N/A \| Sweden \| 11.96679 \| 57.70716 Stockholm \| N/A \| Sweden \| 18.06871 \| 59.32938 Stockholm \| N/A \| Sweden \| 18.06871 \| 59.32938 Stockholm \| N/A \| Sweden \| 18.06871 \| 59.32938 Taichung \| N/A \| Taiwan \| 120.6839 \| 24.1469 Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306 Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306 Harrow \| Middlesex \| United Kingdom \| -0.33208 \| 51.57835 Cambridge \| N/A \| United Kingdom \| 0.11667 \| 52.2 London \| N/A \| United Kingdom \| -0.12574 \| 51.50853 Newcastle upon Tyne \| N/A \| United Kingdom \| -1.61396 \| 54.97328 Sheffield \| N/A \| United Kingdom \| -1.4659 \| 53.38297	826	0	0	0	NCT00151892	1COMPLETED	2009-09-07	2005-04-08	Shire	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	42	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	null	This is a two month study to allow continued treatment with pazopanib eye drops. Study may be extended to 5 months.	null	Macular Degeneration	age-related macular degeneration (AMD) choroidal neovascularization (CNV) vascular endothelial growth factor (VEGF) pazopanib angiogenesis	null	3	arm 1: eligible participants received 5 mg/ml Pazopanib eye drops three times daily (TID) arm 2: eligible participants received 2 mg/ml Pazopanib eye drops three times daily arm 3: eligible participants received 5 mg/ml Pazopanib eye drops once daily (QD)	[ 0, 0, 0 ]	1	[ 0 ]	intervention 1: 5 mg/ml TID, 2 mg/ml TID or 5 mg/ml QD	intervention 1: Pazopanib	17	Beverly Hills \| California \| United States \| -118.40036 \| 34.07362 Sacramento \| California \| United States \| -121.4944 \| 38.58157 Winter Haven \| Florida \| United States \| -81.73286 \| 28.02224 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 Grand Rapids \| Michigan \| United States \| -85.66809 \| 42.96336 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Sydney \| New South Wales \| Australia \| 151.20732 \| -33.86785 Sydney \| New South Wales \| Australia \| 151.20732 \| -33.86785 Melbourne \| Victoria \| Australia \| 144.96332 \| -37.814 Perth \| Western Australia \| Australia \| 115.8614 \| -31.95224 Milan \| Lombardy \| Italy \| 9.18951 \| 45.46427 Milan \| Lombardy \| Italy \| 9.18951 \| 45.46427 Turin \| Piedmont \| Italy \| 7.68682 \| 45.07049 Florence \| Tuscany \| Italy \| 11.24626 \| 43.77925 Padua \| Veneto \| Italy \| 11.88586 \| 45.40797	42	0	0	0	NCT00733304	1COMPLETED	2009-09-09	2008-06-25	GlaxoSmithKline	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	132	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	This single arm study will evaluate the maintenance of hemoglobin levels, safety and tolerability of once-monthly intravenous administration of Mircera in dialysis patients with chronic renal anemia. Patients will receive intravenous Mircera (120, 200 or 360 micrograms) every four weeks depending on the previous dose of epoetin alfa administered in the week preceding first study drug administration. Patients will be treated for 12 weeks with follow up 2 weeks after the last treatment visit. The anticipated time on study treatment is 3-12 months, and the target sample size is 100-500 individuals.	null	Anemia		null	1	arm 1: Participant with chronic renal anemia will receive methoxy polyethylene glycol-epoetin beta \[Mircera\] intravenously (IV) \[(120, 200 or 360 micrograms (mcg)\] every 4 weeks for 12 weeks.	[ 0 ]	1	[ 0 ]	intervention 1: iv (120, 200 or 360 micrograms) every 4 weeks for 12 weeks.	intervention 1: methoxy polyethylene glycol-epoetin beta [Mircera]	17	New Delhi \| National Capital Territory of Delhi \| India \| 77.2148 \| 28.62137 Bangalore \| N/A \| India \| 77.59369 \| 12.97194 Bangalore \| N/A \| India \| 77.59369 \| 12.97194 Chennai \| N/A \| India \| 80.27847 \| 13.08784 Chennai \| N/A \| India \| 80.27847 \| 13.08784 Chennai \| N/A \| India \| 80.27847 \| 13.08784 Guwahati \| N/A \| India \| 91.7458 \| 26.1844 Hyderabad \| N/A \| India \| 78.45636 \| 17.38405 Hyderabad \| N/A \| India \| 78.45636 \| 17.38405 Kanpur \| N/A \| India \| 80.34975 \| 26.46523 Kolkata \| N/A \| India \| 88.36304 \| 22.56263 Meerut \| N/A \| India \| 77.70636 \| 28.98002 Mohali \| N/A \| India \| 76.72211 \| 30.67995 Mumbai \| N/A \| India \| 72.88261 \| 19.07283 Mumbai \| N/A \| India \| 72.88261 \| 19.07283 New Delhi \| N/A \| India \| 77.2148 \| 28.62137 Pune \| N/A \| India \| 73.85535 \| 18.51957	132	0	0	0	NCT00737464	1COMPLETED	2009-09-12	2008-08-26	Hoffmann-La Roche	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	22	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	1FEMALE	false	The purpose of this study is to compare the effect and safety of rHuPH20 or placebo for the prevention and treatment of skin allergic reaction to nickel. The study drug and placebo will be administered by intradermal injection.	This study will involve 2 regimens which will run in parallel. Each participant's upper back will be divided into 2 equal spaces for Regimen 1 and 2. Each of the 4 treatment sites in each space will be independently randomized to placebo or rHuPH20 treatment in a 1:1 ratio. Thus, each participant will serve as their own control. Regimen 1 will evaluate the treatment of cutaneous reactions to nickel and Regimen 2 will evaluate the prevention as well as the treatment of cutaneous reactions to nickel. At screening, the nickel sulfate concentration (1%, 2.5%, or 5%) applied to the skin of the upper back with a patch, that will cause no more than a ++ reaction according to the scale of the International Contact Dermatitis Research Group (ICDRG) will be determined. This concentration will be used to elicit cutaneous reactions during the study period.	Dermatitis, Allergic Contact	rHuPH20 Recombinant Human hyaluronidase	Prot_000.pdf: Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 1 of 53 Version 1.0 27 May 2009 CLINICAL TRIAL PROTOCOL Title: A Prospective, Randomized, Double-blind, Placebo-controlled, Single-center Study of the Intradermal Injection of rHuPH20 or Placebo in Subjects with Nickel Allergic Contact Dermatitis Protocol Number: HALO-114-201 Version Number: 1.0 Version Date: 27 May 2009 Sponsor: Halozyme Therapeutics, Inc. (Halozyme) 11388 Sorrento Valley Road 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# 00928447 Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 2 of 53 Version 1.0 27 May 2009 TABLE OF CONTENTS 1. BACKGROUND AND RATIONALE ........................................................................ 6 1.1. Hyaluronidases and rHuPH20 ......................................................................................6 1.2. Eczema, Spongiosis, and the Role of Hyaluronan ........................................................9 1.3. Rationale for Intra-dermal Injection of rHuPH20 in Subjects with Nickel Allergic Contact Dermatitis ........................................................................................10 2. STUDY OBJECTIVES ............................................................................................. 11 2.1. Primary Objective .......................................................................................................11 2.2. Secondary Objectives ................................................................................................ 11 2.3. Descriptive-Only Parameters ......................................................................................11 3. STUDY DESIGN ...................................................................................................... 12 3.1. Overview of Study Design ..........................................................................................12 3.2. Duration Of Time On Study ...................................................................................... 13 3.3. Planned Total Sample Size .........................................................................................13 3.4. Stopping Rules ........................................................................................................... 14 4. STUDY POPULATION .............................................................................................15 4.1. Inclusion Criteria ....................................................................................................... 15 4.2. Exclusion Criteria ...................................................................................................... 15 4.3. Prohibitions and Restrictions During the Study .........................................................16 4.4. Assessments ............................................................................................................... 16 5. STUDY METHODS AND PROCEDURES ............................................................. 17 5.1. Study Procedures by Visit ......................................................................................... 17 5.1.1. Screening Visit (Visit 1; Day -21 to Day -14) ........................................................... 17 5.1.2. Baseline (Visit 2; Day 1) ........................................................................................... 18 5.1.3. Visit 3: Treatment Day 3 ...........................................................................................19 5.1.4. Visit 4 - 5: Treatment Days 4 - 5 ............................................................................... 19 5.1.5. Visit 6 - 7: Treatment Days 6 - 7 .............................................................................. 20 5.1.6. Follow-up Visit: Day 14 ............................................................................................20 5.2. Subject Replacement/Completion Criteria .................................................................21 5.3. Study Methods and Procedures ................................................................................. 21 5.3.1. Informed Consent ...................................................................................................... 21 5.3.2. Inclusion/Exclusion Criteria Review ..........................................................................21 Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 3 of 53 Version 1.0 27 May 2009 5.3.3. Demographics ............................................................................................................ 21 5.3.4. Medical History ......................................................................................................... 21 5.3.5. Complete Physical Exam ........................................................................................... 21 5.3.6. Targeted Physical Exam ............................................................................................ 21 5.3.7. Vital Signs ................................................................................................................. 22 5.3.8. Pregnancy Testing ..................................................................................................... 22 5.3.9. Hematology. ............................................................................................................... 22 5.3.10. Study Drug Administration. ....................................................................................... 22 5.3.11. Determination of Nickel Sulfate Sensitivity ............................................................... 23 5.3.12. Nickel Sulfate Patch .................................................................................................. 23 5.3.13. Trans-Epidermal Water Loss (TEWL) .......................................................................24 5.3.14. Digital Photographs ................................................................................................... 24 5.3.15. Chromometer ............................................................................................................. 24 5.3.16. Adverse Events .......................................................................................................... 24 5.3.17. Injection Site Assessment .......................................................................................... 24 5.3.18. Prior/Concomitant Medications ................................................................................. 24 5.4. Premature Termination of Treatment/Withdrawal of Subjects ..................................25 6. STUDY MEDICATIONS AND ADMINISTRATION ............................................ 26 6.1. Study Medication ........................................................................................................26 6.2. Packaging and Labeling of Study Products ................................................................26 6.3. Storage and Drug Accountability of Study Products ..................................................26 6.4. Randomization and Blinding ......................................................................................27 6.5. Unblinding Procedures ...............................................................................................27 7. ADVERSE EVENTS AND SAFETY MONITORING ............................................ 28 7.1. Adverse Event Definitions ......................................................................................... 28 7.2. Pre-Treatment-Emergent Adverse Events ..................................................................29 7.3. Laboratory Abnormalities as Adverse Events ............................................................29 7.4. Classification of Adverse Events by Severity .............................................................30 7.5. Classification of Adverse Events by Relationship to Study Drug Administration ........................................................................................................... 30 7.6. Known Toxicity Profiles of Study Drugs .................................................................. 31 7.7. Reporting of Adverse Events ......................................................................................31 Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 4 of 53 Version 1.0 27 May 2009 7.7.1. Reporting of Serious Adverse Events .........................................................................31 7.7.2. Duration of Follow-Up of Adverse Events .................................................................32 7.7.3. Other Information on the Reporting of Adverse Events .............................................32 7.7.4. Reporting of Safety Information to the Institutional Review Board ..........................32 7.7.5. Pregnancy .................................................................................................................. 32 7.8. Precautions/Over-Dosage .......................................................................................... 33 7.9. Prior/Concomitant Medications and Procedures ....................................................... 33 8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ............................ 34 9. REGULATORY/ADMINISTRATIVE PROCEDURES AND DOCUMENTATION ................................................................................................ 35 9.1. Ethics ......................................................................................................................... 35 9.2. Institutional Review Board and Approval ..................................................................35 9.3. Informed Consent .......................................................................................................36 9.4. Laboratory Accreditation ............................................................................................37 9.5. Drug Accountability ...................................................................................................37 9.6. Protocol Compliance and Protocol Deviations ...........................................................38 9.7. Protocol Amendments ............................................................................................... 38 9.8. Data Collection and Case Report Forms.....................................................................39 9.9. Study Initiation, Monitoring and Closeout Visits and Reports .................................. 39 9.10. Study Documentation and Retention of Records ....................................................... 41 9.11. Investigator’s Final Report ......................................................................................... 41 9.12. Financial Disclosure .................................................................................................. 42 9.13. Disclosure of Data and Publication ........................................................................... 42 10. REFERENCES ...........................................................................................................44 11. APPENDICES ........................................................................................................... 45 APPENDIX A. STUDY SCHEDULE OF EVENTS ................................................................ 46 APPENDIX B. INTERNATIONAL CONTACT DERMATITIS RESEARCH GROUP [ICDRG] SCORING SCALE11 ................................................................................. 48 APPENDIX C. NICKEL SULFATE ALLERGY SYSTEM ..................................................... 49 APPENDIX D. PHOTOGRAPHIC PROCEDURE .................................................................. 50 APPENDIX E. ABBREVIATIONS .......................................................................................... 52 Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 5 of 53 Version 1.0 27 May 2009 LIST OF TABLES Table 1: Cumulative Number of Subjects Exposed to rHuPH20 by Dose in Halozyme-Sponsored Clinical Studies ........................................................................ 8 LIST OF FIGURES Figure 1: Study Treatment Arm Randomization ....................................................................... 22 Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 6 of 53 Version 1.0 27 May 2009 1. BACKGROUND AND RATIONALE 1.1. Hyaluronidases and rHuPH20 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 nearly 60 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 Sept 1970) 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 [subcutaneous fluid administration]; as an adjunct in subcutaneous urography; for improving the resorption of radiopaque agents. 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. rHuPH20 is a 447-amino acid single chain polypeptide with N-linked and O-linked glycan structures. rHuPH20 is 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 the reference standard, slaughterhouse-derived hyaluronidase product based on specific activity. rHuPH20 depolymerizes hyaluronan (HA) by hydrolysis of the β-1,4 linkage between the C1 position of N-acetyl glucosamine and the C4 position of glucuronic acid. A drug product formulation of rHuPH20 (HYLENEX) obtained FDA approval on 2 December 2005. The approval indication is an adjuvant to increase absorption and dispersion of other injected drugs; for subcutaneous fluid administration; and as an adjunct in subcutaneous urography for improving resorption of radiopaque agents. HYLENEX was made available as saleable product beginning October 2006 and as of 31 December 2008 a total of 7,284 vials of HYLENEX had been sold. HYLENEX was made available through a product sampling program beginning June 2006, and as of 31 December 2008 a total of 4,384 vials had been received at physician offices. Thus, cumulative patient exposure from marketed HYLENEX product outside of clinical studies could be a high as 11,668 based on the total vials of saleable product and sample product distributed and the unit dose of 150 Units per treated patient. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 7 of 53 Version 1.0 27 May 2009 Across 19 studies, a total of 525 study subjects had been enrolled as of December 31, 2008 among whom 510 subjects are known to have been exposed to at least one dose of HYLENEX/rHuPH20. Of the 510 subjects exposed to HYLENEX/rHuPH20 in clinical studies, 100 received an intradermal injection of a test dose of 15 Units of HYLENEX and 410 subjects received a subcutaneous (SC) injection of HYLENEX/rHuPH20 either immediately before or admixed with a co-injected drug or fluid administration. Table 1 shows the cumulative number of subjects known to have been exposed according to the dose of HYLENEX/rHuPH20. There have been six studies to date in which at least some study subjects are known to have received more than a single exposure to HYLENEX: HZ2-07-03 (two doses per subject), 1838-003 (more than one dose permitted), HZ2-07-02 (a two-part study with some subjects participating in both parts), HZ2-07-04 (up to four doses per subject), HZ2-08-04 (up to six doses per subject) HZ2- 08-05 (up to five doses). Table 1 presents the completed HYLENEX/rHuPH20 clinical studies. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 8 of 53 Version 1.0 27 May 2009 Table 1: Cumulative Number of Subjects Exposed to rHuPH20 by Dose in Halozyme- Sponsored Clinical Studies Dose of rHuPH20 (Units) Number of Subjects Exposed (N = 510a) 15b 100 150 236 240 13 288 4 300 12 750 16 1152 4 1,500 15 1,600 3 3,000 4 3,200 3 6,000 6 6,400 3 12,000 17 12,800 6 24,000 30 36,000 4 48,000 6 96,000 6 a Note: Amongst the 38 subjects exposed to rHuPH20 in Study HZ2-07-02 and 8 subjects in HZ2-08-04, only the patient’s highest dose from either study stage was included in this table. Eleven subjects exposed to HYLENEX in Study HZ2-08-05 were included among the total of 510 subjects. Their dose has not yet been verified and they are not listed in this table. Amongst the 38 subjects exposed to rHuPH20 in Study HZ2-07-02 and 8 subjects in HZ2- 08-04, only the patient’s highest dose from either study stage was included in this table. The 11 patients in Study 160602 were also included in the total of 510. However, their information was not included in the table since there was variability among each subject’s dose between 1050-7800 U (based on U/g of IgG). b The 15 Unit dose was an intradermal test dose; all other administration was subcutaneous. The most commonly reported adverse events (AEs) have been self-limited, transient, localized injection/infusion site observations. Comparison of the nature and incidence of AEs for HYLENEX versus the saline placebo in the double-blinded, placebo-controlled study designs shows that, with few exceptions, there were no AEs clearly attributable to HYLENEX, and in general the AE profile for HYLENEX was similar to that for saline placebo. The clinical data have not prompted any consideration of changes to the HYLENEX product label. The Investigator is to refer to the rHuPH20 Investigator’s Brochure (IB) Version 1.0 for all current safety information. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 9 of 53 Version 1.0 27 May 2009 1.2. Eczema, Spongiosis, and the Role of Hyaluronan Spongiosis is a characteristic histopathological feature in acute eczema1. It is believed to be caused by the secondary loss of cohesion between epidermal cells due to the influx of tissue fluid into the epidermis. Serous exudate extends from the dermis; as it expands, epidermal cells remain in contact with each other only at the site of desmosomes, acquiring a stellate appearance and giving the epidermis a sponge-like morphology2. Investigators have conducted research to better understand the pathogenesis of spongiosis, specifically to understand whether HA may have a functional role in its pathogenesis. HA is a well-known component of the connective tissues, such as in the cartilage of joints and the dermis of the skin. In the human epidermis, Tammi and Wells3,4 have used hyaluronic-acid- binding protein (HABP) to localize HA in the matrix between keratinocytes in the middle and upper parts of the spinous layer. In addition, Sakai reported that even the normal stratum corneum contains HA supplied by keratinocytes5. In the process of assessing whether HA participates in epidermal hyperplasia, Maytin and colleagues6 delivered Streptomyces hyaluronidase (Strep H) topically to degrade epidermal HA and blunt the accumulation of epidermal HA after acetone application. Strep H significantly reduced epidermal HA levels and also significantly inhibited the development of epidermal hyperplasia. This reduction in epidermal thickness was not attributable to any decrease in keratinocyte proliferation, but rather to an apparent acceleration in terminal differentiation. Overall, the data showed that HA is a significant participant in the epidermal response to barrier injury. Ohtani and colleagues7 conducted a series of experiments to clarify the mechanisms for the influx of tissue fluid into the epidermis and the loss of cohesion between keratinocytes in acute eczema that results in spongiosis. First, they demonstrated increased intercellular accumulation of HA in the spongiotic epidermis by immunohistochemical staining using HABP and augmented hylauronan synthase 3 (HAS3) mRNA expression by spongiotic keratinocytes. Secondly, they showed that the epidermis where the intercellular space was strongly stained with HABP showed weaker expression of membrane E-cadherin. Thirdly, IL-4, IL-13, and IFN-γ increased HA production, enhanced HAS3 mRNA expression, and decreased membrane E- cahedrin expression by normal human epidermal keratinocytes in both low- and high Ca+ media. Lastly, they demonstrated that IL-4, IL-13, their combination, and IFN-γ could induce intercellular space widening in the epidermis with increased HA accumulation and decreased E- cadherin expression. These results suggest that the augmented production of HA and the decreased E-cadherin expression by keratinocytes stimulated with IL-4/IL-13 or IFN γ cause spongiosis in acute eczema. Based on these recent preclinical studies, HA appears to be directly involved in the pathogenesis of spongiosis. Further investigation is merited to better understand the role of hyaluronidase, more specifically, rHuPH20 in the prevention and treatment of spongiosis. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 10 of 53 Version 1.0 27 May 2009 1.3. Rationale for Intra-dermal Injection of rHuPH20 in Subjects with Nickel Allergic Contact Dermatitis As discussed in the previous section, HA plays an important role in the pathogenesis of spongiosis, the characteristic histopathological feature in acute eczema. However, there are no clinical data in the current medical literature that demonstrate the safety and efficacy of hyaluronidase for the treatment of eczema. Eczema is one of the most common skin diseases affecting up to 20% of children and up to 3 % of adults8,9. While mild cases can be treated with emollients alone, most cases require the use of pharmacologic interventions. Topical corticosteroids have been the mainstay of pharmacologic treatment for eczema. However due to potential side effects including both local effects (skin atrophy and pigmentary changes) and systemic effects (adrenal suppression) new topical modalities have been developed. The most efficacious of theses topical agents have been the topical calcinerin inhibitors (TCIs), tacrolimus ointment and pimecrolimus cream10. These were widely used until 2006 when the FDA issued a boxed warning due to rare cases of cutaneous and systemic malignancy. Thus there is a significant need for novel safe and effective topical therapies. The dose of rHuPH20 selected for this proof of concept study (3,000 U/dose) is intended to model a future topical formulation of rHuPH20 that will provide controlled release of rHuPH20 into the epidermis through the stratum corneum. The intradermal administration of rHuPH20 in this study will not require diffusion through the stratum corneum, and it is therefore considered a more direct route of administration for this proof of concept study. While daily intradermal injection of 3,000 U of rHuPH20 in 0.25mL is not likely to provide sustained release of enzyme at the injection site, it is anticipated that this dose will be sufficient to temporarily depolymerize the hyaluronan present in the dermis and epithelium. Doses of rHuPH20 in non-human primates up to approximately 3.6 million U/kg were well tolerated, and daily repeat subcutaneous dosing of 600,000 U/kg showed no histologic findings at the injection site. Additionally, in a Halozyme sponsored clinical study, 6 subjects received a single dose of rHuPH20 at a dose of 96,000 U which is greater than the expected cumulative dose in this clinical study. rHuPH20 may prevent and treat acute contact dermatitis/eczema. Therefore, we propose to conduct this Phase II pilot study in subjects who have a + or ++ reaction (see Appendix B) to nickel sulfate as a model of spongiosis. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 11 of 53 Version 1.0 27 May 2009 2. STUDY OBJECTIVES 2.1. Primary Objective • Determine the treatment effect of rHuPH20 or placebo control injection on the exposure to topical nickel allergen (Treatment Regimens 1 and 2) • Determine the time to onset and severity of the cutaneous reaction to nickel allergen after pre-treatment with rHuPH20 or placebo control (Treatment Regimen 2) • Assess the safety and tolerability of the rHuPH20 injection 2.2. Secondary Objectives • Proportion (%) of subjects who, with pre-treatment, have a ≥1 grade reduction of the cutaneous reaction to nickel sulfate in at least one patch region at 48 hours • Proportion (%) of subjects with a ≥1 grade reduction of the cutaneous reaction to nickel sulfate in at least one patch region after treatment • Proportion (%) of subjects that have a ≥1 grade reduction of the cutaneous reaction to nickel sulfate in at least one patch region at Days 2, 3, 4, or 5 • Safety and tolerability of the injection based on AEs, physical examinations, and vital signs 2.3. Descriptive-Only Parameters • Digital photographic images of the allergen test sites at Baseline (Day 1), 48, 72, and 96 hours after the placement of the patches • Chromometer images of the allergen test sites at Baseline (Day 1), 48, 72, and 96 hours after the placement of the patches • TEWL (Trans-epidermal water loss) assessments at Baseline (Day 1), 48, 72, and 96 hours after the placement of the patches Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 12 of 53 Version 1.0 27 May 2009 3. STUDY DESIGN 3.1. Overview of Study Design This is a pilot Phase II, prospective, double-blind, placebo-controlled study to compare the efficacy, safety and tolerability of rHuPH20 or placebo control administered intradermally (ID) in the prevention and treatment of subjects with contact allergy to nickel. This study will involve two treatment regimens, which will run in parallel (Treatment Regimens 1 and 2). A maximum of 30 subjects will be enrolled to achieve a likely estimate of 20 evaluable adult subjects. This study will be conducted at a dermatology unit. Subjects with a known history of contact allergy to nickel will be recruited for the Screening period. During the Screening period, subjects will be tested to confirm the presence of cutaneous nickel sensitivity using the 1, 2.5, and 5% nickel sulfate patch. The concentration of nickel sulfate for each subject that causes no greater than a ++ cutaneous reaction (2 out of 4), International Contact Dermatitis Research Group [ICDRG11] scoring scale will be the concentration administered at Baseline. After re-confirmation of the subject meeting all inclusion/exclusion criteria and prior to dosing, each subject will have the upper half of the posterior aspect of the torso divided into two equal spaces using a template and marking the edges with a medical marking pen. There will be two treatment regimens in this study (1 and 2), which will be conducted in parallel. Within each regimen, the four patch areas will be randomized to rHuPH20 or placebo control for each subject. The randomization for Treatment Regimen 1 will be independent of the randomization for Treatment Regimen 2; thus, two randomization schemes (one for each Treatment Regimen) will be used. Specifically, for each subject, two random patch areas in Treatment Regimen 1 will be assigned rHuPH20; the other two patch areas in Treatment Regimen 1 will receive Placebo control. This same randomization concept will be used in Treatment Regimen 2. Treatment Regimen 1: This regimen will assess the treatment of contact allergy to nickel: At baseline, a single row of four patches (1, 2.5, or 5% nickel sulfate patches; determined for each subject during the Screening period) will be placed on the upper space on the upper back. After 48 hours, the patches will be removed and an assessment will be made of the reaction site as per the ICDRG scoring system. Each subject will receive in the center of the cutaneous reaction an ID syringe push bolus injection of either rHuPH20 or placebo control. Each injection will be administered once daily for 5 days. Prior to each daily injection, subjects will be evaluated for efficacy, safety, and tolerability. A final evaluation will be conducted 7 days after the last dose of study treatment. Treatment Regimen 2: This regimen will assess the prevention and treatment of contact allergy to nickel sulfate. Each subject will receive in the center of each lower space on the back, either an ID syringe push bolus injection of rHuPH20 or placebo control. Exactly 10 minutes after the injection, a single Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 13 of 53 Version 1.0 27 May 2009 row of four patches (1, 2.5, or 5% nickel sulfate patches; determined for each subject during the Screening period) will be placed over the center of the ID injection. After 48 hours, the patches will be removed and an assessment will be made of the reaction site as per the ICDRG scoring system. The subject will receive an ID injection of the same study drug from pre-treatment in the center of the cutaneous reaction once daily for 5 days. Subjects will be evaluated for efficacy, safety, and tolerability, on a daily basis. A final evaluation will be conducted 7 days after the last dose of study treatment. Each of the injections will consist of 0.25 mL of rHuPH20 (3,000 U) or 0.25 mL of placebo control. Safety, tolerability, and efficacy will be assessed through physical examinations, signs and symptoms at injection sites, vital signs, and adverse events. 3.2. Duration Of Time On Study Study subjects will be screened (Visit 1) for eligibility within 21 days prior to receiving study drug. The baseline nickel allergy patch test must be administered no less than 14 days after the screening nickel allergy test. • Visit 2 (Day 1) will consist of the nickel patch test (Treatment regimen 1) and pre- treatment and then the nickel patch test (Treatment regimen 2) • Visit 3 (Day 3) is the day of first treatment dose and conducted 2 days (no less than 48 hours) after V2 • Visits 4-7 (Days 4-7) are dose days • Visit 8 will be conducted seven days after the last dose Therefore, the anticipated duration of time on study for a given subject, from Screening to completion of the study is up to 35 days. 3.3. Planned Total Sample Size At enrollment, subjects will be assigned a unique identifier according to the randomization schedule. A maximum of 30 subjects may be enrolled to ensure that at least approximately 20 evaluable subjects complete the study. The sample size of 20 evaluable subjects is intended to provide a sufficient sample size to allow for a meaningful comparison between rHuPH20 and placebo control. For Treatment Regimens 1 and 2, an evaluable subject is one who has completed dosing (or prematurely discontinued the administration due to a toxicity) and has undergone sufficient assessments to allow an assessment of the tolerability of the administration. Each subject not meeting the criteria for evaluability will be replaced with the enrollment of another subject. All subjects who receive at least one injection will be included in the safety analysis. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 14 of 53 Version 1.0 27 May 2009 3.4. Stopping Rules Subjects may withdraw from the study at any time and for any reason. Should any subject withdraw, the Investigator should be informed immediately. The Investigator may decide to terminate the participation of any subject for reasons not limited to the following criteria: • The occurrence of serious or unexpected unwanted effects attributable to the study drug(s) or study procedure(s) • In the event of abnormal laboratory results judged to be related to study drug(s) or study procedure(s) and of clinical significance • Any significant protocol violation (including demonstrated lack of compliance) • Serious difficulty in obtaining blood samples • Enrolled subject withdraws consent • Intercurrent illness requiring medication that might interfere with the study • Other reasons as determined by the Investigator Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 15 of 53 Version 1.0 27 May 2009 4. STUDY POPULATION 4.1. Inclusion Criteria Subjects must satisfy all of the following inclusion criteria in order to be enrolled in the study. 1. Females 18-60 years of age. Females of child-bearing potential must use a standard and effective means of birth control for the duration of the study. 2. Known contact dermatitis to nickel with a confirmed positive patch-test result to nickel sulfate. 3. Intact normal skin without potentially obscuring tattoos, acne, dermatitis, pigmentation or lesions on the posterior aspect of the torso (back) in the area intended for allergen testing and dose administration. 4. Vital signs (BP, HR, temperature, respiratory rate) within normal range or, if out of range, assessed by the Investigator as not clinically significant and it is mutually agreed by both Investigator and Sponsor Medical Monitor that the subject need not be excluded from the study for this reason. 5. A negative serum or urine pregnancy test (if female of child-bearing potential) within 14 days of initial study drug administration. 6. Subject should be in good general health based on medical history and physical examination, without medical conditions that might prevent the completion of study drug injections and assessments required in this protocol. 7. Decision-making capacity and willingness and ability to comply with the requirements for full completion of the study. 8. Signed, written Institutional Review Board (IRB)/EC-approved informed consent. 4.2. Exclusion Criteria Subjects satisfying any one or more of the following exclusion criteria are not allowed in this study. 1. Nickel allergen patch test greater than a ++ reaction. 2. Subjects who were treated with chemotherapy agents or systemic corticosteroids within the past 3 months. 3. Use of topical steroids, antihistamines, or immunosuppressants used near the site of allergen testing/injection within 14 days. 4. Use of oral antihistamines within 14 days of study conduct. 5. Extensive ongoing outbreaks of contact dermatitis anywhere on the body. 6. Pregnant or women who are breast-feeding. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 16 of 53 Version 1.0 27 May 2009 7. Subjects with a current disease state that can affect immune response (e.g., flu, cancer, HIV). 8. Known allergy to any hyaluronidase or the ingredients in the dose preparation. 9. History of autoimmune disorder. 10. Subjects with any other medical condition that, in the opinion of the investigator, might significantly affect their ability to safely participate in the study or affect the conduct of this study. Examples might include asthma, diabetes, heart disease, epilepsy, cancer, etc. 4.3. Prohibitions and Restrictions During the Study The following medications / conditions are prohibited during the subject’s time on study: • Oral antihistamines within 14 days of study conduct • Topical steroids, antihistamines, or immunosuppressants used near the site of allergen testing/injection within 14 days of study conduct • A current disease state that can affect immune response (e.g., flu, cancer, HIV) 4.4. Assessments • Complete medical history at screening • Complete physical exam at screening • A physical exam including visual inspection of the injection site at baseline, treatment days 3 – 7, and at follow-up visit • A complete blood count (WBC with differential, Hgb, Hct, and platelets) at screening • Vital signs Body Temperature (screening), BP, Heart Rate, Respiration Rate at screening, baseline, before each injection on treatment days 3 - 7, and within 10 minutes following each injection • Pregnancy test at screening and baseline • Targeted physical exam (positive findings on a review of systems and follow-up of findings from previous physical examinations) at baseline and treatment days 3 - 7 • Concomitant medications from 21 days before screening through the follow-up evaluation at 7-10 days after final injection • TEWL (Trans-epidermal water loss) assessment at Baseline (Day 1)and treatment days 3 – 5 • Digital photographs of each allergen test site at Baseline (Day 1) and treatment days 3 – 5 • Chromometer images of each allergen test site at Baseline (Day 1) and treatment days 3 – 5 • Subject questionnaire at treatment days 3 - 5 • Adverse events / toxicity assessment at baseline through follow-up visit Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 17 of 53 Version 1.0 27 May 2009 5. STUDY METHODS AND PROCEDURES 5.1. Study Procedures by Visit 5.1.1. Screening Visit (Visit 1; Day -21 to Day -14) Before the screening takes place, potential subjects for the study will be provided with written and oral information about the study and the procedures involved. Subjects will be fully informed of all the procedures involved in the study, the possible risks and disadvantages of the study drugs and study procedures, and their rights and responsibilities while participating in the study. They will be allowed enough time to consider their participation in the study and will have the opportunity to ask questions. If the patient wishes to participate in the study, the patient will sign and date the IRB approved Informed Consent Form (ICF) prior to any screening procedures. Screening will be performed within 21 days prior to the first dosing visit, Visit 2. As shown in Appendix A, Study Schedule of Events, the following activities are to be completed during this visit. • Obtain signed informed consent • Review subject eligibility based on Inclusion/Exclusion Criteria • See Section 4.1 and Section 4.2. • Review demographic information and perform a complete medical history • Review prior and concomitant medication taken within 21 days of enrollment • Perform a complete physical exam • Vital signs collection (BP, heart rate, respiration rate and body temperature) • Collect blood samples for hematology • Sample collection for pregnancy testing • Apply the nickel sulfate and vehicle control patches Nickel Sulfate and Vehicle Control Patches Follow the instructions in Appendix C. Follow the manufacturer’s instructions for filling the unit chambers. Concentrations of 1%, 2.5% and 5% nickel sulfate solution will be used to determine the subject’s allergic reaction to nickel. Apply the test patches to a clean surface on the upper back (at least 2 cm above the area to be used for the post-screening visits). Have the subject return to the study site after 48 hours to have the test results interpreted. The concentration of nickel sulfate that causes no greater than + + cutaneous reaction (International Contact Dermatitis Research Group [ICDRG11] scoring scale, see Appendix B) will be the assigned dose for use per subject for the study. One half (50%) of study subjects will Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 18 of 53 Version 1.0 27 May 2009 be treated using the nickel concentration that elicits a + cutaneous reaction and the other half (50%) of study subjects will be treated with the nickel concentration that elicits a ++ cutaneous reaction. Any subjects not meeting the cutaneous reaction scale will be a screen failure. Record the nickel sulfate concentration to be used for the subject in the subject’s source documentation. 5.1.2. Baseline (Visit 2; Day 1) Subject Arrival at Site: As shown in Appendix A, Study Schedule of Events, the following activities are to be completed during this visit. • Confirm subject meets inclusion and exclusion criteria • Assign Randomization Number (at Baseline visit only) • Review concomitant medication use • Vital signs collection (BP, heart rate, respiration rate) • Pregnancy test (only for females of child bearing potential) • Targeted physical exam • Physical examination of the administration site • Perform baseline TEWL, Chromometer, digital photography assessments • Mark the upper back into 2 rows of 4 areas each (see Figure 1) • Treatment Regimen 1 - Apply the nickel sulfate patches (see Appendix C) at the concentration that caused no greater than a ++ cutaneous reaction (ICDRG11 scoring scale, see Appendix B) • Treatment Regimen 2 - Administer the intra-dermal injection of rHuPH20 or placebo. Exactly 10 minutes after the injection, apply a single row of four patches (1%, 2.5%, or 5% nickel sulfate patches; determined for each subject during the Screening period) over the center of the intra-dermal injection • Assess Adverse Events (AE’s) • Assess injection site After Study Patch Placement: • Vital signs collection (BP, heart rate, respiration rate) within 10 minutes post- injection • Physical examination of the administration injection site • Review for adverse events (After 30 minutes post-injection if no safety issues are observed, the subject will be allowed to leave) Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 19 of 53 Version 1.0 27 May 2009 5.1.3. Visit 3: Treatment Day 3 As shown in Appendix A, Study Schedule of Events, the following activities are to be completed during this visit. • Review concomitant medication use • Targeted physical exam • Vital signs collection (BP, heart rate, respiration rate) • Physical examination of the administration injection sites immediately after patch removal (Treatment regimen 2) • Administer/review the subject questionnaire • Perform the TEWL, Chromometer, digital photography assessments • Administer the intra-dermal injection of rHuPH20 or placebo (Treatment regimens 1 and 2). • Review for adverse events / toxicity After Study Drug Administration: • Vital signs collection (BP, heart rate, respiration rate) within 10 minutes post- injection • Physical examination of the administration site • Review for adverse events (After 30 minutes post-injection if no safety issues are observed, the subject will be allowed to leave) 5.1.4. Visit 4 - 5: Treatment Days 4 - 5 As shown in Appendix A, Study Schedule of Events, the following activities are to be completed during this visit. • Review concomitant medication use • Vital signs collection (BP, heart rate, respiration rate) • Targeted physical exam • Physical examination of the administration injection site • Administer/review the subject questionnaire • Perform the TEWL, Chromometer, digital photography assessments • Administer the intra-dermal injection of rHuPH20 or placebo (Treatment regimen 1 and 2). • Review for adverse events / toxicity Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 20 of 53 Version 1.0 27 May 2009 After Study Drug Administration: • Vital signs collection (BP, heart rate, respiration rate) within 10 minutes post- injection • Physical examination of the administration site • Review for adverse events (After 30 minutes post-injection if no safety issues are observed, the subject will be allowed to leave) 5.1.5. Visit 6 - 7: Treatment Days 6 - 7 As shown in Appendix A, Study Schedule of Events, the following activities are to be completed during this visit. • Review concomitant medication use • Vital signs collection (BP, heart rate, respiration rate) • Targeted physical exam • Physical examination of the administration injection site • Administer the intra-dermal injection of rHuPH20 or placebo (Treatment regimen 1 and 2). • Review for adverse events / toxicity After Study Drug Administration: • Vital signs collection (BP, heart rate, respiration rate) within 10 minutes post- injection • Physical examination of the administration site • Review for adverse events (After 30 minutes post-injection if no safety issues are observed, the subject will be allowed to leave) 5.1.6. Follow-up Visit: Day 14 As shown in Appendix A, Study Schedule of Events, the following activities are to be completed during this visit. • Review concomitant medication use • Vital signs collection (BP, heart rate, respiration rate) • Targeted physical exam • Physical examination of the administration site • Review adverse events / toxicity Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 21 of 53 Version 1.0 27 May 2009 5.2. Subject Replacement/Completion Criteria Subjects who are not evaluable will be replaced. An evaluable subject is one who has completed dosing (or prematurely discontinued the administration due to a toxicity) and has undergone sufficient assessments to allow an assessment of the tolerability of the administration. As this study is being conducted at a single site, the site personnel, in conjunction with the Sponsor, will make the determination when a subject will need to be replaced in the study. This information will be collected on the Enrollment Log. Each subject not meeting the completion criteria will be replaced by the enrollment of an additional subject. In the event that a subject withdraws from the study prematurely or does not meet the completion criteria, every effort will be made to document the reason for termination and obtain follow-up safety data. 5.3. Study Methods and Procedures 5.3.1. Informed Consent The Investigator or designee must present and explain the study protocol to prospective study subjects prior to any screening procedures. Once the subject has had an opportunity to read the IRB-approved ICF, the Investigator (or designee) must be available to answer any questions the subject may have regarding the study protocol and procedures. 5.3.2. Inclusion/Exclusion Criteria Review Review the inclusion/exclusion criteria (Section 4.1 and Section 4.2) to ensure the subject qualifies for this study at the screening visit. 5.3.3. Demographics Collect demographic information, including the subject’s initials, date of birth, gender, race and ethnic origin at the screening visit. 5.3.4. Medical History A complete medical history will be collected at the screening visit. 5.3.5. Complete Physical Exam Physical examination, including ears/eyes/nose/throat/neck, respiratory, cardiovascular, gastrointestinal including mouth, musculo-skeletal, central and peripheral nervous system and dermatological assessments will be performed by the Investigator at the screening visit. 5.3.6. Targeted Physical Exam An abbreviated physical exam, reviewing only those body systems for which an abnormality was noted during the complete review of systems or a follow up of previous physical exam(s), will be performed by the Investigator prior to study drug injection at Visits 1-7, and at the Follow-up Visit. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 22 of 53 Version 1.0 27 May 2009 5.3.7. Vital Signs Assessment of vital signs includes the measurement of blood pressure (systolic and diastolic), heart rate, and respiration rate and body temperature (at screening). Blood pressure and heart rate will be measured with the subject at rest and in supine position for at least 5 minutes prior to recording. Vital signs will be recorded at screening, baseline, prior to injection, immediately after each injection, and before discharge. 5.3.8. Pregnancy Testing For females of childbearing potential, serum or urine pregnancy testing will be performed at the screening and baseline visits. 5.3.9. Hematology Hemoglobin, hematocrit, red blood cell count, white blood cell count (differential), and platelet count will be determined at the screening visit. 5.3.10. Study Drug Administration There will be two treatment regimens in this study (1 and 2), which will be conducted in parallel. Within each regimen, the four patch areas will be randomized to rHuPH20 or placebo control for each subject (Figure 1). The randomization for Treatment Regimen 1 will be independent of the randomization for Treatment Regimen 2; thus, two randomization schemes (one for each Treatment Regimen) will be used. Specifically, for each subject, two random patch areas in Treatment Regimen 1 will be assigned rHuPH20; the other two patch areas in Treatment Regimen 1 will receive Placebo control. This same randomization concept will be used in Treatment Regimen 2. Figure 1: Study Treatment Arm Randomization Allergen Allergen Allergen Allergen Placebo rHuPH20 Placebo rHuPH20 or or or or rHuPH20 Placebo rHuPH20 Placebo (1) (2) (3) (4) Allergen Allergen Allergen Allergen Placebo rHuPH20 Placebo rHuPH20 or or or or rHuPH20 Placebo rHuPH20 Placebo (5) (6) (7) (8) Treatment Regimen 2 Treatment Regimen 1 Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 23 of 53 Version 1.0 27 May 2009 Treatment Regimen 1 (Spaces 1-4): This regimen will assess the treatment of contact allergy to nickel: At baseline, a single row of four patches (1, 2.5, or 5% nickel sulfate patches; determined for each subject during the Screening period) will be placed on the upper space on the upper back. After 48 hours, the patches will be removed and an assessment will be made of the reaction site as per the ICDRG scoring system, Appendix B. Each subject will receive in the center of the cutaneous reaction an ID syringe push bolus injection of either rHuPH20 or placebo control. Each injection will be administered once daily for 5 days. Prior to each daily injection, subjects will be evaluated for efficacy, safety, and tolerability. A final evaluation will be conducted 7 days after the last dose of study treatment. Treatment Regimen 2 (Spaces 5-8): This regimen will assess the prevention and treatment of contact allergy to nickel sulfate. Each subject will receive in the center of each lower space on the back, either an ID syringe push bolus injection of rHuPH20 or placebo control. Exactly 10 minutes after the injection, a single row of four patches (1, 2.5, or 5% nickel sulfate patches; determined for each subject during the Screening period) will be placed over the center of the ID injection. After 48 hours, the patches will be removed and an assessment will be made of the reaction site as per the ICDRG scoring system. The subject will receive an ID injection of the same study drug from pre-treatment in the center of the cutaneous reaction once daily for 5 days. Subjects will be evaluated for efficacy, safety, and tolerability, on a daily basis. A final evaluation will be conducted 7 days after the last dose of study treatment. Each of the injections will consist of 0.25 mL of rHuPH20 (3,000 U) or 0.25 mL of placebo control. 5.3.11. Determination of Nickel Sulfate Sensitivity During the Screening period, subjects will be tested to confirm the presence of cutaneous nickel sensitivity using the 1, 2.5, and 5% nickel sulfate patch. The test site will not be in the same area where patches will be placed at Baseline. The concentration of nickel sulfate for each subject that causes no greater than a ++ cutaneous reaction (2 out of 4, International Contact Dermatitis Research Group [ICDRG11] scoring scale will be the concentration administered at Baseline (Day 1). 5.3.12. Nickel Sulfate Patch At baseline the nickel sulfate patch will be applied. For Treatment regimen 1, the nickel sulfate patches will be applied and the subject will return within 48 hours for removal and to begin treatment intra-dermal injections. For Treatment regimen 2, the nickel sulfate patches will be applied at baseline after 10 minutes post-injection of either rHuPH20 or placebo. The concentration of nickel sulfate (1, 2.5, or 5%) will be determined during the Screening period. Once the concentration is confirmed, this will be the concentration applied on the subject at the baseline visit. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 24 of 53 Version 1.0 27 May 2009 At the baseline visit, the patches will be inoculated with the correct nickel sulfate concentration. The procedure for using the allergy patch system is found in Appendix C. 5.3.13. Trans-Epidermal Water Loss (TEWL) All measurements should be conducted in an enclosed room in which air movement is minimized. Subjects must equilibrate for 30 minutes prior to testing in the controlled environment of 72 plus/minus 2 degrees F and a relative humidity (RH) of less than 50% prior to measurement reading. Make sure the skin area to be read is dry and clean. Press and securely hold the evaporimeter probe to the skin surface for 45 seconds. A validated Evaporimeter Operator should only be used to collect data. 5.3.14. Digital Photographs In these clinical photographs, for the duration of the study, the only variable allowed to change is the skin condition itself. Therefore, anything extraneous to the condition (jewelry, clothing, furniture, walls, etc.) is to be eliminated from the fields to be photographed, from the baseline through the final photographs. The necessity of good end-of-study photos should be stressed to the subjects to ensure their cooperation. Lighting, framing, exposure and reproduction ratios must be held constant. In the end, the pictures should read like a time-lapse movie. Detailed instructions are found in Appendix D. 5.3.15. Chromometer Make sure the skin area to be read is dry and clean. To collect data, position the device directly over the skin area without applying pressure to the skin surface. Ensure the position of the device on the skin is level or parallel with the surface of the skin. Press the trigger once on the chromometer. A reading will be recorded on the program. Data collection should be done by a validated Chromometer Operator only. 5.3.16. Adverse Events Each study participant will be carefully monitored for the development of adverse events (Section 7). 5.3.17. Injection Site Assessment An assessment of local tolerability at the injection site will be performed prior to and 10 minutes after the injection for site reactions such as erythema, pruritus, and edema. If an injection site reaction is observed, it must be recorded as an adverse event. Local tolerability will be assessed by a qualified person. 5.3.18. Prior/Concomitant Medications Review any concomitant medications the subject is taking at each study visit, beginning 21 days prior to Visit 1. See Section 4.3 for a list of prohibited medications. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 25 of 53 Version 1.0 27 May 2009 5.4. Premature Termination of Treatment/Withdrawal of Subjects The Investigator must guard the subject’s welfare and should discontinue study drug treatment at any time that this action appears to be in the subject’s best interest. Subjects 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: • The occurrence of serious or unexpected unwanted effects attributable to the study drug(s) or study procedure(s) • In the event of abnormal laboratory results judged to be related to study drug(s) or study procedure(s) and of clinical significance • Any significant protocol violation (including demonstrated lack of compliance) • Serious difficulty in obtaining blood samples • Enrolled subject withdraws consent • Intercurrent illness requiring medication that might interfere with the study • Other reasons as determined by the Investigator It is the right and duty of the Investigator to interrupt the treatment of any study subject whose health or well-being may be threatened by continuation in this study. Once a study subject has received study drug under this protocol, the subject must be followed for safety as required in the protocol (see Section 7). In the event that a study subject discontinues treatment prematurely, every effort will be made to document the reason for premature termination and obtain follow-up safety data. Should the enrollment rate lag or significant numbers of clearly non-eligible and/or non-evaluable subjects be entered in the study, Halozyme may elect to terminate the study at any and all investigational sites. 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. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 26 of 53 Version 1.0 27 May 2009 6. STUDY MEDICATIONS AND ADMINISTRATION 6.1. Study Medication rHuPH20 (recombinant hyaluronidase human injection), also designated as Study Drug, will be provided as 12,000 USP units/mL in 1 mL vial. This Study Drug is a concentrated formulation of the FDA-approved rHuPH20 drug product known as HYLENEX (150 USP units/mL), with the exception that Study Drug does not contain calcium chloride and disodium edentate. Clinical Study Drug placebo will consist of the same formulation of rHuPH20 Clinical Study Drug without active drug substance. The manufacturing and packaging of the study products will be in accordance with GMP. 6.2. Packaging and Labeling of Study Products Labeling of study products will be in accordance with local law and study requirements. Blinding of the study products will be done at the investigational site. Before dosing, the unblinded person at the investigational site, the pharmacist or designee, will prepare the dosing syringe containing the study products. The pharmacist or designee will give the dosing syringe to the physician for dose administration, making sure that the content of the syringe is not revealed to the subject or the study staff. 6.3. Storage and Drug Accountability of Study Products All study drug products will be stored refrigerated (2ºC to 8ºC) at the Investigator’s site and should not be exposed to excessive heat, direct sunlight and never be frozen. All used and unused vials must be kept by the Investigator and stored between 2ºC and 8ºC. Used and unused vials must be stored separately. All study-specific supplies must be kept in a secure area with access limited to only authorized clinical investigation personnel. No study products may be dispensed to any person not enrolled in the study. In order to ensure that the vials reach room temperature prior to performing the study drug preparation procedure, they will be removed from the refrigerator / storage approximately 1-2 hours prior to dose administration. The study drug preparation procedure must take place within 2 hours of dosing. The Investigator must keep an accurate record of all study products received and the products used for each subject. The Monitor will check the drug accountability periodically and after completion of the study. The Sponsor will maintain a record of supplies dispatched to and returned from the site. Study drug will only be destroyed on the authorization of the Sponsor. The destruction of study products will be recorded on a Destruction Form signed by the person responsible for the destruction. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 27 of 53 Version 1.0 27 May 2009 The drug supplies will be stored at the site as noted on the Form FDA 1572. These samples will be stored under conditions consistent with the product labeling, in an area segregated from the area where testing is conducted. Access will be limited to authorized personnel only. Retained clinical supplies will be kept at the site until the completion of the study. Once the study is completed, the Sponsor will inform the site of any final disposition or shipment of retained study materials. None of the retained clinical supplies may be destroyed by the site without the written permission of Halozyme Therapeutics. 6.4. Randomization and Blinding This is a double-blind randomized study. Subjects and the investigative staff will be blinded to the contents of each study drug injection. The pharmacist or designee at the investigative site preparing syringes for injection will not be blinded. The randomization list will be provided by the designated data management team. When a subject is randomized in the study, they must always be assigned to the lowest randomization number (e.g., subject number) available at the time of randomization. Replacement subjects will be added if a subject discontinues prior to fulfilling the evaluability criteria (Section 5.2). Replacement subjects must always be assigned to the lowest available subject ID number available from the replacement randomization code. 6.5. Unblinding Procedures The randomization code will be kept in a secure, limited-access area, so that no one other than the pharmacist or designee preparing the syringes has access. The rest of the investigational staff, the study subjects, and the Sponsor and representatives of the Sponsor will not have access to the randomization code until the study as a whole has been unblinded, after the last data have been collected for the last subject in the study. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 28 of 53 Version 1.0 27 May 2009 7. ADVERSE EVENTS AND SAFETY MONITORING The safety parameters collected and monitored during this study include AEs, concomitant medications, laboratory determinations, physical examination, vital signs, and local tolerability at injection sites. 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 IRB reporting requirements. If the patient is withdrawn from the study as a result of this AE, the reason will be appropriately documented. 7.1. Adverse Event Definitions The following definitions of terms are guided by the International Conference on Harmonization and the U.S. Code of Federal Regulations (21 CFR 1998) and are included herein. The terms "serious adverse event" and "adverse event," inserted in parentheses, are commonly used terminology. 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 (serious adverse event, SAE) is any adverse drug experience (AE) occurring at any dose that results in any of the following outcomes: • Is 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 hospitalization. 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. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 29 of 53 Version 1.0 27 May 2009 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 IB. 7.2. Pre-Treatment-Emergent Adverse Events Halozyme considers AEs that occur between the time the subject signs the informed consent document for the study to the time leading up to when that subject is first exposed to study drug as “pre-treatment-emergent” events. All known pre-treatment-emergent AEs that are serious (see Section 7.1) should be immediately 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 does not intend to 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, unless the event was related to a study procedure. Events occurring during or immediately after first administration of study drug will be considered treatment-emergent AEs and will be captured on the AE CRF. 7.3. 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 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 HALO-114-201 CONFIDENTIAL Page 30 of 53 Version 1.0 27 May 2009 7.4. 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 (CTCAE, National Cancer Institute). Mild: Grade 1 NCI Common Terminology Criteria AE; 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; 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; 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. 7.5. 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. Investigators will consider AEs to be either causally related to the therapy or to be not causally related; the following definitions apply: Causally Related: The event follows a reasonable temporal sequence from administration of the study drug or in which the drug level has been established in body fluid or tissue; it follows a known or expected pattern of response to the study drug; or it can not be readily explained by well- documented concurrent or co-existent pathological processes, environmental or toxic factors, or other therapy administered to the subject. A causal relationship may be confirmed by improvement following cessation of the study drug or dose reduction, especially if the Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 31 of 53 Version 1.0 27 May 2009 reaction reappears following subsequent study drug exposure. The Investigator should refer to the SAE sections in the protocol and to the IB for additional guidance. If the clinical data are not clear, the Investigator must use his or her best judgment. The AE should be recorded as causally related if the Investigator considers the balance of the available data to be consistent with a study drug effect. Not Causally Related: The event does not meet the “causally related” criteria. The Investigator should record an AE as not causally related if the Investigator concludes that the balance of all available data is in keeping with an effect unrelated to the study drug. 7.6. Known Toxicity Profiles of Study Drugs As noted in Section 7.5 the Investigator is expected to make his/her best assessment of the causal relationship of each AE in this clinical study. The Investigator should base the assessment on all available information including, but not limited to, the Investigator’s Brochure. 7.7. Reporting of Adverse Events For the purpose of this study, all AEs, regardless of seriousness, severity, expectedness, or relationship to the study drug, will be collected if the date and time of onset of the AE was after the subject’s first exposure to any study drug and through Visit 8 (Day 14 follow up visit). There is no time 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 after Visit 8). 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 7.2), and these observations will be captured on the patient’s Medical History CRF. Events occurring during or after first administration of study drug will be considered treatment-emergent AEs and will be captured on the AE CRF. Subjects will be questioned and/or examined by the Investigator and his/her designee for evidence of AEs. The questioning of study subjects 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 subjects regarding the presence or absence of specific AEs. All serious AEs (SAEs) occurring with any patient participating in this clinical study must be immediately reported to Halozyme as described in Section 7.7.1. 7.7.1. Reporting of Serious Adverse Events All SAEs must be reported to Halozyme or designee WITHIN 1 BUSINESS DAY of discovery or notification of the event. Initial SAE information and all amendments or additions must be recorded on a Serious Adverse Event Form and faxed along with all available pertinent information to: Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 32 of 53 Version 1.0 27 May 2009 Halozyme Safety Department Fax: The minimum required information for an initial report of an SAE is: 1. Reporter’s name and contact information, 2. Protocol number, 3. Site and patient identification information, and 4. The SAE term(s) with a brief summary of the event(s) including the causality assessment, if possible. 7.7.2. Duration of Follow-Up of Adverse Events Ongoing AEs and laboratory abnormalities that are considered by the Investigator to be CAUSALLY RELATED to the study drug will be followed until resolved, returned to pre-study drug exposure level, stabilized at a level acceptable to the Investigator, or later determined by the Investigator to be Not causally related to the study drug. Ongoing events and laboratory abnormalities that are considered Not Causally Related to the study drug need only be followed until the patient’s final study visit (i.e., Visit 8, or earlier if the patient is withdrawn from study). 7.7.3. Other Information on the Reporting of Adverse Events Follow-up information regarding serious AEs must be provided to Halozyme promptly as it becomes known to the Investigator. The Institutional Review Board (IRB) that approved the clinical investigation must be notified of any fatal, life-threatening and/or serious AEs regardless of cause on a timely basis, according to the IRB’s established procedures (see Section 7.7.4). A written report of all serious AEs and deaths will be submitted by the Investigator to the IRB and to Halozyme. In this report, the Investigator will advise whether or not the AE is judged to be related to the study drug administration. All such subjects 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. 7.7.4. 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) of all SAEs and other safety information in accordance with applicable IRB’s requirements. At the completion or early termination of the study, a final report should be made to the IRB by the Investigator within the applicable IRB time frames. 7.7.5. Pregnancy A negative pregnancy test during screening for women of childbearing potential and the use of effective contraceptive methods for the duration of the study are required. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 33 of 53 Version 1.0 27 May 2009 Any pregnancy in a study patient must be immediately reported to the Investigator and in turn to Halozyme (see Section 7.7.1 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. 7.8. Precautions/Over-Dosage Normal precautions taken for a human study, including the provision of emergency equipment, will be taken during this study. Qualified and well trained physicians and medical staff will instruct the subjects. 7.9. Prior/Concomitant Medications and Procedures Any medication taken during the study other than study drug is regarded as concomitant medication. A history of current medications will be obtained from each subject during screening and recorded in the CRF under Prior/Concomitant medications. Subjects must be queried regarding both prescription and over-the-counter medications that they take. Prior/Concomitant medications taken during the time period beginning 21 days prior to initial dosing, Visit 1, through the last visit on study, anticipated to the be the follow-up visit, Visit 8, will be collected for all subjects. Concomitant medications will be updated at each subsequent visit according to the Study Schedule of Activities (see Appendix A), including any medication taken to treat an AE. At each study visit, subjects 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 the Prior/Concomitant Medications CRF. 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. Subjects may receive medical care during the study including but not limited to antibiotics, analgesics, antipyretics, etc., when clinically indicated. Whenever possible, the subject 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 4.3 of this protocol. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 34 of 53 Version 1.0 27 May 2009 8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS Primary and Secondary Analysis The primary analysis is the pair-wise intra-subject comparison of endpoint parameters for the injections with and without rHuPH20. The primary analysis is the observer’s assessment of the nickel sulfate allergen reaction site. The ICDRG scoring system will be used to conduct this assessment, which is either + (Weak [non-vesicular] positive reaction: Erythema, infiltration, possibly papules) or ++ (Strong [vesicular] positive reaction: Erythema, infiltration, papules, vesicles). Secondary analysis of the study is the comparison of safety and other endpoint parameters for the SC administration between rHuPH20 and placebo control. Dataset for Analysis The primary analysis data set for this study will consist of all evaluable subjects. An evaluable subject is one who has completed dosing (or prematurely discontinued the administration due to a toxicity) and has undergone sufficient assessments to allow an assessment of the tolerability of the administration. A secondary analysis data set will consist of all intent-to treat subjects (ITT) (i.e., all subjects enrolled, defined as subjects assigned a subject identification number at the time of study enrollment in anticipation of receiving a dose of study drug). The safety analysis data set is all subjects exposed to rHuPH20 or placebo control. The hypothesis is that 1) pre-treatment of rHuPH20 prior to nickel allergy testing will decrease the severity of the allergic skin reaction as compared to placebo control and 2) rHuPH20 will decrease the severity of nickel contact dermatitis as compared to control. The null hypothesis for this study is that rHuPH20 will not be different than what will be observed from placebo control. The alternative hypothesis is that rHuPH20 will be better than placebo control. The sample size of 20 evaluable subjects is intended to provide a sufficient sample size to allow for a meaningful comparison between rHuPH20 and placebo control. All data collected, including demographics, baseline information, contact dermatitis scoring, safety data, will be summarized by treatment group. Descriptive statistics including the number of observations (N), mean, standard deviation, median, and range will be presented for the continuous variables. Frequency and percentage will be presented for categorical variables. Figures of the individual measurements over time by subject and means by treatment group may also be provided. Descriptive statistics will be used to summarize all efficacy variables. No formal statistical comparisons between treatments are planned. All safety data will be examined, including AEs, physical examination findings, and vital signs. The incidence of subjects with AEs will be tabulated by MedDRA System Organ Class (SOC) and Preferred Term, seriousness, severity grade, relatedness to study drug, and localization to infusion site. Descriptive statistics will be used to summarize all safety variables. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 35 of 53 Version 1.0 27 May 2009 9. REGULATORY/ADMINISTRATIVE PROCEDURES AND DOCUMENTATION 9.1. 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 are necessary to comply with the principals of Good Clinical Practice (GCP). 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 Human Subjects. The study has been designed to involve the participation of representative subjects 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) and subjects as necessary in order that they may consider relevant and emerging information that could affect their willingness to continue participation in this study. 9.2. 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) with all appropriate material, including a copy of the protocol, ICF, IB, and any proposed advertisement for the study prior to the start of the study. The proposed ICF and any proposed advertisement must also be agreed to by the Sponsor (Halozyme). A copy of the IRB approval letter of the protocol and the ICF must be supplied to Halozyme prior to consent of any subjects for the study. A copy of the IRB 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 subjects until the Investigator has obtained IRB 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 members to demonstrate compliance with membership requirements. If the Investigator or a sub-investigator is a routine voting member of the IRB, Halozyme will be provided with a statement from the IRB that the Investigator/sub-investigator 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 on the progress of the study, at intervals not exceeding one year, as well as satisfying any other local IRB regulations regarding reporting. Copies of all reports to and correspondence with and from the IRB must be provided to Halozyme. Furthermore, at the completion or early termination of the study, a final report should be made to the IRB by the Investigator within the applicable IRB time frames. A copy of this report will be provided to Halozyme. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 36 of 53 Version 1.0 27 May 2009 Any significant changes or revisions in the study protocol or any changes that may alter subject risk must be approved by Halozyme (and may require FDA/other regulatory agency review and/or approval) and must be approved in writing by the IRB prior to implementation (see Section 9.7 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 notified and an amendment is subsequently provided by Halozyme and approved by the IRB. It is the Investigator's obligation to maintain an IRB correspondence file, and to make this available for review by Halozyme or its designated representatives as part of the study monitoring process. 9.3. Informed Consent A copy of the proposed ICF document must be submitted to Halozyme for review and comment prior to submission to the reviewing IRB. The ICF must be approved by the IRB and contain all elements required by all applicable federal, state, local, and institutional regulations or requirements prior to consenting a subject. 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 subject. 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 subject 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 subject’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 subject, or where appropriate, legal guardian/representative, permits access to relevant medical records by the 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 subjects prior to any study specific screening and entry into the study. The research study will be completely explained to each prospective study subject. The Investigator or designee must explain that the subject 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 subjects (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 HALO-114-201 CONFIDENTIAL Page 37 of 53 Version 1.0 27 May 2009 Each subject (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-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 subject care). A copy of the signed and dated ICF document will be provided to the subject, and a copy will be maintained with the subject'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 subject can read and understand. 9.4. 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, as necessary, the following. • College of American Pathologists (CAP) accreditation, and/or • Clinical Laboratory Improvement Amendments (CLIA) accreditation • Listing of laboratory normal reference values (for all protocol required tests) • Laboratory license • Curriculum vitae of laboratory director may also be requested 9.5. 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 Section 6. The investigational drug is to be administered/ prescribed only by the Principal Investigator or appropriately qualified physician sub-investigators named on the Form FDA 1572. Under no circumstances will the Investigator(s) allow the investigational drug to be used other than as directed by this 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 Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 38 of 53 Version 1.0 27 May 2009 drug inventory record will be provided to Halozyme or its designee, and the original will be retained at the site. 9.6. Protocol Compliance and Protocol Deviations Except for a change that is intended to eliminate an apparent immediate hazard to a study subject, the protocol shall be conducted as specified. Any such change must be reported immediately to Halozyme and to the IRB. From time to time, it is possible that Halozyme may prospectively authorize protocol deviations if the deviation is minor, and does not place subject 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 subject’s study records. The Investigator must notify the IRB of any and all protocol deviations according to the applicable IRB policy. Written documentation of all major protocol deviations must be kept in the study center file and provided to Halozyme. Examples of possible major 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 • failure to file protocol modifications, and failure to adhere to an approved protocol 9.7. 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 for review and approval prior to implementation. However, as discussed in Section 9.2, immediate implementation of a protocol amendment may be necessary if the nature of the amendment concerns the safety of subjects and is required to be implemented on an urgent basis to protect the safety of subjects. Any such immediate implementation of protocol amendments must be agreed to in advance and in writing by Halozyme. Hard copy documentation of IRB 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 ICF, the ICF must be revised accordingly and submitted to the IRB for review and approval (see Section 9.3). The approved ICF must be used to obtain informed consent from new subjects prior to enrollment and must be used to obtain informed consent from subjects already enrolled if they are potentially affected by the amendment and wish to continue participation. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 39 of 53 Version 1.0 27 May 2009 9.8. Data Collection and Case Report Forms In accordance with 21 CFR 312.62, a case report form (CRF) must be completed for each subject enrolled in the study. CRFs are an integral part of the study and subsequent reports. All data collected for each study subject 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 subject. 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 the 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 subject, the completed CRFs must be promptly reviewed, and required pages signed and dated by the 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. 9.9. 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 ensure adequacy of facilities to conduct the protocol, and to discuss with the Investigator the general obligations regarding studies with investigational new drugs. This visit will be documented in a report. If the study center has participated in a clinical study 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 Form FDA 1572, an executed Clinical Trials Agreement, and IRB approval of the protocol and informed consent form), Halozyme or its designee 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. Subject 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 Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 40 of 53 Version 1.0 27 May 2009 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 study 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 subjects 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 subject 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 subject, 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 that the study has been completed (see Section 9.11). 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 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 subjects participating in the study • Instructions for retention of study documents 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. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 41 of 53 Version 1.0 27 May 2009 9.10. 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 approvals, correspondence and reports • Signed and dated informed consent forms for each subject • Completed CRFs for each subject • Copies of any other material distributed to subjects • Any advertisements for this study • The Investigator’s final report to the IRB • 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 fifteen (15) 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. 9.11. 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, which will include, but not be limited to; notification that the study has Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 42 of 53 Version 1.0 27 May 2009 concluded, the number of subjects enrolled/ treated, and the number of adverse and serious AEs that occurred during the study. The report to the IRB will be consistent with the applicable IRB regulations and time frames. 9.12. Financial Disclosure Each investigator is required to provide financial disclosure statements or certifications to Halozyme prior to study initiation. In accordance with 21 CFR 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 (21 CFR 312.64(d)). 9.13. 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 Sponsor 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 appropriate reason, withhold approval for publication or presentation. If the Investigator is to be listed as an author of a publication prepared by the Sponsor (Halozyme), the Investigator will be given 40 days for review of the manuscript prior to publication. The Investigator expressly agrees that no publication 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 if the Study is part of a multi-center study, any publication of Results by Investigator shall not be made prior to a first multi-center publication, unless the Sponsor has provided prior written consent to do so. The Investigator also agrees that publication by Investigator of interim, non-final Results from any study shall not be made prior Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 43 of 53 Version 1.0 27 May 2009 to publication of the Final Results, unless the Sponsor has provided prior written consent to do so. 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. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 44 of 53 Version 1.0 27 May 2009 10. REFERENCES 1. Holden CA, Berth-Jones J (2004) Eczema, lichenification, prurigo and erythroderma. In: Rook’s Textbook of Dermatology. (Burns T, Breathnach S, Cox N, Griffiths C, eds), 7th edn, vol. 1. Blackwell Science Ltd: Oxford, 17.1. 2. Wolff K, Kibbi AG, Mihm MC (2003). Basic pathologic reaction of the skin. In: Frredberg IM, Eizen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI. Dermatology in General Medicine. 6th ed, vol. 1. McGraw-Hill: New York, 30-43. 3. Tammi R, Ripellino JA, Margolis RU, Tammi M (1988) Localization of epidermal hyaluronic acid using the hyaluronate binding region of cartilage proteoglycan as a specific probe. J Invest Dermatol 90:412–4. 4. Wells AF, Lundin A, Michae¨lsson G (1991) Histochemical localization of hyaluronan in psoriasis, allergic contact dermatitis and normal skin. Acta Derm Venereol 71:232–8. 5. Sakai S, Yasuda R, Sayo T, Ishikawa O, Inoue S (2000) Hyaluronan exists in the normal stratum corneum. J Invest Dermatol 114:1184–7. 6. Maytin EV, Chung HH, Seetharaman VM. Hyaluronan participates in the Epidermal Response to Disruption of the Permeability Barrier in vivo. Am J Pathology. 165(4). Oct 2004 p.p. 1331-1341. 7. Ohtani T, Memezawa A, Okuyama R, Sayo T, Sugiyama Y, Inoue S, and Aiba S. Increased Hyaluronan Production and Decreased E-Cadherin Expression by Cytokine- Stimulated Keratinocytes Lead to Spongiosis Formation. Journal of Investigative Dermatology advance online publication 1 January 2009. Available at: http://www.nature.com/jid/journal/vaop/ncurrent/abs/jid2008394a.html. 8. Williams H, Roberston C, Stewart A et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the international study of asthma and allergies in childhood. J Allergy Clinic Immunol 1999; 103:125-138. 9. Orlow Seth J Topical Calcinerin Inhibitors in Pediatric Atopic Dermatitis Pediatr Drugs 2007; 9 (5) 289-299. 10. US Food and Drug Administration. FDA Public Advisory: Elidel (pimecrolimus) cream and Protopic (tacrolimus) ointment (online) Available from URL:http://www.fda.gov/cder/drug/advisory/elidel_protopic.htm. 11. Rietschel RL and Fowler, Jr. JF. In: Fisher’s Contact Dermatitis. 4th edition Baltimore, Williams and Wilkins, 1995:29. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 45 of 53 Version 1.0 27 May 2009 11. APPENDICES Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 46 of 53 Version 1.0 27 May 2009 APPENDIX A. STUDY SCHEDULE OF EVENTS Event Screening Baseline Treatment Follow- up Day -21 to Day -14 Day 1 Day 3 Day 4 Day 5 Day 6 Day 7 Day 14 VISIT 1 VISIT 2 VISIT 3 VISIT 4 VISIT 5 VISIT 6 VISIT 7 VISIT 8 Signed and Dated Informed Consent X Inclusion/Exclusion Criteria X X Medical History X Concomitant Medicationsa X X X X X X X X Complete Physical Exam X Vital Signs (Body temperature, BP, HR, Resp. rate) Xb X X X X X X X CBCc X Pregnancy Test, Serum or Urine X X Targeted Physical Examd X X X X X X X Physical Examination of the Administration Sitee X X X X X X X Nickel Sulfate and Vehicle Control Patch Placement and Interpretation X X Dose Administration X X X X X X Test Area Assessment X X X X X X Trans-epidermal Water Loss Assessmentf X X X X Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 47 of 53 Version 1.0 27 May 2009 Event Screening Baseline Treatment Follow- up Day -21 to Day -14 Day 1 Day 3 Day 4 Day 5 Day 6 Day 7 Day 14 VISIT 1 VISIT 2 VISIT 3 VISIT 4 VISIT 5 VISIT 6 VISIT 7 VISIT 8 Digital Photographs of the Allergen Test Sitesf X X X X Chromometer Images of the Allergen Test Sitesf X X X X AE/Toxicity Assessment X X X X X X X a Con meds within 21 days prior to dosing and through the follow-up assessment on Visit 8/Day 14 to be recorded. b Include body temperature at screening visit. c WBC (with differential), Hgb, Hct, and platelets. d Includes positives on a review of systems and follow-up of findings from previous physical examinations. e Conducted immediately before patch administration, after dose administration (Treatment Regimen 2), immediately after patch removal, and prior to and 10 minutes post-dose on Study Days 3-7, and Day 14. f To be conducted at Baseline and on Days 3-5 and includes subject questionnaire (Days 3-5). Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 48 of 53 Version 1.0 27 May 2009 APPENDIX B. INTERNATIONAL CONTACT DERMATITIS RESEARCH GROUP [ICDRG] SCORING SCALE11 International Contact Dermatitis Research Group Scoring Scale Score Interpretation ? Doubtful reaction; faint macular erythema only + Weak (nonvesicular) positive reaction; erythema infiltration, possibly papules ++ Strong (vesicular) positive reaction; erythema, infiltration, papules, vesicles +++ Extreme positive reaction; bullous reaction - Negative reaction IR Irritant reaction of different types Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 49 of 53 Version 1.0 27 May 2009 APPENDIX C. NICKEL SULFATE ALLERGY SYSTEM Application for Nickel Sulfate Concentration Determination: Preparing Patch: Place a filter paper disc in the chamber and moisten thoroughly with the 1%, 2.5% or 5% nickel sulfate solution. Applying Patch: 1. Skin should be clean, healthy, and free of ointments, lotions, powders, acne, dermatitis, scars, hair or any other condition that might interfere with the application of the chamber or interpretation of the results. 2. The subject should stand or sit in a relaxed position. Apply prepared patches to the back. 3. Affix tape to the skin at the lower end and slowly roll patches up the back, pushing out air. Gently press patch to skin to ensure an even distribution of allergens. Rub the tape gently but firmly to ensure good adherence. 4. Mark the four corners of each unit with Chemotechnique Skin Markers to indicate each unit’s location on the subject’s skin. 5. Subjects should refrain from exposing patch tests to excess moisture or sweat and should return for patch test removal in 48 hours. 6. Record in the source documentation the location of the patch and the nickel sulfate concentration for each location. Removing Patch: After 48 hours, remove the patch. The initial visual patch imprint on the patient's back indicates excellent occlusion. Reading the Results: 1. Allow about 20 to 30 minutes for the transient skin irritation and visual patch imprints to subside before interpreting the test results. 2. Reading will be done at approximately48 hours post application. 3. Use the Reading Plate to facilitate the reading. 4. Use the International Contact Dermatitis Research Group Scoring Scale to interpret the test results (Appendix B). Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 50 of 53 Version 1.0 27 May 2009 APPENDIX D. PHOTOGRAPHIC PROCEDURE Serial Photography for Contact Dermatitis Locations: ID card/color card view: 2 each Close-up view of target area(s): 2 each Anatomical location view of target area(s): 2 each Digital Format Photography Equipment: Media: SD Memory card, 1GB Camera: Nikon D80 (10.2MP) Lens: Nikkor 60mm f2.8 Flash: Canfield TwinFlash system Other: Canfield MM scale arm attachment Blue deluxe felt backdrop (3’x8’) Color card/Patient ID card holder Digital Format Photographic Considerations: Each memory card will contain one patient photo session. Procedure: In these clinical photographs, for the duration of the study, the only variable allowed to change is the skin condition itself. Therefore, anything extraneous to the condition (jewelry, clothing, furniture, walls, etc.) is to be eliminated from the fields to be photographed, from the baseline through the final photographs. The necessity of good end-of-study photos should be stressed to the patients to ensure their cooperation. Lighting, framing, exposure and reproduction ratios must be held constant. In the end, the pictures should read like a time-lapse movie. 1. The supplied equipment is to be used exclusively for this study. Modifications, adjustments or repairs of the camera equipment are not to be undertaken without the expressed instruction of Canfield Scientific, Inc. 2. After obtaining informed consent, the patients are prepped for photography. All jewelry, makeup and clothing are to be removed from the photographic field prior to photography. Target area(s) are identified for photos. The supplied standardized blue deluxe felt background is to be used for the photographs. Do not use folded or crimped material. 3. Magnifications for digital camera: A standardized reproduction ratio (35MM film equivalent) of 1:3 (red index on lens focusing barrel) is used for the target area close-up views. Focusing at 1:3 is accomplished with the use of the mm scale arm attachment dictating distance. A standardized reproduction ratio of 1:9 (green index on lens focusing barrel) is used for the target area anatomical views. Focusing at 1:9 is accomplished by moving the camera/lens close to/away from the target area until it is in focus. 4. Apertures for digital camera: Each and every target area close-up view is taken at f/22. Each and every target area anatomical location view is taken at f/16. 5. SD is the media format used to capture images. If there is any doubt as to the correctness of technique or data, re-shoots are strongly urged. Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 51 of 53 Version 1.0 27 May 2009 6. Each SD memory card at every photographic session includes an exposure series of: a. Two exposures of patient’s ID card which includes the following legible information in black indelible ink: Protocol No. Date Investigator Number Visit Week Number Patient's Initials Patient's ID Number Photographer's Initials Color card b. Two exposures of close-up view of target area(s) c. Two exposures of anatomical location view of target area(s) 7. Upon completion of the photographic session, the contents of the SD memory card are uploaded to the Canfield Clinical Website once a patient’s photographic session has been recorded on it. A secure, validated, compliant web server set up at Canfield is used for this secure transfer of study images by study sites. Images are transferred the day recorded. Remote access to all images by the sponsor is also provided. Only approved individuals by sponsor have access to the website. 8. Upon a successful upload of all images contained on the SD memory card, the memory card’s images are deleted and the memory card re-used for the next photographic session. These memory cards are reserved for use on this project only. Any doubt as to the correctness of technique or data warrants a re-shoot then and there. 9. All images are monitored for technical adherence according to Canfield’s internal SOPs. The study site is contacted if errors or deviation from photographic guidelines are observed. All communication to the study site relating to the photography is the responsibility of Canfield. 10. All supplied photographic equipment and photographic originals remain the property of the sponsor. One set of photography result report forms for all photographic time-points is supplied for the Investigators' study records. 11. Questions or problems regarding the photographic portion of this study protocol should be directed to the respective Canfield Project Manager assigned to the study. Canfield Scientific, Inc. 253 Passaic Ave. Fairfield, NJ 07004 Telephone: Toll- Free: Facsimile: E-mail: Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 52 of 53 Version 1.0 27 May 2009 APPENDIX E. ABBREVIATIONS ABBREVIATION TERM AE Adverse event BP Blood pressure BUN Blood urea nitrogen ºC Degrees Celsius CAP College of American Pathologists CFR Code of Federal Regulations CLIA Clinical Laboratory Improvement Amendments CRF Case report form CTCAE Common Terminology Criteria for Adverse Events DESI Drug Efficacy Study Implementation EC Ethics Committee FDA U.S. Food and Drug Administration GCP Good Clinical Practice Hct Hematocrit Hgb Hemoglobin HIPAA Health Insurance Portability Act of 1996 HIV Human immunodeficiency virus HR Heart rate IB Investigator’s Brochure ICDRG International Contact Dermatitis Research Group ICF Informed consent form ICH International Conference on Harmonization ID Intradermally IND Investigational New Drug IRB Institutional Review Board NCI National Cancer Institute PHI Personal Health Information RH Relative humidity rHuPH20 Recombinant human hyaluronidase enzyme PH20 SAE Serious adverse event Halozyme Therapeutics, Inc. Protocol HALO-114-201 CONFIDENTIAL Page 53 of 53 Version 1.0 27 May 2009 ABBREVIATION TERM SC Subcutaneous SD Secure digital SGOT Serum glutamic-oxaloacetic transaminase SGPT Serum glutamate pyruvate transaminase SOPs Standard operating procedures TEWL Trans-epidermal water loss USP United States Pharmacopoeia VAS Visual analog scale WBC White blood cells SAP_001.pdf: Statistical Analysis Plan Halozyme Therapeutics, Inc. Protocol Number: HALO-114-201 A Prospective, Randomized, Double-blind, Placebo-controlled, Single-center Study of the Intradermal Injection of rHuPH20 or Placebo in Subjects with Nickel Allergic Contact Dermatitis Protocol Version 1.0 (27May2008) Sponsor: Halozyme Therapeutics, Inc. (Halozyme) 11388 Sorrento Valley Road San Diego, California 92121 Prepared by: Synteract, Inc. 5759 Fleet Street, Suite 100 Carlsbad, CA 92008 Version: Final Date of Creation: 28 July 2009 Last Updated: 9 October 2009 NCT# 00928447 Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 2 of 64 TABLE OF CONTENTS LIST OF ABBREVIATIONS ....................................................................................................... 3 DEFINITIONS ............................................................................................................................... 4 1. INTRODUCTION .................................................................................................................. 5 2. OBJECTIVES ........................................................................................................................ 5 3. STUDY OVERVIEW ............................................................................................................ 5 TREATMENT REGIMEN 1 (TR1-1 – TR1-4): ............................................................................. 6 TREATMENT REGIMEN 2 (TR2-5 – TR2-8): ............................................................................. 7 4. GENERAL ANALYSIS CONSIDERATIONS ................................................................... 7 5. ANALYSIS POPULATIONS ................................................................................................ 8 6. SUBJECT DISPOSITION..................................................................................................... 9 7. DEMOGRAPHIC AND BASELINE CHARACTERISTICS ............................................ 9 8. EFFICACY ANALYSES ........................................................................................................... 9 8.1 PRIMARY VARIABLES .......................................................................................................................... 9 8.2 SECONDARY VARIABLES ..................................................................................................................10 8.3 DESCRIPTIVE PARAMETERS .............................................................................................................10 8.4 BASELINE VALUES .............................................................................................................................10 8.5 HANDLING MISSING DATA ..............................................................................................................11 8.6 INTERIM ANALYSES ...........................................................................................................................11 9. STUDY ANALYSIS ............................................................................................................. 11 9.1 STATISTICAL ANALYSES ..................................................................................................................11 9.2 EXPLORATORY ANALYSES ..............................................................................................................12 10. SAFETY ANALYSES .......................................................................................................... 12 10.1 ADVERSE EVENTS ...............................................................................................................................12 10.2 VITAL SIGNS .........................................................................................................................................13 10.3 PHYSICAL EXAMINATION .................................................................................................................13 10.4 PRIOR AND CONCOMITANT MEDICATIONS .................................................................................13 11. SAMPLE SIZE CALCULATION ...................................................................................... 14 APPENDIX A: LIST OF TABLES, LISTINGS AND FIGURES .......................................... 15 APPENDIX B: TABLE LAYOUTS .......................................................................................... 18 APPENDIX C: LISTING LAYOUTS ....................................................................................... 34 APPENDIX D: FIGURE LAYOUTS ........................................................................................ 61 Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 3 of 64 LIST OF ABBREVIATIONS AEs Adverse Events ATC Anatomical/Therapeutic/Chemical BP Blood Pressure CBC Complete Blood Count CRF Case Report Form CTCAE Common Terminology Criteria for Adverse Events CSR Clinical Study Report ET Early Termination ICDRG International Contact Dermatitis Research Group ID Intradermally ITT Intent-to-Treat MedDRA Medical Dictionary for Regulatory Activities RBC Red Blood Cell Count rHuPH20 Recombinant Human Hyaluronidase enzyme PH20 RTF Rich Text Format SAE Serious Adverse Event SD Standard Deviation TEWL Trans-Epidermal Water Loss TEAE Treatment-Emergent Adverse Event WBC White Blood Cells WHO World Health Organization Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 4 of 64 DEFINITIONS Adverse Event An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. Injection Type rHuPH20 or Placebo Pre-Treatment-emergent AE AEs occur between the time the subject signs the informed consent document for the study to the time leading up to when that subject is first exposed to study drug. Serious AE An AE occurring at any dose that: results in death; is a life-threatening event; requires in-subject hospitalization or prolongation of an existing hospitalization; results in a persistent or significant disability/incapacity; results in a congenital anomaly/birth defect in the offspring of a subject who received study drug, or is any other important medical event. Treatment-emergent AE AEs with an onset time during or after the initial administration of study drug. Treatment Regimens Treatment Regimen 1 and Treatment Regimen 2 Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 5 of 64 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 HALO-114-201 [A prospective, randomized, double-blind, placebo-controlled, single-center study of the intradermal injection of rHuPH20 or placebo in subjects with nickel allergic contact dermatitis]. The purpose of this plan is to provide specific guidelines from which the analysis will proceed. Any deviations from these guidelines will be documented in the clinical study report (CSR). 2. OBJECTIVES The primary objectives of the study are: • Determine the treatment effect of rHuPH20 or placebo control injection on the exposure to topical nickel allergen (Treatment Regimens 1 and 2) • Determine the time to onset and severity of cutaneous reaction to nickel allergen after pre-treatment with rHuPH20 or placebo control (Treatment Regimen 2) • Assess the safety and tolerability of the rHuPH20 injection Secondary objectives include: • Proportion (%) of subjects who, with pre-treatment, have a ≥ 1 grade reduction of the cutaneous reaction to nickel sulfate in at least one patch region at 48 hours • Proportion (%) of subjects with a ≥ 1 grade reduction of the cutaneous reaction to nickel sulfate in at least one patch region after treatment • Proportion (%) of subjects that have a ≥ 1 grade reduction of the cutaneous reaction to nickel sulfate in at least one patch region at Days 4, 5, 6, 7 and 14. • Safety and tolerability of the injection based on AEs, physical examinations, and vital signs Descriptive-Only parameters include: • Chromometer readings of the allergen test sites on Day 1, Day 3 (48 hrs), Day 4 (72 hrs) and Day 5 (96 hrs) after the placement of the patches • TEWL (Trans-epidermal water loss) assessment on Day 1, Day 3 (48 hrs), Day 4 (72 hrs) and Day 5 (96 hrs) after the placement of the patches 3. STUDY OVERVIEW This is a pilot Phase II, prospective, double-blind, placebo-controlled study to compare the efficacy, safety, and tolerability of rHuPH20 or placebo control administered Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 6 of 64 intradermally (ID) in the prevention and treatment of subjects with contact allergy to nickel. A maximum of 30 subjects may be enrolled to ensure that at least approximately 20 evaluable subjects complete the study. This study will be conducted at a dermatology unit. There are two treatment regimens (Treatment Regimens 1 and 2) in this study, which will run in parallel. Within each regimen, four nickel sulfate patches will be used. The four patch areas will be randomized to rHuPH20 or placebo for each subject with 1:1 ratio. The randomization for Treatment Regimen 1 will be independent of the randomization for Treatment Regimen 2. Figure 1: Study Treatment Arm Randomization rHuPH20 or Placebo (TR1-1) rHuPH20 or Placebo (TR1-2) rHuPH20 or Placebo (TR1-3) rHuPH20 or Placebo (TR1-4) rHuPH20 or Placebo (TR2-5) rHuPH20 or Placebo (TR2-6) rHuPH20 or Placebo (TR2-7) rHuPH20 or Placebo (TR2-8) Subjects with a known history of contact allergy to nickel will be recruited. During the screening period, subjects will be tested to confirm the presence of cutaneous nickel sensitivity using 1, 2.5 and 5% nickel sulfate patches. The concentration of nickel sulfate for each subject that causes no greater than a ++ cutaneous reaction using the International Contact Dermatitis Research Group (ICDRG) scoring scale will be the concentration administered on Day 1. Once the concentration is determined for the subject, the patches in Treatment Regimen 1 and Treatment Regimen 2 will use the same concentration patches. Treatment Regimen 1 (TR1-1 – TR1-4): This regimen will assess the treatment of contact allergy to nickel: On Day 1, a single row of four patches (1, 2.5, or 5% nickel sulfate patches; determined for each subject during the Screening period) will be placed on the upper space on the upper back. After 48 hours, the patches will be removed and an assessment will be made of the reaction site as per the ICDRG scoring system. Each subject will receive in the center of the Treatment Regimen 2 Treatment Regimen 1 Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 7 of 64 cutaneous reaction an ID syringe push bolus injection of either rHuPH20 or placebo control. Each injection will be administered once daily for 5 days. Prior to each daily injection, subjects will be evaluated for efficacy, safety, and tolerability. A final evaluation will be conducted 7 days after the last dose of study treatment. Treatment Regimen 2 (TR2-5 – TR2-8): This regimen will assess the prevention and treatment of contact allergy to nickel sulfate. Each subject will receive in the center of each lower space on the back, either an ID syringe push bolus injection of rHuPH20 or placebo control. Exactly 10 minutes after the injection, a single row of four patches (1, 2.5, or 5% nickel sulfate patches; determined for each subject during the Screening period) will be placed over the center of the ID injection. After 48 hours, the patches will be removed and an assessment will be made of the reaction site as per the ICDRG scoring system. The subject will receive an ID injection of the same study drug from pre-treatment in the center of the cutaneous reaction once daily for 5 days. Subjects will be evaluated for efficacy, safety, and tolerability, on a daily basis. A final evaluation will be conducted 7 days after the last dose of study treatment. For a given subject, the anticipated duration of time on study is up to 35 days, which include Visit 1 (screening, within 21 days prior to receiving study drug), Visit 2 (Day 1), Visit 3 (Day 3), Visits 4 – 7 (Day 4 – 7) and Visit 8 (Day 14). 4. GENERAL ANALYSIS CONSIDERATIONS The statistical analyses will be reported using summary tables, figures, and data listings. Descriptive statistics will be used to summarize all efficacy variables. No formal statistical comparisons between treatments are planned. Continuous variables will be summarized with means, standard deviations, medians, minimums, and maximums. Categorical variables will be summarized by counts and by percentage of subjects in corresponding categories. Individual subject data obtained from the case report forms (CRFs), local lab and any derived data will be presented by subject in data listings. The analyses described in this plan are considered a priori, in that they have been defined prior to database lock and prior to breaking the blind. Any analyses performed subsequent to breaking the blind will be considered post-hoc. Post-hoc analyses will be identified in the CSR. Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 8 of 64 All analyses and tabulations will be performed using SAS Version 9.1 on a PC platform. Tables and listings will be presented in RTF format. Figures will be presented in PDF format. Upon completion, all SAS programs will be validated by an independent programmer. In addition, all program output will undergo a senior level statistical review. The validation process will be used to confirm that statistically valid methods have been implemented and that all data manipulations and calculations are accurate. Checks will be made to ensure accuracy, consistency with this plan, consistency within tables, and consistency between tables and corresponding data listings. Upon completion of validation and quality review procedures, all documentation will be collected and filed by the project statistician or designee. 5. ANALYSIS POPULATIONS The ITT population will include all enrolled subjects (all subjects who got a subject identification number assigned at the time of study enrollment in anticipation of receiving a dose of study drug). The Safety population will include all subjects who receive at least one dose of study drug. The Evaluable population will include all evaluable subjects. An evaluable subject is one who has completed dosing (or prematurely discontinued the administration due to a toxicity) and has undergone sufficient assessments to allow an assessment of the tolerability of the administration. A subject is considered to have undergone sufficient assessments to allow an assessment of the tolerability of the administration if the subject has at least one ICDRG score reported on Day 4 or later. A subject is considered to have prematurely discontinued the administration due to toxicity if the subject has Adverse Event checked as the reason for not completing the study on the Study Completion/Termination CRF page, and has Drug Withdrawn as the action taken with study drug checked on the Adverse Event CRF page. Efficacy analyses will be run on the Evaluable population and the ITT (Intent-to-Treat) population. Analyses run on the Evaluable population will be considered the primary analyses. Safety analyses will be run on the Safety population. Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 9 of 64 6. SUBJECT DISPOSITION Subject disposition information will be summarized for all subjects. Summaries will include: the number of subjects in each analysis (ITT, Safety, Evaluable) population, the number of subjects replaced, the number of subjects completing the study and the primary reason for discontinuation. 7. DEMOGRAPHIC AND BASELINE CHARACTERISTICS Demographic and baseline characteristics variables include: age, sex, ethnicity, race and the concentration of nickel sulfate assigned. Other baseline characteristics include: medical history and hematology and CBC with differential, including incidence rates of clinically significant abnormalities at screening. Demographic and baseline characteristics will be summarized for the Safety, ITT and Evaluable analysis populations. 8. EFFICACY ANALYSES Efficacy analyses will be carried out on both the Evaluable and the ITT analysis populations. 8.1 Primary Variables The primary efficacy endpoint will be based on the International Contact Dermatitis Research Group (ICDRG) Scoring Scale. Using the ICDRG Scoring Scale, each score will be assigned a Sponsor-defined “grade”. Scores with stronger reactions will be assigned grades with higher values with a maximum grade of 3; scores with weaker reactions will receive lower values with a minimum grade of 0. Grade assignments based on the ICDRG Scoring Scale are shown in the table below. International Contact Dermatitis Research Group (ICDRG) Scoring Scale Grade Score Interpretation 0 - Negative reaction 1/2 ? Doubtful reaction; faint macular erythema only 1 + Weak (nonvesicular) positive reaction; erythema, infiltration, papules, vesicles 2 ++ Strong (vesicular) positive reaction; erythema, infiltration, papules, vesicles 3 +++ Extreme positive reaction; bullous reaction NA IR Irritant reaction of different types Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 10 of 64 Treatment effect of rHuPH20 or placebo control injection on the exposure to topical nickel allergen will be assessed using ICDRG grades for Treatment Regimens 1 and 2 at Day 3 through Day 7 and Day 14. Regimen 2 only: For each subject, the day of maximal ICDRG score will be determined for each injection type (rHuPH20 and Placebo). The maximal ICDRG score will be the highest score reported for each subject. If the maximal ICDRG score for a particular subject is reported more than one time, the first instance will be used to determine the day when the maximal ICDRG score was reached. 8.2 Secondary Variables Analyses of the secondary endpoints will be based on the grades shown in ICDRG table in Section 8.1. For Treatment Regimen 1 and 2, proportion of subjects that have a ≥ 1 grade reduction of the cutaneous reaction to nickel sulfate in at least one patch region after treatment. For Treatment Regimen 2, proportion of subjects that have a ≥ 1 grade reduction of the cutaneous reaction to nickel sulfate in at least one patch region at 48 hours (Day 3) will be assessed. 8.3 Descriptive Parameters TEWL (Trans-epidermal water loss) measurements and Chromometer readings will be carried out at Day 1, Day 3, Day 4 and Day 5. On each day, TEWL (Trans-epidermal water loss) measurements and Chromometer readings will be collected for each treatment region. 8.4 Baseline Values For analyses based on grades, each treatment region will be assigned its own baseline value. The baseline values for regions under Treatment Regimen 1 and 2 will be the values collected at Day 3. The baseline values for TEWL measurements and Chromometer readings will be the assessments collected on Day 1. Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 11 of 64 8.5 Handling Missing Data No missing values will be imputed. 8.6 Interim Analyses No interim analyses are planned for this study. 9. STUDY ANALYSIS The hypothesis for this study is that 1) pre-treatment or rHuPH20 prior to nickel allergy testing will decrease the severity of the allergic skin reaction as compared to placebo control and 2) rHuPH20 will decrease the severity of nickel contact dermatitis as compared to control. The null hypothesis is that rHuPH20 will not be different than what will be observed from placebo control. Figures, listings and descriptive statistics will be used to summarize all efficacy variables. No formal statistical comparisons between treatments are planned. 9.1 Statistical Analyses The primary analysis is the pair-wise intra-subject comparison of endpoint parameters for the injections with and without rHuPH20. The secondary analysis covers safety and other endpoint parameters (see Section 10). ICDRG scores will be shown for Treatment Regimen 1 and Treatment Regimen 2 by injection types (rHuPH20 or Placebo) at Baseline, Day 4, Day 5, Day 6, Day 7 and Day 14. ICDRG scores will be reported by subject using figures (Figure 1) and listings (Listing 8). A qualitative medical review of the ICDRG scores will be used to investigate: • Possible treatment effect of rHuPH20 or placebo control injection on the exposure to topical nickel allergen. • Proportion of subjects that have a ≥ 1 grade reduction in at least one patch region. At the conclusion of the study, findings from the medical review will be summarized in the clinical study report. For Treatment Regimen 2, the day of maximal ICDRG Score will be used to assess the possible effect each injection type has on the onset of reaction to topical nickel allergen. The day of maximal ICDRG Score will be summarized for each injection type using counts and percentages (Table 6.1/6.2). Possible days of maximal ICDRG Score include Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 12 of 64 the following: Day 4, Day 5, Day 6, Day 7, and Day 14. If the maximal ICDRG Score for an injection type occurred prior to treatment, the subject will be reported as never having had an ICDRG Score more severe than Day 3 for summary purposes. 9.2 Exploratory Analyses TEWL (Trans-epidermal water loss) assessments at Baseline (Day 1), Day 3, Day 4 and Day 5 will be summarized for Treatment Regimen 1 and Treatment Regimen 2 by injections type (rHuPH20 or Placebo). Summaries of TEWL assessments will be generated by subject using figures (Figure 2) and listings (Listing 9). A review of the TEWL assessments summaries will be used to investigate possible treatment effect of rHuPH20 or placebo control injection on the exposure to topical nickel allergen. Analysis of Chromometer readings will be carried in the same manner as the analysis for TEWL assessments (Figure 3, Listing 11). All Chromometers readings reported will be presented in listings; however, only reported “a” scale readings will be considered for figures. 10. SAFETY ANALYSES All subjects who received study drug will be included in the safety analyses, analyzed according to the study treatment actually received. 10.1 Adverse Events All adverse event summaries will be restricted to Treatment Emergent Adverse Events (TEAE), which are defined as those AEs that occurred after dosing and those existing AEs that worsened during the study. Verbatim terms on case report forms will be mapped to preferred terms and system organ classes using the MedDRA dictionary (version 12.0). Each adverse event summary will be displayed for the Safety population. Summaries that are displayed by system organ class and preferred terms will be ordered by descending order of incidence of system organ class and preferred term within each system organ class. Summaries of the following types will be presented: • Subject incidence of TEAEs and total number of unique TEAEs by MedDRA system organ class and preferred term. • Subject incidence of TEAEs by MedDRA system organ class, preferred term, and highest severity. At each level of subject summarization a subject is classified according to the highest severity if the subject reported one or more events. A Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 13 of 64 missing column will be added to the summary table if any TEAEs are reported with missing severity. • Subject incidence of TEAEs by MedDRA system organ class, preferred term, and closest relationship to study drug (Related/Not Related). At each level of subject summarization a subject is classified according to the closest relationship if the subject reported one or more events. AEs with a missing relationship will be considered related for this summary. • Subject incidence of serious TEAEs and total number of unique serious TEAEs by MedDRA system organ class and preferred term. • Subject incidence of TEAEs and total number of unique serious TEAEs leading to discontinuation of study drug or premature withdrawal from study. • Subject incidence of TEAEs reported after physical examination of injection site and safety review on Day 1 (for Treatment Regimen 2 only), Day 3 through Day 7 and Day 14 will be presented by injection type. 10.2 Vital Signs Assessment of vital signs includes the measurement of blood pressure (systolic and diastolic), heart rate, and respiration rate and body temperature (at screening). Vital signs will be recorded one time at Screening; pre- and post injection vital sign results will be collected on the following days: Day 1, Day 3, Day 4, Day 5, Day 6, Day 7, Day 14. Vital signs will be summarized using descriptive statistics at each visit time point. Changes from baseline will also be summarized. Baseline is defined as the pre-dose result for the visit under consideration. 10.3 Physical Examination Physical examination results will be summarized with shift tables comparing baseline to the most abnormal post baseline assessment. Possible assessments for each body system include: Normal/Return to Normal and Abnormal. Baseline will be defined as the last non-missing result recorded before injection. 10.4 Prior and Concomitant Medications Verbatim terms on case report forms will be mapped to Anatomical/Therapeutic/Chemical (ATC) Level 4 categories and Drug Reference Names using the World Health Organization (WHO) dictionary (March 1, 2009). Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 14 of 64 Prior medications are those medications taken within 21 days prior to the initial dose of study drug. Concomitant medications are those medications taken after the initial dose of study drug. Prior and concomitant medications will be summarized for each treatment by WHO ATC class and medication name. These summaries will present the number and percentage of subjects using each medication. Subjects may have more than one medication per ATC category and medication. At each level of subject summarization, a subject is counted once if he/she reported one or more medications at that level. Each summary will be ordered by descending order of incidence of ATC class and medication within each ATC class. 11. SAMPLE SIZE CALCULATION The sample size of 20 evaluable subjects is intended to provide a sufficient sample size to allow for a meaningful comparison between rHuPH20 and placebo control. Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 15 of 64 APPENDIX A: LIST OF TABLES, LISTINGS AND FIGURES List of Tables Table Number Table Description 1 Subject Disposition 2 Demographic and Baseline Characteristics 3 Abnormal Medical History 4 Hematology and CBC with Differential at Screening 5 Incidence of Clinically Significant Laboratory Abnormalities at Screening 6 Day of Maximal ICDRG Score 7 Adverse Events by System Organ Class (Safety Population) 8 Adverse Events by System Organ Class and Severity [1] (Safety Population) 9 Adverse Events by System Organ Class and Relationship to Study Drug [1] (Safety Population) 10 Serious Adverse Events by System Organ Class (Safety Population) 11 Adverse Events Leading to Discontinuation of Study Drug or Premature Withdrawal of From Study 12 Adverse Events by System Organ Class and Injection Type (Safety Population) 13 Vital Signs (Safety Population) 14 Physical Examination (Safety Population) 15 Concomitant Medications (Safety Population) Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 16 of 64 List of Data Listings Listing Number Listing Description CRF Plate(s) 1 Subject Disposition Derived 2 Inclusion/Exclusion Criteria 2,3,4 3 Demographics 1 4 Medical History 5 5 Hematology and CBC with Differential 8 6 Lab Normal - Hematology 350 7 Pregnancy Test 9 8 ICDRG Score 13,15 9 TEWL (Trans-Epidermal Water Loss) Assessment 17 10 Digital Photographs 17 11 Chromometer 18 12 Subject Diary 19 13 Screening Nickel Sulfate and Vehicle Control Patches 11 14 Study Drug Administration – Treatment Regimen 1 12,13,14 15 Study Drug Administration – Treatment Regimen 2 15,16 16 Adverse Events 97 17 Serious Adverse Events 97 18 Vital Signs 7 19 Physical Examination 6,10 20 Comments 96 21 Prior and Concomitant Medications 98 22 Deaths 101 23 Subject Visit Derived Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 17 of 64 List of Figures Figure Number Figure Description 1 ICDRG Scores by Day 2 Individual TEWL Scores by Day and Injection Site 3 Individual a-Scale Chromometer Baseline Corrected Scores by Day and Injection Site Halozyme Therapeutics, Inc. Protocol HALO-114-201 Statistical Analysis Plan 9 October 2009 Page 18 of 64 APPENDIX B: TABLE LAYOUTS Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Table 1 Page 19 of 64 Subject Disposition All Subjects Total ITT Population[1] N Safety Population [2] n (%) Evaluable Population [3] n (%) Number of Subjects Replaced [4] n (%) Completed Study Yes n (%) No n (%) Primary Reason for Discontinuation Protocol Violation n (%) Lost to Follow-up n (%) Adverse Event n (%) Non-compliance n (%) Subject Decision n (%) Investigator Decision n (%) Other n (%) [1] Intent to Treat (ITT): Enrolled subjects who signed informed consent. [2] Received at least one dose of study drug. [3] An evaluable subject is one who has completed dosing (or prematurely discontinued the administration due to a toxicity) and has undergone sufficient assessments to allow an assessment of the tolerability of the administration. [4] Enrolled subjects but not meeting the criteria of evaluability. path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Table 2 Page 20 of 64 Demographic and Baseline Characteristics All Subjects ITT Safety Evaluable (N= ) (N= ) (N= ) Age (years) [1] N n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx Sex Male n (%) n (%) n (%) Female n (%) n (%) n (%) Ethnicity Hispanic or Latino n (%) n (%) n (%) Not Hispanic or Latino n (%) n (%) n (%) Race American Indian or Alaska Native n (%) n (%) n (%) Asian n (%) n (%) n (%) Black or African American n (%) n (%) n (%) Native Hawaiian or Other Pacific Islander n (%) n (%) n (%) White n (%) n (%) n (%) Other n (%) n (%) n (%) More than one race marked n (%) n (%) n (%) Concentration of nickel sulfate (%) 1 n (%) n (%) n (%) 2.5 n (%) n (%) n (%) 5 n (%) n (%) n (%) [1] Age at the date of informed consent signed. path\t_program.sas date time Page 1 of x Halozyme Therapeutics, Inc. Protocol HALO-114-201 Table Page 21 of 64 Abnormal Medical History All Subjects ITT Safety Evaluable Body System (N= ) (N= ) (N= ) Respiratory n (%) n (%) n (%) Cardiovascular n (%) n (%) n (%) Gastrointestinal n (%) n (%) n (%) Hepatic n (%) n (%) n (%) Endocrine/Metabolic n (%) n (%) n (%) Central and Peripheral Nervous System n (%) n (%) n (%) Hematopoietic/Lymphatic n (%) n (%) n (%) Dermatological n (%) n (%) n (%) Musculoskeletal n (%) n (%) n (%) Genitourinary/Reproductive n (%) n (%) n (%) Psychiatric n (%) n (%) n (%) Alcohol/Drug Abuse n (%) n (%) n (%) Drug Allergy n (%) n (%) n (%) Non-Drug Allergy n (%) n (%) n (%) HEENT n (%) n (%) n (%) Other n (%) n (%) n (%) path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Table Page 22 of 64 Hematology and CBC with Differential at Screening All Subjects ITT Safety Evaluable Laboratory Parameter (N= ) (N= ) (N= ) WBC (X 1000/uL) N n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx RBC (X Mil/uL) N n n n Mean (SD) xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) Median xx.x xx.x xx.x Min, Max xx, xx xx, xx xx, xx .. path\t_program.sas date time Programmer note: Table will include the following hematology parameters: Hemoglobin (g/dL), Hematocrit (%), Platelets (X 1000/uL), Neutrophils (segs) (%), Neutrophils (bands) (%), Lymphocytes (%), Monocytes (%), Eosinophils (%) and Basophils (%). Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Table Page 23 of 64 Incidence of Clinically Significant Laboratory Abnormalities at Screening All Subjects Any Clinically Significant Abnormalities? ITT (N= ) Safety (N= ) Evaluable (N= ) WBC n (%) n (%) n (%) RBC n (%) n (%) n (%) Hemoglobin n (%) n (%) n (%) Hematocrit n (%) n (%) n (%) Platelets n (%) n (%) n (%) Neutrophils (segs) n (%) n (%) n (%) Neutrophils (bands) n (%) n (%) n (%) Lymphocytes n (%) n (%) n (%) Monocytes n (%) n (%) n (%) Eosinophils n (%) n (%) n (%) Basophils n (%) n (%) n (%) path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Table 6.1 Page 24 of 64 Day of Maximal ICDRG Score Evaluable Population Treatment Regimen 2 (N=) Day of ICDRG Maximal Severity Score rHuPH20 Placebo Never had an ICDRG Score More Severe than Day 3 n (%) n (%) Day 4 n (%) n (%) Day 5 n (%) n (%) Day 6 n (%) n (%) Day 7 n (%) n (%) Day 14 n (%) n (%) Note: For both injection types (rHuPH20 and Placebo), each subject will contribute one result based on the single most severe patch assessment reported. path\t_program.sas date time Programmer Note: Table 6.2 will contain the same information for the ITT population. Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Table Page 25 of 64 Treatment Emergent Adverse Events by System Organ Class Safety Population Safety Population (N= ) Number of Number of System Organ Class / Preferred Term Subjects [1] Events Subjects Reporting at Least One Adverse Event n (%) n System Organ Class 1 n (%) n Preferred Term 1 n (%) n Preferred Term 2 . . n (%) n System Organ Class 2 n (%) n Preferred Term 1 n (%) n Preferred Term 2 n (%) n [1] At each level of summation (overall, system organ class, preferred term), subjects reporting more than one adverse event are counted only once. path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Table Page 26 of 64 Treatment Emergent Adverse Events by System Organ Class and Severity Safety Population Safety Population (N= ) System Organ Class / Preferred Term [1] Mild Moderate Severe Life Threatening Fatal Subjects Reporting at Least One Adverse Event n (%) n (%) n (%) n (%) n (%) System Organ Class 1 n (%) n (%) n (%) n (%) n (%) Preferred Term 1 n (%) n (%) n (%) n (%) n (%) Preferred Term 2 . . n (%) n (%) n (%) n (%) n (%) System Organ Class 2 n (%) n (%) n (%) n (%) n (%) Preferred Term 1 n (%) n (%) n (%) n (%) n (%) Preferred Term 2 . . n (%) n (%) n (%) n (%) n (%) [1] At each level of summation (overall, system organ class, preferred term), subjects reporting more than one adverse event are counted only once using the highest severity. path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Table Page 27 of 64 Treatment Emergent Adverse Events by System Organ Class and Relationship to Study Drug Safety Population Safety Population (N= ) System Organ Class / Preferred Term [1] Related Not Related Subjects Reporting at Least One Adverse Event n (%) n (%) System Organ Class 1 n (%) n (%) Preferred Term 1 n (%) n (%) Preferred Term 2 . . n (%) n (%) System Organ Class 2 n (%) n (%) Preferred Term 1 n (%) n (%) Preferred Term 2 n (%) n (%) [1] At each level of summation (overall, system organ class, preferred term), subjects reporting more than one adverse event are counted only once using the closest relationship to study drug. path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Table 28 Page 28 of 64 Treatment Emergent Serious Adverse Events by System Organ Class Safety Population Safety Population (N= ) Number of Number of System Organ Class / Preferred Term Subjects [1] Events Subjects Reporting at Least One Serious Adverse Event n (%) n System Organ Class 1 n (%) n Preferred Term 1 n (%) n Preferred Term 2 . . n (%) n System Organ Class 2 n (%) n Preferred Term 1 n (%) n Preferred Term 2 n (%) n [1] At each level of summation (overall, system organ class, preferred term), subjects reporting more than one serious adverse event are counted only once. path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Table 29 Page 29 of 64 Treatment Emergent Adverse Events Leading to Discontinuation of Study Drug or Premature Withdrawal of From Study Safety Population Safety Population (N= ) Number of Number of System Organ Class / Preferred Term Subjects [1] Events Subjects Reporting at Least One Serious Adverse Event n (%) n System Organ Class 1 n (%) n Preferred Term 1 n (%) n Preferred Term 2 . . n (%) n System Organ Class 2 n (%) n Preferred Term 1 n (%) n Preferred Term 2 n (%) n [1] At each level of summation (overall, system organ class, preferred term), subjects reporting more than one adverse event are counted only once. path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Page 30 of 64 Table 12 Treatment Emergent Adverse Events by System Organ Class and Injection Type Safety Population Treatment Regimen 1 (N= ) Treatment Regimen 2 (N= ) rHuPH20 Placebo rHuPH20 Placebo System Organ Class / Preferred Term Number of Subjects [1] Number of Events Number of Subjects [1] Number of Events Number of Subjects [1] Number of Events Number of Subjects [1] Number of Events Subjects Reporting at Least One Serious Adverse Event n (%) n n (%) n n (%) n n (%) n System Organ Class 1 n (%) n n (%) n n (%) n n (%) n Preferred Term 1 n (%) n n (%) n n (%) n n (%) n Preferred Term 2 . . n (%) n n (%) n n (%) n n (%) n System Organ Class 2 n (%) n n (%) n n (%) n n (%) n Preferred Term 1 n (%) n n (%) n n (%) n n (%) n Preferred Term 2 n (%) n n (%) n n (%) n n (%) n Note: For this summary, only Adverse Events reported during the physical examinations/safety reviews at Day 1 (TR 2 only), Day 3 through Day 7, and Day 14 are considered. [1] At each level of summation (overall, system organ class, preferred term), subjects reporting more than one adverse event are counted only once. path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Table 31 Page 31 of 64 Vital Signs Safety Population Safety Population Vital Sign Time Point (N= ) Systolic BP (mmHg) Screening N n Mean (SD) xx.x (xx.xx) Median xx.x Min, Max xx, xx Day 1 Pre-Injection N n Mean (SD) xx.x (xx.xx) Median xx.x Min, Max xx, xx Day 1 Post-Injection N n Mean (SD) xx.x (xx.xx) Median xx.x Min, Max xx, xx Day 1 Change from Baseline [1] N n Mean (SD) xx.x (xx.xx) Median xx.x Min, Max xx, xx … Diastolic BP (mmHg) [1] Baseline is defined as pre-injection assessment for the visit under consideration. path\t_program.sas date time Programmer note: Table will include the following vital signs: systolic BP (mmHg), diastolic BP (mmHg),Heart Rate (bpm) and Respiration (breaths/min). for each vital sign, time points will include: Screening, Day 1 Pre-Injection, Day 1 Post-Injection, Day 1 Change from Baseline, Day 3 Pre-Injection, Day 3 Post-Injection, Day 3 Change from Baseline, Day 4 Pre-Injection, Day 4 Post-Injection, Day 4 Change from Baseline, Day 5 Pre-Injection, Day 5 Post-Injection, Day 5 Change from Baseline, Day 6 Pre-Injection, Day 6 Post-Injection, Day 6 Change from Baseline, Day 7 Pre-Injection, Day 7 Post-Injection, Day 7 Change from Baseline, Day 14. Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Table 32 Page 32 of 64 Physical Examination Safety Population Safety Population (N= ) Baseline Assessment Most Abnormal Post-Baseline Assessment Normal Abnormal HEENT Normal (N= ) n (%) n (%) Abnormal n (%) n (%) Respiratory Normal (N= ) n (%) n (%) Abnormal n (%) n (%) Cardiovascular . . path\t_program.sas date time Programmer note: Table will include all physical examination body systems. Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Table 15 Concomitant Medications [1] Safety Population Page 33 of 64 Safety Population ATC Drug Class / Medication Term (N= ) Subjects Receiving any Concomitant Medications n (%) Drug Class 1 n (%) Medication Term 1 n (%) Medication Term 2 . . n (%) Drug Class 2 n (%) Medication Term 1 n (%) Medication Term 2 . . n (%) [1] At each level of summation (overall, ATC drug class, medication term), subjects reporting more than one medication are counted only once. path\t_program.sas date time Page 34 of 64 APPENDIX C: LISTING LAYOUTS Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing Page 35 of 64 Subject Disposition Concentration of Nickel First Injection Last Injection Total # Primary Reason for Subject ITT[1] Safety[2] Evaluable[3] Replaced[4] Sulfate Used Date Date of Injection(s) Complete? Not Completing [1] Intent to Treat (ITT): Enrolled subjects who signed informed consent. [2] Received at least one dose of study drug. [3] An evaluable subject is one who has completed dosing (or prematurely discontinued the administration due to a toxicity) and has undergone sufficient assessments to allow an assessment of the tolerability of the administration. [4] Enrolled subjects but not meeting the criteria of evaluability. path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing Page 36 of 64 Inclusion/Exclusion Criteria Part 1 of 4 Inclusion Criteria: 1: 2: 3: 4: 5: 6: 7: 8: Exclusion Criteria: 1: 2: 3: 4: 5: 6: 7: 8: 9: 10: path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 2(cont.) Inclusion/Exclusion Criteria Page 37 of 64 Part 2 of 4: Inclusion Criteria Date Informed Inclusion Criteria Subject Consent Signed 1 2 3 4 5 6 7 8 path\t_program.sas date time Halozyme Therapeutics, Inc. Page 1 of x Protocol HALO-114-201 Date Informed Listing 2(cont.) Inclusion/Exclusion Criteria Part 3 of 4: Exclusion Criteria Exclusion Criteria Subject Consent Signed 1 2 3 4 5 6 7 8 9 10 path\t_program.sas date time Halozyme Therapeutics, Inc. Page 1 of x Protocol HALO-114-201 Comply with ALL Entry Criteria Listing 2(cont.) Inclusion/Exclusion Criteria Part 4 of 4: Waiver Subject Entry Criteria Not Met Exemption Explanation Exemption Granted By Date Inclusion:1 path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 3 Demographics Page 38 of 64 Subject Date of Birth Age Sex Ethnicity Race [1] Age is calculated by comparing the date of birth and the informed consent date. path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 4 Medical History Page 39 of 64 Subject Mark if None MH # Body System Description Diagnosis/Onset Mark if Ongoing path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 5 Hematology and CBC with Differential Page 40 of 64 Part 1 of 2 Mark if Not Done WBC RBC Hemoglobin Hematocrit Platelets Neutrophils Neutrophils Subject Visit Not Done Reason Collection Date/Time (X1000/uL) (XMil/uL) (g/dL) (%) (X1000/uL) (segs) (%) (bands) (%) Note: A result marked with “” indicates a result that is abnormal and clinically significant. path\t_program.sas date time Halozyme Therapeutics, Inc. Page 1 of x Protocol HALO-114-201 Listing 5 (cont.) Hematology and CBC with Differential Part 2 of 2 Mark if Not Done Lymphocytes Monocytes Eosinophils Basophils Subject Visit Not Done Reason Collection Date/Time (%) (%) (%) (%) Other Note: A result marked with “” indicates a result that is abnormal and clinically significant. path\t_program.sas date time Programmer note: for “other”, put test name instead of “other” in the column name. Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 6 Lab Normal - Hematology Page 41 of 64 Lab Lab Test Sex Low High Lab Units If Other, Specify WBC X1000/uL path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 7 Pregnancy Test Page 42 of 64 Mark if Not Done Subject Visit Not Done Reason Collection Date Sample Type Result path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing Page 43 of 64 ICDRG Score [1] Treatment Treatment Regimen 1 Treatment Regimen 2 Subject Visit Date TR 1-1 TR 1-2 TR 1-3 TR 1-4 TR 2-5 TR 2-6 TR 2-7 TR 2-8 Day 3 ? (A) + (P) * Day 4 Note: A= rHuPH20; P= Placebo Note: Results marked with “*” indicate Maximal Severity Score. [1] ICDRG Score: Score (Grade) Score Interpretation ? (1/2) Doubtful reaction; faint macular erythema only + (1) Weak (nonvesicular) positive reaction; erythema infiltration, possibly papules ++ (2) Strong (vesicular) positive reaction; erythema, infiltration, papules, vesicles +++ (3) Extreme Positive reaction; bullous reaction - (0) Negative reaction IR (NA) Irritant reaction of different types path\t_program.sas date time Programmer Note: Each subject will have one Maximal Severity Score marked for each injection type (for a total of 2 scores marked per subject). Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing Page 44 of 64 TEWL (Trans-Epidermal Water Loss) Assessment (g/m2h) Was TEWL Collection Result Subject Visit Day 1 Day 3 .. path\t_program.sas date time Completed? Date/Time TR 1-1 TR 1-2 TR 1-3 TR 1-4 TR 2-5 TR 2-6 TR 2-7 TR 2-8 Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 45 Page 45 of 64 path\t_program.sas date time Digital Photographs Subject Visit Were Digital Photos Taken? Collection Date Collection Time Uploaded to Website? No:reason No:reason Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 46 Page 46 of 64 Chromometer Part 1 of 3: a-Scale Subject Visit Was a Chromometer Reading Completed? Collection Date Collection Time Category TR 1-1 TR 1-2 TR 1-3 TR 1-4 TR 2-5 TR 2-6 TR 2-7 TR 2-8 Day 1 No:reason Day 3 Result Change from Day 1 path\t_program.sas date time Halozyme Therapeutics, Inc. Page 1 of x Protocol HALO-114-201 Listing 11 Chromometer Part 2 of 3: b-Scale Subject Visit Was a Chromometer Reading Completed? Collection Date Collection Time Category TR 1-1 TR 1-2 TR 1-3 TR 1-4 TR 2-5 TR 2-6 TR 2-7 TR 2-8 Day 1 No:reason Day 3 Result Change from Day 1 path\t_program.sas date time Halozyme Therapeutics, Inc. Page 1 of x Protocol HALO-114-201 Listing 11 Chromometer Part 3 of 3: l-Scale Subject Visit Was a Chromometer Reading Completed? Collection Date Collection Time Category TR 1-1 TR 1-2 TR 1-3 TR 1-4 TR 2-5 TR 2-6 TR 2-7 TR 2-8 Day 1 No:reason Day 3 Result Change from Day 1 path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 47 Page 47 of 64 Subject Diary Subject Visit Mark if Not Done Not Done Reason Date Start Time End Time Symptom Severity[1] Comments ongoing Dispense next Diary to subject? [1] 1 – Least Discomfort, 5 – Most Discomfort. path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 48 Page 48 of 64 Screening Nickel Sulfate and Vehicle Control Patches Application of Patches Test Results (48 Hours After Application) Patches 48 hours ICDRG Subject Applied? Date Time Date Time After App.? 1% 2.5% 5% Dose Assigned? Assigned Dose No:reason No:reason No:reason path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 49 Page 49 of 64 Study Drug Administration – Treatment Regimen 1 Part 1 of 4: Application of Nickel Sulfate Patches Subject Visit Treatment Date 8 Areas Normal? No:reason Application Time 4 Patches applied? Concentrations of Nickel Sulfate path\t_program.sas date time Halozyme Therapeutics, Inc. Page 1 of x Protocol HALO-114-201 Listing 14 (cont.) Study Drug Administration – Treatment Regimen 1 Part 2 of 4: Physical Examination Prior to Injection Subject Visit Subject Randomized? Treatment Date Asse. Time ICDRG Score AE # TR 1-1 TR 1-2 TR 1-3 TR 1-4 TR 1-1 TR 1-2 TR 1-3 TR 1-4 None None None None path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 14 (cont.) Study Drug Administration – Treatment Regimen 1 Page 50 of 64 Part 3 of 4: Study Drug Administration Subject Visit Treatment Date TR 1-1 TR 1-2 TR 1-3 TR 1-4 Drug Injected? Time Drug Injected? Time Drug Injected? Time Drug Injected? Time No:reason path\t_program.sas date time Halozyme Therapeutics, Inc. Page 1 of x Protocol HALO-114-201 Listing 14 (cont.) Study Drug Administration – Treatment Regimen 1 Part 4 of 4: Physical Examination and Safety Review after Injection Treatment Asse. AE # Subject Visit Date Test Category Time TR 1-1 TR 1-2 TR 1-3 TR 1-4 Physical Exam. (10 mins. Post) None None None None Safety Review (30 mins Post) path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 15 Study Drug Administration – Treatment Regimen 2 Page 51 of 64 Part 1 of 4: Physical Examination Prior to Injection Subject Treatment Asse. ICDRG Score AE # path\t_program.sas date time Halozyme Therapeutics, Inc. Page 1 of x Protocol HALO-114-201 Listing 15 (cont.) Study Drug Administration – Treatment Regimen 2 Part 2 of 4: Study Drug Administration Subject Visit Treatment Date TR 2-5 TR 2-6 TR 2-7 TR 2-8 Drug Injected? Time Drug Injected? Time Drug Injected? Time Drug Injected? Time No:reason path\t_program.sas date time Subject Visit Randomized? Date Time TR 2-5 TR 2-6 TR 2-7 TR 2-8 TR 2-5 TR 2-6 TR 2-7 TR 2-8 None None None None Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 15 (cont.) Study Drug Administration – Treatment Regimen 2 Page 52 of 64 Part 3 of 4: Physical Examination and Safety Review after Injection Treatment Asse. AE # Subject Visit Date Test Category Time TR 2-5 TR 2-6 TR 2-7 TR 2-8 Physical Exam. (10 mins. Post) None None None None Safety Review (30 mins Post) path\t_program.sas date time Halozyme Therapeutics, Inc. Page 1 of x Protocol HALO-114-201 Listing 15 (cont.) Study Drug Administration – Treatment Regimen 2 Part 4 of 4: Application of Nickel Sulfate Patches Treatment Application Mark if Not 4 Patches Not applied Concentrations of Subject Visit Date Time Done Reason Nickel Sulfate path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 16 Adverse Events Page 53 of 64 Mark if Start Resolved Severity Action Taken with Relationship to Other Action Subject None AE Term Date/Time Date/Time Serious (CTCAE3) Study Drug Study Drug Taken Outcome path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 17 Serious Adverse Events Page 54 of 64 Mark if Start Resolved Severity Action Taken with Relationship to Other Action Subject None AE Term Date/Time Date/Time (CTCAE3) Study Drug Study Drug Taken Outcome path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 18 Vital Signs Page 55 of 64 Subject Visit Mark if Not Done Not Done Reason Visit Date Category Visit Time Heart Rate (bpm) Blood Pressure (mmHg) Respiration (breaths/min) Body Temperature (oF) Screening Sys/Dia Day 1 Pre-injection Post-injection … Day 14 path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 19 Physical Examination Page 56 of 64 Subject Visit path\t_program.sas date time Mark if Not Done Not Done Reason Date of Exam Any Change from Previous Exam Body System Result Normal Abnormal Abnormal, Clinically Significant Description of Abnormality Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 20 Comments Page 57 of 64 Subject Mark if None Comment # Pertains to Visit Date CRF Page Comment path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 21 Prior and Concomitant Medications Page 58 of 64 Subject Mark if None CM # Medication Indication Start Date Stop Date Dose Unit Route Frequency onging Taken for AE? AE # path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 22 Deaths Page 59 of 64 Date of Date Death Was Autopsy Signature of Signature Subject Death Reported to Site Primary Cause of Death Performed? Comment Investigator Date path\t_program.sas date time Halozyme Therapeutics, Inc. Protocol HALO-114-201 Page 1 of x Listing 23 Subject Visit Page 60 of 64 Subject Initials Visit Visit Date path\t_program.sas date time Page 61 of 64 APPENDIX D: FIGURE LAYOUTS Page 62 of 64 Halzoyme Therapeutics, Inc Protocol HALO-114-201 Figure 1 ICDRG Scores- Subject 001XXX Day 3 Day 4 Day 5 Regimen 1 + P ++ A + P ++ A Regimen 2 + P ++ A ++ P + A Day 6 Note: A= rHuPH20, P= Placebo, NR= Not Reported. Only subjects reported in both the Demographic and ICDRG datasets are considered. Regimen 1 from left to right- TR1-1, TR1-2, TR1-3, TR1-4 and Regimen 2 from left to right- TR2-5, TR2-6, TR2-7, TR2-8 path\program.sas date time Regimen 1 ++ P ++ A ++ P ++ A Regimen 2 ++ P ++ A ++ P ++ A Regimen 1 ++ P ++ A ++ P ++ A Regimen 2 ++ P ++ A ++ P ++ A Regimen 1 ++ P ++ A ++ P ++ A Regimen 2 ++ P ++ A +++ P ++ A Regimen 1 Regimen 1 + P ++ A + P + A ? P + A ? P + A Regimen 2 Regimen 2 + + ? + + + + ? P A P A P A P A Day 7 Day 14 Halozyme Therapeutics, Inc Protocol HALO-114-201 Figure 2 Page 63 of 64 Individual TEWL Scores by Day and Injection Site Subject 001XXX- Regimen 1 20 15 10 5 0 Day 1 Day 3 Day 4 Day 5 Regimen 1 TR1-1(P) TR1-2(P) TR1-3(A) TR1-4(A) Note: A= rHuPH20, P= Placebo. path/program.sas date time TEWL (unit) Halozyme Therapeutics, Inc Protocol HALO-114-201 Figure 3 Page 64 of 64 Individual a-Scale Chromometer Baseline Corrected Scores by Day and Injection Site Subject 001XXX- Regimen 1 10 5 0 -5 -10 Day 1 Day 3 Day 4 Day 5 Regimen 1 TR1-1(P) TR1-2(P) TR1-3(A) TR1-4(A) Note: A= rHuPH20, P= Placebo. path/program.sas date time a-scale (unit)	2	arm 1: Participant's upper back will be divided into 2 equal spaces and will receive Regimen 1 and 2 in 4 spaces respectively. In Regimen 1, a single row of 4 patches, each with the nickel sulfate concentration (NSC) (1, 2.5, or 5%) determined at screening, will be applied to the upper space at Day 1. After 48 hours, the patches will be removed and the reactions will be graded on the ICDRG scale. An ID injection containing rHuPH20 (3,000 Units \[U\]) will be administered once daily (QD) for 5 days at the center of each area of reaction. In Regimen 2, a single row of 4 sites in the lower space will be injected intradermally with drug rHuPH20 (3,000 U) at Day 1. Ten minutes after the injections, patches with the NSC (1, 2.5, or 5%) determined at screening will be applied to the injection sites. After 48 hours, the patches will be removed and the reactions will be graded on the ICDRG scale. As during pretreatment, an ID injection containing rHuPH20 will be then administered QD for 5 days. arm 2: Participant's upper back will be divided into 2 equal spaces and will receive Regimen 1 and 2 in 4 spaces respectively. In Regimen 1, a single row of 4 patches, each with the NSC (1, 2.5, or 5%) determined at screening, will be applied to the upper space at Day 1. After 48 hours, the patches will be removed and the reactions will be graded on the ICDRG scale. An ID injection containing placebo will be administered QD for 5 days at the center of each area of reaction. In Regimen 2, a single row of 4 sites in the lower space will be injected intradermally with placebo at Day 1. Ten minutes after the injections, patches with the NSC (1, 2.5, or 5%) determined at screening will be applied to the injection sites. After 48 hours, the patches will be removed and the reactions will be graded on the ICDRG scale. As during pretreatment, an ID injection containing placebo will be then administered QD for 5 days.	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: 0.25 milliliter (mL) Intradermal (ID) syringe push bolus injection of rHuPH20 intervention 2: 0.25 mL ID syringe push bolus injection of placebo control	intervention 1: rHuPH20 intervention 2: Placebo	1	Michigan City \| Indiana \| United States \| -86.89503 \| 41.70754	21	0	0	0	NCT00928447	1COMPLETED	2009-09-13	2009-06-23	Halozyme Therapeutics	4INDUSTRY	true	true	false	https://cdn.clinicaltrials.gov/large-docs/47/NCT00928447/Prot_000.pdf https://cdn.clinicaltrials.gov/large-docs/47/NCT00928447/SAP_001.pdf	0	0	0	0	0	0	0	0	0
[ 4 ]	307	RANDOMIZED	PARALLEL	1PREVENTION	3TRIPLE	false	0ALL	true	The purpose of this research study is to investigate whether or not oral maribavir is safe and effective compared to oral ganciclovir for preventing CMV disease when administered for up to 14 weeks in patients who have had a liver transplant.	Cytomegalovirus (CMV) infections remain a significant problem following various types of transplants that are associated with strong immunosuppressive therapy. Maribavir is a new oral anti-CMV drug with a novel mechanism of action compared to currently available anti-CMV drugs. This study will test the safety and efficacy of maribavir for the prevention of CMV disease when given as prophylaxis for up to 14 weeks following orthotopic liver transplantation.	Cytomegalovirus Infections	cytomegalovirus CMV prophylaxis liver liver transplant	null	2	arm 1: None arm 2: None	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: 100mg twice a day for 14 weeks. intervention 2: 1000mg three times per day for 14 weeks.	intervention 1: maribavir intervention 2: ganciclovir	55	Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 La Jolla \| California \| United States \| -117.2742 \| 32.84727 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Stanford \| California \| United States \| -122.16608 \| 37.42411 Aurora \| Colorado \| United States \| -104.83192 \| 39.72943 Washington D.C. \| District of Columbia \| United States \| -77.03637 \| 38.89511 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Iowa City \| Iowa \| United States \| -91.53017 \| 41.66113 Kansas City \| Kansas \| United States \| -94.62746 \| 39.11417 Lexington \| Kentucky \| United States \| -84.47772 \| 37.98869 Louisville \| Kentucky \| United States \| -85.75941 \| 38.25424 New Orleans \| Louisiana \| United States \| -90.07507 \| 29.95465 New Orleans \| Louisiana \| United States \| -90.07507 \| 29.95465 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Burlington \| Massachusetts \| United States \| -71.19561 \| 42.50482 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 Detroit \| Michigan \| United States \| -83.04575 \| 42.33143 Minneapolis \| Minnesota \| United States \| -93.26384 \| 44.97997 Rochester \| Minnesota \| United States \| -92.4699 \| 44.02163 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 Newark \| New Jersey \| United States \| -74.17237 \| 40.73566 New York \| New York \| United States \| -74.00597 \| 40.71427 New York \| New York \| United States \| -74.00597 \| 40.71427 Rochester \| New York \| United States \| -77.61556 \| 43.15478 Valhalla \| New York \| United States \| -73.77513 \| 41.07482 Chapel Hill \| North Carolina \| United States \| -79.05584 \| 35.9132 Durham \| North Carolina \| United States \| -78.89862 \| 35.99403 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Oklahoma City \| Oklahoma \| United States \| -97.51643 \| 35.46756 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 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 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Houston \| Texas \| United States \| -95.36327 \| 29.76328 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Charlottesville \| Virginia \| United States \| -78.47668 \| 38.02931 Richmond \| Virginia \| United States \| -77.46026 \| 37.55376 Seattle \| Washington \| United States \| -122.33207 \| 47.60621 Milwaukee \| Wisconsin \| United States \| -87.90647 \| 43.0389	303	0	0	0	NCT00497796	1COMPLETED	2009-09-14	2007-07-23	Shire	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	120	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	The purpose of this non-randomized, open-label, multicenter, Phase II, 2-stage design, RESCUE study is to test the hypothesis that continuous 28-day oral dosing (28/28) with dose-intense temozolomide (50 mg/m\^2) for up to 12 months may overcome resistance and be effective in the management of adult patients with malignant glioma who have failed following at least 2 cycles (2 months) of conventional 5-day (5/28) cycles of high-dose temozolomide (150-200 mg/m\^2).	null	Glioma Astrocytoma Oligodendroglioma Glioblastoma		null	1	arm 1: Temozolomide will be administered at a dose of 50 mg/m\^2 for cycles of 28 days for 12 months or until progression.	[ 0 ]	1	[ 0 ]	intervention 1: Subjects will receive temozolomide 50 mg/m\^2 for cycles of 28 days for 12 months or until progression	intervention 1: Temozolomide	0	null	120	0	0	0	NCT00392171	1COMPLETED	2009-09-15	2006-06-09	Merck Sharp & Dohme LLC	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	9	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	This study evaluated the safety and efficacy of LBH589B in adult participants with refractory/resistant Cutaneous T-Cell Lymphoma and prior Histone Deacetylase (HDAC) inhibitor therapy.	null	Cutaneous T-Cell Lymphoma	Cutaneous T-Cell Lymphoma adults Mycosis Fungoides Sézary Syndrome CTCL	null	1	arm 1: Participants received panobinostat, 20 milligrams (mg), capsules, orally, thrice weekly on alternate Days 1, 3, and 5 per week of a 28-day treatment cycle until unacceptable toxicity, disease progression, and/or physician's discretion to discontinue the treatment.	[ 0 ]	1	[ 0 ]	intervention 1: Panobinostat, 20 mg, hard gelatin capsules, orally, thrice weekly.	intervention 1: Panobinostat	18	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Aurora \| Colorado \| United States \| -104.83192 \| 39.72943 Miami \| Florida \| United States \| -80.19366 \| 25.77427 Augusta \| Georgia \| United States \| -81.97484 \| 33.47097 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 Buffalo \| New York \| United States \| -78.87837 \| 42.88645 New York \| New York \| United States \| -74.00597 \| 40.71427 The Bronx \| New York \| United States \| -73.86641 \| 40.84985 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Tulsa \| Oklahoma \| United States \| -95.99277 \| 36.15398 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Germantown \| Tennessee \| United States \| -89.81009 \| 35.08676 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Seattle \| Washington \| United States \| -122.33207 \| 47.60621	9	0	0	0	NCT00490776	6TERMINATED	2009-09-22	2007-07-05	Novartis Pharmaceuticals	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 2, 3 ]	9	NON_RANDOMIZED	SEQUENTIAL	0TREATMENT	0NONE	false	0ALL	true	This is a phase I/II study of an investigational drug called ABT-751, produced by Abbott Laboratories, given in combination with chemotherapy drugs used to treat acute lymphoblastic leukemia (ALL) that has come back (recurred). The phase I portion of this study is being done to find the highest dose of ABT-751 that can be given safely in combination with other chemotherapy drugs. A safe dose is one that does not result in unacceptable side effects. After a safe dose for ABT-751 given with chemotherapy has been found, the study will add additional patients to find out if ABT-751 (given at the maximal safe dose) when given with additional chemotherapy is an effective therapy for the treatment of children with relapsed ALL. It is expected that approximately 15-35 children and young adults will take part in this study.	All patients will receive the 2 courses of chemotherapy unless medical complications prevent the administration of some of the drugs. Treatment for the first 2 courses of therapy will last about 2 months. Treatment on this study will consist of a combination of 8 anti-cancer medications. The 8 anticancer medicines are ABT-751, dexamethasone, PEG-asparaginase, doxorubicin, cytarabine (Ara-C), methotrexate (MTX), cyclophosphamide, and 6-thioguanine. All the drugs except ABT-751 are well known anti-cancer drugs and have been used extensively in the treatment of cancer. During the Phase I portion of this study, when you enroll, you will be given an assigned dose of ABT-751. The dose of ABT-751 will be based on doses given in previous studies done with adults and children. At each dose level of ABT-751, between 3 and 6 children will receive ABT-751 in combination with chemotherapy. If the side effects are not too severe, the next group of children will receive a higher dose. The dose will continue to be increased until we find the dose that causes serious side effects. Your dose of ABT-751 will not be increased. If you have bad side effects, your dose may be decreased. The dose used during the Phase 2 part of this study will be determined by the outcome of the Phase I study. The highest dose used in Phase I that was tolerated without serious side effects will be the one used in Phase 2.	Recurrent Pediatric ALL Relapsed Pediatric ALL Acute Lymphoblastic Leukemia Refractory Pediatric ALL	Acute Lymphoblastic Leukemia Pediatrics Relapsed Recurrence ABT-751 Therapeutic Advances in Childhood Leukemia Investigational Childhood ALL Relapsed ALL Refractory ALL Relapsed pediatric ALL Refractory pediatric ALL TACL	null	7	arm 1: Treatment Dose of ABT-751 is 80 mg/m2/day Tx Course 1: • ABT-751, Dexamethasone, PEG-asparaginase, Doxorubicin, Cytarabine, IT Methotrexate Tx Course 2: • Cyclophosphamide, 6-Thioguanine, IT Methotrexate, Cytarabine, PEG-asparaginase, ABT-751 Tx Courses 3-12 (maintenance courses): • ABT-751, IT Methotrexate arm 2: Treatment Dose of ABT-751 is 100 mg/m2/day Tx Course 1: • ABT-751, Dexamethasone, PEG-asparaginase, Doxorubicin, Cytarabine, IT Methotrexate Tx Course 2: • Cyclophosphamide, 6-Thioguanine, IT Methotrexate, Cytarabine, PEG-asparaginase, ABT-751 Tx Courses 3-12 (maintenance courses): • ABT-751, IT Methotrexate arm 3: Treatment Dose of ABT-751 is 125 mg/m2/day Tx Course 1: • ABT-751, Dexamethasone, PEG-asparaginase, Doxorubicin, Cytarabine, IT Methotrexate Tx Course 2: • Cyclophosphamide, 6-Thioguanine, IT Methotrexate, Cytarabine, PEG-asparaginase, ABT-751 Tx Courses 3-12 (maintenance courses): • ABT-751, IT Methotrexate arm 4: Treatment Dose of ABT-751 is 150 mg/m2/day Tx Course 1: • ABT-751, Dexamethasone, PEG-asparaginase, Doxorubicin, Cytarabine, IT Methotrexate Tx Course 2: • Cyclophosphamide, 6-Thioguanine, IT Methotrexate, Cytarabine, PEG-asparaginase, ABT-751 Tx Courses 3-12 (maintenance courses): • ABT-751, IT Methotrexate arm 5: Treatment Dose of ABT-751 is 175 mg/m2/day Tx Course 1: • ABT-751, Dexamethasone, PEG-asparaginase, Doxorubicin, Cytarabine, IT Methotrexate Tx Course 2: • Cyclophosphamide, 6-Thioguanine, IT Methotrexate, Cytarabine, PEG-asparaginase, ABT-751 Tx Courses 3-12 (maintenance courses): • ABT-751, IT Methotrexate arm 6: Treatment Dose of ABT-751 is 65 mg/m2/day Tx Course 1: • ABT-751, Dexamethasone, PEG-asparaginase, Doxorubicin, Cytarabine, IT Methotrexate Tx Course 2: • Cyclophosphamide, 6-Thioguanine, IT Methotrexate, Cytarabine, PEG-asparaginase, ABT-751 Tx Courses 3-12 (maintenance courses): • ABT-751, IT Methotrexate arm 7: Treatment Dose of ABT-751 is 50 mg/m2/day Tx Course 1: • ABT-751, Dexamethasone, PEG-asparaginase, Doxorubicin, Cytarabine, IT Methotrexate Tx Course 2: • Cyclophosphamide, 6-Thioguanine, IT Methotrexate, Cytarabine, PEG-asparaginase, ABT-751 Tx Courses 3-12 (maintenance courses): • ABT-751, IT Methotrexate	[ 0, 0, 0, 0, 0, 0, 0 ]	8	[ 0, 0, 0, 0, 0, 0, 0, 0 ]	intervention 1: Treatment Course 1: Oral capsule to be given daily for 21 days at assigned dose. Treatment Course 2: ABT-751 will be taken once daily, by mouth, at the assigned dose on days 15-35. Treatment Course 3: ABT-751 will be taken once daily, by mouth, at the assigned dose on days 1-21 followed by 1 week of rest. intervention 2: In Treatment Course 1 only: * 10 mg/m2/day divided BID. * Take dexamethasone by mouth days 1-14. intervention 3: In Treatment Course 1: * 2500 IU's/m2/day. * Intramuscular injection (IM) on days 4, 11 and 18. In Treatment Course 2: * 2500 IU's/m2/day. * Intramuscular injection (IM) on day 15. intervention 4: In Treatment Course 1 only: • 60 mg/m2/day IV over 15 minutes on day 1. intervention 5: * Given Intrathecally on day 1 of course 1 at the dose defined by age below. * 30 mg for patients age 1-1.99 * 50 mg for patients age 2-2.99 * 70 mg for patients \>3 years of age * Omit IT Ara-C on Day 1 if patient received IT therapy prior to study enrollment as part of diagnostic lumbar puncture procedure. In Treatment Course 2: • 75 mg/m2/day IV on days 2 through 5 and days 9 through 12. intervention 6: In Treatment Course 1: • Given Intrathecally on day 15 at the dose defined by age below. * 8 mg for patients age 1-1.99 * 10 mg for patients age 2-2.99 * 12 mg for patients 3-8.99 years of age * 15 mg for patients \>9 years of age In Treatment Course 2: • Given Intrathecally on day 1, 8, 15 and 22 at the dose defined by age below. * 8 mg for patients age 1-1.99 * 10 mg for patients age 2-2.99 * 12 mg for patients 3-8.99 years of age * 15 mg for patients \>9 years of age In Treatment Course 3: Intrathecally on day 1 at the age-defined dose intervention 7: Course 2 only: • 1000mg/m2/day IV over 30 minutes to be given on day 1. intervention 8: Treatment Course 2 only: • 60 mg/m2/day to be given orally on days 1 through 14.	intervention 1: ABT-751 intervention 2: Dexamethasone intervention 3: PEG-asparaginase intervention 4: Doxorubicin intervention 5: Cytarabine intervention 6: Methotrexate intervention 7: Cyclophosphamide intervention 8: 6-thioguanine	5	Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Palo Alto \| California \| United States \| -122.14302 \| 37.44188 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 Seattle \| Washington \| United States \| -122.33207 \| 47.60621	9	0	0	0	NCT00439296	6TERMINATED	2009-09-23	2006-05-22	Therapeutic Advances in Childhood Leukemia Consortium	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	25	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	This is an open-label, multicenter study to assess the systemic exposure to calcitriol in the adolescent population. Calcitriol 3µg/g ointment (2 mg/cm² per application) is to be applied twice daily to involved skin (10 - 35% BSA involved, excluding face, scalp and intertriginous areas) for 56 days (8 weeks). Full Pharmacokinetic (PK) and Pharmacodynamic (PD) profile will be collected during the first 3 weeks of the study; safety and efficacy data will be collected for the 8 weeks of the treatment.	null	Chronic Plaque Psoriasis	Calcitriol Psoriasis PK Adolescents	null	1	arm 1: Participants receive calcitriol 3 micrograms per gram (mcg/g) ointment applied topically twice daily for 56 days.	[ 0 ]	1	[ 0 ]	intervention 1: Calcitriol 3mcg/g ointment applied twice daily for 56 weeks.	intervention 1: Calcitriol 3mcg/g	7	Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 San Diego \| California \| United States \| -117.16472 \| 32.71571 Eagan \| Minnesota \| United States \| -93.16689 \| 44.80413 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Webster \| Texas \| United States \| -95.11826 \| 29.53773 St. John's \| Newfoundland and Labrador \| Canada \| -52.70931 \| 47.56494 St. John's \| Newfoundland and Labrador \| Canada \| -52.70931 \| 47.56494	25	0	0	0	NCT00419666	1COMPLETED	2009-09-24	2006-08-01	Galderma R&D	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 2, 3 ]	66	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	true	The purpose of this study is to determine the efficacy of an anti-asthma herbal medicine intervention (ASHMI) in adult asthmatics	Asthma is a major public health problem worldwide, particularly in westernized societies and has continued to increase in prevalence over the past two decades. Inhaled corticosteroids have become the first-line treatment for persistent asthma even though side effects have been reported. New asthma medications, including leukotriene inhibitors and anti-IgE, have shown limited benefits. Patients have increasingly turned to complementary and alternative medicine (CAM) for treatment of their asthma, despite the uncertainty of its benefits due a lack of well-controlled scientific studies. We have developed a Chinese herbal formula composed of 3 herbs called ASHMI. It has been previously shown in murine studies that ASHMI (a formula containing Ling Zhi, Ku Shen and Gan Cao) has therapeutic effects on the major pathogenic mechanisms of asthma-airway hyperreactivity, pulmonary inflammation, and airway remodeling, as well as a down-regulating of TH2 response. A subsequent study in 91 asthmatic patients in Weifang, China found ASHMI to be a safe and effective alternative to prednisone for treating asthma and exhibited a beneficial effect on TH1 and TH2 balance. Additionally, a Phase I study conducted in the United States showed good tolerability to ASHMI. Based on these preliminary studies, we hypothesize that ASHMI will be a safe medication in patients with asthma.	Asthma	Asthma alternative medicine complementary medicine herbal therapy	null	3	arm 1: ASHMI 4 capsules twice a day arm 2: ASHMI 12 capsules twice a day arm 3: Placebo 6 capsules twice a day	[ 0, 0, 2 ]	3	[ 0, 0, 0 ]	intervention 1: 4 capsules orally twice a day intervention 2: 12 capsules orally twice a day intervention 3: Placebo 6 capsules twice a day	intervention 1: ASHMI 4 intervention 2: ASHMI 12 intervention 3: Placebo	1	New York \| New York \| United States \| -74.00597 \| 40.71427	66	0	0	0	NCT00712296	6TERMINATED	2009-09-29	2008-08-01	Icahn School of Medicine at Mount Sinai	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 2 ]	16	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	true	2MALE	false	The purpose of this randomized, double-blind, placebo-controlled study is to evaluate the safety, pharmacokinetics and pharmacodynamics of rising, single oral doses MK-1064 in healthy, young, male participants. The primary pharmacokinetic hypothesis is that at least one dose of MK-1064 that is generally safe and well tolerated produces an average MK-1064 plasma concentration from 0 to 4 hours of ≥2.2 μM. Since this is an early Phase I assessment of MK-1064 in humans, the study protocol allows for modifications to the outlined dose, dosing regimen and/or clinical or laboratory procedures, if required to address study objectives and/or to ensure appropriate safety monitoring of participants.	Two panels (Panels A and B), will receive alternating single rising oral doses of MK-1064/placebo (i.e., order of administration will be Panel A 5 mg, Panel B 10 mg, Panel A 25 mg, Panel B 50 mg, and continuing in this alternating sequence). Following dosing for a given treatment period, a minimum of 3 days will elapse before administration of the next scheduled dose. After administration of each dose, safety and tolerability will be reviewed. The decision to proceed to the next Panel/Period in the alternating sequence will be contingent on acceptable safety and tolerability data from the preceding Panels/Periods.	Pharmacokinetics		null	11	arm 1: Within each of up to 4 treatment periods, 6 participants were randomly assigned to receive single oral doses of MK-1064 5 mg in a fasted state. There was to be a minimum 7-day washout between treatment periods for any given participant. arm 2: Within each of up to 4 treatment periods, 6 participants were randomly assigned to receive single oral doses of MK-1064 10 mg in a fasted state. There was to be a minimum 7-day washout between treatment periods for any given participant. arm 3: Within each of up to 4 treatment periods, 6 participants were randomly assigned to receive single oral doses of MK-1064 25 mg in a fasted state. There was to be a minimum 7-day washout between treatment periods for any given participant. arm 4: Within each of up to 4 treatment periods, 6 participants were randomly assigned to receive single oral doses of MK-1064 50 mg in a fasted state. There was to be a minimum 7-day washout between treatment periods for any given participant. arm 5: Within each of up to 4 treatment periods, 6 participants were randomly assigned to receive single oral doses of MK-1064 100 mg in a fasted state. There was to be a minimum 7-day washout between treatment periods for any given participant. arm 6: Within each of up to 4 treatment periods, 6 participants were randomly assigned to receive single oral doses of MK-1064 150 mg in a fasted state. There was to be a minimum 7-day washout between treatment periods for any given participant. arm 7: Within each of up to 4 treatment periods, 6 participants were randomly assigned to receive single oral doses of MK-1064 200 mg in a fasted state. There was to be a minimum 7-day washout between treatment periods for any given participant. arm 8: Within each of up to 4 treatment periods, 6 participants were randomly assigned to receive single oral doses of MK-1064 250 mg in a fasted state. There was to be a minimum 7-day washout between treatment periods for any given participant. arm 9: In Period 5, participants received a single MK-1064 dose of 25 mg administered in the evening following a standard high-fat breakfast. arm 10: In Period 5, participants received a single MK-1064 dose of 50 mg administered in the evening after a 4-hour fast. arm 11: Within each of up to 5 treatment periods, 2 participants were randomly assigned to receive single oral doses of matching placebo in a fasted stated. There was to be a minimum 7-day washout between treatment periods for any given participant.	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 2 ]	2	[ 0, 0 ]	intervention 1: Dose for each period administered as oral MK-1064 tablets (1, 10 and 50 mg strengths) intervention 2: Dose for each period administered as oral placebo tablets matching active MK-1064 tablets	intervention 1: MK-1064 intervention 2: Placebo	0	null	76	0	0	0	NCT02549014	1COMPLETED	2009-09-29	2009-07-06	Merck Sharp & Dohme LLC	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	150	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	The purpose of this study is to determine whether the combination of aerobic physical exercise and alprazolam in patients with panic disorder has a better therapeutic response than the treatment with alprazolam alone.	We have observed in our clinical practice that patients who practiced aerobic physical exercise had faster remissions and better improvement in their treatments that those who did not. There are also some scientific studies that included physical exercise in the treatment for panic disorder and compared them to other single pharmacological treatments. So our objective will be to compare the efficacy of a pharmacological monotherapy (alprazolam), that is one of the options for the pharmacological treatment of panic disorder, with other treatment such as the combination of aerobic physical exercise and alprazolam, and to determine if this combination results in a better therapeutic response.	Panic Disorder	Panic disorder Exercise Alprazolam Aerobic	null	2	arm 1: Patients assigned to the pharmacological plan arm 2: Patients assigned to mix plan	[ 1, 1 ]	2	[ 0, 0 ]	intervention 1: The patients assigned to the pharmacological plan will receive 4 mg alprazolam daily for 12 weeks. Two weeks after the first interview they have their first baseline psychiatric control, where all the patients are tested. Then, at the same visit, all the patients are indicated 4 mg of alprazolam. The dose is gradually increased from 1 to 4 mg along the first week of treatment. The test is repeated during weeks 2, 4, 8 and 12. intervention 2: The patients assigned to exercise have to pass an ergometric test to determine their functional capacity expressed in METs for future exercise indication. Two weeks after the first interview they have their first baseline psychiatric control and at the same time they are indicated a 4 mg dose of alprazolam, gradually increased from 1 to 4 mg along the first week of treatment. The test is repeated during weeks 2, 4, 8 and 12. Then they follow a protocolized aerobic exercise plan for this study during 12 weeks. The type of selected exercise consists of a rapid walk for 30 minutes divided in stages. After each stage the patient has to control his own heart frequency that has to be between 50 and 75% of their maximum to assure an aerobic condition (American Cardiological Association).	intervention 1: Alprazolam intervention 2: Alprazolam + Aerobic exercise	1	Buenos Aires \| Buenos Aires F.D. \| Argentina \| -58.37723 \| -34.61315	150	0	0	0	NCT00803400	1COMPLETED	2009-09-30	2008-10-01	University of Buenos Aires	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	1,250	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	null	Short Term: The purpose of this clinical research study is to learn if abatacept (BMS-188667) in combination with methotrexate is better than methotrexate alone in participants that have active rheumatoid arthritis and are not responding to methotrexate. The safety of this treatment will also be studied. Long Term Extension: The purpose of this amendment is to provide participants who have completed the initial 12-month double-blind treatment period the opportunity to receive open label treatment with active drug treatment until abatacept is approved in the local country or until clinical development has been discontinued.	null	Rheumatoid Arthritis		null	3	arm 1: Short Term: Abatacept was dosed by weight with participants weighing \< 60 kg received abatacept 500 mg; participants ≥ 60 kg and ≤ 100 kg received abatacept 750 mg; and participants \> 100 kg received abatacept 1 g. Participants continued treatment with methotrexate (MTX) either orally or parenterally at a minimum dose of 15 mg. arm 2: Short Term: Participants received a placebo solution intravenously and methotrexate at the dose employed prior to study enrollment and a minimum of 15 mg. arm 3: Open Label: Abatacept was dosed intravenously by weight at 10 mg/kg in the OL period under tiered dosing such that participants weighing \< 60 kg received abatacept 500 mg; participants ≥ 60 kg and ≤ 100 kg received abatacept 750 mg; and participants \> 100 kg received abatacept 1 g. MTX was continued at the dose used in the DB period.	[ 0, 1, 0 ]	3	[ 0, 0, 0 ]	intervention 1: Intravenous (IV) Solution, - Weight Titered (500 mg \< 60 kg); (750 mg 60-100 kg), )1 gram \> 100 kg), Day 1, Day 15, Day 29; every 28 days thereafter, 1 year intervention 2: Tablets, Oral, \>= 15 mg, weekly, 1 year intervention 3: IV solution, Intravenous, D5W, Day 1, Day 15, Day 29; every 28 days thereafter, 1 year	intervention 1: Abatacept intervention 2: Methotrexate intervention 3: Placebo	48	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Huntsville \| Alabama \| United States \| -86.58594 \| 34.7304 Mobile \| Alabama \| United States \| -88.04305 \| 30.69436 Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 Scottsdale \| Arizona \| United States \| -111.89903 \| 33.50921 Corona \| California \| United States \| -117.56644 \| 33.87529 Irvine \| California \| United States \| -117.82311 \| 33.66946 La Jolla \| California \| United States \| -117.2742 \| 32.84727 Long Beach \| California \| United States \| -118.18923 \| 33.76696 Rancho Mirage \| California \| United States \| -116.41279 \| 33.73974 Aurora \| Colorado \| United States \| -104.83192 \| 39.72943 Colorado Springs \| Colorado \| United States \| -104.82136 \| 38.83388 Denver \| Colorado \| United States \| -104.9847 \| 39.73915 Hamden \| Connecticut \| United States \| -72.89677 \| 41.39593 Washington D.C. \| District of Columbia \| United States \| -77.03637 \| 38.89511 Fort Lauderdale \| Florida \| United States \| -80.14338 \| 26.12231 Gainsville \| Florida \| United States \| N/A \| N/A Palm Harbor \| Florida \| United States \| -82.76371 \| 28.07807 Sarasota \| Florida \| United States \| -82.53065 \| 27.33643 St. Petersburg \| Florida \| United States \| -82.67927 \| 27.77086 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Rockford \| Illinois \| United States \| -89.094 \| 42.27113 Wichita \| Kansas \| United States \| -97.33754 \| 37.69224 Coeur d'Alene \| Maryland \| United States \| N/A \| N/A Cumberland \| Maryland \| United States \| -78.76252 \| 39.65287 Springfield \| Massachusetts \| United States \| -72.58981 \| 42.10148 Duluth \| Minnesota \| United States \| -92.10658 \| 46.78327 Lincoln \| Nebraska \| United States \| -96.66696 \| 40.8 New Brunswick \| New Jersey \| United States \| -74.45182 \| 40.48622 Albuquerque \| New Mexico \| United States \| -106.65114 \| 35.08449 Albany \| New York \| United States \| -73.75623 \| 42.65258 Binghamton \| New York \| United States \| -75.91797 \| 42.09869 Mineola \| New York \| United States \| -73.64068 \| 40.74927 New York \| New York \| United States \| -74.00597 \| 40.71427 Syracuse \| New York \| United States \| -76.14742 \| 43.04812 The Bronx \| New York \| United States \| -73.86641 \| 40.84985 Wilmington \| North Carolina \| United States \| -77.94604 \| 34.23556 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 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 Sellersville \| Pennsylvania \| United States \| -75.3049 \| 40.35399 Willow Grove \| Pennsylvania \| United States \| -75.11573 \| 40.144 North Charleston \| South Carolina \| United States \| -79.97481 \| 32.85462 Austin \| Texas \| United States \| -97.74306 \| 30.26715 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Arlington \| Virginia \| United States \| -77.10428 \| 38.88101 Milwaukee \| Wisconsin \| United States \| -87.90647 \| 43.0389	1,191	4	0.003359	1	NCT00048568	1COMPLETED	2009-10-01	2002-12-01	Bristol-Myers Squibb	4INDUSTRY	false	false	false	null	2	0	1	0	0	0	1	0	0.001307
[ 4 ]	1,795	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	null	The purpose of this clinical research study is to learn if abatacept is safe when co-administered with other approved rheumatoid arthritis medications.	This was a multinational, multicenter, randomized, double-blind, 2-arm, parallel-dosing designed study. The treatment period was 12 months. Eligible participants were randomized to 1 of 2 treatment groups: abatacept fixed dose approximating 10 mg/kg (based on participant's body weight; 500 mg for participants weighing \< 60kg; 750 mg for participants weighing 60 to 100 kg; and 1 gram for participants weighing \> 100 kg, monthly) or placebo intravenous (IV) infusion. All participants continued their background therapy(ies) for rheumatoid arthritis (RA) (non-biologic or biologic disease-modifying drugs \[DMARDs\], or combination) throughout the double-blind treatment period. Double-blind study medication (abatacept or placebo) was administered on Days 1, 15, 29, and every 28 days thereafter, for a total of 14 doses. All participants who completed the 12-month double-blind study period (Day 1 through Day 365), were eligible to continue into the open-label period. All eligible participants (active or placebo) were re-allocated to receive abatacept at a weight-tiered dose that approximated 10 mg/kg, based on their Day 365 body weight. Participants continued to receive infusions every 28 days.	Rheumatoid Arthritis		null	3	arm 1: Participants received a fixed dose of abatacept approximating 10 mg/kg (500 mg for participants \< 60 kg, 750 mg for participants 60 to 100 kg and 1 g for participants \> 100 kg). Abatacept was administered intravenously (IV) on Days 1, 15, 29, and every 28 days thereafter, for a total of 14 doses. Participants also received background therapy(ies) for rheumatoid arthritis (RA) (non-biologic or biologic disease-modifying drugs \[DMARDs\], or combination) throughout the double-blind treatment period arm 2: Participants received Placebo (dextrose 5% water \[D5W\] for injection U.S.P or normal saline \[NS\]) for IV infusion administered on Days 1, 15, 29, and every 28 days thereafter, for a total of 14 doses. Participants also received background therapy(ies) for rheumatoid arthritis (RA) (non-biologic or biologic disease-modifying drugs \[DMARDs\], or combination) throughout the double-blind treatment period. arm 3: Participants received abatacept (weight-tiered 10 mg/kg dose) IV every 28 days during the open-label period.	[ 1, 2, 1 ]	3	[ 0, 0, 0 ]	intervention 1: Concentrate and diluted in a solution, IV, 500 mg (body weight \< 60 Kg); 750 mg (body weight 60-100 Kg); 1000 mg (body weight \> 100 Kg), Once daily, Day 1, 15, and 29. intervention 2: Concentrate and diluted in a solution, IV, 0 mg, Once daily, Day 1, 15, and 29. intervention 3: Concentrate and diluted in a solution, IV, 500 mg (body weight \< 60 Kg); 750 mg (body weight 60-100 Kg); 1000 mg (body weight \> 100 Kg), Once daily, Every 28 days.	intervention 1: Double-blind Abatacept intervention 2: Double-blind Placebo intervention 3: Open-label Abatacept	44	Decatur \| Alabama \| United States \| -86.98334 \| 34.60593 Paradise \| Arizona \| United States \| -109.21895 \| 31.93481 Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Loveland \| Colorado \| United States \| -105.07498 \| 40.39776 Hamden \| Connecticut \| United States \| -72.89677 \| 41.39593 Lake Worth \| Florida \| United States \| -80.07231 \| 26.61708 Largo \| Florida \| United States \| -82.78842 \| 27.90979 Blairsville \| Georgia \| United States \| -83.95824 \| 34.8762 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Evansville \| Indiana \| United States \| -87.55585 \| 37.97476 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Wichita \| Kansas \| United States \| -97.33754 \| 37.69224 Louisville \| Kentucky \| United States \| -85.75941 \| 38.25424 New Orleans \| Louisiana \| United States \| -90.07507 \| 29.95465 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Cumberland \| Maryland \| United States \| -78.76252 \| 39.65287 Westminster \| Maryland \| United States \| -76.99581 \| 39.57538 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Grand Rapids \| Michigan \| United States \| -85.66809 \| 42.96336 Royal Oak \| Michigan \| United States \| -83.14465 \| 42.48948 Toms River \| New Jersey \| United States \| -74.19792 \| 39.95373 Los Alamos \| New Mexico \| United States \| -106.30697 \| 35.88808 New York \| New York \| United States \| -74.00597 \| 40.71427 Durham \| North Carolina \| United States \| -78.89862 \| 35.99403 Hickory \| North Carolina \| United States \| -81.3412 \| 35.73319 Canton \| Ohio \| United States \| -81.37845 \| 40.79895 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Columbus \| Ohio \| United States \| -82.99879 \| 39.96118 Elyria \| Ohio \| United States \| -82.10765 \| 41.36838 Youngstown \| Ohio \| United States \| -80.64952 \| 41.09978 Oklahoma City \| Oklahoma \| United States \| -97.51643 \| 35.46756 Wyomissing \| Pennsylvania \| United States \| -75.96521 \| 40.32954 Columbia \| South Carolina \| United States \| -81.03481 \| 34.00071 Sioux Falls \| South Dakota \| United States \| -96.70033 \| 43.54997 Ducktown \| Tennessee \| United States \| -84.3827 \| 35.03591 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 Richmond \| Virginia \| United States \| -77.46026 \| 37.55376 Edmonds \| Washington \| United States \| -122.37736 \| 47.81065 Olympia \| Washington \| United States \| -122.90169 \| 47.04491 Tacoma \| Washington \| United States \| -122.44429 \| 47.25288 Menomonee Falls \| Wisconsin \| United States \| -88.11731 \| 43.1789 Milwaukee \| Wisconsin \| United States \| -87.90647 \| 43.0389	2,625	8	0.003048	1	NCT00048932	1COMPLETED	2009-10-01	2002-12-01	Bristol-Myers Squibb	4INDUSTRY	false	false	false	null	0	1	2	0	1	0	3	1	0.001545
[ 4 ]	1,783	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	0ALL	true	The purpose of this study is to determine the safety and efficacy of MDX-010 (ipilimumab, BMS-734016) (anti-CTLA4) in combination with MDX-1379 (gp100, BMS-734019) in patients with previously treated, unresectable Stage III or IV melanoma. Survival time will be evaluated, as well as patient responses and time to disease progression. Eligible patients are those who in response to a single regimen containing interleukin-2 (IL-2), dacarbazine, and/or temozolomide, have 1) relapsed following an objective response (partial response/complete response \[PR/CR\]); 2) failed to demonstrate an objective response (PR/CR); or 3) could not tolerate such a regimen due to unacceptable toxicity. Patients will be randomized into one of three groups, and will receive one of the following treatments: MDX-010 alone, MDX-1379 alone, or MDX-010 in combination with MDX-1379.	Melanoma accounts for approximately 5% of all skin cancers in the United States, but it accounts for about 75% of all skin cancer deaths. In 2004, the expected prevalence of melanoma is 627,252, with about 119,178 of these cases being Stage III or IV (metastatic melanoma). First line treatments for metastatic melanoma, usually IL-2, dacarbazine and/or temozolomide, are associated with significant toxicities. MDX-010 (anti-CTLA4) antibodies are designed to keep the immune system running by blocking CTLA-4 from down-regulating T cell activation. MDX-1379 is made up of two peptides that are pieces of a bigger melanoma protein (gp100). These peptides bind to HLA-A2 which is then recognized by T cells.	Melanoma Metastases	melanoma metastatic melanoma skin cancer	null	3	arm 1: Melanoma Peptide Vaccine (MDX-1379) (gp100) + Placebo arm 2: MDX-010 (ipilimumab) + MDX-1379 (gp100) (Melanoma Peptide Vaccine) arm 3: MDX-010 (ipilimumab) + Placebo	[ 1, 0, 1 ]	2	[ 0, 2 ]	intervention 1: 3mg/kg (intravenous \[iv\] infusion over 90 minutes), every 3 weeks for 4 doses intervention 2: 2mL (2 subcutaneous injections of 2 mL each, 1 to each thigh), every 3 weeks for 4 doses.	intervention 1: MDX-010 (anti-CTLA4) monoclonal antibody intervention 2: MDX-1379 (gp100) Melanoma Peptide Vaccine	209	Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 Duarte \| California \| United States \| -117.97729 \| 34.13945 Encinitas \| California \| United States \| -117.29198 \| 33.03699 La Jolla \| California \| United States \| -117.2742 \| 32.84727 La Jolla \| California \| United States \| -117.2742 \| 32.84727 La Jolla \| California \| United States \| -117.2742 \| 32.84727 Long Beach \| California \| United States \| -118.18923 \| 33.76696 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Oceanside \| California \| United States \| -117.37948 \| 33.19587 Pasadena \| California \| United States \| -118.14452 \| 34.14778 San Diego \| California \| United States \| -117.16472 \| 32.71571 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Santa Monica \| California \| United States \| -118.49138 \| 34.01949 Vista \| California \| United States \| -117.24254 \| 33.20004 Aurora \| Colorado \| United States \| -104.83192 \| 39.72943 Aurora \| Colorado \| United States \| -104.83192 \| 39.72943 Aurora \| Colorado \| United States \| -104.83192 \| 39.72943 Boulder \| Colorado \| United States \| -105.27055 \| 40.01499 Colorado Springs \| Colorado \| United States \| -104.82136 \| 38.83388 Denver \| Colorado \| United States \| -104.9847 \| 39.73915 Denver \| Colorado \| United States \| -104.9847 \| 39.73915 Lakewood \| Colorado \| United States \| -105.08137 \| 39.70471 Littleton \| Colorado \| United States \| -105.01665 \| 39.61332 Lone Tree \| Colorado \| United States \| -104.8863 \| 39.55171 Longmont \| Colorado \| United States \| -105.10193 \| 40.16721 New Haven \| Connecticut \| United States \| -72.92816 \| 41.30815 Aventura \| Florida \| United States \| -80.13921 \| 25.95648 Hollywood \| Florida \| United States \| -80.14949 \| 26.0112 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 Miami \| Florida \| United States \| -80.19366 \| 25.77427 Miami \| Florida \| United States \| -80.19366 \| 25.77427 Miami Beach \| Florida \| United States \| -80.13005 \| 25.79065 Miami Beach \| Florida \| United States \| -80.13005 \| 25.79065 Orlando \| Florida \| United States \| -81.37924 \| 28.53834 Palm Beach Gardens \| Florida \| United States \| -80.13865 \| 26.82339 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 Wellington \| Florida \| United States \| -80.24144 \| 26.65868 West Palm Beach \| Florida \| United States \| -80.05337 \| 26.71534 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Decatur \| Illinois \| United States \| -88.9548 \| 39.84031 Decatur \| Illinois \| United States \| -88.9548 \| 39.84031 Effingham \| Illinois \| United States \| -88.54338 \| 39.12004 Maywood \| Illinois \| United States \| -87.84312 \| 41.8792 Goshen \| Indiana \| United States \| -85.83444 \| 41.58227 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Noblesville \| Indiana \| United States \| -86.0086 \| 40.04559 Lexington \| Kentucky \| United States \| -84.47772 \| 37.98869 Louisville \| Kentucky \| United States \| -85.75941 \| 38.25424 Louisville \| Kentucky \| United States \| -85.75941 \| 38.25424 Louisville \| Kentucky \| United States \| -85.75941 \| 38.25424 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Lutherville \| Maryland \| United States \| -76.62608 \| 39.42122 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Dearborn \| Michigan \| United States \| -83.17631 \| 42.32226 Detroit \| Michigan \| United States \| -83.04575 \| 42.33143 West Bloomfield \| Michigan \| United States \| -83.38356 \| 42.56891 Coon Rapids \| Minnesota \| United States \| -93.28773 \| 45.11997 Fridley \| Minnesota \| United States \| -93.26328 \| 45.08608 Robbinsdale \| Minnesota \| United States \| -93.33856 \| 45.03219 Olive Branch \| Mississippi \| United States \| -89.82953 \| 34.96176 Columbia \| Missouri \| United States \| -92.33407 \| 38.95171 Saint Joseph \| Missouri \| United States \| -94.84663 \| 39.76861 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Hackensack \| New Jersey \| United States \| -74.04347 \| 40.88593 Hackensack \| New Jersey \| United States \| -74.04347 \| 40.88593 Morristown \| New Jersey \| United States \| -74.48154 \| 40.79677 New Brunswick \| New Jersey \| United States \| -74.45182 \| 40.48622 New Brunswick \| New Jersey \| United States \| -74.45182 \| 40.48622 Summit \| New Jersey \| United States \| -74.36468 \| 40.71562 Albuquerque \| New Mexico \| United States \| -106.65114 \| 35.08449 East Syracuse \| New York \| United States \| -76.07853 \| 43.06534 New York \| New York \| United States \| -74.00597 \| 40.71427 New York \| New York \| United States \| -74.00597 \| 40.71427 Chapel Hill \| North Carolina \| United States \| -79.05584 \| 35.9132 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Hershey \| Pennsylvania \| United States \| -76.65025 \| 40.28592 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Easley \| South Carolina \| United States \| -82.60152 \| 34.82984 Greenville \| South Carolina \| United States \| -82.39401 \| 34.85262 Seneca \| South Carolina \| United States \| -82.9532 \| 34.68566 Spartanburg \| South Carolina \| United States \| -81.93205 \| 34.94957 Bartlett \| Tennessee \| United States \| -89.87398 \| 35.20453 Collierville \| Tennessee \| United States \| -89.66453 \| 35.04204 Memphis \| Tennessee \| United States \| -90.04898 \| 35.14953 Memphis \| Tennessee \| United States \| -90.04898 \| 35.14953 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 Arlington \| Texas \| United States \| -97.10807 \| 32.73569 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Lubbock \| Texas \| United States \| -101.85517 \| 33.57786 Richardson \| Texas \| United States \| -96.72972 \| 32.94818 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Burlington \| Vermont \| United States \| -73.21207 \| 44.47588 Ciudad de Buenos Aires \| Buenos Aires \| Argentina \| N/A \| N/A La Plata \| Buenos Aires \| Argentina \| -57.95442 \| -34.92126 Santa Fe \| Santa Fe Province \| Argentina \| -60.70868 \| -31.64881 Buenos Aires \| N/A \| Argentina \| -58.37723 \| -34.61315 Buenos Aires \| N/A \| Argentina \| -58.37723 \| -34.61315 Ciudad de Buenos Aires \| N/A \| Argentina \| N/A \| N/A Ciudad de Buenos Aires \| N/A \| Argentina \| N/A \| N/A Ciudad de Buenos Aires \| N/A \| Argentina \| N/A \| N/A Ciudad de Buenos Aires \| N/A \| Argentina \| N/A \| N/A Ciudad de Buenos Aires \| N/A \| Argentina \| N/A \| N/A Ciudad de Buenos Aires \| N/A \| Argentina \| N/A \| N/A Córdoba \| N/A \| Argentina \| -64.18853 \| -31.40648 Córdoba \| N/A \| Argentina \| -64.18853 \| -31.40648 Santa Fe \| N/A \| Argentina \| -60.70868 \| -31.64881 Brussels \| N/A \| Belgium \| 4.34878 \| 50.85045 Brussels \| N/A \| Belgium \| 4.34878 \| 50.85045 Brussels \| N/A \| Belgium \| 4.34878 \| 50.85045 Ghent \| N/A \| Belgium \| 3.71667 \| 51.05 Leuven \| N/A \| Belgium \| 4.70093 \| 50.87959 Yvoir \| N/A \| Belgium \| 4.88059 \| 50.3279 Goiânia \| Goiás \| Brazil \| -49.25389 \| -16.67861 Londrina \| Paraná \| Brazil \| -51.16278 \| -23.31028 Porto Alegre \| Rio Grande do Sul \| Brazil \| -51.23019 \| -30.03283 Barretos \| São Paulo \| Brazil \| -48.56778 \| -20.55722 Jaú \| São Paulo \| Brazil \| -48.55778 \| -22.29639 Santo André \| São Paulo \| Brazil \| -46.53833 \| -23.66389 São Paulo \| São Paulo \| Brazil \| -46.63611 \| -23.5475 Barretos - SP \| N/A \| Brazil \| N/A \| N/A Belo Horizonte - MG \| N/A \| Brazil \| N/A \| N/A Goiania - GO \| N/A \| Brazil \| N/A \| N/A Londrina - PR \| N/A \| Brazil \| N/A \| N/A Porto Alegre \| N/A \| Brazil \| -51.23019 \| -30.03283 Porto Alegre - RS \| N/A \| Brazil \| N/A \| N/A Porto Alegre - RS \| N/A \| Brazil \| N/A \| N/A Santo Andre-SP \| N/A \| Brazil \| N/A \| N/A Sao Paulo - SP \| N/A \| Brazil \| N/A \| N/A Sao Paulo-SP \| N/A \| Brazil \| N/A \| N/A Calgary \| Alberta \| Canada \| -114.08529 \| 51.05011 Edmonton \| Alberta \| Canada \| -113.46871 \| 53.55014 Winnipeg \| Manitoba \| Canada \| -97.14704 \| 49.8844 St. John's \| Newfoundland and Labrador \| Canada \| -52.70931 \| 47.56494 Kingston \| Ontario \| Canada \| -76.48098 \| 44.22976 London \| Ontario \| Canada \| -81.23304 \| 42.98339 Ottawa \| Ontario \| Canada \| -75.69812 \| 45.41117 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Independencia \| Santiago Metropolitan \| Chile \| -70.66647 \| -33.41167 Recoleta \| Santiago Metropolitan \| Chile \| -70.65 \| -33.41667 Santiago \| Santiago Metropolitan \| Chile \| -70.64827 \| -33.45694 Santiago \| Santiago Metropolitan \| Chile \| -70.64827 \| -33.45694 Reñaca \| Vina Del Mar \| Chile \| -71.54374 \| -32.98298 Lille \| N/A \| France \| 3.05858 \| 50.63297 Lyon \| N/A \| France \| 4.84671 \| 45.74846 Marseille \| N/A \| France \| 5.38107 \| 43.29695 Montpellier \| N/A \| France \| 3.87635 \| 43.61093 Nantes \| N/A \| France \| -1.55336 \| 47.21725 Nice \| N/A \| France \| 7.26608 \| 43.70313 Paris \| N/A \| France \| 2.3488 \| 48.85341 Rennes \| N/A \| France \| -1.67429 \| 48.11198 Saint-Etienne \| N/A \| France \| 4.39 \| 45.43389 Vandœuvre-lès-Nancy \| N/A \| France \| 6.17114 \| 48.66115 Villejuif \| N/A \| France \| 2.35992 \| 48.7939 Hufelandstr. 55 \| Hesse \| Germany \| N/A \| N/A Augsburg \| N/A \| Germany \| 10.89851 \| 48.37154 Berlin \| N/A \| Germany \| 13.41053 \| 52.52437 Berlin \| N/A \| Germany \| 13.41053 \| 52.52437 Düsseldorf \| N/A \| Germany \| 6.77616 \| 51.22172 Erlangen \| N/A \| Germany \| 11.00783 \| 49.59099 Essen \| N/A \| Germany \| 7.01228 \| 51.45657 Heidelberg \| N/A \| Germany \| 8.69079 \| 49.40768 Jena \| N/A \| Germany \| 11.5899 \| 50.92878 Mannheim \| N/A \| Germany \| 8.46694 \| 49.4891 Mannheim \| N/A \| Germany \| 8.46694 \| 49.4891 München \| N/A \| Germany \| 13.31243 \| 51.60698 Tübingen \| N/A \| Germany \| 9.05222 \| 48.52266 Würzburg \| N/A \| Germany \| 9.95121 \| 49.79391 Budapest \| N/A \| Hungary \| 19.04045 \| 47.49835 Debrecen \| N/A \| Hungary \| 21.62444 \| 47.53167 Miskolc \| N/A \| Hungary \| 20.77806 \| 48.10306 Szeged \| N/A \| Hungary \| 20.14824 \| 46.253 Amsterdam \| N/A \| Netherlands \| 4.88969 \| 52.37403 Amsterdam \| N/A \| Netherlands \| 4.88969 \| 52.37403 Maastricht \| N/A \| Netherlands \| 5.68889 \| 50.84833 Groenkloof \| N/A \| South Africa \| 25.50906 \| -31.78089 Panorama \| N/A \| South Africa \| 31.89113 \| -28.75383 Pretoria \| N/A \| South Africa \| 28.18783 \| -25.74486 Sandton \| N/A \| South Africa \| 28.054 \| -26.104 Lausanne \| Rue Du Bugnon 46 \| Switzerland \| 6.63282 \| 46.516 Lausanne \| N/A \| Switzerland \| 6.63282 \| 46.516 Zurich \| N/A \| Switzerland \| 8.55 \| 47.36667 Guildford \| Surry \| United Kingdom \| -0.57427 \| 51.23536 Cardiff \| N/A \| United Kingdom \| -3.18 \| 51.48 Dundee \| N/A \| United Kingdom \| -2.97489 \| 56.46913 Manchester \| N/A \| United Kingdom \| -2.23743 \| 53.48095 Nottingham \| N/A \| United Kingdom \| -1.15047 \| 52.9536 Oxford \| N/A \| United Kingdom \| -1.25596 \| 51.75222 Poole \| N/A \| United Kingdom \| -1.98458 \| 50.71429 Sheffield \| N/A \| United Kingdom \| -1.4659 \| 53.38297 Southampton \| N/A \| United Kingdom \| -1.40428 \| 50.90395	643	1	0.001555	1	NCT00094653	1COMPLETED	2009-10-01	2004-09-01	Bristol-Myers Squibb	4INDUSTRY	false	false	false	null	1	0	0	0	0	0	0	0	0.000275
[ 4 ]	9,306	RANDOMIZED	FACTORIAL	1PREVENTION	2DOUBLE	false	0ALL	true	This study is a test of the safety and effectiveness of two drugs, one for diabetes and one for hypertension, in keeping patients with high lab values of glucose from progressing to frank diabetes and developing cardiovascular complications. People in this study cannot have frank diabetes but are considered "borderline" based on blood tests. People in the study take none, one or both of the drugs and do not know which one(s) they are taking.	null	Diabetes Mellitus, Type 2	Prevention Diabetes type 2 valsartan nateglinide	null	4	arm 1: For the first 2 weeks of treatment, patients took the combination of nateglinide 30 mg (3 times daily, ante cibum \[ac\] before meals) and valsartan 80 mg (once daily \[od\] in the morning). After 2 weeks, patients were up-titrated to nateglinide 60 mg ac and valsartan 160 mg od. arm 2: For the first 2 weeks of treatment, patients took valsartan 80 mg capsules (once daily \[od\] in the morning). After 2 weeks, patients were up-titrated to 160 mg valsartan od. Patients also received nateglinide placebo tablets (3 times daily, ante cibum \[ac\] before meals). arm 3: For the first 2 weeks of treatment, patients took nateglinide 30 mg tablets (3 times daily, ante cibum \[ac\] before meals). After 2 weeks, patients were uptitrated to 60 mg nateglinide ac. Patients also received valsartan placebo capsules (once daily \[od\] in the morning). arm 4: Patients took 3 nateglinide placebo tablets (3 times daily, ante cibum \[ac\] before meals) and 1 valsartan placebo capsule (once daily \[od\] in the morning).	[ 0, 0, 0, 2 ]	4	[ 0, 0, 0, 0 ]	intervention 1: The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure. intervention 2: The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure. intervention 3: The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure. intervention 4: The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure.	intervention 1: Valsartan 160 mg + nateglinide 60 mg intervention 2: Valsartan 160 mg + nateglinide placebo intervention 3: Nateglinide 60 mg + valsartan placebo intervention 4: Valsartan placebo + nateglinide placebo	38	Multiple Locations \| New Jersey \| United States \| N/A \| N/A Investigative Site \| N/A \| Argentina \| N/A \| N/A Investigative Site \| N/A \| Australia \| N/A \| N/A Multiple Locations \| N/A \| Austria \| N/A \| N/A Investigative Site \| N/A \| Belgium \| N/A \| N/A Investigative Site \| N/A \| Brazil \| N/A \| N/A Investigative Site \| N/A \| Canada \| N/A \| N/A Investigative Site \| N/A \| Chile \| N/A \| N/A Investigative Site \| N/A \| China \| N/A \| N/A Investigative Site \| N/A \| Colombia \| N/A \| N/A Investigative Site \| N/A \| Czechia \| N/A \| N/A Investigative Site \| N/A \| Denmark \| N/A \| N/A Investigative Site \| N/A \| Ecuador \| N/A \| N/A Investigative Site \| N/A \| Finland \| N/A \| N/A Investigative Site \| N/A \| France \| N/A \| N/A Investigative Site \| N/A \| Germany \| N/A \| N/A Investigative Site \| N/A \| Greece \| N/A \| N/A Investigative Site \| N/A \| Guatemala \| N/A \| N/A Investigative Site \| N/A \| Hong Kong \| N/A \| N/A Investigative Site \| N/A \| Hungary \| N/A \| N/A Investigative Site \| N/A \| Italy \| N/A \| N/A Investigative Site \| N/A \| Malaysia \| N/A \| N/A Investigative Site \| N/A \| Mexico \| N/A \| N/A Investigative Site \| N/A \| Netherlands \| N/A \| N/A Investigative Site \| N/A \| Norway \| N/A \| N/A Investigative Site \| N/A \| Peru \| N/A \| N/A Investigative Site \| N/A \| Poland \| N/A \| N/A Investigative Site \| N/A \| Russia \| N/A \| N/A Investigative Site \| N/A \| Singapore \| N/A \| N/A Investigative Site \| N/A \| Slovakia \| N/A \| N/A Investigative Site \| N/A \| South Africa \| N/A \| N/A Investigative Site \| N/A \| Spain \| N/A \| N/A Investigative Site \| N/A \| Sweden \| N/A \| N/A Investigative Site \| N/A \| Switzerland \| N/A \| N/A Investigative Site \| N/A \| Taiwan \| N/A \| N/A Investigative Site \| N/A \| Turkey (Türkiye) \| N/A \| N/A Investigative Site \| N/A \| United Kingdom \| N/A \| N/A Investigative Site \| N/A \| Uruguay \| N/A \| N/A	9,201	11	0.001196	1	NCT00097786	1COMPLETED	2009-10-01	2002-01-01	Novartis Pharmaceuticals	4INDUSTRY	false	false	false	null	4	0	0	1	1	1	4	0	0.000668
[ 4 ]	225	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	true	The purpose of this study is to determine if Thalidomide + Dexamethasone or DOXIL (doxorubicin HCl liposome injection) + Thalidomide + Dexamethasone is more effective in treating newly diagnosed patients with multiple myeloma. The number of patients whose multiple myeloma disappears for a period of time (complete Response) will be studied to make the determination of which treatment is more effective.	This is a multi-center, open-label (all people know the identity of the intervention), randomized (the study medication is assigned by chance) study to compare the safety and effectiveness of Thalidomide + Dexamethasone versus DOXIL (doxorubicin HCl liposome injection) + Thalidomide + Dexamethasone in patients with newly diagnosed multiple myeloma. Treatments are administered in 28-day cycles. Patients will receive 4 to 12 treatment cycles, depending on the response of their multiple myeloma to the treatment (measured according to the European Group for Blood and Marrow Transplant Response Criteria). Patients will have additional tests that include Multiple Gated Acquisition (MUGA) scans or echocardiograms to assess the patients for potential cardiotoxicity that could be related to treatment with DOXIL (doxorubicin HCl liposome injection). Maximum duration of study participation for each participant will be 48 weeks.	Multiple Myeloma	Multiple myeloma Newly diagnosed multiple myeloma Thalidomide Dexamethasone DOXIL Pegylated liposomal hydrochloride doxorubicin injection	null	2	arm 1: None arm 2: None	[ 1, 0 ]	3	[ 0, 0, 0 ]	intervention 1: Participants will receive thalidomide orally every night (at bedtime) without food on days 1-28 and dosing will gradually increase during Cycle 1 starting at 50 mg on 1 to 7 days, 100 mg on 8 to 14 days, 150 mg on 15 to 21 days, and 200 mg 22 to 28 days. Thalidomide 200 mg per day will be administered for subsequent cycles. Participants will receive thalidomide for minimum of 4 cycles and a maximum of 12 cycles. intervention 2: Participants will receive dexamethasone 40 mg orally on Days 1 to 4, 9 to 12 and 17 to 20. intervention 3: DOXIL 40 mg/m2 will be administered iintravenously (into a vein) on Day 1.	intervention 1: Thalidomide intervention 2: Dexamethasone intervention 3: DOXIL	58	Fountain Valley \| California \| United States \| -117.95367 \| 33.70918 Greenbrae \| California \| United States \| -122.5247 \| 37.94854 La Verne \| California \| United States \| -117.76784 \| 34.10084 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Denver \| Colorado \| United States \| -104.9847 \| 39.73915 New London \| Connecticut \| United States \| -72.09952 \| 41.35565 Boca Raton \| Florida \| United States \| -80.0831 \| 26.35869 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 Miami \| Florida \| United States \| -80.19366 \| 25.77427 Orange City \| Florida \| United States \| -81.29867 \| 28.94888 Ormond Beach \| Florida \| United States \| -81.05589 \| 29.28581 Lawrenceville \| Georgia \| United States \| -83.98796 \| 33.95621 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Wichita \| Kansas \| United States \| -97.33754 \| 37.69224 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Bethesda \| Maryland \| United States \| -77.10026 \| 38.98067 Minneapolis \| Minnesota \| United States \| -93.26384 \| 44.97997 Saint Louis Park \| Minnesota \| United States \| -93.34801 \| 44.9483 Columbia \| Missouri \| United States \| -92.33407 \| 38.95171 Kansas City \| Missouri \| United States \| -94.57857 \| 39.09973 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 Englewood \| New Jersey \| United States \| -73.97264 \| 40.89288 Hackensack \| New Jersey \| United States \| -74.04347 \| 40.88593 Jersey City \| New Jersey \| United States \| -74.07764 \| 40.72816 Voorhees Township \| New Jersey \| United States \| -74.49062 \| 40.4795 Albany \| New York \| United States \| -73.75623 \| 42.65258 Armonk \| New York \| United States \| -73.71402 \| 41.12648 Box 302 \| New York \| United States \| N/A \| N/A Brooklyn \| New York \| United States \| -73.94958 \| 40.6501 Nyack \| New York \| United States \| -73.91791 \| 41.09065 The Bronx \| New York \| United States \| -73.86641 \| 40.84985 Valhalla \| New York \| United States \| -73.77513 \| 41.07482 Durham \| North Carolina \| United States \| -78.89862 \| 35.99403 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Oklahoma City \| Oklahoma \| United States \| -97.51643 \| 35.46756 Tulsa \| Oklahoma \| United States \| -95.99277 \| 36.15398 Eugene \| Oregon \| United States \| -123.08675 \| 44.05207 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Wynnewood \| Pennsylvania \| United States \| -75.27074 \| 40.00289 Columbia \| South Carolina \| United States \| -81.03481 \| 34.00071 Easley \| South Carolina \| United States \| -82.60152 \| 34.82984 Sumter \| South Carolina \| United States \| -80.34147 \| 33.92044 Memphis \| Tennessee \| United States \| -90.04898 \| 35.14953 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 Bedford \| Texas \| United States \| -97.14307 \| 32.84402 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Fort Worth \| Texas \| United States \| -97.32085 \| 32.72541 Fredericksburg \| Texas \| United States \| -98.87198 \| 30.2752 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Burlington \| Vermont \| United States \| -73.21207 \| 44.47588 Fairfax \| Virginia \| United States \| -77.30637 \| 38.84622 Norfolk \| Virginia \| United States \| -76.28522 \| 36.84681 Richmond \| Virginia \| United States \| -77.46026 \| 37.55376 Spokane \| Washington \| United States \| -117.42908 \| 47.65966 Vancouver \| Washington \| United States \| -122.66149 \| 45.63873 Yakima \| Washington \| United States \| -120.5059 \| 46.60207	216	1	0.00463	1	NCT00097981	1COMPLETED	2009-10-01	2005-01-01	Johnson & Johnson Pharmaceutical Research & Development, L.L.C.	4INDUSTRY	false	false	false	null	1	0	0	0	0	0	0	0	0.000818
[ 4 ]	1,553	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	To learn about the safety and any side effects of atomoxetine when given to children and adolescents for about 5 years (long-term) and to learn whether atomoxetine can help children and adolescents with attention-deficit/hyperactivity disorder (ADHD) who take the drug for about 5 years (long-term). Study participants can be atomoxetine naive, atomoxetine experienced whose therapy has been interrupted or, atomoxetine experienced on a known stable dose.	null	Attention Deficit Hyperactivity Disorder		null	1	arm 1: Atomoxetine-naive patients will have an acute titration to a stable dose, atomoxetine experienced patients whose therapy has been interrupted with be rapidly titrated to their previously established stable dose, and atomoxetine patients on a known stable dose may continue treatment at that dose.	[ 0 ]	1	[ 0 ]	intervention 1: 0.5-1.8 mg/kg/day, by mouth (PO), for up to 5 years	intervention 1: atomoxetine	100	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 El Centro \| California \| United States \| -115.56305 \| 32.792 Irvine \| California \| United States \| -117.82311 \| 33.66946 Lafayette \| California \| United States \| -122.11802 \| 37.88576 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 San Diego \| California \| United States \| -117.16472 \| 32.71571 Spring Valley \| California \| United States \| -116.99892 \| 32.74477 Walnut Creek \| California \| United States \| -122.06496 \| 37.90631 Norwich \| Connecticut \| United States \| -72.07591 \| 41.52426 Boca Raton \| Florida \| United States \| -80.0831 \| 26.35869 Gainsville \| Florida \| United States \| N/A \| N/A Miami \| Florida \| United States \| -80.19366 \| 25.77427 Orlando \| Florida \| United States \| -81.37924 \| 28.53834 Tallahassee \| Florida \| United States \| -84.28073 \| 30.43826 West Palm Beach \| Florida \| United States \| -80.05337 \| 26.71534 Boise \| Idaho \| United States \| -116.20345 \| 43.6135 Northbrook \| Illinois \| United States \| -87.82895 \| 42.12753 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Lafayette \| Indiana \| United States \| -86.87529 \| 40.4167 Iowa City \| Iowa \| United States \| -91.53017 \| 41.66113 Bardstown \| Kentucky \| United States \| -85.4669 \| 37.80923 Lexington \| Kentucky \| United States \| -84.47772 \| 37.98869 New Orleans \| Louisiana \| United States \| -90.07507 \| 29.95465 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Cambridge \| Massachusetts \| United States \| -71.10561 \| 42.3751 Worcester \| Massachusetts \| United States \| -71.80229 \| 42.26259 Detroit \| Michigan \| United States \| -83.04575 \| 42.33143 Kalamazoo \| Michigan \| United States \| -85.58723 \| 42.29171 Troy \| Michigan \| United States \| -83.14993 \| 42.60559 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 Cherry Hill \| New Jersey \| United States \| -75.03073 \| 39.93484 Clementon \| New Jersey \| United States \| -74.98294 \| 39.8115 Moorestown \| New Jersey \| United States \| -74.94267 \| 39.96706 Piscataway \| New Jersey \| United States \| -74.39904 \| 40.49927 Manhasset \| New York \| United States \| -73.69957 \| 40.79788 New Hyde Park \| New York \| United States \| -73.68791 \| 40.7351 New York \| New York \| United States \| -74.00597 \| 40.71427 Rochester \| New York \| United States \| -77.61556 \| 43.15478 Stony Brook \| New York \| United States \| -73.14094 \| 40.92565 Chapel Hill \| North Carolina \| United States \| -79.05584 \| 35.9132 Charlotte \| North Carolina \| United States \| -80.84313 \| 35.22709 Durham \| North Carolina \| United States \| -78.89862 \| 35.99403 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Columbus \| Ohio \| United States \| -82.99879 \| 39.96118 Oklahoma City \| Oklahoma \| United States \| -97.51643 \| 35.46756 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Hershey \| Pennsylvania \| United States \| -76.65025 \| 40.28592 Media \| Pennsylvania \| United States \| -75.38769 \| 39.91678 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Rydal \| Pennsylvania \| United States \| -75.10851 \| 40.1065 Providence \| Rhode Island \| United States \| -71.41283 \| 41.82399 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Galveston \| Texas \| United States \| -94.7977 \| 29.30135 Lake Jackson \| Texas \| United States \| -95.43439 \| 29.03386 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Fairfax \| Virginia \| United States \| -77.30637 \| 38.84622 Herndon \| Virginia \| United States \| -77.3861 \| 38.96955 Midlothian \| Virginia \| United States \| -77.64916 \| 37.50598 Norfolk \| Virginia \| United States \| -76.28522 \| 36.84681 Richmond \| Virginia \| United States \| -77.46026 \| 37.55376 Vienna \| Virginia \| United States \| -77.26526 \| 38.90122 Spokane \| Washington \| United States \| -117.42908 \| 47.65966 Marshfield \| Wisconsin \| United States \| -90.1718 \| 44.66885 Middleton \| Wisconsin \| United States \| -89.50429 \| 43.09722 Milwaukee \| Wisconsin \| United States \| -87.90647 \| 43.0389 Wallsend \| New South Wales \| Australia \| 151.66432 \| -32.90133 South Brisbane \| Queensland \| Australia \| 153.02049 \| -27.48034 West Perth \| Western Australia \| Australia \| 115.84199 \| -31.94896 Antwerp \| N/A \| Belgium \| 4.40026 \| 51.22047 Leuven \| N/A \| Belgium \| 4.70093 \| 50.87959 Edmonton \| Alberta \| Canada \| -113.46871 \| 53.55014 Halifax \| Nova Scotia \| Canada \| -63.57688 \| 44.64269 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Québec \| Quebec \| Canada \| -71.21454 \| 46.81228 Bordeaux \| N/A \| France \| -0.5805 \| 44.84044 Lyon \| N/A \| France \| 4.84671 \| 45.74846 Paris \| N/A \| France \| 2.3488 \| 48.85341 Paris \| N/A \| France \| 2.3488 \| 48.85341 Heiligenstadt/Ofr \| N/A \| Germany \| N/A \| N/A Mannheim \| N/A \| Germany \| 8.46694 \| 49.4891 Holon \| N/A \| Israel \| 34.77918 \| 32.01034 Ness Ziona \| N/A \| Israel \| 34.79868 \| 31.92933 Cagliari \| N/A \| Italy \| 9.11917 \| 39.23054 Pisa \| N/A \| Italy \| 10.4036 \| 43.70853 Groningen \| N/A \| Netherlands \| 6.56667 \| 53.21917 Utrecht \| N/A \| Netherlands \| 5.12222 \| 52.09083 Oslo \| N/A \| Norway \| 10.74609 \| 59.91273 Rio Piedras \| N/A \| Puerto Rico \| -66.04989 \| 18.39745 San Juan \| N/A \| Puerto Rico \| -66.10572 \| 18.46633 Benmore \| Sandown \| South Africa \| N/A \| N/A Garsfontein \| N/A \| South Africa \| 28.3 \| -25.7935 Panorama \| N/A \| South Africa \| 31.89113 \| -28.75383 Gothenburg \| N/A \| Sweden \| 11.96679 \| 57.70716 Glasgow \| Scotland \| United Kingdom \| -4.25763 \| 55.86515 Sheffield \| South Yorkshire \| United Kingdom \| -1.4659 \| 53.38297	1,551	2	0.001289	1	NCT00190684	1COMPLETED	2009-10-01	2000-08-01	Eli Lilly and Company	4INDUSTRY	false	false	false	null	0	0	0	1	0	0	1	0	0.000354
[ 5 ]	502	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	0ALL	false	This is a parallel design, double-blind, placebo-controlled, multi-center, 38-week treatment trial of atomoxetine in adults with attention deficit hyperactivity disorder (ADHD) who are currently living in a family situation with at least one child. The primary objective of the study is to demonstrate the efficacy of atomoxetine compared to placebo in the reduction of ADHD symptoms over 12 and 24 weeks of blinded treatment.	The initial study was 34 weeks long; however, the protocol was amended to extend the open-label period of the study from 8 weeks to 12 weeks (38 weeks total).	Attention Deficit Hyperactivity Disorder		null	2	arm 1: Atomoxetine 40 milligrams (mg) once daily (QD) for 3 days followed by 80 mg QD for 11 days OR 40 mg QD for 7 days followed by 80 mg QD for 7 days, then 60/80/100 mg as determined by the investigator up to 24 weeks, orally arm 2: Placebo is administered once daily (QD), orally for 24 weeks. At the end of 24 weeks, the placebo arm is titrated to atomoxetine 40 mg QD for 3 days followed by 80 mg QD for 11 days OR 40 mg QD for 7 days followed by 80 mg QD for 7 days, then 40-100 mg QD, orally.	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: Atomoxetine 40 mg QD for 3 days followed by 80 mg QD for 11 days OR 40 mg QD for 7 days followed by 80 mg QD for 7 days, then 60/80/100 mg as determined by the investigator up to 24 weeks, orally intervention 2: Placebo is administered QD, orally for 24 weeks. At the end of 24 weeks, the placebo arm is titrated to atomoxetine 40 mg QD for 3 days followed by 80 mg QD for 11 days OR 40 mg QD for 7 days followed by 80 mg QD for 7 days, then 40-100 mg QD, orally.	intervention 1: Atomoxetine Hydrochloride intervention 2: Placebo	21	Irvine \| California \| United States \| -117.82311 \| 33.66946 Gainesville \| Florida \| United States \| -82.32483 \| 29.65163 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Libertyville \| Illinois \| United States \| -87.95313 \| 42.28308 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Bardstown \| Kentucky \| United States \| -85.4669 \| 37.80923 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Rochester Hills \| Michigan \| United States \| -83.14993 \| 42.65837 Troy \| Michigan \| United States \| -83.14993 \| 42.60559 Mount Kisco \| New York \| United States \| -73.72708 \| 41.20426 Chapel Hill \| North Carolina \| United States \| -79.05584 \| 35.9132 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Toledo \| Ohio \| United States \| -83.55521 \| 41.66394 Media \| Pennsylvania \| United States \| -75.38769 \| 39.91678 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Herndon \| Virginia \| United States \| -77.3861 \| 38.96955 Middleton \| Wisconsin \| United States \| -89.50429 \| 43.09722 West Allis \| Wisconsin \| United States \| -88.00703 \| 43.01668 Santurce \| N/A \| Puerto Rico \| -67.14018 \| 18.19523	500	1	0.002	1	NCT00190775	1COMPLETED	2009-10-01	2004-09-01	Eli Lilly and Company	4INDUSTRY	false	false	false	null	1	0	0	0	0	0	0	0	0.000353
[ 5 ]	1,270	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	false	The purpose of this clinical research study is to learn if outpatients with bipolar mania who are partially nonresponsive to lithium or valproate monotherapy can achieve stable symptoms on a combination treatment of aripiprazole plus lithium or valproate.	null	Bipolar Disorder	Bipolar I Disorder with a recent manic or mixed episode	null	2	arm 1: /Active Comparator arm 2: None	[ 2, 0 ]	2	[ 0, 0 ]	intervention 1: Tablets, Oral, once daily lithium 250-2100 mg/day valproate 250-2500mg/day Placebo once daily intervention 2: Tablets, Oral, once daily, 52 weeks post randomization (Pre-Randomization Phases 13-24 weeks) lithium 250-2100 mg/day valproate 250-2500mg/day aripiprazole 15-30 mg/day	intervention 1: Lithium or Valproate with placebo (PBO) intervention 2: Lithium or Valproate with Aripiprazole	83	Tuscaloosa \| Alabama \| United States \| -87.56917 \| 33.20984 Anaheim \| California \| United States \| -117.9145 \| 33.83529 Cerritos \| California \| United States \| -118.06479 \| 33.85835 Costa Mesa \| California \| United States \| -117.91867 \| 33.64113 Costa Mesa \| California \| United States \| -117.91867 \| 33.64113 Long Beach \| California \| United States \| -118.18923 \| 33.76696 National City \| California \| United States \| -117.0992 \| 32.67811 Orange \| California \| United States \| -117.85311 \| 33.78779 Orlando \| Florida \| United States \| -81.37924 \| 28.53834 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 Smyrna \| Georgia \| United States \| -84.51438 \| 33.88399 Worcester \| Massachusetts \| United States \| -71.80229 \| 42.26259 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Clementon \| New Jersey \| United States \| -74.98294 \| 39.8115 New York \| New York \| United States \| -74.00597 \| 40.71427 Staten Island \| New York \| United States \| -74.13986 \| 40.56233 Staten Island \| New York \| United States \| -74.13986 \| 40.56233 Raleigh \| North Carolina \| United States \| -78.63861 \| 35.7721 Beachwood \| Ohio \| United States \| -81.50873 \| 41.4645 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Dayton \| Ohio \| United States \| -84.19161 \| 39.75895 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Austin \| Texas \| United States \| -97.74306 \| 30.26715 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 DeSoto \| Texas \| United States \| -96.85695 \| 32.58986 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Bellevue \| Washington \| United States \| -122.20068 \| 47.61038 Salvador \| Estado de Bahia \| Brazil \| -38.49096 \| -12.97563 Aparecida de Goinia \| Goiás \| Brazil \| N/A \| N/A Pelotas \| Rio Grande do Sul \| Brazil \| -52.34101 \| -31.76997 Rio de Janeiro \| N/A \| Brazil \| -43.18223 \| -22.90642 São Paulo \| N/A \| Brazil \| -46.63611 \| -23.5475 São Paulo \| N/A \| Brazil \| -46.63611 \| -23.5475 Burgas \| N/A \| Bulgaria \| 27.46781 \| 42.50606 Rousse \| N/A \| Bulgaria \| 25.9534 \| 43.84872 Rijeka \| N/A \| Croatia \| 14.44241 \| 45.32673 Split \| N/A \| Croatia \| 16.43915 \| 43.50891 Zadar \| N/A \| Croatia \| 15.22514 \| 44.11578 Zagreb \| N/A \| Croatia \| 15.97798 \| 45.81444 Brno \| N/A \| Czechia \| 16.60796 \| 49.19522 Brno \| N/A \| Czechia \| 16.60796 \| 49.19522 Havířov \| N/A \| Czechia \| 18.43688 \| 49.77984 Litoměřice \| N/A \| Czechia \| 14.1318 \| 50.53348 Prague \| N/A \| Czechia \| 14.42076 \| 50.08804 Prague \| N/A \| Czechia \| 14.42076 \| 50.08804 Přerov \| N/A \| Czechia \| 17.4509 \| 49.45511 Nantes \| Cedex 01 \| France \| -1.55336 \| 47.21725 Dole \| N/A \| France \| 5.48966 \| 47.09225 Hénin-Beaumont \| N/A \| France \| 2.96485 \| 50.41359 Jonzac \| N/A \| France \| -0.43485 \| 45.44636 La Seyne-sur-Mer \| N/A \| France \| 5.87816 \| 43.10322 Marseille \| N/A \| France \| 5.38107 \| 43.29695 Nantes \| N/A \| France \| -1.55336 \| 47.21725 Nîmes \| N/A \| France \| 4.35788 \| 43.83665 Rennes \| N/A \| France \| -1.67429 \| 48.11198 Hyderabad \| Andhra Pradesh \| India \| N/A \| N/A Ahmedabad \| Gujarat \| India \| 72.58727 \| 23.02579 Ahmedabad \| Gujarat \| India \| 72.58727 \| 23.02579 Kalyan (West) \| Maharashtra \| India \| 73.13554 \| 19.2437 Nāgūr \| Maharashtra \| India \| 76.38645 \| 18.02544 Pune \| Maharashtra \| India \| 73.85535 \| 18.51957 Mangalore \| Manipal \| India \| 74.85603 \| 12.91723 Mumbai \| Sion (W) \| India \| 72.88261 \| 19.07283 Delhi \| N/A \| India \| 77.23149 \| 28.65195 Hyderabad \| N/A \| India \| 78.45636 \| 17.38405 Mumbai \| N/A \| India \| 72.88261 \| 19.07283 Mumbai \| N/A \| India \| 72.88261 \| 19.07283 New Delhi \| N/A \| India \| 77.2148 \| 28.62137 New Delhi \| N/A \| India \| 77.2148 \| 28.62137 Izhevsk \| N/A \| Russia \| 53.20448 \| 56.84976 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 Saratov \| N/A \| Russia \| 46.00861 \| 51.54056 Tomsk \| N/A \| Russia \| 84.98204 \| 56.50032 Pretoria \| Gauteng \| South Africa \| 28.18783 \| -25.74486 Berea \| KwaZulu-Natal \| South Africa \| 30.99337 \| -29.85185 Durban \| KwaZulu-Natal \| South Africa \| 31.0292 \| -29.8579 Cape Town \| Western Cape \| South Africa \| 18.42322 \| -33.92584 Paarl \| Western Cape \| South Africa \| 18.97523 \| -33.73378	1,057	2	0.001892	1	NCT00261443	1COMPLETED	2009-10-01	2005-09-01	Otsuka Pharmaceutical Development & Commercialization, Inc.	4INDUSTRY	false	false	false	null	2	0	0	0	0	0	0	0	0.000519
[ 5 ]	566	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	false	This is a randomized, multi-center, parallel-group, active-controlled, double-blind study evaluating the effects of mometasone furoate (MF) dry powder inhaler (DPI) on bone mineral density (BMD) in subjects with asthma. The mean percent change in lumbar spine BMD from the averaged baseline value (the average of the two scan results prior to treatment) to the endpoint of treatment time point (the average of the last two valid post-baseline scan results during treatment) for the comparison of MF DPI 400 mcg daily in the evening versus montelukast (ML) 10 mg daily in the evening.	null	Asthma		null	4	arm 1: MF DPI 400 mcg once a day (QD) in the evening (PM) arm 2: MF DPI 200 mcg QD PM arm 3: Fluticasone propionate (FP) metered dose inhaler (MDI) 250 mcg twice a day (BID) arm 4: ML 10 mg QD PM	[ 0, 0, 1, 1 ]	4	[ 0, 0, 0, 0 ]	intervention 1: 400 mcg MF DPI via a breath-actuated, dry-powder inhaler and a placebo tablet given by mouth once daily in the evening for 1 year. intervention 2: 200 mcg MF DPI via a breath-actuated, dry-powder inhaler and a placebo tablet given by mouth once daily in the evening for 1 year. intervention 3: 250 mcg FP HFA given twice a day via a metered-dose inhaler and a placebo tablet given once daily in the evening for 1 year intervention 4: 10 mg given once daily in the evening by mouth for 1 year.	intervention 1: mometasone furoate dry powder inhaler intervention 2: mometasone furoate dry powder inhaler intervention 3: fluticasone propionate hydrofluoroalkane (HFA) intervention 4: montelukast	0	null	566	1	0.001767	1	NCT00394355	1COMPLETED	2009-10-01	2006-09-01	Organon and Co	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	1	0	0.000312
[ 5 ]	1,531	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	To investigate whether a Caduet based treatment strategy might result in greater reduction in total cardiovascular risk as compared to usual care in subjects with hypertension and additional risk factors.	null	Hypertension Hypercholesterolemia		null	1	arm 1: Open label caduet added to usual care regimen followed by investigators.	[ 0 ]	1	[ 0 ]	intervention 1: Open label amlodipine besylate/atorvastatin calcium single pill combination at multiple doses: 5/10, 10/10, 5/20, 10/20 mg prescribed at the investigator's discretion	intervention 1: Amlodipine besylate/atorvastatin calcium single pill combination	125	Desamparados \| Provincia de San José \| Costa Rica \| -84.06345 \| 9.89747 Heredia \| N/A \| Costa Rica \| -84.11587 \| 9.99872 San José \| N/A \| Costa Rica \| -84.08489 \| 9.93388 Breznički Hum \| N/A \| Croatia \| 16.27667 \| 46.10722 Crikvenica \| N/A \| Croatia \| 14.69278 \| 45.17722 Čakovec \| N/A \| Croatia \| 16.43389 \| 46.38444 Karlovac \| N/A \| Croatia \| 15.55 \| 45.49167 Rijeka \| N/A \| Croatia \| 14.44241 \| 45.32673 Split \| N/A \| Croatia \| 16.43915 \| 43.50891 Sveti Križ Začretje \| N/A \| Croatia \| 15.91111 \| 46.08083 Špišić-Bukovica \| N/A \| Croatia \| 17.29944 \| 45.85722 Varaždin \| N/A \| Croatia \| 16.33778 \| 46.30444 Zagreb \| N/A \| Croatia \| 15.97798 \| 45.81444 Brno \| N/A \| Czechia \| 16.60796 \| 49.19522 Klatovy \| N/A \| Czechia \| 13.29505 \| 49.39552 Kralupy nad Vltavou \| N/A \| Czechia \| 14.31149 \| 50.24107 Lanškroun \| N/A \| Czechia \| 16.6119 \| 49.91217 Olomouc \| N/A \| Czechia \| 17.25175 \| 49.59552 Pelhřimov \| N/A \| Czechia \| 15.22336 \| 49.43134 Prague \| N/A \| Czechia \| 14.42076 \| 50.08804 Prague \| N/A \| Czechia \| 14.42076 \| 50.08804 Průhonice \| N/A \| Czechia \| 14.55017 \| 49.99962 Ústí nad Labem \| N/A \| Czechia \| 14.03227 \| 50.6607 Vratimov \| N/A \| Czechia \| 18.31015 \| 49.76995 Zlín \| N/A \| Czechia \| 17.67065 \| 49.22645 San Cristóbal \| N/A \| Dominican Republic \| -70.10682 \| 18.41713 Santo Domingo \| N/A \| Dominican Republic \| -69.89232 \| 18.47186 Santo Domingo \| N/A \| Dominican Republic \| -69.89232 \| 18.47186 Cilandak \| Jakarta Selatan \| Indonesia \| 106.0829 \| -6.1596 Bandung \| N/A \| Indonesia \| 107.60694 \| -6.92222 Jakarta \| N/A \| Indonesia \| 106.84513 \| -6.21462 Jakarta \| N/A \| Indonesia \| 106.84513 \| -6.21462 Semarang \| N/A \| Indonesia \| 110.42083 \| -6.99306 Surabaya \| N/A \| Indonesia \| 112.75083 \| -7.24917 Tangerang \| N/A \| Indonesia \| 106.63 \| -6.17806 Tanggerang \| N/A \| Indonesia \| N/A \| N/A Amman \| N/A \| Jordan \| 35.94503 \| 31.95522 Amman \| N/A \| Jordan \| 35.94503 \| 31.95522 Irbid \| N/A \| Jordan \| 35.85 \| 32.55556 Kuwait City \| N/A \| Kuwait \| 47.97429 \| 29.367 Sasat \| N/A \| Kuwait \| N/A \| N/A Beirut \| N/A \| Lebanon \| 35.50157 \| 33.89332 Byblos \| N/A \| Lebanon \| 35.64806 \| 34.12111 Kuala Pilah \| Negeri Sembilan \| Malaysia \| 102.2487 \| 2.7389 Seremban \| Negeri Sembilan \| Malaysia \| 101.9381 \| 2.7297 Batu Caves \| Selangor \| Malaysia \| 101.682 \| 3.238 Petaling Jaya \| Selangor \| Malaysia \| 101.60671 \| 3.10726 Butterworth \| N/A \| Malaysia \| 100.36382 \| 5.3991 Kuala Lumpur \| N/A \| Malaysia \| 101.68653 \| 3.1412 Kuala Lumpur \| N/A \| Malaysia \| 101.68653 \| 3.1412 Guadalajara \| Jalisco \| Mexico \| -103.34749 \| 20.67738 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 Mexico City \| Mexico City \| Mexico \| -99.12766 \| 19.42847 Mexico City \| Mexico City \| Mexico \| -99.12766 \| 19.42847 Toluca \| State of Mexico \| Mexico \| -99.65324 \| 19.28786 Durango \| N/A \| Mexico \| -104.65756 \| 24.02032 San Luis Potosí City \| N/A \| Mexico \| -100.97135 \| 22.15234 Panama City \| N/A \| Panama \| -79.51973 \| 8.9936 San Juan City \| National Capital Region \| Philippines \| 121.0333 \| 14.6 Makati City \| N/A \| Philippines \| 121.03269 \| 14.55027 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 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 Smolensk \| N/A \| Russia \| 32.04371 \| 54.77944 Volgograd \| N/A \| Russia \| 44.50183 \| 48.71939 Voronezh \| N/A \| Russia \| 39.1843 \| 51.67204 Riyadh \| N/A \| Saudi Arabia \| 46.72185 \| 24.68773 Wŏnju \| Gangwon-do \| South Korea \| 127.94528 \| 37.35139 Seongnam-si \| Gyeonggi-do \| South Korea \| 127.13778 \| 37.43861 Busan \| N/A \| South Korea \| 129.03004 \| 35.10168 Busan \| N/A \| South Korea \| 129.03004 \| 35.10168 Daegu \| N/A \| South Korea \| 128.59111 \| 35.87028 Daegu \| N/A \| South Korea \| 128.59111 \| 35.87028 Daejeon \| N/A \| South Korea \| 127.38493 \| 36.34913 Gwangju \| N/A \| South Korea \| 126.91556 \| 35.15472 Incheon \| N/A \| South Korea \| 126.70515 \| 37.45646 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 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 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 \| N/A \| South Korea \| 127.00889 \| 37.29111 Kaohsiung City \| N/A \| Taiwan \| 120.31333 \| 22.61626 Kaohsiung City \| N/A \| Taiwan \| 120.31333 \| 22.61626 Taichung \| N/A \| Taiwan \| 120.6839 \| 24.1469 Taichung \| N/A \| Taiwan \| 120.6839 \| 24.1469 Tainan City \| N/A \| Taiwan \| 120.21333 \| 22.99083 Tainan City \| N/A \| Taiwan \| 120.21333 \| 22.99083 Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306 Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306 Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306 Rajthevee \| Bangkok \| Thailand \| N/A \| N/A Saimai \| Bangkok \| Thailand \| N/A \| N/A Bangkok \| N/A \| Thailand \| 100.50144 \| 13.75398 Ankara \| N/A \| Turkey (Türkiye) \| 32.85427 \| 39.91987 Ankara \| N/A \| Turkey (Türkiye) \| 32.85427 \| 39.91987 Istanbul \| N/A \| Turkey (Türkiye) \| 28.94966 \| 41.01384 Istanbul \| N/A \| Turkey (Türkiye) \| 28.94966 \| 41.01384 Istanbul \| N/A \| Turkey (Türkiye) \| 28.94966 \| 41.01384 Istanbul \| N/A \| Turkey (Türkiye) \| 28.94966 \| 41.01384 Izmir \| N/A \| Turkey (Türkiye) \| 27.13838 \| 38.41273 Izmir \| N/A \| Turkey (Türkiye) \| 27.13838 \| 38.41273 Abu Dhabi \| N/A \| United Arab Emirates \| 54.39696 \| 24.45118 Al Ain City \| N/A \| United Arab Emirates \| 55.76056 \| 24.19167 Dubai \| N/A \| United Arab Emirates \| 55.30927 \| 25.07725 Naguanagua/Valencia \| Carabobo \| Venezuela \| N/A \| N/A Valencia \| Carabobo \| Venezuela \| -68.00044 \| 10.16153 Caracas \| Dtto Capital/Municipio Libertador \| Venezuela \| -66.87919 \| 10.48801 Caracas \| Dtto Capital/Municipio Libertador \| Venezuela \| -66.87919 \| 10.48801	1,461	3	0.002053	1	NCT00407537	1COMPLETED	2009-10-01	2007-03-01	Pfizer's Upjohn has merged with Mylan to form Viatris Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	3	0	0	0	0.000699
[ 4 ]	308	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	The purpose of this trial is to determine whether lacosamide is safe and effective for long-term use in patients with partial-seizures from epilepsy	null	Partial Epilepsies	Adjunctive treatment in epilepsy add-on treatment for epilepsy partial seizures AEDs antiepileptic drugs seizures	null	1	arm 1: Up to 800 mg/day lacosamide (flexible dosing)	[ 0 ]	1	[ 0 ]	intervention 1: 50mg or 100 mg tablets, up to 800 mg/day given twice daily (BID) throughout the trial	intervention 1: lacosamide	60	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Mobile \| Alabama \| United States \| -88.04305 \| 30.69436 Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Englewood \| Colorado \| United States \| -104.98776 \| 39.64777 Fairfield \| Connecticut \| United States \| -73.26373 \| 41.14121 Bradenton \| Florida \| United States \| -82.57482 \| 27.49893 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 Maitland \| Florida \| United States \| -81.36312 \| 28.62778 St. Petersburg \| Florida \| United States \| -82.67927 \| 27.77086 Tallahassee \| Florida \| United States \| -84.28073 \| 30.43826 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Springfield \| Illinois \| United States \| -89.64371 \| 39.80172 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Wichita \| Kansas \| United States \| -97.33754 \| 37.69224 Lexington \| Kentucky \| United States \| -84.47772 \| 37.98869 Louisville \| Kentucky \| United States \| -85.75941 \| 38.25424 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Bethesda \| Maryland \| United States \| -77.10026 \| 38.98067 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Golden Valley \| Minnesota \| United States \| -93.34912 \| 45.00969 Saint Cloud \| Minnesota \| United States \| -94.16249 \| 45.5608 Saint Paul \| Minnesota \| United States \| -93.09327 \| 44.94441 Chesterfield \| Missouri \| United States \| -90.57707 \| 38.66311 Somerset \| New Jersey \| United States \| -74.48849 \| 40.4976 Albuquerque \| New Mexico \| United States \| -106.65114 \| 35.08449 Buffalo \| New York \| United States \| -78.87837 \| 42.88645 New York \| New York \| United States \| -74.00597 \| 40.71427 Rochester \| New York \| United States \| -77.61556 \| 43.15478 Syracuse \| New York \| United States \| -76.14742 \| 43.04812 Asheville \| North Carolina \| United States \| -82.55402 \| 35.60095 Durham \| North Carolina \| United States \| -78.89862 \| 35.99403 Greenville \| North Carolina \| United States \| -77.36635 \| 35.61266 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Columbus \| Ohio \| United States \| -82.99879 \| 39.96118 Toledo \| Ohio \| United States \| -83.55521 \| 41.66394 Tulsa \| Oklahoma \| United States \| -95.99277 \| 36.15398 Medford \| Oregon \| United States \| -122.87559 \| 42.32652 Hershey \| Pennsylvania \| United States \| -76.65025 \| 40.28592 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Providence \| Rhode Island \| United States \| -71.41283 \| 41.82399 Beaufort \| South Carolina \| United States \| -80.66993 \| 32.4317 Charleston \| South Carolina \| United States \| -79.93275 \| 32.77632 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Charlottesville \| Virginia \| United States \| -78.47668 \| 38.02931 Newport News \| Virginia \| United States \| -76.42975 \| 36.98038 Norfolk \| Virginia \| United States \| -76.28522 \| 36.84681 Richmond \| Virginia \| United States \| -77.46026 \| 37.55376 Seattle \| Washington \| United States \| -122.33207 \| 47.60621 Morgantown \| West Virginia \| United States \| -79.9559 \| 39.62953 Marshfield \| Wisconsin \| United States \| -90.1718 \| 44.66885 Milwaukee \| Wisconsin \| United States \| -87.90647 \| 43.0389	308	1	0.003247	1	NCT00522275	1COMPLETED	2009-10-01	2004-10-01	UCB BIOSCIENCES, Inc.	4INDUSTRY	false	false	false	null	1	0	0	0	0	0	0	0	0.000573
[ 3 ]	40	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	In this study we will measure the concentration of the drug called voriconazole which is used to fight infections caused by fungus in children who usually are cancer patients and have their immune system down. Since we know the dose in adults, and we think we know the matching doses in the young patients ages 2 to 12 years old, we will compare the amount of drug that goes into the system with what we know works in adults. We give the drug by a needle directly into the blood, then few days later we stop that and give the drug by mouth. Meanwhile, we draw a little bit of blood at certain times to measure the drug in it.	null	Candidiasis Candidemia	Open-Label Pharmacokinetics Intravenous to oral switch Safety Voriconazole Immunocompromise Children High Risk For Systemic Fungal Infection.	null	1	arm 1: Immunocompromised children aged 2 to \<12 years who are at high risk for systemic fungal infection.	[ 0 ]	1	[ 0 ]	intervention 1: Study Days 1 to 7: IV voriconazole 7 mg/kg q12h. Study Days 8 to 14: Oral voriconazole (POS) 200 mg q12h Notes: 1. If unable to switch to oral medication on Day 8, subjects can continue with IV treatment up to Day 20 before switching to oral dose. 2. Only morning oral dose will be given on Day 14 (or the seventh day of oral dosing if IV regimen is extended). However, if clinically indicated, voriconazole treatment may be continued up to Day 30. (IV = Intravenous; POS = Powder for oral suspension)	intervention 1: voriconazole (Vfend)	14	Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 Orange \| California \| United States \| -117.85311 \| 33.78779 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 New Orleans \| Louisiana \| United States \| -90.07507 \| 29.95465 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Durham \| North Carolina \| United States \| -78.89862 \| 35.99403 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 Houston \| Texas \| United States \| -95.36327 \| 29.76328	74	1	0.013514	1	NCT00739934	1COMPLETED	2009-10-01	2008-12-01	Pfizer	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	1	0	0.002389
[ 4 ]	565	RANDOMIZED	FACTORIAL	0TREATMENT	3TRIPLE	false	1FEMALE	false	Depomed's Gabapentin Extended Release is an investigational, extended release formulation of gabapentin that is being studied for the treatment of hot flashes in postmenopausal women	The primary study objective is to assess the efficacy of G-ER dosed in either of the following regimens: G-ER 1200mg daily (single evening dose) G-ER 1800mg daily (dosed asymmetrically; 600mg AM/1200mg PM) compared to placebo in reducing the average daily frequency and severity score of moderate to severe hot flashes in postmenopausal women after 4 weeks and 12 weeks of treatment with a stable dose, compared with the baseline week.	Hot Flashes	Hot Flashes Hot Flushes Postmenopausal symptoms Vasomotor symptoms	null	3	arm 1: Gabapentin extended-release (G-ER) 1200 mg arm 2: Gabapentin extended-release (G-ER) 1800 mg arm 3: Placebo 1200 mg or 1800 mg	[ 0, 0, 2 ]	3	[ 0, 0, 0 ]	intervention 1: G-ER 1200 mg daily dosage given as two 600-mg tablets. intervention 2: G-ER 1800 mg daily dosage given as one 600-mg tablet in the morning and two 600-mg tablets in the evening. intervention 3: Matching placebo dosages of 1200 mg daily (two 600-mg tablets) and 1800 mg daily (one 600-mg tablet in the morning and two 600-mg tablets in the evening).	intervention 1: Gabapentin Extended-Release (G-ER) 1200 mg intervention 2: Gabapentin Extended-Release (G-ER) 1800 mg intervention 3: Placebo	45	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Chandler \| Arizona \| United States \| -111.84125 \| 33.30616 Scottsdale \| Arizona \| United States \| -111.89903 \| 33.50921 Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 Foothill Ranch \| California \| United States \| -117.66088 \| 33.68641 San Diego \| California \| United States \| -117.16472 \| 32.71571 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 Danbury \| Connecticut \| United States \| -73.45401 \| 41.39482 Milford \| Connecticut \| United States \| -73.0565 \| 41.22232 Bradenton \| Florida \| United States \| -82.57482 \| 27.49893 Brooksville \| Florida \| United States \| -82.38991 \| 28.55554 Clearwater \| Florida \| United States \| -82.8001 \| 27.96585 Gainsville \| Florida \| United States \| N/A \| N/A Lauderdale Lakes \| Florida \| United States \| -80.20838 \| 26.16647 Pembroke Pines \| Florida \| United States \| -80.22394 \| 26.00315 Pinellas Park \| Florida \| United States \| -82.69954 \| 27.8428 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Douglasville \| Georgia \| United States \| -84.74771 \| 33.7515 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Marrero \| Louisiana \| United States \| -90.10035 \| 29.89937 Haverhill \| Massachusetts \| United States \| -71.07728 \| 42.7762 Paw Paw \| Michigan \| United States \| -85.89112 \| 42.21782 Saginaw \| Michigan \| United States \| -83.95081 \| 43.41947 Saint Paul \| Minnesota \| United States \| -93.09327 \| 44.94441 Las Vegas \| Nevada \| United States \| -115.13722 \| 36.17497 New York \| New York \| United States \| -74.00597 \| 40.71427 High Point \| North Carolina \| United States \| -80.00532 \| 35.95569 Bismarck \| North Dakota \| United States \| -100.78374 \| 46.80833 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Columbus \| Ohio \| United States \| -82.99879 \| 39.96118 Eugene \| Oregon \| United States \| -123.08675 \| 44.05207 Medford \| Oregon \| United States \| -122.87559 \| 42.32652 Jenkintown \| Pennsylvania \| United States \| -75.12517 \| 40.09594 Greenville \| South Carolina \| United States \| -82.39401 \| 34.85262 Mt. Pleasant \| South Carolina \| United States \| -79.86259 \| 32.79407 Clarksville \| Tennessee \| United States \| -87.35945 \| 36.52977 Knoxville \| Tennessee \| United States \| -83.92074 \| 35.96064 Memphis \| Tennessee \| United States \| -90.04898 \| 35.14953 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 West Jordan \| Utah \| United States \| -111.9391 \| 40.60967	559	1	0.001789	1	NCT00777023	1COMPLETED	2009-10-01	2008-10-01	Depomed	4INDUSTRY	false	false	false	null	1	0	0	0	0	0	0	0	0.000316
[ 3 ]	6	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	Vitamin D in the diet undergoes changes in the liver and kidneys to several forms. Patients suffering from disorders with Vitamin D resistance are unable to absorb calcium from food. Patients diagnosed with these disorders will be evaluated and treated with high doses of another form of Vitamin D (1,25-dihydroxyvitamin D3). Patients will be monitored and observed throughout the study to avoid experiencing side effects from the medication.	Patients with extreme resistance to 1,25-dihydroxyvitamin D will be evaluated and treated with high doses of 1,25-dihydroxyvitamin D3. Plan: In previously untreated patients the study will be divided into a control and one or more treatment periods. During the control period, parathyroid status will be assessed by parameters nos. 1\& 2 (below). In previously treated patients maintenance vitamin D will be gradually replaced with 1,25(OH)2D3. This will be accomplished by withdrawal of vitamin D and institution of 1,25(OH)2D3 when the serum calcium shows a downward trend. 1,25(OH)2D3 as 0.25 or 0.5 ug capsules (though IND 20,889) or as a solution of I microgram per ml will be administered orally. In most cases, because of consideration of time and expense, the cooperation of the patient's local physician will be enlisted. The following will be monitored: 1. Serum calcium, phosphorus,alkaline phosphatase,creatinine at twice weekly intervals. After a maintenance dose has been established, this will be decreased to a monthly, and subsequently 3-6 monthly interval. 2. Urine calcium, phosphorus,creatinine and cAMP before therapy and, when appropriate, during therapy. The dose of 1,25(OH)2D3 will be 0.125 to 50.0 ug/day. Serum calcium will not be allowed to rise above the normal range (2.0 -2.4 mM at NIH). Should hypercalcemia occur, appropriate treatment will be initiated and the drug dosage will be decreased.	Hypocalcemia Rickets	Calciferol Hypocalcemia Rickets	null	1	arm 1: 1,25-Dihydroxycholecalciferol 5 ug orally per day for 2 years	[ 0 ]	1	[ 0 ]	intervention 1: Usual doses of 1,25-dihydroycholecalciferol are 0.25-1 ug per day. All patients in this study received very high doses or 5-20 ug per day.	intervention 1: 1,25-Dihydroxycholecalciferol	1	Bethesda \| Maryland \| United States \| -77.10026 \| 38.98067	6	0	0	0	NCT00001151	6TERMINATED	2009-10-01	1976-03-01	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	0NIH	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	1,050	RANDOMIZED	PARALLEL	1PREVENTION	0NONE	false	0ALL	true	The HALT-C Trial is a National Institute of Diabetes and Digestive and Kidney Diseases sponsored, randomized clinical trial of long-term use of Peginterferon alfa-2a (pegylated interferon) in patients who failed to respond to prior interferon treatment. All patients who enter the trial will be treated for 6 months with Peginterferon alfa-2a and Ribavirin. Patients who respond to this 6 month treatment will continue to be treated for an additional 6 months. Patients who do not respond to this treatment will be eligible for the long-term maintenance phase of this study where patients will be randomly selected to be treated with Peginterferon alfa-2a or to discontinue treatment for 3.5 years. Patients in both arms of this study will be followed closely with quarterly study visits. The combination of peginterferon plus ribavirin has recently been approved by the FDA for treatment of chronic hepatitis C. Patients who remain HCV-RNA positive after being treated for at least 6 months with peginterferon and ribavirin outside of this study may be eligible to directly enter the randomized portion of the HALT-C Trial. The HALT-C study is designed to determine if continuing interferon long-term over several years will suppress Hepatitis C virus, prevent progression to cirrhosis, prevent liver cancer and reduce the need for liver transplantation.	null	Chronic Hepatitis c Cirrhosis, Liver Fibrosis, Liver Hepatic Cirrhosis	liver disease hepatitis c virus antiviral agent cirrhosis	null	2	arm 1: Peg-interferon alfa-2a 90 mcg/week arm 2: Standard of care followup	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: Peginterferon alfa-2a 180 mcg/week injection, for 24 weeks, plus 1000-1200 mg Ribavirin oral (prescribed according to weight \<75 kg, \>75 kg) daily in two divided doses for 24 weeks intervention 2: 90 mcg/week injection, for 3.5 years	intervention 1: Peginterferon alfa-2a + Ribavirin intervention 2: Peginterferon alfa-2a	11	Long Beach \| California \| United States \| -118.18923 \| 33.76696 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Denver \| Colorado \| United States \| -104.9847 \| 39.73915 Farmington \| Connecticut \| United States \| -72.83204 \| 41.71982 Bethesda \| Maryland \| United States \| -77.10026 \| 38.98067 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Worcester \| Massachusetts \| United States \| -71.80229 \| 42.26259 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Richmond \| Virginia \| United States \| -77.46026 \| 37.55376	1,050	0	0	0	NCT00006164	1COMPLETED	2009-10-01	2000-06-01	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	0NIH	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	208	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	1FEMALE	null	This 2 arm study assessed the safety and efficacy of adding intravenous trastuzumab (Herceptin®) to daily oral anastrozole (Arimidex®) tablets as first- and second-line treatment in postmenopausal patients with human epidermal growth factor receptor-2 (HER2) overexpressing metastatic breast cancer (ER+ve and/or PR+ve). Patients were randomized to receive either anastrazole 1 mg per os (po) daily, or anastrazole 1 mg po daily + a loading dose of Herceptin® 4 mg/kg intravenous (iv) followed by weekly doses of Herceptin® 2 mg/kg iv. The anticipated time on study treatment was until disease progression, and the target sample size was 100-500 individuals.	null	Breast Cancer		null	2	arm 1: Trastuzumab 4 mg/kg loading dose intravenous (iv) over 90 minutes, followed by weekly doses of 2 mg/kg iv over 30 minutes plus 1 mg oral dose of anastrozole every day for 24 Months in the Main phase and in the Extension Phase. arm 2: 1 mg oral dose of anastrozole every day for 24 Months in the Main phase. In the Extension Phase participants could cross-over to also receive trastuzumab 4 mg/kg initial loading dose intravenous (iv) over 90 minutes, followed by weekly doses of 2 mg/kg iv over 30 minutes.	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: 4mg/kg iv loading dose, followed by 2mg/kg iv weekly intervention 2: 1 mg tablet taken orally daily	intervention 1: trastuzumab (Herceptin®) intervention 2: anastrazole (Arimidex®)	132	Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Vallejo \| California \| United States \| -122.25664 \| 38.10409 Gainsville \| Florida \| United States \| N/A \| N/A Miami \| Florida \| United States \| -80.19366 \| 25.77427 Plantation \| Florida \| United States \| -80.23184 \| 26.13421 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Kansas City \| Kansas \| United States \| -94.62746 \| 39.11417 Scarborough \| Maine \| United States \| -70.32172 \| 43.57814 Detroit \| Michigan \| United States \| -83.04575 \| 42.33143 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 Hackensack \| New Jersey \| United States \| -74.04347 \| 40.88593 Albuquerque \| New Mexico \| United States \| -106.65114 \| 35.08449 Santa Fe \| New Mexico \| United States \| -105.9378 \| 35.68698 Rochester \| New York \| United States \| -77.61556 \| 43.15478 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Hershey \| Pennsylvania \| United States \| -76.65025 \| 40.28592 Box Hill \| N/A \| Australia \| 145.12545 \| -37.81887 Darlinghurst \| N/A \| Australia \| 151.21925 \| -33.87939 Waratah \| N/A \| Australia \| 151.72647 \| -32.90667 Porto Alegre \| N/A \| Brazil \| -51.23019 \| -30.03283 Plovdiv \| N/A \| Bulgaria \| 24.75 \| 42.15 Sofia \| N/A \| Bulgaria \| 23.32415 \| 42.69751 Stara Zagora \| N/A \| Bulgaria \| 25.64194 \| 42.43278 Calgary \| Alberta \| Canada \| -114.08529 \| 51.05011 Edmonton \| Alberta \| Canada \| -113.46871 \| 53.55014 Victoria \| British Columbia \| Canada \| -123.35155 \| 48.4359 Winnipeg \| Manitoba \| Canada \| -97.14704 \| 49.8844 Oshawa \| Ontario \| Canada \| -78.84957 \| 43.90012 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Québec \| Quebec \| Canada \| -71.21454 \| 46.81228 Beijing \| N/A \| China \| 116.39723 \| 39.9075 Beijing \| N/A \| China \| 116.39723 \| 39.9075 Shanghai \| N/A \| China \| 121.45806 \| 31.22222 Shanghai \| N/A \| China \| 121.45806 \| 31.22222 Wuhan \| N/A \| China \| 114.26667 \| 30.58333 Avignon \| N/A \| France \| 4.80892 \| 43.94834 Nice \| N/A \| France \| 7.26608 \| 43.70313 Frankfurt \| N/A \| Germany \| 10.53333 \| 49.68333 Kiel \| N/A \| Germany \| 10.13489 \| 54.32133 München \| N/A \| Germany \| 13.31243 \| 51.60698 Trier \| N/A \| Germany \| 6.63935 \| 49.75565 Hong Kong \| N/A \| Hong Kong \| 114.17469 \| 22.27832 Budapest \| N/A \| Hungary \| 19.04045 \| 47.49835 Ahmedabad \| N/A \| India \| 72.58727 \| 23.02579 Bangalore \| N/A \| India \| 77.59369 \| 12.97194 Chennai \| N/A \| India \| 80.27847 \| 13.08784 Cuttack \| N/A \| India \| 85.87927 \| 20.46497 Ludhiana \| N/A \| India \| 75.85379 \| 30.91204 Mumbai \| N/A \| India \| 72.88261 \| 19.07283 New Delhi \| N/A \| India \| 77.2148 \| 28.62137 New Delhi \| N/A \| India \| 77.2148 \| 28.62137 New Delhi \| N/A \| India \| 77.2148 \| 28.62137 Haifa \| N/A \| Israel \| 34.99928 \| 32.81303 Haifa \| N/A \| Israel \| 34.99928 \| 32.81303 Petah Tikva \| N/A \| Israel \| 34.88747 \| 32.08707 Ramat Gan \| N/A \| Israel \| 34.81065 \| 32.08227 Rehovot \| N/A \| Israel \| 34.81199 \| 31.89421 Tel Aviv \| N/A \| Israel \| 34.78057 \| 32.08088 Genova \| N/A \| Italy \| 11.87211 \| 45.21604 Vilnius \| N/A \| Lithuania \| 25.2798 \| 54.68916 Guadalajara \| N/A \| Mexico \| -103.34749 \| 20.67738 Mexico City \| N/A \| Mexico \| -99.12766 \| 19.42847 Amsterdam \| N/A \| Netherlands \| 4.88969 \| 52.37403 Rotterdam \| N/A \| Netherlands \| 4.47917 \| 51.9225 Trondheim \| N/A \| Norway \| 10.39506 \| 63.43049 Bialystok \| N/A \| Poland \| 23.16433 \| 53.13333 Bydgoszcz \| N/A \| Poland \| 18.00762 \| 53.1235 Gliwice \| N/A \| Poland \| 18.67658 \| 50.29761 Krakow \| N/A \| Poland \| 19.93658 \| 50.06143 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 Barnaul \| N/A \| Russia \| 83.7456 \| 53.3598 Izhevsk \| N/A \| Russia \| 53.20448 \| 56.84976 Kazan' \| N/A \| Russia \| 49.12214 \| 55.78874 Krasnodar \| N/A \| Russia \| 38.97603 \| 45.04484 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 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 Ufa \| N/A \| Russia \| 55.96779 \| 54.74306 Floracliffe \| N/A \| South Africa \| N/A \| N/A Pretoria \| N/A \| South Africa \| 28.18783 \| -25.74486 Barcelona \| N/A \| Spain \| 2.15899 \| 41.38879 Córdoba \| N/A \| Spain \| -4.77275 \| 37.89155 Girona \| N/A \| Spain \| 2.82493 \| 41.98311 Madrid \| N/A \| Spain \| -3.70256 \| 40.4165 Madrid \| N/A \| Spain \| -3.70256 \| 40.4165 Madrid \| N/A \| Spain \| -3.70256 \| 40.4165 Mataró \| N/A \| Spain \| 2.4445 \| 41.54211 Reus \| N/A \| Spain \| 1.10687 \| 41.15612 Valencia \| N/A \| Spain \| -0.37966 \| 39.47391 Borås \| N/A \| Sweden \| 12.9401 \| 57.72101 Gaelve \| N/A \| Sweden \| N/A \| N/A Örebro \| N/A \| Sweden \| 15.2066 \| 59.27412 Stockholm \| N/A \| Sweden \| 18.06871 \| 59.32938 Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306 Taoyuan District \| N/A \| Taiwan \| 121.3187 \| 24.9896 Ankara \| N/A \| Turkey (Türkiye) \| 32.85427 \| 39.91987 Ankara \| N/A \| Turkey (Türkiye) \| 32.85427 \| 39.91987 Istanbul \| N/A \| Turkey (Türkiye) \| 28.94966 \| 41.01384 Istanbul \| N/A \| Turkey (Türkiye) \| 28.94966 \| 41.01384 Izmir \| N/A \| Turkey (Türkiye) \| 27.13838 \| 38.41273 Shhiye, Ankara \| N/A \| Turkey (Türkiye) \| 32.85427 \| 39.91987 Kiev \| N/A \| Ukraine \| 30.5238 \| 50.45466 Kiev \| N/A \| Ukraine \| 30.5238 \| 50.45466 Lviv \| N/A \| Ukraine \| 24.02324 \| 49.83826 Odesa \| N/A \| Ukraine \| 30.74383 \| 46.48572 Sumy \| N/A \| Ukraine \| 34.79906 \| 50.91741 Zaporizhzhya \| N/A \| Ukraine \| 35.11714 \| 47.85167 Cardiff \| N/A \| United Kingdom \| -3.18 \| 51.48 Edinburgh \| N/A \| United Kingdom \| -3.19648 \| 55.95206 Guildford \| N/A \| United Kingdom \| -0.57427 \| 51.23536 Ipswich \| N/A \| United Kingdom \| 1.15545 \| 52.05917 London \| N/A \| United Kingdom \| -0.12574 \| 51.50853 London \| N/A \| United Kingdom \| -0.12574 \| 51.50853 Manchester \| N/A \| United Kingdom \| -2.23743 \| 53.48095 Merseyside \| N/A \| United Kingdom \| N/A \| N/A Newcastle upon Tyne \| N/A \| United Kingdom \| -1.61396 \| 54.97328 Southampton \| N/A \| United Kingdom \| -1.40428 \| 50.90395 Swansea \| N/A \| United Kingdom \| -3.94323 \| 51.62079	265	0	0	0	NCT00022672	1COMPLETED	2009-10-01	2001-01-01	Hoffmann-La Roche	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	97	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining radiation therapy with chemotherapy before and after surgery may kill more tumor cells. PURPOSE: Randomized phase II trial to compare the effectiveness of combining radiation therapy with two different chemotherapy regimens before and after surgery in treating patients who have esophageal cancer.	OBJECTIVES: * Compare the pathologic complete response rate in patients with adenocarcinoma of the esophagus or gastroesophageal junction treated with radiotherapy with pre- and post-operative cisplatin plus paclitaxel versus cisplatin plus irinotecan. * Compare the survival outcome in patients treated with these regimens. * Compare the toxicity of these regimens in these patients. * Compare the tolerability of these adjuvant chemotherapy regimens after neoadjuvant chemoradiotherapy in these patients. * Compare time to progression or recurrence in patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to ECOG performance status (0 vs. 1) and stage of disease (T2-3, N0, M0 vs. T1-3, N0-1, M0 or M1A). Patients are randomized to 1 of 2 treatment arms. * Arm A: Patients receive neoadjuvant radiotherapy once daily, 5 days a week, for 5 weeks beginning on day 1 concurrently with neoadjuvant chemotherapy comprising cisplatin IV (Intravenous) over 2-3 hours followed by irinotecan IV over 30-60 minutes once daily on days 1, 8, 22, and 29. Four to six weeks after completion of neoadjuvant chemoradiotherapy, patients undergo surgical resection. A minimum of 4 weeks after resection, patients receive adjuvant chemotherapy comprising cisplatin and irinotecan as above on days 1 and 8. Treatment with adjuvant chemotherapy repeats every 3 weeks for 3 courses. * Arm B: Patients receive neoadjuvant radiotherapy as in arm A concurrently with neoadjuvant chemotherapy comprising paclitaxel IV (Intravenous) over 1 hour followed by cisplatin IV over 2-3 hours once daily on days 1, 8, 15, 22, and 29. Patients then undergo surgical resection as in arm A. A minimum of 4 weeks after resection, patients receive adjuvant chemotherapy comprising paclitaxel IV over 3 hours followed by cisplatin as above on day 1. Treatment with adjuvant chemotherapy repeats every 3 weeks for 3 courses. In both arms, treatment continues in the absence of disease progression or unacceptable toxicity. Patients are followed at 1 month, every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years. ACCRUAL: A total of 97 patients (50 on Arm A and 47 on Arm B) were accrued for this study.	Esophageal Cancer Gastric Cancer	stage I gastric cancer stage II gastric cancer stage III gastric cancer stage IV gastric cancer stage I esophageal cancer stage II esophageal cancer stage III esophageal cancer stage IV esophageal cancer adenocarcinoma of the stomach adenocarcinoma of the esophagus	null	2	arm 1: Days 1 - 35 : Concurrent radiation therapy (RT) and Cisplatin / Irinotecan Chemotherapy. Radiotherapy 45 Gy administered at 1.8 Gy per day, 5 days a week for 5 weeks. Cisplatin 30 mg/m² days 1, 8, 22, 29. Irinotecan 65 mg/m² days 1, 8, 22, 29. Chemotherapy should begin within 24 hours of start of radiotherapy Days 63 - 77 : Surgical Resection At least 28 days after surgical resection, begin adjuvant chemotherapy: cisplatin 30 mg/m² and irinotecan 65 mg/m² days 1 and 8 of three 3-week cycles arm 2: Days 1 - 35 : Concurrent radiation therapy (RT) and Paclitaxel/Cisplatin Chemotherapy. Radiotherapy 45 Gy administered at 1.8 Gy per day, 5 days a week for 5 weeks. Paclitaxel 50 mg/m² (1 hr) days 1, 8, 15, 22, 29. Cisplatin 30 mg/m² days 1, 8, 15, 22, 29. Chemotherapy should begin within 24 hours of start of radiotherapy. Days 63 - 77 : Surgical Resection At least 28 days after surgical resection, begin adjuvant chemotherapy: paclitaxel 175 mg/m² and cisplatin 75 mg/m² day 1 of three 3-week cycles.	[ 0, 0 ]	5	[ 0, 0, 0, 3, 4 ]	intervention 1: Days 1 - 35 : Cisplatin 30 mg/m² days 1, 8, 15, 22, 29 Days 63 - 77 : cisplatin 30 mg/m² and irinotecan 65 mg/m² days 1 and 8 of three 3-week cycles intervention 2: Days 1 - 35 : Irinotecan 65 mg/m² days 1, 8, 22, 29 Days 63 - 77 : irinotecan 65 mg/m² days 1 and 8 of three 3-week cycles intervention 3: Days 1 - 35 : Paclitaxel 50 mg/m² (1 hr) days 1, 8, 15, 22, 29 Days 63 - 77 : paclitaxel 175 mg/m² and cisplatin 75 mg/m² day 1 of three 3-week cycles intervention 4: The type of resection (lvor-Lewis, Transhiatal, etc.) was left to the discretion of the operating surgeon. One lymph node dissection was required. intervention 5: The total dose to the prescription point was 4500 cGy given in 25 fractions. The patient was treated with one fraction per day with all fields treated per day. 180 cGy was delivered to the isocenter. If the dose to the supraclavicular fossa (SCF) was less than 4500 cGy, a localized photon or electron boost was allowed in order to increase the SCF dose to 4500 cGy, specified at 3 cm depth from the anterior skin surface.	intervention 1: cisplatin intervention 2: irinotecan hydrochloride intervention 3: paclitaxel intervention 4: conventional surgery intervention 5: radiation therapy	23	Denver \| Colorado \| United States \| -104.9847 \| 39.73915 Newark \| Delaware \| United States \| -75.74966 \| 39.68372 Gainesville \| Florida \| United States \| -82.32483 \| 29.65163 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Urbana \| Illinois \| United States \| -88.20727 \| 40.11059 Des Moines \| Iowa \| United States \| -93.60911 \| 41.60054 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 Rochester \| Minnesota \| United States \| -92.4699 \| 44.02163 Saint Louis Park \| Minnesota \| United States \| -93.34801 \| 44.9483 Saint Paul \| Minnesota \| United States \| -93.09327 \| 44.94441 New Brunswick \| New Jersey \| United States \| -74.45182 \| 40.48622 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Toledo \| Ohio \| United States \| -83.55521 \| 41.66394 Wynnewood \| Pennsylvania \| United States \| -75.27074 \| 40.00289 Wynnewood \| Pennsylvania \| United States \| -75.27074 \| 40.00289 Sioux Falls \| South Dakota \| United States \| -96.70033 \| 43.54997 Temple \| Texas \| United States \| -97.34278 \| 31.09823 Green Bay \| Wisconsin \| United States \| -88.01983 \| 44.51916 Madison \| Wisconsin \| United States \| -89.40123 \| 43.07305 Marshfield \| Wisconsin \| United States \| -90.1718 \| 44.66885	151	0	0	0	NCT00033657	1COMPLETED	2009-10-01	2002-08-15	Eastern Cooperative Oncology Group	5NETWORK	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	108	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	1FEMALE	false	To evaluate the preliminary activity and pharmacokinetics of 2 separate doses and schedules of orally administered Temsirolimus (CCI-779) given in combination with daily letrozole, compared to letrozole alone, in the treatment of locally advanced or metastatic breast cancer in postmenopausal women. All patients must be appropriate to receive endocrine therapy as treatment for advanced disease.	null	Breast Neoplasms	breast neoplasms	null	3	arm 1: None arm 2: None arm 3: None	[ 0, 0, 1 ]	3	[ 0, 0, 0 ]	intervention 1: Letrozole 2.5 mg daily + Temsirolimus (CCI-779) 10 mg daily intervention 2: Letrozole 2.5 mg daily + Temsirolimus (CCI-779) intermittent 30 mg daily for five days every 2 weeks intervention 3: Letrozole 2.5 mg daily	intervention 1: Letrozole / Temsirolimus (CCI-779) intervention 2: Letrozole / Temsirolimus (CCI-779) intervention 3: Letrozole	0	null	126	0	0	0	NCT00062751	1COMPLETED	2009-10-01	2002-12-01	Wyeth is now a wholly owned subsidiary of Pfizer	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	56	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	1FEMALE	true	RATIONALE: Vaccines may make the body build an immune response to kill tumor cells. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as vinorelbine, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining vaccine therapy with monoclonal antibody therapy and chemotherapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving vaccine therapy together with trastuzumab and vinorelbine works in treating women with locally recurrent or metastatic breast cancer.	OBJECTIVES: Primary * Determine the efficacy of multiepitope autologous dendritic cell vaccine, trastuzumab (Herceptin\^®), and vinorelbine by measuring the change in the largest dimension of metastatic lesions, in women with locally recurrent or metastatic breast cancer that does not overexpress human epidermal growth factor receptor 2 (HER2)/neu. Secondary * Determine the ability of this regimen to induce functional antigen-specific T cells in these patients by measuring ex-vivo antigen-specific T-cell activity against peptide-pulsed dendritic cells and tumor targets by tetramer staining and intracellular cytokine assays. OUTLINE: * Autologous dendritic cell mobilization and harvest: All patients undergo autologous dendritic cell mobilization with filgrastim (G-CSF) and/or sargramostim (GM-CSF) subcutaneously daily for 4 days followed by apheresis. Mobilized peripheral blood is processed for the production of dendritic cells by cluster of differentiation (CD)34-positive cell selection. The dendritic cells are expanded and then pulsed with E75 and E90 peptides. * Treatment: Patients receive vinorelbine IV over 6-10 minutes and trastuzumab (Herceptin \^®) IV over 90 minutes on day 1. Patients also receive autologous dendritic cells pulsed with E75 and E90 peptides subcutaneously over 2-5 minutes on day 1\. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Note: \If treatment is given locally, the vaccine therapy will be given at University of North Carolina (UNC) -Chapel Hill the following day. Patients are followed every 3 months. PROJECTED ACCRUAL: A total of 17-37 patients will be accrued for this study.	Breast Cancer	recurrent breast cancer stage IIIB breast cancer stage IIIC breast cancer stage IV breast cancer	null	1	arm 1: Dendritic Cells: Dosage: 20 x 106 dendritic cells (DCs) given per treatment Vinorelbine:25 mg/m2 will be administered i.v biweekly Trastuzumab: 6mg/Kg administered by i.v. biweekly	[ 0 ]	3	[ 2, 2, 0 ]	intervention 1: 10 μg/kg subcutaneously (sc) each day for four days or g-CSF at 5 μg/kg sc each day for four days with GM-CSF 250 μg/m2 sc each day for four days. G-CSF and/or GM- CSF will be self-administered. On the fifth day patients will have two intravenous lines placed in the apheresis area of the Blood Bank and then undergo a 15 litre apheresis collection intervention 2: 4 mg/kg intravenously, every 14 days intervention 3: Vinorelbine 25 mg/m2 will be administered intravenously, every 14 days	intervention 1: therapeutic autologous dendritic cells intervention 2: trastuzumab intervention 3: vinorelbine ditartrate	1	Chapel Hill \| North Carolina \| United States \| -79.05584 \| 35.9132	7	0	0	0	NCT00088985	6TERMINATED	2009-10-01	2004-01-01	UNC Lineberger Comprehensive Cancer Center	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	150	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	1FEMALE	true	The purpose of this study is to compare the progression-free survival of two treatment regimens for relapsed ovarian cancer.	Primary Objective The primary objective of the study is to compare the progression-free survival of two treatment regimens: Taxotere® 30 mg/m2 IV on Days 1 and 8, combined with carboplatin AUC 6 IV on Day 1, repeated every 21 days for 6 cycles or until disease progression. (A patient who has completed 6 cycles of treatment and who has achieved a partial response or stable disease may either continue or stop treatment at the investigator's discretion.) Versus Taxotere® 30 mg/m2 IV on Days 1 and 8, repeated every 21 days up to 6 cycles or until disease progression. Followed by carboplatin (AUC 6) IV every 21 days if the patient does not achieve a complete response or has disease progression on Taxotere®. A patient who has achieved a complete response on Taxotere® will be followed until the subsequent recurrence at which time she will then receive single-agent carboplatin. Carboplatin treatment will be discontinued if the patient has completed 6 cycles of treatment and has achieved a complete response or has disease progression. (A patient who has completed 6 cycles of carboplatin treatment and who has achieved a partial response or stable disease may either continue or stop treatment at the investigator's discretion.) Secondary Objectives The secondary objectives of the study are to compare the objective response rates (defined as a complete response plus partial response), duration of tumor response, median survival, QOL and safety in patients treated with the two regimens described above.	Ovarian Cancer	Relapsed ovarian cancer	null	2	arm 1: Docetaxel 30mg/m2 mg IV on Days 1 and 8, in combination with carboplatin AUC 6 IV on Day 1, repeated every 21 days X 6 cycles or until disease progression arm 2: Docetaxel 30mg/m2 IV on Days 1 and 8, repeated every 21 days for 6 cycles until disease progression. Once subjects have completed 6 cycles of docetaxel, they receive carboplatin AUC 6 IV every 21 days for 6 cycles or until disease progression.	[ 0, 0 ]	2	[ 0, 0 ]	intervention 1: For Arm 1: 30mg/m2 mg IV on Days 1 and 8 repeated every 21 days for six cycles until disease progression combined with carboplatin For Arm 2: 30mg/m2 IV on Days 1 and 8 repeated every 21 days for six cycles until disease progression followed by carboplatin intervention 2: Arm 1: AUC 6 IV on Days 1 and 8, repeated every 21 days for 6 cycles or until disease progression, combined with docetaxel. Arm 2: AUC 6 IV every 21 days for 6 cycles or until disease progression, following six cycles of treatment with docetaxel	intervention 1: Docetaxel intervention 2: Carboplatin	19	Fort Myers \| Florida \| United States \| -81.84059 \| 26.62168 Jupiter \| Florida \| United States \| -80.09421 \| 26.93422 Orlando \| Florida \| United States \| -81.37924 \| 28.53834 Bettendorf \| Iowa \| United States \| -90.51569 \| 41.52448 Iowa City \| Iowa \| United States \| -91.53017 \| 41.66113 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Hackensack \| New Jersey \| United States \| -74.04347 \| 40.88593 New York \| New York \| United States \| -74.00597 \| 40.71427 Asheville \| North Carolina \| United States \| -82.55402 \| 35.60095 Chapel Hill \| North Carolina \| United States \| -79.05584 \| 35.9132 Charlotte \| North Carolina \| United States \| -80.84313 \| 35.22709 Durham \| North Carolina \| United States \| -78.89862 \| 35.99403 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Oklahoma City \| Oklahoma \| United States \| -97.51643 \| 35.46756 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Charleston \| South Carolina \| United States \| -79.93275 \| 32.77632 Memphis \| Tennessee \| United States \| -90.04898 \| 35.14953 Austin \| Texas \| United States \| -97.74306 \| 30.26715	149	0	0	0	NCT00090610	1COMPLETED	2009-10-01	2003-10-01	Duke University	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	172	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	0ALL	true	Weight gain after quitting smoking is an important barrier to treatment for many smokers. This study will test a drug called naltrexone with weight-concerned smokers to investigate whether or not this drug both improves smoking cessation quit rates and minimizes post quit weight gain.	This is a 6-month randomized, double-blind, placebo controlled trial of 25 mg naltrexone for smoking cessation in a sample of 270 male and female weight-concerned smokers. Participants also receive transdermal nicotine replacement therapy during the first 8 weeks of the study, which they begin on their quit date. Naltrexone study medication will be started a week before their quit date and continued through the six-month period. Brief behavioral counseling and research assessments are provided for two sessions prior to the quit date and then weekly for two weeks, bi-weekly for a month and every four weeks thereafter. A follow-up appointment is completed at 12 months after participants' quit date. The primary outcomes are six-month point prevalence abstinence and post-cessation weight gain for those who are continuously abstinent (not even a puff). Secondary outcomes include an examination of alcohol consumption, evaluation of urges, other measures of smoking cessation success, point prevalence abstinence at 12 months, and food preferences. A number of tertiary measures will be obtained for examining predictors of smoking cessation, weight gain, and naltrexone response.	Nicotine Dependence	Tobacco Smoking Weight Weight perception Naltrexone	null	2	arm 1: Arm 1 (Experimental) = Transdermal nicotine replacement (21 mg for first 6 weeks post-quit then 14 mg for 2 weeks) once per day + Naltrexone 25 mg oral capsule once per day arm 2: Arm 2 (Placebo Comparator) = Transdermal nicotine replacement (21 mg for first 6 weeks post-quit then 14 mg for 2 weeks) once per day + Placebo Naltrexone 25 mg oral capsule once per day	[ 0, 2 ]	3	[ 0, 0, 5 ]	intervention 1: Drug: Naltrexone 12.5 mg oral capsule once per day for 1 day then 25 mg oral capsule once per day for 27 weeks intervention 2: Transdermal nicotine replacement (21 mg for first 6 weeks post-quit then 14 mg for 2 weeks) once per day + naltrexone 25 mg oral capsule once per day intervention 3: Brief behavioral counseling and research assessments are provided for two sessions prior to the quit date and then weekly for two weeks, bi-weekly for a month and every four weeks thereafter.	intervention 1: Naltrexone intervention 2: Transdermal nicotine replacement intervention 3: Behavioral counseling	1	New Haven \| Connecticut \| United States \| -72.92816 \| 41.30815	172	0	0	0	NCT00105482	1COMPLETED	2009-10-01	2005-01-01	Yale University	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 2, 3 ]	14	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	The purpose of this study is to find out if patients with high risk disease because of age or kidney status can be treated more safely with a drug called Busulfex® followed by autologous transplant compared to treatment with the standard drug called melphalan, which has been shown to be quite difficult to tolerate in patients with poor kidney function and patients over the age of 65 when given in high doses.	This trial will determine the maximal dose of Busulfex® that can be given in a two, three, or four day period with acceptable toxicity to myeloma patients, who either are \> or = 65 years of age or have renal insufficiency, defined as creatinine \> 3g/dL or creatinine clearance \< 30 ml/min.	Multiple Myeloma	Myeloma, MM	null	1	arm 1: study-specific treatment: Busulfex according to study design: Level I 3.2 mg/kg over 6 hours x 2 days Level II 3.2 mg/kg over 6 hours x 3 days Level III 3.2 mg/kg over 6 hours x 4 days Level IV 4.3 mg/kg over 6 hours x 3 days Level V 5.6 mg/kg over 6 hours x 2 days Level VI 6.4 mg/kg over 6 hours x 2 days	[ 0 ]	1	[ 0 ]	intervention 1: Dexamethasone 40 mg PO 1-4 Thalidomide 200 mg PO 1-6 Cisplatin\* 10 mg/m, Continuous infusion 1-4 Adriamycin\\ 10 mg/m2, Continuous infusion 1-4 Cyclophosphamide 400 mg/2, Continuous infusion 1-4 Etoposide 40 mg/m2, Continuous infusion 1-4 All doses will be based on calculated body weight (actual weight + ideal body weight ÷ 2) and height, and not to exceed a BSA of 2.0 m2 The daily dose of cyclophosphamide, etoposide, and cisplatin will be mixed in a 1L bag of NS to be UAMS infused over 24 hours. Adriamycin will be mixed in at least 50cc D5W to be infused over 24 hours	intervention 1: Busulfan	2	Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648	14	0	0	0	NCT00113919	6TERMINATED	2009-10-01	2004-06-01	University of Arkansas	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	88	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	2MALE	false	The purpose of the study is to assess the effects of sustained aromatase inhibitor therapy to reduce estrogen levels in elderly men with mild hypogonadism (a decreased level of sex hormones).	It has long been accepted that aging in men is associated with a slow, steady decline in gonadal androgen (male sex hormone) production. Several studies have explored androgen replacement, but the safety and efficacy of testosterone administration remains controversial. Aromatase inhibitors may provide a particularly useful way to restore normal androgen production in aging men. This study will recruit 150 male volunteers, 60 years of age or older, to be randomized to receive either anastrozole or a placebo for 24 months. Six visits are planned over the 96-week treatment period.	Hypogonadism	Aging	null	2	arm 1: anastrozole arm 2: placebo	[ 0, 2 ]	1	[ 0 ]	intervention 1: 1 mg QD	intervention 1: anastrozole	1	Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843	69	0	0	0	NCT00136695	1COMPLETED	2009-10-01	2004-10-01	Massachusetts General Hospital	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 2 ]	48	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	The purpose of this study is to test the safety and tolerability of carfilzomib at different dose levels on hematological cancers such as multiple myeloma, non-Hodgkin's lymphoma, Hodgkin's disease, or Waldenstrom's macroglobulinemia. Carfilzomib is a proteasome inhibitor, an enzyme responsible for degrading a wide variety of cellular proteins.	null	Waldenstrom's Macroglobulinemia Non-Hodgkin's Lymphoma Hodgkin's Disease Multiple Myeloma	Hematological Proteasome Myeloma Lymphoma	null	11	arm 1: Participants received carfilzomib (CFZ) 1.2 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. arm 2: Participants received carfilzomib 2.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. arm 3: Participants received carfilzomib 4.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. arm 4: Participants received carfilzomib 6.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. arm 5: Participants received carfilzomib 8.4 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. arm 6: Participants received carfilzomib 11.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. arm 7: Participants received carfilzomib 115.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. arm 8: Participants received carfilzomib 20.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. arm 9: Participants received carfilzomib 27.0 mg/m² administered by intravenous bolus on Days 1, 2, 8, 9, 15 and 16 in 28-day treatment cycles for up to 12 cycles. arm 10: Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. arm 11: Participants received carfilzomib 20 mg/m² administered by intravenous bolus on Cycle 1 Days 1, 2, 8, 9, 15 and 16, then 27 mg/m² in all subsequent cycles, for up to 12 cycles. Participants also received 20 mg dexamethasone (DEX) administered before each dose of carfilzomib (i.e. 40 mg weekly).	[ 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	2	[ 0, 0 ]	intervention 1: Administered as an IV bolus dose intervention 2: Administered orally prior to carfilzomib	intervention 1: Carfilzomib intervention 2: Dexamethasone	5	Beverly Hills \| California \| United States \| -118.40036 \| 34.07362 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 New York \| New York \| United States \| -74.00597 \| 40.71427 New York \| New York \| United States \| -74.00597 \| 40.71427 New York \| New York \| United States \| -74.00597 \| 40.71427	48	0	0	0	NCT00150462	1COMPLETED	2009-10-01	2005-09-01	Amgen	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	394	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	true	The study is designed to evaluate whether the initiation of everolimus together with the reduction or discontinuation of calcineurin inhibitors (CNIs) will improve graft function in the maintenance of renal transplant recipients with renal impairment by reducing the progression of chronic allograft nephropathy. The development of atherosclerosis in the native arteries of the patients will also be explored.	null	Renal Transplantation	Renal transplantation, everolimus, calcineurin inhibitors, GFR	null	3	arm 1: Calcineurin Inhibitors (CNI) ± Mycophenolate Acid (MPA)/Azathioprine (AZA) ± Steroids arm 2: Initiation of everolimus (8-12 ng/mL) with discontinuation of CNI. Everolimus(RAD001) 4 mg initial daily dose. arm 3: Initiation of everolimus (3-8 ng/mL) with reduction by 70-90% in CNI blood levels. Everolimus (RAD001) 3 mg initial daily dose.	[ 1, 0, 0 ]	4	[ 0, 0, 0, 0 ]	intervention 1: None intervention 2: None intervention 3: None intervention 4: None	intervention 1: Everolimus (RAD001) intervention 2: Calcineurin Inhibitors (CNI) intervention 3: Mycophenolate acid (MPA)/Azathioprine (AZA) intervention 4: Steroids	1	Basel \| N/A \| Switzerland \| 7.57327 \| 47.55839	394	0	0	0	NCT00170846	1COMPLETED	2009-10-01	2005-02-01	Novartis Pharmaceuticals	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	31	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	RATIONALE: Drugs used in chemotherapy, such as epirubicin and vinorelbine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving epirubicin together with vinorelbine may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving epirubicin together with vinorelbine works in treating patients with stage II, stage III, or stage IV breast cancer.	OBJECTIVES: * Assess the efficacy of sequential use of epirubicin hydrochloride followed by vinorelbine ditartrate in patients with stage IIB, IIIA, IIIB, or IV breast cancer. * Measure the biological response to this regimen in sequential tumor biopsies and peripheral mononuclear cells from these patients. * Correlate tumor response with changes in the gene expression of microtubule-associated protein 4. OUTLINE: Patients receive epirubicin hydrochloride IV on day 1 and vinorelbine ditartrate IV over 6-10 minutes on days 3 and 17. Patients also receive filgrastim (G-CSF) subcutaneously on days 4-14 or pegfilgrastim IV on day 4. For patients with stage IIB (T3, N0), IIIA, or IIIB disease, treatment repeats every 21 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. For patients with stage IV disease, treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and after course 1 for research studies. Patients with accessible tumor for biopsy undergo sequential biopsies and core needle biopsies at baseline and after course 1. Tumor tissue samples are used for determination of p53 status by western blot analysis, immunohistochemistry, and DNA sequencing. Microtubule-associated protein 4, p53, and p21/WAF1 expression is analyzed by western blotting. After completion of study treatment, patients are followed for 1 month. PROJECTED ACCRUAL: A total of 46 patients will be accrued for this study.	Breast Cancer	recurrent breast cancer stage II breast cancer stage IIIA breast cancer stage IIIB breast cancer stage IV breast cancer male breast cancer	null	1	arm 1: For patients with stage IIB (T3N0), IIIA, or IIIB breast cancer, epirubicin and vinorelbine will be administered for up to 5 cycles. For patients with stage IV breast cancer, epirubicin and vinorelbine will be administered as long as there is evidence of continued response or stable disease and no evidence of cardiac or other serious toxicities.	[ 0 ]	2	[ 0, 0 ]	intervention 1: Epirubicin (100 mg/m2) will be given on Day 1 intervention 2: Vinorelbine (18.75 mg/m2) will be given on Days 3 and 17.	intervention 1: epirubicin intervention 2: vinorelbine	1	New Brunswick \| New Jersey \| United States \| -74.45182 \| 40.48622	31	0	0	0	NCT00176488	6TERMINATED	2009-10-01	2003-06-01	University of Medicine and Dentistry of New Jersey	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	1,469	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	The two objectives of this study were to evaluate long-term efficacy and safety of adalimumab treatment in participants who had moderate to severe chronic plaque psoriasis and to evaluate the effectiveness of adalimumab retreatment in participants who had therapeutic response to adalimumab and were then withdrawn from adalimumab treatment.	Study M03-658 was a continuation study for participants with moderate to severe psoriasis who had participated in a prior psoriasis adalimumab study. Study M03-658 consisted of three sequential treatment periods. The first period was Period O, in which participants received open-label treatment with adalimumab (40 mg every other week or 40 mg every week) for a minimum of 104 weeks and a maximum of 252 weeks. Period O was the only period of the study until May 2008, when the subsequent periods were added via amendment to the protocol. At that time, participants who had achieved satisfactory therapeutic response (a Physician's Global Assessment \[PGA\] of 0, 1, or 2 \[clear, minimal, or mild\]) were given the opportunity to discontinue from the study or to continue and participate in the subsequent two periods. The second period was Period W, a maximum of 52 weeks, in which participants with a PGA of 2 (mild) or less were withdrawn from adalimumab treatment (i.e., participants received no treatment) until relapse of their psoriasis occurred (defined as a PGA of 3 \[moderate\] or worse). The third period was Period R, a 16-week period in which participants were retreated with open-label adalimumab (80 mg initial dose followed by 40 mg every other week). Period O was designed to evaluate the first objective regarding long-term efficacy and safety of adalimumab treatment, and Period R was designed to evaluate the effectiveness of adalimumab retreatment following relapse. Specific subsets of the study population that were identified as the populations of interest were the modified intent-to-treat populations for Period W and Period R, and these are described further in the outcome measures.	Psoriasis		null	1	arm 1: None	[ 5 ]	1	[ 0 ]	intervention 1: 40 mg every other week or 40 mg every week by subcutaneous injection	intervention 1: adalimumab	104	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Buckner 13075 PI \| Alabama \| United States \| N/A \| N/A Scottsdale \| Arizona \| United States \| -111.89903 \| 33.50921 Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 Bakersfield \| California \| United States \| -119.01871 \| 35.37329 Fresno \| California \| United States \| -119.77237 \| 36.74773 Irvine \| California \| United States \| -117.82311 \| 33.66946 Oceanside \| California \| United States \| -117.37948 \| 33.19587 San Diego \| California \| United States \| -117.16472 \| 32.71571 Santa Monica \| California \| United States \| -118.49138 \| 34.01949 Torrance \| California \| United States \| -118.34063 \| 33.83585 Longmont \| Colorado \| United States \| -105.10193 \| 40.16721 New Haven \| Connecticut \| United States \| -72.92816 \| 41.30815 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 Pinellas Park \| Florida \| United States \| -82.69954 \| 27.8428 South Miami \| Florida \| United States \| -80.29338 \| 25.7076 West Palm Beach \| Florida \| United States \| -80.05337 \| 26.71534 Alpharetta \| Georgia \| United States \| -84.29409 \| 34.07538 Newnan \| Georgia \| United States \| -84.79966 \| 33.38067 Snellville \| Georgia \| United States \| -84.01991 \| 33.85733 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Maywood \| Illinois \| United States \| -87.84312 \| 41.8792 Springfield \| Illinois \| United States \| -89.64371 \| 39.80172 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Louisville \| Kentucky \| United States \| -85.75941 \| 38.25424 Shreveport \| Louisiana \| United States \| -93.75018 \| 32.52515 Andover \| Massachusetts \| United States \| -71.137 \| 42.65843 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Worcester \| Massachusetts \| United States \| -71.80229 \| 42.26259 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 Fridley \| Minnesota \| United States \| -93.26328 \| 45.08608 Minneapolis \| Minnesota \| United States \| -93.26384 \| 44.97997 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 New Brunswick \| New Jersey \| United States \| -74.45182 \| 40.48622 New York \| New York \| United States \| -74.00597 \| 40.71427 New York \| New York \| United States \| -74.00597 \| 40.71427 New York \| New York \| United States \| -74.00597 \| 40.71427 New York \| New York \| United States \| -74.00597 \| 40.71427 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 Lake Oswego \| Oregon \| United States \| -122.67065 \| 45.42067 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Hershey \| Pennsylvania \| United States \| -76.65025 \| 40.28592 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Johnston \| Rhode Island \| United States \| -71.50675 \| 41.82186 Providence \| Rhode Island \| United States \| -71.41283 \| 41.82399 Greer \| South Carolina \| United States \| -82.22706 \| 34.93873 Mt. Pleasant \| South Carolina \| United States \| -79.86259 \| 32.79407 Goodlettsville \| Tennessee \| United States \| -86.71333 \| 36.32311 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Houston \| Texas \| United States \| -95.36327 \| 29.76328 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Tyler \| Texas \| United States \| -95.30106 \| 32.35126 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Norfolk \| Virginia \| United States \| -76.28522 \| 36.84681 Seattle \| Washington \| United States \| -122.33207 \| 47.60621 Graz \| N/A \| Austria \| 15.45 \| 47.06667 Innsbruck \| N/A \| Austria \| 11.39454 \| 47.26266 Vienna \| N/A \| Austria \| 16.37208 \| 48.20849 Brussels \| N/A \| Belgium \| 4.34878 \| 50.85045 Edegem \| N/A \| Belgium \| 4.44504 \| 51.15662 Calgary \| Alberta \| Canada \| -114.08529 \| 51.05011 Edmonton \| Alberta \| Canada \| -113.46871 \| 53.55014 Vancouver \| British Columbia \| Canada \| -123.11934 \| 49.24966 St. John's \| Newfoundland and Labrador \| Canada \| -52.70931 \| 47.56494 St. John's \| Newfoundland and Labrador \| Canada \| -52.70931 \| 47.56494 Halifax \| Nova Scotia \| Canada \| -63.57688 \| 44.64269 Hamilton \| Ontario \| Canada \| -79.84963 \| 43.25011 London \| Ontario \| Canada \| -81.23304 \| 42.98339 North Bay \| Ontario \| Canada \| -79.46633 \| 46.3168 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Waterloo \| Ontario \| Canada \| -80.51639 \| 43.4668 Windsor \| Ontario \| Canada \| -83.01654 \| 42.30008 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Québec \| Quebec \| Canada \| -71.21454 \| 46.81228 Westmount \| Quebec \| Canada \| -73.59918 \| 45.48341 Créteil \| N/A \| France \| 2.46569 \| 48.79266 Nice \| N/A \| France \| 7.26608 \| 43.70313 Paris \| N/A \| France \| 2.3488 \| 48.85341 Saint-Etienne \| N/A \| France \| 4.39 \| 45.43389 Frankfurt \| N/A \| Germany \| 10.53333 \| 49.68333 Kiel \| N/A \| Germany \| 10.13489 \| 54.32133 Münster \| N/A \| Germany \| 7.62571 \| 51.96236 Tübingen \| N/A \| Germany \| 9.05222 \| 48.52266 Gdansk \| N/A \| Poland \| 18.64912 \| 54.35227 Płock \| N/A \| Poland \| 19.70638 \| 52.54682 Cagaus \| N/A \| Puerto Rico \| N/A \| N/A Carolina \| N/A \| Puerto Rico \| -65.95739 \| 18.38078 Madrid \| N/A \| Spain \| -3.70256 \| 40.4165 Seville \| N/A \| Spain \| -5.97317 \| 37.38283 Valencia \| N/A \| Spain \| -0.37966 \| 39.47391 Geneva \| N/A \| Switzerland \| 6.14569 \| 46.20222	1,468	0	0	0	NCT00195676	1COMPLETED	2009-10-01	2004-05-01	Abbott	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	53	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	The standard treatment for non-small cell lung cancer, stage IV or IIIB malignant pleural effusion is chemotherapy. The decision to use a regimen is currently determined by toxicity or by physician's preference. In this protocol, the treatment regimen will be assigned based on the patients' tumor molecular profile. A tumor molecular profile analysis will allow the physician to define a specific molecular portrait that shows the genetic basis of the tumor. This analysis results in a detailed report that will determine which chemotherapy will be assigned to the patient.	Evaluation at study entry will include blood tests, computerized tomography (CT) scans or other types of scans needed to measure other disease sites. A biopsy of one tumor is required for tumor analysis. If the patient's cancer has spread to other locations that may be easier to obtain tissue from and be less invasive, then the biopsy specimen may be collected from one of several possible locations that may exist within the patient's body. These possible sites include lung, bone, liver, adrenal glands, lymph nodes, nodules under the skin, or in cases of brain involvement requiring surgery, brain tissue. Sometimes fluids build up between the lining of the lung and the lung itself. If this happened to the patient and their doctor tells them the fluid should be drained, then this fluid may also be a source of cells we can use to analyze the patients cancer. In very rare cases, other sites might be identified. Chemotherapy will consist of the assigned two drugs. Chemotherapy will be repeated every three or four weeks for at least two times. Patients will then have a CT scan to measure their tumor's response. Response can be reduction of tumor size, no change of tumor size, or increased tumor size. Doing CT Scans or other tests after every two cycles of chemotherapy will assess for response. If we see a favorable response we will continue chemotherapy for a maximum of two times after the best response we can see in the patient's tumor. If the patient's tumor grows larger, then we discontinue the study and the patient will discuss other treatment options with their doctor. During treatment, a blood specimen will be obtained to check the patient's blood counts at the beginning and end of study, and prior to administration of every dose of chemotherapy. Approximately 3 teaspoonfuls (15 mls) of blood will be drawn each time.	Carcinoma, Non-Small-Cell Lung	malignant pleural effusion	null	1	arm 1: Molecular Analysis-Directed Chemotherapy Assignment based on gene expression of ERCC1 and RRM1.	[ 0 ]	4	[ 0, 0, 0, 0 ]	intervention 1: Ribonucleotide reductase subunit 1(RRM1)above 16.5 and Excision repair cross-complementing group 1 gene(ERCC1)above 8.7: Treat patients with Docetaxel and Vinorelbine (DV). DV group was treated with vinorelbine (45mg/m2ondays 1 and 15) and docetaxel (60mg/m2ondays 1 and 15) every 28 days. intervention 2: RRM1 below 16.5 and ERCC1 above 8.7: Treat patients with Gemcitabine and Docetaxel (GD). GD group was treated with gemcitabine (1,250 mg/m2 on days 1 and 8) and docetaxel (40 mg/m2 on days 1 and 8) every 21 days. RRM1 above 16.5 and ERCC1 below 8.7: Treat patients with Docetaxel and Carboplatin (DC). DC group was treated with docetaxel (75 mg/m2 on day 1) and carboplatin (AUC 5 on day 1) every 21 days. RRM1 above 16.5 and ERCC1 above 8.7: Treat patients with Docetaxel and Vinorelbine (DV). DV group was treated with vinorelbine (45mg/m2ondays 1 and 15) and docetaxel (60mg/m2ondays 1 and 15) every 28 days. intervention 3: Ribonucleotide reductase subunit 1(RRM1) below 16.5, and Excision repair cross-complementing group 1 gene(ERCC1) below 8.7: Patients treated with Gemcitabine and Carboplatin (GC). GC group was treated with gemcitabine (1,250 mg/m2 on days 1 and 8) and carboplatin (area under the concentration-time curve \[AUC\] of 5 on day 1) every 21 days. RRM1 below 16.5 and ERCC1 above 8.7: Treat patients with Gemcitabine and Docetaxel (GD). GD group was treated with gemcitabine (1,250 mg/m2 on days 1 and 8) and docetaxel (40 mg/m2 on days 1 and 8) every 21 days. intervention 4: Ribonucleotide reductase subunit 1(RRM1) below 16.5, and Excision repair cross-complementing group 1 gene(ERCC1) below 8.7: Patients treated with Gemcitabine and Carboplatin (GC). GC group was treated with gemcitabine (1,250 mg/m2 on days 1 and 8) and carboplatin (area under the concentration-time curve \[AUC\] of 5 on day 1) every 21 days. RRM1 above 16.5 and ERCC1 below 8.7: Treat patients with Docetaxel and Carboplatin (DC). DC group was treated with docetaxel (75 mg/m2 on day 1) and carboplatin (AUC 5 on day 1) every 21 days.	intervention 1: Vinorelbine intervention 2: Docetaxel intervention 3: Gemcitabine intervention 4: Carboplatin	1	Tampa \| Florida \| United States \| -82.45843 \| 27.94752	53	0	0	0	NCT00215930	1COMPLETED	2009-10-01	2004-02-01	H. Lee Moffitt Cancer Center and Research Institute	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	20	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	A study to determine the effect on renal function in renal transplant patients with biopsy proven Chronic allograft nephropathy (CAN) nephropathy who are switched from a Calcinerin inhibitor (CI) triple drug regimen to a Rapamycin based triple drug regimen or maintained on their CI protocol	null	Kidney Transplant		null	2	arm 1: pt will switch from calcineurin inhibitor (CYA, prograf) to Rapamycin arm 2: Patient will remain on calcineruin inhibitor	[ 1, 4 ]	1	[ 0 ]	intervention 1: Rapamycin will start within 24 hours of last calcineurin inhibitors (Cya, Prograf). Initial dose of Rapamune 10mg will be given for 3 days and then dose will be adjusted to attain a target whole blood trough of 5-15	intervention 1: Rapamycin	1	Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589	20	0	0	0	NCT00223678	1COMPLETED	2009-10-01	2000-06-01	Vanderbilt University Medical Center	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	19	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	1FEMALE	true	RATIONALE: Drugs used in chemotherapy, such as gemcitabine hydrochloride and genistein, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving gemcitabine hydrochloride together with genistein may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving gemcitabine hydrochloride together with genistein works in treating women with stage IV breast cancer.	OBJECTIVES: Primary * Determine the objective response rate in patients with stage IV breast cancer treated with gemcitabine hydrochloride and genistein. Secondary * Determine the duration of response and survival of patients treated with this regimen. * Determine the time to disease progression in patients treated with this regimen. * Determine the quantitative and qualitative toxic effects of this regimen in these patients. * Correlate plasma genistein levels with response in patients treated with this regimen. OUTLINE: Patients receive oral genistein once daily on days -7 to 1. Patients also receive gemcitabine hydrochloride IV on days 1 and 8 and oral genistein once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. PROJECTED ACCRUAL: A total of 36 patients will be accrued for this study.	Breast Cancer	stage IV breast cancer recurrent breast cancer	Prot_SAP_000.pdf: D-2597 Page 1 of 32 Karmanos Cancer Institute Wayne State University Phase II trial of gemcitabine and genistein in metastatic breast cancer patients, with biomarker assays PRINCIPAL INVESTIGATOR: Amy M. Weise, D.O. KARMANOS CANCER INSTITUTE WAYNE STATE UNIVERSITY 4100 John R, 4-HWCRC Detroit, MI 48201 OFFICE: (313) 576-8952 FAX: (313) 576-8767 PAGER: (313) 745-5111 #0585 E-MAIL: weise@karmanos.org CO-PRINCIPAL INVESTIGATOR: Fazlul Sarkar, Ph.D. (Correlative Research) HWCRC, Room 715 KARMANOS CANCER INSTITUTE WAYNE STATE UNIVERSITY 4100 John R, 7-HWCRC Detroit, MI 48201 OFFICE: (313) 576-8327 E-MAIL: sarkar@karmanos.org CO-INVESTIGATORS: Lawrence Flaherty, MD Omer Kucuk, MD Michael Simon, MD, MPH Pat LoRusso, DO Elaina Gartner, MD Zeina Nahleh, MD DATA MANAGER: Matthew Gretkiewicz CLINICAL TRIALS OFFICE (CTO) KARMANOS CANCER INSTITUTE HARPER PROFESSIONAL BUILDING, Room 711 4160 JOHN R DETROIT, MI 48201 TEL: (313) 576-9369 PAGER: (313) 745-5111 #9067 FAX: (313) 576-8368 E-MAIL: gretkiem@karmanos.org BIOSTATISTICIAN: Judith Abrams, Ph.D. KARMANOS CANCER INSTITUTE 4160 JOHN R DETROIT, MI 48201 OFFICE: (313) 576-8651 FAX: (313) 576-8656 E-MAIL: abramsj@karmanos.org Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 2 of 32 TABLE OF CONTENTS PAGES PRECIS 3 1.0 OBJECTIVES 4 2.0 BACKGROUND 4 3.0 DRUG INFORMATION 10 4.0 ELIGIBILITY CRITERIA 12 5.0 TREATMENT PLAN 14 6.0 TREATMENT MODIFICATIONS FOR TOXICITY, AND 15 CRITERIA FOR DISCONTINUATION FROM STUDY 7.0 CRITERIA FOR RESPONSE EVALUATION AND TOXICITY REPORTING 17 8.0 SCHEDULED EVALUATIONS ON STUDY 18 9.0 CORRELATIVE STUDIES: INSTRUCTIONS 19 10.0 REGISTRATION PROCEDURE 21 11.0 REPORTING OF ADVERSE EVENTS 22 12.0 DATA AND SAFETY MONITORING 23 13.0 STATISTICAL CONSIDERATIONS 23 14.0 BIBLIOGRAPHY 25 15.0 APPENDICES: 29 APPENDIX I: STUDY SCHEMA 29 APPENDIX II: STUDY CALENDAR 30 APPENDIX III: SWOG PERFORMANCE STATUS 31 APPENDIX IV: NCI-CTEP COMMON TOXICITY CRITERIA 32 Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 3 of 32 Phase II trial of gemcitabine and genistein in metastatic breast cancer patients, with biomarker assays PRECIS Metastatic breast cancer remains an incurable disease. Single agent conventional chemotherapy such as gemcitabine yields response rates in the 20-25 % response rates, with progression free survival durations of ~6 months. There is public and scientific interest in soy isoflavones such as genistein as a breast cancer prevention or treatment agent. Recently, genistein has been shown to induce breast cancer growth inhibition and apoptosis in preclinical studies, in part by inhibiting Akt and NF-κB signal pathways. When soy isoflavones are administered to humans at a well tolerated dose, NF-κB signaling is inhibited in human peripheral lymphocytes, demonstrating bioactivity at these doses. Moreover, combinations of gemcitabine and genistein have demonstrated at least additive inhibitory effects in vitro in carcinoma cells. Although there is significant lay and scientific interest in genistein’s effects in human breast cancer, there are no peer-reviewed published data regarding the in vivo effects of genistein in patients with breast cancer. Thus, the major rationale is that the addition of genistein may increase the effectiveness without added toxicity. Therefore, we propose to combine gemcitabine 1,000 mg/m2 IV days 1 and 8, with genistein 100mg PO BID days 1-21, with cycles q21 days, for first or second line treatment of patients with metastatic breast cancer. Prior to cycle 1, day 1, genistein will be administered alone for seven days for the collection of baseline plasma levels, and for the collection of accessible tumor tissue for molecular biomarker studies. Along with standard dose modification guidelines for toxicity, prospective safety monitoring and stopping rules are incorporated into the study design insure the safety of this protocol. The primary objective is to estimate the objective response rate. Secondary clinical objectives are to obtain data on the quality of the responses, overall survival, and the toxicity and tolerance to this combination. Secondary translational objectives are to assess plasma genistein levels and explore associations with responses, and to explore the effect of genistein alone on tumor biomarkers in order to better understand its mechanisms. Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 4 of 32 1.0 OBJECTIVES 1.1 Primary Objective 1.1.1 To estimate the objective response rate in patients with metastatic breast cancer treated with the combination of gemcitabine and genistein as first or second line therapy. 1.2 Secondary Objectives 1.2.1 To obtain data on duration of response, time to disease progression, and duration of survival. 1.2.2 To estimate the quantitative and qualitative toxicities of this regimen. 1.2.3 To assay the plasma genistein levels and explore associations with responses. 1.2.4 Explore the in vivo effects of genistein in human breast cancer tissue biomarkers (Ki67, TUNEL, phosphorylated-Akt, and NF-κB), and by cDNA microarray analysis. 2.0 BACKGROUND 2.1 Metastatic Breast Adenocarcinoma Approximately 190,000 new cases of breast cancer are diagnosed each year in the USA (1). Although early stage disease is potentially curable through a multimodality approach involving surgery, chemotherapy and radiation, metastatic breast cancer remains a largely incurable disease accounting for 41,000 deaths each year (1, 2). For the vast majority of these patients, metastatic breast cancer is an incurable disease with a median survival of only 2 to 3 years after diagnosis (2). Long-term remissions with combination chemotherapy have been reported to occur in only 2-3% of patients (3). Historically, the main objective of treatment in the metastatic setting was the improvement in the quality of life. Recently, several trials have demonstrated a prolongation in median survival of women with metastatic breast cancer with effective systemic therapy (4, 5). These trials demonstrate the importance of introducing novel active agents or combinations of agents that could potentially improve survival as well as palliate symptoms. 2.2 Gemcitabine Gemcitabine (2,2’-difluorodeoxcytidine, dFdC) is a nucleoside analog initially synthesized as a potential anti-viral drug and had excellent activity against both RNA and DNA viruses using cell culture assays. Despite early encouraging in vitro results, the in vivo therapeutic index was disappointingly low and the drug was not developed further. Concurrent evaluation of the cytotoxic activity of the compound demonstrated that gemcitabine was a potent and specific deoxycytidine analog with an acceptable in vivo therapeutic index. The mechanism of action and metabolism of gemcitabine have been well characterized. Gemcitabine inhibits the synthesis of DNA by at least two mechanisms. Gemcitabine is phosphorylated by deoxycytidine kinase to dFdC-5'-monophosphate (dFdCMP). Difluorodeoxyuridine is a product of gemcitabine deaminations and is inactive. dFdCMP is further metabolized to dFdC5'- diphosphate (dFdCDP) and dFdC-5'triphosphate (dFdCTP), which when incorporated into DNA, results in masked chain termination. In comparison to Ara-C incorporation into DNA, dFdCTP is less readily excised from DNA by DNA exonuclease. Thus, dFdCTP accumulates intracellularly to a greater degree than Ara-C-CTP, which may account, at least in part, for its different spectrum of pre-clinical and clinical activity. In addition, dFdCDP inhibits ribonucleotide reductase resulting in reduced formation of deoxyribonucleotides (6). Other intracellular effects of gemcitabine include stimulation of deoxycytidine kinase and inhibition of deoxycytidine monophosphate deaminase (7). Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 5 of 32 Of particular importance is the fact that the therapeutic effects of gemcitabine at the maximum tolerated dose level are dependent on the administration schedule. The drug was injected intraperitoneally to mice in various schedules at equitoxic maximum tolerated dose levels, resulting in a reversible weight loss that varied between 5% and 15%. Generally, it was found that treatment with 120 mg/kg gemcitabine, injected four times at 3-day intervals, was more effective than the schedules of daily (five times 2.5 to 3.5 mg/kg) or weekly (two times 240 mg/kg) injections (8). Gemcitabine, but not cytosine arabinoside (Ara-C), had a broad spectrum of anti-tumor activity against seven different types of murine solid tumors. The activity of gemcitabine was also schedule dependent (9). Additional experiments were performed on normal mice bearing the colon 26-10 murine colon carcinoma. The effect of a continuous intravenous infusion system was investigated by giving two injections of 15 mg/kg gemcitabine over 24 hours at a 7-day interval. Interestingly, the efficacy of treatment increased dramatically with this infusion schedule, producing complete remissions in most tumors (8). Other investigators have shown that the 3-day interval schedule also was active in human pancreas and lung carcinoma xenografts (8). Gemcitabine was tested against 12 human carcinoma xenografts. When given on an every 3 day x 4 schedule, the following percent inhibitions (at maximally tolerated doses (MTD); MTD/2) in tumor growth were seen: MX-1 mammary (93%; 80%), CX-1 colon (92%; 82%), HC-1 colon (96%; 92%), GC3 colon (98%; 94%), VRC5 colon (99%; 100%), LX-1 lung (76%; 61%), CALU-6 lung (75%; 38%), NCI-H460 lung (45%; 46%), HS766T pancreatic (73%; not tested), PaCa-2 pancreatic (69%; 40%), PANC-1 pancreatic (70%; 60%), and BxPC-3 pancreatic (9%; 19%). In contrast, only the LX-1 lung carcinoma xenograft was responsive to Ara-C treatment, which inhibited tumor growth by a marginal 62%. Thus, like its activity against murine solid tumors, gemcitabine has excellent anti-tumor activity against a broad spectrum of human solid tumors (9). Following the demonstration of broad-spectrum cytotoxic activity in pre-clinical models, Phase I human studies for gemcitabine began in September 1987 (10). Doses ranging from 10 to 1,000 mg/m2 were administered over 30 minutes weekly times 3 weeks every 4 weeks. The maximum-tolerated dose was 790 mg/m2. The dose-limiting toxicity was myelosuppression, with thrombocytopenia and anemia quantitatively more important than granulocytopenia. Non-hematologic toxicity was minimal. The maximum dFdC plasma concentration, reached after 15 minutes of infusion, was proportional to the total dose administered. Elimination, due mainly to deamination, was rapid (terminal half-life (t1/2), 8.0 minutes) and dose independent. The deamination product 2', 2’-difluorodeoxyuridine (dFdU) was eliminated with biphasic kinetics characterized by a long terminal phase (t1/2, 14 hours); it was the sole metabolite detected in urine. The plasma and cellular pharmacology of gemcitabine was studied during a Phase I trial. The steady-state concentration of dFdC in plasma was directly proportional to the dFdC dose, which ranged between 53 and 1,000 mg/m2 per 30 min. The cellular pharmacokinetics of an active metabolite, dFdC 5'-triphosphate (dFdCTP) was determined in mononuclear cells of 22 patients by anion-exchange high-pressure liquid chromatography. The rate of dFdCTP accumulation and the peak cellular concentration were highest at a dose rate of 350 mg/m2 per 30 min, during which steady-state dFdC levels of 15-20 µM were in plasma. A comparison of patients infused with 800 mg/m2 over 60 min. with those receiving the same dose over 30 min. demonstrated that the dFdC steady-state concentrations were proportional to the dose rate, but that cellular dFdCTP accumulation rates were similar at each dose rate. At the lower dose rate, the AUC for dFdCTP accumulation was 4-fold that observed at the higher dose rate. Consistent with these observations, the accumulation of dFdCTP by mononuclear cells incubated in vitro was maximal at 10-15 µM dFdC. These studies suggest that the ability of mononuclear cells to use dFdC for triphosphate formation is saturable (11). A Phase I study utilizing twice-weekly injections was conducted in 50 eligible and evaluable patients. Twenty-nine patients received drug by 30-minute infusion at doses of 5-90 mg/m2, and 22 patients by 5- minute bolus at 30-150 mg/m2. The primary dose limiting toxicities were marrow suppression and flu- like symptomatology. Thrombocytopenia was dose limiting at 75 mg/m2 on the infusion schedule and 150 mg/m2 on the 5-minute schedule. Flu-like symptoms with fever rigors and malaise occurred the day of injection in many patients (12). In another Phase I study, patients received gemcitabine at therapeutically active doses (> 875 mg/m2/week x 3 every 28 days) (13). Except for one patient, all were given gemcitabine doses exceeding 1,000 mg/m2 (1 patient at 875, 3 at 1,095 and 11 at 1,370 Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 6 of 32 mg/m2) for a total of 50 delivered courses. Dose-limiting hematologic toxicity was found at 1,370 mg/m2/wk as underscored by the higher number of toxic treatment delays requiring subsequent dose attenuation in 6 of 11 patients. Toxicity was mild and easily managed. WHO grade 2-3 toxicity included leukopenia (53%), thrombocytopenia (20%), anemia (53%), AST/ALT rises (27%), emesis (40%) and fever (grade 2 only) (60%). An integrated database of toxicity was also analyzed according to starting dose (800, 1000 or 1250 mg/m2) in a subset of 665 chemo-naive patients to see whether an increased dose resulted in increased toxicity. In general, only small, clinically insignificant differences in toxicity were seen between the three dose groups. Although neutropenia appeared to increase as starting dose increased (grade 3 or 4, 19.4%, 23.2%, 28.3%, respectively), this was not associated with an increased incidence of infection. In some cases, toxicity decreased with increasing dose but this may have been because of imbalances between the patient groups. These findings indicate that not only is gemcitabine well tolerated, but also the use of higher doses may be possible (13) 2.2 Gemcitabine In Breast Cancer Table 1. Phase II trials of single agent gemcitabine in advanced breast cancer Author Year N Resp. Eval. Pts. % prior chemo % prior chemo. for met. disease No. prior chemo. treatments for met. disease % with prior anthra. mg/m 2 dose and schedule mg/m 2/week Response rate % grade 4 neutropenia % FN (3) Carmichael 1995 44 40 65% 43% 0 - 1 39% 800 q wk x 3, q 4 wks 600 25% 7% 2% Brodowicz(1) 1998 24 100% 2 - 3 100% 1250 q wk x 3, q 4 wks 937.5 12% Possinger 1999 42 42 24% 0% 0 1000 q wk x 3, q 4 wks 750 14% 5% 0% Spielman(2) 2001 47 41 100% 100% 1 - 2 100% 1200 q wk x 3, q 4 wks 900 29% 4% 0% Blackstein 2002 39 35 49% 0% 0 1200 q wk x 3, q 4 wks 900 37% 0% 0% Proposed trial 0-1 1200 q wk x 2, q 3 weeks 800 ____________________________________ 1. Abstract 2. All patients had a prior response to the anthracycline for metastatic disease 3. Febrile neutropenia Five Phase II studies have evaluated the activity of gemcitabine in metastatic breast cancer (Table 1). In the first study, Carmichael et al. reported 44 patients with advanced disease were given a dose of 800 mg/m2 on days 1, 8, and 15 every 28 days (14). Twenty-six patients had received prior chemotherapy either in the adjuvant (7 patients) or metastatic setting (19 patients). The mean administered dose of gemcitabine was 725 mg/m2/injection, or 543 mg/m2/week. The response rate was 25%. In the second study Brodowicz preliminarily reported a response rate of only 12%, but all patients had prior chemotherapy and gemcitabine was third or fourth line chemotherapy for metastatic disease (15). In the fourth study, only patients with previous metastatic disease responsive to anthracycline-based chemotherapy were enrolled (16). Forty-seven patients were treated with gemcitabine at a dose of 1,200 mg/m2 on days 1,8 and 15 every 28 days, with a delivered dose of 754 mg/m2/week. The median time to progression of the responders and the median survival of all the patients were 8.1 and 18.6 months, respectively. The response rate was 29% of which 11% were complete responses. In the fifth study, Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 7 of 32 Blackstein reported 39 patients with advanced breast cancer of whom 21 had received prior adjuvant chemotherapy were treated with gemcitabine 1,200 mg/m2 on days 1, 8 and 15 every 28 days (17), with a delivered dose of 1,053 mg/m2/week. The response rate in this study was 37% of which 4 were complete responses. In comparison, the response rates in anthracycline-resistant disease reported with paclitaxel (18) and docetaxel (19) were 6-29% and 30-41%, respectively. In conclusion gemcitabine administered at a dose of 800-1,250 mg/m2 on days 1 and 8 every 21 days, or days 1,8, and 15 every 28 days is tolerable and active in metastatic breast cancer. Thus, gemcitabine appears to be a very reasonable single agent for patients with metastatic breast disease. The main toxicity of gemcitabine is myelosuppression. However, in all these studies, in which gemcitabine is administered at an intended dose of 600 – 900 mg/m2/wk, the incidence of grade 4 neutropenia was < 7%, with rare instances of febrile neutropenia (Table 1). Therefore, it is reasonable to propose gemcitabine at a dose of 1,000 mg/m2 on days 1 and 8 every 21 days, which would yield a dose of 800 mg/m2/wk, which is well within the dose range of achieving clinical responses dosing that produces a very low incidence of neutropenia or febrile neutropenia. 2.3 Aberrant Akt and NF-κB signaling in human breast cancer 2.3.1 Akt pathway in breast cancer Akt is an oncogenic serine-threonine kinase that is significantly activated by the estrogen receptor (ER) and breast cancer related receptor tyrosine kinases (RTKs) such as EGFR, Her-2, insulin receptor (IR) and the insulin like growth factor-1 receptor (IGF-1R). We and others have shown that Akt1 is overexpressed or activated in the majority of breast cancer cell lines and tumors (20, 21). Roth et al. has reported that Akt1 and Akt3 is overexpressed in most breast cancer cell lines and in the majority of primary breast cancer samples, especially in ER negative tumors (20). Thirty-eight percent of breast cancers have elevated Akt1 kinase activity or expression of phosphorylated Akt (pAkt) by immunohistochemistry (IHC) (21). Ahmad et al. has reported that Akt1 levels are elevated in a panel of human breast cancer cell lines, and that MCF-7 cells stably overexpressing WT-Akt1 exhibited increased anchorage independent growth in response to serum, IGF-1, or estrogen (22). Heregulin and amplified Her-2 may both activate Akt in human breast cancer cell lines (23, 24). Recent in vitro data also indicate that Akt may augment ERα signaling by specific phosphorylation of ERα at Ser167. Stable overexpression of Akt1 in MCF-7 cells confers ligand independent activation and increased transactivation by ERα, and decreases growth inhibition and apoptosis in response to tamoxifen. Bcl-2 is also significantly induced in these cells (25). A recent multivariate analysis of a cohort of tamoxifen and/or goserelin treated breast cancer showed that expression of pAkt in tumors was an independent predictor of distant metastatic relapse (26). These data together suggest that Akt plays a mechanistic or predictive role in tamoxifen resistance, and that inhibition of Akt may be therapeutic in breast cancer. 2.3.2 NF-κB pathway in breast cancer The nuclear factor kappa B (NF-κB) transcription factor is often activated in tumor cells. Growth factors such as the epidermal growth factor (EGF), cytokines and mitogens activate the phosphatidyinositol 3- kinase, protein kinase C and subsequently NF-κB (27). Activation of NF-κB by Akt may explain the pro-transforming effects of Akt. When the pathway is unstimulated NF-κB is sequestered in the cytosol of cells by the inhibitory I-κB protein. NF-κB activity is induced by Akt via activation of a kinase, IKK, a direct Akt substrate, which then phosophorylates I-κB at two conserved serines in the N-terminal domain, leading to its ubiquitin mediated degradation (28, 29). This releases NF-κB to translocate into the nucleus where it transactivates promoters of genes involved with cell cycle progression, such as cyclin D1 (30) or survival function such as cellular inhibitors of apoptosis (CIAPs) (31). NF-κB is constitutively elevated in human breast cancer cell lines compared to untransformed breast cells, and its inhibition causes apoptosis (32, 33). Her-2 activation of NF-κB also occurs through Akt– Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 8 of 32 IKK mediated degradation of IKB (34). NF-κB expression is also elevated in the majority of human breast cancer tissues (33, 35). Furthermore NF-κB has been shown to be low in the cytosol but elevated in the nucleus of breast cancer cells indicating that NF-κB is not only overexpressed but also is functional (35). The role of NF-κB in anti-apoptosis (36, 37), invasion (38), cell cycle regulation (39) and growth of cells has been clearly demonstrated in breast cancer. In breast cancer cells NF-κB has been shown to upregulate secretion of urokinase-type plasminogen activator (38) and transcription of matrix metalloproteinase (40) both of which are promote cell invasion and metastasis. NF-κB has also been shown to disturb the cell cycle regulation in breast cancer cells through increased cyclin D1 transcription and retinoblastoma phosphorylation (39). Hence, NF-κB is a molecular target in breast and other cancers, in its own right, as numerous drugs are being developed which antagonize NF-κB activity (41). NF-κB also appears to have a role in chemoresistance. Inhibition of NF-κB via adenoviral delivery of I- ĸB (42), or inhibition of proteasome-mediated degradation of I-ĸB increases apoptosis and chemosensitizes cancer cell lines (43). Introduction of the I-ĸB vector into breast cancer cell lines sensitizes these cells to the effects of paclitaxel (44). In a preclinical model, non-small cell lung cancer cells treated with a plasmid expressing I-ĸB resulted in increased apoptosis with gemcitabine as compared to the cells not treated with the vector (45). On the other hand, introduction of the NF-κB gene into cell lines lacking the NF-κB overexpression resulted in resistance to gemcitabine (46). Thus, inhibition of NF-κB activity may sensitize cancer cells to gemcitabine chemotherapy. 2.4 Genistein Flavonoids compromise the most common group of plant polyphenols. More than 5,000 different flavonoids have been described and classified based on chemical structure into six subgroups (47). Genistein (4,5,7-trihydroxyisoflavone) is a naturally occurring flavonoid of the isoflavone subgroup present in soybeans (47). Genistein containing nutritional supplements have become popular in the public domain, with claims for potential breast cancer prevention or treatment, such that patients will seek administration of these without prospective vigorous clinical trial data. However, there is accumulating preclinical data that indicate that genistein has potential for the treatment or prevention of breast cancer, and suggest that careful clinical studies are warranted. Genistein has been shown to elicit molecular changes that result in inhibition of cell growth and induction of apoptosis in different cancer cell lines. In the squamous cell cancer cell lines, genistein can induce cell cycle arrest through upregulation of p21waf1 and downregulation of cyclin B1 (48). Genistein also induces apoptosis via upregulation of bax and downregulation of Bcl-2 gene expression (48). Furthermore, it downregulates the expression of matrix metalloproteinase 2 and 9 (48). In testicular cancer cell lines, genistein can induce apoptosis through activation of caspase-3 protease (49). In colon cancer cell lines, genistein can induce apoptosis through topo-isomerase II-mediated DNA breakage (50). In the breast cancer cell lines, genistein has been shown to block cells at the G2M phase (51). Genistein also can induce apoptosis through modulation of ERK phosphorylation and c-fos expression in breast cancer cell lines (52). Recent evidence indicates that genistein is also a potent inhibitor of Akt and NF-κB pathways. Our laboratory has shown that genistein may facilitate apoptosis in cancer cells by inhibiting several critical intracellular survival pathways, including the inhibition of the PI3-kinase – Akt dependent signaling and NF-κB activation (48, 53). Genistein has also been shown to inhibit NF-κB activation in prostate cancer (53) and head and neck squamous cell cancer cell lines (48). Several clinical studies have been done with soy products or supplements. We have shown that Novasoy, which contains ~40% genistein, inhibits NF-κB activation in humans without toxicity. In a clinical study involving six healthy male volunteers, 50 mg of genistein administered twice daily for three weeks resulted in inhibition of NF-κB activation by TNF-α in peripheral lymphocytes. The Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 9 of 32 volunteers experienced no side effects (54). Moreover, a phase II clinical study at Wayne State University has been completed in which 41 patients with prostate cancer received Novasoy at 100 mg BID for six months. Overall a decrease in PSA was noted, without any side effects (Hussein et al., manuscript submitted) (55). Recently, a limited, preliminary phase I clinical study with pharmacokinetics was reported in male volunteers with a soy supplement similar in content to Novasoy. Fifteen healthy volunteers were given single doses at 1, 2, 4, 8 or 16 mg/kg, with three patients at each level. At 1 and 2 mg/kg doses levels (equivalent to 70 and 140mg for a 70kg man), no clinical or laboratory toxicity was observed. At 4, 8 and 16 mg/kg (~280, 560, and 1120 mg doses, respectively), there were 7 cases of grade 1 - 2 adverse events, including 3 episodes of hypophosphatemia judged to be “clinically insignificant,” one pedal edema, one loss of appetite, one abdominal tenderness, and one leukopenia (grade 2 at 16 mg/kg). Mean peak plasma total genistein levels in three men receiving 8mg/kg (~560 mg) was ~ 20 µM, with a pseudo t1/2 of ~9.2 h, and the major route of elimination through the urine (56). Thus, safe, biologically active does of genistein may prevent or treat breast cancer by not only inhibiting Akt and its downstream effector, NF-κB, but by increasing the efficacy of chemotherapy such as genistein. Moreover, monitoring NF-κB activity in peripheral blood mononuclear cells (PBMNC) may serve as an surrogate marker of genistein activity in clinical trials. 2.5 Rationale of the study 2.5.1 Clinical Rationale Systemic chemotherapy can palliate symptoms as well as prolong survival of patients with metastatic breast cancer (4, 5). Introduction of novel agents in this setting is important in order to further improve the clinical outcome of patients. Gemcitabine at a dose of 800-1200 mg/m2 has significant activity comparable to the taxanes as second line agent in breast cancer (14, 17, 57). The toxicity of gemcitabine is mainly myelosuppression. Dose limiting myelosuppression occurs in about 10% of patients treated with gemcitabine (16). However, in the Phase II trials in metastatic breast cancer no treatment related mortality was observed (16). Genistein has garnered increasing scientific interest as a breast chemoprevention agent. Genistein may inhibit several molecular targets that are relevant to human breast cancer, and may modulate sensitivity to gemcitabine. These include Akt and NF-κB, which are overexpressed and/or activated in the majority of breast cancer cell lines and primary tumors (39, 58). Overexpression of the NF-κB in cancer cell lines results in resistance to gemcitabine (45). Inhibition of NF-κB can sensitize cells to the effects of chemotherapeutic agents (44), including gemcitabine (46). Genistein is an inhibitor of the NF-κB pathway as demonstrated in healthy volunteers (54) as well as in cancer cell lines (48, 59). Genistein at doses proposed in this study has no side effects (Hussein et al., manuscript submitted) (55). Thus, there is increasing evidence that genistein may have chemoprevention, or chemotherapeutic applications, especially in combination with other cytotoxic chemotherapies such as gemcitabine. Further clinical studies with genistein are clearly indicated. We hypothesize that combining genistein and gemcitabine in patients with metastatic breast cancer could improve the therapeutic effectiveness of gemcitabine through decreasing chemo-resistance via modulation of the Akt and NF-κB pathways without added toxicity. 2.5.2 Translational Rationale The two general translational aims are to: 1. Determine if higher plasma levels of genistein are associated with clinical responses to the combined treatment; and 2. Explore effects of genistein alone on in vivo tumor biology. Although there have been numerous recent reports of the in vitro effects of genistein on human cancer cell lines (reviewed in Section 2.5), there are no studies that have corroborated or even explored the in vivo effects in human tumor specimens. Therefore, in patients who Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 10 of 32 have easily accessible tumor and are willing to undergo biopsies before and after seven days of genistein, we will perform studies to determine if genistein inhibits cell cycle, induces apoptosis, and inhibits Akt and NF-κB activation as would be predicted from preclinical studies. Further, we will explore the effects on other potential biomarkers through cDNA microarray analysis when sufficient cDNA can be prepared from paired specimens. This will provide novel insights and a better understanding on the mechanisms of genistein effects on malignant breast cancer cells. 3.0 DRUG INFORMATION 3.1 Gemcitabine (Gemzar) Chemistry: Gemcitabine HCl is 2-deoxy-2, 2-difluorocytidine monohydrochloride (beta isomer). Clinical Pharmacology: Gemcitabine pharmacokinetics are linear and are described by a 2- compartment model. Population pharmacokinetic analyses of combined single-and multiple-dose studies showed that the volume of distribution of gemcitabine was significantly influenced by duration of infusion and gender. Clearance was affected by age and gender. Differences in either clearance of volume of distribution based on patient characteristics or the duration of infusion; result in changes in half-life and plasma concentrations. Gemcitabine half-life for short infusions ranged from 32-94 minutes, and the value for long infusions varied from 245-638 minutes, depending on age and gender, reflecting a greatly increased volume of distribution with longer infusions. The lower clearance in women and the elderly result in higher concentrations of gemcitabine for any given dose. The volume of distribution was increased with infusion length. Volume of distribution of gemcitabine was 50 L/m2 following infusions lasting <70 minutes, indicating that gemcitabine, after short infusions, is not extensively distributed into tissues. For long infusions, the volume of distribution rose to 370 L/m2, reflecting slow equilibration of gemcitabine within the tissue compartment. The maximum plasma concentrations of dFdU (inactive metabolite) were achieved up to 30 minutes after discontinuation of infusions, and the metabolite is excreted in urine without undergoing further biotransformation. The metabolite did not accumulate with weekly dosing, but its elimination is dependent on renal excretion, and could accumulate with decreased renal function. The effects of significant renal or hepatic insufficiency on the disposition of gemcitabine have not been assessed. Human Toxicity: Hematologic: Myelosuppression is the dose-limiting toxicity with gemcitabine, but <1% of patients discontinued therapy for anemia, leukopenia, or thrombocytopenia. Red blood cell transfusions were required by 19% of patients. The incidence of sepsis was less than 1%. Petechiae or mild blood loss (hemorrhage), from any cause, were reported in 16% of patients; less than 1% of patients required platelet transfusions. Patients should be monitored for myelosuppression during gemcitabine therapy and dosage modified or suspended according to the degree of hematologic therapy (see Section 8.0). Gastrointestinal: Nausea and vomiting were commonly reported (69%) but were usually mild to moderate. Severe nausea and vomiting (WHO grade 3/4) occurred in <15% of patients. Diarrhea was reported by 19% of patients, and stomatitis by 11% of patients. Hepatic: gemcitabine was associated with transient elevations of serum transaminases in approximately two-thirds of patients, but there was no evidence of increasing hepatic toxicity with either longer duration of exposure to gemcitabine or with greater total cumulative dose. Renal: Mild proteinuria and hematuria were commonly reported. Clinical findings consistent with the hemolytic-uremic syndrome (HUS) were reported in 6/24 patients (0.25%) receiving gemcitabine in clinical trials. Four patients developed HUS on gemcitabine therapy, two immediately post-therapy. Renal failure may not be reversible, even with discontinuation of therapy, and dialysis may be required. Fever: The overall incidence of fever was 41%. This is in contrast to the incidence of infection (16%) and indicates that gemcitabine may cause fever in the absence of clinical infection. Fever was frequently associated with other flu-like symptoms and was usually mild and clinically manageable. Rash: Rash was reported in 30% of patients. The rash was typically a macular or finely granular maculopapular pruritic eruption of mild-to-moderate severity, involving the trunk and extremities. Pruritus was reported for 13% of patients. Pulmonary: Dyspnea Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 11 of 32 was reported in 23% of patients, severe dyspnea in 3%. Dyspnea may be due to underlying disease, such as lung cancer (40% of study population) or pulmonary manifestations of other malignancies. Dyspnea was occasionally accompanied by bronchospasm (<2% of patients). Rare reports of parenchymal lung toxicity consistent with drug-induced pneumonitis have been associated with the use of gemcitabine. Edema: Edema (13%), peripheral edema (20%), and generalized edema (<1%) were reported. Less than 1% of patients discontinued due to edema. Flu-like Symptoms: "Flu syndrome" was reported for 19% of patients. Individual symptoms of fever, asthenia, anorexia, headache, cough, chills, and myalgia, were commonly reported. Fever and asthenia were also reported frequently as isolated symptoms. Insomnia, rhinitis, sweating, and malaise were reported infrequently. Less than 1% of patients discontinued due to flu-like symptoms. Infection: Infections were reported for 16% of patients. Sepsis was rarely reported (<1%). Alopecia: Hair loss, usually minimal, was reported by 15% of patients. Neurotoxicity: There was a 10% incidence of mild parasthesias and a <1% rate of severe parasthesias. Extravasation: Injection-site-related events were reported for 4% of patients. There were no reports of injection-site necrosis. Gemcitabine is not a vesicant. Allergic: Bronchospasm was reported for less than 2% of patients. Anaphylactoid reaction has been reported rarely. Gemcitabine should not be administered to patients with a known hypersensitivity to this drug. Cardiovascular: Two percent of patients discontinued therapy with gemcitabine due to cardiovascular events such as myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension. Many of these patients had a prior history of cardiovascular disease. Pharmaceutical Data: Gemcitabine is supplied as a lyophilized powder in sterile vials containing 200 mg or 1 g of gemcitabine as the hydrochloride salt (expressed as the free base), mannitol, and sodium acetate. Drug vials will be reconstituted with normal saline added to the vial to make a solution ideally containing 10 mg/mL or less. The concentration for 200 mg and 1 g vials should be nor greater than 40 mg/mL. An appropriate amount of drug will be prepared with normal saline and administered as a continuous infusion for 30 minutes. Once the drug has been reconstituted, it should be stored at room temperature and used within 24 hours. Storage and Stability: Store at controlled room temperature (20-250C), should be handled and disposed of in a manner consistent with other anti-cancer drugs. Route of Administration: Intravenous infusion over 30 minutes. Supplier: Commercially available from Eli Lilly and Company, Indianapolis, Indiana, 46285. 3.2 Genistein (Soy Isoflavones) Novasoy ® tablets containing 50 mg soy isoflavones will be obtained at no charge from Archer Daniels Midland (ADM) Company (Decatur, IL). Novasoy tablet is a well-defined soy concentrate tablet manufactured to contain 50 mg soy isoflavones per tablet. The contents have been analyzed by HPLC and contain soy isoflavones genistein, daidzein and glycitein at a ratio of 1.1:1:0.1, thus each 50 mg tablet provides roughly 25 mg of genistein. The isoflavones are present in both conjugated (40%) and unconjugated (60%) forms. In our previous studies we have measured serum genistein and daidzein levels and found them to significant increase after one week and remain stable for the remaining period upon continuous dosing without change in serum concentrations. The half-life of genistein after a single oral dose is approximately 3-4 hours. We have shown in our previous studies that Novasoy taken 1 tablet (50 mg) daily is sufficient to have a biological effect with significant reduction in oxidative stress markers. Soy isoflavones are generally considered safe and are available in nutrition stores and pharmacies without prescription. No adverse health effects have been attributed to use of soy isoflavone supplements. Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 12 of 32 Chemistry: Genistein is supplied as a major component of an isoflavone extract of soy and is classified as a nutritional product. Genistein’s chemical structure is 4,5,7-trihydroxyisoflavone. Administration: Patients will be instructed to take their capsules twice daily with breakfast and dinner. They may also take the study capsules at any time during the day if they forget to take them with the designated meals. Patients will return their remaining study capsules. A capsule count will be made and the number of remaining capsules will be placed in patient’s study folder by the study coordinator. Capsule containers (partial and empty) need to be returned for accountability. Human toxicity: Genistein did not have any side effects in previous studies; therefore, we do not expect toxicity in this study. Storage: At room temperature. Supplier: Archer Daniels Midland, Decatur, IL 4.0 ELIGIBILITY CRITERIA 4.1 Inclusion Criteria a) Patients must have histological or cytological diagnosis of breast cancer. b) Patients must have clinical and/or radiological evidence of metastatic disease (stage IV). c) Patients must have measurable disease by RECIST criteria. Prior radiation permitted as long as at least one measurable disease site is outside the radiation field d) Patients may have had any prior cytotoxic chemotherapy treatments for metastatic disease excluding gemcitabine. Any prior adjuvant therapy is permitted (except for gemcitabine). Patients must have failed within 24 months of completion of adjuvant (or neoadjuvant) taxane- based therapy or after a taxane therapy for metastatic disease. e) Patients with prior hormone therapy must have documented disease progression on the hormone therapy. f) Patients must not have received any prior gemcitabine. g) Patients must have performance status of 0-2 on SWOG scale (see Appendix III). h) Patients must have adequate bone marrow function: absolute neutrophil count >1,500/cmm, platelet count >100,000/cmm, and hemoglobin > 10g/l. i) Adequate liver function: bilirubin < 3.0 mg/dL; transaminases (AST/ALT) < 2.5 times upper limit of institutional normal. j) Adequate renal function: creatinine < 1.5 mg/dL. k) Patients must be informed of the investigational nature of this study and must give written informed consent prior to the receiving of treatment per this protocol. Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, l) Women with child bearing potential must practice effective birth control while receiving treatment. revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 13 of 32 m) Prior chemotherapy, biologic, investigational , or major surgical therapy must be completed at least 3 weeks prior to initiation of protocol therapy. n) Prior radiation therapy is allowed, however, patients must have recovered from the acute effects of the treatment, and have completed radiation at least 4 weeks prior to starting protocol therapy. o) Patients may have hormone receptor positive or negative breast cancer. Any prior hormonal therapy, either adjuvant or for metastatic disease is permitted, as long as patients are off all hormone therapy for at least 2 weeks prior to starting protocol therapy. p) All soy supplements (including all soy based pills, liquids, concentrates) must be discontinued for at least 1 week. Dietary soy that may be normally part of a meal (e.g., tofu) may be ingested once per week. A daily multivitamin pill is permitted. q) Patients must discontinue all other nutritional supplements, herbal agents, high doses of antioxidants (e.g., vitamin C, D, or E) including any that may interact with, antagonize, or alter or imitate the potential effects of either gemcitabine or genistein. 4.2 Exclusion Criteria a) History of active central nervous system (CNS) metastases. Patients with previously treated CNS metastases are permitted if > 3 months prior to enrollment, clinically stable without steroids or antiseizure medications. b) Serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator). c) History of other malignancy, except for cervical carcinoma, or basal or squamous skin cancers. For these cancers, patient must have been treated with a curative intent be in complete in remission. d) Unresolved bacterial infection requiring treatment with antibiotics. e) Pregnant or lactating women may not participate in the study. j) Patients infected with HIV-1 virus because of the undetermined effect of this chemotherapy regimen in these patients, and the potential for interaction with anti-HIV medications. 5.0 TREATMENT PLAN 5.1 Dosage Selection and Administration Procedures TABLE 2. The Starting Dose Levels Cycle and Day Gemcitabine (I.V.) Novasoy (P.O.)1 Dose 1000 mg/m2 100 mg Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 14 of 32 Cycle 1, Days -7 to -1 ----------------------- BID x 7 days2 Schedule Cycles 1 to N, Days 1-21 Days 1 and 8 Q 21 days BID2 Days 1-21 Q21 days 1Genistein (Novasoy) should be taken with breakfast and dinner. 2Patients should be told not to take genistein A.M. dose on cycle 1, days –7 and –1, and on cycle 2, day 1, until plasma for genistein level is collected in clinic. The body surface area will be calculated according to actual height and weight at the beginning of treatment and this will be used to calculate the dose of gemcitabine. Doses can be recalculated if weight declines by >10%. Treatment may be administered on an outpatient basis. Gemcitabine 1,000 mg/m2 intravenously administered over 30 minutes on days 1 and 8 of each 21-day cycle. Please refer to Table 2 for the initial dose level. 5.2 Duration of Therapy Patients with metastatic cancer will continue until disease progression and/or undue or intolerable toxicity. 5.3 Concomitant Therapy No other chemotherapy, immunotherapy, hormonal therapy (excluding anticoagulants, appetite stimulants and replacement steroids), nutritional or herbal supplements (except for a multi-vitamin) radiation therapy, or experimental medications will be permitted while the patients are on study. To prevent nausea and vomiting, the prophylactic use of anti-emetics including dexamethasone, is allowed. Any disease progression requiring other forms of specific anti-tumor therapy will be a cause for early discontinuation from this study. Bisphosphonates are permitted. Patients should receive full supportive care as necessary. Patients may receive hematopoietic growth factors as clinically indicated. 6.0 TREATMENT MODIFICATIONS FOR TOXICITY, AND CRITERIA FOR DISCONTINUATION FROM STUDY * Dose reductions and treatment delays only apply to gemcitabine 6.1 Dose delay and modification on day 1 of each cycle based on toxicities on day of treatment TABLE 3. Day 1 dose delay or modification due to hematologic toxicity on day of treatment Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 15 of 32 ANC Platelet Delay, until ANC> 1500 and Platelet > 100,000 Percent dose reduction of gemcitabine Percent dose reduction of genistein > 1,500 >100,000 None 0 0 < 1 week 0 0 > 1 to 2 weeks 25 0 <1,500 <100,000 > 2 weeks Off treatment TABLE 4. Day 1 dose delay or modification due to non-hematologic toxicity on day of treatment (excludes alopecia, nausea, or vomiting, based on NCI Common Tox. Criteria 3.0) Grade Delay, until non- hematologic toxicity = 0-1 Percent dose reduction of gemcitabine Percent dose reduction of genistein 0-1 None 0 0 0 to 1 week 0 0 > 1 to 3 weeks 25 0 2 > 3 weeks Off treatment 0 to 1 week 0 0 > 1 to 3 weeks 25 0 3-4 > 3 weeks Off treatment 6.2 Dose modification on day 1 of each cycle based on toxicity of the previous cycle TABLE 5. Dose modification on day 1 of each cycle based on previous cycle’s hematologic toxicity Worst toxicity during previous cycle Percent reduction in gemcitabine dose from the previous cycle Percent reduction of the genistein dose from previous cycle ANC or Platelets >0.250 >40 0 0 <0.250 <40 25 0 Note: Dose modifications should be repeated in subsequent cycles if hematologic toxicity recurs. TABLE 6. Dose modification on day 1 of each cycle based on previous cycle’s non- hematological toxicity during previous cycle (excluding pulmonary toxicity, alopecia, nausea and vomiting) Worst toxicity during previous cycle Percent reduction in gemcitabine dose from the previous cycle Percent reduction of the genistein dose from previous cycle 0 0 0 1-2 0 0 3-4 25 0 Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 16 of 32 TABLE 7. Dose modification on day 1 of each cycle based on previous cycle’s non- hematological pulmonary toxicity during previous Pulmonary toxicity Percent reduction in gemcitabine dose from the previous cycle Percent reduction of the genistein dose from previous cycle 0 0 0 1 25 0 2-4 Off treatment Off treatment If pneumonitis grade 2 or higher develops in a given cycle and is related to gemcitabine, gemcitabine should be promptly discontinued and the patient should be removed from protocol treatment. Treatment with corticosteroids should be given according to established guidelines. 6.3 Dose modifications on day 8 of each cycle based on hematologic toxicities TABLE 8. Dose modifications on day 8 of each cycle ANC Platelet (X 109) Percent dose reduction of gemcitabine Percent dose reduction of genistein > 1.0 >75 0 0 0.75-0.999 50-74 25 0 0.50-0.749 40-49 50 0 <0.50 <40 100 100 6.4 Discontinuation from the Study Treatment A patient will be discontinued from the study under the following circumstances: 6.4.1 There is evidence of progressive disease. 6.4.2 The attending physician thinks the best interests of the patient require a change of therapy. 6.4.3 The patient requests discontinuation. 6.4.4 The drug exhibits unacceptable toxicity. 6.5.5 Patient becomes pregnant or fails to use adequate birth control (for those patients who are potentially able to conceive). 7.0 CRITERIA FOR RESPONSE EVALUATION AND TOXICITY REPORTING 7.1 Definition of clinical response: 7.1.1 Measurable lesions: Lesions that can be measured in at least one dimension as > 20 mm with conventional techniques or as > 10 mm with spiral CT scan. 7.1.2 Evaluable disease: Includes unidimensionally measurable lesions, masses with poorly defined margins, palpable nodal disease (measured by two observers), lesions with diameter less than 0.5 cm. 7.1.3 Non-measurable lesions: All other lesions including small lesions (longest diameter < 20 mm Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 17 of 32 with conventional techniques) and other non-measurable lesions including: pleural effusions, ascites, lesions on bone scans and disease documented by indirect evidence (e.g. biochemical abnormalities). Non-evaluable disease does not influence objective response assessment except for the determination of CR when all disease must be absent and in the determination of progression (if new non-evaluable disease develops). 7.1.4 Target lesions: All measurable lesions up to a maximum of 10 lesions. Target lesions are selected for their size and suitability for accurate repetitive measurements. The sum of the longest diameter of all target lesions will be calculated and reported as the baseline sum longitudinal diameter (LD). This will be used as a reference to further quantify objective response. 7.1.5 Non-target lesions: All other lesions are identified as non-target lesions and should be followed as present or absent. 7.1.6 Objective response criteria: Complete response (CR): Complete disappearance of all measurable and evaluable disease for at least 3 weeks without the appearance of any new lesions. Persistent effusions after therapy should be cytologically negative of malignant cells. Partial Response (PR): Greater than or equal to 30% reduction in the sum longest diameters of target lesions taking as reference the baseline sum of the longest diameters without the appearance of any new lesions. Progressive disease (PD): Greater than 20% increase in the sum of longest diameter of target lesions taking as reference the smallest sum of the longest diameter recorded since the treatment started OR appearance of new lesions. Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of the longest diameters of target lesions since treatment started for a minimum interval of 6 weeks. Best objective response: This will be determined from serial objective response assessments in a given patient using the response criteria mentioned above. For patients whose disease sites are assessed every three to six weeks, two consecutive objective CRs are required to assign the best response of CR. Similarly, two successive evaluations documenting PR or SD are required before assigning the patient to either. Best overall response: This is the best response from the start of the treatment until disease progression/recurrence. In general, the patient’s best response assignment will depend on the achievement of both measurement and confirmation criteria. 7.1.7 Evaluable Patients: A participant who completes 2 cycles of therapy is evaluable for response. A patient who receives any amount of drug is evaluable for toxicity. TABLE 9. Overall response definitions Target lesions Non-Target lesions New lesions Overall response CR CR No CR CR Non-CR/Non-PD No PR PR Non-PD No PR SD Non-PD No SD Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 18 of 32 PD Any Yes or No PD Any PD Yes or No PD Any Any Yes or No PD 7.1.7 Duration of response: Time from point at which response (PR or CR) is first noted, until first clinical or radiologic evaluation that shows progressive disease. 7.1.8 Time to progression: Time from date of registration to the date of documented progressive disease or death. 7.1.9 Overall survival: Time from date of registration to date of death or last follow up. 7.2 Toxicity definitions for evaluation of this protocol Toxicity reported for patients in this trial will be defined by NCI CTC 3.0 criteria. 8.0 SCHEDULED EVALUATIONS ON STUDY 8.1 Within 4 weeks before study initiation all patients must have: • Bone scan. • Chest x-ray. • Tumor imaging to document measurable disease (Chest and abdominal CT scans, or MRI scans). 8.2 Within two weeks before study initiation all patients must have: • History and physical exam, including height and weight. • Performance status. • CBC with differential white cell and platelet counts • Serum chemistries: electrolytes, BUN, creatinine, LDH, alk. phosphatase, total bilirubin, AST(GOT), ALT(GPT), magnesium, calcium, phosphate and albumin. • Amylase and lipase. • Tumor biopsy from easily accessible tumor, before first genistein dose (Optional – if patient has easily accessible tumor and patient agrees to procedure). 8.3 On treatment evaluations: 8.3.1 On cycle 1, day –7 5 ml plasma for genistein level, before A.M. genistein dose Tumor biopsy before A.M. dose, or earlier (Optional) 8.3.2 On cycle 1, day –1, on day 7 of genistein alone (before cycle 1, day 1) 5 ml plasma for genistein level, before A.M. genistein dose, and 4 h after A.M. dose Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 19 of 32 Tumor biopsy from same site as before (Optional) 8.3.3 On cycle 2 only, day 1 5 ml plasma for genistein level, before A.M. genistein dose, and 4 h after A.M. dose. 8.3.3 On cycles 2 through cycle N, day 1 (before genistein and gemcitabine administration): History and physical examination. Performance status. Toxicity evaluation using NCI-CTC criteria. CBC with differential white cell and platelet counts. Electrolytes, SGOT (AST), SGPT (ALT), alkaline phosphatase, bilirubin, creatinine, calcium, phosphate. Amylase and lipase. 8.3.4 On day 8 and 15 of every cycle: CBC with differential white cell and platelet counts. Therefore all patients will have weekly CBC and differential throughout their treatment period. 8.3.5 After every 2 cycles: Repeat all imaging tests to evaluate objective tumor response 9.0 CORRELATIVE STUDIES: INSTRUCTIONS For schedule please see Appendix, Study Calendar. 9.1 Blood samples for plasma genistein and other isoflavone levels: • Plasma will be collected: • before first dose of genistein on cycle 1, day –7 (or earlier) • cycle 1, day –1 (on day 7 of genistein alone) before A.M. dose, then 4 h after A.M. dose • cycle 2, day 1 before A.M. dose, then 4 h after A.M. dose • Blood will be collected into (1) 10 ml or (2) 5 ml citrated tubes. Within 2 hours of collection tubes should be spun at 1000g for 10 m and plasma stored at -70° C in (2) cryovials, each with ~2 ml aliquots. • Cryovials should be labeled with: • Institution name • patient number (assigned at registration) • plasma • date and time collected • cycle number • either as “cycle 1, day-7” or “cycle 1, day-1” or “cycle 2, day 1” • either as “pre-AM dose” or “4-hour post AM dose” • Samples should be sent on dry ice by next AM express mail to: Translational Research Lab (Dr. Sarkar’s lab) HWCRC, room 703 Karmanos Cancer Institute Lab Phone: (313) 576-8314 or (313) 576-8315 Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 20 of 32 • Contact Dr. F. Sarkar’s lab at (313) 576-8314 or( 313) 576-8315, for questions or sample pick up. 9.2 Tumor tissue samples to assess effects of genistein alone on Akt and NF-κB activation and on potential cDNA biomarkers: • Patients with tissue easily accessible for biopsy (i.e. skin metastasis) should be requested to volunteer to biopsy for tumor tissue. This is a recommended but optional study component. • Tumor tissue collection should be arranged at least 2 days in advance of treatment initiation by calling Dr. Sarkar’s lab at (313) 576-8315, or (313) 576-8314. • Tumor tissue will be obtained, before first genistein on cycle 1, day –7 (or earlier), and on cycle 1 day–1 (day 7 of genistein alone). • At least 0.1 g of tumor should be collected (equivalent to a 5 mm cube of tumor, or 3 core (not FNA) cutting needle biopsies should be taken at each time point. • Tumor will be immersed immediately into sterile plastic containers with at least 4 volumes of RNAlater solution (Ambion, 800-888-8804). • The container should be labeled with: • Institution name • patient number (assigned at registration) • metastatic site biopsied • date and time • “pre-genistein” or “post 7 days of genistein.” • After immersion in RNAlater, the tumor samples must be refrigerated or iced until brought to the Translational Lab (Room 703 HWCRC, (313) 576-8314, or (313) 576-8315) before 5 pm the day of collection. From outside institutions, they should be stored in ice or 4C and delivered the same day, or express shipped for delivery the morning after the biopsy in a container containing 4C cold packs). • Upon arrival to the lab: • For core biopsies, one will be sent to pathology for routine H and E staining. The other two cores will be transferred to one labeled 2 ml cryovial with 4 volumes RNAzol and stored at –70C. • For incision or excision biopsies, they will be divided in 3 parallel sections, and the middle 1/3 of the sample will be sent to pathology for routine H and E staining, while the two flanking 1/3 pieces will be transferred to one labeled 2 ml cryovial with 4 volumes RNAzol and stored at –70C • Shipping address: Karmanos Cancer Institute Translational Research Lab 4100 John R HWCRC, room 703 Detroit, MI 48201 Lab Phone: (313) 576-8314 or (313) 576-8315 Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 21 of 32 • Histologic analysis of tumor biopsies taken before and on day 7 of genistein alone: • Routine H and E staining • TUNEL staining for determination of percent apoptotic tumor cells (Calbiochem) • IHC will be performed using established staining methods for: • Ki67 to estimate percent cells in G1-S phase using specific antibody (Dako, #Ki-S5). • Expression of activated Akt using anti-phosphoserine473-Akt antibody (Cell Signaling, #9277). • Expression of activated NF-κB using an antibody specific for the activated form of NF-κB p65 that is free of IκB (Chemicon, #12H11). • Interpretation of IHC for activated Akt or NF-κB: For p-Ser473-Akt and activated NF-κB, IHC each stain will be interpreted based a composite score of two parameters: percent tumor cell staining (0 = 0 - 9%, 1 = 10 - 49%, 2 = > 50%), and relative staining intensity (0 = absent - minimal, 1 = moderate, 2 = strong staining). Appropriate controls will include tumor xenografts that are known to overexpress either marker. A tumor will be positive for expression only it scores 1 or 2 for both percent and intensity parameters; otherwise expression will be considered negative. In addition, the sum score of the parameters for each biomarker will be recorded (i.e., 0 – 4). • CDNA microarray analysis of tumor biopsies taken before and on day 7 of genistein alone • Paired analysis of each patient’s pre- and post- gensistien effects will be done if the H and E staining demonstrates >50 % tumor cells. • The –70C frozen tumor specimens will be crushed on dry ice, then processed in RNAzol to collect total RNA. If the quantity and quality of the pair of tumor RNAs is confirmed (each specimen yielding > 10 ug of non-degraded RNA gel analysis), pairs of matched RNAs will be subjected to microarray analysis. • Microarray analysis will be performed using established methods ((60) and manuscript in preparation). 10.0 REGISTRATION PROCEDURE All patients entering into this study will be registered with the Clinical Trials Office (CTO) at the Karmanos Cancer Institute, Detroit, Michigan, within 7 days prior to starting treatment (313) 576-8994. Each patient will be assigned an alphanumeric code, indicating the overall number of the patient on study, and the institution acronym (e.g., “05-KCI” would indicate the fifth patient registered, and he/she was from KCI. 11.0 REPORTING OF ADVERSE EVENTS 11. 1 General principles: • Reporting of adverse events will include those that occur within 60 days of last treatment (FDA requirement is 30 days). • All adverse events that warrant reporting should use the Wayne State University (WSU) adverse event (AE) form, available on the Human Investigations Committee (HIC) web site: www.hic.wayne.edu). Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 22 of 32 • Note that certain events require reporting within 3 calendar days of awareness of adverse event, while less urgent events are to be reported within 10 days of awareness. These deadlines may be met by verified fax, with the original sent by mail. In addition, for deaths and immediately life threatening events, the Principle Investigator (PI) and WSU Clinical Trials Office (CTO) should be contacted by phone immediately so that compliance with contacting other agencies within 24 h can be facilitated. • The WSU CTO staff will coordinate the reporting process between the PI and the WSU human Investigations Committee (HIC, a.k.a. IRB) as well as other applicable reporting agencies (FDA, CTEP, NIH, OBA, and industry). Copies of all related correspondence and reporting documents will be maintained in the regulatory file. All deaths, immediately life threatening, and reportable serious adverse events will be reported and documented on Form FDA 3500 A (MedWatch Form) and forwarded directly to Eli Lilly. This includes serious, related, expected and serious, related, unexpected events. Reports should be sent to Eli Lilly, US Pharmacovigilance Department by fax at 908-243-6800, within 24 hours of receipt by the investigator. Fax transmission should include the Grant-In-Aid Study Number, Study Title, and name of Principal Investigator. • Reporting of AEs: Contact information: • Study PI of the lead institution, WSU/KCI: Amy M. Weise, D.O. Phone: (313) 576-8952 E-mail: weise@karmanos.org Pager: (313) 745-5111 #0585 Fax: (313) 576-8767 Address: Karmanos Cancer Institute 4100 John R 4-HWCRC Detroit, MI 48201 • Data Manager, Clinical Trials Office (CTO) at WSU/KCI: Matthew Gretkierewicz Phone: (313) 576-8994 E-mail: gretkiem@karmanos.org Pager: (313) 745-5111 #98026 Fax: (313) 576-8368 Address: Clinical Trials Office Harper Professional Bldg., Room 711 Karmanos Cancer Institute 4160 John R Detroit, MI 48201 11.2 Events to be reported by phone within 24 h, and within 3 calendar days, by WSU AE form. • Deaths Death from any cause must be reported by phone to the Karmanos Cancer Institute Clinical Trials Office within 24 hours of the death (while receiving this treatment or up to 60 days from the last dose of treatment). Any death that occurs after 60 days of the last treatment that is felt to be a drug-related toxicity should also be reported. An WSU AE form must be faxed/sent to the WSU Clinical Trials Office within 3 calendar days. In addition, the PI and CTO will be responsible for reporting deaths to the HIC of WSU/KCI (phone 313-577-1628, fax 313-993- Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 23 of 32 7122), with formal written notification faxed within 3 days of the event. Formal notification includes the FDA and/or sponsor AE reporting forms attached to the completed WSU AE reporting form. Deaths must be reported to the FDA within 3 days. • Immediately life threatening events These events must be reported by phone to the Karmanos Cancer Institute Clinical Trials Office within 24 hours of the event (while receiving this treatment or up to 60 days from the last dose of treatment). An WSU AE form must be sent to the WSU Clinical Trials Office within 3 days. In addition, the PI and CTO will be responsible for reporting of immediately life threatening events to the HIC of WSU/KCI (phone 313-577-1628, fax 313-993-7122), with formal written notification within 3 days of the event. Formal notification includes the FDA and/or sponsor AE reporting forms attached to the completed WSU AE reporting form. Deaths must also be reported to the FDA within 3 days. 11.3 Events to be reported within 3 calendar days, by WSU AE form. • Serious Adverse Events (SAEs) that are grade 3 and 4, and: • Unexpected, and/or • Expected, but definitely or probably related to protocol therapy (i.e., relationship to treatment cannot be ruled out) These SAEs should reported to the PI and CTO of WSU within 3 days of awareness. Serious adverse events that are expected, but a relationship to the study treatment is ruled out do not have to be reported. 11.4 Non-serious adverse events that are to be reported within 10 days by WSU AE form. • Non-serious adverse events (generally grade 1 – 2) that are: • Unexpected, and/or • Expected, but more intense, longer in duration, or permanent, and definitely, or probably related to protocol therapy (i.e., relationship to treatment cannot be ruled out) Non-serious adverse events that are expected, but a relationship to the study treatment is ruled out, do not have to be reported. 11.5 If the adverse event requires modification of the study protocol and the informed consent document, then they should be provided to the local IRB with the report of the adverse event. Consent revisions for sponsored research studies must receive sponsor approval prior to submission to the local IRB. 11.6 Any serious clinical adverse event or laboratory value occurring during the course of the study even if unrelated to the therapy should be reported to the Karmanos Cancer Institute Clinical Trials Office. All adverse events will be noted in the case report forms. Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, 12.0 DATA AND SAFETY MONITORING revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 24 of 32 12.1 Scheduled meetings or conference calls will occur every month. These meetings will include the protocol principal investigators and any data managers involved with the conduct of the protocol. 12.2 During these meetings the investigators will discuss: 1. Safety of protocol participants (AE reporting and regulatory compliance) 2. Monitoring for excessive toxicity after the first 9, 11, 17 and 20 patients enrolled and treated, as described in Section 13.2; 3. Validity and integrity of the data; 4. Enrollment rate relative to expectations and the characteristics of participants; 5. Retention of participants and adherence to the protocol (potential or real protocol violations); 6. Completeness of collected data. 12.3 Data and Safety Monitoring Reports of these regular meetings will be kept on file in the Karmanos Cancer Institute Clinical Trials Office. The data manager assigned to the trial will be responsible for completing the report. These reports will be signed by the PI or one of the Co-PI’s. 13.0 STATISTICAL CONSIDERATIONS 13.1 Primary Objective: To estimate the objective response rate of patients with metastatic breast cancer treated with the combination of gemcitabine and genistein. 13.1.1 Assumptions/Hypothesis The primary statistical endpoint is the objective (complete plus partial) response rate. We would consider this regimen not promising if the true response rate was 0.20 in these pretreated patients, since the average response rate of the 5 phase II studies in Table 1 that have an average of 1 prior chemotherapy treatment, is 0.23. The regimen would be promising for further study if the true response rate were at least 0.40. Only response evaluable (RE) patients will contribute to this assessment. In designing this Phase II trial, we have set significance level = 0.05, and power = 0.80. 13.1.2 Estimation of response rate: Based upon the Simon minimax design (61), stage 1 will accrue 18 response RE patients. If 4 or fewer responses are observed, we will recommend the trial for early termination and conclude that the regimen has a true response rate of 0.20 or less. If there are > 5 responders, we will proceed to stage 2 and enroll and additional 15 RE patients. If at least 11 responders are observed among the 33 RE patients, we will conclude that the regimen has a true response rate of 0.40 or more. Otherwise, we will conclude that the true response rate is 0.20 or less. 13.1.3 Sample size, accrual rate, and follow-up: In this two-stage Simon minimax design 18 RE patients will be accrued in stage 1, and 15 RE patients will be accrued in stage 2 (if necessary), for a total of 33 RE patients. Three extra patients should insure 33 RE patients. Therefore, 36 total patients are anticipated for accrual at a combined rate equivalent to about 36 patients over 18 months (1.5 years) (i.e., about 2/month). We anticipate accrual from two other institutions so that each institution would contribute 12 patients over 18 months, or 8 patients per 12 months (or 0.5 – 1 per month). Thus, we expect to enroll the 18 patients needed for Stage 1 in about 9 months, and (if necessary) the additional 15 – 18 patients for Stage 2 in about 9 more months. Additional time (a few months beyond 18 months) may be required to assess response in the last few patients, and because some patients will not become response evaluable until after registration and treatment is started. Patients will be followed for 60 days after the development of disease progression. Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 25 of 32 13.2 Monitoring for excessive toxicity Using exact upper 1-sided 80% confidence limits (computed in StatXact 4 via the Casella methodology (62)), we have determined a monitoring plan for excessive toxicity for the first 20 patients entered. From prior studies of gemcitabine alone, we expect about a 10% rate of grade 4 toxicity (of any type). We wish to have 80% confidence that the true grade 4 toxicity rate of this new regimen is less than 30%. That will be assured if, among the first 9 patients there is at most 1 patient with a grade 4 toxicity, and if among the first 11 patients at most 2 Grade 4 toxicities, and if among the first 17 patients at most 3 grade 4 toxicities, and if among the first 20 patients at most 4 grade 4 toxicities. If at any of these accrual points, these respective numbers of grade 4 toxicity are exceeded, then the potential incidence of grade 4 toxicity would be > 30% and enrollment will be terminated. 13.3 Secondary endpoints: Since all the secondary endpoints are exploratory and intended for hypothesis generation, the results will primarily descriptive, and no formal hypothesis testing is presented. 13.3.1 Overall survival: Patients will be followed from the time the last patient comes off study treatment for one year to monitor survival 13.3.2 Duration of response: For patients with an objective response, this will be measured from the time when response is first documented, to the last restaging that continues to confirm the response. 13.3.3 Time to disease progression: This will be measured from the time that treatment is initiated until the time restaging indicates progressive disease. 13.3.4 Explore if there is an association between plasma genistein levels and responses. • Exploratory associations: The response evaluable patients will be grouped by whether the cycle 1 day –1, or cycle 2 day 1 trough (if elevated) or 4 h peak fall above (“high genistein”) or below the median values (“low genistein”). The number of responses will be determined for either high or low level genistein groups. The possible association of genistein levels with responses will be tested by the Fisher exact test. 13.3.5 Explore the in vivo effects of genistein on human breast cancer tumor biomarkers (Ki67, TUNEL, p-Akt and activated NF-κB immunohistochemistry (IHC), and cDNA expression by microarray analysis. • Exploratory associations: Genistein treatment for 7 days will be associated with: 1. Decreased tumor cell cycling by Ki67 staining; 2. Increased apoptosis as detected by TUNEL staining; 3. Decreased expression of activated Akt or NF-κB by IHC; and 4. Modulation in expression of other potential cDNA biomarkers. • Methods: • The mean and S.D. of the Ki67 or TUNEL percentages all pre-genistein versus post-genistein tumor biopsies will be calculated, along with 95% confidence intervals. • The mean and S.D. of the sum expression of p-Akt or NF-κB of all pre- genistein versus post-genistein tumor biopsies will be calculated, along with 95% confidence intervals. • For each tumor after normalization for control housekeeping gene expression, genes that have > 3 fold induction or repression by genistein will be identified. Those genes which are found to be modulated consistently in all of the paired specimens (e.g., occurring in 5 out of 5 patients in whom paired tumor biopsies Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 26 of 32 are collected and technically successful cDNA array analysis is done) will be preliminarily considered as a significant results. These results are to be used in association with ongoing in vitro cell culture and animal models, as well as for hypothesis generation for future research. 14.0 BIBLIOGRAPHY 1. Jemal, A., Thomas, A., Murray, T., and Thun, M. Cancer Statistics, 2002. CA Cancer J Clin, 52: 23-47, 2002. 2. Olin, J. J. and Muss, H. B. New strategies for managing metastatic breast cancer. Oncology (Huntington), 14: 629- 641; discussion 642-624, 647-628, 2000. 3. Greenberg, P. A., Hortobagyi, G. N., Smith, T. L., Ziegler, L. D., Frye, K. K., and Buzdar, A. U. Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncology, 14: 2197-21205, 1996. 4. Nabholtz, J. M., Senn, H. J., Bezwoda, W. R., Melnychuk, D., Deschenes, L., Douma, J., Vandenberg, T. A., Rapoport, B., Rosso, R., Trillet-Lenoir, V., and al., e. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 Study Group. J Clin Oncology, 17: 1413-1424, 1999. 5. Bishop, J. F., Dewar, J., Toner, G. C., Smith, J., Tattersall, M. H., Olver, I. N., Ackland, S., Kennedy, I., Goldstein, I., H, D. G., and al., e. Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J Clin Oncology, 17: 2355-2364, 1999. 6. Plunkett, W., Huang, P., Xu, Y. Z., Heinemann, V., Grunewald, R., and Gandhi, V. Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Seminars in Oncology., 22: 3-10, 1995. 7. Huang, P., Chubb, S., Hertel, L. W., Grindey, G. B., and Plunkett, W. Action of 2',2'-difluorodeoxycytidine on DNA synthesis. Cancer Research, 51: 6110-6117, 1991. 8. Braakhuis, B. J., Haperen, V. R. v., Welters, M. J., and Peters, G. J. Schedule-dependent therapeutic efficacy of the combination of gemcitabine and cisplatin in head and neck cancer xenografts. Eur J Cancer, 31A: 2335-2340, 1995. 9. Merriman, R. L., Hertel, L. W., Schultz, R. M., Houghton, P. J., Houghton, J. A., Rutherford, P. G., Tanzer, L. R., Boder, G. B., and Grindey, G. B. Comparison of the antitumor activity of gemcitabine and ara-C in a panel of human breast, colon, lung and pancreatic xenograft models. Investigational New Drugs., 14: 243-247, 1996. 10. Lund, B., Kristjansen, P. E., and Hansen, H. H. 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Cusack, J., Jr., Liu, R., Houston, M., Abendroth, K., Elliott, P., Adams, J., and Baldwin, A., Jr. Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Research, 61: 3535-3540, 2001. 44. Patel, N. M., Nozaki, S., Shortle, N. H., Bhat-Nakshatri, P., Newton, T. R., Rice, S., Gelfanov, V., Boswell, S. H., Goulet, R. J., Jr., and Sledge, G. W., Jr. Paclitaxel sensitivity of breast cancer cells with constitutively active NF- kappaB is enhanced by IkappaBalpha super-repressor and parthenolide. Oncogene, 19: 4159-4169, 2000. 45. Jones, D. R., Broad, R. M., Madrid, L. V., Baldwin, A. S., Jr., and Mayo, M. W. Inhibition of NF-kappaB sensitizes non-small cell lung cancer cells to chemotherapy-induced apoptosis. Annals of Thoracic Surgery, 70: 930-936; discussion 936-937, 2000. 46. Jones, D. R., Broad, R. M., Comeau, L. D., Parsons, S. J., and Mayo, M. W. Inhibition of nuclear factor kappaB chemosensitizes non-small cell lung cancer through cytochrome c release and caspase activation. J Thorac Cardiovasc Surg, 123: 310-317, 2002. Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 28 of 32 47. Ross, J. A. and Kasum, C. M. Dietary flavenoids: Bioavailability, metabolic effects, and safety. Annu Rev Nutrition, 22: 19-34, 2002. 48. Alhasan, S. A., Aranha, O., and Sarkar, F. H. Genistein elicits pleiotropic molecular effects on head and neck cancer cells. Clinical Cancer Research., 7: 4174-4181, 2001. 49. Kumi-Diaka, J. and Butler, A. Caspase-3 protease activation during the process of genistein-induced apoptosis in TM4 testicular cells. Biology of the Cell., 92: 115-124, 2000. 50. Salti, G. I., Grewal, S., Mehta, R. R., Das Gupta, T. K., Boddie, A. W., Jr., and Constantinou, A. I. 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Statistics, 14: 113-129, 1987. 15.0 APPENDICES Appendix I: Study Schema Metastatic Breast Cancer any prior chemotherapies for metastatic disease Except Gemcitabine Pretreatment baseline studies Registration Baseline genistein plasma levels Baseline Tumor biopsy (optional) Genistein 100 mg PO BID x 7 days (Day –7 to –1) Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 29 of 32 Day –1 Genistein plasma levels (trough and 4h peak) Tumor biopsy (optional) Cycle 1, Day 1 Gemcitabine 1000 mg/m2 IV days 1 and 8, q 21 days Genistein 100 mg PO BID days 1-21 Repeat cycle q 21 days Cycle 2, Day 1 Genistein plasma trough level Restage for response evaluation every 2 cycles Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, Progressive disease SD, PR, or CR or unacceptable toxicity Off protocol, event monitoring for 60 days (*Day-1 = day before cycle 1 day 1 of Gemcitabine and Genistein) revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 30 of 32 Appendix II: Study Calendar Pre- study Cycle 1 Day-7 (Day 1 of genistein alone) Cycle 1 Day-11 (Day 7 of genistein alone) Cycle 1, Day 1 (gemcitabine and genistein) Cycle N, Day 1 Cycle N, Day 8 and 15 After every 2 cycles History and Physical X2 X X Performance status X2 X X Height and Weight X2 X X CBC, differential and platelets X2 X X X (weekly) Serum Chemistry4 X2 X X Amylase and Lipase X2 X X CXR X3 Bone Scan X3 Tumor site(s) imaging5 X3 X Toxicity assessment X X Genistein plasma level before a.m. dose6 X X X7 Genistein peak plasma level 4 h after a.m. dose6 X X7 Tumor biopsy8 X9 X9 1. Day –1 = day before Cycle 1, Day1 of gemcitabine and genistein 2. Within two weeks of registration. 3. Within four weeks of registration. 4. Serum chemistry: electrolytes, BUN, creatinine, LDH, alk. phosphatase, total bilirubin, AST(SGOT), ALT(SGPT), magnesium, calcium, phosphate and albumin. 5. Radiologic studies to document measurable disease; i.e., CT and/or MRI scans. 6. Collection of 5 ml of plasma and store at –70C, then shipped on dry ice to Translational Lab, 703 HWCRC, KCI, 4100 John R, Detroit, MI 48201; (313) 576-8314, or (313) 576-8315. 7. Cycle 2 only. 8. Optional. Pre-arrange tissue collection > 1 day prior, by calling (313) 576-8314, or (313) 576-8315. Tissue must be immediately placed in RNAlater solution, then kept at 4C or on ice until transported same day, or next-A.M. express shipped at 4°C to Translational Lab, 703 HWCRC, KCI, 4100 John R, Detroit, MI 48201; (313) 576-8314, or (313) 576-8315. 9. Biopsies are prior to first dose of genistein alone (on cycle 1, day-7, or earlier), and then on day 7 of genistein alone (on day-1). Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 31 of 32 Appendix III: Performance Status SWOG Scale Grade Scale 0 Fully active; able to carry on all pre-disease activities without restriction. (Karnofsky 90-100) 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work. (Karnofsky 70-80) 2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. (Karnofsky 50-60) 3 Capable of only limited self-care; confined to bed or chair. Up and about less than 50% of waking hours (Karnofsky 30-40) 4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. (Karnofsky 10-20) 5 Dead Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09 D-2597 Page 32 of 32 APPENDIX IV: NCI-CTEP COMMON TOXICITY CRITERIA (CTC version 3.0) (see Internet Website http://www.ctep.info.nih.gov) Version 12/15/03, revised 2-11-04, revised 1-4-05, revised 2-7-05, revised 2-22-05, revised 3-11-05, revised 7-17-06, revised 10-9-06, revised 06-02-08, revised 01-09-09	1	arm 1: Gemcitabine IV-1000mg/m2: Days 1 \& 8 every 21 days Novasoy Orally-100 mg 2 times/day for 7 days; 2 times/day on Days 1-21 every 21 days.	[ 0 ]	3	[ 7, 0, 3 ]	intervention 1: Novasoy Orally-100 mg 2 times/day for 7 days; 2 times/day on Days 1-21 every 21 days. intervention 2: Gemcitabine IV-1000mg/m2: Days 1 \& 8 every 21 days intervention 3: Biopsy of tumor prior to dose of genistein (Novasoy)	intervention 1: genistein intervention 2: gemcitabine intervention 3: Tumor biopsy	1	Detroit \| Michigan \| United States \| -83.04575 \| 42.33143	19	0	0	0	NCT00244933	1COMPLETED	2009-10-01	2004-02-01	Barbara Ann Karmanos Cancer Institute	7OTHER	true	true	false	https://cdn.clinicaltrials.gov/large-docs/33/NCT00244933/Prot_SAP_000.pdf	0	0	0	0	0	0	0	0	0
[ 5 ]	16	NA	SINGLE_GROUP	0TREATMENT	0NONE	true	0ALL	false	To evaluate the efficacy, safety, and tolerability of combination therapy with intramuscular interferon beta-1a and oral doxycycline, a potent inhibitor of matrix metalloproteinases, in patients with relapsing remitting multiple sclerosis (RRMS) having breakthrough disease activity.	Eligible individuals were evaluated monthly for 3 months while taking intramuscular interferon beta-1a, 30 micrograms weekly, then monthly for 4 months while receiving intramuscular interferon beta-1a, 30 micrograms and oral doxycycline, 100 mg daily.	Multiple Sclerosis		null	1	arm 1: Interferon beta 1a, oral doxycycline	[ 0 ]	1	[ 0 ]	intervention 1: Patients took intramuscular interferon beta 1a, 30 micrograms, for 3 months then added oral doxycycline, 100 daily with the interferon for 4 months.	intervention 1: Interferon beta 1a, oral doxycycline	1	Shreveport \| Louisiana \| United States \| -93.75018 \| 32.52515	16	0	0	0	NCT00246324	1COMPLETED	2009-10-01	2003-12-01	Louisiana State University Health Sciences Center Shreveport	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	833	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	null	The purpose of this study was to compare the safety and efficacy of three immunosuppressive treatment regimens following a kidney transplant.	null	Kidney Transplantation Graft Rejection	Renal transplantation, kidney, and organ transplant Renal transplant rejection	null	3	arm 1: 1.5 mg everolimus (one 0.75-mg tablet bis in diem/twice a day (bid)) + basiliximab + reduced-dose Cyclosporine A (CsA) ± corticosteroids. The CsA dose was adjusted to attain a trough (C0) value within the pre-specified target ranges: starting at the day 5 visit: 100-200 ng/mL, starting at the month 2 visit: 75-150 ng/mL, starting at the month 4 visit: 50-100 ng/mL and starting at the month 6 visit: 25-50 ng/mL. Patients received their first dose of basiliximab within 2 hours prior to transplant surgery and on day 4 post-transplant or according to local practice. Corticosteroids were administered according to local therapy. arm 2: 3.0 mg everolimus (two 0.75-mg tablets bid) + basiliximab + reduced-dose CsA ± corticosteroids. The CsA dose was adjusted to attain a trough (C0) value within the pre-specified target ranges: starting at the day 5 visit: 100-200 ng/mL, starting at the month 2 visit: 75-150 ng/mL, starting at the month 4 visit: 50-100 ng/mL and starting at the month 6 visit: 25-50 ng/mL. Patients received their first dose of basiliximab within 2 hours prior to transplant surgery and on day 4 post-transplant or according to local practice. Corticosteroids were administered according to local therapy. arm 3: 1.44 g Mycophenolic Acid (two 360-mg tablets bid) + basiliximab + standard-dose CsA ± corticosteroids. The CsA dose was adjusted to attain a C0 value within the following range for the time of the study: starting at the day 5 visit: 200-300 ng/mL, starting at the month 2 visit and thereafter: 100-250 ng/mL. Patients received their first dose of basiliximab within 2 hours prior to transplant surgery and on day 4 post-transplant or according to local practice. Corticosteroids were administered according to local therapy.	[ 0, 0, 1 ]	5	[ 0, 0, 0, 0, 0 ]	intervention 1: oral, bis in diem/twice a day (bid) intervention 2: 2 oral capsules of mycophenolic acid 360mg administered bid intervention 3: CsA dose adjustments were based on CsA trough levels (C0). intervention 4: All patients received two 20 mg doses of basiliximab administered intravenously. The first dose was to be given within 2 hours prior to transplant surgery and the second dose was to be administered on day 4, or each dose could have been administered according to local practice. intervention 5: Oral corticosteroids were administered according to local practice during the trial. At the same center, all patients were to follow the same steroid administration protocol.	intervention 1: Everolimus intervention 2: Mycophenolic Acid (MPA) intervention 3: Cyclosporine A (CsA) intervention 4: Basiliximab intervention 5: Corticosteroids	1	East Hanover \| New Jersey \| United States \| -74.36487 \| 40.8201	825	0	0	0	NCT00251004	1COMPLETED	2009-10-01	2005-10-01	Novartis	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	64	RANDOMIZED	PARALLEL	1PREVENTION	3TRIPLE	false	0ALL	true	The purpose of this study is to test whether the drug, atorvastatin, will be able to reduce the rate of return of the abnormal beats after using cardioversion. Atorvastatin is a drug approved by the Food and Drug Administration (FDA) for the treatment of high cholesterol but is not approved for preventing abnormal heartbeats. In addition to lowering cholesterol, the drug reduces inflammation. Inflammation seems to help cause atrial fibrillation, a certain type of abnormal heartbeat. In animals, atorvastatin reduces the risk of this type of abnormal beats, and preliminary data in humans supports an effect of atorvastatin and other similar drugs that have the same action on reducing the risk of this type of abnormal beats. We, the researchers at Emory University, would like to learn if this drug could prevent the return of these abnormal heartbeats.	Atrial fibrillation (AF) and its related disorder, atrial flutter (AFlut), are common abnormal heartbeats. Because they are similar and AFlut is rare compared to AF, they are usually treated similarly and discussed as one disorder. AF is an extremely common arrhythmia affecting more that 5% of the population over 65 years of age. It is an independent risk factor for death. AF is considered a progressive disease increasing in prevalence with age and converting from paroxysmal to permanent within a single individual. The projected lifetime risk of AF is 1 in 4 for men. AF occurs when there is an electrical short circuit in the top parts of the heart (atria). This causes the atria to beat at \>300 times per min in an irregular and ineffective manor. This has two consequences. The blood tends to pool in the atria allowing for clotting. Second, the bottom parts of the heart (ventricles) beat too rapidly in response to impulses arising in the atria. The rapid ventricular contraction without adequate filling time results in a reduced ejection of blood. This can cause heart failure symptoms such as shortness of breath and reduced blood flow to organs resulting in lightheadedness or collapse. One logical therapy to correct the defects arising from AF is return the abnormal heartbeats back to the normal rhythm. This can be done with electrical shock therapy (cardioversion) or by drugs called antiarrhythmic agents. Often, they are used together. While its stands to reason that using these techniques to restore rhythm to normal would be beneficial, clinical trials show that leaving patients in AF and thinning the blood to prevent blood clots is equally efficacious to trying to restore normal beating (sinus rhythm). The common explanations for this are that AF returns rapidly despite antiarrhythmic drugs and that antiarrhythmic drugs can make worse abnormal heart beats, a phenomenon known as proarrhythmia. Based on the lack of efficacy of current therapies and similarities between risk factors for atherosclerosis (hardening of the arteries) and AF, we began to investigate whether oxidative stress, a mechanism similar to inflammation thought to be responsible for atherosclerosis, might be playing a role in causing AF. We studied this in pigs first and found that when we put pigs into AF, they had a large increase in oxidative stress markers. Then, we made a mouse that had too much oxidative stress in the heart, and this mouse developed AF. Based on this and other data in humans, we hypothesized that oxidative stress can cause AF. Atorvastatin is a cholesterol lowering medication that works by blocking production of cholesterol at an early stage. This has the effect of preventing the synthesis of molecules required to assemble the most common enzymatic source of oxidative stress, the NADPH oxidase. Therefore, atorvastatin decreases oxidative stress in addition to reducing cholesterol, and if our hypothesis is correct, atorvastatin should reduce the incidence of AF. In this study we chose to look at patients undergoing cardioversion. This is because this group has a high likelihood of recurrence of AF and would benefit most by an effective drug. Once the decision is made to have the patient undergo cardioversion, we will approach the patient about enrolling in this trial. The only change in their medical therapy will be the addition of the study drug. The study requires no other alterations to the standard of care. If patients agree to participate, then they will be started on the study drug and followed for recurrence of AF by a variety of surface electrocardiogram techniques. All of which are noninvasive. To insure the medicine is not causing side effects, examinations and blood tests will be done, and to study whether the drug actually affects oxidative stress, blood will be analyzed. The subjects participation ends when AF recurs or after 1 year. This will be a double blind, placebo controlled trial and will be analyzed on an intention to treat basis. The risks of this study to the patient are likely to be small compared to the potential benefit of reduced AF burden. Based on a previous trial using the same dose of study medication, the risks of all study drug related adverse events is likely to be \<3%. All of these are expected to be reversible with discontinuation of the drug. The significance of this research is that currently treatments to address AF are less than optimal. Antiarrhythmic drugs are variably effective and are associated with potentially lethal proarrhythmic side effects. The common treatment to prevent strokes in subjects with AF is chronic warfarin administration, but warfarin therapy requires frequent monitoring and adjustment of dose and is associated with bleeding complications. This research may provide the first new therapeutic strategy in many years for AF and the most serious consequence of AF, stroke.	Atrial Fibrillation Inflammation	Reactive Oxgen Speers Atrial Fibrillation Oxidative Stress Inflammation	null	2	arm 1: Placebo taken daily arm 2: Atorvastatin at a dose of 80 mg daily	[ 2, 0 ]	2	[ 0, 0 ]	intervention 1: 80 mg of Atorvastatin intervention 2: None	intervention 1: Atorvastatin intervention 2: Placebo	3	Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749	64	0	0	0	NCT00252967	6TERMINATED	2009-10-01	2005-10-01	Emory University	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 2, 3 ]	60	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	RATIONALE: Drugs used in chemotherapy, such as treosulfan and fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving treosulfan and fludarabine together with a donor bone marrow transplant or a peripheral stem cell transplant may be an effective treatment for acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. PURPOSE: This phase II trial is studying giving treosulfan together with fludarabine to see how well it works in treating patients who are undergoing a donor stem cell transplant for acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.	OBJECTIVES: Primary Phase * Determine the best dose of treosulfan when administered with fludarabine as a reduced-intensity conditioning regimen followed by allogeneic hematopoietic stem cell transplantation, in terms of incidence of severe to fatal toxicity to major organ systems and incidence of graft failure, in patients with acute myeloid leukemia, lymphoblastic leukemia, or myelodysplastic syndrome. Secondary Phase * Determine the safety of this regimen, in terms of incidence of grade II-IV acute and chronic graft-versus-host disease, in these patients. * Determine, preliminarily, the efficacy of this regimen, in terms of incidence of relapse, overall and disease-free survival, donor chimerism on days 28 and 100, and incidence of 200-day and 1-year nonrelapse mortality, in these patients. * Determine the pharmacokinetic and pharmacodynamic profile of treosulfan in patients treated with this regimen. OUTLINE: This is a multicenter, dose-finding study of treosulfan. * Reduced-intensity conditioning: Patients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Cohorts of 5-10 patients receive escalating/de-escalating doses of treosulfan until the best dose is determined among the 3 pre-selected doses. The best dose is defined as the dose preceding that at which 4 of 10 patients experience dose-limiting toxicity. * Allogeneic hematopoietic cell transplantation (AHCT): Patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation on day 0. All male patients with acute lymphoblastic leukemia OR male patients with acute myeloid leukemia who have prior or current testicular involvement receive external-beam radiotherapy to the testicles before AHCT. After completion of study treatment, patents are followed periodically. PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study.	Leukemia Myelodysplastic Syndromes	adult acute lymphoblastic leukemia in remission adult acute myeloid leukemia in remission childhood acute lymphoblastic leukemia in remission recurrent adult acute lymphoblastic leukemia recurrent adult acute myeloid leukemia recurrent childhood acute lymphoblastic leukemia recurrent childhood acute myeloid leukemia secondary acute myeloid leukemia myelodysplastic syndromes childhood myelodysplastic syndromes	null	0	null	null	3	[ 0, 0, 3 ]	intervention 1: 30 mg/m2, IV for 5 days intervention 2: 12 or 14 g/m2, IV for 5 days intervention 3: bone marrow or peripheral blood stem cells	intervention 1: fludarabine intervention 2: treosulfan intervention 3: allogeneic blood or bone marrow transplantation	3	Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Seattle \| Washington \| United States \| -122.33207 \| 47.60621 Seattle \| Washington \| United States \| -122.33207 \| 47.60621	60	0	0	0	NCT00253513	1COMPLETED	2009-10-01	2005-06-01	OHSU Knight Cancer Institute	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	86	RANDOMIZED	PARALLEL	1PREVENTION	3TRIPLE	false	2MALE	true	This is a randomized study evaluating the effectiveness and direct effect a commercial soy supplement has on prostate cancer and normal prostate tissue. Patient will be randomized it either receive placebo or a commercial soy supplement for 2-4 weeks prior to the planned surgery for treatment of their prostate cancer. Patient's blood and prostate tissue will be evaluated to determine the effects of the soy supplement on the prostate tissue.	This is a randomized study evaluating the effectiveness and direct effect a commercial soy supplement has on prostate cancer and normal prostate tissue. Patients will be randomized to either receive placebo or a commercial soy supplement for 2-4 weeks prior to the planned surgery for treatment of their prostate cancer. The specific objectives are: 1. To assess the effect of soy supplementation on endogenous hormone production levels and serum prostate specific antigens. 2. To assess the impact of soy supplementation on estrogen receptor expression(ER). 3. To determine the impact of soy isoflavones on cell cycle regulation and associated gene expression.	Prostate Neoplasm	Estrogen Receptor Isoflavones Prostate Neoplasm Soy Supplementation	null	2	arm 1: Placebo arm 2: Soy Supplement	[ 2, 0 ]	2	[ 0, 0 ]	intervention 1: Soy protein supplement will be taken for 2-4 weeks until surgery to remove the prostate or start of radiation treatment. Patient will receive 4 capsules twice a day (8 capsules) daily to be taken with water or juice (except grapefruit juice). intervention 2: Placebo will consist of a capsule without the soy protein added to be taken for 2-4 weeks until surgery to remove the prostate or start of radiation treatment. Patient will receive 4 capsules twice a day (8 capsules) daily to be taken with water or juice (except grapefruit juice).	intervention 1: Soy Supplement intervention 2: Placebo	1	Kansas City \| Missouri \| United States \| -94.57857 \| 39.09973	86	0	0	0	NCT00255125	1COMPLETED	2009-10-01	2005-09-01	VA Office of Research and Development	1FED	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	75	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	true	Hereditary angioedema ("HAE") is a genetic disorder characterized by sudden recurrent attacks of local swelling (angioedema). These attacks are often painful and disabling, and, in some cases, life-threatening. "HAE" is caused by mutations in the "C1INH" gene that leads to a decrease in the blood level of functional "C1INH". This multi-center study was designed to assess the safety and tolerability, efficacy and pharmacodynamics/ pharmacokinetics of recombinant human C1 inhibitor ("rhC1INH") in the treatment of acute hereditary angioedema attacks.	A prospectively planned interim analysis will be performed on the double-blind data.	Hereditary Angioedema Angioneurotic Edema Genetic Disorders		null	2	arm 1: 100 IU/kg recombinant human C1 inhibitor arm 2: Saline solution	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: IV intervention 2: IV	intervention 1: recombinant human C1 inhibitor intervention 2: Placebo	2	Leiden \| N/A \| Netherlands \| 4.49306 \| 52.15833 Târgu Mureş \| N/A \| Romania \| 24.55747 \| 46.54245	89	0	0	0	NCT00262301	1COMPLETED	2009-10-01	2004-06-01	Pharming Technologies B.V.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	17	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	This phase II study will test the response rate of combined oxaliplatin and capecitabine treatment when administered at a given dose and schedule, in patients with Head and Neck cancer for which there is no curative treatment.	The optimal dose and schedule for the combined treatment with oxaliplatin and capecitabine have not been defined. The aim of this Phase II study is to determine the response rate of combined oxaliplatin and capecitabine treatment at a given dose and schedule in patients with Head and Neck cancer for which there is no curative treatment. The study also aims to determine the qualitative and quantitative toxicity and reversibility of toxicity of the above combination and to evaluate any changes in performance status, quality of life, overall survival and progression-free survival.	Head or Neck Cancer		null	1	arm 1: Treatment with combination of oxaliplatin and capecitabine using study dose and schedule.	[ 0 ]	1	[ 0 ]	intervention 1: Agent, DOSE AND SCHEDULE (28-days cycle): Oxaliplatin 85 mg/m2 IV on days 1 and 15 Capecitabine 1500 mg PO BID on days 1-7 and 15-21	intervention 1: Oxaliplatin, Capecitabine	1	Louisville \| Kentucky \| United States \| -85.75941 \| 38.25424	15	0	0	0	NCT00266279	1COMPLETED	2009-10-01	2005-04-01	University of Louisville	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	402	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	The main objective of this study is to compare three strategies of evening insulin glargine dosing to preoperative glucose values in patients with diabetes undergoing surgery to determine which dosing strategies most often achieves the admission target study values of 100-179 mg/dl.	There are no evidence-based guidelines for insulin glargine (Lantus) dosing in the perioperative setting. Insulin glargine provides peakless 24-hour coverage of basal insulin needs for people with both Type 1 and Type 2 diabetes. Insulin glargine may be used as the sole insulin or in combination with other rapid-acting insulin to achieve glycemic control. Anesthesia literature recommends that blood sugar values on insulin-dependent patients be maintained between 120-180 mg/dl in most surgeries. Symptoms of low blood sugar are undetectable in anesthetized patients, and blood glucose is tested at least hourly. Since patients are still awake and alert toward hypoglycemic symptoms in the preoperative area, the admission target study values are 100-179 mg/dl. Glucose values greater than 200 mg/dl have been associated with increased rates of infection, and exacerbated complications if a major cardiovascular event happens. Frequently insulin glargine is administered in the evening. Patients who are scheduled for surgery in the morning are asked not to eat or drink after midnight. Some endocrinology experts recommend that all or part of the patient's usual insulin glargine should be given to avoid high blood sugar; however, whenever insulin is given without food, the possibility of low blood sugar exists. 1. Patients in Group 1 will administer 80% of their usual insulin glargine dose. 2. Group 2 patients will contact their own diabetes care physician and follow those recommendations for the dose. 3. Group 3 patients will take 50%, 80%, or 100% of their usual insulin glargine dose. Which of those three percentages will be determined by the midpoint of the patient's usual self-reported fasting blood sugar (FBS) range and whether the patients is also taking a rapid-acting insulin.	Diabetes Surgery	Diabetes Insulin Glargine Surgery	null	3	arm 1: Patients in Group 1 will administer 80% of their usual insulin glargine dose. arm 2: Group 2 patients will contact their own diabetes care physician and follow those recommendations for the dose. arm 3: Group 3 patients will take 50%, 80%, or 100% of their usual insulin glargine dose. Which of those three percentages will be determined by the midpoint of the patient's usual self-reported fasting blood sugar (FBS) range and whether the patients is also taking a rapid-acting insulin.	[ 0, 1, 0 ]	3	[ 0, 10, 0 ]	intervention 1: Patients in Group 1 will administer 80% of their usual insulin glargine dose. intervention 2: Group 2 patients will contact their own diabetes care physician and follow those recommendations for the dose intervention 3: Group 3 patients will take 50%, 80%, or 100% of their usual insulin glargine dose. Which of those three percentages will be determined by the midpoint of the patient's usual self-reported fasting blood sugar (FBS) range and whether the patients is also taking a rapid-acting insulin.	intervention 1: Lantus intervention 2: Insulin intervention 3: Lantus	2	Royal Oak \| Michigan \| United States \| -83.14465 \| 42.48948 Troy \| Michigan \| United States \| -83.14993 \| 42.60559	401	0	0	0	NCT00309465	1COMPLETED	2009-10-01	2005-10-01	Tamra Dukatz	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3, 4 ]	58	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	1FEMALE	true	This study was designed to characterize the effect of aflibercept in participants with advanced chemoresistant ovarian cancer. Primary objective: Compare the effect of aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®) to placebo treatment on repeat paracentesis in symptomatic malignant ascites in participants with advanced ovarian cancer Secondary objectives: Safety, tolerability, paracentesis-related parameters, participant-reported outcome.	The study included: * A Thirty (30)-day screening phase * The double blind treatment period for a minimum of 60 days. Day 1 of the double-blind treatment period was defined as the date of the qualifying paracentesis (ie, withdrawal of \>= 1 Liter of ascitic fluid). Participants were randomized after adequate recovery from the qualifying paracentesis (The first dose was administered on Day 1 or Day 2). * The optional open-label extension (until treatment discontinuation criteria were met) * A posttreatment follow-up phase lasting 60 days. Criteria for discontinuation included: 1. Participant or his legally authorized representative request discontinuation 2. In the Investigator's opinion, continuation of treatment would be detrimental to the participant's well being, such as disease progression, unacceptable toxicity, noncompliance, or logistical considerations 3. Sponsor request 4. Intercurrent illness that prevented further administration of investigational product(IP) 5. More than 2 IP dose reductions 6. Unacceptable adverse events (AE) not manageable by symptomatic therapy, dose delay, or dose modification 7. Arterial thromboembolic events, including cerebrovascular accidents, myocardial infarctions, transient ischemic attacks, new onset or worsening of preexisting angina 8. Radiographic evidence of intestinal obstruction (for example, dilated loops of bowel accompanied by air-fluid levels) or gastrointestinal perforation (for example, presence of extraluminal gas) requiring surgical intervention	Ovarian Neoplasms Ascites	Ovarian neoplasm Ascites Angiogenesis inhibitor Vascular Endothelial Growth Factor A Recombinant fusion protein	null	2	arm 1: Participants with advanced ovarian cancer administered placebo in the double-blind (DB) period. In the open-label (OL) period, participants had the option to receive aflibercept or be withdrawn from the study. arm 2: Participants with advanced ovarian cancer administered aflibercept in the double-blind (DB) period. In the open-label (OL) period, participants had the option to continue to receive aflibercept or be withdrawn from the study.	[ 2, 0 ]	3	[ 0, 0, 0 ]	intervention 1: 4.0 mg/kg aflibercept was administered intravenously (IV) over 1 hour once every 2 weeks in the DB period. intervention 2: Placebo was administered intravenously (IV) over 1 hour once every 2 weeks in the DB period. intervention 3: 4.0 mg/kg aflibercept was administered intravenously (IV) over 1 hour once every 2 weeks in the OL period.	intervention 1: aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®) intervention 2: Placebo intervention 3: aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)	9	Bridgewater \| New Jersey \| United States \| -74.64815 \| 40.60079 Vienna \| N/A \| Austria \| 16.37208 \| 48.20849 Diegem \| N/A \| Belgium \| 4.43354 \| 50.89727 Laval \| N/A \| Canada \| -73.692 \| 45.56995 Budapest \| N/A \| Hungary \| 19.04045 \| 47.49835 Mumbai \| N/A \| India \| 72.88261 \| 19.07283 Netanya \| N/A \| Israel \| 34.85992 \| 32.33291 Barcelona \| N/A \| Spain \| 2.15899 \| 41.38879 Guildford Surrey \| N/A \| United Kingdom \| N/A \| N/A	55	0	0	0	NCT00327444	1COMPLETED	2009-10-01	2006-07-01	Sanofi	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	1,004	RANDOMIZED	PARALLEL	0TREATMENT	1SINGLE	false	0ALL	true	This study will compare the effectiveness of an intervention strategy for the treatment of people with post traumatic stress disorder, generalized anxiety disorder, panic disorder, and social anxiety disorder in the primary care setting.	Anxiety disorders are highly prevalent, distressing, and disabling. Most patients with anxiety disorders who do receive mental health treatment receive it in primary care settings, where the quality of care is generally insufficient. This intervention is geared towards testing the clinical effectiveness of a care-manager assisted chronic disease management program for four common anxiety disorders (post-traumatic stress disorder, generalized anxiety disorder, panic disorder, and social anxiety disorder) in the primary care setting. This approach has been shown to be effective for the treatment of depression. Participants in this randomized, controlled trial will either be assigned to the control group: treatment-as-usual (TAU) from their primary care provider (PCP); or to the intervention group: CALM (Coordinated Anxiety Learning and Management). Intervention subjects will choose to receive CBT, medication, or both for the treatment of their anxiety. Those who choose CBT will receive it from a study-trained Anxiety Clinical Specialist (ACS) in their respective clinic. For those who choose medication, the ACS will facilitate the delivery of, and adherence to, anti-anxiety medication which will be prescribed by the participant's PCP. In this stepped-care design, subject progress will be formally re-evaluated at 8-12 week intervals. If treatment progress is not satisfactory, options include: additional or modified treatment with current modality, switching to the other treatment modality, or adding the other modality. When remission is attained, the ACS will follow-up with participants on a monthly basis to review progress and practice anxiety-reduction strategies. Treatment will continue for up to 12 months. Participants in both study arms will undergo formal baseline and outcome assessment interviews conducted at the 6, 12, and 18 month follow-up time-points.	Post-traumatic Stress Disorder Generalized Anxiety Disorder Panic Disorder Social Anxiety Disorder	Anxiety Disorders Post-traumatic Stress Disorder Generalized Anxiety Disorder Panic Disorder Social Anxiety Disorder Stress Stress Disorders, Traumatic Stress Disorders, Post-Traumatic Mental Health Disorders	null	2	arm 1: Participant choice of: Cognitive Behavioral Therapy (CBT) Psychotropic (anti-anxiety) medication optimization arm 2: Participants assigned to TAU with their primary care provider (PCP)	[ 0, 1 ]	3	[ 5, 0, 5 ]	intervention 1: Participants in CALM will choose to receive CBT, medication, or both for the treatment of their anxiety. CBT includes computer-assisted CBT with an anxiety clinical specialist. intervention 2: For those participants in CALM who choose medication, the ACS will facilitate the delivery of, and adherence to, anti-anxiety medication which will be prescribed by the participants' PCP. intervention 3: Participants in the control group will receive standard treatment from their PCP.	intervention 1: Cognitive-behavioral therapy intervention 2: Psychotropic medication optimization intervention 3: Treatment as Usual	4	Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 La Jolla \| California \| United States \| -117.2742 \| 32.84727 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Seattle \| Washington \| United States \| -122.33207 \| 47.60621	1,004	0	0	0	NCT00347269	1COMPLETED	2009-10-01	2006-06-01	University of Washington	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	10	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	RATIONALE: Giving chemotherapy drugs, such as busulfan, melphalan, and thiotepa, before a donor stem cell transplant helps stop the growth of tumor cells and prepares the patient's bone marrow for the stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal tissues. Giving tacrolimus, sirolimus, and mycophenolate mofetil may stop this from happening. PURPOSE: This phase II trial is studying how well giving busulfan together with melphalan and thiotepa followed by a donor stem cell transplant works in treating patients with high-risk Ewing's tumors.	OBJECTIVES: * Evaluate disease-free and overall survival of patients with high-risk tumors of the Ewing's family treated with unmodified T-cell depleted allogeneic hematopoietic stem cell transplantation after cytoreduction comprising busulfan, melphalan, and thiotepa. * Determine the regimen-related morbidity and mortality in these patients. * Determine the incidence of acute and chronic graft-vs-host disease in patients treated with this regimen. * Determine the biologic response of minimal residual disease in patients treated with this regimen. OUTLINE: This is a prospective study. * Myeloablative preparative regimen: Patients receive busulfan IV over 2 hours every 6 hours on days -8 to -6, melphalan IV over 20 minutes on days -5 to -3, and thiotepa IV over 4 hours on day -2. * Allogeneic hematopoietic stem cell transplant: Patients undergo allogeneic bone marrow or T-cell depleted peripheral blood stem cell transplantation on day 0. * Graft-vs-host disease (GVHD) prophylaxis: Patients receive treatment according to institutional guidelines and are given treatment against infection. After completion of study treatment, patients are followed periodically for at least 3 years.	Sarcoma	metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor	null	1	arm 1: * Myeloablative preparative regimen: Patients receive busulfan IV over 2 hours every 6 hours on days -8 to -6, melphalan IV over 20 minutes on days -5 to -3, and thiotepa IV over 4 hours on day -2. * Allogeneic hematopoietic stem cell transplant: Patients undergo allogeneic bone marrow or T-cell depleted peripheral blood stem cell transplantation on day 0. * Graft-vs-host disease (GVHD) prophylaxis: Patients receive treatment according to institutional guidelines and are given treatment against infection. After completion of study treatment, patients are followed periodically for at least 3 years.	[ 0 ]	7	[ 2, 0, 0, 0, 3, 3, 3 ]	intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None	intervention 1: graft versus host disease prophylaxis/therapy intervention 2: busulfan intervention 3: melphalan intervention 4: thiotepa intervention 5: allogeneic bone marrow transplantation intervention 6: allogeneic hematopoietic stem cell transplantation intervention 7: peripheral blood stem cell transplantation	1	New York \| New York \| United States \| -74.00597 \| 40.71427	10	0	0	0	NCT00357396	1COMPLETED	2009-10-01	2005-06-01	Memorial Sloan Kettering Cancer Center	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	32	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	true	Gaucher disease, the most prevalent lysosomal storage disorder, is caused by mutations in the human glucocerebrosidase gene (GCD) leading to reduced activity of the lysosomal enzyme glucocerebrosidase and thereby to the accumulation of substrate glucocerebroside (GlcCer) in the cells of the monocyte-macrophage system. This is the second trial to utilize a recombinant active form of lysosomal enzyme, glucocerebrosidase, (human prGCD) which is expressed and purified in a bioreactor system from transformed carrot plant root cell line.	This will be a multi-center, randomized, double-blind, parallel group, dose-ranging trial to assess the safety and efficacy of prGCD in 30 untreated patients with Gaucher disease. Patients will receive IV infusion of prGCD every two weeks at the selected medical center. The duration of the study will be nine months. At the end of the 9-month treatment period (20 visits, 38 weeks) eligible patients will be offered enrollment in an open-label extension study. There will be two treatment groups, 15 patients in each treatment group. Treatment Group I: 30 units/kg every 2 weeks. Treatment Group II: 60 units/kg every 2 weeks. All patients will have pharmacokinetic data collected over approximately 3 hours with frequent blood samples following the first and final doses of prGCD.	Gaucher Disease		null	2	arm 1: None arm 2: None	[ 0, 0 ]	2	[ 0, 0 ]	intervention 1: Intravenous infusion every two weeks for 9 months intervention 2: Intravenous infusion every 2 weeks for 9 months	intervention 1: Plant cell expressed recombinant glucocerebrosidase (prGCD) intervention 2: Plant cell expressed recombinant glucocerebrosidase (prGCD)	11	Coral Springs \| Florida \| United States \| -80.2706 \| 26.27119 Decatur \| Georgia \| United States \| -84.29631 \| 33.77483 New York \| New York \| United States \| -74.00597 \| 40.71427 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Santiago \| N/A \| Chile \| -70.64827 \| -33.45694 Haifa \| N/A \| Israel \| 34.99928 \| 32.81303 Jerusalem \| N/A \| Israel \| 35.21633 \| 31.76904 Rome \| N/A \| Italy \| 12.51133 \| 41.89193 Morningside \| N/A \| South Africa \| 31.01736 \| -29.82021 Zaragoza \| N/A \| Spain \| -0.87734 \| 41.65606 London \| N/A \| United Kingdom \| -0.12574 \| 51.50853	32	0	0	0	NCT00376168	1COMPLETED	2009-10-01	2007-08-01	Pfizer	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	64	RANDOMIZED	FACTORIAL	0TREATMENT	4QUADRUPLE	false	0ALL	true	The purpose of this study is to determine whether aspirin and simvastatin are safe and effective for the treatment of pulmonary arterial hypertension (PAH).	PAH is characterized by dyspnea, fatigue, and lower extremity edema as a result of heart failure. In PAH, in situ thrombosis may occur in the lungs, and pulmonary endothelial dysfunction is well-recognized. As aspirin inhibits platelet aggregation, there may be value in using aspirin to treat PAH. Simvastatin has beneficial effects on blood vessels in other types of cardiovascular disease. Therefore, simvastatin may similarly benefit patients with PAH. Participants in this study will be randomly assigned to receive 6 months of daily placebo tablets, daily aspirin and daily placebo, daily simvastatin and daily placebo, or daily aspirin and daily simvastatin in a double-blind fashion. The study will compare the safety and efficacy of aspirin to placebo and simvastatin to placebo.	Hypertension, Pulmonary	Pulmonary Arterial Hypertension	null	4	arm 1: Simvastatin: Simvastatin 40 mg, taken orally, once a day for 6 months Aspirin: Aspirin 81 mg, taken orally, once a day for 6 months arm 2: Aspirin: Aspirin 81 mg, taken orally, once a day for 6 months Placebo taken orally, once a day for 6 months arm 3: Placebo taken orally, once a day for 6 months Simvastatin: Simvastatin 40 mg, taken orally, once a day for 6 months arm 4: Placebo taken orally, once a day for 6 months Placebo taken orally, once a day for 6 months	[ 1, 1, 1, 2 ]	3	[ 0, 0, 0 ]	intervention 1: Simvastatin 40 mg, taken orally, once a day for 6 months intervention 2: Aspirin 81 mg, taken orally, once a day for 6 months intervention 3: Placebo, taken orally, once a day for 6 months	intervention 1: Simvastatin intervention 2: Aspirin intervention 3: Placebo	4	Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 New York \| New York \| United States \| -74.00597 \| 40.71427 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238	130	0	0	0	NCT00384865	6TERMINATED	2009-10-01	2006-09-01	University of Pennsylvania	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	46	NON_RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	true	This study investigates the safety and tolerability as well as the efficacy and pharmacokinetics of caspofungin in four escalating dosages in adult patients with hematologic malignancies and proven or probable invasive aspergillosis.	Due to its efficacy and a broad antifungal spectrum against relevant fungal pathogens, lack of cross-resistance to azoles and amphotericin B, documented efficacy against human Aspergillus infections, favorable pharmacokinetic properties, and excellent tolerability according to the current data, caspofungin is a highly promising candidate for improving the results of treatment of invasive fungal infections. Preclinical and clinical data indicate a dose dependent antifungal efficacy of caspofungin as well as of other echinocandins such as micafungin and anidulafungin. Thus it appears reasonable to investigate the impact of higher doses of caspofungin to improve the results already achieved with this component so far. The maximum tolerated dose (MTD) of caspofungin and the distribution of the drug in patients following administration of doses of 70 mg or more are not yet known. We therefore investigate the safety, tolerability and pharmacokinetics of caspofungin in rising doses in a dose escalation study in adult patients with proven or probable invasive aspergillosis.	Invasive Aspergillosis	aspergillosis caspofungin maximum tolerated dose	null	4	arm 1: 70mg caspofungin 1x/day arm 2: 100mg caspofungin 1x/day arm 3: 150mg caspofungin 1x/day arm 4: 200mg caspofungin 1x/day	[ 0, 0, 0, 0 ]	1	[ 0 ]	intervention 1: i.v.	intervention 1: caspofungin	4	Leuven \| N/A \| Belgium \| 4.70093 \| 50.87959 Berlin \| N/A \| Germany \| 13.41053 \| 52.52437 Cologne \| N/A \| Germany \| 6.95 \| 50.93333 Münster \| N/A \| Germany \| 7.62571 \| 51.96236	46	0	0	0	NCT00404092	1COMPLETED	2009-10-01	2006-10-01	University of Cologne	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	5	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	1FEMALE	true	The primary objective is to determine whether the addition of bevacizumab to a regimen of carboplatin plus paclitaxel significantly improves Progression Free Survival (PFS) for patient with Stage III suboptimally cytoreduced or Stage IV ovarian, primary peritoneal or fallopian tube carcinomas.	The aim of this study is to determine if the addition of bevacizumab to a regimen of carboplatin/paclitaxel increases the time to disease recurrence (longer remission for patients) in women that have Stage III suboptimally reduced or Stage IV ovarian cancer. The hypothesis is that the addition of bevacizumab to a carboplatin/paclitaxel regimen will increase progression free survival in subjects that have Stage III suboptimal cytoreduced or Stage IV ovarian cancer. Scientific Background and Significance: Vascular endothelial growth factor (VEGF) is found in most tissues, and is known to regulate angiogenesis in both normal (e.g. ovulation) and abnormal (e.g. malignant tumors) conditions. VEGF has been found to be overexpressed in several tumor types, including breast, bladder, uterine, cervical, and relevant to this application, primary and metastatic tumors of patients with advanced ovarian cancer. It is widely believed that the overexpression of this factor contributes to tumorigenesis by supplying a conduit through which oxygen and nutrients can reach and feed the growing malignancy. Treatment with an anti-VEGF antibody may help to exert a direct anti-angiogenic effect by binding to and clearing VEGF from the tumor microenvironment, thus preventing the formation of new blood vessels. Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody that inhibits the growth of a number of human cancers, including ovarian cancer. Additional antitumor activity may be obtained through the effects of bevacizumab on tumor vasculature, interstitial pressure, and blood vessel permeability, all of which could allow for enhanced delivery of concurrently administered chemotherapeutic agents to tumor cells. Based on preliminary data (Proc Am Soc Clin Oncol 2005; 23:A5000 and A 5009), there is biologic rationale to use bevacizumab in the treatment of advanced ovarian cancer. These 2 preliminary studies reported an improved progression-free survival in patients with recurrent ovarian cancer with the use of bevacizumab in combination with chemotherapy. Based on this activity in the recurrent setting, the activity of bevacizumab needs to be evaluated in chemotherapy-naïve patients with advanced ovarian cancer. The purpose of this clinical trial is to determine whether the addition of bevacizumab to a regimen of carboplatin and paclitaxel significantly improves Progression Free Survival (PFS) in patients with Stage III suboptimally cytoreduced or Stage IV ovarian, primary peritoneal or fallopian tube carcinomas. It is apparent that newer innovative therapies are needed in the front line setting to decrease recurrences and improve survival. The addition of bevacizumab, the anti-vascular endothelial growth factor antibody, to the standard carboplatin/taxol treatment paradigm might help to increase the long-term survival rates in patients newly diagnosed with advanced suboptimal ovarian cancer. The proposed study addresses this issue. The investigational plan that will be utilized to test the hypothesis that the addition of bevacizumab extends the survival time of the affected patients is outlined below. Women with Stage III or IV ovarian cancer/primary peritoneal cancer/fallopian tube cancer that have undergone surgery with residual suboptimally cytoreduced disease (suboptimal defined as \>1cm disease) will be eligible for treatment with one 21-day cycle of carboplatin and paclitaxel and five 21-day cycles of bevacizumab, carboplatin and paclitaxel for a total of six treatment cycles; bevacizumab treatment is delayed by one cycle to ensure adequate post-surgical healing. Subjects will be evaluated by CT scans to determine response to therapy; individuals that progress will be withdrawn from the study. The CT scan conducted after the completion of therapy will dictate the next course of action. Patients demonstrating a complete response will be maintained on bevacizumab as consolidation therapy; subjects demonstrating a partial response will continue to receive bevacizumab, carboplatin and paclitaxel. The total treatment time for patients with a clinical response following the initial 6 cycles of therapy will be 12 months. Prior to starting consolidation therapy, all patients with a complete clinical response or in those for whom surgery may result in a complete secondary cytoreduction, will be given the option of undergoing a second look surgery. The findings at surgery in combination with the CT scan will determine the response to initial therapy. The decision not to participate in the second look surgery will not affect the follow-up treatment that the patient will receive.	Ovarian Cancer Peritoneal Cancer Fallopian Tube Cancer Stage 3 Cancer Stage 4 Cancer	ovarian cancer fallopian tube cancer peritoneal cancer	null	1	arm 1: This is a single Arm study. Two of the study drugs used are non-experimental. One of the study drugs is experimental.	[ 0 ]	3	[ 0, 0, 0 ]	intervention 1: cycle 2 (6 cycles re-evaluated and follow up) intervention 2: cycle #1 and continuous through entire regimen; treated every 3 weeks intervention 3: cycle #1 and continuous through entire regimen; treated every 3 weeks	intervention 1: Bevacizumab intervention 2: Carboplatin intervention 3: Paclitaxel	1	Farmington \| Connecticut \| United States \| -72.83204 \| 41.71982	5	0	0	0	NCT00408070	6TERMINATED	2009-10-01	2006-10-01	UConn Health	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	78	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	Objectives: 1.1 To determine the efficacy, as measured by 6 month progression-free survival, of therapy with thalidomide combined with CPT-11 in the treatment of patients with recurrent and/or progressive malignant gliomas. 1.2 To determine the rate of measureable clinical response in patients treated with Thalidomide and CPT-11. 1.3 To determine Thrombotic thrombocytopenic purpura (TTP), overall survival and unexpected toxicity of Thalidomide and CPT-11 used in recurrent malignant gliomas. 1.4 To determine changes in dynamic magnetic resonance imaging (MRI) as a surrogate marker for treatment effect.	Thalidomide is a drug that interferes with the growth of blood vessels. Thalidomide may help to decrease the blood supply in the tumor and make it unable to grow. CPT-11 is a drug that was designed to stop cancer cells from dividing. All participants will take thalidomide capsules by mouth every evening at bedtime. You will begin with 1 capsule every night for the first week then increase to 2 capsules every night for a week and then 3 capsules a night for the third week. After that, you will increase the dose to 4 capsules each night for the rest of the study. The dosages may be adjusted if you experience any severe side effects. In addition to thalidomide, you will receive treatment with CPT-11 through a continuous injection into a vein over 90 minutes once a week for 4 weeks followed by 2 weeks of rest from the drug. This 6 week period is called a course of therapy. The courses of therapy will be repeated as long as the disease is responding to treatment for up to 2 years. THIS IS AN INVESTIGATIONAL STUDY. Both drugs are commercially available. Thalidomide and CPT-11 are FDA approved for the treatment of some cancers. The combination of these drugs is investigational. Up to 78 participants will take part in this study. All will be enrolled at M. D. Anderson.	Glioblastoma Multiforme Glioma	Glioblastoma Multiforme Glioma Thalidomide Thalomid CPT-11 Irinotecan malignant glioma	null	1	arm 1: Oral Thalidomide 100 mg daily for 8 weeks + CPT-11 125 mg/m\^2 by vein weekly over 90 minutes for 4 weeks, followed by 2 weeks rest.	[ 0 ]	4	[ 0, 0, 3, 3 ]	intervention 1: 100 mg PO (by mouth) daily for 8 weeks intervention 2: 125 mg/m\^2 by vein weekly over 90 minutes for 4 weeks, followed by 2 weeks rest intervention 3: Dynamic MRI scan with dye injection through vein, every 6 weeks intervention 4: QST, every 12 weeks, to check for any nerve problems that may be present before starting treatment; by touching a small machine tests are done on feeling of touch, vibration, and temperature.	intervention 1: Thalidomide intervention 2: CPT-11 intervention 3: MRI Scan intervention 4: Quantitative Sensory Tests (QST)	1	Houston \| Texas \| United States \| -95.36327 \| 29.76328	75	0	0	0	NCT00412542	1COMPLETED	2009-10-01	2003-10-01	M.D. Anderson Cancer Center	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	120	RANDOMIZED	PARALLEL	1PREVENTION	0NONE	false	0ALL	true	The goal of this clinical research study is to compare the effectiveness of liposomal amphotericin B given three times per week , versus liposomal amphotericin B given once per week, versus oral voriconazole in the prevention of fungal infections in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes MDS who are receiving chemotherapy. The safety of these treatments will also be studied and compared.	Ambisome and voriconazole are drugs that have been used to fight fungal infections, which typically occur during chemotherapy as a result of lowered immune system functioning. Ambisome works by binding to the sterol component of the fungal cell membrane. This causes "holes" to appear in the membrane, which leads to death of the fungal cell. Voriconazole inhibits an essential step of the biosynthesis of an important component of the fungal cell wall (ergosterol). This causes the impairment of the fungal cell wall. Before you can start treatment on this study, you will have "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. You will be asked questions about your medical history. You will have a complete physical exam and a chest x-ray. You will have computed tomography (CT) scans of the chest. You will also have about 1 teaspoon of blood drawn for routine tests. Test results from the pregnancy test that you will have before your leukemia treatment will be looked at for this study. You will not have a pregnancy test performed for this study. If you are found to be eligible to take part in this study, you will be randomly assigned (as in the roll of dice) to one of 3 treatment groups (Group 1, Group 2, or Group 3). Participants in Groups 1 and 2 will receive treatment with ambisome. Participants in Group 3 will receive treatment with voriconazole. Participants in all 3 groups will begin treatment 24 hours after the last dose of chemotherapy. If you are assigned to Group 1, you will receive ambisome by vein as a continuous infusion over 2 hours 1 time per day, 3 times each week. If you are assigned to Group 2, you will receive ambisome by vein as a continuous infusion over 2 hours 1 time per week. If you are assigned to Group 3, you will take 2 pills by mouth (1 hour after breakfast) and 2 pills by mouth (1 hour after dinner) for 1 day, which amounts to 4 pills in total on Day 1. You will then take 1 pill by mouth (1 hour after breakfast) and 1 pill by mouth (1 hour after dinner) everyday for the remainder of this study, which amounts to 2 pills in total each day. You will have about 1 teaspoon of blood drawn for routine tests 2 times each week. You will also receive treatment with standard of care medications. These medications (which will be specified by your doctor) will be used to help decrease the risk of developing bacterial infections and viral infections. If you develop a fever during treatment on this study, you will have a chest x-ray and a CT scan of the chest within 3 days after the fever started. You may remain on this study for up to 35 days (if you are receiving chemotherapy for the first time) and up to 42 days (if you have had prior chemotherapy). Your participation may end on this study if your study doctor thinks it is necessary, if other antifungal therapy is required, or if you develop any intolerable side effects.	Acute Myelogenous Leukemia Myelodysplastic Syndrome	Voriconazole Vfend Liposomal amphotericin B Ambisome Acute Myelogenous Leukemia Myelodysplastic Syndrome AML MDS	null	3	arm 1: 3 mg/kg intravenously (IV) three times per week arm 2: 9 mg/kg IV once per week arm 3: 400 mg oral twice daily day 1 followed by 200 mg twice daily	[ 0, 0, 0 ]	3	[ 0, 0, 0 ]	intervention 1: 400 mg by mouth twice daily on day 1, followed by 200 mg by mouth twice daily intervention 2: 3 mg/kg intravenously three times per week over 2 hours +/- 15 minutes intervention 3: 9 mg/kg intravenously once per week over 2 hours +/- 15 minutes	intervention 1: Voriconazole intervention 2: Liposomal amphotericin B intervention 3: Liposomal amphotericin B	1	Houston \| Texas \| United States \| -95.36327 \| 29.76328	112	0	0	0	NCT00418951	1COMPLETED	2009-10-01	2006-11-01	M.D. Anderson Cancer Center	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	56	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	This is a Phase IIIB randomized, controlled, multi-centre, open-label study of 24 versus 48 weeks therapy with Pegetron® (peginterferon alfa-2b + ribavirin) at standard doses in naïve Hepatitis C Virus (HCV) genotype 1 high viral load (HVL) participants who are Hepatitis C Virus-Ribonucleic Acid (HCV-RNA) negative at Week 4. HVL will be defined as HCV-RNA of \>600,000 IU/mL prior to the initiation of therapy. Participants with genotype 1 baseline HVL prescribed Pegetron® (peginterferon and ribavirin) in the usual manner in accordance with the marketing authorization and who are viral negative at Week 4 will be randomized at Week 8 to receive a total of 24 or 48 weeks of therapy. Participants will be required to have their baseline and Week-12 viral load analyzed by the same local laboratory using the standard of care test used by the site. Qualitative testing at Week 4, 8, 16-20, 24, and 48 may be conducted either by local laboratory or a central laboratory identified by the sponsor using an assay specified by the sponsor. No additional interventions outside of the clinic's standard of care and the conditions of the Canadian product monograph for Pegetron® will be applied to participants.	null	Hepatitis C, Chronic		null	2	arm 1: Participants are treated with Pegetron® (pegylated interferon alfa-2b and ribavirin) for 8 weeks and then randomized to an additional 16 weeks of treatment arm 2: Participants are treated with Pegetron® (pegylated interferon alfa-2b and ribavirin) for 8 weeks and then randomized to an additional 40 weeks of treatment.	[ 0, 1 ]	1	[ 0 ]	intervention 1: 1. Powder for Solution in Redipen® (pegylated interferon alfa-2b) (80, 100, 120, and 150 microgram strengths), subcutaneous, dose of 1.5 micrograms/kg, weekly for up to 24 or 48 weeks 2. 200 mg ribavirin capsules, oral, weight-based dose of 800, 1000, or 1200 mg, daily for up to 24 or 48 weeks	intervention 1: Combination of pegylated interferon alfa-2b (PEG) and ribavirin (RBV)	0	null	7	0	0	0	NCT00423800	6TERMINATED	2009-10-01	2006-12-01	Merck Sharp & Dohme LLC	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	274	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	null	The 12-week core study was designed to evaluate risk-benefit of three subcutaneous dose regimens of ACZ885, added on to stable methotrexate (MTX) therapy (greater than or equal to 7.5 mg/week), compared to placebo in patients with active rheumatoid arthritis (RA). The study investigated the magnitude of effect as well as onset of effect for the different dose regimens. The primary objective of the extension studies was to assess long-term safety and tolerability of canakinumab (ACZ885) in patients with active RA. CACZ885A2201E1 evaluated this objective in patients who had participated in the core study (CACZ885A2201) and CACZ885A2201E2 did the same in patients who completed the first extension study.	null	Rheumatoid Arthritis	Active Rheumatoid Arthritis anti-interleukin-1beta monoclonal antibody methotrexate	null	4	arm 1: Participants received canakinumab 600 mg intravenous (IV) loading dose on Day 1 and 300 mg subcutaneous injections every 2 weeks (q2wk) for 12 weeks in the Core Phase. In the Extension Phase, participants received 300 mg canakinumab every 4 weeks subcutaneously, until a protocol amendment in January 2009 decreased the dose to 150 mg every 4 weeks. arm 2: Participants received canakinumab 300 mg subcutaneous injections every 2 weeks (q2wk) for 12 weeks in the Core Phase. In the Extension Phase, participants received 300 mg canakinumab every 4 weeks subcutaneously, until a protocol amendment in January 2009 decreased the dose to 150 mg subcutaneous injection every 4 weeks. arm 3: Participants received canakinumab 150 mg subcutaneous injections every 4 weeks (q4wk) for 12 weeks in the Core Phase. In the Extension Phase, participants received 300 mg canakinumab every 4 weeks subcutaneously, until a protocol amendment in January 2009 decreased the dose to 150 mg subcutaneous injection every 4 weeks. arm 4: Participants received placebo subcutaneous injections every 2 weeks for 12 weeks in the Core Phase. In the Extension Phase, participants received 300 mg canakinumab every 4 weeks subcutaneously, until a protocol amendment in January 2009 decreased the dose to 150 mg subcutaneous injection every 4 weeks.	[ 0, 0, 0, 2 ]	2	[ 0, 0 ]	intervention 1: None intervention 2: None	intervention 1: Canakinumab intervention 2: Placebo	17	Anniston \| Alabama \| United States \| -85.83163 \| 33.65983 Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Peoria \| Arizona \| United States \| -112.23738 \| 33.5806 Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 Palm Harbor \| Florida \| United States \| -82.76371 \| 28.07807 Palm Harbor \| Florida \| United States \| -82.76371 \| 28.07807 Springfield \| Illinois \| United States \| -89.64371 \| 39.80172 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Albany \| New York \| United States \| -73.75623 \| 42.65258 Rochester \| New York \| United States \| -77.61556 \| 43.15478 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Tacoma \| Washington \| United States \| -122.44429 \| 47.25288 Vienna \| N/A \| Austria \| 16.37208 \| 48.20849 Vilvoorde \| N/A \| Belgium \| 4.42938 \| 50.92814 Dorval \| Quebec \| Canada \| -73.75335 \| 45.4473 Nuremberg \| N/A \| Germany \| 11.07752 \| 49.45421 Barcelona \| N/A \| Spain \| 2.15899 \| 41.38879	274	0	0	0	NCT00424346	1COMPLETED	2009-10-01	2006-11-01	Novartis	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	20	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	This single arm study will evaluate the efficacy and safety of MabThera in patients with active rheumatoid arthritis whose current treatment with one or more TNF blocker had produced an inadequate response. Patients will receive MabThera (1g infusion) on day 1 and day 15, and will continue on their basic methotrexate therapy (10-25mg/week). The anticipated time on study treatment is 3-12 months, and the target sample size is \<100 individuals.	null	Rheumatoid Arthritis		null	1	arm 1: None	[ 0 ]	2	[ 0, 0 ]	intervention 1: 1g iv on days 1 and 15 intervention 2: 10-25mg po/week	intervention 1: rituximab [MabThera/Rituxan] intervention 2: Methotrexate	3	Budapest \| N/A \| Hungary \| 19.04045 \| 47.49835 Budapest \| N/A \| Hungary \| 19.04045 \| 47.49835 Debrecen \| N/A \| Hungary \| 21.62444 \| 47.53167	20	0	0	0	NCT00424502	1COMPLETED	2009-10-01	2007-01-01	Hoffmann-La Roche	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	29	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	This is an open label dose adjusted phase II trial of the oral farnesyltransferase inhibitor (FTI) lonafarnib (SCH66336) for patients with HGPS and progeroid laminopathies.	Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare "premature aging" disease in which all children die at an average age of thirteen years (range 8-20 years) of severe atherosclerosis leading to strokes and heart attacks. It is a multisystem disease with objective clinical markers for disease progression. These include abnormalities in growth and body composition, bone mineral density, joint function, endocrine function, alopecia, and vascular disease. There is no effective therapy for any of the progressive and deleterious aspects of this disorder. The gene defect causing HGPS and most progeroid laminopathies has been identified as a mutation in the gene LMNA, coding for the nuclear protein lamin A. Lamin A is normally expressed by most differentiated cells, and requires posttranslational farnesylation to incorporate into the nuclear membrane. The lamin A C-terminal peptide, including the farnesyl group, is subsequently cleaved, and mature lamin A becomes a prominent component of the nuclear scaffold just internal to the nuclear membrane, affecting nuclear structure and function. In most cases, HGPS is a sporadic autosomal dominant disease caused by a single base alteration (henceforth designated as G608G) in the LMNA gene, which creates a cryptic splice site giving rise to an altered lamin A protein product in which 50 amino acids are deleted. The defective protein product in HGPS (henceforth progerin) lacks the cleavage site for removal of the C-terminal farnesylated peptide, and likely produces disease via dominant negative effects on the nuclear structure and function of various cell types that express lamin A. Most other progeroid laminopathies are caused by various mutations in the LMNA gene, which also subsequently creates abnormally functioning lamin A. Lonafarnib is a farnesyltransferase inhibitor that blocks the post-translational farnesylation of prelamin A and other proteins that are targets for farnesylation. Farnesylation is essential for the function of both mutant and non-mutant lamin A proteins, including progerin. Therefore, farnesyltransferase inhibitors are ideal candidates for treatment of HGPS, which is caused by a protein (progerin) that likely depends on carrying a farnesyl group to execute its aberrant functions. Both cell culture and mouse model studies of HGPS demonstrate improved phenotype after exposure to FTI. In vitro, exposure of HGPS skin fibroblasts and progerin-transfected HeLa cells to FTIs, including lonafarnib, prevents preprogerin from intercalating into the nuclear membrane where it normally functions, and eliminates nuclear deformity. In vivo, three Progeria-like mouse models show no appreciable signs of toxicity after FTI administration. In all three of these models, disease is significantly reduced when compared to age-matched controls after oral administration of FTI. We propose that clinical features of HGPS can be ameliorated or reversed by blocking posttranslational farnesylation via treating patients with lonafarnib. We hypothesize that reduction of the quantity of functional progerin or, in the case of other progeroid laminopathies, other abnormal lamin proteins, will improve disease signs, symptoms and outcome. We also hypothesize that the toxicity profile of FTI inhibition using lonafarnib will be similar to that observed in children with malignant brain tumors treated with the compound.	Progeria Hutchinson-Gilford Syndrome	Hutchinson-Gilford Progeria Syndrome HGPS Progeria FTI Farnesyltransferase Inhibitor Lonafarnib	null	1	arm 1: All subjects initiated oral Lonafarnib twice daily at a dose of 115mg/m2 and escalated to 150 mg/m2. Two subjects de-escalated to 115mg/m2 following toxicity.	[ 0 ]	1	[ 0 ]	intervention 1: Lonafarnib will be taken orally, twice per day, by all patients enrolled on this study. The drug is supplied to patients in capsule form, and for patients who are unable to swallow pills, the drug may be dissolved into solution. Every patient will start lonafarnib therapy at a dose of 115mg/kg. The study allows for patients to receive a dose escalation (up to 150mg/kg) if the drug is being well-tolerated. Every patient enrolled on this study will undergo two years of lonafarnib therapy.	intervention 1: Lonafarnib	1	Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843	28	0	0	0	NCT00425607	1COMPLETED	2009-10-01	2007-05-01	Monica E. Kleinman	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	23	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	true	Primary Objective: * To determine the progression free survival (PFS) of the preparative regimen rituximab, etoposide and total body irradiation (TBI), in patients with acute lymphoblastic leukemia (ALL) receiving allogeneic hematopoietic stem cell transplantation (SCT). Secondary Objectives: * To determine the effect of rituximab on the incidence of acute graft vs. host disease (GVHD). * To determine the efficacy of adding imatinib mesylate post transplant in ALL patients with the t(9;22)(q34;q11) cytogenetic abnormality. * To estimate the probability of molecular complete remission at one year for the described treatment approach as determined by serial minimal residual disease (MRD) monitoring. * To determine the rate of GVHD, engraftment, toxicity, and overall survival (OS) for this treatment regimen.	Disease relapse and GVHD are 2 factors that significantly impact survival in ALL patients who receive SCT. GVHD occurs when donor cells (graft) attack the stem cell recipient's (host's) cells. The term "acute" refers to the time it takes for the GVHD to appear after the transplant. This time frame is usually within the first 100 days after the transplant. GVHD occurs in up to 50% of patients who receive a transplant. Etoposide is a traditional chemotherapy drug that is designed to interfere with the production of cancer cells at the DNA and RNA level. Total body irradiation (TBI) uses low level radiation to also interfere with the production of cancer cells at the DNA and RNA level. The combination of etoposide and TBI is a standard transplant conditioning therapy used for ALL patients. Rituximab is a monoclonal antibody that is designed to work against cells that express the antigen CD20. In addition, some studies suggest that it may decrease the risk of GVHD. Before you can start treatment on this study, you will have what are called "screening tests". These tests will help the doctor decide if you are eligible to take part in the study. You will have a complete medical history and physical exam, including routine blood (2-3 teaspoons) and urine tests. You will have a chest x-ray, heart scan (echocardiogram or MUGA scan (Multi Gated Acquisition Scan)), lung function test, and a bone marrow biopsy with aspirate to evaluate the status of your disease before transplant. To collect a bone marrow biopsy and aspirate, an area of the hip or chest bone is numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a large needle. A bone marrow core (a solid piece from the bone marrow) is also collected through a hollow needle inserted into the hip bone. Women who are able to have children must have a negative blood pregnancy test. If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of a coin) to one of 2 treatment groups. Participants in one group will receive etoposide and TBI before their transplant. Participants in the other group will receive etoposide, TBI, and rituximab before their transplant. There is an equal chance of being assigned to either group. You will receive treatment on this study as an inpatient. On the 1st day of hospitalization, you will receive fluids by vein through a central venous catheter (a plastic tube inserted into a large vein under your collar bone). You will receive TBI, once a day for the next 4 days. During TBI, you will lie flat on a table and receive radiation beams to all parts of the body, with shielding over certain parts of the body. On the following day, you will receive etoposide through the catheter over 4 hours. You will then have 2 days of rest, followed by your transplant of stem cells. The stem cells will be infused into your vein. The infusion can last from 30 minutes to several hours. If you are assigned to the rituximab group, you will also receive rituximab once a week for 4 weeks by vein over 4-8 hours. The first dose will be given on the first day you receive etoposide. If you are receiving a mismatched-related allogeneic stem cell transplant or an unrelated allogeneic stem cell transplant, you will also receive Thymoglobulin by vein on the 3 days before the stem cell infusion. This is given to decrease the risk of GVHD and graft rejection in mismatched transplants. In addition, you may receive a supportive care drug called palifermin (Kepivance®), which is a human keratinocyte growth factor (KGF) produced by recombinant DNA technology in E. coli. Its use has been shown to decrease mucositis resulting from high dose chemotherapy used in stem cell transplantation. You may receive palifermin for 3 days before starting radiation therapy, and for 2 days beginning on the day of your stem cell infusion. You may not receive palifermin but you will still receive transplant. After you blood counts have normalized following your stem cell transplant, you will start taking imatinib mesylate by mouth only if your disease has the Philadelphia chromosome (Ph+ ALL). Approximately 25-30% of adults with ALL harbor the Philadelphia chromosome. You will take it once a day until 1 year after your transplant. Imatinib mesylate should be taken with a meal and a glass of water, preferably in the morning. The dose will be gradually increased as long as you don't experience severe side effects. If severe side effects occur, imatinib will be stopped, either temporarily or permanently. You will receive several other medications to help the treatment work and to help decrease the risk of infections while your immune system is weak. Tacrolimus and methotrexate will be given to decrease the risk of GVHD. The tacrolimus will be started on the day before the transplant and will continue for up to 6 months. Tacrolimus is given by vein at first and then by mouth when you are able to eat. Methotrexate is given by vein on Days 1, 3, 6, and 11 after the transplant. Sulfamethoxazole (Bactrim) or pentamidine will be given to fight bacteria. Bactrim is given by mouth when your blood counts are good. Pentamidine is given by vein when the counts are low. Acyclovir will be given at first by vein and then Valtrex (valacyclovir) will be given by mouth to decrease the risk of viral infections. Both of these will be given as per standard of care. Granulocyte colony-stimulating factor (G-CSF) will be given to help the new bone marrow grow. It is given as an injection under the skin after the transplant. It will continue until the white blood cells reach an acceptable level. These are all routine supportive medications used during bone marrow transplantation. Overall, some of these drugs will be given for as long as 6 months or possibly longer. Other medications may be necessary. If you are allergic to some of these drugs, changes will be made. You will be in the hospital for about 3-4 weeks. You will have checkups every day until you are discharged from the hospital. You will then be seen in the outpatient clinic at least 3 times a week until your blood counts improve. You will be seen by your doctor at least every week until 100 days after the bone marrow transplant. You must stay in Houston during this time. After 100 days, you will be required to return to Houston every 3 months for tests and evaluation over the next 2 years. At these visits, you will have blood (about 2-3 teaspoons) collected for routine tests. You will also have a bone marrow biopsy. Some participants may need to receive spinal taps with chemotherapy (methotrexate or cytarabine given through the spine) several times over the year after transplantation. This is only for patients with a previous clinical history of leukemic involvement of the brain or high risk of developing leukemia relapse in the brain. The spinal tap is performed in the clinic. If you are one of these participants, you will be given local anesthetic at the lower back site where a small needle will be inserted in the space between 2 spinal bones. A small amount of fluid that bathes the brain (cerebrospinal fluid) will be removed for testing, and a small amount of chemotherapy will be given. This is an investigational study. The FDA has approved all of the drugs used in this study for use in stem cell transplantation. However, their use together in this study is experimental. Up to 80 patients will take part in this study. All will be enrolled at UT MD Anderson Cancer Center.	Leukemia	Acute Lymphoblastic Leukemia Leukemia Total Body Irradiation Etoposide Rituximab Rituxan TBI ALL	null	2	arm 1: Etoposide 60 mg/kg intravenous (IV) Daily Over 4 Hours for 1 Day + Total Body Irradiation (TBI) 3 Gy Daily for 4 Days + Rituximab 375 mg/m\^2 IV Weekly Over 4-8 Hours for 4 Weeks arm 2: Etoposide 60 mg/kg IV Daily Over 4 Hours for 1 Day + TBI 3 Gy Daily for 4 Days	[ 0, 0 ]	3	[ 0, 4, 0 ]	intervention 1: 60 mg/kg IV Daily Over 4 Hours for 1 Day intervention 2: 3 Gy Daily for 4 Days intervention 3: 375 mg/m\^2 IV Weekly Over 4-8 Hours for 4 Weeks	intervention 1: Etoposide intervention 2: Total Body Irradiation intervention 3: Rituximab	1	Houston \| Texas \| United States \| -95.36327 \| 29.76328	23	0	0	0	NCT00427791	1COMPLETED	2009-10-01	2005-07-01	M.D. Anderson Cancer Center	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	71	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	The purpose of this study is to show that the use of cinacalcet in patients with End Stage Renal Disease can help achieve NKF K/DOQI targets for both serum calcium and calcium phosphorous product.	null	Anemia Secondary Hyperparathyroidism	Anemia Intact Parathyroid Hormone (iPTH) Secondary Hyperparathyroidism (SHPT)	null	1	arm 1: Cinacalcet was administered orally at a starting dose of 30 mg/day for 23 weeks. Possible sequential doses during the study were 30, 60, 90, 120, and 180 mg. Dose escalation of cinacalcet occurred if the intact parathyroid hormone (iPTH) level from the previous study visit was \> 31.8 pmol/L (300 pg/mL) unless the participant had either reached the maximum dose (180 mg/day), the serum corrected total calcium was \< 2.1 mmol/L (8.4 mg/dL), or the participant experienced an adverse event that precluded a dose increase.	[ 0 ]	1	[ 0 ]	intervention 1: Cinacalcet tablets	intervention 1: Cinacalcet	0	null	71	0	0	0	NCT00431496	1COMPLETED	2009-10-01	2006-09-01	Amgen	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 4 ]	321	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	null	This study evaluated the effect of combination therapy with verteporfin photodynamic therapy and ranibizumab on visual acuity and anatomic outcomes compared to ranibizumab monotherapy and the durability of response observed in patients with choroidal neovascularization secondary to age-related macular degeneration.	null	Macular Degeneration Choroidal Neovascularization	Age-related macular degeneration; AMD choroidal neovascularization verteporfin ranibizumab	null	3	arm 1: Patients received three consecutive monthly ranibizumab injections on Day 1 and at Months 1 and 2, and thereafter as needed at intervals of at least 30 days based on retreatment criteria. These patients also received verteporfin photodynamic therapy (PDT) with standard fluence (SF) rate on Day 1 and then as needed from Month 3 at intervals of at least 90 days based on the retreatment criteria. From month 3 onward, retreatments were determined based on study-specific retreatment criteria that included retinal thickness by Optical Coherence Tomography (OCT), sub-retinal hemorrhage evaluated by ophthalmoscopic examination, visual acuity assessed using Early treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart and choroidal neovascularization (CNV) leakage assessed by fluorescein angiography (FA). Patients received sham intravitreal injections for the first 12 months if retreatment with ranibizumab was not warranted based on the retreatment criteria. arm 2: Patients received monthly ranibizumab injections for 12 months and thereafter as needed based on the retreatment criteria. These patients were also administered verteporfin placebo infusion with sham PDT on Day 1 and then as needed from Month 3 at intervals of at least 90 days based on the retreatment criteria. Retreatments were determined based on study specific retreatment criteria that included retinal thickness by Optical Coherence Tomography (OCT), sub-retinal hemorrhage evaluated by ophthalmoscopic examination, visual acuity assessed using Early treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart and choroidal neovascularization (CNV) leakage assessed by fluorescein angiography (FA). arm 3: Patients received three consecutive monthly ranibizumab injections on Day 1 and at Months 1 and 2, and thereafter as needed at intervals of at least 30 days based on retreatment criteria. These patients also received verteporfin PDT with reduced fluence (RF) rate on Day 1 and then as needed from Month 3 at intervals of at least 90 days based on the retreatment criteria. From month 3 onward, retreatments were determined based on study-specific retreatment criteria that included retinal thickness by Optical Coherence Tomography (OCT), sub-retinal hemorrhage evaluated by ophthalmoscopic examination, visual acuity assessed using Early treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart and choroidal neovascularization (CNV) leakage assessed by fluorescein angiography (FA). Patients received sham intravitreal injections for the first 12 months if retreatment with ranibizumab was not warranted based on the retreatment criteria.	[ 0, 1, 0 ]	4	[ 0, 0, 0, 0 ]	intervention 1: After a 10-minute intravenous infusion of verteporfin at a dose of 6 mg/m\^2 body surface area, verteporfin was activated by light application of 50 J/cm\^2 (Standard Fluence rate) or 25 J/cm\^2 (Reduced Fluence rate) to the study eye, begun 15 minutes after the start of the infusion. intervention 2: Ranibizumab 0.5 mg administered as an intravitreal injection. intervention 3: To maintain masking, as a placebo for verteporfin photodynamic therapy, patients were administered a 10-minute intravenous infusion of 5% dextrose solution, followed by light application of 50 J/cm\^2 to the study eye, begun 15 minutes after the start of infusion. intervention 4: To maintain masking, patients in the combination groups received sham intravitreal injections whenever retreatment with active Ranibizumab was not warranted based on the retreatment algorithm.	intervention 1: Verteporfin Photodynamic Therapy intervention 2: Ranibizumab intervention 3: Verteporfin Placebo intervention 4: Ranibizumab Placebo	43	Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 Beverly Hills \| California \| United States \| -118.40036 \| 34.07362 Oakland \| California \| United States \| -122.2708 \| 37.80437 Pasadena \| California \| United States \| -118.14452 \| 34.14778 Sacramento \| California \| United States \| -121.4944 \| 38.58157 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Santa Ana \| California \| United States \| -117.86783 \| 33.74557 Denver \| Colorado \| United States \| -104.9847 \| 39.73915 ‘Aiea \| Hawaii \| United States \| -157.93361 \| 21.38222 Iowa City \| Iowa \| United States \| -91.53017 \| 41.66113 Wichita \| Kansas \| United States \| -97.33754 \| 37.69224 Lexington \| Kentucky \| United States \| -84.47772 \| 37.98869 Paducah \| Kentucky \| United States \| -88.60005 \| 37.08339 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Grand Rapids \| Michigan \| United States \| -85.66809 \| 42.96336 Royal Oak \| Michigan \| United States \| -83.14465 \| 42.48948 Williamsburg \| Michigan \| United States \| -85.40396 \| 44.77361 Independence \| Missouri \| United States \| -94.41551 \| 39.09112 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Toms River \| New Jersey \| United States \| -74.19792 \| 39.95373 Lynbrook \| New York \| United States \| -73.6718 \| 40.65483 Rochester \| New York \| United States \| -77.61556 \| 43.15478 Beachwood \| Ohio \| United States \| -81.50873 \| 41.4645 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 West Mifflin \| Pennsylvania \| United States \| -79.86644 \| 40.3634 West Columbia \| South Carolina \| United States \| -81.07398 \| 33.99349 Rapid City \| South Dakota \| United States \| -103.23101 \| 44.08054 Kingsport \| Tennessee \| United States \| -82.56182 \| 36.54843 Knoxville \| Tennessee \| United States \| -83.92074 \| 35.96064 Austin \| Texas \| United States \| -97.74306 \| 30.26715 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Fairfax \| Virginia \| United States \| -77.30637 \| 38.84622 Richmond \| Virginia \| United States \| -77.46026 \| 37.55376 Milwaukee \| Wisconsin \| United States \| -87.90647 \| 43.0389 Edmonton \| Alberta \| Canada \| -113.46871 \| 53.55014 Vancouver \| British Columbia \| Canada \| -123.11934 \| 49.24966 Halifax \| Nova Scotia \| Canada \| -63.57688 \| 44.64269 London \| Ontario \| Canada \| -81.23304 \| 42.98339 London \| Ontario \| Canada \| -81.23304 \| 42.98339 Ottawa \| Ontario \| Canada \| -75.69812 \| 45.41117 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884	321	0	0	0	NCT00436553	1COMPLETED	2009-10-01	2007-02-01	Novartis	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	12	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	1FEMALE	false	Background: * Vandetanib is a drug that attacks a group of proteins on the surface of many cells, especially blood vessel cells and tumor cells. * Tumors require the development of new blood vessels in order to grow and spread. * In laboratory experiments, vandetanib slowed the growth of certain tumors and regulated their blood vessel growth. * In early clinical trials, some patients' tumors did not grow for a period of time while they were receiving vandetanib. Objectives: * To determine whether vandetanib can cause tumors to shrink or stabilize in some patients with ovarian cancer, fallopian tube cancer or primary peritoneal cancer. * To determine, by tumor biopsy, if features of the tumor change with vandetanib treatment may predict if the tumor will likely respond to vandetanib. Eligibility: * Women 18 years of age and older with ovarian, fallopian tube or primary peritoneal cancer that does not respond to standard treatment. Design: * Patients take vandetanib daily, by mouth in 28-day cycles until their disease worsens or they develop unacceptable side effects. * Tumor biopsies (surgical removal of a sample of tumor tissue) are done before starting vandetanib treatment and after 6 weeks of treatment. * Patients are followed in the clinic every 4 weeks during treatment for a physical examination, blood tests, and review of laboratory studies and side effects. * Patients have a computed tomography (CT) scan every 8 weeks to monitor tumor growth and magnetic resonance imaging (MRI) before starting vandetanib treatment, on the third day after taking vandetanib and 6 weeks into treatment. * Patients quality of life is assessed with regularly scheduled questionnaires.	Background: * Epithelial ovarian cancer requires neovascularization for growth and metastasis. Anti-angiogenesis agents have been shown to have promise in the treatment of recurrent disease. Expression of vascular endothelial growth factor 2 (VEGFR2) and epidermal growth factor receptor (EGFR) has been demonstrated in ovarian cancer specimens in stroma and tumor. Blocking autocrine and paracrine loops acting through these receptors may inhibit downstream phosphorylation targets in the mitogen activated protein kinase (MAPK) and AKT pathways, thereby influencing disease progression and patient outcome. * The multi-kinase inhibitor ZD6474 (vandetanib, AstraZeneca, Zactima) blocks angiogenesis by targeting VEGFR2, and shows in vitro activity against a number of other receptor tyrosine kinases including resonance energy transfer (RET), vascular endothelial growth factor 3 (VEGFR3) and EGFR. * Clinical efficacy of ZD6474 (vandetanib) in women with refractory or relapsed epithelial ovarian cancer is unknown, but preclinical data suggests potential value. * The maximum tolerated dose of ZD6474 (vandetanib) has been determined at 300mg/day, limited by the dose-responsive adverse effect of prolonged (Q wave, T wave)QT interval. Objectives: * To assess the clinical activity (CR - complete response, PR - partial response, or disease stabilization) of the VEGFR2 inhibitor ZD6474 (vandetanib), 300mg/d, in women with ovarian, fallopian tube or primary peritoneal cancer. * To study target signal events: quantity and activation of VEGFR2, EGFR, AKT and extracellular signal-regulated kinases (ERK). Eligibility: * Women with biopsy-proven epithelial ovarian, fallopian tube or primary peritoneal cancer that is relapsed and/or refractory to prior therapy. * Women must have measurable disease by NCI Response Evaluation Criteria in Solid Tumors (RECIST) criteria and a sentinel lesion adequate for core biopsy through percutaneous biopsy. * Women must have had no more than four prior treatment regimens. Design: * Women will receive 300mg of ZD6474 (vandetanib) daily, orally in 28-day cycles until disease progression, excessive toxicity, or withdrawal from study. * Biopsy of tumor will be performed prior to starting ZD6474 (vandetanib) and after six weeks of treatment. The quantity of phosphorylated VEGFR2, EGFR, ERK and AKT in the biopsy tissue will be analyzed. * Clinical outcome and toxicity will be measured and correlated with target inhibition. * Women will also undergo serial imaging with dynamic contrast-enhanced MRI to estimate tumor blood flow. * Research blood samples will be taken to assess changes in circulating cytokine concentrations. * Quality of life will be assessed during treatment.	Ovarian Neoplasms Fallopian Tube Neoplasms Peritoneal Neoplasms	Ovarian VEGFR2 EGFR Angiogenesis Tyrosine Kinase Protein Phosphorylation Vandetanib Ovarian Cancer Fallopian Tube Cancer Peritoneal Cancer	null	1	arm 1: 300 mg daily oral dose, 28 day cycle	[ 0 ]	1	[ 0 ]	intervention 1: 300 mg daily dose, 28 day cycle	intervention 1: Vandetanib	1	Bethesda \| Maryland \| United States \| -77.10026 \| 38.98067	12	0	0	0	NCT00445549	6TERMINATED	2009-10-01	2007-01-01	National Cancer Institute (NCI)	0NIH	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	10	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	The goal of this clinical research study is to see if RAD001 can help to control the disease in patients with systemic mastocytosis (SM). The safety of this treatment will also be studied.	RAD001 is designed to stop cancer cells from multiplying. It may also stop the growth of new blood vessels that help tumor growth, which may cause the tumor cells to die. Before you can start treatment on this study, you will have "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. They will be performed within 2 weeks before starting the study, unless listed otherwise. You will have a complete physical exam, including measurement of vital signs (blood pressure, heart rate, temperature, and breathing rate). Blood (about 2 tablespoons) will be drawn for routine tests. This routine blood draw will include a pregnancy test for women who are able to have children. To be eligible to take part in this study, the pregnancy test must be negative. You will need to "fast" for 6 hours before having these blood tests performed. This means you will not be able to have food or drink (except water) during this time. Also as part of the screening tests, you will have an electrocardiogram (ECG)a test that measures the electrical activity of the heart). You will have a bone marrow biopsy and aspiration within 3 months of starting the study (or within 2 weeks of starting the study, if you have received treatment for SM). To collect a bone marrow biopsy/aspirate, an area of the hip bone is numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a large needle. The bone marrow samples will be used not only to check the status of the disease, but also for a routine test to see if there is a mutation (change) in a certain gene. If your doctor feels it is necessary, you may need to have additional screening tests (such as a bone scan) to check the status of the disease. If you are found to be eligible to take part in this study, you will receive your first supply of RAD001. You will take 1-2 pills of RAD001 by mouth once a day while you are on study. During the 3 hours before each dose of RAD001, you must eat no more than a light fat-free meal (such as a salad with no dressing, or a bowl of cereal with skim milk). You should also try to keep your dietary habits consistent before each dose. This means that you should eat at about the same time, and about the same amount of food each time. Each "cycle" of RAD001 lasts 1 month. You will have study visits on Day 1 of Cycles 1, 2, and 3. At each visit, you will receive a new supply of RAD001. You will have a physical exam, including measurement of vital signs. You will be asked about any side effects you may have had. While you are on study, you must not take any additional medications (including over-the-counter products) without asking the study doctor first. At each study visit, you will be asked if you have taken any additional medications. You will also be asked if you have had any non-drug therapies or blood transfusions. Blood (about 2 tablespoons) will be drawn for routine tests. Like you did at screening, you will need to fast for 6 hours before having these blood tests performed. Halfway through each cycle (at about the beginning of Week 3 of each cycle), blood will be drawn for routine tests. This will be about 2 tablespoons of blood each time. You will need to fast for 6 hours before having these blood tests performed. It is your choice whether to have these blood tests performed at M.D. Anderson or at an outside laboratory. On Day 1 of Cycle 4, you will have another study visit. You will have all of the same tests performed as you did at the study visits on Day 1 of Cycles 1, 2, and 3. You will also have a bone marrow aspirate and biopsy in order to check the status of the disease. If your bone marrow sample collected at the time of screening showed that you have a mutation in a certain gene, the bone marrow sample collected at this time will be studied further (for a routine test). If this test result shows that the disease has not responded by this time, you will be taken off study. If the disease has responded by Day 1 of Cycle 4 (or if certain signs and symptoms related to SM have improved), you will continue taking RAD001 for as long as you are benefitting. You will continue having blood (about 2 tablespoons) drawn for routine tests every other week. You will also continue having study visits (with the same tests performed as on Day 1 of Cycle 4), but the visits will be once every 3 months. In other words, you will return on Day 1 of Cycles 4, 7, 10, and so on. On Day 1 of the months when you do not have study visits (Cycles 5, 6, 8, 9, and so on), you will be called on the telephone by the research staff. During these phone calls, you will be asked about any side effects you may have had. You will also be asked about the results of the study-related blood tests that you have had since the last phone call or study visit. If the disease gets worse, you begin another therapy for cancer, or intolerable side effects occur, you will be taken off study. This is an investigational study. RAD001 is not Food and Drug Administration (FDA) approved or commercially available. It has been authorized for use in research only. Up to 25 patients will take part in this study. All will be enrolled at M.D. Anderson.	Systemic Mastocytosis	Systemic Mastocytosis RAD001	null	1	arm 1: Oral 10 mg daily for 30 days	[ 0 ]	1	[ 0 ]	intervention 1: Oral RAD001 10 mg daily for 30 days	intervention 1: RAD001 (Everolimus)	1	Houston \| Texas \| United States \| -95.36327 \| 29.76328	10	0	0	0	NCT00449748	1COMPLETED	2009-10-01	2007-04-01	M.D. Anderson Cancer Center	7OTHER	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	59	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	false	This is a study to test lozenges of interferon-alpha that are dissolved in the mouth as a treatment of oral warts in HIV-positive adults. The hypothesis of this study is that interferon-alpha will be safe and that a higher percentage of subjects given interferon-alpha will experience a complete or nearly complete remission of their oral warts compared to subjects given placebo.	Human papilloma virus (HPV) can cause warts to form in the mouth of infected patients, particularly those with reduced immunity such as people infected with HIV. This is a randomized, double-blind, placebo-controlled trial to determine whether interferon-alpha, delivered in low doses via orally dissolving lozenges, can reduce or eliminate these warts in HIV+ subjects who are receiving combination anti-retroviral therapy (HAART). All potential subjects will have their warts examined and measured at a screening visit. A small amount of one wart (i.e. a biopsy) will be removed for microscopic evaluation to confirm HPV infection and a small amount of blood will be collected for testing. Subjects that qualify for entry will return for a baseline visit at which they will be randomized to active or placebo treatment for 24 weeks. Three out of four subjects will receive active treatment in this study. Subjects must return to the clinic every 6 weeks during treatment to have their warts re-examined. At these follow-up visits, subjects will be asked to complete a brief questionnaire regarding any perceived changes in their warts and their overall mouth condition. A small amount of blood will be taken at the final study visit at week 24 to assess the safety of the interferon lozenges.	Papillomatosis HIV Infections	human immunodeficiency virus human papilloma virus warts, oral papillomatosis treatment experienced	null	2	arm 1: 500 IU Interferon-alpha lozenges for oral dissolution arm 2: 200 mg lozenges containing anhydrous crystalline maltose	[ 0, 2 ]	2	[ 0, 10 ]	intervention 1: 500 IU interferon-alpha lozenges taken 3 times per day for 24 weeks intervention 2: 200 mg lozenges containing anhydrous crystalline maltose taken three times per day for 24 weeks	intervention 1: Interferon-alpha intervention 2: placebo	12	San Francisco \| California \| United States \| -122.41942 \| 37.77493 Fort Lauderdale \| Florida \| United States \| -80.14338 \| 26.12231 Augusta \| Georgia \| United States \| -81.97484 \| 33.47097 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Lexington \| Kentucky \| United States \| -84.47772 \| 37.98869 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Newark \| New Jersey \| United States \| -74.17237 \| 40.73566 New York \| New York \| United States \| -74.00597 \| 40.71427 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412	59	0	0	0	NCT00454181	1COMPLETED	2009-10-01	2007-02-01	Ainos, Inc. (f/k/a Amarillo Biosciences Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	158	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	true	The purpose of this study is to determine whether ODSH, when added to conventional treatment, is more effective in treating COPD exacerbations than conventional therapy alone.	The management of acute exacerbations of COPD today is qualitatively the same as it was 40 years ago: bronchodilators, corticosteroids, and antibiotics. Because of the prominent pathophysiological role of neutrophils in exacerbations of COPD, neutrophils and their toxic oxidants and proteases represent therapeutic targets which are currently unchallenged in the treatment of this aspect of the disease. Ideally, to disrupt neutrophilic airway inflammation, one would both block neutrophilic influx from the vascular space into the airway, as well as neutralize or inactivate prominent neutrophilic toxins such as the proteases HLE and cathepsin G. Heparin is a sulfated mucopolysaccharide that slows blood clot formation by inhibiting the reactions that lead to formation of fibrin clots. Physicians use heparin to prevent blood clot formation during open-heart surgery, bypass surgery and dialysis. Heparin also prevents previously formed clots from becoming larger and causing more serious problems. Heparin has other biological properties, most notably anti-inflammatory activity. At doses required to be therapeutically beneficial as an anti-inflammatory, heparin can cause severe, potentially life-threatening hemorrhage. ParinGenix has chemically modified heparin to retain the anti-inflammatory activity while reducing anti-coagulant properties. Heparin has long been known to be a potent inhibitor, both in vitro and in vivo, of the cationic neutrophil proteases HLE and cathepsin G. However, heparin also has numerous other important anti-inflammatory effects. P-selectin is the primary endothelial attachment molecule mediating neutrophil rolling along the vessel wall. At concentrations close to those achieved in plasma near the high range of therapeutic anticoagulation, heparin inhibits P-selectin and P-selectin mediated interaction of leukocytes with endothelium. Heparin also blocks the leukocyte integrin Mac-1 (CD11b/CD18) and Mac-1-dependent leukocyte adherence to endothelial ICAM. These combined effects on rolling, integrin-dependent attachment and perhaps other aspects of cellular passage through the basement membrane prevent neutrophil accumulation in areas of inflammation. As an example, when given in much higher concentrations than those appropriate for therapeutic anticoagulation, heparin efficiently blocks neutrophilic influx into ischemic reperfused myocardium and brain reducing the size of both myocardial infarction and ischemic stroke. Thus, heparin and heparin analogues may have the potential to also reduce inflammatory influx of neutrophils into the airway during exacerbations of COPD. All subjects will receive standard of care treatment, including corticosteroids, beta-2 agonists, and antibiotics as well as ODSH or placebo.	Chronic Obstructive Pulmonary Disease	Chronic Obstructive Pulmonary Disease COPD Heparin ODSH Exacerbations of COPD	null	3	arm 1: Initial six subjects treated with ODSH open-label to confirm safety in subjects with an acute exacerbation of COPD; six additional patients will be enrolled following safety review. arm 2: Placebo Comparator: Placebo-Control Arm 0.9% Sodium Chloride Solution bolus; dose of 0.375mg/kg/hr over 96 hours. arm 3: Subjects will receive standard of care treatment. ODSH is administered in bolus doses estimated to inhibit inflammatory mediators randomized 1:1 to ODSH 8mg/kg or placebo. The continuous infusion dose will be 0.375 mg/kg/hr over 96 hours.	[ 0, 2, 1 ]	3	[ 0, 0, 0 ]	intervention 1: ODSH administered open-label intervention 2: Placebo-Control Arm: Bolus infusion followed by a 96 hour continuous infusion of 0.9%Sodium Chloride intervention 3: Randomized, Blinded, ODSH Arm	intervention 1: Open-Label intervention 2: Placebo Comparator: Placebo-Control Arm 0.9% Sodium Chloride intervention 3: ODSH	38	Orange \| California \| United States \| -117.85311 \| 33.78779 Marietta \| Georgia \| United States \| -84.54993 \| 33.9526 Shreveport \| Louisiana \| United States \| -93.75018 \| 32.52515 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Tyler \| Texas \| United States \| -95.30106 \| 32.35126 Everett \| Washington \| United States \| -122.20208 \| 47.97898 Leuven \| N/A \| Belgium \| 4.70093 \| 50.87959 Liège \| N/A \| Belgium \| 5.56749 \| 50.63373 Yvior \| N/A \| Belgium \| N/A \| N/A Edmonton \| Alberta \| Canada \| -113.46871 \| 53.55014 Kelowna \| British Columbia \| Canada \| -119.48568 \| 49.88307 Vancouver \| British Columbia \| Canada \| -123.11934 \| 49.24966 Winnipeg \| Manitoba \| Canada \| -97.14704 \| 49.8844 Halifax \| Nova Scotia \| Canada \| -63.57688 \| 44.64269 Mississauga \| Ontario \| Canada \| -79.6583 \| 43.5789 Ottawa \| Ontario \| Canada \| -75.69812 \| 45.41117 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Québec \| Quebec \| Canada \| -71.21454 \| 46.81228 Gerlingen \| N/A \| Germany \| 9.06316 \| 48.79954 Großhansdorf \| N/A \| Germany \| 10.28333 \| 53.66667 Hanover \| N/A \| Germany \| 9.73322 \| 52.37052 Mainz \| N/A \| Germany \| 8.2791 \| 49.98419 München \| N/A \| Germany \| 13.31243 \| 51.60698 Częstochowa \| N/A \| Poland \| 19.12409 \| 50.79646 Katowice \| N/A \| Poland \| 19.02754 \| 50.25841 Krakow \| N/A \| Poland \| 19.93658 \| 50.06143 Lodz \| N/A \| Poland \| 19.47395 \| 51.77058 Lublin \| N/A \| Poland \| 22.56667 \| 51.25 Lublin \| N/A \| Poland \| 22.56667 \| 51.25 Oława \| N/A \| Poland \| 17.2926 \| 50.9466 Poznan \| N/A \| Poland \| 16.92993 \| 52.40692 Warsaw \| N/A \| Poland \| 21.01178 \| 52.22977 Warsaw \| N/A \| Poland \| 21.01178 \| 52.22977 Wroclaw \| N/A \| Poland \| 17.03333 \| 51.1	147	0	0	0	NCT00457951	6TERMINATED	2009-10-01	2007-04-01	Chimerix	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	46	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	The purpose of this study is to evaluate the efficacy and tolerability of Vicinium when administered as a monotherapy intravesical instillation in patients with non-invasive urothelial carcinoma in situ (CIS) who failed previous treatment with Bacille Calmette Guérin (BCG).	A phase II study was performed to assess the efficacy and tolerability of intravesical Vicinium in patients with urothelial carcinoma in situ of the bladder. Bacillus Calmette-Guérin treatment had previously failed in all patients. A total of 46 patients were treated with Vicinium with half being administered 30mg/dose once per week for 6 weeks (cohort 1) and the other half (cohort 2) the same dose but administered once per week for 12 consecutive weeks. Disease assessments consisting of urine cytology, cystoscopy and, if indicated, biopsy were performed at 3 month intervals. Patients that were disease-free at the assessment time point were allowed to continue treatment in the maintenance phase which consisted of three weekly doses, followed by 9 weeks of no treatment. As long as the patient remained disease-free, treatment continued for a total of one year.	Urinary Bladder Cancer Bladder Cancer Bladder Neoplasms Bladder Tumors		null	2	arm 1: Induction Phase is a single intravesical dose of Vicinium at 30 mg in 40 mL PBS once per week for 6 weeks. If free of disease at 12 weeks after the first instillation, the subject enters Maintenance dosing in which 30 mg of Vicinium is administered once per week for 3 weeks followed by 9 weeks of no therapy. If the subject had histologically confirmed disease that is stage \<T2, they repeat the Induction phase dosing. If the subject is free of disease, the subject enters the maintenance dosing phase of every 12 weeks (3 weeks of therapy followed by 9 weeks of no therapy until disease recurrence is confirmed by positive biopsy or up to a maximum of Week 51 (end-of-study \[EOS\]). arm 2: Induction Phase is a single intravesical dose of Vicinium at 30 mg in 40 mL PBS once per week for 12 weeks followed by 1 week of no therapy. If 13 weeks after the first instillation of Vicinium the subject is free of disease, they have a break from therapy before entering Maintenance dosing in which 30 mg of Vicinium is administered once weekly for 3 weeks followed by 9 weeks of no therapy. If the subject is free of disease, additional maintenance cycle(s) are repeated every 12 weeks (3 weeks of therapy followed by 9 weeks of no therapy until disease recurrence is confirmed by positive biopsy or up to a maximum of Week 57 (EOS).	[ 1, 1 ]	1	[ 0 ]	intervention 1: Intravesical administration of Vicinium	intervention 1: Vicinium	21	Tallahassee \| Florida \| United States \| -84.28073 \| 30.43826 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Lawrenceville \| New Jersey \| United States \| -74.7296 \| 40.29733 Durham \| North Carolina \| United States \| -78.89862 \| 35.99403 Springfield \| Oregon \| United States \| -123.02203 \| 44.04624 Myrtle Beach \| South Carolina \| United States \| -78.88669 \| 33.68906 Corpus Christi \| Texas \| United States \| -97.39638 \| 27.80058 Newport News \| Virginia \| United States \| -76.42975 \| 36.98038 Surrey \| British Columbia \| Canada \| -122.82509 \| 49.10635 Victoria \| British Columbia \| Canada \| -123.35155 \| 48.4359 Barrie \| Ontario \| Canada \| -79.66634 \| 44.40011 Burlington \| Ontario \| Canada \| -79.83713 \| 43.38621 Hamilton \| Ontario \| Canada \| -79.84963 \| 43.25011 Kingston \| Ontario \| Canada \| -76.48098 \| 44.22976 London \| Ontario \| Canada \| -81.23304 \| 42.98339 Oakville \| Ontario \| Canada \| -79.68292 \| 43.45011 Owen Sound \| Ontario \| Canada \| -80.94349 \| 44.56717 Scarborough Village \| Ontario \| Canada \| -79.22124 \| 43.73899 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Sherbrooke \| Quebec \| Canada \| -71.89908 \| 45.40008	46	0	0	0	NCT00462488	1COMPLETED	2009-10-01	2007-03-01	Sesen Bio, Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 3 ]	123	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	0ALL	true	The primary objective was to estimate the tolerability and safety of 2 doses of Teriflunomide administered once daily for 24 weeks, compared to placebo, in patients with multiple sclerosis \[MS\] with relapses who were on a stable dose of Glatiramer Acetate \[GA\]. The secondary objectives were: * to estimate the effect of the 2 doses of Teriflunomide, compared to placebo, in combination with a stable dose of GA on Magnetic Resonance Imaging \[MRI\] parameters, relapse rate and patient-reported fatigue; * to perform pharmacokinetic analyses of the 2 doses of teriflunomide in combination with a stable dose of GA.	The duration of the study period for a participant was approximatively 44 weeks broken down as follows: * Screening period up to 4 weeks, * 24-week double-blind treatment period\, 16-week post-treatment elimination follow-up period. '\*' Participants successfully completing the week 24 visit were offered the opportunity to enter the optional long-term extension study LTS6047 - NCT00811395.	Multiple Sclerosis	MS glatiramer acetate adjunctive therapy relapses	null	3	arm 1: Placebo (for teriflunomide) once daily concomitantly with glatiramer acetate (GA) for 24 weeks arm 2: Teriflunomide 7 mg once daily concomitantly with glatiramer acetate (GA) for 24 weeks arm 3: Teriflunomide 14 mg once daily concomitantly with glatiramer acetate (GA) for 24 weeks	[ 2, 0, 0 ]	3	[ 0, 0, 0 ]	intervention 1: Film-coated tablet Oral administration intervention 2: Film-coated tablet Oral administration intervention 3: Solution in prefilled syringe for subcutaneous injection	intervention 1: Teriflunomide intervention 2: Placebo (for teriflunomide) intervention 3: Glatiramer Acetate (GA)	6	Bridgewater \| New Jersey \| United States \| -74.64815 \| 40.60079 Vienna \| N/A \| Austria \| 16.37208 \| 48.20849 Laval \| N/A \| Canada \| -73.692 \| 45.56995 Berlin \| N/A \| Germany \| 13.41053 \| 52.52437 Milan \| N/A \| Italy \| 9.18951 \| 45.46427 Guildford \| N/A \| United Kingdom \| -0.57427 \| 51.23536	123	0	0	0	NCT00475865	1COMPLETED	2009-10-01	2007-04-01	Sanofi	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 2, 3 ]	4	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	OncoGel™ is a new, experimental drug delivery system that allows the slow continuous release of paclitaxel (an approved intravenous anticancer drug), from a gel (ReGel™) over a long period of time. The gel will disappear in 4 to 6 weeks as it releases the paclitaxel. The purpose of this study is to evaluate the safety and tolerability of OncoGel when placed into the tumor resection cavity in the brain following surgical removal of the tumor. Dose escalation is conducted by gradually increasing the amount of OncoGel placed in the resection cavity in small groups of patients, and watching the patients closely for side effects before moving to the next dose level. The study will also test whether OncoGel helps to prevent or delay the tumor from regrowing.	This study is for patients with recurrent glioblastoma multiforme. Because most recurrences are in the area of the original resection, local delivery of a chemotherapeutic agent may prevent or delay additional recurrences. Paclitaxel has demonstrated activity against 9L glioma tumor lines, but has poor central nervous system penetration after intravenous administration. OncoGel is a new formulation of paclitaxel in a bioerodible gel that can be administered directly to the brain, thereby bypassing the blood-brain barrier.	Glioblastoma Multiforme Brain Neoplasms	glioblastoma multiforme recurrent Phase 1 Phase 2 Phase I Phase II brain cancer paclitaxel intracranial tumor local chemotherapy brain tumor brain cancer glioma OncoGel	null	1	arm 1: OncoGel administered into remaining cavity after surgical resection. Each dose cohort will receive a different volume of OncoGel	[ 0 ]	1	[ 0 ]	intervention 1: OncoGel administered into cavity after surgical resection of recurrent glioma. Each subject will receive one dose of OncoGel on the day of surgical resection.	intervention 1: OncoGel (ReGel/Paclitaxel)	5	Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Rochester \| New York \| United States \| -77.61556 \| 43.15478 Chapel Hill \| North Carolina \| United States \| -79.05584 \| 35.9132 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589	4	0	0	0	NCT00479765	6TERMINATED	2009-10-01	2007-03-01	Boston Scientific Corporation	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	12	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	true	0ALL	true	The purpose of this study is to determine whether naratriptan, a medication approved for treatment of migraine, is effective in the treatment of post traumatic headache associated with cognitive dysfunction.	Naratriptan has demonstrated efficacy in relieving headache. Other studies have demonstrated that primary headaches with at least one headache feature are likely to respond to triptans. In addition, there are anecdotal reports of triptans being effective in post traumatic headaches, especially if headache features are noted in the patient's history. Further, there are several small pilot studies with triptans demonstrating a prompt improvement in headache-induced cognitive changes. Cognitive performance can be measured by the Mental Efficiency Workload Test (MEWT), a handheld Palm neuropsychological test battery that measures mental efficiency. This tool can be used to demonstrate short and long term improvement in mental status beyond that seen at baseline. Informal observations by the protocol authors have suggested that the use of triptans on a routine basis may ameliorate the headache and associated symptomatology of post traumatic headache. Therefore, this study is undertaken to study the use of naratriptan in the treatment of post traumatic headache. Roger K. Cady, MD, serves as the sponsor. The study is funded by GlaxoSmithKline. 56 subjects with a formal diagnosis of Chronic post-traumatic headache attributed to mild head injury (IHS/ICHD-II 5.2.2) and with self-reported mild cognitive inefficiency secondary to headache will be enrolled. Subjects meeting inclusion criteria will complete a physical examination and baseline testing and be randomized 1:1 to naratriptan 2.5mg bid x 30 days or a matched placebo bid x 30 days. A daily diary will document response to treatment. Subjects will return to the clinic at Day 10 and Day 30 and complete phone contacts at Days 5, 15, 21, 32 and 90. Information will be collected throughout the study on questionnaires related to headache impact, general health, satisfaction with medication, and quality of life. Cognition will be measured using the MEWT.	Post Traumatic Headache	Post traumatic headache Head trauma Head injury Headache Naratriptan	null	2	arm 1: Naratriptan 2.5 mg tablet bid x 30 days arm 2: placebo matching naratriptan 2.5 mg tablet	[ 1, 2 ]	1	[ 0 ]	intervention 1: naratriptan 2.5mg tablet bid x 30 days OR matching placebo	intervention 1: naratriptan HCl	3	Springfield \| Missouri \| United States \| -93.29824 \| 37.21533 Charlotte \| North Carolina \| United States \| -80.84313 \| 35.22709 Dallas \| Texas \| United States \| -96.80667 \| 32.78306	12	0	0	0	NCT00487578	6TERMINATED	2009-10-01	2006-10-01	Cady, Roger, M.D.	3INDIV	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	18	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	This single arm study will assess the efficacy and safety of PEGASYS in patients with chronic hepatitis B who are either treatment-naive, or who have failed lamivudine- or interferon-treatment in the past. All patients will receive PEGASYS, 180 micrograms s.c. weekly for 48 weeks, followed by 48 weeks of treatment-free follow-up. The anticipated time on study treatment is 3-12 months, and the target sample size is 100-500 individuals.	null	Hepatitis B, Chronic		null	1	arm 1: None	[ 0 ]	1	[ 0 ]	intervention 1: 180 micrograms sc weekly for 48 weeks	intervention 1: peginterferon alfa-2a [Pegasys]	23	Chelyabinsk \| N/A \| Russia \| 61.42915 \| 55.15402 Irkutsk \| N/A \| Russia \| 104.29585 \| 52.29795 Kazan' \| N/A \| Russia \| 49.12214 \| 55.78874 Krasnoyarsk \| N/A \| Russia \| 92.90765 \| 56.02668 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 Moscow \| N/A \| Russia \| 37.61556 \| 55.75222 Nizhny Novgorod \| N/A \| Russia \| 44.00205 \| 56.32867 Novokuznetsk \| N/A \| Russia \| 87.13599 \| 53.75752 Novosibirsk \| N/A \| Russia \| 82.94339 \| 55.03442 Rostov-on-Don \| N/A \| Russia \| 39.72328 \| 47.23135 Saint Petersburg \| N/A \| Russia \| 30.31413 \| 59.93863 Samara \| N/A \| Russia \| 50.15 \| 53.20007 Stavropol \| N/A \| Russia \| 41.9734 \| 45.0428 Tomsk \| N/A \| Russia \| 84.98204 \| 56.50032 Tyumen \| N/A \| Russia \| 65.52722 \| 57.15222 Ufa \| N/A \| Russia \| 55.96779 \| 54.74306 Volgograd \| N/A \| Russia \| 44.50183 \| 48.71939 Yakutsk \| N/A \| Russia \| 129.73306 \| 62.03389 Yekaterinburg \| N/A \| Russia \| 60.6122 \| 56.8519 Yekaterinburg \| N/A \| Russia \| 60.6122 \| 56.8519	18	0	0	0	NCT00487747	1COMPLETED	2009-10-01	2006-08-01	Hoffmann-La Roche	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	59	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	This is a Phase 3b/4, prospective, open-label, randomized, multicenter study of peginterferon alfa-2b plus ribavirin in participants with chronic hepatitis C, genotype 1. The study consists of two parts: (1) a noninterventional arm (HOMA IR \<= 2) and (2) an interventional arm (HOMA IR \> 2), where HOMA IR is the insulin resistance index for the participants calculated by fasting insulin (uU/mL) x \[fasting glucose (mmol/L)/22.5\]. Participants in the noninterventional arm are treated according to the European labeling and response rates are evaluated at Month 1 (optional), 3, 6, 12, and follow up. Participants in the interventional arm are treated with PEG-Intron 1.5 ug/kg (subcutaneous) once weekly plus weight-based REBETOL 800-1400 mg (oral capsules) daily for a variable period depending on their response at Week 12: (1) HCV-RNA positive with \< 2-log drop in viral load, treatment will be discontinued; (2) HCV-RNA positive with \>= 2-log drop in viral load; participants will be randomized (1:1) to Group A (stop treatment at Week 48) or Group B (stop treatment at Week 72); and (3) HCV-RNA negative, treatment will be changed to be according to the European labeling and response rates will be evaluated at Month 6, 12, and follow up. All participants will go on with their treatment after Week 12 until the results of the HCV polymerase chain reaction (PCR) are available (maximum of 4 weeks).	null	Hepatitis C, Chronic Insulin Resistance	homeostasis model assessment of insulin resistance	null	2	arm 1: HOMA IR (homeostasis model assessment-estimated insulin resistance) of \> 2 These participants received PEG-Intron 1.5 μg /kg subcutaneously (SC) once weekly plus weight based Rebetol 800-1400 mg by mouth (PO) administered twice daily (BID) for a variable period depending on their response to treatment. arm 2: HOMA IR \<= 2 These participants received PEG-Intron 1.5 μg /kg subcutaneously (SC) once weekly plus weight based Rebetol 800-1400 mg PO administered twice daily (BID) for 48 weeks. (Participants are treated according to European labeling).	[ 0, 0 ]	2	[ 0, 0 ]	intervention 1: 1. Powder for injection in Redipen (50, 80, 100, 120, and 150 microgram strengths), subcutaneous, dose of 1.5 micrograms/kg, weekly for 12 weeks, then up to 4 weeks until HCV PCR results are available, and then for another 36 weeks(Group A) or 60 weeks (Group B) postrandomization. 2. 200 mg capsules, oral, weight based dose of 800-1400 mg, daily for up to 12 weeks, then up to 4 weeks until HCV PCR results are available, and then for another 36 weeks (Group A) or 60 weeks (Group B) postrandomization intervention 2: 1. Powder for injection in Redipen (50, 80, 100, 120, and 150 microgram strengths), subcutaneous, dose of 1.5 micrograms/kg, weekly for 48 weeks 2. 200 mg capsules, oral, weight based dose of 800-1400 mg, daily for 48 weeks	intervention 1: Combination of pegylated interferon alfa-2b and ribavirin intervention 2: Combination of pegylated interferon alfa-2b and ribavirin	0	null	59	0	0	0	NCT00493805	6TERMINATED	2009-10-01	2007-04-01	Merck Sharp & Dohme LLC	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0
[ 5 ]	31	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	false	This was a study of the effects of VIVITROL® on alcohol cue-induced craving and the associated brain activation patterns in alcohol-dependent adults who had recently completed alcohol detoxification and were seeking further treatment for their alcohol dependence. The study was powered to to detect whether VIVITROL attenuates or blocks the BOLD signal increases in response to alcohol-related cues. In the double-blind portion, subjects received a single administration of study drug (VIVITROL 380 mg or placebo). Subjects who completed the double-blind portion could opt to continue to the open-label portion and receive 2 additional months of treatment with VIVITROL 380 mg.	The double-blind phase consisted of 6 visits over a 5- to 6-week period and included 2 telephone contacts and 2 functional magnetic resonance imaging (fMRI) scans. The optional open-label extension included 2 visits approximately 1 month apart. Subjects who completed both phases participated in a total of 8 scheduled visits (including 2 fMRI scans and 2 telephone contacts) over a period of up to 14 weeks. At screening, eligible, consenting subjects were given an Actiwatch®-Score device. They were instructed to record their alcohol craving using this device throughout the double-blind phase. The Actiwatch was programmed to beep every 3 hours ±20 minutes, thereby signaling the subjects to enter their craving or desire to use alcohol, at that exact moment, on a scale of 0 to 10 (with 0 being no craving at all and 10 being extreme craving). In addition, subjects entered any drug and/or alcohol use at the time of occurrence. The Actiwatch was not utilized in the open-label portion of the study.	Alcohol Dependence	alcoholism addiction alcohol detoxification	null	2	arm 1: None arm 2: None	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: Administered via intramuscular (IM) injection once during the double-blind phase and for 2 additional injections, 4 weeks apart, during the optional open-label extension. intervention 2: Placebo matching VIVITROL 380 mg was administered by IM injection once during the double-blind phase, only.	intervention 1: VIVITROL 380 mg intervention 2: Placebo	1	Belmont \| Massachusetts \| United States \| -71.17867 \| 42.39593	53	0	0	0	NCT00511836	1COMPLETED	2009-10-01	2007-07-01	Alkermes, Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0	0	0	0	0

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