Split (3)

train · 29.5k rows

FEATURE_phases list	FEATURE_enrollmentCount int64	FEATURE_allocation string	FEATURE_interventionModel string	FEATURE_primaryPurpose class label	FEATURE_masking class label	FEATURE_healthyVolunteers bool	FEATURE_sex class label	FEATURE_oversightHasDmc bool	FEATURE_briefSummary string	FEATURE_detailedDescription string	FEATURE_conditions string	FEATURE_conditionsKeywords string	FEATURE_protocolPdfText string	FEATURE_numArms int64	FEATURE_armDescriptions string	FEATURE_armGroupTypes list	FEATURE_numInterventions int64	FEATURE_interventionTypes list	FEATURE_interventionDescriptions string	FEATURE_interventionNames string	FEATURE_numLocations int64	FEATURE_locationDetails string	LABEL_ct_level_ade_population int64	LABEL_sum_dosing_errors int64	LABEL_dosing_error_rate float32	LABEL_wilson_label int64	METADATA_nctId string	METADATA_overallStatus class label	METADATA_completionDate date32	METADATA_startDate date32	METADATA_leadSponsorName string	METADATA_leadSponsorClass class label	METADATA_hasProtocol bool	METADATA_hasSap bool	METADATA_hasIcf bool	METADATA_protocolPdfLinks string	METADATA_count_Accidental overdose int64	METADATA_count_Incorrect dose administered int64	METADATA_count_Intentional overdose int64	METADATA_count_Overdose int64	METADATA_wilson_lower_bound float32
[ 4 ]	1,584	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	1FEMALE	true	This trial is designed to assess the safety and efficacy of flibanserin in the treatment of premenopausal women with Hypoactive Sexual Desire Disorder (HSDD) that meets standard diagnostic criteria. Efficacy for flibanserin will be assessed vs. a parallel placebo group.	null	Sexual Dysfunctions, Psychological		null	4	arm 1: flibanserin 25 mg b.i.d arm 2: flibanserin 50mg qhs/b.i.d arm 3: flibanserin 50mg b.i.d./100mg qhs arm 4: placebo comparator	[ 0, 0, 0, 2 ]	4	[ 0, 0, 0, 0 ]	intervention 1: flibanserin 25 mg b.i.d intervention 2: flibanserin 50mg qhs/b.i.d. intervention 3: flibanserin 50 mg b.i.d/100mg qhs intervention 4: placebo comparator	intervention 1: flibanserin intervention 2: flibanserin 50mg intervention 3: flibanserin 100mg intervention 4: placebo	77	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 Berkeley \| California \| United States \| -122.27275 \| 37.87159 Encinitas \| California \| United States \| -117.29198 \| 33.03699 Fair Oaks \| California \| United States \| -121.27217 \| 38.64463 Irvine \| California \| United States \| -117.82311 \| 33.66946 La Jolla \| California \| United States \| -117.2742 \| 32.84727 Sacremento \| California \| United States \| N/A \| N/A San Diego \| California \| United States \| -117.16472 \| 32.71571 Aurora \| Colorado \| United States \| -104.83192 \| 39.72943 Englewood \| Colorado \| United States \| -104.98776 \| 39.64777 Washington D.C. \| District of Columbia \| United States \| -77.03637 \| 38.89511 Coral Gables \| Florida \| United States \| -80.26838 \| 25.72149 Fort Meyers \| Florida \| United States \| N/A \| N/A Gainesville \| Florida \| United States \| -82.32483 \| 29.65163 Hollywood \| Florida \| United States \| -80.14949 \| 26.0112 Ocala \| Florida \| United States \| -82.14009 \| 29.1872 Orlando \| Florida \| United States \| -81.37924 \| 28.53834 Palm Bay \| Florida \| United States \| -80.58866 \| 28.03446 Sarasota \| Florida \| United States \| -82.53065 \| 27.33643 South Miami \| Florida \| United States \| -80.29338 \| 25.7076 St. Petersburg \| Florida \| United States \| -82.67927 \| 27.77086 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 West Palm Beach \| Florida \| United States \| -80.05337 \| 26.71534 Sandy Springs \| Georgia \| United States \| -84.37854 \| 33.92427 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Fort Wayne \| Indiana \| United States \| -85.12886 \| 41.1306 Lafayette \| Louisiana \| United States \| -92.01984 \| 30.22409 Bingham Farms \| Michigan \| United States \| -83.27326 \| 42.51587 Chaska \| Minnesota \| United States \| -93.60218 \| 44.78941 Chesterfield \| Missouri \| United States \| -90.57707 \| 38.66311 Kansas City \| Missouri \| United States \| -94.57857 \| 39.09973 Las Vegas \| Nevada \| United States \| -115.13722 \| 36.17497 New Brunswick \| New Jersey \| United States \| -74.45182 \| 40.48622 Chapel Hill \| North Carolina \| United States \| -79.05584 \| 35.9132 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Beachwood \| Ohio \| United States \| -81.50873 \| 41.4645 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Columbus \| Ohio \| United States \| -82.99879 \| 39.96118 Tulsa \| Oklahoma \| United States \| -95.99277 \| 36.15398 Eugene \| Oregon \| United States \| -123.08675 \| 44.05207 Medfod \| Oregon \| United States \| N/A \| N/A Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Jenkintown \| Pennsylvania \| United States \| -75.12517 \| 40.09594 Columbia \| South Carolina \| United States \| -81.03481 \| 34.00071 Greenville \| South Carolina \| United States \| -82.39401 \| 34.85262 Knoxville \| Tennessee \| United States \| -83.92074 \| 35.96064 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 Austin \| Texas \| United States \| -97.74306 \| 30.26715 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Fort Worth \| Texas \| United States \| -97.32085 \| 32.72541 Houston \| Texas \| United States \| -95.36327 \| 29.76328 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Waco \| Texas \| United States \| -97.14667 \| 31.54933 Charlottesville \| Virginia \| United States \| -78.47668 \| 38.02931 Norfolk \| Virginia \| United States \| -76.28522 \| 36.84681 Richmond \| Virginia \| United States \| -77.46026 \| 37.55376 Seattle \| Washington \| United States \| -122.33207 \| 47.60621 Middleton \| Wisconsin \| United States \| -89.50429 \| 43.09722 Coquitlam \| British Columbia \| Canada \| -122.78217 \| 49.2846 North Vancouver \| British Columbia \| Canada \| -123.06934 \| 49.31636 Woodstock \| New Brunswick \| Canada \| -67.58377 \| 46.15796 Mount Pearl \| Newfoundland and Labrador \| Canada \| -52.78135 \| 47.51659 Barrie \| Ontario \| Canada \| -79.66634 \| 44.40011 London \| Ontario \| Canada \| -81.23304 \| 42.98339 Ottawa \| Ontario \| Canada \| -75.69812 \| 45.41117 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Québec \| Quebec \| Canada \| -71.21454 \| 46.81228 Québec \| Quebec \| Canada \| -71.21454 \| 46.81228 Sherbrooke \| Quebec \| Canada \| -71.89908 \| 45.40008 Trois-Rivières \| Quebec \| Canada \| -72.5477 \| 46.34515 Saskatoon \| Saskatchewan \| Canada \| -106.66892 \| 52.13238	1,581	0	0	0	NCT00360555	1COMPLETED	2008-03-01	2006-07-01	Sprout Pharmaceuticals, Inc	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	15	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	The purpose of this study is to assess the safety of Beta-hCG + Erythropoietin in patients with acute ischemic stroke.	Patients with a new stroke will be evaluated at the University of California Irvine Medical Center (UCIMC), a JCAHO-certified Stroke Center, and at Hoag Memorial Hospital Presbyterian. Standard stroke pathways will be used to identify such patients and to initiate standard of care therapy. Patients potentially eligible for study enrollment will be identified, screened, then consented and enrolled. Those meeting all entry criteria, and no exclusion criteria, will undergo additional baseline testing including brain MRI. A 9-day course of B-E therapy will then begin, always within 48 hours after stroke onset. This therapy will consist of hCG (3 once-daily IM doses at 10,000 IU per dose, one day apart, on days 1, 3 and 5 of study participation), followed by a one day washout period (day 6), followed by Epo (three once-daily i.v. doses at 30,000 IU per dose on days 7, 8, and 9 of study participation). Patients will be examined at several time points during therapy, as well as 6 weeks and 3 months after stroke onset. The primary outcome measures are related to safety, while secondary outcome measures are related to disability, neurological status, and MRI measures.	Acute Stroke	Stroke	null	1	arm 1: All patients received erythropoietin and beta-hCG. This was the only treatment arm in the study, i.e., all enrollees received active therapy.	[ 0 ]	1	[ 0 ]	intervention 1: 10,000 IU Beta-hCG IV on days 1, 3, and 5 of study participation 30,000 IU Erythropoietin IV on days 7, 8 and 9 of study participation	intervention 1: Dual Growth Factor	1	Orange \| California \| United States \| -117.85311 \| 33.78779	15	0	0	0	NCT00362414	1COMPLETED	2008-03-01	2006-08-01	University of California, Irvine	7OTHER	false	false	false	null	0	0	0	0	0
[ 0 ]	24	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	false	The study hypothesis is that dextro-amphetamine (d-amphetamine) will be safe and effective when used to augment treatment for Obsessive-Compulsive Disorder (OCD), and that tolerance (loss of therapeutic effect) to the medication will not develop over a period of several weeks.	The study will investigate whether dextro-amphetamine (d-amphetamine) is safe and effective compared to caffeine as an active placebo when used to augment treatment for Obsessive-Compulsive Disorder (OCD), and whether tolerance (loss of therapeutic effect) to the medication will develop over a period of several weeks D-amphetamine is approved by the U.S. Food and Drug Administration to treat Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents. Because of the effects that d-amphetamine has on the brain, Dr. Koran believes it may be helpful in treating OCD. A positive finding in this study may stimulate research aimed at improving OCD treatment and understanding of the neurochemistry involved. This research study will enroll 24 people who are taking medication for their OCD but are not receiving sufficient benefit. The research will be performed only at Stanford University.	Obsessive-Compulsive Disorder	D-amphetamine, dextro-amphetamine, stimulant drug	null	2	arm 1: dextro-amphetamine capsules, 15 mg per capsule, in Bottles A and B, dose: one from Bottle A each morning and 1 from Bottle B each morning arm 2: caffeine in capsules identical to those containing d-amphetamine, with 200 mg of caffeine in Bottle A capsules, and 100 mg of caffeine in Bottle B capsules, dose was 1 capsule from Bottle A and 1 capsule from Bottle B each morning	[ 0, 3 ]	2	[ 0, 0 ]	intervention 1: dextro-amphetamine dosage form: 15 mg capsules, in Bottles A and B. Dosage: One capsule from Bottle A and one capsule from bottle B each morning. Frequency: once daily. Duration: 5 weeks. intervention 2: caffeine dosage form: capsules identical to those in dextro-amphetamine arm, but containing 200 mg caffeine in Bottle A and 100 mg caffeine in Bottle B. Frequency: once daily. Duration: 5 weeks	intervention 1: dextro-amphetamine intervention 2: Sham Comparison	1	Stanford \| California \| United States \| -122.16608 \| 37.42411	24	0	0	0	NCT00363298	1COMPLETED	2008-03-01	2006-08-01	Stanford University	7OTHER	false	false	false	null	0	0	0	0	0
[ 4 ]	115	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	This study is undertaken to compare the efficacy and onset of action of infliximab plus methotrexate (IFX + MTX) versus methotrexate alone (MTX) in methotrexate naïve active psoriatic arthritis patients.	null	Arthritis, Psoriatic		null	2	arm 1: Remicade (infliximab \[IFX\]) 5 mg/kg infusions at Weeks 0, 2, 6, 14 and oral methotrexate (MTX) 15 mg/week arm 2: Oral methotrexate (MTX) 15 mg/week	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: Infliximab 5 mg/kg infusion at Weeks 0, 2, 6, 14 and oral methotrexate 15 mg/week for 16 weeks. Methotrexate dose can be increased to 20 mg/week at week 6. intervention 2: Oral methotrexate 15 mg/week for 15 weeks. Dose can be increased to 20 mg/week at Week 6.	intervention 1: Infliximab + methotrexate (IFX + MTX) intervention 2: Methotrexate (MTX)	0	null	111	0	0	0	NCT00367237	1COMPLETED	2008-03-01	2006-05-01	Merck Sharp & Dohme LLC	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	44	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	true	The purpose of this study is to see if a naturally-occurring hormone called erythropoietin changes the action of platelets in the blood. Patients with heart attacks are treated with medicines to reduce the clotting action of platelets. This study is trying to determine whether erythropoietin alters the clotting action of platelets in patients receiving anti-platelet medicines. It is important to understand the effects of erythropoietin on platelets since preliminary studies in animals suggest that erythropoietin may protect the heart from damage during a heart attack.	Anti-apoptotic effects of erythropoietin in experimental myocardial infarction (MI) and ischemia-reperfusion injury suggest potential for therapeutic benefit in patients with acute MI. Before the therapeutic potential of recombinant human erythropoietin (rHuEpo) in acute MI can be tested in large clinical trials, more information on the effects of short-term rHuEpo on platelet function are needed. Accordingly, the current proposal aims to determine the effects of rHuEpo (at a dose previously shown not to inhibit the anti-platelet effects of aspirin and clopidogrel in healthy subjects) on platelet function and other safety measures and measure of infarct size in patients with acute coronary syndromes receiving clinically-indicated standard anti-platelet therapy with aspirin, clopidogrel and glycoprotein Iib-IIIa inhibitors. Specific Aim 1: To determine the effects of intravenous rHuEpo 400 U/kg daily for 3 days vs. placebo on in vivo and in vitro platelet function in patients with acute MI undergoing percutaneous revascularization. Specific Aim 2: To obtain pilot data to estimate the effects of administration of rHuEpo 400 U/kg daily for 3 days vs. placebo on biochemical markers of myocardial infarction size and left ventricular ejection fraction in patients with acute MI undergoing percutaneous revascularization	Myocardial Infarction	Platelet function tests Erythropoietin Myocardial infarction	null	2	arm 1: recombinant human erythropoietin 200 U/kg IV daily for 3 days arm 2: Normal saline volume to match active treatment IV daily for 3 days	[ 1, 2 ]	2	[ 0, 0 ]	intervention 1: 200 U/kg IV daily for 3 days vs. matched volume of normal saline IV daily for 3 days intervention 2: Normal saline to match active drug (rHuEpo)	intervention 1: Recombinant human erythropoietin alfa (drug) intervention 2: Placebo	1	New Haven \| Connecticut \| United States \| -72.92816 \| 41.30815	44	0	0	0	NCT00367991	1COMPLETED	2008-03-01	2006-11-01	Yale University	7OTHER	false	false	false	null	0	0	0	0	0
[ 2 ]	36	RANDOMIZED	CROSSOVER	7BASIC_SCIENCE	2DOUBLE	true	0ALL	null	The purpose of this study is to investigate the effects of smoked marijuana on both risk taking and decision making tasks.	Cannabis abuse and dependence are the most prevalent drug use disorders in the United States (Compton et al., 2004), yet little is known about the factors contributing to successful marijuana treatment. Previously, we have shown that cognitive impairments in patients treated for substance disorders are associated with premature treatment dropout. However, little is known about whether such impairments are the result of drug use per se. The objective of this within-subject study is to determine whether decision-making and risk-taking are affected by acute cannabis intoxication. The Balloon Analogue Risk Task (BART; Lejuez et al. 2002) assesses decision making in a context of increasing risk, and the Iowa Gambling Task (IGT; Bechara et al. 1994) tests the ability to balance immediate rewards against long-term negative consequences; both tasks have strong face validity for evaluating cognitive deficits that may contribute to poor treatment outcome. Research volunteers will be current marijuana smokers. Each will participate in three, 4-hour outpatient sessions in the Substance Use Research Center (SURC) in the Division of Substance Abuse at NYSPI. They will smoke a different strength marijuana cigarette (0.0, 1.98, 3.9% THC) in each session in counter-balanced order. After baseline data have been collected (risk taking and decision making behaviors, heart rate, blood pressure, mood scales, exhaled carbon monoxide), participants will take 3-6 puffs, 5 seconds in duration, from a National Institute on Drug Abuse (NIDA) marijuana cigarette. After smoking, we will repeatedly re-assess risk taking and decision making abilities with the BART and IGT. We will also measure subjective mood ratings, heart rate and blood pressure repeatedly for 180 minutes following smoking. This study is the first controlled investigation of the effects of smoked marijuana on both risk taking and decision making tasks. The data obtained will be used to guide treatment development for marijuana use disorders.	Marijuana Use Disorder	Cannabinoids Risk taking Decision making	null	2	arm 1: In this randomized, placebo-controlled study, every participant received all 3 treatment interventions in randomized order. Inactive marijuana (0% THC) served as a placebo comparator. Participants received an inactive marijuana cigarette (0% THC; provided by NIDA) in 1 of the 3 outpatient sessions in randomized order. arm 2: In this randomized, placebo-controlled study, every participant received all 3 treatment interventions in randomized order. Participants received active marijuana cigarettes (1.8, or 3.9% THC; provided by NIDA) over 2 of 3 outpatient sessions in randomized order.	[ 2, 0 ]	3	[ 0, 0, 0 ]	intervention 1: Placebo marijuana was administered using a cued-smoking procedure, which produces reliable increases in heart-rate and plasma THC. All marijuana cigarettes were administered in a double-blind fashion. intervention 2: Active marijuana (1.8 % THC) was administered using a cued-smoking procedure, which produces reliable increases in heart-rate and plasma THC. All marijuana cigarettes were administered in a double-blind fashion. intervention 3: Active marijuana (3.9%) was administered using a cued-smoking procedure, which produces reliable increases in heart-rate and plasma THC. All marijuana cigarettes were administered in a double-blind fashion.	intervention 1: Inactive Marijuana (0% THC) intervention 2: Low THC marijuana (1.8 %THC) intervention 3: High THC marijuana (3.9% THC)	1	New York \| New York \| United States \| -74.00597 \| 40.71427	108	0	0	0	NCT00373399	1COMPLETED	2008-03-01	2006-05-01	New York State Psychiatric Institute	7OTHER	false	false	false	null	0	0	0	0	0
[ 5 ]	64	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	true	Prevention and treatment of the severity of symptoms of chemotherapy-induced peripheral neuropathy.	This study was terminated on July 15, 2008. The results of an interim analysis showed that the conditional power to detect a difference in treatment groups was insufficient to warrant study continuation and therefore termination of the trial was recommended. The decision to terminate the trial was not based on safety concerns.	Chemotherapy-Induced Peripheral Neuropathy	Pain chemotherapy	null	2	arm 1: flexible dosing arm 2: None	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: 150- 600 mg/day (double blind in divided doses) intervention 2: Placebo	intervention 1: Pregabalin intervention 2: Placebo	15	St Leonards \| New South Wales \| Australia \| 151.19836 \| -33.82344 Adelaide \| South Australia \| Australia \| 138.59863 \| -34.92866 Bielefeld \| N/A \| Germany \| 8.53333 \| 52.03333 Essen \| N/A \| Germany \| 7.01228 \| 51.45657 Hamm \| N/A \| Germany \| 7.82089 \| 51.68033 Chieti Scalo \| N/A \| Italy \| N/A \| N/A Potenza \| N/A \| Italy \| 15.80794 \| 40.64175 Goyang-si \| Gyeonggi-do \| South Korea \| 126.835 \| 37.65639 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Santander \| Cantabria \| Spain \| -3.80444 \| 43.46472 Alicante \| N/A \| Spain \| -0.48149 \| 38.34517 Jaén \| N/A \| Spain \| -3.79028 \| 37.76922 Niao-Sung Hsiang \| Kaohsiung Hsien \| Taiwan \| N/A \| N/A Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306	61	0	0	0	NCT00380874	6TERMINATED	2008-03-01	2007-01-01	Pfizer's Upjohn has merged with Mylan to form Viatris Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 0 ]	9	RANDOMIZED	CROSSOVER	0TREATMENT	3TRIPLE	true	1FEMALE	true	The purpose of this research study is to evaluate if the medication gabapentin lessens the vulvar pain some women experience.	There is not a "best" treatment plan for vulvar pain including vulvodynia (chronic vulvar pain) and vulvar vestibulitis syndrome (VVS, chronic vulvar pain localized to the vaginal opening). We propose that vulvodynia is a neuropathic pain (pain that effects the nervous system) as characterized by pain from stimuli that is not usually painful, stimuli that would not usually be painful causing significant pain, and burning pain. Gabapentin has been shown to be effective in treating chronic pain.	Vulvar Pain Symptoms Vulvodynia (Chronic Vulvar Pain)	Vulvar Pain	null	2	arm 1: Gabapentin (Neurontin) titration and dosing for total of 8 weeks (Cross over) arm 2: Placebo titration and dosing for total of 8 weeks (Cross over)	[ 1, 2 ]	2	[ 0, 0 ]	intervention 1: 300 mg. capsules Dosage schedule for weeks 1 and 2 and weeks 12 and 13: 1. day 1 you will take 1 capsule for the day 2. day 2 you will take 1 capsule 2 times for that day 3. days 3-6 you will take 1 capsule 3 times for those days 4. days 7-9 you will take 1 capsule in am and 1 capsule at noon, 2 capsules at bedtime each day 5. days 10-12 you will take 1 capsule in am and 2 capsules at noon and 2 capsules at bedtime each day 6. days 13-14 you will take 2 capsules 3 times each day 7. continue on 2 capsules 3 times each day for 6 weeks after maximum dose of 1800 mg is reached after weeks 2 and 13. 8. at completion of study treatment you will titrate off study drug over a weeks time. intervention 2: Placebo capsules Dosage schedule for weeks 1 and 2 and weeks 12 and 13: 1. day 1 you will take 1 capsule for the day 2. day 2 you will take 1 capsule 2 times for that day 3. days 3-6 you will take 1 capsule 3 times for those days 4. days 7-9 you will take 1 capsule in am and 1 capsule at noon, 2 capsules at bedtime each day 5. days 10-12 you will take 1 capsule in am and 2 capsules at noon and 2 capsules at bedtime each day 6. days 13-14 you will take 2 capsules 3 times each day 7. continue on 2 capsules 3 times each day for 6 weeks after maximum dose of 1800 mg is reached after weeks 2 and 13. 8. at completion of study treatment you will titrate off study drug over a weeks time.	intervention 1: Gabapentin intervention 2: Placebo oral capsule	1	Iowa City \| Iowa \| United States \| -91.53017 \| 41.66113	12	0	0	0	NCT00390013	6TERMINATED	2008-03-01	2007-01-01	Colleen Stockdale	7OTHER	false	false	false	null	0	0	0	0	0
[ 0 ]	80	NON_RANDOMIZED	CROSSOVER	7BASIC_SCIENCE	2DOUBLE	true	0ALL	false	Treatment studies have demonstrated that current smoking cessation techniques are less effective for women. The purpose of this study is to determine the role that gender plays in the effectiveness of nicotine replacement therapy. In addition, the purpose of this study is to determine whether men and women differ in their response to smoking-related stimuli (e.g., taste or smell of a lit cigarette). Conclusions drawn from this study may help to improve cessation interventions for all smokers, particularly women.	Currently,about 70 percent of smokers who try to quit by using smoking cessation treatments are unsuccessful. Treatment studies have demonstrated that current smoking cessation techniques are less effective for women. There is no clear explanation for this difference, but it may involve a differential response to nicotine replacement treatments (NRTs) and/or smoking-related stimuli. For women, NRT may be less effective at suppressing withdrawal or blunting the effects of smoking during a quit attempt. Women may also be more sensitive to smoking-related stimuli, suc has the taste, sight, or smell of cigarette smoke. Tailoring treatments to the separate needs of smoker subgroups , such as men and women, my produce better cessation outcomes. The purpose of this study is to assess whether men and women differ in the their response to NRT (i.e., transdermal nicotine) and smoking-related stimuli. Participants in this double-blind, dose-comparison study will complete separate sessions in random order. Each session will last approximately 6.5 hours and will correspond to a transdermal patch dose (0 or 21mg) and cigarette type (denicotinized and nicotinized). Objectively verified cigarette abstinence will be required before each session. Sessions will occur at least 48 hours apart to avoid carryover. At the beginning of each session a patch will be placed on the participant's back and at 4, 5, and 6 hours after patch application the participant will smoke a cigarette (all identifying marking on the cigarette will be covered for blinding purposes). Physiological, subjective, cognitive, and smoking behavior outcomes will be collected during study visits.	Drug Addiction Smoking Cessation	Nicotine Replacement Therapy Tobacco Smoking Smoking stimuli Gender	null	4	arm 1: 21 mg patch/Nicotine-containing cigarette arm 2: 0 mg patch/nicotine-containing cigarette arm 3: 21 mg patch/no nicotine cigarette arm 4: 0 mg patch/no nicotine cigarette	[ 0, 0, 0, 0 ]	4	[ 0, 0, 10, 10 ]	intervention 1: 21 mg nicotine transdermal system intervention 2: Placebo nicotine patch intervention 3: Nicotine containing cigarette intervention 4: Non nicotine containing cigarette	intervention 1: nicotine transdermal system intervention 2: Nicotine transdermal system intervention 3: Nicotine containing cigarette intervention 4: Placebo cigarette	1	Richmond \| Virginia \| United States \| -77.46026 \| 37.55376	320	0	0	0	NCT00390559	1COMPLETED	2008-03-01	2005-10-01	Virginia Commonwealth University	7OTHER	false	false	false	null	0	0	0	0	0
[ 4 ]	154	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	null	The objective of double blind phase in this trial is to compare the efficacy and safety at the fixed dose of 0.25 mg,0.5 mg and 0.75 mg pramipexole in RLS. The objective of open label phase in this trial is to investigate the long term safety and efficacy of pramipexole in RLS.	null	Idiopathic Restless Legs Syndrome		null	3	arm 1: Pramipexole 0.25 mg given once daily arm 2: Pramipexole 0.5 mg given once daily arm 3: Pramipexole 0.75 mg given once daily	[ 0, 0, 0 ]	2	[ 0, 0 ]	intervention 1: None intervention 2: None	intervention 1: Pramipexole 0.125 mg tablet intervention 2: Pramipexole 0.5 mg tablet	34	Aichi-gun, Aichi \| N/A \| Japan \| 130.62158 \| 32.51879 Fujisawa, Kanagawa \| N/A \| Japan \| N/A \| N/A Fukuoka, Fukuoka \| N/A \| Japan \| N/A \| N/A Hiroshima, Hiroshima \| N/A \| Japan \| N/A \| N/A Kagoshima, Kagoshima \| N/A \| Japan \| N/A \| N/A Kanagawa, Yokohama \| N/A \| Japan \| N/A \| N/A Kanazawa, Ishikawa \| N/A \| Japan \| N/A \| N/A Kawasaki, Kanagawa \| N/A \| Japan \| N/A \| N/A Kitakyusyu, Fukuoka \| N/A \| Japan \| N/A \| N/A Kitakyusyu, Fukuoka \| N/A \| Japan \| N/A \| N/A Kochi, Kochi \| N/A \| Japan \| N/A \| N/A Kodaira, Tokyo \| N/A \| Japan \| N/A \| N/A Koriyama, Fukushima \| N/A \| Japan \| N/A \| N/A Koriyama, Fukushima \| N/A \| Japan \| N/A \| N/A Kumamoto, Kumamoto \| N/A \| Japan \| N/A \| N/A Kurume, Fukuoka \| N/A \| Japan \| N/A \| N/A Minato-ku, Tokyo \| N/A \| Japan \| N/A \| N/A Mitaka-shi, Tokyo \| N/A \| Japan \| 139.69171 \| 35.6895 Nagoya, Aichi \| N/A \| Japan \| N/A \| N/A Osaka, Osaka \| N/A \| Japan \| N/A \| N/A Otaru, Hokkaido \| N/A \| Japan \| 141.00222 \| 43.18944 Otsu, Shiga \| N/A \| Japan \| N/A \| N/A Sakai,Osaka \| N/A \| Japan \| N/A \| N/A Sapporo, Hokkaido \| N/A \| Japan \| 141.35 \| 43.06667 Sapporo, Hokkaido \| N/A \| Japan \| 141.35 \| 43.06667 Sendai, Miyagi \| N/A \| Japan \| N/A \| N/A Shibuya-ku, Tokyo \| N/A \| Japan \| 139.69171 \| 35.6895 Shimotsuga-gun,Tochigi \| N/A \| Japan \| 139.73333 \| 36.38333 Shinjuku-ku, Tokyo \| N/A \| Japan \| 139.69171 \| 35.6895 Takatsuki,Osaka \| N/A \| Japan \| N/A \| N/A Tokorozawa, Saitama \| N/A \| Japan \| N/A \| N/A Tokushima, Tokushima \| N/A \| Japan \| N/A \| N/A Toyohashi, Aichi \| N/A \| Japan \| N/A \| N/A Urasoe, Okinawa \| N/A \| Japan \| N/A \| N/A	440	0	0	0	NCT00390689	1COMPLETED	2008-03-01	2006-10-01	Boehringer Ingelheim	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	567	RANDOMIZED	PARALLEL	1PREVENTION	2DOUBLE	true	1FEMALE	false	This is a 4-arm study to evaluate and compare bleeding patterns between three different doses of DR-1031 oral contraceptive with Seasonale oral contraceptive. Study participants will receive physical and gynecological exams, including Pap smear. During the study, all participants will be required to complete a diary	This Phase 2, prospective, multicenter, double-blinded, randomized study is designed to evaluate and compare bleeding patterns in women using one of three different doses of DR-1031 oral contraceptive with Seasonale oral contraceptive. Patients who meet all study entrance criteria will be randomly assigned to one of four treatment groups, The overall study duration will be approximately 9 months; this will include a screening period of approximately 4 weeks, a run-in period of 4 weeks, a treatment period of approximately 6 months (two,91-day cycles) and a final study visit occurring 14-21 days after completion of study drug.	Breakthrough Bleeding	oral contraceptives breakthrough bleeding spotting	null	4	arm 1: 42 days combination active tablets (20 mcg EE /150 mcg LNG) followed by 21 days combination active tablets (25 mcg EE/150 mcg LNG) followed by 21 days combination active tablets (30 mcg EE/ 150 mcg LNG) followed by 7 days of 10 mcg EE tablets. arm 2: 21 days combination active tablets (20 mcg EE /150 mcg LNG) followed by 42 days combination active tablets (25 mcg EE/ 150 mcg LNG) followed by 21 days combination active tablets (30 mcg EE/ 150 mcg LNG) followed by 7 days of 10 mcg EE tablets. arm 3: 21 days combination active tablets (20 mcg EE /150 mcg LNG) followed by 21 days combination active tablets (25 mcg EE/150 mcg LNG) followed by 42 days combination active tablets (30 mcg EE/ 150 mcg LNG) followed by 7 days of 10 mcg EE tablets. arm 4: 84 days of combination active tablets, each containing 30 mcg EE and 150 mcg LNG, followed by 7 days of placebo tablets.	[ 0, 0, 0, 1 ]	3	[ 0, 0, 0 ]	intervention 1: Active therapy cycle of 84 days taking combination tablets containing ascending doses of ethinyl estradiol (EE) and 150 mcg levonorgestrel (LNG), followed by a 7-day withdrawal cycle of 10 mcg EE. The total extended cycle was 91 days and participants were to complete two extended cycles. Active therapy dosage of EE varied by treatment arm. intervention 2: 84 days of combination active tablets, each containing 30 mcg EE and 150 mcg LNG, followed by 7 days of placebo tablets for two consecutive 91-day cycles. intervention 3: Portia® 28 consists of 21 pink active tablets, each containing 0.15 mg of levonorgestrel and 0.03 mg of ethinyl estradiol, and seven white inert tablets. Portia was taken as a pre-study run-in medication.	intervention 1: DR-1031 intervention 2: Seasonale® intervention 3: Portia®	50	Huntsville \| Alabama \| United States \| -86.58594 \| 34.7304 Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 San Diego \| California \| United States \| -117.16472 \| 32.71571 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Santa Ana \| California \| United States \| -117.86783 \| 33.74557 Vista \| California \| United States \| -117.24254 \| 33.20004 Pueblo \| Colorado \| United States \| -104.60914 \| 38.25445 Stratford \| Connecticut \| United States \| -73.13317 \| 41.18454 DeLand \| Florida \| United States \| -81.30312 \| 29.02832 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 Melbourne \| Florida \| United States \| -80.60811 \| 28.08363 Miami \| Florida \| United States \| -80.19366 \| 25.77427 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 West Palm Beach \| Florida \| United States \| -80.05337 \| 26.71534 West Palm Beach \| Florida \| United States \| -80.05337 \| 26.71534 Alpharetta \| Georgia \| United States \| -84.29409 \| 34.07538 Douglasville \| Georgia \| United States \| -84.74771 \| 33.7515 Savannah \| Georgia \| United States \| -81.09983 \| 32.08354 Boise \| Idaho \| United States \| -116.20345 \| 43.6135 Meridian \| Idaho \| United States \| -116.39151 \| 43.61211 Fort Wayne \| Indiana \| United States \| -85.12886 \| 41.1306 Wichita \| Kansas \| United States \| -97.33754 \| 37.69224 Baton Rouge \| Louisiana \| United States \| -91.18747 \| 30.44332 Metairie \| Louisiana \| United States \| -90.15285 \| 29.98409 Shreveport \| Louisiana \| United States \| -93.75018 \| 32.52515 Riverdale \| Maryland \| United States \| -76.5358 \| 39.09928 Kansas City \| Missouri \| United States \| -94.57857 \| 39.09973 Las Vegas \| Nevada \| United States \| -115.13722 \| 36.17497 Las Vegas \| Nevada \| United States \| -115.13722 \| 36.17497 North Las Vegas \| Nevada \| United States \| -115.1175 \| 36.19886 Lebanon \| New Hampshire \| United States \| -72.25176 \| 43.64229 Cary \| North Carolina \| United States \| -78.78112 \| 35.79154 New Bern \| North Carolina \| United States \| -77.04411 \| 35.10849 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Mayfield Heights \| Ohio \| United States \| -81.4579 \| 41.51922 Eugene \| Oregon \| United States \| -123.08675 \| 44.05207 Medford \| Oregon \| United States \| -122.87559 \| 42.32652 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Charleston \| South Carolina \| United States \| -79.93275 \| 32.77632 Columbia \| South Carolina \| United States \| -81.03481 \| 34.00071 Hilton Head Island \| South Carolina \| United States \| -80.73816 \| 32.19382 Jackson \| Tennessee \| United States \| -88.81395 \| 35.61452 Austin \| Texas \| United States \| -97.74306 \| 30.26715 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 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Williston \| Vermont \| United States \| -73.06818 \| 44.43755	567	0	0	0	NCT00394771	1COMPLETED	2008-03-01	2006-10-01	Duramed Research	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 5 ]	46	RANDOMIZED	CROSSOVER	2DIAGNOSTIC	3TRIPLE	false	0ALL	false	Compare the efficacy of MultiHance and Magnevist	The purpose of this study was to evaluate whether Multihance is superior to Magnevist in terms of qualitative and quantitative assessment of unenhanced MRI and contrast-enhanced MRI for the visualization of brain disease.	Brain Tumor		null	2	arm 1: 0.5 M MultiHance at a single injection arm 2: 0.5 M Magnevist at a single injection	[ 1, 1 ]	2	[ 0, 0 ]	intervention 1: 0.5 M at a single injection intervention 2: 0.5 M Magnevist at a single dose injection	intervention 1: Multihance intervention 2: Arm 2 - Magnevist	1	Princeton \| New Jersey \| United States \| -74.65905 \| 40.34872	87	0	0	0	NCT00395863	1COMPLETED	2008-03-01	2006-11-01	Bracco Diagnostics, Inc	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	243	RANDOMIZED	FACTORIAL	0TREATMENT	4QUADRUPLE	false	0ALL	null	To deterime the efficacy of 500 μg and 300 μg darbepoetin alfa administered subcutaneously (SC) on an every 3 weeks (Q3W) schedule, and the effect of intravenous (IV) iron supplementation in the treatment of anemia in patients with non-myeloid malignancies who were receiving multicycle chemotherapy.	null	Anemia Non-Myeloid Malignancies	anemia chemotherapy induced anemia darbepoetin alfa cancer	null	4	arm 1: Darbepoetin alfa 300 μg subcutaneous injection plus intravenous (IV) iron 400 mg, every three weeks (Q3W), for up to 15 weeks (a total of 5 doses). arm 2: Darbepoetin alfa 300 μg subcutaneous injection every three weeks (Q3W), for up to 15 weeks (a total of 5 doses). arm 3: Darbepoetin alfa 500 μg subcutaneous injection every three weeks (Q3W), for up to 15 weeks (a total of 5 doses). arm 4: Darbepoetin alfa 500 μg subcutaneous injection plus intravenous (IV) iron 400 mg, every three weeks (Q3W), for up to 15 weeks (a total of 5 doses).	[ 0, 0, 0, 1 ]	2	[ 0, 0 ]	intervention 1: Darbepoetin alfa administered by subcutaneous injection. intervention 2: Administered by intravenous (IV) injection.	intervention 1: darbepoetin alfa intervention 2: IV iron dextran	0	null	238	0	0	0	NCT00401544	1COMPLETED	2008-03-01	2006-12-01	Amgen	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	118	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	true	0ALL	null	After a steady decline for the last 50 years, the prevalence of tobacco use in the United States has reached a plateau of approximately 23%. Currently available treatments among adults are expensive and not efficacious for all tobacco users. New pharmacologic agents need to be developed and tested to achieve the Healthy People 2010 goal of less than a 12% adult tobacco use prevalence. Bupropion, an FDA approved agent for tobacco cessation, acts by inhibiting central synaptosomal reuptake of dopamine and norepinephrine. A widely used herbal antidepressant, St. John's Wort (SJW), shares a similar mechanism of action and is effective for treating mild to moderate depression. SJW is well tolerated, available over the counter, and is significantly less expensive than the established treatments for tobacco dependence. To date, no prospective clinical trial evaluating the efficacy of SJW for the treatment of tobacco use has been published. We propose to evaluate the efficacy of SJW for increasing tobacco abstinence and decreasing nicotine withdrawal symptoms in a randomized, double-blind, placebo-controlled, three-arm, parallel group, dose-ranging clinical trial. Participants (N=120) will be randomly assigned to one of the three groups and will receive a twelve-week course of SJW 900 mg per day, 1800 mg per day, or a matching placebo. This study is anticipated to provide the data needed to develop a larger randomized controlled clinical trial submitted through the R01 funding mechanism.	Cigarette smoking is the single most important preventable cause of morbidity, mortality and excess health care costs in the United States. The prevalence of cigarette smoking among U.S. adults has declined from 42% in 1965 to 20.9% in 2004. However, the overall decline is not occurring at a rate that will meet national health objectives by 2010. Available pharmacotherapies for the treatment of tobacco dependence are not efficacious for all tobacco users and have an overall estimated efficacy of approximately 20% for long-term tobacco cessation. Thus, novel pharmacotherapies for tobacco cessation need to be explored. Current smokers tend to be younger with less education and belong to a lower socioeconomic status. Tobacco cessation treatments are expensive and often not covered by Medicare, Medicaid, or third party-payers. Our goal is to evaluate novel, safe, acceptable, effective, and inexpensive therapies that will increase tobacco abstinence rates. The United States Public Health Service (USPHS) guideline recommends nicotine replacement therapy and bupropion as first-line agents for the treatment of tobacco dependence. Bupropion acts by central dopamine and norepinephrine reuptake inhibition. St. John's Wort (SJW), a widely used herbal product to treat mild to moderate depression, shares a similar mechanism of action and is available as a tobacco cessation aid in a number of over-the-counter preparations. While currently approved pharmacotherapies for tobacco dependence cost between $120-$240 per month, SJW is relatively inexpensive ($15 per month) and is well-tolerated. At present, no randomized prospective study of St. John's Wort for tobacco cessation has been published. We plan to test the efficacy of SJW for tobacco cessation in a randomized, double-blind, placebo-controlled, three-arm, parallel group, dose-ranging clinical trial. We will obtain preliminary data about the efficacy of two different oral doses of SJW for improving tobacco abstinence rates and decreasing symptoms of nicotine withdrawal. All subjects will receive a behavioral intervention during participation in the study. A total of 120 subjects will be recruited into the study and randomly allocated to one of the three groups (groups A, B, and C). Participants in group A will receive SJW 300-mg three times a day for twelve weeks while participants in group B will receive SJW 600-mg three times a day for twelve weeks. Participants in group C will receive a matching placebo for the same duration. We will conduct this research through the Nicotine Research Program (NRP) at the Mayo Clinic in Rochester, Minnesota. We are uniquely situated for completing this research as more than 7,500 patients have been enrolled in over 75 clinical trials conducted through the NRP. We propose the following specific aims: Primary Aims: 1\. To obtain preliminary evidence of the effect of a 12-week course of SJW in two different oral doses of 300-mg three times a day or 600-mg three times a day compared to placebo on the 7-day point prevalence tobacco abstinence rates at end of treatment and six months in 120 smokers. Hypothesis: Cigarette smokers who receive SJW in two different oral doses of 300-mg three times a day or 600-mg three times a day for 12 weeks will have higher 7-day point prevalence tobacco abstinence rates at end of treatment and six months compared to cigarette smokers receiving placebo. Secondary Aim: 1\. To obtain preliminary estimates of the effect of a 12-week course of SJW in two different oral doses of 300-mg three times a day or 600-mg three times a day compared to placebo on prolonged tobacco abstinence rates at six months. Hypothesis: Cigarette smokers who receive SJW in two different oral doses of 300-mg three times a day or 600-mg three times a day for 12-weeks will have higher prolonged tobacco abstinence rates at six months compared to cigarette smokers receiving placebo. This study is innovative in that we are testing a novel therapeutic agent for the treatment of tobacco use. At the completion of this study, we expect to have obtained preliminary evidence regarding the effect of two different doses of SJW on symptoms of nicotine withdrawal and tobacco abstinence. We will also collect information on adverse effects of SJW in tobacco users and obtain data to plan a larger Phase III clinical trial, if the results from this trial suggest a potential for efficacy.	Smoking Nicotine Dependence		null	3	arm 1: Placebo pill was identical in appearance to the active medication. arm 2: St. John's Wort - 300 mg tablets, 3 times a day. arm 3: St. John's Wort - 600 mg 3 times per day	[ 2, 0, 0 ]	3	[ 0, 0, 0 ]	intervention 1: Placebo (inactive drug) given 3 times per day intervention 2: St. John's Wort - 300 mg tables -3 times per day intervention 3: St. John's Wort - 600 mg tables - 3 times per day	intervention 1: Placebo intervention 2: St. John's Wort-900 mg/day intervention 3: St. John's Wort-1800mg/day	1	Rochester \| Minnesota \| United States \| -92.4699 \| 44.02163	118	0	0	0	NCT00405912	1COMPLETED	2008-03-01	2005-09-01	Mayo Clinic	7OTHER	false	false	false	null	0	0	0	0	0
[ 3 ]	142	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	null	This study will assess the frequency of chromosomal abnormalities measured in circulating lymphocytes in treatment-naive children with Attention Deficit Hyperactivity Disorder (ADHD) treated for 3 months with either extended release methylphenidate or behavioral therapy.	This study will determine whether the administration of extended-release methylphenidate in treatment-naïve children with Attention Deficit Hyperactivity Disorder (ADHD) affects the frequency of chromosomal abnormalities.	Attention Deficit Hyperactivity Disorder	Attention Deficit Hyperactivity Disorder, ADHD Cytogenetic abnormalities, extended-release methylphenidate,	null	2	arm 1: None arm 2: None	[ 1, 5 ]	2	[ 0, 5 ]	intervention 1: None intervention 2: None	intervention 1: Extended Release Methylphenidate (Ritalin LA ) plus Behavior Therapy intervention 2: Behavior Therapy	1	Houston \| Texas \| United States \| -95.36327 \| 29.76328	104	0	0	0	NCT00409708	1COMPLETED	2008-03-01	2006-11-01	Novartis	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 4 ]	467	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	Open-Label, Safety Study to evaluate the long-term safety of Kadian NT (ALO-01) administered for up to 12 months.	null	Pain	chronic pain joint pain back pain diabetic peripheral neuropathy post herpetic neuralgia ALO-01 Embeda Chronic Non-Malignant Pain	null	1	arm 1: Doses given once or twice daily	[ 0 ]	1	[ 0 ]	intervention 1: capsules, available dosage strengths 20, 30, 40, 50, 60, 80, and 100 mg morphine sulfate with 4% by weight naltrexone hydrochloride given once or twice daily	intervention 1: ALO-01 (Morphine Sulfate Plus Naltrexone Hydrochloride ER)	58	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 Tempe \| Arizona \| United States \| -111.90931 \| 33.41477 Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 Anaheim \| California \| United States \| -117.9145 \| 33.83529 Anaheim \| California \| United States \| -117.9145 \| 33.83529 Bakersfield \| California \| United States \| -119.01871 \| 35.37329 Beverly Hills \| California \| United States \| -118.40036 \| 34.07362 Fair Oaks \| California \| United States \| -121.27217 \| 38.64463 Delray Beach \| Florida \| United States \| -80.07282 \| 26.46146 Hialeah \| Florida \| United States \| -80.27811 \| 25.8576 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 Kissimmee \| Florida \| United States \| -81.41667 \| 28.30468 Largo \| Florida \| United States \| -82.78842 \| 27.90979 Ormond Beach \| Florida \| United States \| -81.05589 \| 29.28581 Plantation \| Florida \| United States \| -80.23184 \| 26.13421 St. Petersburg \| Florida \| United States \| -82.67927 \| 27.77086 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 Blue Ridge \| Georgia \| United States \| -84.32409 \| 34.86397 Marietta \| Georgia \| United States \| -84.54993 \| 33.9526 Marietta \| Georgia \| United States \| -84.54993 \| 33.9526 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Peoria \| Illinois \| United States \| -89.58899 \| 40.69365 Evansville \| Indiana \| United States \| -87.55585 \| 37.97476 West Des Moines \| Iowa \| United States \| -93.71133 \| 41.57721 Shreveport \| Louisiana \| United States \| -93.75018 \| 32.52515 North Dartmouth \| Massachusetts \| United States \| -70.97032 \| 41.63899 Springfield \| Massachusetts \| United States \| -72.58981 \| 42.10148 Saginaw \| Michigan \| United States \| -83.95081 \| 43.41947 Florissant \| Missouri \| United States \| -90.32261 \| 38.78922 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Missoula \| Montana \| United States \| -113.994 \| 46.87215 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 Henderson \| Nevada \| United States \| -114.98194 \| 36.0397 Las Vegas \| Nevada \| United States \| -115.13722 \| 36.17497 Las Vegas \| Nevada \| United States \| -115.13722 \| 36.17497 Voorhees Township \| New Jersey \| United States \| -74.49062 \| 40.4795 Albuquerque \| New Mexico \| United States \| -106.65114 \| 35.08449 Mount Vernon \| New York \| United States \| -73.83708 \| 40.9126 Charlotte \| North Carolina \| United States \| -80.84313 \| 35.22709 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Toledo \| Ohio \| United States \| -83.55521 \| 41.66394 Oklahoma City \| Oklahoma \| United States \| -97.51643 \| 35.46756 Eugene \| Oregon \| United States \| -123.08675 \| 44.05207 Tipton \| Pennsylvania \| United States \| -78.29585 \| 40.6359 Greer \| South Carolina \| United States \| -82.22706 \| 34.93873 Knoxville \| Tennessee \| United States \| -83.92074 \| 35.96064 Milan \| Tennessee \| United States \| -88.75895 \| 35.91979 Austin \| Texas \| United States \| -97.74306 \| 30.26715 Richardson \| Texas \| United States \| -96.72972 \| 32.94818 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Roanoke \| Virginia \| United States \| -79.94143 \| 37.27097	465	0	0	0	NCT00415597	1COMPLETED	2008-03-01	2006-12-01	Pfizer	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 2 ]	60	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	The purpose of this trial is to evaluate the safety and effectiveness of lowering blood pressure using nicardipine in persons with acute hypertension associated with intracerebral hemorrhage.	An estimated 37,000 to 52,400 people in the United States have intracerebral hemorrhage (ICH) every year. ICH--a form of stroke that has poor outcome and is difficult to treat--is associated with the highest mortality rate of all strokes. Hematoma expansion has been identified as the most common cause of neurological deterioration in persons with ICH. Early evidence suggests that acute hypertension (HTN)-or elevated blood pressure-may make some individuals more susceptible to hematoma expansion. Treating HTN acutely may prevent hematoma expansion, however, the effect of aggressive HTN treatment has not been determined. The purpose of this trial is to evaluate the treatment feasibility and safety of lowering blood pressure using nicardipine--an antihypertensive medication--in persons who have acute HTN associated with ICH. This pilot study will enroll 60 individuals who qualify with a presenting systolic blood pressure of at least 170 mmHg, have an ICH, and can be evaluated and treatment initiated within 6 hours of onset of stroke symptoms. In a stepwise fashion, the scientists will investigate the potential consequences of controlling blood pressure with intravenous nicardipine at 3 sequential levels: 170 to 200 mmHg, 140 to 170 mmHg, and 110 to 140 mmHg. Twenty participants will be enrolled per level. Treatment will last 18 to 24 hours. Participants will stay in the hospital for about 7 days (including 24 hours in the intensive care unit for close monitoring) and will return for 1-hour follow-up visits at 30 days and at 90 days after discharge from the hospital. During these visits participants will receive neurological assessments to determine their functional outcome. For participants, the study will be completed after the 90-day follow-up visit.	Intracerebral Hemorrhage Hypertension Stroke	cerebral hemorrhage intracerebral hemorrhage stroke hypertension blood pressure nicardipine antihypertensive agent hematoma expansion	null	3	arm 1: Dose escalation: The scientists will investigate the potential consequences of controlling blood pressure with intravenous nicardipine to a range between 170 to 200 mmHg. Treatment with nicardipine must begin within 6 hours of symptom onset and will continue for an estimated 18 - 24 hours, until SBP is stabilized. The assigned SBP range will be maintained for 24 hours. After 24 hours, management of blood pressure is at the discretion of the primary physician. arm 2: Dose escalation: The scientists will investigate the potential consequences of controlling blood pressure with intravenous nicardipine to a range between 140 to 170 mmHg. Treatment with nicardipine must begin within 6 hours of symptom onset and will continue for an estimated 18 - 24 hours, until SBP is stabilized. The assigned SBP range will be maintained for 24 hours. After 24 hours, management of blood pressure is at the discretion of the primary physician. arm 3: Dose escalation: The scientists will investigate the potential consequences of controlling blood pressure with intravenous nicardipine to a range between 110 to 140 mmHg. Treatment with nicardipine must begin within 6 hours of symptom onset and will continue for an estimated 18 - 24 hours, until SBP is stabilized. The assigned SBP range will be maintained for 24 hours. After 24 hours, management of blood pressure is at the discretion of the primary physician.	[ 5, 5, 5 ]	1	[ 0 ]	intervention 1: Intravenous (IV) nicardipine infusion. It is expected that the treatment duration will vary between 18 and 24 hours. * Started at 5mg/h * Titrated by 2.5mg/hour every 15 minutes to bring systolic blood pressure in target range for the applicable Tier. Max dose 15mg/hour \*Once target systolic blood pressure reached, dose decreased by 2.5mg/hour every 15 minutes until systolic blood pressure maintained in the target range or the medication is discontinued.	intervention 1: nicardipine	12	Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Kansas City \| Kansas \| United States \| -94.62746 \| 39.11417 Kansas City \| Kansas \| United States \| -94.62746 \| 39.11417 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Minneapolis \| Minnesota \| United States \| -93.26384 \| 44.97997 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Edison \| New Jersey \| United States \| -74.4121 \| 40.51872 Newark \| New Jersey \| United States \| -74.17237 \| 40.73566 New York \| New York \| United States \| -74.00597 \| 40.71427 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Columbus \| Ohio \| United States \| -82.99879 \| 39.96118 Charleston \| South Carolina \| United States \| -79.93275 \| 32.77632	60	0	0	0	NCT00415610	1COMPLETED	2008-03-01	2005-07-01	University of Minnesota	7OTHER	false	false	false	null	0	0	0	0	0
[ 3 ]	48	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	null	This is a randomized, double-blind, placebo-controlled, parallel group study to determine the maximum tolerated dose of E2007. Epilepsy patients with refractory partial seizures will be divided into two groups of 24 patients each. One group will be patients who take concomitant inducing AEDs (anti-epileptic drugs) and the second group will be patients who do not take concomitant inducing AEDs. In each group, 18 patients will receive E2007 (dose escalating to a maximum of 12 mg per day) and six will receive placebo.	null	Epilepsy		null	2	arm 1: 2 mg E2007 once daily for 2 weeks (Days 1 to 14), then 4 mg E2007 once daily for 2 weeks (Days 15 to 28), then 6 mg E2007 once daily for 2 weeks (Days 29 to 42), then 8 mg E2007 once daily for 2 weeks (Days 43 to 56), then 10 mg E2007 once daily for 2 weeks (Days 57 to 70), then 12 mg E2007 once daily for 6 weeks (Days 71 to 112). arm 2: Matching placebo once daily for 16 weeks (Days 1 to 112)	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: None intervention 2: None	intervention 1: E2007 intervention 2: Placebo	2	Riga \| N/A \| Latvia \| 24.10589 \| 56.946 Riga \| N/A \| Latvia \| 24.10589 \| 56.946	48	0	0	0	NCT00416195	1COMPLETED	2008-03-01	2006-12-01	Eisai Co., Ltd.	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	1	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	RATIONALE: Giving low doses of chemotherapy, such as fludarabine, and total-body irradiation (TBI) before a donor stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) that have been treated in the laboratory after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine and alemtuzumab, and removing the T lymphocyte cells(T cells) from the donor cells before transplant, may stop this from happening. PURPOSE: This clinical trial is studying how well giving fludarabine, alemtuzumab, and total-body irradiation together with donor stem cell transplant and donor white blood cell (WBC) infusion works in treating patients with chronic phase chronic myelogenous leukemia (CML) that did not respond to previous imatinib mesylate.	OBJECTIVES: * Determine the treatment-related mortality in patients with imatinib mesylate-resistant chronic phase chronic myelogenous leukemia treated with nonmyeloablative conditioning comprising fludarabine, alemtuzumab, and total-body irradiation followed by T-cell-depleted allogeneic stem cell transplantation and post-transplantation allogeneic T-cell infusion. * Determine if donor engraftment can be safely established using partial T-cell depletion with additional T-cell infusions in these patients. OUTLINE: Patients receive alemtuzumab IV over 5-6 hours on day -8 and fludarabine IV on days -4 to -2. Patients undergo total-body irradiation followed by T-cell-depleted (CD34+ selected) allogeneic stem cell transplantation on day 0. Patients receive allogeneic T-cell infusion on days 30 and 60. Patients also receive cyclosporine twice daily beginning on day -3 and continuing until day 100 followed by a taper until day 177. PROJECTED ACCRUAL: Not specified.	Leukemia	chronic phase chronic myelogenous leukemia childhood chronic myelogenous leukemia relapsing chronic myelogenous leukemia	null	1	arm 1: (Campath) 30 mg on day -8 over 5-6 hours, Fludarabine 30 mg/m\^2 on day -4 through day -2, Total body irradiation single fraction 200 cGy at 7 cGy per minute on day 0., Stem cells will be T cell depleted and given on day 0	[ 0 ]	4	[ 0, 0, 4, 10 ]	intervention 1: 30 mg on day -8 over 5-6 hours intervention 2: Fludarabine 30 mg/m\^2 on day -4 through day -2 intervention 3: Total body irradiation single fraction 200 cGy at 7 cGy per minute on day 0 intervention 4: Stem cells will be T cell depleted and given on day 0	intervention 1: Campath intervention 2: Fludarabine intervention 3: Total Body Irradiation (TBI) intervention 4: T-Cell Deplete	1	Portland \| Oregon \| United States \| -122.67621 \| 45.52345	1	0	0	0	NCT00416884	6TERMINATED	2008-03-01	2003-05-01	OHSU Knight Cancer Institute	7OTHER	false	false	false	null	0	0	0	0	0
[ 3 ]	469	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	false	This is a study to assess the safety and effectiveness of LY2216684 compared to placebo in treating adults with major depressive disorder.	null	Major Depressive Disorder		null	3	arm 1: LY2216684: flexible dose of 3, 6, 9, or 12 milligrams (mg), tablets, administered orally, once daily for 8 weeks. For the first week of treatment, participants received a starting dose of 3 mg/day. Then, based on tolerability, for the next 7 weeks, the dose could remain at 3 mg/day; it could be increased 3 mg at a time (scheduled visit) to a maximum dose of 12 mg/day; or it could be decreased 3 mg at any time (scheduled or unscheduled visits) to a minimum dose of 3 mg/day. All participants were required to take an equal number of tablets (2) and capsules (2) per day. Therefore, participants on 3 mg/day and 6 mg/day of LY2216684 also received 1 LY2216684-matching placebo tablet + 2 escitalopram-matching placebo capsules. Participants on 9 mg/day and 12 mg/day of LY2216684 also received 2 escitalopram-matching placebo capsules. arm 2: Placebo: tablet and capsule equivalents to LY2216684 and escitalopram, respectively, administered orally, once daily for 8 weeks. arm 3: Escitalopram: flexible dose of 10 or 20 milligram (mg), capsules, administered orally, once daily for 8 weeks. For the first week of treatment, participants received a starting dose of 10 mg/day. Then, based on tolerability, for the next 7 weeks, the dose could remain at 10 mg/day; it could be increased up to a maximum dose of 20 mg/day; or it could be decreased back to 10 mg/day. All participants were required to take an equal number of tablets (2) and capsules (2) per day. Therefore, participants on 10 mg/day of escitalopram also received 1 escitalopram-matching placebo capsule + 2 LY2216684-matching placebo tablets. Participants on 20 mg/day of escitalopram also received 2 LY2216684-matching placebo tablets.	[ 0, 2, 1 ]	3	[ 0, 0, 0 ]	intervention 1: 3-mg and 6-mg tablets intervention 2: None intervention 3: 10-mg capsules	intervention 1: LY2216684 intervention 2: Placebo intervention 3: Escitalopram	7	Orlando \| Florida \| United States \| -81.37924 \| 28.53834 Prairie Village \| Kansas \| United States \| -94.63357 \| 38.99167 Allentown \| Pennsylvania \| United States \| -75.49018 \| 40.60843 Media \| Pennsylvania \| United States \| -75.38769 \| 39.91678 Bucharest \| N/A \| Romania \| 26.10626 \| 44.43225 Cluj-Napoca \| N/A \| Romania \| 23.6 \| 46.76667 Lasi \| N/A \| Romania \| N/A \| N/A	938	0	0	0	NCT00420004	1COMPLETED	2008-03-01	2006-12-01	Eli Lilly and Company	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 5 ]	120	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	false	This study is being conducted to compare the efficacy, safety, and tolerability of ezetimibe/simvastatin 10/20 mg when administered daily versus doubling the dose of simvastatin to 40 mg in patients with hypercholesterolemia and coronary heart disease.	null	Hypercholesterolemia Coronary Disease		null	2	arm 1: Subjects will receive 2 tablets. The first tablet is Ezetimibe/Simvastatin 10/20 mg. The second tablet is simvastatin placebo. Subjects will receive a maximum of 6 weeks of treatment arm 2: Subjects will receive 2 tablets. The first tablet is Ezetimibe/Simvastatin placebo. The second tablet is simvastatin 40 mg. Subjects will receive a maximum of 6 weeks of treatment.	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: 1 tablet containing 10 mg of ezetimibe and 20 mg of simvastatin per day for 6 weeks intervention 2: 1 tablet containing 40 mg of simvastatin per day for 6 weeks	intervention 1: Ezetimibe/Simvastatin 10/20 mg intervention 2: simvastatin 40 mg	0	null	120	0	0	0	NCT00423579	1COMPLETED	2008-03-01	2006-07-01	Organon and Co	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3, 4 ]	1,474	RANDOMIZED	FACTORIAL	0TREATMENT	3TRIPLE	false	0ALL	null	The purpose of this study is to evaluate the safety and efficacy of fixed combination of valsartan (40 mg and 80 mg) and amlodipine (2.5 mg and 5 mg), valsartan and amlodipine alone, and placebo in reducing blood pressure. The study will investigate the dose response relationship for the combinations, monotherapies, and placebo.	null	Essential Hypertension	Hypertension, Valsartan, Amlodipine, high blood pressure	null	9	arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None arm 9: None	[ 0, 0, 0, 0, 1, 1, 1, 1, 2 ]	9	[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	intervention 1: Valsartan + amlodipine 40/2.5 mg tablet plus 3 tablet and 2 capsule placebos taken once daily intervention 2: Valsartan + amlodipine 40/5mg tablet plus 3 tablet and 2 capsule placebos taken once daily intervention 3: Valsartan + amlodipine 80/2.5 mg tablet plus 3 tablet and 2 capsule placebos taken once daily intervention 4: Valsartan + amlodipine 80/5mg tablet plus 3 tablet and 2 capsule placebos taken once daily intervention 5: Valsartan 40 mg tablet plus 3 tablet and 2 capsule placebos taken once daily intervention 6: Valsartan 80 mg tablet plus 3 tablet and 2 capsule placebos taken once daily intervention 7: Amlodipine 2.5 mg capsule plus 4 tablet and 1 capsule placebos taken once daily intervention 8: Amlodipine 5 mg capsule plus 4 tablet and 1 capsule placebos taken once daily intervention 9: 4 tablet and 2 capsule placebos taken once daily	intervention 1: Valsartan + amlodipine 40/2.5 mg intervention 2: Valsartan + amlodipine 40/5 mg intervention 3: Valsartan + amlodipine 80/2.5 mg intervention 4: Valsartan + amlodipine 80/5 mg intervention 5: Valsartan 40 mg intervention 6: Valsartan 80 mg intervention 7: Amlodipine 2.5 mg intervention 8: Amlodipine 5 mg intervention 9: Placebo	1	Tokyo \| N/A \| Japan \| 139.69171 \| 35.6895	1,468	0	0	0	NCT00425373	1COMPLETED	2008-03-01	2006-11-01	Novartis Pharmaceuticals	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	40	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	true	Primary Objectives: 1. To compare the overall survival of metastatic renal cell carcinoma (RCC) patients undergoing HLA-matched related donor nonmyeloablative allogeneic hematopoietic stem cell transplantation (NST) using fludarabine-melphalan (FM) versus fludarabine-cyclophosphamide (FC) conditioning regimen. 2. To assess both cytotoxic T lymphocyte reactivity and antibodies activity against potential tumor antigenic peptides involved in graft-versus-RCC effect. Secondary Objectives: 1. To study the patient characteristics of metastatic RCC patients who undergo NST and those who do not undergo NST. 2. To compare the incidence of Day-100 treatment-related mortality in FM group and FC group.	Registration: When you are willing to undergo stem cell transplantation for kidney cancer, have possible related donors, and the study doctor decides you are eligible to participate, you will be enrolled in this study. Before treatment begins, you will have a complete physical exam, including blood (about 1-2 tablespoons) and urine tests. An electrocardiogram (ECG--a test to measure the electrical function of the heart) and a heart scan will be done. A test of lung function will be done. This will involve blowing into a machine that records your lung capacity. Tissue typing will also be done by blood test on you and your possible donors to find out if you have a donor or not. Women who are able to have children must have a negative blood test in order to participate. If you have a suitable related donor, have financial approval for the transplant procedure, and are still eligible in this study, you will go for the stem cell transplantation. A separate informed consent about the transplant procedure will be provided to you. You will need to sign and agree with the second informed consent before the start of treatment. This informed consent is only for you to be enrolled and registered in the study. If you have no suitable related donor, no financial approval for the transplant procedure, and/or you refuse to undergo transplant for non-medical reasons, you will not have a stem cell transplant but will still remain in our study. You can receive any form of non-transplant treatment from your physician. Study researchers will only follow your progress, so that in the future, they can compare your progress with those who had the stem cell transplant. This is an investigational study. About 480 patients will take part in this study. All patients will be enrolled at M. D. Anderson Cancer Center. Treatment: The two different chemotherapy regimens used in this study are fludarabine and melphalan, or fludarabine and cyclophosphamide. They act by suppressing our immune system and make space in our bone marrow so as to prepare for the new bone marrow to grow. Before treatment starts, you will have a complete physical exam, including blood (about 1-2 tablespoons) and urine tests. An electrocardiogram (ECG-a test to measure the electrical activity of the heart) and a heart scan will be done. A test of lung function will be done. This will involve blowing into a machine that records your lung capacity. Tests will be performed to look at the status of your cancer, including chest x-ray, bone scan, CT scans, and MRI scan if needed. You will have a dental exam. Women who are able to bear children must have a negative blood pregnancy test in order to participate. In this study, you will receive high-dose chemotherapy to prepare for the blood stem cell transplant. Two different types of chemotherapy will be used. You will be assigned to receive one of the chemotherapy treatments. As the study moves forward, the group treatment that is shown to be more effective will receive more new participants than the other one. The first chemotherapy treatment is a combination of fludarabine and melphalan. The second chemotherapy treatment is a combination of fludarabine and cyclophosphamide. The drug fludarabine will be given through a needle in your vein on Days 1-5. Depending on which treatment group you are assigned to, the drugs melphalan or cyclophosphamide will be given through a needle in your vein on Days 4 and 5, along with your scheduled dose of fludarabine. Day 6 will be a rest day; no drugs will be given. The stem cell transplant will be performed on Day 7. Bone marrow from the donor may be used instead of blood stem cells, if the collection of blood stem cells is not enough. A catheter (a tube) will be placed in a large vein in your chest to decrease the number of times you are stuck with a needle. Blood stem cells will be collected from your family member, who has been using G-CSF to prepare for the transplant. They will need to have enough stem cells before transplantation. The drugs tacrolimus and methotrexate will be given to ease side effects after the transplant. Tacrolimus is given by vein or by mouth for 2 to 3 months after the transplant. During the last month it is given, the dose will be decreased gradually. Methotrexate is given by vein on Days 1, 3, and 6 after the transplant. An extra dose of methotrexate will be given on Day 11, if your donor is your parent or child. Blood transfusions may be needed also. Sometimes, the transplanted cells attack the normal cells in your body instead of the cancer cells. This is called graft-versus-host disease (GVHD). The drug methylprednisolone will be given by vein or by mouth to fight GVHD if it happens. You must stay in the hospital for about 3 to 4 weeks. You must stay in the Houston area for about 100 days after the transplant. Blood tests (about 1-2 tablespoons) will be done every day while you are in the hospital. Chest x-rays, CT scans, and bone scans will be done once a month during the 100 days, and then every 3 months for the first year after that, so that researchers can follow your disease response. If there are no signs of disease after 100 days, treatment will stop. You must return to the clinic for checkups every 3 months for the first year, then 3 times a year for the next 4 years, and once a year after that. If the disease is still present after 2 months, but you do not have GVHD, the anti-rejection medicine tacrolimus will be stopped within 2 weeks. Then if the disease is still present after another 6 weeks, but you do not have GVHD, you may receive an injection of donor lymphocytes by vein. This treatment may be repeated up to 3 times, with 6 weeks between each time. If no disease is found or if GVHD occurs, treatment will stop. This is an investigational study. About 80 participants enrolled in this study will take part in the stem cell transplant. All will be enrolled at M. D. Anderson Cancer Center.	Renal Cell Cancer	Kidney Cancer Renal Cell Cancer Stem Cell Transplant Cyclophosphamide Fludarabine Melphalan NST	null	2	arm 1: ASCT=Allogeneic Hematopoietic Stem Cell Transplantation arm 2: ASCT=Allogeneic Hematopoietic Stem Cell Transplantation	[ 0, 0 ]	4	[ 0, 0, 0, 3 ]	intervention 1: 25 mg/m\^2 intravenous (IV) daily for 5 Days intervention 2: 70 mg/m\^2 IV Daily for 2 Days intervention 3: 60 mg/kg IV Daily for 2 Days intervention 4: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation Using HLA-Matched Related Donor	intervention 1: Fludarabine intervention 2: Melphalan intervention 3: Cyclophosphamide intervention 4: Stem Cell Transplant	1	Houston \| Texas \| United States \| -95.36327 \| 29.76328	40	0	0	0	NCT00429026	6TERMINATED	2008-03-01	2004-01-01	M.D. Anderson Cancer Center	7OTHER	false	false	false	null	0	0	0	0	0
[ 4 ]	194	RANDOMIZED	PARALLEL	0TREATMENT	1SINGLE	false	0ALL	null	This study evaluated the efficacy and safety of daptomycin compared to vancomycin or teicoplanin for the treatment of complicated skin and soft tissue infections	null	Skin Diseases, Infectious Soft Tissue Infections	Complicated Skin and Soft Tissue Infections. Daptomycin, Vancomycin, Teicoplanin Complicated skin and soft tissue infections	null	2	arm 1: 4 mg/kg intravenous (i.v.) once daily arm 2: None	[ 0, 1 ]	3	[ 0, 0, 0 ]	intervention 1: 4 mg/kg intravenous once daily intervention 2: 1 g intravenous twice daily intervention 3: 400 mg intravenous once daily following a loading dose of 400 mg administered at 0, 12, 24 hours on day one.	intervention 1: Daptomycin intervention 2: Vancomycin intervention 3: Teicoplanin	0	null	189	0	0	0	NCT00430937	6TERMINATED	2008-03-01	2006-04-01	Novartis Pharmaceuticals	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	46	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	Patients with intra-aortic balloon pumps (catheters placed in the groin connected to a pump which assists the heart by opening and closing a balloon in the aorta, thereby decreasing the work of the heart and improving blood flow to the coronary arteries) often receive intravenous (IV) heparin (a "blood thinner") to prevent circulation problems in the leg (where they are inserted). When intra-aortic balloon pumps were initially developed, the catheters were larger than the catheters used today. Due to the large size of the catheter and the material used to make the catheter, it was thought that intravenous heparin would prevent poor blood flow to the leg that contained the temporary catheter. Intravenous heparin, however, has never been proven to maintain good blood flow in these patients. The catheters used with intra-aortic balloon pumps are now smaller in size and made of a material that is less likely to produce blood clots. It is not clear that heparin is needed with intra-aortic balloon pumps. Bleeding complications associated with intra-aortic balloon pumps may be decreased if heparin is not used. In 2004, 99 patients received intra-aortic balloon pumps in the cardiac catheterization labs at William Beaumont Hospital. These patients received intravenous heparin and experienced a large number of bleeding complications (27 patients required a blood transfusion). This study will help the investigators to clarify if heparin should or should not be routinely used in patients with intra-aortic balloon pumps.	Potential patients will be identified in the cardiac catheterization lab when an intra-aortic balloon pump is placed. Patients who agree to participate in this study will be randomized (they will be selected to receive heparin or not to receive heparin with their intra-aortic balloon pump) by a process that is similar to flipping a coin. Patients will have a 50% chance of receiving heparin and a 50% chance of not receiving heparin. If a patient does not want to participate in the study, his/her cardiologist will decide if the patient will receive or not receive heparin. Intra-aortic balloon pumps have been used with and without intravenous heparin and there is no known increase in complications in patients who do not receive heparin. Risks include bleeding and possible blood clots/decreased blood flow to the leg with the catheter in both groups (due to different medical reasons). The patients in both groups will be monitored closely in the cardiac care unit while the intra-aortic balloon pump is in place to prevent and/or minimize complications.	Cardiogenic Shock	Intraaortic balloon pumping Heparin Limb ischemia Bleeding	null	2	arm 1: Intra-Aortic Balloon Pump (IABP) with Heparin arm 2: Intra-Aortic balloon Pump (IABP) without Heparin	[ 1, 1 ]	2	[ 0, 10 ]	intervention 1: Heparin administered at 500units/hour while on Intra-Aortic balloon Pump (IABP). intervention 2: Intra-Aortic balloon Pump (IABP) without Heparin.	intervention 1: Heparin intervention 2: Without Heparin	1	Royal Oak \| Michigan \| United States \| -83.14465 \| 42.48948	46	0	0	0	NCT00445211	6TERMINATED	2008-03-01	2006-01-01	William Beaumont Hospitals	7OTHER	false	false	false	null	0	0	0	0	0
[ 5 ]	31	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	true	The aim of this study is to evaluate the expression of IgE high affinity receptors (the part of the cell associated with allergic response) in patients suffering from uncontrolled severe asthma despite long term treatment with high dose of inhaled corticosteroid and long acting Beta-2 agonist.	Double blind placebo controlled study to assess the expression of IgE on blood basophils and dendritic cells in patients with uncontrolled, severe, persistent allergic asthma after a 16-week Omalizumab treatment.	Asthma	Asthma, anti-immunoglobulin E, omalizumab, IgE receptors	null	2	arm 1: Omalizumab was injected subcutaneously every 2 weeks or every 4 weeks for 16 weeks. Dose and dosing interval were determined based on patient body weight and pre-treatment serum IgE level. arm 2: Placebo was injected subcutaneously every 2 weeks or every 4 weeks for 16 weeks.	[ 1, 2 ]	2	[ 0, 0 ]	intervention 1: Omalizumab was supplied as a sterile, freeze dried preparation, to be reconstituted to deliver 150mg of omalizumab. Each vial was reconstituted with 1.4ml of sterile water for injection. The appropriate dose and dosing frequency of omalizumab were determined by baseline total IgE and body weight. A dosing table was used following the European Summary of Product Characteristics (SmPC) of omalizumab. intervention 2: Placebo was a physiological salt solution, administered according to the same administration scheme to respect the same dosing frequency and injected volume.	intervention 1: Omalizumab intervention 2: placebo	1	Rueil-Malmaison \| N/A \| France \| 2.18967 \| 48.8765	31	0	0	0	NCT00454051	1COMPLETED	2008-03-01	2006-12-01	Novartis Pharmaceuticals	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 4 ]	1,420	NON_RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	false	The BEYOND Follow-Up study will give patients who participated in the preceding BEYOND study the opportunity to continue treatment with the 500µg dose of interferon beta (IFNB) 1b and will further investigate the safety and tolerability profile of interferon beta 1b 500µg during longer-term treatment.	Phase A (3 arm parallel group): All patients randomized during the BEYOND study (Bayer 306440) to either IFNB 1b group (250µg or 500µg) will continue their previously assigned study medication, applying the same level of blinding as during the BEYOND study, All patients randomized during the BEYOND study to Copaxone and all patients with premature discontinuation of study medication during the BEYOND study will receive open-label IFNB 1b 250µg. Phase B (single arm): All patients will receive open-label IFNB 1b 500µg) Randomization: No randomization in this trial, patient's allocation in this follow-up study depends only on prior trial groups. The preceding study was randomized. The trial is sponsored by Bayer Schering Pharma AG, Germany, Bayer HealthCare and Bayer HealthCare Pharmaceuticals Inc. Secondary outcome measure "Assessment of patient-reported outcomes (FAMS and EQ 5D: The variables FAMS and EQ-5D were not analyzed due to the termination of the study before start of Phase B.	Multiple Sclerosis, Relapsing-Remitting	Relapsing multiple sclerosis interferon beta 1b Betaferon Betaseron	null	3	arm 1: Interferon beta 1b (\[IFNB 1b\] Betaseron) 500 mcg administered s.c. every other day (double blind) arm 2: Interferon beta 1b (\[IFNB 1b\] Betaseron) 250 mcg administered s.c. every other day (double blind) arm 3: Interferon beta 1b (\[IFNB 1b\] Betaseron) 250 mcg administered s.c. every other day \*(Subjects who were administered Copaxone and subjects who had prematurely discontinued medication during BEYOND study.)	[ 0, 0, 0 ]	3	[ 0, 0, 0 ]	intervention 1: Phase A: 250ug administrated s.c. every other day (double blind). For patients previously randomized in Bayer study 91162 to the same treatment. Phase B: All patients will receive 500µg s.c.every other day (open-label). intervention 2: Phase A: 500ug administrated s.c. every other day (double blind). For patients previously randomized in Bayer study 91162 to the same treatment. Phase B: All patients will receive 500µg s.c.every other day (open-label). intervention 3: Phase A: 250ug administrated s.c. every other day (open-label). For patients previously randomized in Bayer study 91162 to 20mg Copaxone® administrated s.c. once daily and patients with premature discontinuation of study medication during the study 91162. Phase B: All patients will receive 500µg s.c.every other day (open-label).	intervention 1: Interferon beta-1b (Betaseron, BAY86-5046) intervention 2: Interferon beta-1b (Betaseron, BAY86-5046) intervention 3: Interferon beta-1b (Betaseron, BAY86-5046)	184	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Cullman \| Alabama \| United States \| -86.84361 \| 34.17482 Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 Berkeley \| California \| United States \| -122.27275 \| 37.87159 La Jolla \| California \| United States \| -117.2742 \| 32.84727 Sacramento \| California \| United States \| -121.4944 \| 38.58157 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Fort Collins \| Colorado \| United States \| -105.08442 \| 40.58526 Newark \| Delaware \| United States \| -75.74966 \| 39.68372 Washington D.C. \| District of Columbia \| United States \| -77.03637 \| 38.89511 Maitland \| Florida \| United States \| -81.36312 \| 28.62778 Miami \| Florida \| United States \| -80.19366 \| 25.77427 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Augusta \| Georgia \| United States \| -81.97484 \| 33.47097 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Fort Wayne \| Indiana \| United States \| -85.12886 \| 41.1306 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Des Moines \| Iowa \| United States \| -93.60911 \| 41.60054 Kansas City \| Kansas \| United States \| -94.62746 \| 39.11417 Louisville \| Kentucky \| United States \| -85.75941 \| 38.25424 Shreveport \| Louisiana \| United States \| -93.75018 \| 32.52515 Detroit \| Michigan \| United States \| -83.04575 \| 42.33143 Duluth \| Minnesota \| United States \| -92.10658 \| 46.78327 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Henderson \| Nevada \| United States \| -114.98194 \| 36.0397 Reno \| Nevada \| United States \| -119.8138 \| 39.52963 Newark \| New Jersey \| United States \| -74.17237 \| 40.73566 Albuquerque \| New Mexico \| United States \| -106.65114 \| 35.08449 Mineola \| New York \| United States \| -73.64068 \| 40.74927 Rochester \| New York \| United States \| -77.61556 \| 43.15478 Stony Brook \| New York \| United States \| -73.14094 \| 40.92565 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 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Columbus \| Ohio \| United States \| -82.99879 \| 39.96118 Tualatin \| Oregon \| United States \| -122.76399 \| 45.38401 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Providence \| Rhode Island \| United States \| -71.41283 \| 41.82399 Charleston \| South Carolina \| United States \| -79.93275 \| 32.77632 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 Houston \| Texas \| United States \| -95.36327 \| 29.76328 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Fairfax \| Virginia \| United States \| -77.30637 \| 38.84622 Seattle \| Washington \| United States \| -122.33207 \| 47.60621 Tacoma \| Washington \| United States \| -122.44429 \| 47.25288 Milwaukee \| Wisconsin \| United States \| -87.90647 \| 43.0389 Buenos Aires \| Buenos Aires \| Argentina \| N/A \| N/A Buenos Aires \| Ciudad Auton. de Buenos Aires \| Argentina \| -58.37723 \| -34.61315 Buenos Aires \| Ciudad Auton. de Buenos Aires \| Argentina \| -58.37723 \| -34.61315 Córdoba \| Córdoba Province \| Argentina \| -64.18853 \| -31.40648 Rosario \| Santa Fe Province \| Argentina \| -60.63932 \| -32.94682 Rosario \| Santa Fe Province \| Argentina \| -60.63932 \| -32.94682 Kogarah \| New South Wales \| Australia \| 151.13564 \| -33.9681 Fitzroy \| Victoria \| Australia \| 144.97833 \| -37.79839 Parkville \| Victoria \| Australia \| 144.95 \| -37.78333 Nedlands \| Western Australia \| Australia \| 115.8073 \| -31.98184 Liverpool \| N/A \| Australia \| 150.92588 \| -33.91938 Wyoming \| N/A \| Australia \| 151.36254 \| -33.40387 Sankt Pölten \| Lower Austria \| Austria \| 15.63333 \| 48.2 Graz \| N/A \| Austria \| 15.45 \| 47.06667 Innsbruck \| N/A \| Austria \| 11.39454 \| 47.26266 Linz \| N/A \| Austria \| 14.28611 \| 48.30639 Brussels \| N/A \| Belgium \| 4.34878 \| 50.85045 Leuven \| N/A \| Belgium \| 4.70093 \| 50.87959 Melsbroek \| N/A \| Belgium \| 4.47985 \| 50.91559 Curitiba \| Paraná \| Brazil \| -49.27306 \| -25.42778 Recife \| Pernambuco \| Brazil \| -34.88111 \| -8.05389 Rio de Janeiro \| Rio de Janeiro \| Brazil \| -43.18223 \| -22.90642 Porto Alegre \| Rio Grande do Sul \| Brazil \| -51.23019 \| -30.03283 Campinas \| São Paulo \| Brazil \| -47.06083 \| -22.90556 São Paulo \| São Paulo \| Brazil \| -46.63611 \| -23.5475 São Paulo \| São Paulo \| Brazil \| -46.63611 \| -23.5475 São Paulo \| São Paulo \| Brazil \| -46.63611 \| -23.5475 Calgary \| Alberta \| Canada \| -114.08529 \| 51.05011 Vancouver \| British Columbia \| Canada \| -123.11934 \| 49.24966 Halifax \| Nova Scotia \| Canada \| -63.57688 \| 44.64269 London \| Ontario \| Canada \| -81.23304 \| 42.98339 Mississauga \| Ontario \| Canada \| -79.6583 \| 43.5789 Nepean \| Ontario \| Canada \| -75.7225 \| 45.33619 Ottawa \| Ontario \| Canada \| -75.69812 \| 45.41117 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Greenfield Park \| Quebec \| Canada \| -73.46223 \| 45.48649 Hull \| Quebec \| Canada \| -75.74105 \| 45.4445 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Aarhus \| N/A \| Denmark \| 10.21076 \| 56.15674 Oulu \| N/A \| Finland \| 25.46816 \| 65.01236 Tampere \| N/A \| Finland \| 23.78712 \| 61.49911 Rennes \| Brittany Region \| France \| -1.67429 \| 48.11198 Bordeaux \| Gironde \| France \| -0.5805 \| 44.84044 Clermont-Ferrand \| N/A \| France \| 3.08682 \| 45.77969 Dijon \| N/A \| France \| 5.01667 \| 47.31667 Lille \| N/A \| France \| 3.05858 \| 50.63297 Nancy \| N/A \| France \| 6.18496 \| 48.68439 Nantes \| N/A \| France \| -1.55336 \| 47.21725 Nice \| N/A \| France \| 7.26608 \| 43.70313 Nîmes \| N/A \| France \| 4.35788 \| 43.83665 Toulouse \| N/A \| France \| 1.44367 \| 43.60426 Heidelberg \| Baden-Wurttemberg \| Germany \| 8.69079 \| 49.40768 Bayreuth \| Bavaria \| Germany \| 11.57893 \| 49.94782 Regensburg \| Bavaria \| Germany \| 12.10161 \| 49.01513 Hennigsdorf \| Brandenburg \| Germany \| 13.20419 \| 52.63598 Hamburg \| City state of Hamburg \| Germany \| 9.99302 \| 53.55073 Hamburg \| City state of Hamburg \| Germany \| 9.99302 \| 53.55073 Giessen \| Hesse \| Germany \| 8.67554 \| 50.58727 Marburg \| Hesse \| Germany \| 8.77069 \| 50.80904 Offenbach \| Hesse \| Germany \| 8.76647 \| 50.10061 Göttingen \| Lower Saxony \| Germany \| 9.93228 \| 51.53443 Hanover \| Lower Saxony \| Germany \| 9.73322 \| 52.37052 Hanover \| Lower Saxony \| Germany \| 9.73322 \| 52.37052 Greifswald \| Mecklenburg-Vorpommern \| Germany \| 13.40244 \| 54.08905 Düsseldorf \| North Rhine-Westphalia \| Germany \| 6.77616 \| 51.22172 Essen \| North Rhine-Westphalia \| Germany \| 7.01228 \| 51.45657 Münster \| North Rhine-Westphalia \| Germany \| 7.62571 \| 51.96236 Dresden \| Saxony \| Germany \| 13.73832 \| 51.05089 Leipzig \| Saxony \| Germany \| 12.37129 \| 51.33962 Halle \| Saxony-Anhalt \| Germany \| 11.97947 \| 51.48158 Berlin \| State of Berlin \| Germany \| 13.41053 \| 52.52437 Berlin \| State of Berlin \| Germany \| 13.41053 \| 52.52437 Athens \| Attica \| Greece \| 23.72784 \| 37.98376 Thessaloniki \| N/A \| Greece \| 22.93086 \| 40.64361 Budapest \| N/A \| Hungary \| 19.04045 \| 47.49835 Budapest \| N/A \| Hungary \| 19.04045 \| 47.49835 Győr \| N/A \| Hungary \| 17.63512 \| 47.68333 Miskolc \| N/A \| Hungary \| 20.77806 \| 48.10306 Pécs \| N/A \| Hungary \| 18.23083 \| 46.0725 Zalaegerszeg-Pozva \| N/A \| Hungary \| N/A \| N/A Dublin \| Dublin \| Ireland \| -6.24889 \| 53.33306 Cork \| N/A \| Ireland \| -8.47061 \| 51.89797 Dublin \| N/A \| Ireland \| -6.24889 \| 53.33306 Dublin \| N/A \| Ireland \| -6.24889 \| 53.33306 Tel Aviv \| Israel \| Israel \| 34.78057 \| 32.08088 Tel Litwinsky \| Israel \| Israel \| 34.84588 \| 32.05096 Ẕerifin \| Israel \| Israel \| 34.84852 \| 31.95731 Ashkelon \| N/A \| Israel \| 34.57149 \| 31.66926 Haifa \| N/A \| Israel \| 34.99928 \| 32.81303 Jerusalem \| N/A \| Israel \| 35.21633 \| 31.76904 Orbassano \| Torino \| Italy \| 7.53813 \| 45.00547 Bari \| N/A \| Italy \| 16.86982 \| 41.12066 Florence \| N/A \| Italy \| 11.24626 \| 43.77925 Milan \| N/A \| Italy \| 12.59836 \| 42.78235 Padua \| N/A \| Italy \| 11.88586 \| 45.40797 Roma \| N/A \| Italy \| 11.10642 \| 44.99364 Riga \| N/A \| Latvia \| 24.10589 \| 56.946 Breda \| N/A \| Netherlands \| 4.77596 \| 51.58656 Nijmegen \| N/A \| Netherlands \| 5.85278 \| 51.8425 Sittard \| N/A \| Netherlands \| 5.86944 \| 50.99833 Bergen \| N/A \| Norway \| 5.32415 \| 60.39299 Gdansk \| N/A \| Poland \| 18.64912 \| 54.35227 Katowice \| N/A \| Poland \| 19.02754 \| 50.25841 Lodz \| N/A \| Poland \| 19.47395 \| 51.77058 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 Moskva \| N/A \| Russia \| 32.16579 \| 56.91775 Moskva \| N/A \| Russia \| 32.16579 \| 56.91775 Moskva \| N/A \| Russia \| 32.16579 \| 56.91775 Moskva \| N/A \| Russia \| 32.16579 \| 56.91775 Moskva \| N/A \| Russia \| 32.16579 \| 56.91775 Nizhy Novgorod \| N/A \| Russia \| N/A \| N/A Novosibirsk \| N/A \| Russia \| 82.94339 \| 55.03442 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 Yaroslavl \| N/A \| Russia \| 39.87368 \| 57.62987 Ljubljana \| N/A \| Slovenia \| 14.50513 \| 46.05108 Maribor \| N/A \| Slovenia \| 15.64667 \| 46.55472 L'Hospitalet de Llobregat \| Barcelona \| Spain \| 2.10028 \| 41.35967 Málaga \| N/A \| Spain \| -4.42034 \| 36.72016 Seville \| N/A \| Spain \| -5.97317 \| 37.38283 Stockholm \| N/A \| Sweden \| 18.06871 \| 59.32938 Uppsala \| N/A \| Sweden \| 17.63889 \| 59.85882 Bern \| N/A \| Switzerland \| 7.44744 \| 46.94809 Sankt Gallen \| N/A \| Switzerland \| 9.37477 \| 47.42391 Donetsk \| N/A \| Ukraine \| 37.80224 \| 48.023 Kharkiv \| N/A \| Ukraine \| 36.25475 \| 49.98177 Kiev \| N/A \| Ukraine \| 30.5238 \| 50.45466 Lviv \| N/A \| Ukraine \| 24.02324 \| 49.83826	1,411	0	0	0	NCT00459667	1COMPLETED	2008-03-01	2007-05-01	Bayer	4INDUSTRY	false	false	false	null	0	0	0	0	-0
[ 4 ]	374	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	false	The purpose of the study is to evaluate the effectiveness and safety of Avelox in a 5 day treatment of adult patients with acute bacterial sinusitis and to measure the amount of time it takes for symptom relief. Avelox is currently not approved for the 5 day treatment of acute bacterial sinusitis, therefore in this study Avelox is considered an investigational drug. In this study Avelox will be compared to placebo.	null	Sinusitis	Respiratory Tract Infection Bacterial Sinusitis	null	2	arm 1: Moxifloxacin 400mg once daily for 5 days arm 2: Matching placebo for 5 days	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: Moxifloxacin - 400 mg once a day for 5 days intervention 2: Placebo - 380 mg Microcrystalline Cellulose	intervention 1: Moxifloxacin (Avelox, BAY12-8039) intervention 2: Placebo	51	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Northport \| Alabama \| United States \| -87.57723 \| 33.22901 Jonesboro \| Arkansas \| United States \| -90.70428 \| 35.8423 Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 Fresno \| California \| United States \| -119.77237 \| 36.74773 Fresno \| California \| United States \| -119.77237 \| 36.74773 Garden Grove \| California \| United States \| -117.94145 \| 33.77391 Orange \| California \| United States \| -117.85311 \| 33.78779 Roseville \| California \| United States \| -121.28801 \| 38.75212 San Diego \| California \| United States \| -117.16472 \| 32.71571 San Luis Obispo \| California \| United States \| -120.65962 \| 35.28275 Colorado Springs \| Colorado \| United States \| -104.82136 \| 38.83388 Bridgeport \| Connecticut \| United States \| -73.18945 \| 41.17923 Dunnellon \| Florida \| United States \| -82.46093 \| 29.04914 Hialeah \| Florida \| United States \| -80.27811 \| 25.8576 North Miami Beach \| Florida \| United States \| -80.16255 \| 25.93315 Pembroke Pines \| Florida \| United States \| -80.22394 \| 26.00315 Plantation \| Florida \| United States \| -80.23184 \| 26.13421 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Warner Robbins \| Georgia \| United States \| N/A \| N/A Warner Robins \| Georgia \| United States \| -83.62664 \| 32.61574 Louisville \| Kentucky \| United States \| -85.75941 \| 38.25424 Detroit \| Michigan \| United States \| -83.04575 \| 42.33143 Livonia \| Michigan \| United States \| -83.35271 \| 42.36837 Portage \| Michigan \| United States \| -85.58 \| 42.20115 Butte \| Montana \| United States \| -112.53474 \| 46.00382 Elizabeth \| New Jersey \| United States \| -74.2107 \| 40.66399 Lawrenceville \| New Jersey \| United States \| -74.7296 \| 40.29733 Somerville \| New Jersey \| United States \| -74.60988 \| 40.57427 Rochester \| New York \| United States \| -77.61556 \| 43.15478 Charlotte \| North Carolina \| United States \| -80.84313 \| 35.22709 Raleigh \| North Carolina \| United States \| -78.63861 \| 35.7721 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Dayton \| Ohio \| United States \| -84.19161 \| 39.75895 Eugene \| Oregon \| United States \| -123.08675 \| 44.05207 Levittown \| Pennsylvania \| United States \| -74.82877 \| 40.15511 Norristown \| Pennsylvania \| United States \| -75.3399 \| 40.1215 Palmyra \| Pennsylvania \| United States \| -76.5933 \| 40.30898 Clarksville \| Tennessee \| United States \| -87.35945 \| 36.52977 Austin \| Texas \| United States \| -97.74306 \| 30.26715 College Station \| Texas \| United States \| -96.33441 \| 30.62798 El Paso \| Texas \| United States \| -106.48693 \| 31.75872 Houston \| Texas \| United States \| -95.36327 \| 29.76328 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 West Jordan \| Utah \| United States \| -111.9391 \| 40.60967 West Jordan \| Utah \| United States \| -111.9391 \| 40.60967 Tappahannock \| Virginia \| United States \| -76.85913 \| 37.92541 Bellingham \| Washington \| United States \| -122.48822 \| 48.75955 Greenfield \| Wisconsin \| United States \| -88.01259 \| 42.9614	374	0	0	0	NCT00492024	1COMPLETED	2008-03-01	2005-01-01	Bayer	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	60	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	A three sequence, open-label, multi-center, prospective, study in stable kidney transplant patients to assess and compare the pharmacokinetics (Cmax, C24, and AUC), and safety of LCP-Tacro (tacrolimus) tablets versus Prograf (tacrolimus) capsules.	A three sequence, open-label, multi-center, prospective, study in stable kidney transplant patients to assess and compare the pharmacokinetics (Cmax, C24, and AUC), and safety of LCP-Tacro (tacrolimus) tablets versus Prograf (tacrolimus) capsules. Stable kidney transplant patients who fulfill all I/E criteria will be enrolled and kept on Prograf for 7 days. Following a 24-hour PK study on Day 7 to determine pharmacokinetics for Prograf, all patients will be converted to once daily LCP-Tacro for 7 days with no dose changes allowed. On Day 14 and Day 21 a 24-hour LCP-Tacro PK study will be performed. On Day 22 patients will be converted back to their original twice daily dose of Prograf for a safety follow-up period of 30 days ending with a safety assessment on day 53.	Renal Failure	Tacrolimus Pharmacokinetics Kidney Transplantation	null	1	arm 1: Experimental: LCP Tacro; investigational product LCP-Tacro tablets were provided in 3 strengths: 1 mg, 2 mg, and 5 mg oral tablets.	[ 1 ]	2	[ 0, 0 ]	intervention 1: Prograf will be administrated twice a day, per product labeling, with an interval of 12 ± 1 hours between the morning and evening doses. Patients will continue on the same dose on Day0 through Day 7 to maintain target trough levels of 7-12 ng/mL. On the morning of Day 8, following the final blood draw for the PK assessment, patient will be converted to LCP-Tacro using the conversion Ratio 0.66-0.8. LCP-Tacro tablets will be administered orally once daily in the morning, with an interval of 24 ± 1 hours between doses. Other Names: Tacrolimus modified-release LCP-Tacro tablets were provided in 3 strengths: 1 mg, 2 mg, and 5 mg oral tablets. intervention 2: Prograf will be administrated twice a day, per product labeling, with an interval of 12 ± 1 hours between the morning and evening doses. Patients will continue on the same dose on Day0 through Day 7 to maintain target trough levels of 7-12 ng/mL. On the morning of Day 8, following the final blood draw for the PK assessment, patient will be converted to LCP-Tacro using the conversion Ratio 0.66-0.8. LCP-Tacro tablets will be administered orally once daily in the morning, with an interval of 24 ± 1 hours between doses. Other Names: Tacrolimus modified-release LCP-Tacro tablets were provided in 3 strengths: 1 mg, 2 mg, and 5 mg oral tablets.	intervention 1: LCP Tacro (tacrolimus) intervention 2: Prograf	2	Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Houston \| Texas \| United States \| -95.36327 \| 29.76328	110	0	0	0	NCT00496483	1COMPLETED	2008-03-01	2007-07-01	Veloxis Pharmaceuticals	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 4 ]	35	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	false	This study will assess the effect of pancrelipase delayed release 24,000 unit capsules on fat and nitrogen absorption in subjects with PEI due to Cystic Fibrosis.	null	Cystic Fibrosis	Pancreatic exocrine insufficiency Cystic Fibrosis	null	2	arm 1: None arm 2: None	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: 24000 unit Capsule intervention 2: Placebo	intervention 1: Pancrelipase Delayed Release intervention 2: Placebo Comparator	23	Long Beach \| California \| United States \| -118.18923 \| 33.76696 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Miami \| Florida \| United States \| -80.19366 \| 25.77427 Orlando \| Florida \| United States \| -81.37924 \| 28.53834 Iowa City \| Iowa \| United States \| -91.53017 \| 41.66113 Louisville \| Kentucky \| United States \| -85.75941 \| 38.25424 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 Minneapolis \| Minnesota \| United States \| -93.26384 \| 44.97997 Long Branch \| New Jersey \| United States \| -73.99236 \| 40.30428 Albuquerque \| New Mexico \| United States \| -106.65114 \| 35.08449 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Dayton \| Ohio \| United States \| -84.19161 \| 39.75895 Toledo \| Ohio \| United States \| -83.55521 \| 41.66394 Oklahoma City \| Oklahoma \| United States \| -97.51643 \| 35.46756 Hershey \| Pennsylvania \| United States \| -76.65025 \| 40.28592 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 Petrofi \| N/A \| Hungary \| N/A \| N/A Jerusalem \| N/A \| Israel \| 35.21633 \| 31.76904 Johannesburg \| N/A \| South Africa \| 28.04363 \| -26.20227 Barcelona \| N/A \| Spain \| 2.15899 \| 41.38879	63	0	0	0	NCT00510484	1COMPLETED	2008-03-01	2007-11-01	Solvay Pharmaceuticals	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 2, 3 ]	47	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	RATIONALE: Drugs used in chemotherapy, temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or stopping them from dividing. Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving temozolomide together with bortezomib may kill more tumor cells. PURPOSE: To determine the best dose of bortezomib and temozolomide and to see how well they work in treating patients with advanced refractory solid tumors or melanoma.	null	Brain and Central Nervous System Tumors Melanoma Solid Tumor	stage III melanoma stage IV melanoma recurrent melanoma unspecified adult solid tumor, protocol specific recurrent adult brain tumor melanoma (skin)	null	2	arm 1: None arm 2: None	[ 0, 0 ]	5	[ 0, 0, 10, 0, 0 ]	intervention 1: Dose Levels PS-341 (day 1) * Level -1 0.7 mg/m2 * Level 1 1.0 mg/m2 * Level 2 1.0 mg/m2 * Level 3 1.3 mg/m2 * Level 4 1.5 mg/m2 intervention 2: Temozolomide (day 8) * Level - 1 50 mg/m2 * Level 1 50 mg/m2 * Level 2 75/mg/m2 * Level 3 75 mg/m2 * Level 4 75 mg/m2 intervention 3: Not noted intervention 4: 1.3 mg/m2 by IV on days 1, 4, 8, and 11 of every 21 days intervention 5: 75 mg/m2 by mouth, daily, during weeks 2-8 (42 days) of every 9-week course.	intervention 1: PS-341 (VELCADE) intervention 2: temozolomide intervention 3: immunoenzyme technique intervention 4: PS-341 (VELCADE) intervention 5: Temozolomide	1	Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589	47	0	0	0	NCT00512798	6TERMINATED	2008-03-01	2003-06-01	Vanderbilt-Ingram Cancer Center	7OTHER	false	false	false	null	0	0	0	0	0
[ 3 ]	6	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	1FEMALE	null	RATIONALE: Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. PURPOSE: This phase II trial is studying how well sorafenib works in treating patients with ovarian epithelial cancer, fallopian tube cancer, or peritoneal cancer in at least the second remission.	OBJECTIVES: Primary * To determine the 12-month progression-free survival (PFS) rate of women with ovarian epithelial, fallopian tube, or peritoneal cancer in second or greater remission treated with oral sorafenib tosylate. Secondary * To determine the safety and tolerability of prolonged treatment with oral sorafenib tosylate in women with a history of recurrent ovarian cancer. * To correlate serum markers of angiogenesis (i.e., VEGF and bFGF) and tumor markers pAKT, HIF-1 α , and VEGF with 12-month PFS. OUTLINE: Patients receive oral sorafenib twice a day on days 1-28. Treatment repeats every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients undergo tumor tissue and blood sample collection at baseline, every 12 weeks during study, and after completion of study therapy for pharmacokinetic studies. Samples are analyzed for soluble markers of angiogenesis (i.e., VEGF and bFGF) via ELISA and HIF-1 α, VEGF, and pAKT via IHC staining. After completion of study treatment, patients are followed at 4 weeks.	Fallopian Tube Cancer Ovarian Cancer Primary Peritoneal Cavity Cancer	recurrent ovarian epithelial cancer fallopian tube cancer primary peritoneal cavity cancer stage I ovarian epithelial cancer stage II ovarian epithelial cancer stage III ovarian epithelial cancer stage IV ovarian epithelial cancer	null	1	arm 1: Sorafenib is supplied as 200-mg tablets. Sorafenib will be administered as 400 mg orally daily x 28 days (continuous). One cycle = 28 days. There is no planned treatment interruption between cycles. Sorafenib should be taken without food (at least 1 hour before or 2 hours after eating). In the absence of intolerable toxicity, a patient may continue to receive treatment with sorafenib until disease progression, or until 24 months have elapsed.	[ 0 ]	5	[ 0, 10, 10, 10, 10 ]	intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None	intervention 1: sorafenib tosylate intervention 2: immunoenzyme technique intervention 3: immunohistochemistry staining method intervention 4: laboratory biomarker analysis intervention 5: pharmacological study	1	New York \| New York \| United States \| -74.00597 \| 40.71427	5	0	0	0	NCT00522301	6TERMINATED	2008-03-01	2007-07-01	Memorial Sloan Kettering Cancer Center	7OTHER	false	false	false	null	0	0	0	0	0
[ 4 ]	149	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	2MALE	null	Low testosterone is a condition that occurs when the body is unable to produce sufficient quantities of testosterone. The medical name for low testosterone is hypogonadism. Hypogonadism can be caused by many factors. Symptoms include: decrease in libido, lack of energy and mood swings. The goal of testosterone replacement therapy is to return testosterone levels to the normal range and relieve symptoms. The purpose of this study is to evaluate the ability of Fortigel testosterone gel 2% to maintain serum (blood) testosterone levels within the normal range in hypogonadal men aged 18 to 75 years. This will be determined by blood sampling at specified times during the study. The study is also intended to evaluate the tolerability of Fortigel, which will be applied to the skin each day throughout the study period.	null	Hypogonadism	Hypogonadism	null	1	arm 1: 2% testosterone gel	[ 0 ]	1	[ 0 ]	intervention 1: 2% gel	intervention 1: Testosterone	0	null	149	0	0	0	NCT00522431	1COMPLETED	2008-03-01	2007-08-01	Endo Pharmaceuticals	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 0 ]	18	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	This study will assess whether varenicline (chantix) has antidepressant properties when used in addition to other psychiatric medication. It will also assess whether varenicline improves the inability to feel pleasure (i.e. anhedonia), and if it is well-tolerated when used with psychiatric medications. Enrolled patients will be assessed for improved mood, improved anhedonia, overall sense of health, side effects as well as tobacco use for 6-8 weeks. Medication will be provided free of charge.	Outpatient smokers who are depressed despite current stable psychiatric medication regimens will be invited to participate. They will receive varenicline dosed according to FDA-approved smoking cessation regime; patients will be assessed using QIDS-SR16, snaith-hamilton anhedonia rating scale, SAFTEE and clinical global improvement self-report scales and clinician global improvement scales at the above time intervals. Concurrent medication, psychiatric and non-psychiatric, will be recorded, as will vital signs (BP, HR, weight) and tobacco use.	Depressive Disorder Smoking	varenicline depression anhedonia smoking	null	1	arm 1: open label varenicline	[ 5 ]	2	[ 0, 0 ]	intervention 1: varenicline 0.5 mg po daily for days 1-3, 0.5 twice daily for days 4-7, 1 mg twice daily thereafter for study duration. intervention 2: up to 1 mg twice daily	intervention 1: fixed dose varenicline intervention 2: varenicline	1	Providence \| Rhode Island \| United States \| -71.41283 \| 41.82399	18	0	0	0	NCT00525837	1COMPLETED	2008-03-01	2007-09-01	Butler Hospital	7OTHER	false	false	false	null	0	0	0	0	0
[ 5 ]	70	RANDOMIZED	SINGLE_GROUP	4SUPPORTIVE_CARE	4QUADRUPLE	false	0ALL	true	The study's hypothesis is LMX4 cream, a topical anesthetic cream, will reduce the pain of infants undergoing Lumbar Puncture (spinal tap).	Pain of infants will be measured using the Neonatal Facial Coding System by videotaping the infant's face while they undergo the procedure. A comparison between the group that received active drug and the group that received placebo will allow a measurement of the difference, if any, of the pain experienced during the procedure of the infants.	Pain	pain lumbar puncture neonates infants emergency department topical anesthesia LMX4	null	2	arm 1: Active 4% Lidocaine topical cream (LMX4 cream) applied under occlusive dressing arm 2: Placebo Cream made on same run at factory but without active Lidocaine 4% drug	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: Topical cream, 2g applied under occlusive dressing for 20 minutes prior to the procedure intervention 2: inactive placebo without LMX4	intervention 1: Lidocaine Cream 4% intervention 2: Placebo	1	Buffalo \| New York \| United States \| -78.87837 \| 42.88645	52	0	0	0	NCT00533468	1COMPLETED	2008-03-01	2007-03-01	State University of New York at Buffalo	7OTHER	false	false	false	null	0	0	0	0	0
[ 3 ]	2	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	true	The purpose of this study is to determine efficacy and safety of paclitaxel, bevacizumab and enzastaurin versus paclitaxel, bevacizumab, and placebo in participants who are diagnosed with locally recurrent or metastatic breast cancer.	null	Breast Cancer		null	2	arm 1: Participants randomized to this arm (Arm A) will receive enzastaurin, paclitaxel and bevacizumab until disease progression. Prior to randomization, a safety lead-in will be conducted in 6 participants who will be treated according to Arm A for 2 cycles (1 cycle = 28 days). Only after an acceptable safety analysis of the safety lead-in, will other participants be randomized to Phase 2 (either Arm A or Arm B). In Phase 2, participants from the safety lead-in will continue treatment according to Enzastaurin + Bevacizumab + Paclitaxel (Arm A). arm 2: Participants randomized to this arm (Arm B) will receive bevacizumab, paclitaxel and placebo until disease progression.	[ 0, 2 ]	4	[ 0, 0, 0, 0 ]	intervention 1: 1125 milligrams (mg) loading dose on Day 1 of Cycle 1 only then 500 mg oral once daily, until disease progression intervention 2: 10 milligrams per kilogram (mg/kg) intravenously, Days 1 and 15 every 28 days, until disease progression intervention 3: 90 milligrams per square meter (mg/m\^2), intravenously, Days 1 ,8, and 15 every 28 days until disease progression intervention 4: Oral, daily, until disease progression	intervention 1: Enzastaurin intervention 2: Bevacizumab intervention 3: Paclitaxel intervention 4: Placebo	7	Newark \| Delaware \| United States \| -75.74966 \| 39.68372 Galesburg \| Illinois \| United States \| -90.37124 \| 40.94782 Fort Wayne \| Indiana \| United States \| -85.12886 \| 41.1306 Goshen \| Indiana \| United States \| -85.83444 \| 41.58227 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Lafayette \| Indiana \| United States \| -86.87529 \| 40.4167 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626	2	0	0	0	NCT00536939	6TERMINATED	2008-03-01	2007-11-01	Eli Lilly and Company	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 2 ]	40	RANDOMIZED	PARALLEL	0TREATMENT	1SINGLE	false	0ALL	false	Vitreoretinal surgery for epiretinal proliferation tractional retinal detachment associated with proliferative diabetic retinopathy (PDR) is often complicated by hemorrhage from fibrovascular tissue. To control the bleeding during tissue dissection multiple measures and techniques are used. Bevacizumab is an anti VEGF antibody which has been used to induce regression of ocular neovascularization. Its intraocular injection has been increasingly used for treatment of choroidal neovascularization (CNV) associated with age related macular degeneration (AMD) with fairly good success.Also it has been shown to be effective for treatment of PDR complicated with vitreous hemorrhage and iris neovascularization. We hypothesized that if anti-angiogenic agents, such as bevacizumab are injected into the vitreous cavity before vitrectomy in cases of PDR; there may be partial regression of neovascularization resulting in less intraoperative (and postoperative) hemorrhage. This can make the operation easier and shorter and lessen the need for intraocular cautery.. In this study diabetic patients who are candidated for vitrectomy with similar complexity scores will be randomized to preoperative injection or no injection of 2.5 mg Bevacizumab .In the injection group, 2.5 mg of bevacizumab (0.1 ml of commercially available Avastin vial, Genentech, inc. South San Francisco, CA) will be injected into the vitreous 3-5 days before operation. During each operation, the number of endodiathermy applications, backflush needle applications and the duration of surgery will be recorded by an independent observer. Also, type of tamponade, post operation vitreous hemorrhage and 3 months postoperative visual acuities wil be recorded. all these parameters will be compared in two groups.	Eligibility criteria: Diabetic tractional retinal detachment-complexity score between 4 and 8 Main outcome measures: best corrected visual acuity-anatomic condition of the retine(re-attachment of the retina)	Intravitreal Bevacizumab Injection Pars Plana Vitrectomy Tractional Retinal Detachment Diabetic Retinopathy	Intravitreal Bevacizumab injection Pars plana vitrectomy tractional retinal detachment Diabetic retinopathy	null	2	arm 1: Intravitreal Bevacizumab will be injected 2.5 mg IVB 3-5 days before operation in diabetic patients who were candidates for vitrectomy before performing pars plana vitrectomy arm 2: no injection before performing pars plana vitrectomy in diabetic patients who were candidates for vitrectomy	[ 0, 4 ]	1	[ 0 ]	intervention 1: one intravitreal injection of 2.5 mg Bevacizumab 3-5 days before performing pars plana vitrectomy	intervention 1: Bevacizumab	1	Tehran \| N/A \| Iran \| 51.42151 \| 35.69439	40	0	0	0	NCT00548197	1COMPLETED	2008-03-01	2007-02-01	Iran University of Medical Sciences	7OTHER	false	false	false	null	0	0	0	0	0
[ 3 ]	53	RANDOMIZED	CROSSOVER	1PREVENTION	2DOUBLE	true	2MALE	false	This study will examine whether oral intake of 1200mg N-Acetylcysteine/day will prevent temporary threshold shift in hearing among workers exposed to noise	Both genetic and environmental factors contribute to noise-induced hearing loss (NIHL). The cellular antioxidant system appears to protect cochlear hair cells from oxidative stress due to noise. Previous animal studies showed protective effects of anti-oxidant medicines against NIHL.The objective of this study is to test the hypothesis that preventive medication of antioxidation is related to susceptibility to NIHL. The 53 noise-exposed workers from steel industries in Taiwan will be recruited, and divided into N-Acetylcysteine (NAC)(Acetine, 1200mg/day) group and placebo one. The duration of medication is 2 weeks initially. After washout for 2 weeks, the kinds of medications in these 2 groups will be crossover and used for 2 weeks. Firstly, questionnaires interview about noise exposure, smoking, alcohol drinking, drug habit history and calculation of Body Mass Index (BMI) will be done. The following methods would be performed individually after medication. With detailed local examination with otoscope, these subjects receive hearing tests by pure-tone audiometry (PTA) and distortion product otoacoustic emissions (DPOAE) before and after their daily works. The possible confounding factors including background noise, solvent, heavy metals, carbon monoxide and temperature in the workplaces will be assessed. The amount of noise exposure is evaluated by personal dosimeter. Early morning, Blood samples will be collected. Deletion polymorphisms in the Glutathione S-transferase (GST)T1 and GSTM1 genes will be determined. Statistical analysis will be performed to evaluate the relation between intake of anti-oxidant medicine and noise-induced temporal threshold shift (TTS). The expected results of this study are to determine whether anti-oxidant supplements protect workers from noise-induced TTS. We anticipate that these human studies might help elucidate the relative importance of anti-oxidant enzymes as risk factors for NIHL.	Hearing Loss	noise hearing loss temporary threshold shift	null	2	arm 1: None arm 2: None	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: 600mg twice daily for 2 weeks intervention 2: 1 gm glucose capsule	intervention 1: N-acetylcysteine (NAC) intervention 2: glucose	1	Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306	106	0	0	0	NCT00552786	1COMPLETED	2008-03-01	2007-11-01	National Taiwan University Hospital	7OTHER	false	false	false	null	0	0	0	0	0
[ 3 ]	32	RANDOMIZED	CROSSOVER	0TREATMENT	0NONE	false	0ALL	false	The purpose of this study is to examine the blood levels of two doses of MAP0010 (a corticosteroid) and two doses of an approved corticosteroid in adult asthma and safety with twice daily dosing over 7 days.	null	Asthma	Adult Asthmatics	null	4	arm 1: Subjects received Treatment 1 in period 1 followed by a 7 day washout period and then Treatment 2 in period 2. Treatment 1 was a single dose of MAP0010 low dose delivered by nebulization twice daily for 7 days as per protocol. Treatment 2 was a single dose of Pulmicort Respules® 0.25mg dose delivered by nebulization twice daily for 7 days as per protocol. arm 2: Subjects received Treatment 2 in period 1 followed by a 7 day washout period and then Treatment 1 period 2. Treatment 1 was a single dose of MAP0010 low dose delivered by nebulization twice daily for 7 days as per protocol. Treatment 2 was a single dose of Pulmicort Respules® 0.25mg dose delivered by nebulization twice daily for 7 days as per protocol. arm 3: Subjects received Treatment 3 in period 1 followed by a 7 day washout period and then Treatment 4 period 2. Treatment 3 was a single dose of MAP0010 high dose delivered by nebulization twice daily for 7 days as per protocol. Treatment 4 was a single dose of Pulmicort Respules® 0.5mg dose delivered by nebulization twice daily for 7 days as per protocol. arm 4: Subjects received Treatment 4 in period 1 followed by a 7 day washout period and then Treatment 3 in period 2. Treatment 3 was a single dose of MAP0010 high dose delivered by nebulization twice daily for 7 days as per protocol. Treatment 4 was a single dose of Pulmicort Respules® 0.5mg dose delivered by nebulization twice daily for 7 days as per protocol.	[ 5, 5, 5, 5 ]	4	[ 0, 0, 0, 0 ]	intervention 1: a single dose of MAP0010 low dose delivered by nebulization twice daily for 7 days as per protocol intervention 2: a single dose of MAP0010 high dose delivered by nebulization twice daily for 7 days as per protocol intervention 3: a single dose of Pulmicort Respules® 0.25mg delivered by nebulization twice daily for 7 days as per protocol intervention 4: a single dose of Pulmicort Respules® 0.5mg dose delivered by nebulization twice daily for 7 days as per protocol	intervention 1: MAP0010 low dose intervention 2: MAP0010 high dose intervention 3: Budesonide inhalation suspension 0.25mg intervention 4: Budesonide inhalation suspension 0.5mg	1	Long Beach \| California \| United States \| -118.18923 \| 33.76696	32	0	0	0	NCT00554970	1COMPLETED	2008-03-01	2007-11-01	Allergan	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 5 ]	40	RANDOMIZED	PARALLEL	1PREVENTION	2DOUBLE	false	0ALL	false	This research is to determine which medication, Zegerid (Omeprazole/Sodium Bicarbonate) or Pepcid AC (Famotidine), works best at reducing the chance that a patient will get an ulcer after gastric bypass surgery.	The purpose of this research is to evaluate information about the control of gastric acid in post gastric bypass surgery patients. Goal is to determine which medication best reduces the incidence of anastomotic ulcers post-operatively.	Marginal Ulcers	gastric bypass surgery anastomosis, Roux-en-Y Complication, Postoperative	null	2	arm 1: 40 mg Omeprazole daily arm 2: 40 mg Famotidine daily	[ 1, 1 ]	2	[ 0, 0 ]	intervention 1: 40mg dose administered as a suspension or capsule as physician directs daily at bedtime for 14 weeks beginning day of hospital discharge following gastric bypass surgery. intervention 2: 40mg dose administered as a suspension or capsule as physician directs daily at bedtime for 14 weeks beginning day of hospital discharge following gastric bypass surgery.	intervention 1: Omeprazole intervention 2: Famotidine	1	Columbia \| Missouri \| United States \| -92.33407 \| 38.95171	30	0	0	0	NCT00557349	1COMPLETED	2008-03-01	2006-11-01	University of Missouri-Columbia	7OTHER	false	false	false	null	0	0	0	0	0
[ 5 ]	12	NA	SINGLE_GROUP	7BASIC_SCIENCE	0NONE	true	0ALL	false	The purpose of this study is to determine the effect of rosiglitazone on the genes of the colon	The primary aim of the study is to examine the effect of rosiglitazone (Avandia) on gene regulation in colonic epithelium in the absence of pathologic acute and chronic intestinal inflammation. The secondary aims are to determine the effect of rosiglitazone (Avandia) therapy on T cell activation and cytokine expression in the absence of pathologic acute and chronic intestinal inflammation.	Inflammatory Bowel Disease		null	1	arm 1: Rosiglitazone; 8mg tablet once a day for 14 days	[ 5 ]	1	[ 0 ]	intervention 1: 8mg tablet once a day for 14 days	intervention 1: Rosiglitazone	1	Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238	12	0	0	0	NCT00567593	1COMPLETED	2008-03-01	2007-10-01	James Lewis	7OTHER	false	false	false	null	0	0	0	0	0
[ 5 ]	33	RANDOMIZED	CROSSOVER	0TREATMENT	3TRIPLE	false	0ALL	false	To evaluate the efficacy and safety of arformoterol tartrate inhalation solution 30μg/4mL QD (two 15μg/2mL dosed in combination) over a 24-hour period compared to arformoterol tartrate inhalation solution 15μg/2 mL BID in subjects with COPD.	This is a modified blind, randomized, multicenter, single dose two-way crossover study to assess the efficacy and safety of arformoterol 15μg BID versus arformoterol 30μg QD in subjects with COPD. Subject participation will last approximately three weeks and will include a screening visit, two 24-hour visits, and a follow up telephone call. This study was previously posted by Sepracor Inc. In October 2009, Sepracor Inc. was acquired by Dainippon Sumitomo Pharma., and in October 2010, Sepracor Inc's name was changed to Sunovion Pharmaceuticals Inc.	Chronic Obstructive Pulmonary Disease	COPD Chronic Bronchitis Emphysema	null	2	arm 1: Arformoterol 15 microgram twice a day (BID) taken each morning and evening for one visit followed by Arformoterol 30 microgram once a day (QD) in the morning and placebo in the evening for the next visit. arm 2: Arformoterol 30 microgram once a day (QD) in the morning and placebo in the evening for one visit followed by Arformoterol 15 microgram twice a day (BID) in the morning and evening for the next visit.	[ 0, 0 ]	3	[ 0, 0, 0 ]	intervention 1: Nebulized arformoterol tartrate inhalation solution 15 microgram twice a day (BID) intervention 2: Nebulized arformoterol tartrate inhalation solution 30 microgram once a day (QD) intervention 3: Placebo inhalation solution (citrate buffered 0.9% saline solution) once a day	intervention 1: Arformoterol Tartrate Inhalation Solution intervention 2: Arformoterol Tartrate Inhalation Solution intervention 3: Placebo	4	Medford \| Oregon \| United States \| -122.87559 \| 42.32652 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Spartanburg \| South Carolina \| United States \| -81.93205 \| 34.94957	66	0	0	0	NCT00571428	1COMPLETED	2008-03-01	2007-11-01	Sumitomo Pharma America, Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	75	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	false	The purpose of this study is to determine whether treatment with D9421-C for 8 weeks in Japanese patients with mild to moderate active Crohn's disease will improve their symptoms of Crohn's disease and quality of life.	null	Crohn's Disease	gastrointestinal GI Crohn's disease Japan Japanese	null	3	arm 1: D9421-C 9 mg arm 2: D9421-C 15 mg arm 3: Placebo	[ 1, 1, 2 ]	3	[ 0, 0, 0 ]	intervention 1: D9421-C 9 mg was given once daily for 8 weeks. intervention 2: D9421-C 15 mg was given once daily for 8 weeks. intervention 3: D9421-C matching placebo was given once daily for 8 weeks.	intervention 1: D9421-C, 9mg intervention 2: D9421-C, 15mg intervention 3: Placebo	22	Nagoya \| Aichi-ken \| Japan \| 136.90641 \| 35.18147 Sakura \| Chiba \| Japan \| 140.23333 \| 35.71667 Chikushino-shi \| Fukuoka \| Japan \| 130.5156 \| 33.49631 Fukuoka \| Fukuoka \| Japan \| 130.41667 \| 33.6 Kurume \| Fukuoka \| Japan \| 130.51667 \| 33.31667 Hashima-gun \| Gifu \| Japan \| N/A \| N/A Fukuyama \| Hiroshima \| Japan \| 133.36667 \| 34.48333 Hiroshima \| Hiroshima \| Japan \| 132.45 \| 34.4 Asahikawa \| Hokkaido \| Japan \| 142.36489 \| 43.77063 Sapporo \| Hokkaido \| Japan \| 141.35 \| 43.06667 Kobe \| Hyōgo \| Japan \| 135.183 \| 34.6913 Kyoto \| Kyoto \| Japan \| 135.75385 \| 35.02107 Ōita \| Oita Prefecture \| Japan \| 131.6 \| 33.23333 Kurashiki \| Okayama-ken \| Japan \| 133.76667 \| 34.58333 Osaka \| Osaka \| Japan \| 135.50107 \| 34.69379 Suita \| Osaka \| Japan \| 135.51567 \| 34.76143 Tokorozawa \| Saitama \| Japan \| 139.46903 \| 35.79916 Shinjuku-ku \| Tokyo \| Japan \| N/A \| N/A Toyama \| Toyama \| Japan \| 137.21667 \| 36.7 Itami \| N/A \| Japan \| 135.40126 \| 34.78427 Nishinomiya \| N/A \| Japan \| 135.33199 \| 34.71562 Tokyo \| N/A \| Japan \| 139.69171 \| 35.6895	77	0	0	0	NCT00573469	1COMPLETED	2008-03-01	2006-10-01	AstraZeneca	4INDUSTRY	false	false	false	null	0	0	0	0	-0
[ 3 ]	40	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	null	The purpose of the study is to test the efficacy of the combination treatment AllQbG10 in patients with perennial allergic rhinoconjunctivitis due to house dust mite allergy in a double-blind, placebo-controlled setting	null	Perennial Allergic Rhinoconjunctivitis House Dust Mite Allergy		null	4	arm 1: None arm 2: None arm 3: None arm 4: None	[ 0, 2, 0, 2 ]	4	[ 0, 0, 0, 0 ]	intervention 1: subcutaneous injections at 6 visits intervention 2: subcutaneous injections at 6 visits intervention 3: subcutaneous injections at 6 visits intervention 4: subcutaneous injections at 6 visits	intervention 1: CYT005-AllQbG10 (combination of house dust mite allergen extract with CYT003-QbG10) intervention 2: House dust mite allergen extract in combination with CYT003-QbG10-placebo intervention 3: CYT003-AllQbG10 in combination with house dust mite allergen extract placebo intervention 4: CYT003-QbG10-placebo in combination with house dust mite allergen extract placebo	0	null	40	0	0	0	NCT00574704	1COMPLETED	2008-03-01	2006-09-01	Cytos Biotechnology AG	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 4 ]	221	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	false	The purpose of this study is to describe the differences in efficacy between TOBRADEX Ophthalmic Suspension and Tobramycin 0.3%/Dexamethasone 0.05% Ophthalmic Suspension in the treatment of ocular inflammation and infection associated with blepharaconjunctivitis	null	Ocular Inflammation Associated With Blepharaconjunctivitis	Ocular inflammation blepharaconjunctivitis	null	2	arm 1: Tobramycin 0.3%/Dexamethasone 0.05% 1 drop 4 times daily in both eyes arm 2: TOBRADEX 1 drop 4 times daily in both eyes	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: Tobramycin 0.3%/Dexamethasone 0.05% 1 drop in both eyes 4 times daily for at least 3 days intervention 2: TOBRADEX 1 drop in both eyes 4 times daily for at least 3 days	intervention 1: Tobramycin 0.3%/Dexamethasone 0.05% intervention 2: TOBRADEX	1	Houston \| Texas \| United States \| -95.36327 \| 29.76328	221	0	0	0	NCT00576251	1COMPLETED	2008-03-01	2007-10-01	Alcon Research	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 0 ]	17	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	To evaluate engraftment and toxicity of a reduced intensity preparative regimen for patients who receive a matched related or unrelated donor allogeneic stem cell transplant (ASCT) for malignant hematological diseases	Primary Endpoints: 1. Engraftment of donor cells 2. Regimen related toxicities Secondary Endpoints: 1. Disease-free survival 2. Overall survival	Hematological Neoplasms Hematopoietic Stem Cell Transplantation	Allogenic stem cell transplant Hematologic diseases	null	1	arm 1: Preparative regimen of 1)Busulfex 3.2 mg/kg/day for 2 days, infused over 3 hours, on Day-6 and Day-5 2)Fludarabine 30 mg/m2/day for 5 days on Day-6 to D-2 and 3) Alemtuzumab 10 mg/day IV on days - 5 to -1	[ 5 ]	1	[ 0 ]	intervention 1: Busulfex 3.2 mg/kg/day for 2 days infused over 3 hours, Days -6 and Day-5 Fludarabine 30 mg/m2/day for 5 days on Day -6 to D-2 Alemtuzumab 10 mg/day IV on Days -5 to -1	intervention 1: Busulfex, Fludarabine, ALemtuzumab	1	Oklahoma City \| Oklahoma \| United States \| -97.51643 \| 35.46756	17	0	0	0	NCT00582894	1COMPLETED	2008-03-01	2005-02-01	University of Oklahoma	7OTHER	false	false	false	null	0	0	0	0	0
[ 5 ]	20	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	2MALE	false	The purpose of the study is to evaluate the effect of prophylactic treatment on the number of joint bleeds and quality of life in severe hemophilia A subjects compared to on-demand treatment in a one-group two-treatment schedule design. In addition, the effect of prophylactic treatment on the joint function, the number of all bleeds, and on the quality of life compared to on-demand treatment and health-economic data will be assessed.	null	Hematologic Disease Hemophilia A	Coagulation Disorders	null	1	arm 1: On-demand treatment was to follow the same treatment pattern the subject was using before entering the study. While on prophylactic treatment, all subjects were to be treated at a dose of 20-40 IU/kg, 3 times per week at a stable dose.	[ 0 ]	1	[ 0 ]	intervention 1: One group two treatment schedules, first on-demand then switch to prophylaxis	intervention 1: Kogenate (BAY14-2222)	11	Aurora \| Colorado \| United States \| -104.83192 \| 39.72943 Chapel Hill \| North Carolina \| United States \| -79.05584 \| 35.9132 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Strasbourg \| N/A \| France \| 7.74553 \| 48.58392 Florence \| N/A \| Italy \| 11.24626 \| 43.77925 Pavia \| N/A \| Italy \| 9.15917 \| 45.19205 Roma \| N/A \| Italy \| 11.10642 \| 44.99364 Madrid \| Madrid \| Spain \| -3.70256 \| 40.4165 Santa Cruz de Tenerife \| Santa Cruz de Tenerife \| Spain \| -16.25462 \| 28.46824 Cardiff \| South Glamorgan \| United Kingdom \| -3.18 \| 51.48 Sheffield \| South Yorkshire \| United Kingdom \| -1.4659 \| 53.38297	20	0	0	0	NCT00586521	1COMPLETED	2008-03-01	2006-02-01	Bayer	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	70	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	0ALL	false	This study is being done to see if St. John's wort helps people with irritable bowel syndrome, otherwise known as "IBS". St. John's wort is a herbal supplement derived from the St. John's wort plant. It has been shown to be helpful in several medical conditions such as depression as well as other pain syndromes.	Eligibility criteria: 1. Established diagnosis of IBS 2. 18-70 years of age 4\) U.S. resident 5) English-speaking (able to provide consent and complete questionnaires) 6) Able to participate in all aspects of the study You will be asked to do the following: * Undergo a screening interview and physical examination * Take a urine pregnancy test (if applicable) * Take a study pill twice daily for 12 weeks(3 months) * Complete daily symptom diaries and bi-weekly questionnaires for 12 weeks. * Complete a questionnaire at 6 months after the active phase of the study is over.	Irritable Bowel Syndrome		null	2	arm 1: None arm 2: None	[ 2, 1 ]	2	[ 0, 0 ]	intervention 1: Dosage form: Tablet (450 mg) Dose: 450 mg twice a day, placebo twice a day intervention 2: Dosage form: Tablet (450 mg) Dose: 450 mg twice a day, placebo twice a day	intervention 1: St. John's wort intervention 2: Placebo	1	Rochester \| Minnesota \| United States \| -92.4699 \| 44.02163	70	0	0	0	NCT00587860	1COMPLETED	2008-03-01	2006-02-01	Mayo Clinic	7OTHER	false	false	false	null	0	0	0	0	0
[ 3 ]	1	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	Open label, single-arm phase II study of avastin combined with fluorouracil, doxorubicin and streptozocin administered in 28-day cycles. Treatment will continue until progression of disease, or until withdrawal due to toxicity, or up to a maximum of 12 cycles (48 weeks). In order to reduce the risk of cardiac toxicity, doxorubicin will be administered for a maximum of 8 cycles. If disease has not progressed after 12 cycles of treatment, avastin monotherapy will continue until disease progression or withdrawal due to toxicity.	Patients will need to come for 24 study visits in all. Most study visits will take about 2 hours. At some of these study visits, the doctor * Will do a physical exam * Will take blood for routine lab tests * Will do a urinalysis * Will administer study medication Some study visits may be longer because patient will have a CT scan or an MRI. At patient's last visit, they will have a CT scan or MRI. After treatment starts, patient will: * Have their blood pressure monitored with every dose of Avastin® (about every 2 weeks). * Have a history and physical with every chemotherapy cycle (about every 4 weeks). * Have their blood taken for routine blood tests with every chemotherapy cycle (about every 4 weeks). * Have a CT scan or MRI during every other cycle (about every 8 weeks). * Have a MUGA scan during every 4 cycles (about 16 weeks). * Have blood taken for tumor markers during every cycle only if their markers were high at baseline. * Patients will receive study medication to treat their cancer: * Fluorouracil on days 1 through 5 of each cycle through cycle 12 * Doxorubicin on day 1 of each cycle through cycle 8 * Streptozocin on days 1 through 5 of each cycle through cycle 12 * Avastin® on days 1 and 15 of each cycle through cycle 12	Pancreatic Cancer	advanced unresectable metastatic endocrine tumors	null	1	arm 1: Protocol Specified Chemotherapy Every 28 Days: Avastin, Fluorouracil, Doxorubicin, Streptozocin. Premedications: Dexamethasone, Ondansetron	[ 0 ]	6	[ 0, 0, 0, 0, 0, 0 ]	intervention 1: Every 28 Days: Avastin 5mg/kg iv days 1 and 15 intervention 2: Every 28 Days: Fluorouracil 400mg/m\^2 iv bolus daily days 1-5 intervention 3: Every 28 Days: Doxorubicin 40mg/m\^2 iv bolus day 1 intervention 4: Every 28 Days: Streptozocin 400mg/m2 iv bolus daily days 1-5 intervention 5: Premedication: Dexamethasone 20mg intravenously days 1-5 intervention 6: Premedication: Ondansetron 16mg intravenously days 1-5	intervention 1: Avastin intervention 2: Fluorouracil intervention 3: Doxorubicin intervention 4: Streptozocin intervention 5: Dexamethasone intervention 6: Ondansetron	1	Tampa \| Florida \| United States \| -82.45843 \| 27.94752	1	0	0	0	NCT00609765	6TERMINATED	2008-03-01	2007-08-01	H. Lee Moffitt Cancer Center and Research Institute	7OTHER	false	false	false	null	0	0	0	0	0
[ 0 ]	44	RANDOMIZED	FACTORIAL	null	0NONE	true	0ALL	false	To date, no study has investigated whether there is a drug interaction between the protease inhibitor fosamprenavir and the integrase inhibitor raltegravir. COL111242 is a randomized, open-label, 6-arm, 3-period, drug interaction study to assess steady-state plasma amprenavir (APV) and raltegravir (RTG) pharmacokinetics in 48 healthy, HIV-negative adults after administration of a 7-day regimen of RTG 400mg twice a day (BID) alone and after 14-day regimens of unboosted fosamprenavir (FPV) 1400mg twice daily (BID), FPV 700mg/Ritonavir (RTV) 100mg BID, or FPV 1400mg/ritonavir (RTV) 100mg once daily (QD) with and without concurrent RTG 400mg BID. Blood samples for drug concentration measurement will be collected over 12 hours at the end of each dosing period. Subjects will undergo a physical examination, complete blood count (CBC) with differential, HIV test, hepatitis B/C test, liver function test, renal function analysis, and lipid panel at screening, and all of these tests, except those for HIV and hepatitis B/C, will be repeated at follow-up post-study. Adverse events and adherence (by pill count and medication diary) will be assessed by the investigator/study personnel at the end of each dosing period	This randomized, open-label, six-arm, three-period drug interaction study will recruit 48 healthy volunteers so as to obtain a minimum of 36 evaluable subjects at a single study center in the U.S. The study will have a screening visit, 3 treatment visits for pharmacokinetics (PK) sampling and a follow-up visit. The screening visit will be conducted within 30 days prior to receiving the first dose. Subjects will then be randomized into 1 of 6 treatment groups as shown below: Cohort Size Period 1 Period 2 Period 3 Sample Days 1 to 7 Days 1-14 Days 1-14 A 8 RTG 400mg BID FPV 1400mg BID FPV 1400mg BID * RTG 400mg BID B 8 RTG 400mg BID FPV 1400mg BID FPV 1400mg BID * RTG 400mg BID C 8 RTG 400mg BID FPV 700mg BID FPV 700mg BID * RTV 100mg BID + RTV 100mg BID * RTG 400mg BID D 8 RTG 400mg BID FPV 700mg BID FPV 700mg BID * RTV 100mg BID + RTV 100mg BID * RTG 400mg BID E 8 RTG 400mg BID FPV 1400mg QD FPV 1400mg QD * RTV 100mg QD + RTV 100mg QD * RTG 400mg BID F 8 RTG 400mg BID FPV 1400mg QD FPV 1400mg QD * RTV 100mg QD + RTV 100mg QD * RTG 400mg BID Study subjects will enter the clinic in the morning prior to dosing and remain at the center for 12 hours following each dose. Fourteen to 21 days following completion of the third dosing period, study subjects will return to the clinic for follow-up assessment. The total duration of the study will be approximately 86 days from screening through follow up. Blood samples for drug concentration measurement of amprenavir (APV) and raltegravir (RTG) concentrations will be collected over 12 hours at the end of each dosing period (at 0 \[baseline\], 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose). Subjects will undergo a physical examination, CBC with differential, HIV test, hepatitis B/C test, liver function test, renal function analysis, and lipid panel at screening, and all of these tests except those for HIV and hepatitis B/C will be repeated at follow-up post-study. Adverse events and adherence (by pill count and medication diary) will be assessed by the investigator/study personnel at the end of each dosing period. Evaluable patients will be required to have adhered to at least 95% of their study drug doses. Plasma APV concentrations will be analyzed using a validated high-performance liquid chromatography method with tandem mass spectrometric detection (HPLC/MS/MS) and plasma RTG concentrations by triple quadruple mass spectrometry. Plasma APV and RTG pharmacokinetic parameters measured will include maximum concentration (Cmax), time to maximum concentration (Tmax), minimum concentration (Cmin), and area under the concentration-time curve (AUC). All these parameters, except Tmax, will be log-transformed before statistical analysis. Analysis of variance, considering treatment as a fixed effect and subject as a random effect will be performed using Statistical Analysis Software (SAS), and assuming a treatment ratio for steady-state APV PK parameters as 1.0, the 90% confidence intervals will be within the range 0.81-1.24.	Healthy	Healthy Subjects Pharmacokinetics study Pharmacokinetics of medications	null	6	arm 1: Period 1-Raltegravir 400mg BID Period 2-Fosamprenavir 1400mg BID Period 3-Fosamprenavir 1400mg BID + Raltegravir 400mg BID arm 2: Period 1-Raltegravir 400mg BID Period2-Fosamprenavir 1400mg BID + Raltegravir 400mg BID Period 3-Fosamprenavir 1400mg BID arm 3: Period 1-Raltegravir 400mg BID Period 2-Fosamprenavir 700mg BID + Ritonavir 100mg BID Period 3-Fosamprenavir 700mg BID + Ritonavir 100mg BID + Raltegravir 400mg BID arm 4: Period 1-Raltegravir 400mg BID Period 2-Fosamprenavir 700mg BID + Ritonavir 100mg BID + Raltegravir 400mg BID Period 3-Fosamprenavir 700mg BID + Raltegravir 100mg BID arm 5: Period 1-Raltegravir 400mg BID Period 2-Fosamprenavir 1400mg QD + Ritonavir 100mg QD Period 3-Fosamprenavir 1400mg QD + Ritonavir 100mg QD + Raltegravir 400mg BID arm 6: Period 1-Raltegravir 400mg BID Period 2-Fosamprenavir 1400mg QD + Ritonavir 100mg QD + Raltegravir 400mg BID Period 3-Fosamprenavir 1400mg QD + Ritonavir 100mg QD	[ 1, 1, 1, 1, 1, 1 ]	3	[ 0, 0, 0 ]	intervention 1: 400mg BID intervention 2: 1400mg BID, 700 mg BID or 1400 mg QD intervention 3: 100 mg BID or QD	intervention 1: Raltegravir intervention 2: Fosamprenavir intervention 3: Ritonavir	0	null	37	0	0	0	NCT00614991	1COMPLETED	2008-03-01	2008-01-01	Garden State Infectious Disease Associates, PA	7OTHER	false	false	false	null	0	0	0	0	0
[ 2 ]	89	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	false	The objective of this study is to assess the effect of grass pollen extract SLIT tablets on the Rhinoconjunctivitis Total Symptom Score (RTSS) of the six rhinoconjunctivitis symptoms in response to grass pollen challenge after one week, one, two and four months of treatment in patients suffering from Seasonal Allergic Rhinoconjunctivitis (SAR) due to grass pollen.	The purpose of this study is to determine whether SLIT tablets are effective on symptoms of allergic rhinitis compared to placebo in patients suffering from allergic rhinitis to grass pollen when exposed in an allergen chamber and also to determine the onset of action of SLIT tablets on allergic rhinitis symptoms.	Seasonal Allergic Rhinitis	Sublingual immunotherapy Rhinitis Conjunctivitis Allergen challenge Allergen exposition chamber Grass pollen tablet Allergic rhinoconjunctivitis	null	2	arm 1: 300 IR grass pollen allergen extract tablet arm 2: Placebo tablet	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: 300 IR grass pollen allergen extract tablet once daily during four months intervention 2: Placebo tablet once daily during four months	intervention 1: 300 IR grass pollen allergen extract tablet intervention 2: Placebo tablet	1	Vienna \| N/A \| Austria \| 16.37208 \| 48.20849	89	0	0	0	NCT00619827	1COMPLETED	2008-03-01	2007-09-01	Stallergenes Greer	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	69	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	true	The purpose of this study is to conduct a preliminary evaluation of the efficacy of combined medication and psychotherapy for generalized anxiety disorder (GAD). The general goals of the current study are to conduct a late stage treatment development study. The goal of this stage of research is to provide a preliminary answer to the question and to gather data to estimate intervention parameters (e.g., effect size, attrition rates, response rates) that would assist in planning further research.	The specific aims of this study are to collect preliminary data relevant to the following hypotheses: 1. Primary Hypothesis: Acute phase improvement for combined cognitive behavioral therapy (CBT) plus medication will be superior to medication alone. 2. Secondary Hypotheses: Combined CBT plus medication will be superior to medication alone on a number of secondary outcome measures, including the core feature of GAD (worry), depressive symptoms, functional impairment, and quality of life. 3. Additional Exploratory Aim: We will explore the comparative relapse rates for the combined CBT plus medication treatment and the medication alone treatment condition at 6-month follow-up.	Generalized Anxiety Disorder	Generalized Anxiety Disorder Cognitive Behavioral Therapy Psychotherapy plus medication Combined treatment	null	2	arm 1: Patients who receive combined cognitive behavioral therapy (CBT) plus medication (venlafaxine XR, flexibly dosed between 75-225 mg/day) treatment for GAD. CBT was once/week sessions for 12 weeks. Medication continued for the full 6 months. arm 2: These patients receive only medication treatment for GAD. Patients take venlafaxine (flexibly dosed from 75-225 mg/day) as part of NCT00183274 and are assessed over a 6 month period. Medication continued for the full 6 months.	[ 0, 1 ]	2	[ 5, 0 ]	intervention 1: This cognitive behavioral therapy for GAD has a cognitive restructuring component and an applied relaxation component. Patients will be educated about the nature of anxiety and be trained in the recognition and monitoring of situational, physiological, cognitive, and behavioral cues associated with anxious responding. They will be guided through copings skill rehearsals in addition to imaginal and in vivo exposure to anxiety cues. This cognitive behavioral treatment will consist of 1 to 1.5 hour sessions of psychotherapy, which will be held once weekly over a period of 12 weeks. intervention 2: Venlafaxine XR, 75-225 mg/d, oral administration. 14 days at 75 mg/d, 150 mg/d for the remaining 6 months, 225 mg/3 for patients unimproved at week 6, tapered at 75 mg/week (this intervention is provided by protocol 709012).	intervention 1: Cognitive Behavioral Therapy intervention 2: Venlafaxine XR	1	Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238	61	0	0	0	NCT00620776	1COMPLETED	2008-03-01	2006-10-01	University of Pennsylvania	7OTHER	false	false	false	null	0	0	0	0	0
[ 4 ]	405	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	false	The purpose of this study is to determine whether oxycodone HCl and niacin are effective in the treatment of pain following bunionectomy surgery.	This was a Phase III, randomized, double blind, placebo controlled, multicenter, repeat dose study of the safety and efficacy of 2 dose levels of Acurox™ Tablets versus placebo for the treatment of moderate to severe postoperative pain following bunionectomy surgery. Patients underwent a primary unilateral first metatarsal bunionectomy with or without ipsilateral hammer toe repair during standardized local anesthesia with intravenous (IV) sedation. Eligible patients who reported moderate or severe pain within 6 hours after surgery entered the Treatment Phase and were randomized to 1 of 3 double blind treatments: placebo tablets or 1 of 2 dose levels of Acurox™ Tablets (ocyxcodone HCl/niacin). The Treatment Phase continued with study medication every 6 hours (irrespective of rescue medication use) for 48 hours (8 doses of study medication). Toradol (ketorolac tromethamine) was available as a rescue medication upon request.	Pain	Pain	null	3	arm 1: Tablet arm 2: Oxycodone HCl 5mg/Niacin 30mg tablet arm 3: Oxycodone HCl 7.5mg/Niacin 30mg tablet	[ 2, 1, 2 ]	3	[ 0, 0, 0 ]	intervention 1: 2 tablets every 6 hours for 48 hours intervention 2: 2 tablets every 6 hours for 48 hours intervention 3: 2 tablets every 6 hours for 48 hours	intervention 1: Placebo intervention 2: Acurox 5/30 mg intervention 3: Acurox 7.5/30	0	null	405	0	0	0	NCT00654069	1COMPLETED	2008-03-01	2007-09-01	Acura Pharmaceuticals Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 4 ]	1,498	RANDOMIZED	PARALLEL	1PREVENTION	3TRIPLE	true	1FEMALE	true	The purpose of this study is to assess the effects of tamoxifen and raloxifene on cognitive aging in selected cognitively-healthy women.	Recent reports indicate that hormone therapy (HT) may have a protective effect on the aging brain. Although previous studies have examined the effects of HT on age-related cognitive changes, there is little information on the effect of a new class of estrogenic agents, selective estrogen receptor modulators (SERMs), on cognitive aging. The two most commonly prescribed SERMs are tamoxifen, for treatment and prevention of breast cancer, and raloxifene, for maintaining bone density. In the face of potential widespread use of SERMs in healthy women, information on the effects of these agents on memory and other cognitive functions is essential. The principal goals of Co-STAR are to compare the effects of tamoxifen and raloxifene * on age-associated declines in measures of verbal and nonverbal memory in women over age 65 * other cognitive abilities and mood * with those resulting from more common forms of HT, specifically ET (conjugated equine estrogen) and ET plus progesterone Co-STAR results will be compared to results from the Women's Health Initiative Study of Cognitive Aging (WHISCA), a study involving 6-year longitudinal assessment of cognitive outcomes in 2969 women randomly assigned to receive active treatment (Premarin or Premarin plus medroxyprogesterone acetate) or placebo. A comparison of the Co-STAR treatment groups with the group of WHISCA participants receiving placebo will provide insights into the effects of SERMs relative to no treatment. A comparison of the Co-STAR treatment groups with WHISCA treatment groups receiving ET or ET plus progesterone will provide insights into the effects of SERMs relative to common HT treatments. Co-STAR participants will be recruited from The National Cancer Institute's (NCI) Study of Tamoxifen and Raloxifene (STAR) NCT00003906, a multi-center, 5-year, randomized clinical trial among 22,000 women at increased risk for breast cancer, to compare the effects of tamoxifen and raloxifene on risk for breast cancer.	Cognition Aging	breast cancer Tamoxifen Raloxifene hormone therapy	null	2	arm 1: Participants in the parent study, STAR assigned to Tamoxifen who were 65 or older at time of enrollment. arm 2: Participants in the parent study, STAR assigned to Raloxifene who were 65 or older at time of enrollment.	[ 0, 0 ]	2	[ 0, 0 ]	intervention 1: oral tamoxifen plus placebo daily for 5 years intervention 2: oral raloxifene plus placebo daily for 5 years	intervention 1: tamoxifen intervention 2: raloxifene	134	Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 Camp Pendleton \| California \| United States \| -117.44759 \| 33.35731 Duarte \| California \| United States \| -117.97729 \| 34.13945 Duarte \| California \| United States \| -117.97729 \| 34.13945 Duarte \| California \| United States \| -117.97729 \| 34.13945 Fullerton \| California \| United States \| -117.92534 \| 33.87029 Glendale \| California \| United States \| -118.25508 \| 34.14251 Lancaster \| California \| United States \| -118.13674 \| 34.69804 Oakland \| California \| United States \| -122.2708 \| 37.80437 Oxnard \| California \| United States \| -119.17705 \| 34.1975 Redding \| California \| United States \| -122.39168 \| 40.58654 San Diego \| California \| United States \| -117.16472 \| 32.71571 San Diego \| California \| United States \| -117.16472 \| 32.71571 Santa Barbara \| California \| United States \| -119.69819 \| 34.42083 Woodland Hills \| California \| United States \| -118.60592 \| 34.16834 Colorado Springs \| Colorado \| United States \| -104.82136 \| 38.83388 Denver \| Colorado \| United States \| -104.9847 \| 39.73915 Pueblo \| Colorado \| United States \| -104.60914 \| 38.25445 Hartford \| Connecticut \| United States \| -72.68509 \| 41.76371 New Britain \| Connecticut \| United States \| -72.77954 \| 41.66121 New London \| Connecticut \| United States \| -72.09952 \| 41.35565 Newark \| Delaware \| United States \| -75.74966 \| 39.68372 Washington D.C. \| District of Columbia \| United States \| -77.03637 \| 38.89511 Lakeland \| Florida \| United States \| -81.9498 \| 28.03947 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 Savannah \| Georgia \| United States \| -81.09983 \| 32.08354 Honolulu \| Hawaii \| United States \| -157.85833 \| 21.30694 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Rockford \| Illinois \| United States \| -89.094 \| 42.27113 Urbana \| Illinois \| United States \| -88.20727 \| 40.11059 Goshen \| Indiana \| United States \| -85.83444 \| 41.58227 Munster \| Indiana \| United States \| -87.51254 \| 41.56448 South Bend \| Indiana \| United States \| -86.25001 \| 41.68338 Davenport \| Iowa \| United States \| -90.57764 \| 41.52364 Dubuque \| Iowa \| United States \| -90.66457 \| 42.50056 Wichita \| Kansas \| United States \| -97.33754 \| 37.69224 New Orleans \| Louisiana \| United States \| -90.07507 \| 29.95465 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Pittsfield \| Massachusetts \| United States \| -73.24538 \| 42.45008 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 Battle Creek \| Michigan \| United States \| -85.17816 \| 42.3173 Detroit \| Michigan \| United States \| -83.04575 \| 42.33143 Flint \| Michigan \| United States \| -83.68746 \| 43.01253 Grand Rapids \| Michigan \| United States \| -85.66809 \| 42.96336 Kalamazoo \| Michigan \| United States \| -85.58723 \| 42.29171 Lansing \| Michigan \| United States \| -84.55553 \| 42.73253 Marquette \| Michigan \| United States \| -87.39542 \| 46.54354 Monroe \| Michigan \| United States \| -83.39771 \| 41.91643 Royal Oak \| Michigan \| United States \| -83.14465 \| 42.48948 Duluth \| Minnesota \| United States \| -92.10658 \| 46.78327 Duluth \| Minnesota \| United States \| -92.10658 \| 46.78327 Minneapolis \| Minnesota \| United States \| -93.26384 \| 44.97997 Saint Louis Park \| Minnesota \| United States \| -93.34801 \| 44.9483 Tupelo \| Mississippi \| United States \| -88.70464 \| 34.25807 Columbia \| Missouri \| United States \| -92.33407 \| 38.95171 Joplin \| Missouri \| United States \| -94.51328 \| 37.08423 Springfield \| Missouri \| United States \| -93.29824 \| 37.21533 Springfield \| Missouri \| United States \| -93.29824 \| 37.21533 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Billings \| Montana \| United States \| -108.50069 \| 45.78329 Great Falls \| Montana \| United States \| -111.30081 \| 47.50024 Kearney \| Nebraska \| United States \| -99.08148 \| 40.69946 Lincoln \| Nebraska \| United States \| -96.66696 \| 40.8 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 Red Bank \| New Jersey \| United States \| -74.06431 \| 40.34705 Buffalo \| New York \| United States \| -78.87837 \| 42.88645 Cooperstown \| New York \| United States \| -74.92426 \| 42.70048 East Syracuse \| New York \| United States \| -76.07853 \| 43.06534 Poughkeepsie \| New York \| United States \| -73.92097 \| 41.70037 Rochester \| New York \| United States \| -77.61556 \| 43.15478 Syracuse \| New York \| United States \| -76.14742 \| 43.04812 Charlotte \| North Carolina \| United States \| -80.84313 \| 35.22709 Charlotte \| North Carolina \| United States \| -80.84313 \| 35.22709 Durham \| North Carolina \| United States \| -78.89862 \| 35.99403 Fayetteville \| North Carolina \| United States \| -78.87836 \| 35.05266 Gastonia \| North Carolina \| United States \| -81.1873 \| 35.26208 Goldsboro \| North Carolina \| United States \| -77.99277 \| 35.38488 Greenville \| North Carolina \| United States \| -77.36635 \| 35.61266 Hendersonville \| North Carolina \| United States \| -82.46095 \| 35.31873 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Bedford \| Ohio \| United States \| -81.53651 \| 41.39311 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Columbus \| Ohio \| United States \| -82.99879 \| 39.96118 Lima \| Ohio \| United States \| -84.10523 \| 40.74255 Toledo \| Ohio \| United States \| -83.55521 \| 41.66394 Toledo \| Ohio \| United States \| -83.55521 \| 41.66394 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Scranton \| Pennsylvania \| United States \| -75.6649 \| 41.40916 York \| Pennsylvania \| United States \| -76.72774 \| 39.9626 Charleston \| South Carolina \| United States \| -79.93275 \| 32.77632 Columbia \| South Carolina \| United States \| -81.03481 \| 34.00071 Greenville \| South Carolina \| United States \| -82.39401 \| 34.85262 Spartanburg \| South Carolina \| United States \| -81.93205 \| 34.94957 Sioux Falls \| South Dakota \| United States \| -96.70033 \| 43.54997 Knoxville \| Tennessee \| United States \| -83.92074 \| 35.96064 Amarillo \| Texas \| United States \| -101.8313 \| 35.222 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Garland \| Texas \| United States \| -96.63888 \| 32.91262 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Lackland Air Force Base \| Texas \| United States \| -98.61797 \| 29.38663 Lubbock \| Texas \| United States \| -101.85517 \| 33.57786 Lubbock \| Texas \| United States \| -101.85517 \| 33.57786 Plano \| Texas \| United States \| -96.69889 \| 33.01984 Temple \| Texas \| United States \| -97.34278 \| 31.09823 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Danville \| Virginia \| United States \| -79.39502 \| 36.58597 Bremerton \| Washington \| United States \| -122.63264 \| 47.56732 Seattle \| Washington \| United States \| -122.33207 \| 47.60621 Seattle \| Washington \| United States \| -122.33207 \| 47.60621 Seattle \| Washington \| United States \| -122.33207 \| 47.60621 Yakima \| Washington \| United States \| -120.5059 \| 46.60207 Marshfield \| Wisconsin \| United States \| -90.1718 \| 44.66885 Calgary \| Alberta \| Canada \| -114.08529 \| 51.05011 Vancouver \| British Columbia \| Canada \| -123.11934 \| 49.24966 Winnepeg \| Manitoba \| Canada \| N/A \| N/A Ottawa \| Ontario \| Canada \| -75.69812 \| 45.41117 Thunder Bay \| Ontario \| Canada \| -89.25018 \| 48.38202 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643	1,498	0	0	0	NCT00687102	1COMPLETED	2008-03-01	2001-10-01	Wake Forest University	7OTHER	false	false	false	null	0	0	0	0	0
[ 1 ]	22	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	true	0ALL	true	In this randomized, double-blind, placebo controlled trial we used positron emission tomography to determine if lovastatin or recombinant human activated protein C exhibit anti-inflammatory effects in humans following intrabronchial installation of lipopolysaccharide (LPS or endotoxin).	Quantitative, noninvasive biomarkers for lung-specific inflammation have yet to be developed but can potentially contribute significantly to the development of therapies to treat lung inflammation. The purpose of this study was to demonstrate that positron emission tomographic (PET) imaging with \[18F}fluorodeoxyglucose (FDG-PET) can be used to quantify the change in lung inflammation in healthy volunteers.	Lung Inflammation	randomized positron emission tomography lung inflammation lovastatin recombinant human activated protein C endotoxin fluorodeoxyglucose	null	3	arm 1: None arm 2: None arm 3: None	[ 2, 0, 0 ]	4	[ 0, 0, 0, 2 ]	intervention 1: Placebo pill every four hours, starting 16 hours before intrabronchial LPS and ending 24 hours after intrabronchial LPS Placebo IV starting 2 hours before intrabronchial LPS and ending 24 hours after intrabronchial LPS intervention 2: lovastatin pill every four hours, total of 80 milligrams a day, starting 16 hours before intrabronchial LPS and ending 24 hours after intrabronchial LPS Placebo IV starting 2 hours before intrabronchial LPS and ending 24 hours after intrabronchial LPS intervention 3: placebo pill every four hours, total of 80 milligrams a day, starting 16 hours before intrabronchial LPS and ending 24 hours after intrabronchial LPS recombinant human activated protein C IV 24 micrograms per kg per hour starting 2 hours before intrabronchial LPS and ending 24 hours after intrabronchial LPS intervention 4: Endotoxin 4 ng/kg instilled bronchoscopically in all volunteers 12 hours after starting lovastatin treatment and 2 hours after starting recombinant human activated protein C treatment.	intervention 1: placebo pill and placebo IV intervention 2: Lovastatin pill and placebo IV intervention 3: placebo pill and recombinant human activated protein C IV intervention 4: Endotoxin	1	St Louis \| Missouri \| United States \| -90.19789 \| 38.62727	22	0	0	0	NCT00741013	1COMPLETED	2008-03-01	2007-03-01	Washington University School of Medicine	7OTHER	false	false	false	null	0	0	0	0	0
[ 0 ]	43	RANDOMIZED	CROSSOVER	0TREATMENT	4QUADRUPLE	false	0ALL	false	The purpose of this study was to see if high dose esomeprazole (40mg bid) was effective in treating non-allergic rhinitis	null	Vasomotor Rhinitis	non-allergic rhinitis, laryngopharyngeal reflux	null	2	arm 1: esomeprazole 40mg po bid arm 2: None	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: 40mg by mouth twice daily intervention 2: None	intervention 1: esomeprazole intervention 2: placebo	1	Dallas \| Texas \| United States \| -96.80667 \| 32.78306	74	0	0	0	NCT00745849	1COMPLETED	2008-03-01	2005-06-01	University of Texas Southwestern Medical Center	7OTHER	false	false	false	null	0	0	0	0	0
[ 4 ]	259	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	false	The purpose of this study is to determine the safety and efficacy of 4 mg of Ramelteon, once daily (QD), in subjects with chronic insomnia.	In the western world, there are several people affected by chronic insomnia. Numerous studies estimate that 30% to 40% of the general population is affected at some time in their lives with a form of insomnia that goes on for several months, and about one third of those are described as severely affected. Daytime symptoms of insomnia include tiredness, lack of energy, difficulty concentrating and irritability. Recent epidemiologic research focusing on the quality of life has identified significant insomnia-related morbidities that relate to work productivity, health care utilization, and risk of depression. Insomnia is associated with diminished work output, absenteeism, and greater rates of accidents. Although normal control of the sleep-wake cycle is exerted by the suprachiasmatic nucleus via melatonin receptor subtype 1 and 2 (MT1 and MT2) receptors (melatonin receptor subtype), most current pharmacologic treatments for insomnia mainly involve GABAergic (gamma-aminobutyric acid) mechanisms. Most currently prescribed sleep agents are benzodiazepine receptor agonists, which induce sleep by binding to the benzodiazepine receptor site of the gamma-aminobutyric acid-A receptor complex. Gamma-aminobutyric acid is the major inhibitory transmitter in the central nervous system, and its receptors are distributed widely throughout the brain. In addition to sleep, benzodiazepine receptor agonists can cause a wide range of ancillary effects not directly related to sleep, depending on the precise subset of gamma-aminobutyric acid-A receptors activated. These include sedative, anxiolytic, muscle-relaxant, and amnesic effects. The risk of tolerance, dependence development, and abuse potential associated with the benzodiazepine receptor agonists also may reflect effects of these drugs on the gamma-aminobutyric acid-A receptor complex. The sleep-wake cycle results from the interaction of circadian and homeostatic mechanisms. The homeostatic mechanism refers to the accumulation of sleep load during time awake; the organism falls asleep when the sleep load is high, and the reduction of sleep load during sleep results in waking. A circadian rhythm is superimposed on the homeostatic mechanism. Circadian rhythms are controlled by the suprachiasmatic nucleus, which emits alerting signals; this signal is believed to be attenuated by melatonin, which is produced in response to darkness. It is believed that binding of melatonin to MT1 and MT2 receptors in the suprachiasmatic nucleus inhibits firing of specific neurons, and this is thought to attenuate the alerting signal, allowing the homeostatic mechanism to express itself and promote sleep. An agent that is selective for the MT1 and MT2 receptors would be expected to be devoid of the ancillary effects of agents that act at the gamma-aminobutyric acid-A receptor complex. It would promote sleep by specifically targeting the alerting signal in the suprachiasmatic nucleus, allowing the homeostatic mechanism to produce sleep. Ramelteon is under global development by Takeda Pharmaceuticals as a nonscheduled sleep agent for the treatment of difficulty with sleep initiation, and is marketed under the brand name of Rozerem™ in the United States. In vitro, ramelteon demonstrates affinity and selectivity for human melatonin MT1 and MT2 receptors compared to melatonin. It also demonstrates full agonist activity in cells expressing human MT1 or MT2 receptors relative to melatonin. In the European Union, Takeda is seeking marketing approval for the long-term treatment of transient and chronic insomnia as characterized by difficulty with sleep onset. Because most of the European clinical studies to date have used the 8 mg dose, the aim of this study is to assess the safety and efficacy of 4mg of ramelteon in a larger number of adults with chronic insomnia. Subjects participating in this study will be required to report to a sleep laboratory and have polysomnography recordings over two consecutive nights for three sittings during a five week period. The total duration of the study is approximately 10 weeks.	Sleep Initiation and Maintenance Disorders	Chronic Insomnia DIMS (Disorders of Initiating and Maintaining Sleep) Disorders of Initiating and Maintaining Sleep Insomnia Disorder Sleep Initiation Dysfunction Transient Insomnia Drug Therapy Sleep Disorders, Intrinsic	null	2	arm 1: None arm 2: None	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: Ramelteon 4 mg, tablets, orally, once daily for up to 5 weeks. intervention 2: Ramelteon placebo-matching tablets, orally, once daily for up to 5 weeks.	intervention 1: Ramelteon intervention 2: Placebo	0	null	259	0	0	0	NCT00756002	1COMPLETED	2008-03-01	2007-08-01	Takeda	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 5 ]	37	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	false	To evaluate the IOP (Intraocular Pressure) lowering efficacy and safety of Brinzolamide 1.0% (Azopt), dosed twice daily as adjunctive therapy in patients treated with Travoprost 0.004% (Travatan) once daily. The study is double masked. The patients will receive either treatment for 12 weeks.	null	Intraocular Pressure	IOP lowering efficacy and safety of Azopt plus Travatan	null	2	arm 1: Travoprost 0.004% (once daily) + Brinzolamide 1.0% (twice daily) arm 2: Travoprost 0.004% (once daily) + Tears Naturale (twice daily)	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: Travoprost 0.004% (once daily) + Brinzolamide 1.0% (twice daily) intervention 2: Travoprost 0.004% (once daily) + Tears Naturale (twice daily)	intervention 1: Travoprost 0.004% + Brinzolamide 1.0% intervention 2: Travoprost 0.004% + Tears Natural	0	null	37	0	0	0	NCT00758342	6TERMINATED	2008-03-01	2006-05-01	Alcon Research	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 4 ]	19	RANDOMIZED	CROSSOVER	0TREATMENT	1SINGLE	true	0ALL	false	Investigation of inhibitory effect of prototype toothpaste on dental plaque formation via modified gingival margin plaque index method.	null	Dental Plaque		null	2	arm 1: None arm 2: None	[ 2, 1 ]	2	[ 0, 0 ]	intervention 1: Brush teeth and evaluate plaque score after one use of the study toothpaste intervention 2: Brush teeth and evaluate plaque score after one use of the study toothpaste	intervention 1: Sodium Monofluorophosphate intervention 2: Triclosan/Fluoride/Copolymer	1	New York \| New York \| United States \| -74.00597 \| 40.71427	35	0	0	0	NCT00759031	1COMPLETED	2008-03-01	2008-02-01	Colgate Palmolive	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	35	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	0ALL	false	The purpose of the study is to determine the safety and efficacy of AN2728 Ointment, 5%, compared to Ointment Vehicle in the treatment of plaque type psoriasis.	This is a multi-center, randomized, double-blind bilateral design. Patients will apply the test articles, AN2728 Ointment, 5%, and Ointment Vehicle twice daily. The assigned study medication will be applied to two comparable treatment targeted plaques identified at baseline. One test article will be applied to one plaque and the other test article to an anatomically distinct plaque. All efficacy evaluations will be measured from only the two plaques identified at the baseline visit.	Psoriasis	Plaque Type Psoriasis Topical	null	2	arm 1: AN2728 Ointment, 5% arm 2: AN2728 Ointment Vehicle	[ 1, 2 ]	2	[ 0, 0 ]	intervention 1: AN2728 Ointment, 5%, twice daily for 4 weeks intervention 2: AN2728 Ointment Vehicle, twice daily for 4 weeks.	intervention 1: AN2728 intervention 2: AN2728 Ointment Vehicle	1	Mexico City \| Mexico City \| Mexico \| -99.12766 \| 19.42847	35	0	0	0	NCT00759161	1COMPLETED	2008-03-01	2007-11-01	Pfizer	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	8	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	This is a study to test the safety and efficacy of an investigational chemotherapy agent in patients with advanced prostate cancer. Subjects who meet all entry criteria and have signed the informed consent will be enrolled in the study. Participants will be required to attend regular clinic visits to receive study medication and have their status monitored. A detailed explanation can be provided by the investigator conducting the study.	Prostate cancer is the most common non-cutaneous cancer diagnosed in men in the United States. The majority of deaths occur in men with androgen-independent prostate cancer \[AIPC\]. Although 80% of men with advanced cancer will initially respond to androgen ablation with disease regression or stabilization, their malignancies become resistant to such therapy.	Prostate Cancer	Aplidin Plitidepsin Prostate Cancer	null	1	arm 1: Aplidin (Plitidepsin)	[ 0 ]	1	[ 0 ]	intervention 1: Aplidin® administered at a starting dose of 5 mg/m2, as a 3-hours intravenous infusion, every 2 weeks.	intervention 1: Aplidin (plitidepsin)	2	Ann Arbor \| Michigan \| United States \| -83.74088 \| 42.27756 Seattle \| Washington \| United States \| -122.33207 \| 47.60621	8	0	0	0	NCT00780975	6TERMINATED	2008-03-01	2005-02-01	PharmaMar	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 5 ]	12	RANDOMIZED	CROSSOVER	9OTHER	0NONE	true	0ALL	false	The purpose of this study is to estimate the relative bioavailability of the commercial tablet with one prototype extemporaneous preparation suspension formulation, to assist with internal decision making on formulation development.	Estimation of Relative Bioavailability	Hypercholesterolemia	Cardiovascular Diseases	null	2	arm 1: Extemporaneous preparation suspension Atorvastatin prototype formulation arm 2: Commercial atorvastatin tablet (Lipitor®)	[ 5, 5 ]	2	[ 0, 0 ]	intervention 1: A single dose of 80 mg Atorvastatin suspension intervention 2: A single dose of 80 mg Lipitor tablet	intervention 1: Atorvastatin suspension intervention 2: Lipitor	1	New Haven \| Connecticut \| United States \| -72.92816 \| 41.30815	23	0	0	0	NCT00844376	1COMPLETED	2008-03-01	2008-02-01	Pfizer's Upjohn has merged with Mylan to form Viatris Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 2 ]	24	RANDOMIZED	CROSSOVER	0TREATMENT	0NONE	true	0ALL	null	A study in 24 healthy subjects to assess the bioequivalence of Famotidine/Antacid EZ Chew tablet taken without water and with water compared to the Famotidine/Antacid tablet taken with water. Subjects will be given a single dose of each treatment separated by 5 to 7 days.	null	Heartburn		null	3	arm 1: Famotidine/antacid combination tablet with water arm 2: Famotidine/Antacid EZ Chew tablet without water arm 3: Famotidine/Antacid EZ Chew tablet with water	[ 1, 0, 0 ]	3	[ 0, 0, 0 ]	intervention 1: A single dose of famotidine/antacid tablet with 120 mL of water in one of three treatment periods intervention 2: A single dose of famotidine/antacid combination EZ Chew tablet without water in one of three treatment periods intervention 3: A single dose of famotidine/antacid combination EZ Chew tablet with 120 mL of water in one of three treatment periods	intervention 1: famotidine (+) calcium carbonate (+) magnesium hydroxide tablet intervention 2: Comparator: famotidine (+) calcium carbonate (+) magnesium hydroxide EZ Chew tablet without water intervention 3: Comparator: famotidine (+) calcium carbonate (+) magnesium hydroxide EZ Chew tablet with water	0	null	72	0	0	0	NCT00944671	1COMPLETED	2008-03-01	2008-02-01	Johnson & Johnson Consumer and Personal Products Worldwide	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 4 ]	105	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	true	Dexmedetomidine is an alpha 2-adrenoreceptor agonist, which provides sedation, analgesia and anxiolysis in clinical practice (Cortinez et al., 2004,Hall et al., 2000). Three types of alpha 2-adrenergic receptor subtypes are found in the human body and they have been designated alpha 2A, alpha 2B and alpha 2C. The alpha 2A subtype is most likely responsible for the analgesic properties of dexmedetomidine in both peripheral and central sites (Kingery et al., 2000, Smith et al., 2001). Activation of central alpha 2-adrenoreceptors in the locus ceruleus (Correa-Sales et al., 1992) and the dorsal horn of the spinal cord (Gaumann et al., 1992b) are responsible for both analgesic and sedative effects. Dexmedetomidine has a very high alpha 2 to alpha 1 selectivity, 1620 to 1, or approximately 8 times that of clonidine. It is also 4 to 6 times more potent than clonidine by weight (Bhana et al., 2000). Although dexmedetomidine produces dose dependent sedation upon intravenous administration, its the analgesic effect is of dexmedetomidine is more variable and controversial. In an ischaemic pain model in healthy volunteers, a single bolus of dexmedetomidine produced a 50% reduction in pain scores when compared to placebo (Jaakola et al., 1991). In another volunteer study using the cold pressor test, dexmedetomidine 1 µg/kg over 10 minutes followed by an infusion of 0.2 to 0.6 µg/kg/hour reduced pain by approximately 30% (Hall et al., 2000). However, when administered as a target controlled infusion at concentrations ranging from 0.09 to 1.23 ng/mL, dexmedetomidine had no analgesic effect in human volunteers subjected to heat and electrical pain, although sedation was produced (Memis et al., 2004). Clonidine and dexmedetomidine are two common alpha 2 agonists used clinically. Although clonidine former has been used successfully in regional analgesia and anesthesia (Gabriel et al., 2001)., There are only very few studies evaluating the peripheral analgesic effects of dexmedetomidine. Since acute postoperative dental pain is a common analgesia model (Cooper, 1991; US Food and Drug Administration 1992), the investigators conducted this study, aiming to assess the postoperative analgesic efficacy of peripheral dexmedetomidine after bilateral third molar surgery under general anaesthesia. The analgesic effects were compared up to the 72nd hour postoperatively in order to evaluate any potential preventive analgesic effect.	The study protocol was approved by our local Institutional Review Board and written consent was obtained from all the participants. Eligibility for recruitment included American Society of Anesthesiologists (ASA) physical status I and II, age between 18 and 50 years of age with 4 bilateral impacted third molar teeth scheduled for extraction under general anaesthesia. Exclusion criteria included clinical history or electrocardiographic evidence of heart block, ischaemic heart disease, asthma, sleep apnoea syndrome, impaired liver or renal function, alcohol consumption in excess of 28 units per week, pregnancy, patient refusal, known psychiatric illness, chronic sedative or analgesic use, and regular use of or known allergy to dexmedetomidine, paracetamol or dextropropoxypheneopioids. Patients with preoperative inflammation at the site of surgery were also excluded. After obtaining written, informed consent, patients were randomly allocated to receive 1)Preoperative IV dexmedetomidine 1mcg/kg and normal saline infiltrated to wound at the end of surgery; 2) Preoperative normal saline IV infusion and dexmedetomidine 1mcg/kg infiltrated to wound or 3) Preoperative IV normal saline infusion and normal saline infiltrated to wound at the end of surgery. A computer generated random sequence was used for drug allocation and this was prepared by a statistician who was unaware of the clinical nature of the study. The patients were assessed by the list anaesthetist the day before surgery. They were fasted for at least 6 hours and did not receive any premedication before arrival at the operation theatre. Patients were educated on the use of the Numerical Rating Scale (NRS) for pain assessment, where zero corresponds to no pain and 10 represents the worst pain imaginable. A P-deletion test was performed in the ward preoperatively. The P-deletionThis test consists of 58 lines of closely typed text containing between 74 to 97 occurrences of the letter "p". The patients are instructed to cross out every letter "p" they can find as quickly as possible, reading from left to right down the page. The number deleted in 180 seconds and the number of errors counts. This test assesses speed, accuracy, concentration, mental activity, hand-eye coordination and vigilance. It was firstly described by Dixon and colleagues who found it to be an accurate test for psychomotor recovery from anesthesia and sedation (Dixon et al., 1973). On arrival at the operating theatre, a 20-gauge intravenous cannula was inserted in the dorsum of each patient's left hand. Either dexmedetomidine 1 µg/kg (Group D) diluted to 4ml with normal saline or the same volume of 0.9% saline alone (Group P) was prepared by another anaesthetist who did not participate in patient management or data collection. Both preparations were clear solutions, therefore patients, medical, nursing staff, and data collectors were all blinded to the allocated drug. Heart rate, blood pressure, respiratory rate and oxygen saturation were recorded (S/5 Anesthesia Monitor, Datex-Ohmeda, WI, USA) before general anaesthesia and thereafter at five-minute intervals from the time of commencing surgery until discharge from the recovery room. Induction and maintenance of anaesthesia were done according to a standard protocol. Anaesthesia was induced with propofol titration of 2 to 3 mg/kg, fentanyl 1 µg/kg and muscle relaxation was achieved with rocuronium 1 mg/kg. The trachea was intubated via the nasal route. General anaesthesia was maintained with a mixture of air, oxygen and sevoflurane at 1 to 1.5 MAC. Before the start of the surgical procedures, regional anaesthesia were performed by infiltrating 2.7 mL of 2% lignocaine with 1 in 80,000 adrenaline around the base of the gum of each third molar by the same team of dental surgeons. Sevoflurane was stopped when the last suture had been inserted. andVolume of 1 ml of either dexmedetomidine (Group D, totally dexmedetomidine 1 µg/kg for 4 surgical sites) or saline (Group P) was infiltrated to the submucosa of each surgical site. Neuromuscular block was antagonized with neostigmine 50 µg/kg and atropine 20 µg/kg, and followed by extubation after recovery of consciousness. The patients were then monitored in the recovery room for at least 30 minutes. Resting pain scores, blood pressure, heart rate, oxygen saturation and the Ramsay sedation score (RSS) (appendix 1) were assessed and recorded every 5 minutes. Intravenous ketorolac or morphine would be administered upon patients' request. Patients were transferred back to the general ward when fully consciousness with normal physiological parameters. The P-deletion test was repeated hourly from the first postoperative hour in the general ward until the performance reached the same level as that before surgery. Blood pressure, heart rate, oxygen saturation, and RSS were monitored hourly for 4 hours. NRS pain scores were charted hourly for 6 hours then 4-hourly thereafter. Patients were prescribed two analgesic tablets, each containing paracetamol 320 mg and dextropropoxyphene 32.5 mg (Dolpocetmol®, Synco Limited, Hong Kong, China), on an as required basis to a maximum of four times daily. The patients were explained told that the pain medications prescribed could be taken if the postoperative NRS pain score was more than 3. Final hospital discharge was at the discretion of the attending dental surgeon. The oral analgesic medication described above was prescribed for three days postoperatively and patients were given aA diary was given to our patients. diary to record NRS pain scores at rest and upon mouth opening, analgesic consumption and side effects were self recorded by each patient up to the 72nd hour postoperatively. Global pain satisfaction using NRS (zero being least satisfied and 10 being most satisfied) was recorded on postoperative day 3. By considering a difference of 2 units in NRS pain scores to be clinically significant, and an estimated standard deviation of 2.5 units among patients, we calculated that a sample size of 30 per group would give an 80% power of the test at the 5% level of significance. In order to account for possible dropouts due to protocol violation or missing data, 35 patients were recruited in each group. Statistical analysis was performed using SPSS 14.0 for Windows (SPSS Inc., IL, USA). NRS pain scores, analgesic consumption, NRS global pain satisfaction and the difference in pre- and post-operative P-deletion scores were compared using the Mann-Whitney U test. Perioperative vital signs and NRS pain scores up to the 72nd postoperative 72nd hour were plotted graphically using GraphPad Prism 4.03 (GraphPad Software Inc., CA, USA) and the mean area under the curve AUC were compared between groups using the Mann Whitney U test. All categorical data were analyzed using χ2 test. Time to first analgesic use was compared using the log-rank test in Kaplan-Meier survival analysis. The incidence of side effects was analyzed by χ2 test or Fisher's exact test as appropriate.	Third Molar Extraction	Analgesia Dental pain Dexmedetomidine Pain Peripheral effects	null	3	arm 1: None arm 2: None arm 3: None	[ 1, 2, 1 ]	3	[ 0, 0, 0 ]	intervention 1: Preoperative normal saline infusion and 1mcg/kg dexmedetomidine infiltrated locally to wound at the end of operation. intervention 2: Same volume of normal saline as dexmedetomidine is infiltrated and IV infusion. intervention 3: IV dexmedetomidine 1mcg/kg peroperative and normal saline infiltrated to wound at the end of operation	intervention 1: local dexmedetomidine intervention 2: Peripheral normal saline intervention 3: IV dexmedetomidine	0	null	99	0	0	0	NCT00971178	1COMPLETED	2008-03-01	2006-02-01	The University of Hong Kong	7OTHER	false	false	false	null	0	0	0	0	0
[ 5 ]	20	RANDOMIZED	CROSSOVER	0TREATMENT	0NONE	false	0ALL	false	The null hypothesis is that there is a difference in the the relative rate and extent of absorption into the systemic circulation of Triomune and brand-name Stavudine/Lamivudine/Nevirapine in HIV-infected Africans and the alternative hypothesis is that there is no difference in the the relative rate and extent of absorption into the systemic circulation of Triomune and brand-name Stavudine/Lamivudine/Nevirapine in HIV-infected Africans. This is a non-inferiority study.	Generic antiretroviral therapy is the mainstay of HIV treatment in resource-limited settings, yet there is little evidence confirming the bioequivalence of generic and brand name formulations. We compared the steady-state pharmacokinetics of Lamivudine, Stavudine and Nevirapine in HIV-infected subjects who were receiving a generic formulation (Triomune®) or the corresponding brand formulations (Epivir®, Zerit®, and Viramune®). An open-label, randomized, crossover study was carried out in 18 HIV-infected Ugandan subjects stabilized on Triomune-40. Subjects received Lamivudine (150 mg), Stavudine (40 mg), and Nevirapine (200 mg) in either the generic or brand formulation twice a day for 30 days, before switching to the other formulation. At the end of each treatment period, blood samples were collected over 12 h for pharmacokinetic analysis. The main outcome measures were the mean AUC0-12h and Cmax. Bioequivalence was defined as a geometric mean ratio between the generic and brand-name within the 90% confidence interval of 0.8-1.25.	HIV/AIDS	HIV;Bioequivalence;Triomune	null	2	arm 1: generic fixed dose combination of Stavudine, Lamivudine and Nevirapine (Triomune) arm 2: 3 separate single pills of Zerit (Stavudine)Epivir (Lamivudine) Viramune (Nevirapine)	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: Stavudine (40mg) Lamivudine (150mg) Nevirapine (200mg)All twice a day intervention 2: Stavudine (40mg) Lamivudine (150mg) and Nevirapine (200mg) All taken twice daily.	intervention 1: Triomune intervention 2: Zerit/Epivir/Viramune	1	Kampala \| N/A \| Uganda \| 32.58219 \| 0.31628	40	0	0	0	NCT01025830	1COMPLETED	2008-03-01	2006-02-01	Makerere University	7OTHER	false	false	false	null	0	0	0	0	0
[ 2 ]	30	RANDOMIZED	CROSSOVER	0TREATMENT	0NONE	true	0ALL	null	The purpose of this study was to compare the pharmacokinetic profiles at steady state of the test product, 300 mg trazodone hydrochloride (HCl) extended-release caplets (containing Contramid®), when administered once daily, and the reference product, 100 mg trazodone HCl immediate-release tablets (Apotex Corp.), when administered three times daily, for one week. For this purpose, the rate and extent of absorption of trazodone and formation of m-chlorophenylpiperazine (mCPP) after administration of multiple doses of up to 300 mg of each of the two formulations was compared.	null	Healthy Subjects Bioavailability Pharmacokinetics	Healthy subjects Bioavailability Pharmacokinetics Trazodone Steady-state	null	2	arm 1: OAD: Once A Day arm 2: None	[ 0, 1 ]	2	[ 0, 0 ]	intervention 1: Dosage form: Extended-release caplets containing 300 mg trazodone HCl and extended-release caplets containing 150 mg trazodone HCl (the 150 mg dosage form was only used for the up and down titration, and was not evaluated in the study). Dose regimen: 75 mg trazodone HCl (½ x 150 mg extended-release caplet) on Days 1 and 11, 150 mg trazodone HCl (one extended-release caplet) on Days 2 and 10, 300 mg trazodone HCl (one extended-release caplet) on Days 3 to 9, each at 23:30 after a fast of at least 4 hours. intervention 2: Dosage form: Immediate-release tablet containing 100 mg trazodone HCl Dose regimen: 100 mg trazodone HCl (one immediate-release tablet) once (at 23:30) on Days 1 and 11, 100 mg trazodone HCl (one immediate-release tablet) twice (at 23:30 and 11:30) on Days 2 and 10, 100 mg trazodone HCl (one immediate-release tablet) three times daily (at 23:30, 07:30 and 15:30) on Days 3 to 9. Evening doses were administered after a fast of at least 4 hours.	intervention 1: Trazodone HCl intervention 2: Trazodone HCl	0	null	57	0	0	0	NCT01121926	1COMPLETED	2008-03-01	2008-01-01	Labopharm Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 5 ]	24	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	Elderly persons with dementia are at risk for seizures, however, traditional anticonvulsants are poorly tolerated in this population. Our goal is to examine Levetiracetam (Keppra) in elderly dementia patients with seizures. While it has been established that Keppra controls seizures in this age group, it is important to demonstrate that treatment with Keppra would not affect cognitive abilities in this large population of patients . As this population is already cognitively impaired, the best choice of anticonvulsant would be one that does not further compromise their cognitive abilities. Keppra is an excellent anticonvulsant agent in the elderly for a variety of reasons, including safety, favorable side effect profile, lack of interaction with other drugs, and efficacy. Our retrospective pilot data suggests that cognition is not negatively affected by Keppra. The current prospective study will assess the cognitive abilities of persons with cognitive impairment at baseline and at weeks 4 and 12. The overall objective is to determine the cognitive tolerability of Keppra for seizures in elderly cognitively impaired patients.	This is a prospective, phase 4, open label, twelve week study. The study will consist of a 4 week titration phase followed by an 8 week assessment phase. All clinic visits will be conducted at Drexel University College of Medicine Department of Neurology at 219 N. Broad St., Phila., PA. Visit one will include reviewing and signing the written informed consent form, obtaining relevant demographic data, and then routine blood work. The baseline frequency, duration and type of seizures our subjects experience will be documented, as will their current antiepileptic medications. Baseline history and a physical and neurological examination will be performed, including vital signs. Testing will include baseline measurements of cognition, function (activities of daily living), and behavior. Cognitive testing will include Folstein's Minimental State examination (MMSE), and the ADAS-cog. Our overall assessment will include the Modified Schwab and England Activities of Daily Living Scale. Behavioral assessment will include Tariot's Behavior Ratings Scale and the Cohen-Mansfield Agitation Inventory (CMAI; long form). Levetiracetam will be initiated and instructions for follow up will be given. Because the goal is cognitive tolerability, Levetiracetam will be used as either an add-on agent or as primary monotherapy. During week two, a follow up telephone assessment will be done to review the instructions and to determine whether any medical changes or adverse events occurred. Adverse events will be assessed by direct questioning and spontaneous patient/caregiver reports. The date, number, duration and type of seizures any of our subjects experience will also be documented. At the third assessment (week 4), a follow up physical and neurological examination will be done, including vital signs, and the mental testing, including the tests of cognition, function and behavior will be repeated. An assessment will be made to determine whether adverse events occurred. Adverse events will be assessed by review of the subject's seizure log, physician observation, direct questioning and spontaneous reports. The date, number, duration and type of seizures any subject experiences will also be documented. In cases where levetiracetam is an add-on agent, we will attempt to taper the preceding medications if seizure control has been demonstrated. Cognitive testing will be done when subjects are not in a post-ictal state. Any subject who has had a seizure with generalization within 24 hours of their scheduled testing will be rescheduled to another day within one week. At week twelve, a full follow up mental status assessment will be done for the final assessment. Testing will be the same as that done at weeks 1 (baseline) and 4. Again, cognitive testing will not be done when subjects are in a post-ictal state. Any subject who has had a seizure with generalization within 24 hours of their scheduled testing will be rescheduled to the next available day, within one week. Follow up blood work and a screen for adverse events will also be obtained at that time. Again, adverse events will be assessed by review of their seizure log, physician observation, direct questioning and spontaneous reports. The date, number, duration and type of seizures will be documented.	Epilepsy		null	1	arm 1: Levetiracetam was titrated over 4 weeks, with initial dosing of 250 mg bis in die (BID). Dosing was flexible and was based on the prescribing physician's discretion.	[ 0 ]	1	[ 0 ]	intervention 1: Titration of Keppra will start at 250 mg by mouth twice daily for three days. Then 500 mg by mouth twice daily for three days. Then 750 mg by mouth twice daily for the duration of the study, or for as long as treatment is necessary. This titration schedule is subject to change based on subject's tolerability.	intervention 1: Levetiracetam	1	Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238	24	0	0	0	NCT01318408	1COMPLETED	2008-03-01	2006-11-01	Drexel University College of Medicine	7OTHER	false	false	false	null	0	0	0	0	0
[ 2 ]	36	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	true	0ALL	false	This was a non-randomized, open label study in healthy male and female volunteers. A single intranasal dose of 30 mg ketorolac tromethamine was administered to all subjects on Days 1 and 6; in addition, subjects received a daily intranasal dose of 200 µg fluticasone propionate on Days 2-6. Subjects remained resident in the Clinical Unit from the evening of Day 1 until the morning of Day 2 and from the evening of Day 5 until the morning of Day 7, and made ambulatory visits to the Clinical Unit on the morning of Days 3-5. A post study medical was performed within 7 days of study completion. The objective of this study was to assess the effects of chronic administration of fluticasone propionate on the pharmacokinetics of intranasal ketorolac in healthy male and female subjects.	null	Healthy Subjects		null	1	arm 1: None	[ 0 ]	2	[ 0, 0 ]	intervention 1: A single intranasal dose of 30 mg ketorolac tromethamine was administered to all subjects on Days 1 and 6. intervention 2: Daily intranasal dose of 200 ug fluticasone propionate on Days 2-6	intervention 1: Ketorolac tromethamine intervention 2: Fluticasone Propionate	1	Manchester \| N/A \| United Kingdom \| -2.23743 \| 53.48095	72	0	0	0	NCT01365611	1COMPLETED	2008-03-01	2007-02-01	Egalet Ltd	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 5 ]	245	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	To compare the safety and efficacy of cyclosporine (CsA) + mycophenolate mofetil (MMF) + corticosteroids © to CsA + Rapamune + Cs with CsA elimination in the Rapamune arm with the introduction of MMF in de novo renal allograft recipients.	null	Inflammation		null	2	arm 1: None arm 2: None	[ 1, 0 ]	2	[ 0, 0 ]	intervention 1: Part 1: Rapamune will be given as a loading dose of 6 mg once followed by maintenance dose of 2 mg to achieve a target trough level of 8-15 ng/ml. Part 2: Rapamune dose will be adjusted to achieve a target trough level of 10-15ng/ml through 6 months intervention 2: The control arm is the standard local practice (official protocol) in Iran: Cyclosporine + MMF + Corticosteroid. The time period is from pre-study screening / baseline evaluation up to 12 months for patients who are maintained on CsA + MMF + CS.	intervention 1: CsA+Rapamune+CS intervention 2: CsA+MMF+CS	4	Tehran \| N/A \| Iran \| 51.42151 \| 35.69439 Tehran \| N/A \| Iran \| 51.42151 \| 35.69439 Tehran \| N/A \| Iran \| 51.42151 \| 35.69439 Tehran \| N/A \| Iran \| 51.42151 \| 35.69439	245	0	0	0	NCT01601821	1COMPLETED	2008-03-01	2006-04-01	Pfizer	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 5 ]	53	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	The purpose of this study is to evaluate efficacy, safety and tolerance of long-acting risperidone when switching from oral antipsychotics in participants with schizophrenia (psychiatric disorder with symptoms of emotional instability, detachment from reality, often with delusions and hallucinations, and withdrawal into the self).	This is an open-label (all people know the identity of the intervention), multi-centric (conducted in more than one center) and non-comparative study of long-acting risperidone in participants with schizophrenia who have a previous history (in the last 12 months) of bad adherence to the oral antipsychotic treatment of first or second generation. The duration of this study will be 24 weeks and will include following visits: Screening, Baseline, Week 2, 4, 8, 12, 16, 20, 24, 38 and 50 (End visit or early withdrawal). All the eligible participants (after risperidone intolerance test during screening) will receive a dose of 25 milligram risperidone every two weeks by intramuscular injection (injection of a substance into a muscle). Efficacy and safety of the participants will primarily be evaluated by Positive and Negative Syndromes Scale and Extrapyramidal Symptom Rating Scale, respectively. Participants' safety will be monitored throughout the study.	Schizophrenia	Schizophrenia Risperidone Risperdal consta	null	1	arm 1: Risperidone will be administered as intramuscular injection as 25 milligram (mg) every two weeks, from Week 1 to 50, wherein after Week 3, dose may be adjusted up to 50 mg at physician criterion. For first two weeks, previous oral antipsychotic drug will be maintained and the dose will be gradually decreased and will cease at Week 3.	[ 0 ]	1	[ 0 ]	intervention 1: Risperidone will be administered as intramuscular injection as 25 milligram (mg) every two weeks, from Week 1 to 50, wherein after Week 3, dose may be adjusted up to 50 mg at physician criterion. For first two weeks, previous oral antipsychotic drug will be maintained and the dose will be gradually decreased and will cease at Week 3.	intervention 1: Risperidone prolonged release	5	Curitiba \| N/A \| Brazil \| -49.27306 \| -25.42778 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	53	0	0	0	NCT01726335	1COMPLETED	2008-03-01	2006-01-01	Janssen-Cilag Ltd.	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 5 ]	39	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	The purpose of this study is to evaluate the efficacy and safety of Transdermal Therapeutic System (TTS)-fentanyl patch (transdermal patch containing a drug that is put on the skin so the drug will enter the body through the skin) in Thai participants with chronic (lasting a long time) non-malignant (non-cancerous) pain.	This is an open label (all people know the identity of the intervention), single arm study to assess the efficacy and safety of TTS-fentanyl in Thai participants with chronic non-malignant pain (except for headaches or central spinal cord mediated pain). The study will consist of 2 phases: stabilization phase (up to 7 days before starting the treatment) and treatment phase (30 days). The first patch will be applied by Investigator then by participants themselves until 30 days. All participants will start the treatment with patch releasing 25 micrograms per hour (mcg/h) of fentanyl . The patches will be replaced every 3 days. On Day 3, and every 3 days thereafter, the TTS-fentanyl dose can be titrated (slow increase in drug dosage, guided by participant's responses) as per participant's need. The duration of the treatment will be 30 days after first patch application. The dose of TTS-fentanyl can be slowly increased if needed, by 25 mcg/h to achieve adequate pain control. No increase in TTS-fentanyl dose will be performed within the 72-hour dosing interval. Participants will be allowed the use of oral morphine syrup for the duration of TTS-fentanyl treatment to enable appropriate TTS-fentanyl dose titration. Primary efficacy assessment will be pain control rated by participants. Assessment time points will be Day 0 (Baseline), Day 15 and Day 30 (trial end). At the end of study, global preference on efficacy, side effects and overall satisfaction will also be rated by Investigator and participants. Participants' safety will be monitored throughout the study.	Chronic Pain	Chronic Pain Chronic Non-Malignant Pain TTS-fentanyl Durogesic	null	1	arm 1: Transdermal Therapeutic System (TTS)-fentanyl patches releasing fentanyl in the range of 12.5 to 100 microgram per hour (mcg/hr) rate. The initial dose of fentanyl TTS will be calculated based on each participant's opioid requirement. Patches will be usually replaced every 72 hours. Doses will be escalated in steps of 25 mcg/hr, if pain cannot be controlled. Oral morphine syrup is allowed to titrate the dose of TTS-fentanyl. The study duration will be 30 days after first patch application.	[ 0 ]	2	[ 0, 0 ]	intervention 1: Transdermal Therapeutic System (TTS)-fentanyl patches releasing fentanyl in the range of 12.5 to 100 microgram per hour (mcg/hr) rate. The initial dose of fentanyl TTS will be calculated based on each participant's opioid requirement. Patches will be usually replaced every 72 hours. Doses will be escalated in steps of 25 mcg/hr, if pain cannot be controlled. The study duration will be 30 days after first patch application. intervention 2: Participants will be allowed the use of oral morphine syrup for the duration of TTS-fentanyl treatment to enable appropriate dose titration. It is expected that most of the participants will be titrated to an appropriate dose of TTS-fentanyl within 1 week.	intervention 1: TTS-Fentanyl intervention 2: Morphine	2	Bangkok \| N/A \| Thailand \| 100.50144 \| 13.75398 Bangkok \| N/A \| Thailand \| 100.50144 \| 13.75398	39	0	0	0	NCT01816243	1COMPLETED	2008-03-01	2004-04-01	Janssen-Cilag Ltd.,Thailand	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	45	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	This study will evaluate the efficacy and safety of oral Xeloda (capecitabine) plus intravenous Avastin (bevacizumab) in patients with advanced or metastatic liver cancer. The anticipated time on study treatment is 3-12 months.	null	Liver Cancer		null	1	arm 1: None	[ 0 ]	2	[ 0, 0 ]	intervention 1: 7.5mg/kg iv on day 1 of each 3 week cycle. intervention 2: 1600mg/m2/day po in 2 divided doses, on days 1 to 14 of each 3 week cycle.	intervention 1: bevacizumab [Avastin] intervention 2: capecitabine [Xeloda]	7	Melbourne \| N/A \| Australia \| 144.96332 \| -37.814 Hong Kong \| N/A \| Hong Kong \| 114.17469 \| 22.27832 Singapore \| N/A \| Singapore \| 103.85007 \| 1.28967 Kueishan \| N/A \| Taiwan \| N/A \| N/A Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306 Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306 Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306	45	0	0	0	NCT02013830	1COMPLETED	2008-03-01	2005-05-01	Hoffmann-La Roche	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 5 ]	38	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	false	0ALL	true	This study aims to determine the effect of Coenzyme Q10 supplementation on conventional therapy of children with heart failure due to idiopathic dilated cardiomyopathy.	This study aims to determine the effect of Coenzyme Q10 supplementation on conventional therapy of children with heart failure due to idiopathic dilated cardiomyopathy. In a prospective, randomized, double-blinded, placebo-controlled trial, patients younger than 18 years with idiopathic dilated cardiomyopathy randomizes to receive either Coenzyme Q10 or placebo. Echocardiographic systolic and diastolic function parameters are determined for every patient at baseline, after three,six and nine months of supplementation.	Dilated Cardiomyopathy	Coenzyme O10 Children Idiopathic Dilated Cardiomyopathy	null	2	arm 1: Known cases of idiopathic dilated cardiomyopathy who received supplementation of coenzyme Q10 as a part of their medical regimen. Dosage administered: 2 milligram/kilogram/day in 2 or 3 divided doses, these being increased to the maximum dose of 10 milligram/kilogram/day according to tolerance or the appearance of sideeffects. arm 2: known cases of idiopathic dilated cardiomyopathy who received placebo	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: dose of 2 mg/kg/day in 2 or 3 divided doses and increased to the maximum dose of 10 mg/kg/day according to the patient's tolerance intervention 2: dose of 2 mg/kg/day in 2 or 3 divided doses and increased to the maximum dose of 10 mg/kg/day according to the patient's tolerance	intervention 1: Coenzyme Q10 intervention 2: Placebo	1	Tehran \| Tehran Province \| Iran \| 51.42151 \| 35.69439	38	0	0	0	NCT02115581	1COMPLETED	2008-03-01	2006-09-01	University of Tehran	7OTHER	false	false	false	null	0	0	0	0	0
[ 3 ]	11	RANDOMIZED	CROSSOVER	0TREATMENT	4QUADRUPLE	false	0ALL	false	This study was designed to determine if preladenant (SCH 420814, MK-3814) can reduce drug-induced involuntary movements in participants with schizophrenia or schizoaffective disorder. Participants were to be evaluated for two 14-day treatment periods with a 3-week washout period between treatment periods. The primary outcome measure, Extrapyramidal Symptom Rating Score (ESRS), was to be evaluated frequently during the treatment periods.	null	Akathisia, Drug-Induced Dyskinesia, Drug-Induced Parkinsonian Disorders	Anti-Dyskinesia Agents Antipsychotic Agents	null	2	arm 1: Participants received one preladenant 25 mg capsule twice daily (BID) for 14 days during the first treatment period and received one matching placebo capsule BID during the second treatment period. The 2 treatment periods were separated by a 3-week washout period. arm 2: Participants received one matching placebo capsule BID for 14 days during the first treatment period and received one preladenant 25 mg capsule during the second treatment period. The 2 treatment periods were separated by a 3-week washout period.	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: capsules intervention 2: capsules	intervention 1: Preladenant intervention 2: Placebo	0	null	20	0	0	0	NCT00686699	6TERMINATED	2008-03-06	2006-07-10	Merck Sharp & Dohme LLC	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	5	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	2MALE	true	Study to evaluate the safety, tolerability, and pharmacodynamics of migalastat hydrochloride (HCl) (migalastat) in participants with Fabry disease.	This was a Phase 2, open-label study in male participants with Fabry disease. The study consisted of a 4-week screening period, during which participants' galactosidase (GLA) genotype was assessed for α-galactosidase A (α-Gal A) activity in response to migalastat. Participants were required to have α-Gal A activity responsive to migalastat. The study consisted of a 24-week treatment period, followed by an optional 24-week extension period. Participants received migalastat once every other day (QOD) for 24 weeks during the treatment period and the optional 24-week extension for a total treatment duration of up to 48 weeks.	Fabry Disease	Amicus Therapeutics AT1001 Galafold Migalastat Substrate	null	1	arm 1: Migalastat 150 milligrams (mg) was administered orally QOD during the 24-week treatment period and then during the optional 24-week extension period.	[ 0 ]	1	[ 0 ]	intervention 1: None	intervention 1: migalastat HCl	2	Paris \| N/A \| France \| 2.3488 \| 48.85341 London \| N/A \| United Kingdom \| -0.12574 \| 51.50853	5	0	0	0	NCT00283933	1COMPLETED	2008-03-12	2006-05-09	Amicus Therapeutics	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	265	RANDOMIZED	PARALLEL	0TREATMENT	null	false	0ALL	false	The purpose of this study is to examine the safety and effectiveness of GI262570 compared to placebo (a pill that looks exactly like GI262570 but contains no active medicine) in improving specific tests that indicate the degree of liver fibrosis (scarring). Subjects who are enrolled in the study must have had prior treatment with interferon (either pegylated or standard interferon) plus ribavirin for at least 12 weeks to treat their hepatitis C, but either failed to clear the virus or didn't tolerate the treatment.	null	Cirrhosis, Liver	Hepatitis C liver fibrosis	null	3	arm 1: Participants received GI262570 0.5 milligrams (mg) tablet once daily approximately 30 minutes prior to breakfast for 52 weeks. Participant received their morning dose at the site on Weeks 2, 16, 28, 40, and 52. arm 2: Participants received GI262570 1.0 mg tablet once daily approximately 30 minutes prior to breakfast for 52 weeks. Participant received their morning dose at the site on Weeks 2, 16, 28, 40, and 52. arm 3: Participants received matching placebo tablet once daily approximately 30 minutes prior to breakfast for 52 weeks. Participant received their morning dose at the site on Weeks 2, 16, 28, 40, and 52.	[ 0, 0, 2 ]	3	[ 0, 0, 0 ]	intervention 1: GI262570 0.5 mg intervention 2: GI262570 1.0 mg intervention 3: Placebo	intervention 1: GI262570 0.5 mg intervention 2: GI262570 1.0 mg intervention 3: Placebo	121	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Tucson \| Arizona \| United States \| -110.92648 \| 32.22174 North Little Rock \| Arkansas \| United States \| -92.26709 \| 34.76954 Bakersfield \| California \| United States \| -119.01871 \| 35.37329 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 Newport Beach \| California \| United States \| -117.92895 \| 33.61891 Pasadena \| California \| United States \| -118.14452 \| 34.14778 Sacramento \| California \| United States \| -121.4944 \| 38.58157 San Clemente \| California \| United States \| -117.61199 \| 33.42697 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Santa Clara \| California \| United States \| -121.95524 \| 37.35411 Englewood \| Colorado \| United States \| -104.98776 \| 39.64777 Washington D.C. \| District of Columbia \| United States \| -77.03637 \| 38.89511 Fort Lauderdale \| Florida \| United States \| -80.14338 \| 26.12231 Miami \| Florida \| United States \| -80.19366 \| 25.77427 Orlando \| Florida \| United States \| -81.37924 \| 28.53834 Sarasota \| Florida \| United States \| -82.53065 \| 27.33643 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Marietta \| Georgia \| United States \| -84.54993 \| 33.9526 Honolulu \| Hawaii \| United States \| -157.85833 \| 21.30694 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Iowa City \| Iowa \| United States \| -91.53017 \| 41.66113 Louisville \| Kentucky \| United States \| -85.75941 \| 38.25424 Lutherville-Timonium \| Maryland \| United States \| -76.61099 \| 39.43997 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 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 Detroit \| Michigan \| United States \| -83.04575 \| 42.33143 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Binghamton \| New York \| United States \| -75.91797 \| 42.09869 Manhasset \| New York \| United States \| -73.69957 \| 40.79788 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 Syracuse \| New York \| United States \| -76.14742 \| 43.04812 The Bronx \| New York \| United States \| -73.86641 \| 40.84985 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 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Tulsa \| Oklahoma \| United States \| -95.99277 \| 36.15398 Hershey \| Pennsylvania \| United States \| -76.65025 \| 40.28592 Lancaster \| Pennsylvania \| United States \| -76.30551 \| 40.03788 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 Charlottesville \| Virginia \| United States \| -78.47668 \| 38.02931 Fairfax \| Virginia \| United States \| -77.30637 \| 38.84622 Richmond \| Virginia \| United States \| -77.46026 \| 37.55376 Richmond \| Virginia \| United States \| -77.46026 \| 37.55376 Herston \| Queensland \| Australia \| 153.01852 \| -27.44453 Camperdown \| Victoria \| Australia \| 143.14983 \| -38.23392 Clayton \| Victoria \| Australia \| 145.11667 \| -37.91667 Fitzroy, Melbourne \| Victoria \| Australia \| N/A \| N/A Heidelberg \| Victoria \| Australia \| 145.06667 \| -37.75 Melbourne \| Victoria \| Australia \| 144.96332 \| -37.814 Calgary \| Alberta \| Canada \| -114.08529 \| 51.05011 Vancouver \| British Columbia \| Canada \| -123.11934 \| 49.24966 Victoria \| British Columbia \| Canada \| -123.35155 \| 48.4359 Winnipeg \| Manitoba \| Canada \| -97.14704 \| 49.8844 Halifax \| Nova Scotia \| Canada \| -63.57688 \| 44.64269 London \| Ontario \| Canada \| -81.23304 \| 42.98339 Ottawa \| Ontario \| Canada \| -75.69812 \| 45.41117 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Brno - Bohunice \| N/A \| Czechia \| N/A \| N/A Hradec Králové \| N/A \| Czechia \| 15.83277 \| 50.20923 Prague \| N/A \| Czechia \| 14.42076 \| 50.08804 Prague \| N/A \| Czechia \| 14.42076 \| 50.08804 Freiburg im Breisgau \| Baden-Wurttemberg \| Germany \| 7.85222 \| 47.9959 Heidelberg \| Baden-Wurttemberg \| Germany \| 8.69079 \| 49.40768 Tübingen \| Baden-Wurttemberg \| Germany \| 9.05222 \| 48.52266 Erlangen \| Bavaria \| Germany \| 11.00783 \| 49.59099 Frankfurt am Main \| Hesse \| Germany \| 8.68417 \| 50.11552 Hanover \| Lower Saxony \| Germany \| 9.73322 \| 52.37052 Bonn \| North Rhine-Westphalia \| Germany \| 7.09549 \| 50.73438 Düsseldorf \| North Rhine-Westphalia \| Germany \| 6.77616 \| 51.22172 Münster \| North Rhine-Westphalia \| Germany \| 7.62571 \| 51.96236 Homburg \| Saarland \| Germany \| 7.33867 \| 49.32637 Leipzig \| Saxony \| Germany \| 12.37129 \| 51.33962 Halle \| Saxony-Anhalt \| Germany \| 11.97947 \| 51.48158 Berlin \| N/A \| Germany \| 13.41053 \| 52.52437 Hamburg \| N/A \| Germany \| 9.99302 \| 53.55073 Haifa \| N/A \| Israel \| 34.99928 \| 32.81303 Jerusalem \| N/A \| Israel \| 35.21633 \| 31.76904 Nazareth \| N/A \| Israel \| 35.29719 \| 32.70087 Petah Tikva \| N/A \| Israel \| 34.88747 \| 32.08707 Rehovot \| N/A \| Israel \| 34.81199 \| 31.89421 Tel Aviv \| N/A \| Israel \| 34.78057 \| 32.08088 Bandar Tun Razak, Cheras \| N/A \| Malaysia \| N/A \| N/A Kepong \| N/A \| Malaysia \| 101.64018 \| 3.21398 Auckland \| N/A \| New Zealand \| 174.76349 \| -36.84853 San Juan \| N/A \| Puerto Rico \| -66.10572 \| 18.46633 Bucharest \| N/A \| Romania \| 26.10626 \| 44.43225 Bucharest \| N/A \| Romania \| 26.10626 \| 44.43225 Cluj-Napoca, Cluj \| N/A \| Romania \| N/A \| N/A 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 Singapore \| N/A \| Singapore \| 103.85007 \| 1.28967 Daegu \| N/A \| South Korea \| 128.59111 \| 35.87028 Pusan \| N/A \| South Korea \| 128.3681 \| 36.3809 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Seoul \| N/A \| South Korea \| 126.9784 \| 37.566 Kaohsiung City \| N/A \| Taiwan \| 120.31333 \| 22.61626 Kaohsiung City \| N/A \| Taiwan \| 120.31333 \| 22.61626 Taipei \| N/A \| Taiwan \| 121.52639 \| 25.05306 Taoyuan District \| N/A \| Taiwan \| 121.3187 \| 24.9896	265	0	0	0	NCT00244751	1COMPLETED	2008-03-13	2005-11-02	GlaxoSmithKline	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	111	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	This is a Phase 2 study being conducted at multiple centers in the United States, Europe and Canada. Patients having pancreatic cancer that is locally advanced or that has spread to other parts of the body (i.e., metastatic) are eligible to participate. Patients must have not had any prior systemic treatment for advanced disease. The purpose of the study is to test whether the angiogenesis inhibitor Axitinib \[AG-013736\] in combination with gemcitabine is an effective treatment for advanced pancreatic cancer vs. gemcitabine alone by overall survival.	null	Pancreatic Neoplasms	Randomized Phase 2 Study of AG-013736 in Combination with Gemcitabine versus Gemcitabine Alone in Advanced Pancreatic Cancer	null	2	arm 1: None arm 2: None	[ 1, 0 ]	3	[ 0, 0, 0 ]	intervention 1: Gemcitabine 1000 mg/m\^2 30 minutes IV infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks intervention 2: Axitinib (AG-013736) 5 mg tablet orally BID starting from Day 1 of Cycle 1, in cycles of 4 weeks. intervention 3: Gemcitabine 1000 mg/m\^2 30 minutes IV infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.	intervention 1: Gemcitabine intervention 2: AG-013736 intervention 3: Gemcitabine	38	Antioch \| California \| United States \| -121.80579 \| 38.00492 Berkeley \| California \| United States \| -122.27275 \| 37.87159 Concord \| California \| United States \| -122.03107 \| 37.97798 Concord \| California \| United States \| -122.03107 \| 37.97798 Stamford \| Connecticut \| United States \| -73.53873 \| 41.05343 Miami \| Florida \| United States \| -80.19366 \| 25.77427 Miami \| Florida \| United States \| -80.19366 \| 25.77427 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 Biddeford \| Maine \| United States \| -70.45338 \| 43.49258 Brunswick \| Maine \| United States \| -69.96533 \| 43.91452 Scarborough \| Maine \| United States \| -70.32172 \| 43.57814 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Washington \| Missouri \| United States \| -91.01209 \| 38.55811 Lincoln \| Nebraska \| United States \| -96.66696 \| 40.8 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Madison \| Wisconsin \| United States \| -89.40123 \| 43.07305 Ghent \| N/A \| Belgium \| 3.71667 \| 51.05 Edmonton \| Alberta \| Canada \| -113.46871 \| 53.55014 Winnipeg \| Manitoba \| Canada \| -97.14704 \| 49.8844 Winnipeg \| Manitoba \| Canada \| -97.14704 \| 49.8844 Sault Ste. Marie \| Ontario \| Canada \| -84.33325 \| 46.51677 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Saint-Herblain \| Saint Herblain Cedex \| France \| -1.651 \| 47.21154 Marseille \| N/A \| France \| 5.38107 \| 43.29695 Paris \| N/A \| France \| 2.3488 \| 48.85341 Toulouse \| N/A \| France \| 1.44367 \| 43.60426 Berlin \| N/A \| Germany \| 13.41053 \| 52.52437 Milan \| N/A \| Italy \| 12.59836 \| 42.78235 Roma \| N/A \| Italy \| 11.10642 \| 44.99364 Barcelona \| N/A \| Spain \| 2.15899 \| 41.38879 Barcelona \| N/A \| Spain \| 2.15899 \| 41.38879 Seville \| N/A \| Spain \| -5.97317 \| 37.38283 Southampton \| Hampshire \| United Kingdom \| -1.40428 \| 50.90395 Leicester \| Leicestershire \| United Kingdom \| -1.13169 \| 52.6386 Edinburgh \| N/A \| United Kingdom \| -3.19648 \| 55.95206 London \| N/A \| United Kingdom \| -0.12574 \| 51.50853	107	0	0	0	NCT00219557	1COMPLETED	2008-03-14	2005-07-05	Pfizer	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 2, 3 ]	19	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	Phase Ib/IIa open label safety and efficacy study designed to determine the maximum tolerated dose of inhaled cisplatin liposomal (SLIT cisplatin) administered every 14 days to patients with relapsed/progressive osteosarcoma metastatic to the lung.	null	Osteosarcoma Metastatic	Osteosarcoma relapsed progressive metastatic lung	null	2	arm 1: Inhaled liposomal cisplatin was administered over 1 day in a 14-day treatment cycle by inhalation for a maximum of 6 cycles. arm 2: The study allowed for a dose escalation of liposomal cisplatin to 36 mg/m2 if no adverse events of Grade 3 or higher occurred after at least 3 cycles of drug administration at 24 mg/m2	[ 0, 0 ]	1	[ 0 ]	intervention 1: None	intervention 1: Cisplatin liposomal	2	New York \| New York \| United States \| -74.00597 \| 40.71427 New York \| New York \| United States \| -74.00597 \| 40.71427	19	0	0	0	NCT00102531	1COMPLETED	2008-03-17	2005-01-12	Insmed Incorporated	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 2, 3 ]	144	RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	CPKC412A2104 core had a 2 stage design. In stage 1, eight participants were treated. If at least one participant showed a clinical response, four more participants were recruited to stage 2. The trial was to be stopped if no participants showed a response in stage 1. POC was achieved if at least 2 participants out of 12 responded. In PKC412A2104E1, participants with AML or high risk MDS with wild-type or mutant FTL3 who had not previously received a FLT3 inhibitor were randomized to receive continuous twice daily oral doses of either 50 or 100 mg midostaurin in 1 28-day cycle regimen. Participants were to be treated until disease progression or the occurrence of unacceptable treatment-related toxicity. PKC412A2104 E2 contained 2 dosing regimens: 1) intra-participant midostaurin dose escalation and 2) midostaurin with itraconazole in participants with AML and high risk MDS irrespective of FLT3 status. Eligible participants were alternately assigned to the regimens. At the Investigator's discretion, intra-participant dose escalation was allowed for any previously enrolled CPKC412A2104E1 participant receiving midostaurin at the time of the approval of amendment 4. Participants were treated until the time of disease progression.	null	Acute Myeloid Leukemia Myelodysplastic Syndromes	AML MDS high risk myelodysplastic syndrome	null	9	arm 1: Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. arm 2: Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. arm 3: Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. arm 4: Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. arm 5: Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. arm 6: Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity. arm 7: Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent. arm 8: Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity. arm 9: Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.	[ 0, 0, 0, 0, 0, 0, 0, 0, 0 ]	2	[ 0, 0 ]	intervention 1: Itraconazole was commercially available. intervention 2: PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.	intervention 1: Itraconazole intervention 2: PKC412	4	Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 New York \| New York \| United States \| -74.00597 \| 40.71427 New York \| New York \| United States \| -74.00597 \| 40.71427	144	0	0	0	NCT00045942	1COMPLETED	2008-03-27	2002-01-30	Novartis Pharmaceuticals	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	176	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	The purpose of this trial is to examine the safety and efficacy of deferasirox in patients with Myelodysplastic Syndrome (MDS) and chronic iron overload from blood transfusions.	Study entry requires a diagnosis of low or intermediate (INT-1) risk MDS per International Prognostic Scoring System (IPSS) criteria and serum ferritin ≥ 1000 ng/mL. Patients must have had at least 30 prior red blood cell transfusions. Deferasirox will be administered at an initial dose of 20 mg/kg orally once per day. Patient transfusion history and at least three complete blood count (CBC) values must be available for the 12 weeks prior to study registration for patients with MDS and chronic iron overload from blood transfusions.	Myelodysplastic Syndrome Iron Overload	ICL670 Deferasirox Iron chelation Chelator Desferal	null	1	arm 1: Evaluate the safety and tolerability of deferasirox 20 mg/kg/day over one year in patients with MDS	[ 0 ]	1	[ 0 ]	intervention 1: 20 mg/kg/day over one year in patients with MDS	intervention 1: Deferasirox	48	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Phoenix \| Arizona \| United States \| -112.07404 \| 33.44838 Concord \| California \| United States \| -122.03107 \| 37.97798 Duarte \| California \| United States \| -117.97729 \| 34.13945 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 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Aurora \| Colorado \| United States \| -104.83192 \| 39.72943 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 Atlanta \| Georgia \| United States \| -84.38798 \| 33.749 Honolulu \| Hawaii \| United States \| -157.85833 \| 21.30694 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 Lexington \| Kentucky \| United States \| -84.47772 \| 37.98869 Alexandria \| Louisiana \| United States \| -92.44514 \| 31.31129 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Worcester \| Massachusetts \| United States \| -71.80229 \| 42.26259 Southfield \| Michigan \| United States \| -83.22187 \| 42.47337 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 Lebanon \| New Hampshire \| United States \| -72.25176 \| 43.64229 Hackensack \| New Jersey \| United States \| -74.04347 \| 40.88593 Albuquerque \| New Mexico \| United States \| -106.65114 \| 35.08449 Buffalo \| New York \| United States \| -78.87837 \| 42.88645 Rochester \| New York \| United States \| -77.61556 \| 43.15478 Asheville \| North Carolina \| United States \| -82.55402 \| 35.60095 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Columbus \| Ohio \| United States \| -82.99879 \| 39.96118 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Memphis \| Tennessee \| United States \| -90.04898 \| 35.14953 Nashville \| Tennessee \| United States \| -86.78444 \| 36.16589 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Salt Lake City \| Utah \| United States \| -111.89105 \| 40.76078 Arlington \| Virginia \| United States \| -77.10428 \| 38.88101 Spokane \| Washington \| United States \| -117.42908 \| 47.65966 Milwaukee \| Wisconsin \| United States \| -87.90647 \| 43.0389 Vancouver \| British Columbia \| Canada \| -123.11934 \| 49.24966 Hamilton \| Ontario \| Canada \| -79.84963 \| 43.25011 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884	176	0	0	0	NCT00110266	1COMPLETED	2008-03-28	2005-07-25	Novartis Pharmaceuticals	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 2 ]	20	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	true	2MALE	false	The purpose of the study is to determine the safety and tolerability of PRO 140, an investigational anti-HIV drug, administered via intravenous infusion. Study hypothesis: Single intravenous doses of PRO 140 can be safely administered to humans and will result in measurable concentrations of the product in serum.	PRO 140 is a man-made monoclonal antibody to the chemokine receptor CCR5, which serves as a co-receptor for HIV. In numerous preclinical models of HIV infection, PRO 140 broadly and potently blocks CCR5-mediated HIV entry without blocking the natural activity of CCR5. PRO 140 is being developed for therapy of HIV infected individuals. The purpose of this study is to evaluate the safety and tolerability of PRO 140 in HIV uninfected male volunteers. The pharmacokinetics and pharmacodynamics of PRO 140 will also be assessed in this study. Participants in this study will be randomly assigned to receive a single dose of one of several possible doses of PRO 140 or placebo. Participants will remain in the clinic for observation and evaluation for 24 hours after the single-dose administration. Follow-up visits will occur at 2, 3, 5, 7, 10, 14, 28, 42, and 60 days post-treatment. Physical exams, electrocardiograms (ECGs), vital signs measurement, adverse event reporting, and blood and urine collection will occur at most visits.	HIV Infections		null	5	arm 1: Intravenous placebo for PRO 140 arm 2: 0.1 mg/kg PRO 140 by intravenous infusion arm 3: 0.5 mg/kg PRO 140 by intravenous infusion arm 4: 2.0 mg/kg PRO 140 by intravenous infusion arm 5: 5.0 mg/kg PRO 140 by intravenous infusion	[ 2, 0, 0, 0, 0 ]	1	[ 0 ]	intervention 1: Monoclonal antibody to CCR5	intervention 1: PRO 140	1	Lincoln \| Nebraska \| United States \| -96.66696 \| 40.8	20	0	0	0	NCT00110591	1COMPLETED	2008-03-31	2004-04-16	CytoDyn, Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 4 ]	61	RANDOMIZED	PARALLEL	0TREATMENT	2DOUBLE	true	1FEMALE	false	This is a multi-center study to evaluate hormone levels with the oral contraceptive regimen DR-1021.	Female volunteers, aged 18-35 years old who met all Inclusion and no Exclusion Criteria, were enrolled in this study. All participants were current users of a standard 21/7 oral contraceptive regimen (21 days of combination progestin/estrogen followed by 7 days placebo) and had completed at least one 28-day cycle prior to beginning the Cycle 1 baseline cycle. After completing screening, all enrolled participants continued to receive the same regimen of 150 μg DSG /20 μg EE combination pills once daily for 21 days followed by placebo once daily for 7 days during Cycle 1 (the Run-In phase). Following completion of Cycle 1, participants were randomly assigned to receive either DR-1021 or Mircette during Cycle 2. All participants who completed Cycle 2 were to receive Kariva during Cycle 3; however, participants were only followed for the first 21 days of this 28-day regimen, after which they were considered study completers.	Healthy		null	2	arm 1: After randomization, participants received DR-1021 consisting of 150 μg desogestrel (DSG)/20 μg ethinyl estradiol (EE) administered orally as a combination tablet once daily for 21 days followed by EE 10 μg tablet once daily for 7 days (Cycle 2). Participants who completed Cycle 2 then received Kariva, consisting of 150 μg DSG/20 μg EE administered orally as a combination tablet taken once daily for 21 days followed by placebo tablet once daily for 2 days followed by 10 μg EE taken once daily for 5 days (Cycle 3). arm 2: After randomization, participants received Mircette consisting of 150 μg desogestrel (DSG)/20 μg ethinyl estradiol (EE) administered orally as a combination tablet once daily for 21 days followed by placebo tablet once daily for 2 days followed by 10 μg EE tablet once daily for 5 days (Cycle 2). Participants who completed Cycle 2 then received Kariva, consisting of 150 μg DSG/20 μg EE administered orally as a combination tablet taken once daily for 21 days followed by placebo tablet once daily for 2 days followed by 10 μg EE taken once daily for 5 days (Cycle 3).	[ 0, 1 ]	3	[ 0, 0, 0 ]	intervention 1: Twenty-one 150 μg desogestrel/20 μg ethinyl estradiol (EE) combination tablets plus seven 10 μg EE tablets. intervention 2: Twenty-one 150 μg desogestrel/20 μg ethinyl estradiol (EE) combination tablets plus two placebo tablets plus five 10 μg EE tablets. intervention 3: Twenty-one 150 μg desogestrel/20 μg ethinyl estradiol (EE) combination tablets plus two placebo tablets plus five 10 μg EE tablets.	intervention 1: DR-1021 intervention 2: Mircette® intervention 3: Kariva®	4	Lawrenceville \| New Jersey \| United States \| -74.7296 \| 40.29733 Columbus \| Ohio \| United States \| -82.99879 \| 39.96118 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Seattle \| Washington \| United States \| -122.33207 \| 47.60621	56	0	0	0	NCT00544882	1COMPLETED	2008-03-31	2007-10-31	Teva Branded Pharmaceutical Products R&D, Inc.	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	29	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	This is a multi-center, randomized study of sitaxsentan administered intravenously to subjects who are undergoing elective CABG, cardiac valve replacement, or combined CABG and cardiac valve replacement procedures that require CPB.	null	Cardiac Surgery Subjects Subjects Undergoing CABG and/or Cardiac Valve Replacement	multi-center placebo-controlled randomized study of sitaxsentan administered to subjects post-cross-clamp release and 12 hours post-CPB	null	3	arm 1: None arm 2: None arm 3: None	[ 0, 0, 2 ]	3	[ 0, 0, 0 ]	intervention 1: sitaxsentan (1.0 mg/kg) will begin immediately following cross-clamp release and 12 hours post-CPB. intervention 2: Sitaxsentan (2.0 mg/kg) will begin immediately following cross-clamp release and 12 hours post-CPB. intervention 3: Placebo will begin immediately following cross-clamp release and 12 hours post-CPB.	intervention 1: sitaxsentan (Thelin) intervention 2: sitaxsentan (Thelin) intervention 3: Placebo	3	Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Charleston \| South Carolina \| United States \| -79.93275 \| 32.77632 Chattanooga \| Tennessee \| United States \| -85.30968 \| 35.04563	29	0	0	0	NCT00838383	1COMPLETED	2008-03-31	2006-08-10	Pfizer	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	6	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	1FEMALE	true	The purpose of this study is to evaluate the safety and efficacy of continued administration of paclitaxel given weekly in subjects considered to need to continue treatment after completion of the preceding "Phase II Clinical Study of Weekly Paclitaxel (BMS-181339) with Advanced Breast Cancer (Protocol No. CA139-371)"	null	Breast Cancer		Prot_000.pdf: Page: 1 Protocol Number: CA139387 Date: 25-May-2005 Clinical Protocol CA139387 Rollover Study of weekly Paclitaxel (BMS-181339) in Patients with Breast Cancer Study Director: Taku Seriu, M.D. PhD., Director 24-hr Emergency Telephone Number This protocol contains information that is confidential and proprietary to Bristol-Myers Squibb (BMS)/Bristol-Myers K.K. (BMKK). 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol SYNOPSIS Clinical Protocol CA139387 Title of Study: Protocol CA139387: Rollover Study of Weekly Paclitaxel (BMS-181339) in Patients with Advanced Breast Cancer. Estimated Number of Study Centers and Countries/Regions: 5 sites/Japan Study Phase: II Primary Objective: The primary objective is to provide an access to Paclitaxel therapy to all subjects who have completed previous and are deemed to be benefiting from this treatment (and should continue on this therapy) as assessed by the treating investigator(s). Cond study (CA 139-387) will also evaluate the frequency and the severity of observed adverse events in treated study subjects. Study Design: This study is a rollover study designed to provide an access to Paclitaxel therapy to breast cancer subjects who have completed previous and are believed to be benefiting from this treatment as assessed by the treating investigator(s). Only breast cancer patients who have participated in a previous can enroll in this rollover weekly Paclitaxel trial (CA139387) provided that they meet all eligibility criteria. Study subjects will receive weekly Paclitaxel at the dose consistent with their last dose in the previous Phase II weekly Paclitaxel trial. Paclitaxel will be given as a one hour intravenous (iv) infusion on Days 1, 8 15,22, 29, 36 followed by 2 weeks of no treatment (observation). One treatment course will consist of 49 days. Safety assessment required in the protocol should be done at each of these weekly visits. Tumor response will be assessed at the completion of at least every 7 weeks. Number of Subjects per Group: Approximately 10 subjects. Study Population: Patients with advanced breast cancer that have completed therapy in a previous and are proven to be benefiting from it with recommendation of continuation of this treatment, as assessed by the treating investigator(s). Test Product, Dose and Mode of Administration, Duration of Treatment: Paclitaxel will be administered intravenously by a 1-hour infusion for the first week of each treatment course. All patients will receive premedication with Paclitaxel given at the last dose that each individual patient was receiving on the previous The day of the initial drug dose administration on the given course is defined as Day 1 of the treatment course. Subsequent Paclitaxel administrations will be given on Days 8, 15, 22, 29 and 36 followed by two weeks of rest (i.e. until Day 49). One treatment course consists of 49 days total. Reference Therapy, Dose and Mode of Administration, Duration of Treatment: Not applicable. Criteria for Evaluation: Every adverse event shall be evaluated and its severity be graded according to the NCI- Common Toxicity Criteria (NCI-CTC) Ver.2.0 (see Appendix 10; It also includes Japanese- language version translated by the JCOG.). Responses will be assessed according to the “Evaluation Criteria on the Therapeutic Effects in Patients with Advanced or Recurrent Breast Cancer “(Extract) and RECIST criteria (See Appendix 7). Statistical Methods: Demographic data and safety will be summarized using descriptive statistics. Date: 25-May-2005 2 1.0 Approved 930010978 2.0 v TABLE OF CONTENTS TITLE PAGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 SYNOPSIS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 TABLE OF CONTENTS. . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2 STUDY OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2.1 Primary Objective . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2.2 Secondary Objectives . . . . . . . . . . . . . . . . . . . . . . . 12 3 STUDY DESIGN AND EVALUATION. . . . . . . . . . . . . . . 12 3.1 Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.2 Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.3 Criteria for Evaluation . . . . . . . . . . . . . . . . . . . . . . . 12 3.4 Sample Size Determination . . . . . . . . . . . . . . . . . . . 13 3.5 Interim Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 4 STATISTICAL METHODOLOGY . . . . . . . . . . . . . . . . . . 13 4.1 Data Set Descriptions . . . . . . . . . . . . . . . . . . . . . . . 13 Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 3 1.0 Approved 930010978 2.0 v 4.2 Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 4.2.1 Demographics and Baseline Characteristics. . . . . . . . . 13 4.2.2 Efficacy Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 4.2.3 Safety Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 4.2.5 Other Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 5 SUBJECT SELECTION CRITERIA . . . . . . . . . . . . . . . . 14 5.1 Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 5.2 Exclusion Criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . 16 6 STUDY CONDUCT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 6.1 Ethics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 6.2 Study Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 6.2.2 Treatment Group Assignment . . . . . . . . . . . . . . . . . . . . 19 6.2.3 Treatment Administration . . . . . . . . . . . . . . . . . . . . . . . 20 6.2.3.1 Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 6.2.3.2 Criteria for re-treatment within the course of therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 6.2.3.3 Re-treatment Criteria for Course 2 and thereafter. 22 6.2.4 Dose Modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 6.2.5 Discontinuation of Therapy . . . . . . . . . . . . . . . . . . . . . . 23 6.2.6 Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . 24 6.2.7 Other Guidance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 6.3 Blinding/Unblinding . . . . . . . . . . . . . . . . . . . . . . . . . 24 6.3.1 Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 6.3.2 Unblinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 4 1.0 Approved 930010978 2.0 v 6.5 Non-therapy Precautions and Restrictions . . . . . . . 26 6.5.1 Precautions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 6.5.2 Restrictions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 6.6 Withdrawal of Subjects from Study . . . . . . . . . . . . . 28 7 STUDY PROCEDURES AND OBSERVATIONS . . . . . . 28 7.1 Flow Chart/Time and Events Schedule . . . . . . . . . . 28 7.2 Procedures by Visit . . . . . . . . . . . . . . . . . . . . . . . . . 30 7.2.1 Screening evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . 30 7.2.2 Day 1 of the first therapy course (before infusion) . . . . 30 7.2.3 Evaluations during each therapy course (on Days 8, 15, 22, 29, 36, 43 of each course). . . . . . . . . . . . . . . . . . . 31 7.2.4 Evaluations on Day 1 of Course 2 and thereafter (excluding the first course) . . . . . . . . . . . . . . . . . . . . . . . . 31 7.2.5 Discharge evaluations. . . . . . . . . . . . . . . . . . . . . . . . . . 32 7.3 Details of Procedures . . . . . . . . . . . . . . . . . . . . . . . 32 7.3.1 Study Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 7.3.2 Safety Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 7.3.2.1 Subjective/objective findings . . . . . . . . . . . . . . . . . 32 7.3.2.2 Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 7.3.2.3 Chest X-ray and PaO2 . . . . . . . . . . . . . . . . . . . . . 33 7.3.3 Laboratory Test Assessments. . . . . . . . . . . . . . . . . . . . 33 7.3.4 Efficacy Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . 34 7.3.4.1 Primary Efficacy Assessments . . . . . . . . . . . . . . . 34 7.3.4.2 Secondary Efficacy Assessments . . . . . . . . . . . . . 34 8 INVESTIGATIONAL PRODUCT . . . . . . . . . . . . . . . . . . . 34 Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 5 1.0 Approved 930010978 2.0 v 8.1 Investigational Product Identification . . . . . . . . . . . . 34 8.2 Packaging and Labeling . . . . . . . . . . . . . . . . . . . . . 35 8.3 Handling and Dispensing of Investigational Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 8.4 Investigational Product Records at Investigational Site(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 8.5 Return and Destruction of Investigational Product . 36 8.5.1 Return of Investigational Product . . . . . . . . . . . . . . . . . 36 8.5.2 Destruction of Investigational Product. . . . . . . . . . . . . . 37 8.6 Retained Samples for Bioavailability/Bioequivalence Studies . . . . . . . . . . . 37 9 ADVERSE EVENT REPORTING IN CLINICAL TRIALS 37 9.1 Importance of Adverse Event Reporting . . . . . . . . . 37 9.2 Collection of Safety Information. . . . . . . . . . . . . . . . 37 9.3 Adverse Events Related to Study Conditions . . . . . 40 9.4 Overdose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 9.5 AE Follow up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 9.6 Reporting of AE Information Following Study Completion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 9.7 Handling of Serious Adverse Events (SAEs). . . . . . 41 9.8 Laboratory Test Abnormalities. . . . . . . . . . . . . . . . . 44 9.9 Other Safety Considerations . . . . . . . . . . . . . . . . . . 44 9.10 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 10 ADMINISTRATIVE SECTION. . . . . . . . . . . . . . . . . . . . 46 10.1 Compliance with the Protocol and Protocol Revisions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 10.2 Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . 47 Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 6 1.0 Approved 930010978 2.0 v 10.2.1 Informed Consent Procedures . . . . . . . . . . . . . . . . . . 47 10.2.2 Subjects Unable to Give Informed Consent . . . . . . . . 47 10.2.2.1 Miscellaneous Circumstances. . . . . . . . . . . . . . . 47 10.2.3 Illiterate Subjects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 10.2.4 Update of Informed Consent . . . . . . . . . . . . . . . . . . . . 48 10.3 Monitoring for Protocol Compliance. . . . . . . . . . . . 48 10.4 Records and Reports. . . . . . . . . . . . . . . . . . . . . . . 49 10.5 Institutional Review Board/Independent Ethics Committee (IRB/IEC). . . . . . . . . . . . . . . . . . . . . . . . . 50 10.6 Records Retention. . . . . . . . . . . . . . . . . . . . . . . . . 50 10.7 Study Completion, Termination and Suspension Study Completion . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 10.7.1 Study Completion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 10.7.2 Termination or Suspension of an Entire Study . . . . . . 51 10.7.3 Termination or Suspension of the Study at the Medical Institution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 11 GLOSSARY OF TERMS AND LIST OF ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 11.1 Glossary of Terms . . . . . . . . . . . . . . . . . . . . . . . . . 52 11.2 List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . 52 APPENDIX 1 INFORMED CONSENT ELEMENT . . . . . . . 56 Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 7 1.0 Approved 930010978 2.0 v APPENDIX 4 ROLES AND RESPONSIBILITIES OF STUDY RELATED PERSONNEL AND STUDY PERIODD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 APPENDIX 5 DEFINITION OF ABNORMAL CHANGES AND OUTCOME OF LABORATORY TESTS . . . . . . . . 66 APPENDIX 6 DIRECT ACCESS TO SOURCE DOCUMENTS AND DEFINITION THEREOF . . . . . . . . 68 APPENDIX 7 CRITERIA FOR RESPONSEE . . . . . . . . . . 69 APPENDIX 8 PERFORMANCE STATUS . . . . . . . . . . . . . 77 APPENDIX 9 THERAPEUTIC ACTIONS FOR ACUTE ALLERGIC SYMPTOMS, ARRHYTHMIA, HYPOTENSION OR INTERSTITIAL PNEUMONIAA . . 78 APPENDIX 10 COMMON TOXICITY CRITERIA. . . . . . . . 82 Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 8 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 9 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 10 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 2 STUDY OBJECTIVES 2.1 Primary Objective The primary study objectives are as follow: 1) To provide the access to Paclitaxel therapy to breast cancer subjects who have completed at least 2 course on the previous conducted in Japan and are believed to be benefiting from this treatment, as assessed by the treating investigator(s). 2) To evaluate the frequency and the severity of observed adverse reactions in treated subjects. Date: 25-May-2005 11 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 2.2 Secondary Objectives The secondary objective is to obtain additional data on the response rate and duration of responses to complement information collected on the previous . 3 STUDY DESIGN AND EVALUATION 3.1 Study Design Only subjects who participated in the previous Phase II study may enroll in this rollover study provided that they meet all specified in this protocol inclusion and exclusion criteria. Subjects will receive weekly Paclitaxel at the dose that was their last dose on the previous delivered as a one hour iv infusion on Days 1,8,15,22,29,36 followed by 2 weeks of rest (no therapy). One course of therapy consists of 49 days. The range of doses on this study are expected to be decided based on dose reductions seen in . Safety assessment required in the protocol should be done at each of these weekly visits. Response to therapy will be assessed at least every 7 weeks, if clinically indicated. 3.2 Study Population Patients with advanced breast cancer who have completed weekly Paclitaxel dosing in previous and are believed to benefit from this treatment with recommendation to continue this regimen, as assessed by the treating investigator(s). 3.3 Criteria for Evaluation Observed responses should be evaluated according to the “Evaluation Criteria on the Therapeutic Effects in Patients with Advanced or Recurrent Breast Cancer “(Extracts) and the “RECIST” criteria (See Appendix 7). Every observed adverse event shall be evaluated according to the NCI Common Toxicity Criteria (NCI-CTC) Ver.2.0 (see Appendix 10, translated by the JCOG Japanese language version will also be available). For any toxicity not defined by the NCI-CTC criteria, it must be classified into the category of “Other toxicity” with detailed description on the toxicity observed and be graded according to the following criteria: Date: 25-May-2005 12 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Grade 0: Normal, normal/within normal range, no toxicity Grade 1: Minor/Mild toxicity Grade 2: Medium/Moderate toxicity Grade 3: Severe/High-grade toxicity Grade 4: Life-threatening toxicity Grade 5: Death due to toxicity 3.4 Sample Size Determination Sample size will be determined by the number of appropriate subjects who have completed previous and are eligible to participate in this rollover (CA139387) study. At the present time 9 patients remain on . It is estimated that less than 10 patients will be rolled over to this study from . 3.5 Interim Analyses There are no planned interim analyses. If requested by Japanese regulatory agencies, an interim analysis of this trial may be performed to support the Japanese regulatory filing. 4 STATISTICAL METHODOLOGY 4.1 Data Set Descriptions Subjects who receive at least one dose of weekly Paclitaxel treatment will be included in the baseline, dosing and safety summaries. Data from the previous will be utilized for the demographic data and baseline values in enrolled patients for this rollover trial. To obtain an additional data on a response rate and duration of responses, efficacy data will be collected in this rollover CA139387 study. 4.2 Analyses 4.2.1 Demographics and Baseline Characteristics Demographic data, performance status, diagnosis, stage, disease locations, prior treatment(s), and selected baseline laboratory results will be summarized using Date: 25-May-2005 13 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol descriptive statistics for all patients who received at least one dose of study medication. Baseline laboratory measurements will be collected from the data obtained for the participation in a previous 4.2.2 Efficacy Analyses Duration of response will be summarized using descriptive statistics for all responders among response-evaluable patients. 4.2.3 Safety Analyses All patients who received at least one dose of study medication will be included in the safety analysis. Worst toxicity grades per patient will be tabulated for adverse events and laboratory measurements. . 4.2.5 Other Analyses Not applicable. 5 SUBJECT SELECTION CRITERIA For entry into the study, the following criteria MUST be met. 5.1 Inclusion Criteria Only patients enrolled in the previous who have completed dosing and are believed to be benefiting from this treatment with advice to continue this regimen, as assessed by the treating investigator(s), may be considered for this rollover study after meeting study eligibility criteria as listed below. Signed written informed consent 1) Give written and voluntary informed consent. Date: 25-May-2005 14 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Target population 2) Patients should receive at least 2 courses, or more, of in the previous study ( )and the efficacy evaluation should be completed and confirmed by the treating investigator(s). 3) Patients who maintain bone marrow function and meet the following standards at the time of laboratory test obtained prior to the 1st Paclitaxel administration in this rollover study; • WBC count of 3,000/µL or higher, or absolute neutrophile count (ANC) of 1,500/µL or above. • Platelet count of 75,000/µL or above. 4) Performance Status (PS) of 0 - 2 (according to Classification Criteria of Performance Status by the Eastern Cooperative Oncology Group-ECOG. (See Appendix 8). Age and Sex 5) Women, ages 20 or older. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 2 weeks after the study in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea ≥ 12 consecutive months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35mIU/mL]. Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child bearing potential. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study medication. Date: 25-May-2005 15 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 5.2 Exclusion Criteria Sex and Reproductive Status 1) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 2 weeks after the study. 2) WOCBP using a prohibited contraceptive method (however, prohibited contraceptive methods are not specified in this protocol). 3) Women who are pregnant or breastfeeding 4) Women with a positive pregnancy test on enrollment or prior to study drug administration. Target Disease Exceptions 5) Patients with cerebral metastasis that are associated with clinical symptoms, and/or are associated with surrounding edema, or that require ongoing therapy with steroids or anti-convulsants. Medical History and Concurrent Diseases 6) Patients with serious uncontrolled medical illness despite optimal therapy i.e. uncontrolled cardiac disease, unstable angina, cerebrovascular disorder, diabetes mellitus etc; active infection, active gastric ulcer etc. Allergies and Adverse Drug Reactions 7) Patients with previous history of serious hypersensitivity reaction to Paclitaxel. Prohibited Therapies and/or Medications 8) Patients who following their last dose of given on the previous study received chemotherapy other than , surgical procedure, hormonal therapy, immunotherapy, radiotherapy, physiotherapy and/or other therapies against their cancer that may prohibit appropriate evaluation of the efficacy and safety of Paclitaxel on this rollover study. Date: 25-May-2005 16 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Other Exclusion Criteria 9) Subjects who are compulsorily detained for legal reasons or treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study. 10) Patients whose final efficacy evaluation is judged as Progressive Disease (PD) by the treating investigator(s) based on the CT or any other images taken within 4 weeks prior to the enrollment in this study. 11) Patients with grade 2 or higher peripheral neuropathy and/or grade 2 or higher arthralgia/myalgia despite optimal medical therapy that, in the opinion of treating investigator(s), will make unsafe to continue further Paclitaxel therapy. 12) Any serious, clinically unmanageable by standard medical therapy (i.e. G-CSF for neutropenia, blood transfusion for anemia, etc.) adverse event(s), subjective/objective findings, abnormal laboratory values etc. that occur prior to initiation of Paclitxel therapy on this rollover study that, in the opinion of treating investigator(s), will make unsafe to continue further Paclitaxel therapy. 6 STUDY CONDUCT 6.1 Ethics This study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and will be consistent with International Conference on Harmonization Good Clinical Practice (ICH GCP), Japan GCP and regulatory requirements. The study will be conducted in compliance with the protocol. The protocol and any Amendments and the subject informed consent will receive Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approval/favorable opinion prior to initiation of the study. Freely given written informed consent must be obtained from every subject prior to clinical trial participation, including informed consent for any screening procedures conducted to establish subject eligibility for the trial. Date: 25-May-2005 17 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Subjects unable to give their written consent (e.g., stroke patients, or subjects with severe dementia) may only be enrolled in the study with the consent of their legally acceptable representatives. The subject must also be informed about the nature of the study to the extent compatible with the subject’s understanding, and should they become capable, personally sign and date the consent form as soon as possible. For further details on informed consent, see Section 10.2. The rights, safety and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. Study personnel involved in conducting this trial will be qualified by education, training, and experience to perform their respective task(s). This trial will not use the services of study personnel where sanctions have been invoked or where there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). Systems with procedures that assure the quality of every aspect of the study will be implemented. Study site personnel involved in this study must bear in mind that study subjects are at a risk of experiencing adverse events as a result of administration of the investigational product and study-related procedures. Anticipated benefits of the investigational products and anticipated disadvantages to the subjects must be described in the informed consent form and explained to subjects prior to enrollment in this study. During and following a subject’s participation in the trial, the head of the medical institution or the investigator should ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the clinical trial. When serious unexpected events occur in a subject during the course of this study, the investigators should promptly evaluate whether the study should be discontinued, in collaboration with the Sponsor. All study site and sponsor personnel involved in this study must take the necessary actions to ensure that all information collected about study subjects throughout the study appropriately protects subjects’ privacy according to the requirements specified in the criminal law and the pharmaceutical affairs law. This applies, but is not limited to, information collected on the written informed consent, CRFs, source documents, Date: 25-May-2005 18 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol and publication of study results. Consequently, study subjects should, wherever possible, be identified by subject number. A detailed summary of the applicable regulatory requirements is provided in Appendix 2. 6.2 Study Therapy 6.2.2 Treatment Group Assignment Every potential study patient shall, when she/he fully meets all the eligibility criteria and submits a signed freely given informed consent, be eligible for this study registration. For each study participant, an Investigator/Sub-investigator is required to fill in all necessary items on a case registration form and send it to the Case Registration Center via facsimile as specified below. The Case Registration Center shall confirm that the data described in a registration card sent by an Investigator/Sub-investigator fulfills all inclusion criteria and does not meet any of the exclusion criteria before a case registration. The Case Registration Center shall inform an Investigator/Sub-investigator of the registration number for a registered case by telephone or facsimile. If the data described in a registration card does not fulfill the inclusion criteria or does meet any of the exclusion criteria, the Case Registration Center shall confirm the data in question by discussing it with an Investigator/Sub-investigator and, if the case is ineligible for the study, inform an Investigator/Sub-investigator of this decision by telephone and facsimile. Date: 25-May-2005 19 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 6.2.3 Treatment Administration 6.2.3.1 Method The firs Paclitaxel dose on a given course is defined as Day 1 of therapy with subsequent drug administrations being given on Days 8, 15, 22, 29 and 36 followed by 2 weeks of rest (no drug given). One course of treatment will therfore consist of total of 49 days. 1) Pre-medications (also see Section 6.5.1) The following premedications must be given before each paclitaxel infusion • Dexamethasone 8 mg i.v.(: Dose can be reduced to 4mg → 2mg → 1mg) administered 1 hour before and completed 30 minutes prior to the initiation of the paclitaxel infusion • Ranitidine 50 mg i.v.- administered 1 hour before and completed 30 minutes prior to the initiation of the paclitaxel infusion • Diphenhydramine 50 mg p.o. (): Dexamethasone: Dexamethasone dose at the initial administration day (Day 1) shall be the same as the last dose in the previous . If any hypersensitivity reaction was observed at the last dose in the previous Phase II study, a dosage of dexamethasone shall be double of the last dose. During the observation period (Days 1 – 7), if there are no specific clinical problems, dexamethasone dose for the subsequent week (Day 8) would be allowed to be decreased by half the dose from the previous week (i.e.4mg), if necessary. Consequently, if no clinically significant hypersensitivity reaction is observed in a week following the drug administration, it would be possible to use again a half of the previous dexamethasone dose (i.e. 2mg), if necessary. The minimum dexamethasone dosage however, can not be less then 1 mg). If clinically significant hypersensitivity reaction develops, and it is judged that further continuation of weekly Paclitaxel is in the best patient’s interest, dexamethasone dose shall be double the previous dose (e.g. if 8 mg was given and there was an event observed then, the next dexamethasone should be 16 mg) for the subsequent Paclitaxel administrations. 2) Paclitaxel (Day1, 8, 15, 22, 29, 36) ( see Section 6.5.1) Date: 25-May-2005 20 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol After administration of the pre-medications, the patient should receive Paclitaxel dose that is consistent with the last dose() of Paclitaxel that the given patient has received in the previous study ). This Paclitaxel dose shall be mixed with 250 mL of a saline solution or 5% glucose solution for intravenous infusion given over 1-hour. () weekly Paclitaxel dose should be reduced, if appropriate, according to the severity of adverse effect(s) observed at the last Paclitaxel treatment in the previous Phase II study according to the “Dose Modification” criteria (See Section 6.2.3)”. Administration of weekly Paclitaxel dose should be given on the expected date of treatment + one day. course 1 course 2 Days Day1 Day8 Day15 Day22 Day29 Day36 Day43 Day50 +++ Paclitaxel O O O O O O ˜ O +++ 6.2.3.2 Criteria for re-treatment within the course of therapy (Days: 8, 15, 22, 29, 36 of a therapy course) An in-course repeated dosing could be allowed only when the laboratory test values and clinical assessments in the previous week or immediately before Paclitaxel administration meet the following requirements; • WBC count of 2,000/µL or above, or absolute neutrophile count (ANC) of 1,000/µL or above. • Platelet count of 75,000/µL or above. • No Grade 2 or higher peripheral neuropathy and/or Grade 2 arthralgia/myalgia despite optimal medical therapy which, in the opinion of treating investigator(s), will make further Paclitaxel therapy unsafe. • Any serious, clinically unmanageable by standard medical therapy (i.e. G-CSF for neutropenia, blood transfusion for anemia, etc.) adverse event(s), subjective/objective findings, abnormal laboratory values etc. occur that, in the opinion of treating investigator(s), will make unsafe to continue further Paclitaxel therapy. If the patient does not meet above requirements or if the investigator/sub-investigator judges that, it is in the best patient’s interest to delay Paclitaxel dosing, the drug administration shall be postponed by one week. Reasons for this decision should be described in a case report form. A dose modification, if appropriate, should be Date: 25-May-2005 21 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol performed for a successive in-course dosing. (See Section 6.2.3 “Dose Modification"). The study should be discontinued if more than two consecutive Paclitaxel administrations or more than three out of six doses total within the given treatment course are not delivered. However, in patients with evidence of Paclitaxel anti-tumor effects, as judged by the treating investigator(s), subsequent Paclitaxel therapy following longer than allowed suspension of treatment may be allowed. The reasons for this decision shall be described in a case report form and all safety precautions should be observed. 6.2.3.3 Re-treatment Criteria for Course 2 and thereafter The second and consequent courses of therapy should be started after confirmation that the following criteria are all met prior to the drug administration. • WBC count of 3,000/µL or above, or ANC of 1,500/µL or above. • Platelet count of 75,000/µL or above. • No Grade 2 or higher peripheral neuropathy and/or Grade 2 arthralgia/myalgia despite optimal medical therapy which, in the opinion of treating investigator(s), will make further Paclitaxel therapy unsafe. • Any serious, clinically unmanageable by standard medical therapy (i.e. G-CSF for neutropenia, blood transfusion for anemia, etc.) adverse event(s), subjective/objective findings, abnormal laboratory values etc. occur that, in the opinion of the treating investigator(s), will make unsafe to continue further Paclitaxel therapy. • No Grade 3 or higher non-hematological toxicity despite optimal medical therapy. When any one of the criteria is not met, administration should not be started (a dose modification should be performed for a successive in-course repeated dosing. See Section 6.2.3 “Dose Modification"). Paclitaxel therapy should be started as soon as the laboratory test values and the symptoms are recovered to the acceptable level. However, if the re-treatment criteria are not met following 2 weeks after the scheduled initiation date of the given treatment course, the study therapy shall be discontinued in a given patient. When the initiation of the treatment course is delayed, the delayed initiation date shall be set as Day 1 of the given course with the subsequent treatment schedule adjusted accordingly. However, in the given patient (i.e. in case of electrolytes abnormalities, etc.), if in the opinion of the treating investigator(s) it is still safe and in the best patient’s interest to Date: 25-May-2005 22 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol continue Paclitaxel therapy (with dose adjustment, if clinically indicated), the treatment may continue but the reasons for this decision must be described in the case report form. 6.2.4 Dose Modifications Paclitaxel dose shall be reduced according to the severity of an adverse event using criteria listed below. Paclitaxel dose should be decreased by the increment of 20mg/m2 /dose. Patients who require a decrease below the total of 60mg/m2 /dose will be discontinued from treatment.. • WBC count: less than 1000/µL (1) • Grade 3 neutropenia (neutrophils count <1000/µL but ≥ 500//µL) or higher, neutropenia associated with fever (≥38°C) or infection • Grade 3 or higher non-hematological toxicity (2) • Development of Grade 2 or higher peripheral neuropathy and/or Grade 2 arthralgia/myalgia despite optimal medical therapy which, in the opinion of treating investigator(s), will make further Paclitaxel therapy clinically difficult. • When an investigator/sub-investigator judges to be clinically appropriate to skip a scheduled drug administration and/or to require a dose reduction. • In the opinion of the treating investigator/sub-investigator there is a need for dose modification. Reasons for this decision should be described in a case report form. (1) Dose reduction based on the WBC count being less than 1,000/µL shall depend on a decision of treating investigator/sub-investigator (taking into consideration the time of bone marrow recovery, clinical scenario for a given patient, etc.). (2): For the given patient, if in the opinion of the treating investigator/sub- investigator it is not clinically necessary to reduce the Paclitaxel dose (including Grade 3 or higher electrolyte abnormality, etc.) the dose may stay the same however, the reason for this decision must be described in a case report form. 6.2.5 Discontinuation of Therapy Study therapy MUST be immediately discontinued for the following reasons: • If the clinical efficacy evaluation reveals progressive disease (PD). • Withdrawal of informed consent (subject’s decision to withdraw for any reason). • Any clinical adverse event, laboratory abnormality or intercurrent illness which, in the opinion of the investigator, indicates that continued treatment with study therapy is not in the best interest of the subject. Date: 25-May-2005 23 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol • Pregnancy. • Termination of the study by BPKK. • The compulsory detention for legal reasons or for treatment of either a psychiatric or physical (e.g., infectious disease) illness. • If a patient becomes ineligible after registration for the study. Also, the study subject should be discontinued from the study therapy for the following reasons: • A treatment delay of > 2-weeks because of paclitaxel related toxicity • If in the opinion of the treating investigator(s) further continuation of Paclitaxel therapy is judged to be unsafe or clinically inappropriate based on the development of new or worsening of previous symptoms. • If any clinical findings consistent with the Grade 1 or higher interstitial pneumonia, pneumonia, pulmonary fibrosis or severe infection develops. • If there is a need for dose reduction below the total of 60mg/m2/dose which violates the dose-reduction criteria. • If an alternative systemic or local anti-cancer therapy is initiated. • If the patient has moved away from the area during the study participation that makes the continuation of the study therapy no longer feasible. • If the treating investigator/sub-investigator judges that the discontinuation of study therapy is in the best patient’s interest.. For discontinuation of the study see Section 6.6. 6.2.6 Treatment Compliance Each study drug administration must be conducted under the supervision of an investigator/sub-investigator and the following data must be described in the case report form (CRF); date of paclitaxel administration, dosage, infusion time, body weight, and the pre-medications given. 6.2.7 Other Guidance Not applicable. 6.3 Blinding/Unblinding Not applicable. Date: 25-May-2005 24 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 6.3.1 Blinding Not applicable. 6.3.2 Unblinding Not applicable. . Date: 25-May-2005 25 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 6.5 Non-therapy Precautions and Restrictions 6.5.1 Precautions 1) Pre-medication drugs: Based on the foreign literature, prolonged use of dexamethasone as pre-medication for the weekly Paclitaxel regimen appears is utilized. Compared with the dosing method for every 3 weeks Paclitaxel schedule, the total volume of steroids administered with the weekly regimen(s) appears to be fairly large. Therefore, it is considered highly likely that this may cause suppression of the adrenocortical function hence, lower doses of dexamethasone are permitted based on tolerance of the individual patient. A clinical study reported by using decreasing doses of dexamethasone demonstrated that the dose of 20mg of dexamethasone (administered twice: 12 hours and 6 hours before Paclitaxel infusion) was gradually decreased to 2mg and only 1/22 patients developed skin rash but others tolerated Paclitaxel therapy well. Another report by revealed following results: 16mg of dexamethasone was administered as pre-medication to 43 patients. There was one patient with apnea that resolved without treatment but other 42 patients had no evidence of any hypersensitivity reaction. Based on these reports, in the Japanese Phase I weekly Paclitaxel study, dexamethasone was initially administered at the 16mg dose, which was lower than the approved 20 mg dose, with subsequent decrease to a total of 2 mg. During this study dexamethasone dosing was further changed to the initial dose of 8 mg with subsequent dose decrease to a total of 1mg. With this last dexamethasone pre-medication regimen there were no hypersensitivity reaction observed. Based on these data, the pre-medication regimen shall be used as described in the Section 6.2.2.1 (1). 2) Paclitaxel 2-1) Preparation and i.v. infusion time Date: 25-May-2005 26 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Immediately prior to the infusion, Paclitaxel shall be mixed with 250 ml of a saline solution or 5% glucose solution and administered as a 1-hour IV infusion. Containers for the solution MUST be made of glass, polyethylene or polypropylene. Paclitaxel is known to dissolve the container if it is made of polyvinyl chloride (PVC) and the plasticizer, DEHP[di-(2-ethylhexyl)phthalate], in the container may cause leaching. 2-2) Injection kit An injection kit made of PVC should NOT be used because of a possible leaching caused by plasticizer (DEHP). For the Paclitaxel injection, an in-line filter must be used. 2-3) Other Caution Items Paclitaxel is reconstituted with ethanol as a solvent. For any patient with alcoholic sensitivity, administration shall be made with full care. Upon administration, a patient’s subjective and objective symptoms shall be carefully monitored and a patient should be carefully monitored during the time-points specified below; a) First-at 30 minutes following initiation of IV infusion for possible development of immediate allergy-like symptom or arrhythmia b) Subsequently- during and immediately after completion of IV infusion for possible hypotension. For treatment of immediate allergy-like symptoms, arrhythmia or hypotension, refer to Appendix 9. Date: 25-May-2005 27 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 6.6 Withdrawal of Subjects from Study Subjects MUST be discontinued from the study therapy AND withdrawn from the study participation for the reasons described in Section 6.2.5. 7 STUDY PROCEDURES AND OBSERVATIONS 7.1 Flow Chart/Time and Events Schedule Clinical laboratory testing and monitoring during the study period shall be conducted at every appropriate time-point as detailed in Table 1. For those tests conducted after the final course of treatment on a previous please follow instructions shown in Table 1. Any adverse event that does not recover to a baseline level by the 14th day of observation a follow-up shall be done, as much as possible, until the recovery to baseline or symptoms stabilization. Date: 25-May-2005 28 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Table.7.1: X: required measurement point, XX: Conduct, if possible, at the time of clinic visit. Rollover study (CA139387) As needed after 2nd course 1st course 2nd- course 1st week (Day1) Procedure Last dose Obser- vation Pre-dosea Infusion Post- infusion Day8, 15,22, 29,36 7w Day43 (off) 1w Day1 Patient background X Body weight (BW), Height, and BSA X X Subjective/objective findings and P.S. X X X X X X Blood Test (clinical laboratory) X X X X X X Cab X Xb Chest CT-scanc Conduct when acute lung disorder or interstitial pneumonia were suspected Chest X-rayd Conduct if necessary PaO2 e Conduct if necessary ECGf Conduct if necessary Blood pressureg X X X X Urine test h X Xh Pregnancy testi X XX Observation of lesion for efficacy evaluationj Conduct at least every 7 weeksj * A day that a study drug is administered is Day 1. * Each laboratory test (except for tumor marker test) must be completed prior to administration of each weekly drug administration. * Administration of weekly Paclitaxel doses and initiation of successive treatment courses must be done within an expected date of treatment + one day. a Each required examination before the administration of a 1st course shall be conducted within 2 days before the first dose. Tumor status evaluation (tumor measurements, tumor markers) could be conducted within one month prior to the scheduled 1st Paclitaxel dose. b Once a course evaluation is required. c Conduct when acute lung disorder or interstitial pneumonia is suspected. d Can be done for evaluation of clinical symptoms such as fever, cough, shortness of breath or dyspnea. Can be repeated as clinically indicated. e Conduct if clinically indicated i.e. if any respiratory symptoms such as cough or shortness of breath develops. f Done for patients with suspected cardiac-related toxicity. ECG monitoring during subsequent treatments shall be done when clinically indicated. with strong consideration given to safety of further Paclitaxel therapy. Date: 25-May-2005 29 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol g Frequent monitoring shall be performed. Patients should be closely monitored during and after the study drug infusion. Patients who will be going home following completion of Paclitaxel infusion (outpatient clinic practice) should be thoroughly evaluated for any side effects including vital signs and performance status. h Should be done once prior to each treatment course. If the drug safety can be adequately judged from other evaluation(s) i.e. serum creatinine, etc., this test may not have to be done routinely. i A pregnancy test shall be conducted within 72 hours prior to Day 1 of a 1st course for a WOCBP (WOCBP must have a negative serum or urine pregnancy test which has minimum sensitivity 25 IU/L or equivalent units of HCG). For successive treatment courses, it will be conducted prior to a Day 1 of each treatment course(as much as possible). j To objectively evaluate the anti-tumor effect , an identical imaging diagnostic method shall be utilized for the individual patient More than one diagnostic method could be applied, if clinically indicated. In addition, lesion(s) that can be evaluated only clinically i.e. skin or chest wall lesions , should be, as much as possible, photographed and lesion measurements should be documented. * A day that a study drug is administered is Day 1. * Each laboratory test (except for tumor marker test) must be completed prior to administration of each weekly drug administration. * Administration of weekly Paclitaxel doses and initiation of successive treatment courses must be done within an expected date of treatment + one day. 7.2 Procedures by Visit 7.2.1 Screening evaluation The following tests should be performed within 14 days prior to a first dose of study drug administration. If data (i.e. laboratory test values, etc.) from the time prior to obtaining the informed consent is used for study enrollment, the study subject shall agree to this herself/himself. • Subjective/objective findings(including Performance Status-PS) • Clinical efficacy from • ECG (see Table 1) • Blood test (Hb, WBC, ANC, Plt, T-Bil, AST(GOT), ALT(GPT), BUN, S-Cr, Ca) • Serum or Urine pregnancy test: in case of WOCBP(minimum sensitivity 25IU/L or equivalent units of HCG) 7.2.2 Day 1 of the first therapy course (before infusion) The following evaluation shall be conducted on Day1 of the 1st treatment course prior to a study drug administration; • Body weight and height. Body Surface Area (BSA) Date: 25-May-2005 30 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol • Subjective/objective findings(including PS) • Blood test and urine test (see Section 7.3.3for details) • Blood pressure (pre-dose and post- infusion) • Serum or Urine pregnancy test: in case of WOCBP (minimum sensitivity 25IU/L or equivalent units of HCG within 72 hours prior to the start of study medication. However, if a pregnancy test is already conducted within 72 hours prior to the study drug administration during the enrollment period the repeated test is not needed. 7.2.3 Evaluations during each therapy course (on Days 8, 15, 22, 29, 36, 43 of each course) The following items shall be examined; • Subjective/objective findings (including PS) • Blood test and urine test (see Section 7.3.3 for details) • Blood pressure (pre-dose and post- infusion) See Table 1 for details of evaluation on day 43 (7th week of each course of treatment) 7.2.4 Evaluations on Day 1 of Course 2 and thereafter (excluding the first course) Following evaluation should be done on Day1 of the second therapy course and each subsequent treatment course(excluding the first course). • Body weight, BSA. Serum calcium and urine test shall be conducted at least once a course. When safety of further Paclitaxel therapy is adequately judged from i.e. serum creatinine values, etc., the urine test may not to be done routinely. Tumor status evaluation should be done after completion of each treatment course (i.e. every 4~ 7 weeks or sooner, if clinically indicated) • Measurements of lesion(s) for efficacy evaluation should be done using the same imagining method for each tumor status evaluation i.e. CT and/or MRI and/or bone scan etc. Lesions that can be evaluated only clinically i.e. skin and/or chest wall lesions should be photographed and measurement(s) of such lesions should be documented (as much as possible) Date: 25-May-2005 31 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol • Tumor marker (at least one type regardless of marker type) 7.2.5 Discharge evaluations When the patient is discontinued from the study therapy (taken off the study) either due to a progressive disease or toxicity, or other (please see Section 6.2.5 for details), the following evaluation shall be done at the 14th day from the last dose (it may also be done on the 15th day or later, if necessary i.e. subject’s personal matters or unexpected inconvenience at a study site,etc). • Subjective/objective findings (including PS) • Blood test, urine test (see Section 7.3.3) 7.3 Details of Procedures 7.3.1 Study Materials The Sponsor will provide the Paclitaxel(BMS-181339) Investigator Brochure, any relevant safety addendum, protocol and any amendments to the protocol, Case Report Forms(CRF), instructions for completing CRFs, case registration forms and Severe Adverse Reaction (SAE) forms etc. 7.3.2 Safety Assessments 7.3.2.1 Subjective/objective findings It shall be conducted weekly on a day of the drug administration and, if possible, during the week when therapy is suspended (during the patient visit at the clinic or in the hospital). Instruct all patients to inform the investigator immediately if the patient develops fever, dry cough, shortness of breath for early detection and diagnosis of acute lung disorder or interstitial pneumonia. Investigator must evaluate carefully each study patient (i.e.auscultation, etc) even without clinical symptoms. Conduct chest CT-scan immediately, if clinically indicated, for proper diagnosis and treatment.. Conduct A-aDO2 or DLCO, if necessary. Date: 25-May-2005 32 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 7.3.2.2 Blood Pressure It should be measured pre-dose and post-dose on every drug administrations. Frequent monitoring should be performed, fully observing the patients during and after the study drug IV infusion. If the patient is treated in the outpatient clinic settings, she/he should be thoroughly evaluated ( i.e. for any side effects, performance status, vital signs, etc) prior to discharge to home. 7.3.2.3 Chest X-ray and PaO2 Monitor carefully for the clinical symptoms such as fever, cough, shortness of breath or dyspnea, and if any of these symptoms develop, chest x-ray and/or PaO2 may be conducted, if clinically indicated. If acute lung disorder or interstitial pneumonia is suspected, a chest CT-scan and, if necessary, additional A-aDO2 or DLCO can be done (cf. 6.2.4 and Appendix 9). Consider consult with experts on respiratory diseases, if needed. 7.3.3 Laboratory Test Assessments The following laboratory tests shall be conducted at the time of registration and prior to the scheduled Paclitaxel administration at each study site (corrected Ca test shall be conducted at least once a course); 1) Hematology RBC count, hemoglobin, WBC count, neutrophil count, and platelet count. 2) Serum Chemistry Total protein, albumin, total bilirubin, ALP, AST, ALT, LDH, BUN, S-Cr, Na, K, Cl and Ca. 3) Others CRP (C-reactive protein) The following tests will be done at least once for each course prior to Paclitaxel administration. 4) Urine test: urine protein, urine sugar, urobilinogen The following obligatory evaluation should be done prior to the administration of a first drug dose on the first treatment course and subsequently, every ~ 7 weeks. 5) Tumor marker Appropriate type (at least one type regardless of marker type) For WOCBP, a pregnancy test must be conducted within 72 hours prior to an initial study drug administration on a 1st course and prior to the1st dose on subsequent treatment courses (as much as possible). Date: 25-May-2005 33 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 6) Pregnancy test Appropriate test (Serum or Urine pregnancy test [minimum sensitivity 25 IU/L or equivalent units of HCG]). Results of all laboratory tests required by this protocol must be recorded on the laboratory pages of the CRF or by another method as agreed upon between the Investigator/Sub-investigator and this, too must be recorded in the CRF (see Section 9.8 Laboratory Test Abnormalities). The following evaluation should be conducted if any respiratory symptoms such as cough or shortness of breath develop. 7) PaO2 7.3.4 Efficacy Assessments 7.3.4.1 Primary Efficacy Assessments The primary efficacy endpoint will not be set in this study. 7.3.4.2 Secondary Efficacy Assessments Not applicable. 8 INVESTIGATIONAL PRODUCT Investigational product is defined as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in the study, whether blinded or unblinded. 8.1 Investigational Product Identification The sponsor will provide Paclitaxel and pre-medication drugs as study drugs. # Study Drug: Code name: BMS-181339 Generic name: Paclitaxel Dosage form/content: Each vial (16.7 mL) contains 100 mg of paclitaxel. Date: 25-May-2005 34 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol # Premedications: Drug Name Formulation Contents Packaging Dexamethasone vial One vial (2 mL) contains 8 mg dexamethasone sodium phosphate (6.6 mg as dexamethasone) 50 vials/box Diphenhydramine tablet One tablet contains 10 mg diphenhydramine hydrochloride 500 tablets/bottle Ranitidine ampule One ampule contains 50 mg ranitidine 10 ampules/box 8.2 Packaging and Labeling A label bearing the following information will be placed on the container or the package of the investigational product (see Appendix 3): • The fact that the drug is for clinical study use • Name of the investigational product (code name) • Lot number • Dosage form and content • Storage condition • Name and address of the sponsor • Use date, if necessary 8.3 Handling and Dispensing of Investigational Product After study contract between the sponsor and the medical institution is finalized, the sponsor will supply the investigational drug to the investigational product storage manager designated by the head of the medical institution. The investigational product storage manager will store and manage the investigational product appropriately, according to the written procedures prepared and provided by the sponsor, and follow up the status of dispensing by keeping the record of the investigational product management sheet. Investigational product should be stored in a secure area according to local regulations. It is the responsibility of the Investigator to ensure that investigational product is only dispensed to study subjects. The investigational product must be dispensed only from official study sites by authorized personnel according to local regulations. Date: 25-May-2005 35 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 8.4 Investigational Product Records at Investigational Site(s) It is the responsibility of the investigational product storage manager designated by the head of the medical institution to ensure that a current record of investigational product disposition is maintained at each study site where investigational product is inventoried and disposed. Records or logs must comply with applicable regulations and guidelines, and should include: • Amount received and placed in storage area. • Amount currently in storage area. • Label ID number or batch number. • Dates and initials of person responsible for each investigational product inventory entry/movement. • Amount dispensed to and returned by each subject, including unique subject identifiers. • Amount transferred to another area for dispensing or storage. • Non-study disposition (e.g., lost, wasted, broken). • Amount returned to Sponsor. Sponsor will provide forms to facilitate inventory control if the staff at the investigational site does not have an established system that meets these requirements. Sponsor should also provide procedures stipulating instructions for the handling, storage and management of investigational products and recording thereof. 8.5 Return and Destruction of Investigational Product 8.5.1 Return of Investigational Product Upon completion or termination of the study, all unused and/or partially used investigational product must be returned to BMKK, if not authorized by BMKK to be destroyed at the site. All investigational products returned to BMKK must be accompanied by the appropriate documentation and be clearly identified by protocol number and study site name. Empty containers should not be returned to BMKK. It is the responsibility of the medical institution to arrange for disposal of all empty containers, provided that procedures for proper disposal have been established according to applicable local Date: 25-May-2005 36 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol and institutional guidelines and procedures. The return of unused investigational product(s) should be arranged by the responsible Study Monitor. Upon completion or termination of the study, all unused and/or partially used investigational product must be returned to BMKK, if not authorized by BMKK to be destroyed at the site. All investigational products and empty containers returned to BMKK must be accompanied by the appropriate documentation and be clearly identified by protocol number and study site name. The return of unused investigational product(s) should be arranged by the responsible Study Monitor. 8.5.2 Destruction of Investigational Product All unused investigational products must be returned to BMKK and therefore, the product can not be destroyed at the site without appropriate reasons. The investigational product storage manager must provide a detailed explanation to BMKK if the drug is destroyed at the site. BMKK will ensure appropriate destruction of investigational product. 8.6 Retained Samples for Bioavailability/Bioequivalence Studies Not Applicable. 9 ADVERSE EVENT REPORTING IN CLINICAL TRIALS 9.1 Importance of Adverse Event Reporting Timely and complete reporting of safety information assists BMS/BMKK in identifying any untoward medical occurrence, thereby allowing: (1) protection of safety of study subjects; (2) a greater understanding of the overall safety profile of the investigational product; (3) recognition of dose-related investigational product toxicity; (4) appropriate modification of study protocols; (5) improvements in study design or procedures; and (6) adherence to worldwide regulatory requirements. 9.2 Collection of Safety Information In BMS/BMKK clinical trials, an Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a patient or clinical investigation subject administered a medicinal product and which Date: 25-May-2005 37 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal (investigational or marketed) product, whether or not considered related to the medicinal (investigational or marketed) product. During clinical trials, adverse events can be spontaneously reported or elicited during open-ended questioning, examination, or evaluation of a subject. (In order to prevent reporting bias, patients should not be questioned regarding the specific occurrence of one or more adverse events.) Following the subject’s written consent to participate in the study, all serious AEs should be collected. The collection of non-serious AE information should begin at initiation of investigational product. Non-serious AE information should also be collected from the start of a placebo lead-in period or other observational period intended to establish a baseline status for the patient. All identified AEs must be recorded and described on the appropriate Non-serious or Serious AE page of the CRF. If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its individual symptoms. The following information should be captured for all AEs: date (and time) of onset and resolution, severity of the event (see definitions), investigator’s opinion of the relationship to investigational product (see definitions), treatment required for the AE (see categories), cause of the event (if known), and information regarding resolution/outcome (see definitions). Severity will be graded according to the... NCI-CTC The following categories and definitions of severity should be used for AEs in this clinical trial: • Mild (Grade I) - Awareness of event but easily tolerated • Moderate (Grade II) - Discomfort enough to cause some interference with usual activity • Severe (Grade III) - Inability to carry out usual activity • Very Severe (Grade IV) - Debilitating, significantly incapacitates subject despite symptomatic therapy The following categories and definitions of causal relationship to study drug should be used for all BMS/BMKK clinical trial AEs: Date: 25-May-2005 38 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol • Certain: There is a reasonable causal relationship between the study drug and the AE. The event responds to withdrawal of study drug (dechallenge), and recurs with rechallenge when clinically feasible. • Probable: There is a reasonable causal relationship between the study drug and the AE. The event responds to dechallenge. Rechallenge is not required. • Possible: There is reasonable causal relationship between the study drug and the AE. Dechallenge information is lacking or unclear. • Not likely: There is a temporal relationship to study drug administration, but there is not a reasonable causal relationship between the study drug and the AE. • Unrelated: There is not a temporal relationship to study drug administration (too early, or late, or study drug not taken), or there is a reasonable causal relationship between another drug, concurrent disease, or circumstance and the AE. The adverse event will be regarded as related to study drug if the causal relationship is assessed as either "1. Certain ","2. Probable" or "3. Possible”. If a causal relation of an adverse event is assessed as “4. Not likely” or "5. Unrelated," reasons for the evaluation are to be described. The following categories and definitions of outcome /resolution should be used for all BMS/BMKK clinical trial AEs 1) Did not resolve (Persisted or Aggravated) 2) Resolved (Recovered) 3) Resolved, but residual effects(s) persist (Relieved) 4) Unknown 5) Subject Died* * “Subject Died” category applies to reporting of Serious AEs only. The following categories and definitions on action taken with respect to investigational product administration should be used for all BMS/BMKK clinical trial AEs 1) None 2) Dose reduced* 3) Interrupted 4) Discontinued 5) Dose Increased* * “Dose reduced” and “dose increased” should be deleted if not applicable Date: 25-May-2005 39 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol The following categories on treatment required should be used for all BMS/BMKK clinical trial AEs 1) No 2) Yes (If Yes, comment on the treatment.) A detailed explanation of the categories and definitions applicable to AEs due to laboratory abnormalities is provided in Appendix 5. 9.3 Adverse Events Related to Study Conditions If the investigator believes that an SAE is not related to the investigational product, but is potentially related to the conditions of the study, (such as withdrawal of previous therapy, or complication of a diagnostic procedure), the relationship should be specified in the narrative section of the SAE page of the CRF. 9.4 Overdose An overdose is defined as the accidental or intentional ingestion of any dose of a product that is considered both excessive and medically important. For reporting purposes, BMS considers an overdose, regardless of adverse outcome, as an important medical event (see Serious Adverse Events). 9.5 AE Follow-up AEs should be followed to resolution or stabilization, and reported as SAEs if they become serious. This also applies to subjects experiencing AEs that cause interruption or discontinuation of investigational product, or those experiencing AEs that are present at the end of their participation in the study; such subjects should receive post-treatment follow-up as appropriate. If an ongoing AE changes in its severity or in its perceived relationship to study drug, a new AE entry for the event should be completed. 9.6 Reporting of AE Information Following Study Completion Collection of safety information following the end of investigational product administration is important in assisting in the identification of possible delayed toxicities or withdrawal effects. In BMS/BMKK trials, all SAEs must be collected which occur within 30 days of discontinuation of dosing or completion of the patient’s participation in the study if the last scheduled visit occurs at a later time. In Date: 25-May-2005 40 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol addition, the investigator should notify BMS/BMKK of any SAE which may occur after this time period which they believe to be certainly, probably or possibly related to investigational product. 9.7 Handling of Serious Adverse Events (SAEs) A serious AE is any untoward medical occurrence that at any dose: • results in death, • is life-threatening (defined as an event in which the subject or patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe), • requires inpatient hospitalization or causes prolongation of existing hospitalization, • results in persistent or significant disability/incapacity, • is a cancer, • is a congenital anomaly/birth defect, • results in the development of drug dependency or drug abuse, • is an important medical event (defined as a medical event(s) that may not be immediately life-threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the patient/subject or may require intervention (e.g., medical, surgical) to prevent one of the other serious outcomes listed in the definition above.) Examples of such events include, but are not limited to, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.) For reporting purposes, BMS/BMKK also considers the occurrences of pregnancy or overdose (regardless of adverse outcome) as events which must be reported as important medical events. Adverse events classified as "serious" must be recorded on the SERIOUS AE (SAE) page of the CRF and require expeditious handling and reporting to BMKK as well as to the head of the medical institutions to comply with regulatory requirements. All serious AEs whether related or unrelated to investigational product, must be immediately reported to BMKK as well as to the head of the medical institution (or designee) by confirmed facsimile transmission. A documented telephone call may be used in lieu of a facsimile. If only limited information is initially available, follow-up reports are required. The original BMKK SAE form must be kept on file at the sponsor. In selected circumstances, the protocol may specify conditions which require additional telephone reporting. Date: 25-May-2005 41 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Cases of pregnancy must be reported on Pregnancy Surveillance Forms in lieu of SAE pages (see Section 9.10). Collection of complete information concerning SAEs is extremely important. Thus, follow-up information which becomes available as the SAE evolves, as well as supporting documentation (e.g., hospital discharge summaries and autopsy reports), should be collected subsequently, if not available at the time of the initial report, and immediately sent using the same procedure as the initial SAE report. As required, BMKK will notify Investigators and the heads of the medical institutions of all AEs that are serious, unexpected, and certainly, probably, or possibly related to the investigational product. This notification will be in the form of a Safety Update. Upon receiving such notices, the Investigator must review and retain the notice with the Investigator Brochure. At the same time sponsor will immediately submit a copy of this information to the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) according to local regulations, via the head of the medical institution. The Investigator and IRB/IEC will determine if the informed consent requires revision. The Investigator should also comply with the IRB/IEC procedures Date: 25-May-2005 42 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol for reporting any other safety information. Where required, submission of Safety Updates by the Investigator to Health Authorities, should be handled according to local regulations. Serious adverse events whose causal relationship to the investigational product cannot be ruled out (adverse drug reactions) and that meet the criteria as specified in Article 273 of the Enforcement Regulations of the Pharmaceutical Affairs Law are to be reported on an expedited basis. The sponsor will report the adverse drug reactions to the regulatory authority. The time limit of reporting varies according to whether the reported adverse drug reactions are expected or unexpected. i. Unexpected “Death” or “cases which might result in death”: within 7 days ii. Unexpected events other than those listed above: within 15 days iii. Expected “Death” or “Cases which might result in death”: within 15 days When necessary, the sponsor will consult with the medical expert on the actions to be taken regarding the conduct of the study, including whether this study is to be continued or not. Procedures for termination or suspension of this study are described in Section 10.7. Reporting of Serious Adverse Events Seen in the Other Studies When serious adverse events possibly related to the investigational product (adverse drug reactions) are reported in other studies, the sponsor will take the following actions. For an unexpected serious adverse drug reaction, the sponsor will consult with the medical expert, if necessary, and the sponsor will notify Investigator and the head of the medical institution promptly. Any serious adverse drug reactions specified in Section 9.7 Serious Adverse events (SAEs) will be reported to the regulatory authority on an expedited basis within the specified time limits. Periodically, according to the Investigator Brochure SOP, the Investigator Brochure will be updated to include new and relevant safety information. Until such time that Date: 25-May-2005 43 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol an AE becomes identified in the Investigator Brochure, it will continue to be reported to Investigators and to health authorities in line with local regulations. 9.8 Laboratory Test Abnormalities All laboratory test values captured as part of the study should be recorded on the appropriate laboratory test results pages of the CRF, or be submitted electronically from a central lab. In addition, in order for BMKK to collect additional information about clinically important laboratory abnormalities, at a minimum, the following laboratory abnormalities should be captured on the non-serious or serious AE pages of the CRF as appropriate: • Any laboratory test result that meets the criteria for a Serious Adverse Event • Any laboratory abnormality that required the patient to have investigational product discontinued or interrupted • Any laboratory abnormality that required the patient to receive specific corrective therapy. It is expected that wherever possible, the clinical, rather than the laboratory term would be used by the reporting investigator (e.g., anemia versus low hemoglobin value). A detailed definition of abnormal laboratory changes and outcome is provided in Appendix 5. 9.9 Other Safety Considerations Any clinically significant changes noted during interim or final physical examinations, electrocardiograms, x-rays, and any other potential safety assessments, whether or not these procedures are required by the protocol, should also be recorded on the appropriate AE page of the CRF (i.e., NON-SERIOUS or SERIOUS). 9.10 Pregnancy Sexually active women of childbearing potential must use an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized. (See Section 5.1 for definition of WOCBP). Date: 25-May-2005 44 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Before enrolling women of childbearing potential (WOCBP) in this clinical trial, Investigators must review the guideline about study participation for WOCBP which can be found in the GCP Manual for Investigators. The topics include the following: • General Information • Informed Consent Form • Pregnancy Prevention Information Sheet • Drug Interactions with Hormonal Contraceptives • Contraceptives in Current Use • Guidelines for the Follow-up of a Reported Pregnancy Prior to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. The subject must sign an informed consent form documenting this discussion. All WOCBP MUST have a negative pregnancy test within 72 hours prior to receiving investigational product. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG. If the pregnancy test is positive, the subject must not receive investigational product and must not be enrolled in the study. Pregnancy testing must also be performed throughout the study as specified in Section 7.3.3 and the results of all pregnancy tests (positive or negative) recorded on the case report form. In addition, all WOCBP should be instructed to contact the Investigator immediately if they suspect they might be pregnant (e.g., missed or late menstrual period) at any time during study participation. If following initiation of study treatment, it is subsequently discovered that a trial subject is pregnant or may have been pregnant at the time of investigational product exposure, including during at least 6 half-lives after product administration, the investigational product will be permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for subject safety). Exceptions to investigational product discontinuation may be considered for life-threatening conditions only after consultation with the BMKK Medical Monitor or as otherwise specified in this protocol. The Investigator must immediately notify the BMKK Medical Monitor of this event and record the pregnancy on the Pregnancy Surveillance Form. Pregnancy Surveillance Forms are forwarded to BMKK as described in Section 9.7 (SAEs). Date: 25-May-2005 45 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Protocol-required procedures for study discontinuation and follow-up must be performed on the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy follow-up procedures should be considered if indicated. In addition, the Investigator must report to BMKK, on the appropriate BMKK pregnancy surveillance forms(s), follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome. Infants should be followed for a minimum of eight weeks. 10 ADMINISTRATIVE SECTION 10.1 Compliance with the Protocol and Protocol Revisions The study shall be conducted as described in this approved protocol. All revisions to the protocol must be discussed with, and be prepared by, BMKK. The Investigator should not implement any deviation or change to the protocol without prior review and documented approval/favorable opinion from the IRB/IEC of an Amendment, except where necessary to eliminate an immediate hazard(s) to study subjects. Any significant deviation must be documented in the CRF or in the specific sheet provided to record these deviations. If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be submitted to: • IRB/IEC, via the head of the medical institution, for review and approval/favorable opinion; • Bristol-Myers K.K.; • The head of the medical institution; • Regulatory Authority(ies), if required by local regulations. Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be sent to BMKK. If the revision is an Administrative Letter, the Sponsor must inform their IRB(s)/IEC(s) via the head of the medical institution. If an Amendment substantially alters the study design or increases the potential risk to the subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and approval/favorable opinion; (2) the revised form must be used to Date: 25-May-2005 46 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol obtain consent from subjects currently enrolled in the study if they are affected by the Amendment; and (3) the new form must be used to obtain consent from new subjects prior to enrollment. 10.2 Informed Consent Investigators must ensure that subjects are clearly and fully informed about the purpose, potential risks and other critical issues regarding clinical trials in which they volunteer to participate. 10.2.1 Informed Consent Procedures Preparation of the consent form is the responsibility of the Investigator and must include all elements required by ICH, GCP and applicable regulatory requirements, and must adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. The consent form must also include a statement that BMKK and regulatory authorities have direct access to subject records. Prior to the beginning of the study, the Investigator must have the IRB/IEC’s written approval/favorable opinion of the written informed consent form and any other information to be provided to the subjects. The Investigator must provide the subject with a copy of the consent form and written information about the study in the language in which the subject is most proficient. The language must be non-technical and easily understood. The Investigator should allow time necessary for subject to inquire about the details of the study, then informed consent must be signed and personally dated by the subject and by the person who conducted the informed consent discussion. The subject should receive a copy of the signed informed consent and any other written information provided to study subjects prior to subject's participation in the trial. 10.2.2 Subjects Unable to Give Informed Consent 10.2.2.1 Miscellaneous Circumstances Subjects who are compulsorily detained for legal reasons or treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study. In circumstances where a subject’s only access to treatment is through enrollment in a clinical trial, e.g., for subjects in developing countries with limited resources or for Date: 25-May-2005 47 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol subjects with no marketed treatment options, the investigator must take special care to explain the potential risks and benefits associated with the trial and ensure that the subject is giving informed consent. When a subject may be in a dependent relationship with the investigator, a subinvestigator who is completely independent of the relationship between the subject and investigator should obtain the subject’s informed consent. 10.2.3 Illiterate Subjects If the subject is unable to read, a reliable and independent witness should be present during the entire informed consent discussion. The choice of the witness must not breach the subject’s rights to confidentiality. A reliable independent witness is defined as one not affiliated with the institution or engaged in the investigation. A family member or acquaintance are appropriate independent witnesses. After the subject orally consents and has signed, if capable, the witness should sign and personally date the consent form attesting that the information is accurate and that the subject has fully understood the content of the informed consent agreement and is giving true informed consent. 10.2.4 Update of Informed Consent The informed consent and any other information provided to subjects, should be revised whenever important new information becomes available that is relevant to the subject's consent, and should receive IRB/IEC approval/favorable opinion prior to use. The Investigator, or a person designated by the head of the medical institution, should fully inform the subject of all pertinent aspects of the study and of any new information relevant to the subject's willingness to continue participation in the study. This communication should be documented. During a subject's participation in the trial, any updates to the consent form and any updates to the written information will be provided to the subject. 10.3 Monitoring for Protocol Compliance Representatives of BMKK/BMS must be allowed to visit all study site locations periodically to assess the data, quality and study integrity. On site they will review study records and directly compare them with source documents and discuss the conduct of the study with the Investigator, and verify that the facilities remain acceptable. Date: 25-May-2005 48 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol In addition, the study may be evaluated by BMS/BMKK internal auditors and government inspectors who must be allowed access to CRFs, source documents and other study files. BMS/BMKK audit reports will be kept confidential. THE HEAD OF THE MEDICAL INSTITUTION MUST NOTIFY BMKK PROMPTLY OF ANY INSPECTIONS SCHEDULED BY REGULATORY AUTHORITIES, AND PROMPTLY FORWARD COPIES OF INSPECTION REPORTS TO BMKK. 10.4 Records and Reports An Investigator is required to prepare and maintain adequate and accurate case histories designed to record all observations and other data pertinent to the investigation on each individual treated with the investigational product or entered as a control in the investigation. Data reported on the CRF, that are derived from source documents, must be consistent with the source documents or the discrepancies must be explained. The CRF must be completed legibly in ink. Subjects are to be identified by birth date and subject number, if applicable. All requested information must be entered on the CRF in the spaces provided. If an item is not available or is not applicable, it must be documented as such; do not leave a space blank. The confidentiality of records that could identify subjects must be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). The Investigator will maintain a copy of the Signature Sheet to document signatures and seals of all persons authorized to make entries and/or corrections on CRFs. The original of this sheet will be kept by the sponsor. A correction must be made by striking through the incorrect entry with a single or double line and entering the correct information adjacent to the incorrect entry. The correction must be dated, signed or sealed and explained (if necessary) by the person making the correction and must not obscure the original entry. The completed CRF must be promptly reviewed, signed or sealed, and dated by a qualified physician who is an Investigator or Subinvestigator. The Investigator must retain a copy of the CRFs including records of the changes and corrections. Date: 25-May-2005 49 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 10.5 Institutional Review Board/Independent Ethics Committee (IRB/IEC) Before study initiation, the Sponsor must have written and dated approval/favorable opinion from the IRB/IEC, via the head of the medical institution, for the protocol, consent form, subject recruitment materials/process (e.g., advertisements), and any other written information to be provided to subjects. The Sponsor should also provide the IRB/IEC, via the head of the medical institution, with a copy of the Investigator Brochure or product labeling, information to be provided to subjects and any updates. The Investigator and Sponsor should provide the IRB/IEC, via the head of the medical institution, with reports, updates, and other information (e.g., Safety Updates, Amendments, Administrative Letters) according to regulatory requirements or Institution procedures. 10.6 Records Retention The head of the medical institution must retain investigational product disposition records, copies of CRFs (or electronic files), and source documents for the maximum period required by applicable regulations and guidelines, or Institution procedures, or for the period specified by the Sponsor, whichever is longer. The head of the medical institution must contact BMKK prior to destroying any records associated with the study. BMKK will notify the head of the medical institution when the trial records are no longer needed. 10.7 Study Completion, Termination and Suspension Study Completion 10.7.1 Study Completion When this study is completed, the investigator will notify the head of the medical institution in writing of the completion and provide a written overview of the study results. The head of the medical institution will in turn notify the Sponsor and the IRB in writing of the completion and send a copy of the written overview of the study results. Date: 25-May-2005 50 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 10.7.2 Termination or Suspension of an Entire Study For an event that may require termination of this study, the sponsor will consult with the medical expert before deciding on the termination or suspension of this study. The sponsor will provide to the medical expert any relevant safety, efficacy or other available information that may justify the need for terminating or suspending the study. The termination or suspension of this study will be decided by the sponsor, taking in consideration the advice given by the medical expert. When the termination of this study is decided, the sponsor will promptly notify the investigator and the head of the medical institution in writing of the decision and reasons for the termination. 10.7.3 Termination or Suspension of the Study at the Medical Institution When the investigator considers it necessary to terminate or suspend this study, the investigator will promptly report the fact and reasons in writing to the head of the medical institution to which the investigator belongs. The head of the medical institution will in turn promptly notify the Sponsor and the IRB in writing of the fact and explain in detail the events and rationale which required the termination or suspension of the study. Date: 25-May-2005 51 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 11 GLOSSARY OF TERMS AND LIST OF ABBREVIATIONS 11.1 Glossary of Terms Not applicable. 11.2 List of Abbreviations Term Definition d.i.v. drip infusion in vein 3w1q 3 weeks administration, 1week quit 6w1q 6 weeks administration, 1week quit 6w2q 6 weeks administration, 2week quit °C degrees centigrade µL microliters µm micrometers A-aDO2 Alveolar to arterial oxygen gradient ADM doxorubicin AE(s) adverse event(s) Alb Albumin ALP alkaline phosphatase ALT (GOT) alanine aminotransferase (Glutamic Oxaloacetic Transaminase) ANC Absolute Neutrophil Count AST (GPT) aspartate aminotransferase (Glutamin Pyruvic Transaminase) A-V atrioventricular BMKK Bristol Myers K.K. BRM biological response modifiers BUN blood urea nitrogen Ca Calcium CAP cyclophosphamide, doxorubicin, cisplatin CHF congestive heart failure Cl Chloride cm3 centimeters cubed CPA cyclophosphamide CR complete response CRF case report form CRP C-reactive protein CT computed tomography DLCO Diffusing capacity of the lung for carbon monoxide Date: 25-May-2005 52 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Term Definition DLT dose-limiting toxicity ECG electrocardiogram ER estrogen receptor GCP Good Clinical Practice Hb Hemoglobin IC50 50% inhibitory concentration IEC Independent Ethics Committee IND Investigational New Drug IRB Institutional Review Board IV intravenous K potassium LDH lactosedehydrogenase mg/m2 milligrams per square meter mL mililiters MRI magnetic resonance imaging MTD maximum tolerated dose Na sodium NCI National Cancer Institute ng/mL nanograms per milliliter NSCLC Non-small cell lung cancer PaO2 Partial pressure oxygen PD progressive disease PgR Progesterone receptor Plt Platelet PO, p.o. orally PR partial response PS performance status PVC polyvinyl chloride RBC red blood cells SAE(s) serious adverse event(s) S-Cr Serum Creatinine SD stable disease T-Bil Total Bilirubin TP Total Protein WBC white blood cells Date: 25-May-2005 53 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 54 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 55 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol APPENDIX 1 INFORMED CONSENT ELEMENT The informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include explanations of the following mandatory topics: 1 That the study involves research. 2 The purpose of the study. 3 The expected duration of the subject’s participation in the study. 4 The study treatment(s) and the probability for random assignment to each treatment. 5 The study procedures to be followed, including all invasive procedures. 6 Those aspects of the study that are experimental. 7 The reasonably foreseeable risks or inconveniences to the subject, and when applicable, to an embryo, fetus, or nursing infant. 8 The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this. 9 The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks. 10 That records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the study are published, the subject's identity will remain confidential. 11 That the BPKK/BMS monitor and/or BPKK/BMS representative, IRB/IEC, and regulatory authority(ies) will be granted direct access to the subject's original medical records for verification of clinical study procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing and dating a written informed consent form, the subject or the subject's legally acceptable representative is authorizing such access. 12 The subject’s responsibilities. Date: 25-May-2005 56 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 13 The compensation and/or treatment available to the subject in the event of study-related injury. 14 The anticipated prorated payment, if any, to the subject for participating in the study. 15 The person(s) to contact for further information regarding the study and the rights of study subject's, and whom to contact in the event of study-related injury. 16 That the subject's participation in the trial is voluntary and that the subject may refuse to participate or withdraw from the study, at any time, without penalty or loss of benefits to which the subject is otherwise entitled. 17 The foreseeable circumstances and/or reasons under which the subject's participation in the study may be terminated. 18 The anticipated expenses, if any, to the subject for participating in the study. 19 The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject. 20 That the subject or the subject's legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the subject's willingness to continue participation in the study. 21 The approximate number of subjects involved in the study. 22 The name, title and address of the Investigator or the subinvestigator to contact. Additional mandatory topics for inclusion in the informed consent of studies enrolling Women of Child Bearing Potential (WOCBP): Date: 25-May-2005 57 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 1 General Statement The subject must not be, and should not become pregnant during exposure to the investigational product. Subjects should be instructed to contact the Investigator if they plan to change their pregnancy avoidance method or if they need to take any prescription drug or other medication not prescribed by Investigator. Sexually active subjects must use an effective method of pregnancy avoidance during the course of the study, in a manner such that risk of failure is minimized. The informed consent must indicate that information on pregnancy prevention for women of child-bearing potential has been reviewed with the subject by the Investigator or study designee. 2 Laboratory & Animal Reproductive Toxicology A statement addressing what is known about the investigational product from laboratory and animal reproductive toxicity studies concerning possible mutagenic and/or teratogenic effects should be included in the consent. The consent should indicate that this information has limited predictive value for humans. 3 Unforeseeable Risks The consent must indicate that exposure to the investigational product may involve currently unforeseeable risks to the subject (or embryo or fetus, if the subject is or may become pregnant). 4 Occurrence of Pregnancy or Suspected Pregnancy The informed consent must include study contact name(s) and telephone number(s) for the subject to call if she becomes pregnant or suspects pregnancy, has missed her period or it is late, or she has a change in her usual menstrual cycle (e.g., heavier bleeding during her period or bleeding between periods). 5 Discontinuation from the Study Any subject who becomes pregnant during the course of the study will be immediately withdrawn (unless allowed or stated differently in the protocol) and referred for obstetrical care. All financial aspects of obstetrical, child or related care are the responsibility of the subject. 6 Pregnancy Follow-up If a subject becomes pregnant, BMS will seek access to the subject's and/or infant's clinic/hospital records through the pregnancy, and for a minimum of 8 weeks following delivery. 7 Use of a Study-prohibited Contraceptive Method Date: 25-May-2005 58 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol When applicable, the informed consent should clearly indicate if a contraceptive method is prohibited (e.g., when hormonal contraceptive interaction with the investigational product(s) is known or suspected). In this situation, a study participant should be instructed to notify the Investigator or study designee if a prohibited contraceptive method is initiated during the course of the study so that additional precautions can be taken or the subject discontinued from the study. 8 Non-investigational product Interactions with Hormonal Contraceptives Women using a hormonal method of contraception (oral contraceptives, implantable or injectable agents) must be instructed to notify the Investigator or study designee of the need to take any prescription drug or other medication not prescribed by the Investigator. The purpose of this statement is to identify any potential non-investigational product interaction with the contraceptive which might reduce the effectiveness of the contraceptive method. Date: 25-May-2005 59 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 60 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 61 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol ku, Tokyo Contact: 03-5323-8366 Date: 25-May-2005 62 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol APPENDIX 4 ROLES AND RESPONSIBILITIES OF STUDY RELATED PERSONNEL AND STUDY PERIOD The study system is described below. 4.1 SPONSOR 4.1.1 Sponsor 4.1.2 Study Director Taku Seriu, M.D., Director 4.1.3 Medical Expert and Roles Thereof Roles The medical expert will, as occasion demands, advise about the following matters etc. from a medical point of view: • Examination of the Protocol • Preparation for and participation, if necessary, at KIKO Consultations • Examination of the Case Report Form (CRF) • Examination of the informed consent form and explanatory document • Examination of investigator’s brochure • Examination of handling for adverse events (AEs) and safety information • Examination of continuation, change, termination and suspension of the study • Review of the clinical study report Date: 25-May-2005 63 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 4.1.4 Monitor 4.1.5 Auditor 4.1.6 Biostatistics Analyst 4.2 PK/PD ANALYST Not applicable. Date: 25-May-2005 64 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 4.3 COORDINATING INVESTIGATOR AND ROLES THEREOF [Roles] • Coordinate the details of the protocol between the study sites. • Coordinate troubles on interpretations of the protocol occurring during the study. • Opinion co-adjustment between the study coordinating investigators and investigators at Evaluation Committee Meeting and other occasions. • Advise about the preparation and revision of the protocol and others. 4.4 COORDINATION COMMITTEE AND ROLES THEREOF Not applicable 4.5 EFFICACY AND SAFETY COMMISSIONER [Roles] 1) The efficacy/safety evaluation commissioner shall evaluate the progress of the study, safety information and others, when appropriate, and advise the sponsor about continuation, change and termination or suspension of the study. The efficacy/safety evaluation committee consists of members independent of the sponsor and the investigator. 2) At the request of the sponsor, the efficacy/safety evaluation committee shall conduct the following tasks; • The committee shall advise the sponsor about the appropriateness of study plan concerning safety assurance and others. The committee shall examine whether the protocol is to be revised or not and, if required, advise the sponsor about the revision. • When a serious adverse event possibly affecting the conduct of the entire study is reported by the sponsor (see 8.2), the committee shall hold a meeting (or handed- round decision-making system) and advise about continuation of the study, changes of the study plan and termination or suspension of the study. Date: 25-May-2005 65 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol • Each committee member shall review the minutes of the meeting (if a handed- round decision-making system is used, replies from each committee member are handled as the minutes) and affix his or her signature or seal. Supplemental information on the handed-round decision-making system. The chairman shall decide whether handed-round decision-making is to be required or not. When it is considered necessary to use a handed-round decision-making system from the standpoint of the items of discussion or because of expedited nature of discussion, the chairman shall ask each member to deliberate the matters in writing, and each member shall report the results of deliberation to the chairman in writing. The sponsor shall receive the report of each member from the chairman and retain the report as the minutes of the committee meeting. 4.6 INVESTIGATORS Refer to an Attachment, “List of Clinical Trial Sites and Investigators” 4.7 ASSIGNMENT MANAGER AND ROLES THEREOF Not applicable. 4. 8 STUDY PERIOD June/2005- Approval APPENDIX 5 DEFINITION OF ABNORMAL CHANGES AND OUTCOME OF LABORATORY TESTS Laboratory values will be monitored, and their significance will be evaluated by the investigator/subinvestigator taking in consideration how they evolve throughout the study. Any abnormal change observed, per the definition below, shall be recorded in the appropriate form as an “Adverse Event”, together with its severity, actions taken and causal relationship to study drug, to be evaluated as described Section 9 in this protocol For details on the follow-up of AEs please refer to Section 9 in this protocol. On laboratory test values: The abnormal values shall be evaluated according to the NCI Common Toxicity Criteria (NCI-CTC) ver.2.0 (Translated version into Japanese Date: 25-May-2005 66 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol by the JCOG will also be available in Appendix 10) . For the item that is not listed in the NCI-CTC, a normal value at each study site shall be applied). 1) Definition of abnormal changes For laboratory test parameters, an "abnormal value" is defined as a value deviated from the normal range specified at the medical institution. When a laboratory value is initially "normal" and becomes "abnormal" during the treatment period or is initially "abnormal" and further "aggravates," such a change in laboratory values, if it is clinically significant (adverse event), is considered to be an "abnormal change." If the investigator/subinvestigator did not assess such a change in laboratory values as an "abnormal change," the investigator/subinvestigator must provide details of and reasons for the assessment in column "Comment" on the laboratory pages of the CRF. 2) Outcome The outcome of an abnormal change will be recorded according to the following criteria: 1) Did not resolve: The value remained outside the normal range and continued to be clinically significant (or worsened with a consequent increase in severity) 2) Resolved: The value was reversed to the pretreatment level or returned to a normal range 3) Resolved, but residual effect(s) persist: The value was not reversed to a normal range but improved to a clinically insignificant level 4) Unknown: Use of an alternative therapeutic method or failure of following-up (the reasons should be described) Date: 25-May-2005 67 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol APPENDIX 6 DIRECT ACCESS TO SOURCE DOCUMENTS AND DEFINITION THEREOF The head of the medical institution and the investigator must permit monitoring and auditing to be performed by the sponsor, reviews by the IRB, and inspection by the regulatory authorities. Direct access to all the study-related records such as source documents should be provided upon request by the monitors and the auditors of the sponsor, the IRB, or the regulatory authorities. In this particular study, source documents, and the CRF data deemed as source data are defined as follows: 1) Source documents • Subject identification code sheet • Medical records • Written consent • Study drug management sheet • Laboratory examination data • Electrocardiography (ECG) charts • Image that can identify the lesion (MRI, CT, etc.). 2) CRF data deemed as source data Of the data directly recorded in the CRFs, the following data are deemed as source data: various comments described in the CRFs, study drug relation to abnormal laboratory test finding, comments of adverse events (event, severity, date of onset, actions taken regarding study drug, treatment required for event, outcome, causal relationship to study drug, comments), comments of discontinuation or drop-outs due to any safety problem, comments of protocol compliance status). The data directly described in the margin area of CRF, they are also deemed as source data. Date: 25-May-2005 68 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol APPENDIX 7 CRITERIA FOR RESPONSE 7.1 Evaluation Criteria on Therapeutic Effects in Patients with Advanced or Recurrent Breast Cancer(Extracts) 7.1.1 Measurement of a Lesion 1-1 Tumor lesion sites are divided into 13, as shown in Table 1, and individually measured site-by-site. These lesions include the 3 categories; 1) bi- directional measurable lesions, 2) one-directional measurable lesions and 3) immeasurable (evaluable) lesions. However, if two or more categories of lesions co-exist in one identical lesion site, these lesions shall independently be measured for records. The measurement shall in principle be made every 4 weeks. 1-2 A bi-directional lesion represents a product multiplying the largest diameter by its vertical counterpart diameter. (cm2) If a plural number of lesions exist in one identical lesion site, a product for each lesion must separately be figured out. In case only one directional measurement could be available in a front view image by X-ray, etc., a measured value of lateral view that is assumed to be vertical to the front view could be allowable for use. 1-3 One directional lesion measurement must always be done on one identical site. (cm) If a plural number of lesions exist in one identical lesion site, a product for each lesion must separately be figured out. 1-4 In an immeasurable (evaluable) lesion, an evaluation must be made as much as possible on a dose-response reaction using various parameters (radiography, diagnostic imaging methods and other useful means to trace the post-dose progresses) before and during the therapeutic period. 1-5 An efficacy evaluation on radiotherapy shall be applied only to the limited area of irradiated lesion. 7.1.2 Definition of Objective Effects 2-1 CR(Complete Response): A disappearance of all tumor lesions confirmed lasts at lest 4 weeks or longer. 2-1-1 For each skeletal (osseous) lesion, a definition shall be made as follows; 1) In osteolytic lesions prior to this study drug therapy, it shall be defined as a fluoroscopically completely hardened or a recovered back-to- normal. 2) In osteogenic lesions prior to this study drug therapy, it shall be defined as a fluoroscopically significant decrease in concentration level. Note 1:Bone scintigraphy findings could be available for use as an auxiliary tool for diagnostics. Date: 25-May-2005 69 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Note 2:For the spinal bones, a diagnosis by CT or MRI is better. 2-2 Partial Response(PR): defined as a decrease by 50% or more in a total product of measurable lesions. In an immeasurable (evaluable) lesion, defined as a clear improvement. As for any bone metastasis, defined as a calcification of bone-soluble lesion or a decrease in concentration of an osteogenic lesion. These phenomena must last at least 4 weeks or longer. During the course, either one of the lesions (secondary lesions included) shall not be increased by 25% or more and not bear any new lesion. 2-3 No Change (NC): defined as a decrease by 50% or less or as an increase by 25% or more in a total product of measurable lesions. In immeasurable (evaluable) and secondary lesions, neither clear improvement nor clear increase is shown and no new lesion appears in either case. These phenomena must last at least 4 weeks or longer, and for a bone lesion 8 weeks or more. 2-4 Progressive Disease(PD): defined as an increase by 25% or more in a total product of measurable lesions; a significant increase of measurable (evaluable) and secondary lesions, or a development of new lesion. However, in case of bone metastasis, a pathological fracture or necrosis (or weakness) will not always be interpreted as an evidence for progressive disease. 2-4-1 Though an improvement seen in some lesions and a total product of lesions reveals a shrinkage, if any one of the lesions that shows an increase by 25% or more at the time of the most shrunken compared with the baseline value, it shall be defined as PD. However, even if any one of the lesions that shows an increase by 25% or more at the time of the most shrinkage compared with the baseline value in patients with PR, it shall be interpreted as PR as long as thr shrinkage rate stays at 50% or lower compared with the baseline values. (Actual cases seen below) Figure 1. the case of CR 0 CR period 25 50 75 Tumor Shrinkage rate 100 Trerapeutic Period A: Day of study therapy initiation B: Day that CR is first confirmed C: Day that CR is last confirmed D: Day that PD is confirmed B-C: CR period Note: Though Point D shows a shrinkage of 50% or more, compared with Point A, but since it shows 25% or more increase in the value at start of study therapy compared with Point C, it shall be interpreted as PD. D B C A Date: 25-May-2005 70 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Figure 2. the case of PR 0 PR period 25 50 75 Tumor Shrinkage rate 100 Therapeutic Period A: Day of study therapy initiation B: Day that PR is first confirmed C: Day that PR is last confirmed D: Day that PD is confirmed B-C: PR period Note: Points C & D show 25% or more increase in the value at start of study therapy compared with Point B. However, since Point C shows 50% or more in shrinkage compared with Point A, it will be PR; in the same manner, Point D 50% or less in shrinkage compared with Point D, be interpreted as PD. Figure 3. the case of NC 0 25 50 NC period 75 Tumor Shrinkage rate 100 Therapeutic Period A: Day of study therapy initiation B: Day that the most tumor shrinkage is first confirmed C: Day that NC is last confirmed D: Day that PD is confirmed A-C: NC period Note: Point D shows an increase of 25% or less compared with Point A, but it shows 25% or more increase in baseline values compared with Point B, be interpreted as PD. Note 1: CR: Complete Response(Complete or significant response), PR: Partial Response(partial or responsed), NC: No Change (Not any changed), PD: Progressive Disease Note 2: A total product of lesions means a total product of the largest diameter and its vertical largest diameter multiplied (cm2) for bi-directional lesions and a product of measured values for one-directional lesions in plural number of lesions of one identical site. Note 3: When a progressive disease stays as NC for long (24 weeks or longer) by the study drug therapy, it will be recorded separately as long NC in efficacy. However, it will not be added to “9. Calculation of Response Rate”. Note 4: Cases that a decrease of 50% or more in a total product of measurable lesions lasts for 4 weeks or less and those that a decrease of 25% or more to 50% or less lasts for 4 weeks or longer could be recorded separately as D B C A D B C A Date: 25-May-2005 71 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol MR(Minor Response). However, it will not be added to “9. Calculation of Response Rate” Note 5: Upon evaluating the effects in a therapeutic plan that a minimum dosage or a minimum dosing period is specified, it requires a regulated observation period of 4 weeks or more and that of 8 weeks or more for bone lesions. However, for a clarified PD, it will not be applied. Note 6: Evaluations for radiotherapy, they will be recorded immediately after, 4 weeks and 12 weeks after radiotherapy. Note 7: For successively planned surgery, etc., an evaluation of objective effects in case of not enough observation period given after study therapy(topical arterial injection therapy, etc.) could well be made by only changes of concerned lesions according to the specifications, regardless of duration. However, it must be described separately to other treatment methods. Date: 25-May-2005 72 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Table 1: Total Evaluation of Objective Effects for Lesions bi-directionally measurable one-directionally measurable Cate- gory Sites Disease Type measured values Judg- ments measured values Judg- ments immea- surable Total Evaluation a. tumor 1 Primary breast and opposite side of breast b. diffuse infiltration a. node b. disperse topical c. diffuse infiltration 2 Dermal(Skin) and Subcutaneous d. distal a. topical/local 3 lymphatic node b. distal Soft tissues 4 mediastinal hilar tumor a. bone bone 5 bone b. bone marrow a. node type b. disperse type 6 lung c. funicular type a. node/thickness 7 pleura b. pleural effusion 8 pericardial humor 9 hepatic 10 intra-abdominal tumor 11 ascites Viscera 12 central nervous system(CNS, brain, eyes, etc.) 13 Others ( ) Note 1: Topical area for skin and subcutaneous tissue means an anterior ipsilateral thorax and others distal. Note 2: A topical/local area of lymphatic node includes ipsilateral axilla, supra- and sub-clavicular and parasternal, and others distal. Note 3: For pleural effusion, pericardial humor and ascites, it requires to be sytologically diagnosed as positive. A cytological negativity without use of diuretics and complete disappearance of lesion with no humoral retention; this is the only one case for PR. Note 4: For hepatic and cerebral tests, lesions must be identified by angiography, scintigraphy, echography and CT, etc. Measurement for hepatic hypertrophy shall be made vertically from the costal end in identical site. Note 5: See Text 2-1,2 and 4. Date: 25-May-2005 73 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Note 6: No CR evaluation will be made in these lesions. 7.2 Response Evaluation Criteria in Solid Tumors (RECIST;Outlines) 7.2.1 Measurability of Tumor Lesions at Baseline At baseline, tumor lesions will be categorized as: measurable lesions: lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as 20 mm with conventional techniques or as 10 mm with spiral CT scan. non- measurable lesions: all other lesions, including small lesions (longest diameter 20 mm with conventional techniques or 10 mm with spiral CT scan) and truly non-measurable lesions. All measurements should be recorded in metric notation, using a ruler or calipers. All baseline evaluations should be performed as close as possible to the treatment start and never more than 4 weeks before the beginning of the treatment. Lesions that are considered as truly non-measurable include the following: • bone lesions; • leptomeningeal disease; • ascites; • pleural/pericardial effusion; • inflammatory breast disease; • lymphangitis cutis/pulmonis; • abdominal masses that are not confirmed and followed by imaging techniques; • cystic lesions; Date: 25-May-2005 74 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 7.2.2 Tumor response evaluation 7.2.2.1 Baseline Documentation of "Target" and "Non-Target" Lesions All measurable lesions up to a maximum of 10 lesions representative of all involved organs should be identified as target lesions and will be recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repetitive measurements (either by imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference to further characterize the objective tumor response of the measurable dimension of the disease. All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at baseline. Measurements are not required and these lesions should be followed as “Present” or “Absent”. 7.2.2.2 Response Criteria 7.2.2.2.1 Evaluation of Target Lesions Complete Response CR disappearance of all target lesions. Partial response PR at least a 30% decrease in the sum of LD of target lesions taking as reference the baseline sum LD. Progression PD at least a 20% increase in the sum of LD of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one and more new lesions. Stable Disease SD neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD since the treatment started. 7.2.2.2.2 Evaluation of non target lesions Complete Response CR disappearance of all non-target lesions and normalization of tumor marker level. Non-Complete Response CR/ Date: 25-May-2005 75 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol Non-Progression(non-PD): persistence of one and more non-target lesion or/and maintenance of tumor marker level above the normal limits. Progression PD appearance of one and more new lesions. Unequivocal progression of existing non-target lesions. 7.2.2.2.3 Evaluation of best overall response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence. The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria (see Section 9.2.3) 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 PD Any Yes or No PD Any PD Yes or No PD Any Any Yes PD 7.2.3 Confirmation Criteria To be assigned a status of PR or CR, the size changes in tumor measurements must be confirmed by repeat studies that should be performed no less than 4 weeks after the criteria for response are first met. In the case of SD, the follow-up measurements conducted at least 6 weeks and longer after registration must have met the SD criteria at least once. Date: 25-May-2005 76 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol APPENDIX 8 PERFORMANCE STATUS CLASSIFICATION OF PERFORMANCE STATUS (GENERAL CONDITIONS) SPECIFIED BY THE EASTERN COOPERATIVE ONCOLOGY GROUP Grade Performance Status 0 Fully active, able to carry on all pre-disease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of walking hours 3 Capable of only limited selfcare, confined to bed or chair more than 50% of walking hours 4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair Date: 25-May-2005 77 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol APPENDIX 9 THERAPEUTIC ACTIONS FOR ACUTE ALLERGIC SYMPTOMS, ARRHYTHMIA, HYPOTENSION OR INTERSTITIAL PNEUMONIA Careful monitoring should be made, especially during the first 30 minutes after initiation of infusion when hypersensitivity reactions (immediate type allergy-like symptoms) or arrhythmia possibly appear, during, and after, the infusion when hypotension may appear. [Hypersensitivity Reactions (Immediate type Allergy-like Symptoms)] In the U.S. clinical studies, the reported hypersensitivity reactions (immediate type allergy-like symptoms) attributed to paclitaxel administration included dyspnea, bronchospasm, decreased blood pressure, increased blood pressure, angioedema (laryngeal stridor, epiglottic swelling, periorbital edema, etc.), urticaria, flushing, erythematous rash, abdominal pain, pain of extremities, vomiting, fever, and rigidity. In the event of clear evidence of hypersensitivity reaction (immediate type allergy-like reactions), paclitaxel should immediately be discontinued, and the following actions should be taken while close cardiopulmonary monitoring: 1) Diphenhydramine-calcium bromide (5 ml; containing 20 mg of diphenhydramine) should be intravenously administered (the dose should be adjusted appropriately according to the patient™s status). 2) Epinephrine (not greater than 0.25 mg) should be diluted with saline or other solvents and administered intravenously as slowly as possible. This course should be repeated at 5- to 15-minute intervals at its need (alternatives are dobutamine and dopamine preparations). a) Hypotension not responding to epinephrine: Central venous pressure and other cardiovascular parameters should be monitored, and intravenous fluid should be given, if necessary. b) Stridor not responding to epinephrine: bronchodilators such as salbutamol sulfate (1.5 - 2.5 mg of salbutamol or equivalent doses of other drugs) should be given by inhalation, using a nebulizer. 3) It is known that corticosteroids are effective in blocking allergic reactions of delayed type due to various antigens. Sodium methylprednisolone succinate Date: 25-May-2005 78 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol 125 mg may be administered intravenously for prevention of recurrence or allergic symptoms. [Arrhythmia] The following therapeutic actions may be taken for arrhythmia: 1) Asymptomatic bradycardia: paclitaxel may be continued. 2) Symptomatic bradycardia: paclitaxel should be discontinued. 3) Marked sinus bradycardia: paclitaxel should be discontinued, and atropine should be administered intravenously at 5-minute intervals (0.5 mg per administration) until the total dose reaches 2.0 mg. 4) Atrioventricular block: paclitaxel should be discontinued. Class I block and block of Mobitz Type I will usually disappear spontaneously. Atropine produces transient improvement of atrioventricular conduction. For severe bradycardia and others (block of Mobitz Type II or complete atrioventricular block), pacing therapy should be used. 5) Marked ventricular ectopy (PVC, non-sustained VT, etc.) and marked tachycardia: paclitaxel should be discontinued, and lidocaine should be used. Intravenous lidocaine therapy should be started with 1 - 2 mg/kg/min and, if effective, followed by drip infusion of 1 - 2 mg/min. [Hypotension] The following therapeutic actions may be taken for hypotension: 1) Mild: Fluid therapy should be used, if necessary, for keeping blood pressure. 2) Moderate or severe: Persistent intravenous infusion of dopamine should immediately be started. Doses (5 - 15 ∝g/kg/min) should be adjusted according to the severity. The infusion should be continued until blood pressure is stabilized. If necessary, norepinephrine should be administered. After confirming that blood pressure remains stable, the dose of dopamine should be reduced, or the use of this drug should be discontinued. Date: 25-May-2005 79 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol [Interstitial pneumonia] The following therapeutic measures may be taken for interstitial pneumonia diagnosed with clinical symptoms and diagnostic imaging after failure of antibiotics treatment: It is reported that following treatment is effective: Discontinue the drug therapy, and apply corticosteroid pulse therapy (methylprednisolone 1000mg in 5% glucose solution or saline solution 200mL for intravenous over 1-hour for consecutive three days (1 course). Repeat 3 courses at maximum with an interval of 1 to 2 week. Following prednisolon 40-60 mg/day p.o. with dose reduction every 1 to 2 weeks). Consult with doctors who are expert in respiratory disease in time of need. Date: 25-May-2005 80 1.0 Approved 930010978 2.0 v Paclitaxel CA139387 BMS-181339 Clinical Protocol APPENDIX 10 NATIONAL CANCER INSTITUTE CTC VERSION 2 PDF file can be found at Date: 25-May-2005 81 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 1 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 COMMON TOXICITY CRITERIA (CTC) Grade Adverse Event 0 1 2 3 4 ALLERGY/IMMUNOLOGY Allergic reaction/ hypersensitivity (including drug fever) none transient rash, drug fever <38°C (<100.4°F) urticaria, drug fever ≥38°C (≥100.4°F), and/or asymptomatic bronchospasm symptomatic bronchospasm, requiring parenteral medication(s), with or without urticaria; allergy-related edema/angioedema anaphylaxis Note: Isolated urticaria, in the absence of other manifestations of an allergic or hypersensitivity reaction, is graded in the DERMATOLOGY/SKIN category. Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip) none mild, not requiring treatment moderate, requiring treatment - - Autoimmune reaction none serologic or other evidence of autoimmune reaction but patient is asymptomatic (e.g., vitiligo), all organ function is normal and no treatment is required evidence of autoimmune reaction involving a non- essential organ or function (e.g., hypothyroidism), requiring treatment other than immunosuppressive drugs reversible autoimmune reaction involving function of a major organ or other adverse event (e.g., transient colitis or anemia), requiring short-term immunosuppressive treatment autoimmune reaction causing major grade 4 organ dysfunction; progressive and irreversible reaction; long-term administration of high- dose immuno- suppressive therapy required Also consider Hypothyroidism, Colitis, Hemoglobin, Hemolysis. Serum sickness none - - present - Urticaria is graded in the DERMATOLOGY/SKIN category if it occurs as an isolated symptom. If it occurs with other manifestations of allergic or hypersensitivity reaction, grade as Allergic reaction/hypersensitivity above. Vasculitis none mild, not requiring treatment symptomatic, requiring medication requiring steroids ischemic changes or requiring amputation Allergy/Immunology - Other (Specify, __________) none mild moderate severe life-threatening or disabling AUDITORY/HEARING Conductive hearing loss is graded as Middle ear/hearing in the AUDITORY/HEARING category. Earache is graded in the PAIN category. External auditory canal normal external otitis with erythema or dry desquamation external otitis with moist desquamation external otitis with discharge, mastoiditis necrosis of the canal soft tissue or bone Note: Changes associated with radiation to external ear (pinnae) are graded under Radiation dermatitis in the DERMATOLOGY/SKIN category. Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 82 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 2 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Inner ear/hearing normal hearing loss on audiometry only tinnitus or hearing loss, not requiring hearing aid or treatment tinnitus or hearing loss, correctable with hearing aid or treatment severe unilateral or bilateral hearing loss (deafness), not correctable Middle ear/hearing normal serous otitis without subjective decrease in hearing serous otitis or infection requiring medical intervention; subjective decrease in hearing; rupture of tympanic membrane with discharge otitis with discharge, mastoiditis or conductive hearing loss necrosis of the canal soft tissue or bone Auditory/Hearing - Other (Specify, __________) normal mild moderate severe life-threatening or disabling BLOOD/BONE MARROW Bone marrow cellularity normal for age mildly hypocellular or ≤25% reduction from normal cellularity for age moderately hypocellular or >25 - ≤50% reduction from normal cellularity for age or >2 but <4 weeks to recovery of normal bone marrow cellularity severely hypocellular or >50 - ≤75% reduction in cellularity for age or 4 - 6 weeks to recovery of normal bone marrow cellularity aplasia or >6 weeks to recovery of normal bone marrow cellularity Normal ranges: children (≤18 years) 90% cellularity average younger adults (19-59) 60 - 70% cellularity average older adults (≥60 years) 50% cellularity average Note: Grade Bone marrow cellularity only for changes related to treatment not disease. CD4 count WNL <LLN - 500/mm3 200 - <500/mm3 50 - <200/mm3 <50/mm3 Haptoglobin normal decreased - absent - Hemoglobin (Hgb) WNL <LLN - 10.0 g/dL <LLN - 100 g/L <LLN - 6.2 mmol/L 8.0 - <10.0 g/dL 80 - <100 g/L 4.9 - <6.2 mmol/L 6.5 - <8.0 g/dL 65 - <80 g/L 4.0 - <4.9 mmol/L <6.5 g/dL <65 g/L <4.0 mmol/L For leukemia studies or bone marrow infiltrative/ myelophthisic processes, if specified in the protocol. WNL 10 - <25% decrease from pretreatment 25 - <50% decrease from pretreatment 50 - <75% decrease from pretreatment ≥75% decrease from pretreatment Hemolysis (e.g., immune hemolytic anemia, drug- related hemolysis, other) none only laboratory evidence of hemolysis [e.g., direct antiglobulin test (DAT, Coombs’) schistocytes] evidence of red cell destruction and ≥2gm decrease in hemoglobin, no transfusion requiring transfusion and/or medical intervention (e.g., steroids) catastrophic consequences of hemolysis (e.g., renal failure, hypotension, bronchospasm, emergency splenectomy) Also consider Haptoglobin, Hemoglobin. Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 83 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 3 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Leukocytes (total WBC) WNL <LLN - 3.0 x 109 /L <LLN - 3000/mm3 ≥2.0 - <3.0 x 109 /L ≥2000 - <3000/mm3 ≥1.0 - <2.0 x 109 /L ≥1000 - <2000/mm3 <1.0 x 109 /L <1000/mm3 For BMT studies, if specified in the protocol. WNL ≥2.0 - <3.0 X 109/L ≥2000 - <3000/mm3 ≥1.0 - <2.0 x 109 /L ≥1000 - <2000/mm3 ≥0.5 - <1.0 x 109 /L ≥500 - <1000/mm3 <0.5 x 109 /L <500/mm3 For pediatric BMT studies (using age, race and sex normal values), if specified in the protocol. ≥75 - <100% LLN ≥50 - <75% LLN ≥25 - 50% LLN <25% LLN Lymphopenia WNL <LLN - 1.0 x 109 /L <LLN - 1000/mm3 ≥0.5 - <1.0 x 109 /L ≥500 - <1000/mm3 <0.5 x 109 /L <500/mm3 - For pediatric BMT studies (using age, race and sex normal values), if specified in the protocol. ≥75 - <100%LLN ≥50 - <75%LLN ≥25 - <50%LLN <25%LLN Neutrophils/granulocytes (ANC/AGC) WNL ≥1.5 - <2.0 x 109 /L ≥1500 - <2000/mm3 ≥1.0 - <1.5 x 109 /L ≥1000 - <1500/mm3 ≥0.5 - <1.0 x 109 /L ≥500 - <1000/mm3 <0.5 x 109 /L <500/mm3 For BMT studies, if specified in the protocol. WNL ≥1.0 - <1.5 x 109 /L ≥1000 - <1500/mm3 ≥0.5 - <1.0 x 109 /L ≥500 - <1000/mm3 ≥0.1 - <0.5 x 109 /L ≥100 - <500/mm3 <0.1 x 109 /L <100/mm3 For leukemia studies or bone marrow infiltrative/ myelophthisic process, if specified in the protocol. WNL 10 - <25% decrease from baseline 25 - <50% decrease from baseline 50 - <75% decrease from baseline ≥75% decrease from baseline Platelets WNL <LLN - 75.0 x 109 /L <LLN - 75,000/mm3 ≥50.0 - <75.0 x 109 /L ≥50,000 - <75,000/mm3 ≥10.0 - <50.0 x 109 /L ≥10,000 - <50,000/mm3 <10.0 x 109 /L <10,000/mm3 For BMT studies, if specified in the protocol. WNL ≥50.0 - <75.0 x 109 /L ≥50,000 - <75,000/mm3 ≥20.0 - <50.0 x 109 /L ≥20,000 - <50,000/mm3 ≥10.0 - <20.0 x 109 /L ≥10,000 - <20,000/mm3 <10.0 x 109 /L <10,000/mm3 For leukemia studies or bone marrow infiltrative/ myelophthisic process, if specified in the protocol. WNL 10 - <25% decrease from baseline 25 - <50% decrease from baseline 50 - <75% decrease from baseline ≥75% decrease from baseline Transfusion: Platelets none - - yes platelet transfusions and other measures required to improve platelet increment; platelet transfusion refractoriness associated with life-threatening bleeding. (e.g., HLA or cross matched platelet transfusions) For BMT studies, if specified in the protocol. none 1 platelet transfusion in 24 hours 2 platelet transfusions in 24 hours ≥3 platelet transfusions in 24 hours platelet transfusions and other measures required to improve platelet increment; platelet transfusion refractoriness associated with life-threatening bleeding. (e.g., HLA or cross matched platelet transfusions) Also consider Platelets. Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 84 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 4 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Transfusion: pRBCs none - - yes - For BMT studies, if specified in the protocol. none ≤2 u pRBC in 24 hours elective or planned 3 u pRBC in 24 hours elective or planned ≥4 u pRBC in 24 hours hemorrhage or hemolysis associated with life-threatening anemia; medical intervention required to improve hemoglobin For pediatric BMT studies, if specified in the protocol. none ≤15mL/kg in 24 hours elective or planned >15 - ≤30mL/kg in 24 hours elective or planned >30mL/kg in 24 hours hemorrhage or hemolysis associated with life-threatening anemia; medical intervention required to improve hemoglobin Also consider Hemoglobin. Blood/Bone Marrow - Other (Specify, __________) none mild moderate severe life-threatening or disabling CARDIOVASCULAR (ARRHYTHMIA) Conduction abnormality/ Atrioventricular heart block none asymptomatic, not requiring treatment (e.g., Mobitz type I second-degree AV block, Wenckebach) symptomatic, but not requiring treatment symptomatic and requiring treatment (e.g., Mobitz type II second-degree AV block, third-degree AV block) life-threatening (e.g., arrhythmia associated with CHF, hypotension, syncope, shock) Nodal/junctional arrhythmia/dysrhythmia none asymptomatic, not requiring treatment symptomatic, but not requiring treatment symptomatic and requiring treatment life-threatening (e.g., arrhythmia associated with CHF, hypotension, syncope, shock) Palpitations none present - - - Note: Grade palpitations only in the absence of a documented arrhythmia. Prolonged QTc interval (QTc >0.48 seconds) none asymptomatic, not requiring treatment symptomatic, but not requiring treatment symptomatic and requiring treatment life-threatening (e.g., arrhythmia associated with CHF, hypotension, syncope, shock) Sinus bradycardia none asymptomatic, not requiring treatment symptomatic, but not requiring treatment symptomatic and requiring treatment life-threatening (e.g., arrhythmia associated with CHF, hypotension, syncope, shock) Sinus tachycardia none asymptomatic, not requiring treatment symptomatic, but not requiring treatment symptomatic and requiring treatment of underlying cause - Supraventricular arrhythmias (SVT/atrial fibrillation/ flutter) none asymptomatic, not requiring treatment symptomatic, but not requiring treatment symptomatic and requiring treatment life-threatening (e.g., arrhythmia associated with CHF, hypotension, syncope, shock) Syncope (fainting) is graded in the NEUROLOGY category. Vasovagal episode none - present without loss of consciousness present with loss of consciousness - Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 85 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 5 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Ventricular arrhythmia (PVCs/bigeminy/trigeminy/ ventricular tachycardia) none asymptomatic, not requiring treatment symptomatic, but not requiring treatment symptomatic and requiring treatment life-threatening (e.g., arrhythmia associated with CHF, hypotension, syncope, shock) Cardiovascular/ Arrhythmia - Other (Specify, ___________) none asymptomatic, not requiring treatment symptomatic, but not requiring treatment symptomatic, and requiring treatment of underlying cause life-threatening (e.g., arrhythmia associated with CHF, hypotension, syncope, shock) CARDIOVASCULAR (GENERAL) Acute vascular leak syndrome absent - symptomatic, but not requiring fluid support respiratory compromise or requiring fluids life-threatening; requiring pressor support and/or ventilatory support Cardiac-ischemia/infarction none non-specific T - wave flattening or changes asymptomatic, ST - and T - wave changes suggesting ischemia angina without evidence of infarction acute myocardial infarction Cardiac left ventricular function normal asymptomatic decline of resting ejection fraction of ≥10% but <20% of baseline value; shortening fraction ≥24% but <30% asymptomatic but resting ejection fraction below LLN for laboratory or decline of resting ejection fraction ≥20% of baseline value; <24% shortening fraction CHF responsive to treatment severe or refractory CHF or requiring intubation CNS cerebrovascular ischemia is graded in the NEUROLOGY category. Cardiac troponin I (cTnI) normal - - levels consistent with unstable angina as defined by the manufacturer levels consistent with myocardial infarction as defined by the manufacturer Cardiac troponin T (cTnT) normal ≥0.03 - <0.05 ng/mL ≥0.05 - <0.1 ng/mL ≥0.1 - <0.2 ng/mL ≥0.2 ng/mL Edema none asymptomatic, not requiring therapy symptomatic, requiring therapy symptomatic edema limiting function and unresponsive to therapy or requiring drug discontinuation anasarca (severe generalized edema) Hypertension none asymptomatic, transient increase by >20 mmHg (diastolic) or to >150/100 if previously WNL; not requiring treatment recurrent or persistent or symptomatic increase by >20 mmHg (diastolic) or to >150/100* if previously WNL; not requiring treatment requiring therapy or more intensive therapy than previously hypertensive crisis Note: For pediatric patients, use age and sex appropriate normal values >95th percentile ULN. Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 86 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 6 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Hypotension none changes, but not requiring therapy (including transient orthostatic hypotension) requiring brief fluid replacement or other therapy but not hospitalization; no physiologic consequences requiring therapy and sustained medical attention, but resolves without persisting physiologic consequences shock (associated with acidemia and impairing vital organ function due to tissue hypoperfusion) Also consider Syncope (fainting). Notes: Angina or MI is graded as Cardiac-ischemia/infarction in the CARDIOVASCULAR (GENERAL) category. For pediatric patients, systolic BP 65 mmHg or less in infants up to 1 year old and 70 mmHg or less in children older than 1 year of age, use two successive or three measurements in 24 hours. Myocarditis none - - CHF responsive to treatment severe or refractory CHF Operative injury of vein/artery none primary suture repair for injury, but not requiring transfusion primary suture repair for injury, requiring transfusion vascular occlusion requiring surgery or bypass for injury myocardial infarction; resection of organ (e.g., bowel, limb) Pericardial effusion/ pericarditis none asymptomatic effusion, not requiring treatment pericarditis (rub, ECG changes, and/or chest pain) with physiologic consequences tamponade (drainage or pericardial window required) Peripheral arterial ischemia none - brief episode of ischemia managed non- surgically and without permanent deficit requiring surgical intervention life-threatening or with permanent functional deficit (e.g., amputation) Phlebitis (superficial) none - present - - Notes: Injection site reaction is graded in the DERMATOLOGY/SKIN category. Thrombosis/embolism is graded in the CARDIOVASCULAR (GENERAL) category. Syncope (fainting) is graded in the NEUROLOGY category. Thrombosis/embolism none - deep vein thrombosis, not requiring anticoagulant deep vein thrombosis, requiring anticoagulant therapy embolic event including pulmonary embolism Vein/artery operative injury is graded as Operative injury of vein/artery in the CARDIOVASCULAR (GENERAL) category. Visceral arterial ischemia (non-myocardial) none - brief episode of ischemia managed non- surgically and without permanent deficit requiring surgical intervention life-threatening or with permanent functional deficit (e.g., resection of ileum) Cardiovascular/ General - Other (Specify, ______________) none mild moderate severe life-threatening or disabling Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 87 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 7 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 COAGULATION Note: See the HEMORRHAGE category for grading the severity of bleeding events. DIC (disseminated intravascular coagulation) absent - - laboratory findings present with no bleeding laboratory findings and bleeding Also consider Platelets. Note: Must have increased fibrin split products or D-dimer in order to grade as DIC. Fibrinogen WNL ≥0.75 - <1.0 x LLN ≥0.5 - <0.75 x LLN ≥0.25 - <0.5 x LLN <0.25 x LLN For leukemia studies or bone marrow infiltrative/ myelophthisic process, if specified in the protocol. WNL <20% decrease from pretreatment value or LLN ≥20 - <40% decrease from pretreatment value or LLN ≥40 - <70% decrease from pretreatment value or LLN <50 mg Partial thromboplastin time (PTT) WNL >ULN - ≤1.5 x ULN >1.5 - ≤2 x ULN >2 x ULN - Phlebitis is graded in the CARDIOVASCULAR (GENERAL) category. Prothrombin time (PT) WNL >ULN - ≤1.5 x ULN >1.5 - ≤2 x ULN >2 x ULN - Thrombosis/embolism is graded in the CARDIOVASCULAR (GENERAL) category. Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura/TTP or hemolytic uremic syndrome/HUS) absent - - laboratory findings present without clinical consequences laboratory findings and clinical consequences, (e.g., CNS hemorrhage/ bleeding or thrombosis/ embolism or renal failure) requiring therapeutic intervention For BMT studies, if specified in the protocol. - evidence of RBC destruction (schistocytosis) without clinical consequences evidence of RBC destruction with elevated creatinine (≤3 x ULN) evidence of RBC destruction with creatinine (>3 x ULN) not requiring dialysis evidence of RBC destruction with renal failure requiring dialysis and/or encephalopathy Also consider Hemoglobin, Platelets, Creatinine. Note: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments). Coagulation - Other (Specify, __________) none mild moderate severe life-threatening or disabling CONSTITUTIONAL SYMPTOMS Fatigue (lethargy, malaise, asthenia) none increased fatigue over baseline, but not altering normal activities moderate (e.g., decrease in performance status by 1 ECOG level or 20% Karnofsky or Lansky) or causing difficulty performing some activities severe (e.g., decrease in performance status by ≥2 ECOG levels or 40% Karnofsky or Lansky) or loss of ability to perform some activities bedridden or disabling Note: See Appendix III for performance status scales. Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 88 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 8 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Fever (in the absence of neutropenia, where neutropenia is defined as AGC <1.0 x 109/L) none 38.0 - 39.0°C (100.4 - 102.2°F) 39.1 - 40.0°C (102.3 - 104.0°F ) >40.0°C (>104.0°F ) for <24hrs >40.0°C (>104.0°F ) for >24hrs Also consider Allergic reaction/hypersensitivity. Note: The temperature measurements listed above are oral or tympanic. Hot flashes/flushes are graded in the ENDOCRINE category. Rigors, chills none mild, requiring symptomatic treatment (e.g., blanket) or non- narcotic medication severe and/or prolonged, requiring narcotic medication not responsive to narcotic medication - Sweating (diaphoresis) normal mild and occasional frequent or drenching - - Weight gain <5% 5 - <10% 10 - <20% ≥20% - Also consider Ascites, Edema, Pleural effusion (non-malignant). Weight gain associated with Veno-Occlusive Disease (VOD) for BMT studies, if specified in the protocol. <2% ≥2 - <5% ≥5 - <10% ≥10% or as ascites ≥10% or fluid retention resulting in pulmonary failure Also consider Ascites, Edema, Pleural effusion (non-malignant). Weight loss <5% 5 - <10% 10 - <20% ≥20% - Also consider Vomiting, Dehydration, Diarrhea. Constitutional Symptoms - Other (Specify, __________) none mild moderate severe life-threatening or disabling DERMATOLOGY/SKIN Alopecia normal mild hair loss pronounced hair loss - - Bruising (in absence of grade 3 or 4 thrombocytopenia) none localized or in dependent area generalized - - Note: Bruising resulting from grade 3 or 4 thrombocytopenia is graded as Petechiae/purpura and Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia in the HEMORRHAGE category, not in the DERMATOLOGY/SKIN category. Dry skin normal controlled with emollients not controlled with emollients - - Erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) absent - scattered, but not generalized eruption severe or requiring IV fluids (e.g., generalized rash or painful stomatitis) life-threatening (e.g., exfoliative or ulcerating dermatitis or requiring enteral or parenteral nutritional support) Flushing absent present - - - Hand-foot skin reaction none skin changes or dermatitis without pain (e.g., erythema, peeling) skin changes with pain, not interfering with function skin changes with pain, interfering with function - Injection site reaction none pain or itching or erythema pain or swelling, with inflammation or phlebitis ulceration or necrosis that is severe or prolonged, or requiring surgery - Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 89 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 9 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Nail changes normal discoloration or ridging (koilonychia) or pitting partial or complete loss of nail(s) or pain in nailbeds - - Petechiae is graded in the HEMORRHAGE category. Photosensitivity none painless erythema painful erythema erythema with desquamation - Pigmentation changes (e.g., vitiligo) none localized pigmentation changes generalized pigmentation changes - - Pruritus none mild or localized, relieved spontaneously or by local measures intense or widespread, relieved spontaneously or by systemic measures intense or widespread and poorly controlled despite treatment - Purpura is graded in the HEMORRHAGE category. Radiation dermatitis none faint erythema or dry desquamation moderate to brisk erythema or a patchy moist desquamation, mostly confined to skin folds and creases; moderate edema confluent moist desquamation ≥1.5 cm diameter and not confined to skin folds; pitting edema skin necrosis or ulceration of full thickness dermis; may include bleeding not induced by minor trauma or abrasion Note: Pain associated with radiation dermatitis is graded separately in the PAIN category as Pain due to radiation. Radiation recall reaction (reaction following chemotherapy in the absence of additional radiation therapy that occurs in a previous radiation port) none faint erythema or dry desquamation moderate to brisk erythema or a patchy moist desquamation, mostly confined to skin folds and creases; moderate edema confluent moist desquamation ≥1.5 cm diameter and not confined to skin folds; pitting edema skin necrosis or ulceration of full thickness dermis; may include bleeding not induced by minor trauma or abrasion Rash/desquamation none macular or papular eruption or erythema without associated symptoms macular or papular eruption or erythema with pruritus or other associated symptoms covering <50% of body surface or localized desquamation or other lesions covering <50% of body surface area symptomatic generalized erythroderma or macular, papular or vesicular eruption or desquamation covering ≥50% of body surface area generalized exfoliative dermatitis or ulcerative dermatitis Also consider Allergic reaction/hypersensitivity. Note: Stevens-Johnson syndrome is graded separately as Erythema multiforme in the DERMATOLOGY/SKIN category. Rash/dermatitis associated with high-dose chemotherapy or BMT studies. none faint erythema or dry desquamation moderate to brisk erythema or a patchy moist desquamation, mostly confined to skin folds and creases; moderate edema confluent moist desquamation ≥1.5 cm diameter and not confined to skin folds; pitting edema skin necrosis or ulcera- tion of full thickness dermis; may include spontaneous bleeding not induced by minor trauma or abrasion Rash/desquamation associated with graft versus host disease (GVHD) for BMT studies, if specified in the protocol. None macular or papular eruption or erythema covering <25% of body surface area without associated symptoms macular or papular eruption or erythema with pruritus or other associated symptoms covering ≥25 - <50% of body surface or localized desquamation or other lesions covering ≥25 - <50% of body surface area symptomatic generalized erythroderma or symptomatic macular, papular or vesicular eruption, with bullous formation, or desquamation covering ≥50% of body surface area generalized exfoliative dermatitis or ulcerative dermatitis or bullous formation Also consider Allergic reaction/hypersensitivity. Note: Stevens-Johnson syndrome is graded separately as Erythema multiforme in the DERMATOLOGY/SKIN category. Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 90 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 10 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Urticaria (hives, welts, wheals) none requiring no medication requiring PO or topical treatment or IV medication or steroids for <24 hours requiring IV medication or steroids for ≥24 hours - Wound-infectious none cellulitis superficial infection infection requiring IV antibiotics necrotizing fasciitis Wound-non-infectious none incisional separation incisional hernia fascial disruption without evisceration fascial disruption with evisceration Dermatology/Skin - Other (Specify, ________) none mild moderate severe life-threatening or disabling ENDOCRINE Cushingoid appearance (e.g., moon face, buffalo hump, centripetal obesity, cutaneous striae) absent - present - - Also consider Hyperglycemia, Hypokalemia. Feminization of male absent - - present - Gynecomastia none mild pronounced or painful pronounced or painful and requiring surgery - Hot flashes/flushes none mild or no more than 1 per day moderate and greater than 1 per day - - Hypothyroidism absent asymptomatic,TSH elevated, no therapy given symptomatic or thyroid replacement treatment given patient hospitalized for manifestations of hypothyroidism myxedema coma Masculinization of female absent - - present - SIADH (syndrome of inappropriate antidiuretic hormone) absent - - present - Endocrine - Other (Specify, __________) none mild moderate severe life-threatening or disabling GASTROINTESTINAL Amylase is graded in the METABOLIC/LABORATORY category. Anorexia none loss of appetite oral intake significantly decreased requiring IV fluids requiring feeding tube or parenteral nutrition Ascites (non-malignant) none asymptomatic symptomatic, requiring diuretics symptomatic, requiring therapeutic paracentesis life-threatening physiologic consequences Colitis none - abdominal pain with mucus and/or blood in stool abdominal pain, fever, change in bowel habits with ileus or peritoneal signs, and radiographic or biopsy documentation perforation or requiring surgery or toxic megacolon Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Melena/GI bleeding, Rectal bleeding/hematochezia, Hypotension. Constipation none requiring stool softener or dietary modification requiring laxatives obstipation requiring manual evacuation or enema obstruction or toxic megacolon Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 91 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 11 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Dehydration none dry mucous membranes and/or diminished skin turgor requiring IV fluid replacement (brief) requiring IV fluid replacement (sustained) physiologic consequences requiring intensive care; hemodynamic collapse Also consider Diarrhea, Vomiting, Stomatitis/pharyngitis (oral/pharyngeal mucositis), Hypotension. Diarrhea patients without colostomy: none increase of <4 stools/day over pre- treatment increase of 4-6 stools/day, or nocturnal stools increase of ≥7 stools/day or incontinence; or need for parenteral support for dehydration physiologic consequences requiring intensive care; or hemodynamic collapse patients with a colostomy: none mild increase in loose, watery colostomy output compared with pretreatment moderate increase in loose, watery colostomy output compared with pretreatment, but not interfering with normal activity severe increase in loose, watery colostomy output compared with pretreatment, interfering with normal activity physiologic consequences, requiring intensive care; or hemodynamic collapse Diarrhea associated with graft versus host disease (GVHD) for BMT studies, if specified in the protocol. None >500 - ≤1000mL of diarrhea/day >1000 - ≤1500mL of diarrhea/day >1500mL of diarrhea/day severe abdominal pain with or without ileus For pediatric BMT studies, if specified in the protocol. >5 - ≤10 mL/kg of diarrhea/day >10 - ≤15 mL/kg of diarrhea/day >15 mL/kg of diarrhea/day - Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Pain, Dehydration, Hypotension. Duodenal ulcer (requires radiographic or endoscopic documentation) none - requiring medical management or non- surgical treatment uncontrolled by outpatient medical management; requiring hospitalization perforation or bleeding, requiring emergency surgery Dyspepsia/heartburn none mild moderate severe - Dysphagia, esophagitis, odynophagia (painful swallowing) none mild dysphagia, but can eat regular diet dysphagia, requiring predominantly pureed, soft, or liquid diet dysphagia, requiring IV hydration complete obstruction (cannot swallow saliva) requiring enteral or parenteral nutritional support, or perforation Note: If the adverse event is radiation-related, grade either under Dysphagia-esophageal related to radiation or Dysphagia-pharyngeal related to radiation. Dysphagia-esophageal related to radiation none mild dysphagia, but can eat regular diet dysphagia, requiring predominantly pureed, soft, or liquid diet Dysphagia, requiring feeding tube, IV hydration or hyperalimentation complete obstruction (cannot swallow saliva); ulceration with bleeding not induced by minor trauma or abrasion or perforation Also consider Pain due to radiation, Mucositis due to radiation. Note: Fistula is graded separately as Fistula-esophageal. Dysphagia-pharyngeal related to radiation none mild dysphagia, but can eat regular diet dysphagia, requiring predominantly pureed, soft, or liquid diet dysphagia, requiring feeding tube, IV hydration or hyperalimentation complete obstruction (cannot swallow saliva); ulceration with bleeding not induced by minor trauma or abrasion or perforation Also consider Pain due to radiation, Mucositis due to radiation. Note: Fistula is graded separately as Fistula-pharyngeal. Fistula-esophageal none - - present requiring surgery Fistula-intestinal none - - present requiring surgery Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 92 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 12 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Fistula-pharyngeal none - - present requiring surgery Fistula-rectal/anal none - - present requiring surgery Flatulence none mild moderate - - Gastric ulcer (requires radiographic or endoscopic documentation) none - requiring medical management or non- surgical treatment bleeding without perforation, uncon- trolled by outpatient medical management; requiring hospitalization or surgery perforation or bleeding, requiring emergency surgery Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia. Gastritis none - requiring medical management or non- surgical treatment uncontrolled by out- patient medical management; requiring hospitalization or surgery life-threatening bleeding, requiring emergency surgery Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia. Hematemesis is graded in the HEMORRHAGE category. Hematochezia is graded in the HEMORRHAGE category as Rectal bleeding/hematochezia. Ileus (or neuroconstipation) none - intermittent, not requiring intervention requiring non-surgical intervention requiring surgery Mouth dryness normal mild moderate - - Mucositis Notes: Mucositis not due to radiation is graded in the GASTROINTESTINAL category for specific sites: Colitis, Esophagitis, Gastritis, Stomatitis/pharyngitis (oral/pharyngeal mucositis), and Typhlitis; or the RENAL/GENITOURINARY category for Vaginitis. Radiation-related mucositis is graded as Mucositis due to radiation. Mucositis due to radiation none erythema of the mucosa patchy pseudomembra- nous reaction (patches generally ≤1.5 cm in diameter and non- contiguous) confluent pseudomem- branous reaction (contiguous patches generally >1.5 cm in diameter) necrosis or deep ulceration; may include bleeding not induced by minor trauma or abrasion Also consider Pain due to radiation. Notes: Grade radiation mucositis of the larynx here. Dysphagia related to radiation is also graded as either Dysphagia-esophageal related to radiation or Dysphagia-pharyngeal related to radiation, depending on the site of treatment. Nausea none able to eat oral intake significantly decreased no significant intake, requiring IV fluids - Pancreatitis none - - abdominal pain with pancreatic enzyme elevation complicated by shock (acute circulatory failure) Also consider Hypotension. Note: Amylase is graded in the METABOLIC/LABORATORY category. Pharyngitis is graded in the GASTROINTESTINAL category as Stomatitis/pharyngitis (oral/pharyngeal mucositis). Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 93 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 13 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Proctitis none increased stool frequency, occasional blood-streaked stools or rectal discomfort (including hemorrhoids) not requiring medication increased stool frequency, bleeding, mucus discharge, or rectal discomfort requiring medication; anal fissure increased stool fre- quency/diarrhea requir- ing parenteral support; rectal bleeding requir- ing transfusion; or per- sistent mucus discharge, necessitating pads perforation, bleeding or necrosis or other life- threatening complication requiring surgical intervention (e.g., colostomy) Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Pain due to radiation. Notes: Fistula is graded separately as Fistula-rectal/anal. Proctitis occurring more than 90 days after the start of radiation therapy is graded in the RTOG/EORTC Late Radiation Morbidity Scoring Scheme. (See Appendix IV) Salivary gland changes none slightly thickened saliva; may have slightly altered taste (e.g., metallic); additional fluids may be required thick, ropy, sticky saliva; markedly altered taste; alteration in diet required - acute salivary gland necrosis Sense of smell normal slightly altered markedly altered - - Stomatitis/pharyngitis (oral/pharyngeal mucositis) none painless ulcers, erythema, or mild soreness in the absence of lesions painful erythema, edema, or ulcers, but can eat or swallow painful erythema, edema, or ulcers requiring IV hydration severe ulceration or requires parenteral or enteral nutritional support or prophylactic intubation For BMT studies, if specified in the protocol. none painless ulcers, erythema, or mild soreness in the absence of lesions painful erythema, edema or ulcers but can swallow painful erythema, edema, or ulcers preventing swallowing or requiring hydration or parenteral (or enteral) nutritional support severe ulceration requiring prophylactic intubation or resulting in documented aspiration pneumonia Note: Radiation-related mucositis is graded as Mucositis due to radiation. Taste disturbance (dysgeusia) normal slightly altered markedly altered - - Typhlitis (inflammation of the cecum) none - - abdominal pain, diarrhea, fever, and radiographic or biopsy documentation perforation, bleeding or necrosis or other life- threatening complication requiring surgical intervention (e.g., colostomy) Also consider Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Hypotension, Febrile neutropenia. Vomiting none 1 episode in 24 hours over pretreatment 2-5 episodes in 24 hours over pretreatment ≥6 episodes in 24 hours over pretreatment; or need for IV fluids requiring parenteral nutrition; or physiologic consequences requiring intensive care; hemodynamic collapse Also consider Dehydration. Weight gain is graded in the CONSTITUTIONAL SYMPTOMS category. Weight loss is graded in the CONSTITUTIONAL SYMPTOMS category. Gastrointestinal - Other (Specify, __________) none mild moderate severe life-threatening or disabling Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 94 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 14 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 HEMORRHAGE Notes: Transfusion in this section refers to pRBC infusion. For any bleeding with grade 3 or 4 platelets (<50,000), always grade Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia. Also consider Platelets, Transfusion: pRBCs, and Transfusion: platelets in addition to grading severity by grading the site or type of bleeding. If the site or type of Hemorrhage/bleeding is listed, also use the grading that incorporates the site of bleeding: CNS Hemorrhage/bleeding, Hematuria, Hematemesis, Hemoptysis, Hemorrhage/bleeding with surgery, Melena/lower GI bleeding, Petechiae/purpura (Hemorrhage/bleeding into skin), Rectal bleeding/hematochezia, Vaginal bleeding. If the platelet count is ≥50,000 and the site or type of bleeding is listed, grade the specific site. If the site or type is not listed and the platelet count is ≥50,000, grade Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia and specify the site or type in the OTHER category. Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia none mild without transfusion requiring transfusion catastrophic bleeding, requiring major non- elective intervention Also consider Platelets, Hemoglobin, Transfusion: platelets, Transfusion: pRBCs, site or type of bleeding. If the site is not listed, grade as Hemorrhage-Other (Specify site, ___________). Note: This adverse event must be graded for any bleeding with grade 3 or 4 thrombocytopenia. Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia none mild without transfusion requiring transfusion catastrophic bleeding requiring major non- elective intervention Also consider Platelets, Hemoglobin, Transfusion: platelets, Transfusion: pRBCs, Hemorrhage - Other (Specify site, ___________). Note: Bleeding in the absence of grade 3 or 4 thrombocytopenia is graded here only if the specific site or type of bleeding is not listed elsewhere in the HEMORRHAGE category. Also grade as Other in the HEMORRHAGE category. CNS hemorrhage/bleeding none - - bleeding noted on CT or other scan with no clinical consequences hemorrhagic stroke or hemorrhagic vascular event (CVA) with neurologic signs and symptoms Epistaxis none mild without transfusion - requiring transfusion catastrophic bleeding, requiring major non- elective intervention Hematemesis none mild without transfusion - requiring transfusion catastrophic bleeding, requiring major non- elective intervention Hematuria (in the absence of vaginal bleeding) none microscopic only intermittent gross bleeding, no clots persistent gross bleeding or clots; may require catheterization or instrumentation, or transfusion open surgery or necrosis or deep bladder ulceration Hemoptysis none mild without transfusion - requiring transfusion catastrophic bleeding, requiring major non- elective intervention Hemorrhage/bleeding associated with surgery none mild without transfusion - requiring transfusion catastrophic bleeding, requiring major non- elective intervention Note: Expected blood loss at the time of surgery is not graded as an adverse event. Melena/GI bleeding none mild without transfusion - requiring transfusion catastrophic bleeding, requiring major non- elective intervention Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 95 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 15 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Petechiae/purpura (hemorrhage/bleeding into skin or mucosa) none rare petechiae of skin petechiae or purpura in dependent areas of skin generalized petechiae or purpura of skin or petechiae of any mucosal site - Rectal bleeding/ hematochezia none mild without transfusion or medication persistent, requiring medication (e.g., steroid suppositories) and/or break from radiation treatment requiring transfusion catastrophic bleeding, requiring major non- elective intervention Vaginal bleeding none spotting, requiring <2 pads per day requiring ≥2 pads per day, but not requiring transfusion requiring transfusion catastrophic bleeding, requiring major non- elective intervention Hemorrhage - Other (Specify site, ___________) none mild without transfusion - requiring transfusion catastrophic bleeding, requiring major non- elective intervention HEPATIC Alkaline phosphatase WNL >ULN - 2.5 x ULN >2.5 - 5.0 x ULN >5.0 - 20.0 x ULN >20.0 x ULN Bilirubin WNL >ULN - 1.5 x ULN >1.5 - 3.0 x ULN >3.0 - 10.0 x ULN >10.0 x ULN Bilirubin associated with graft versus host disease (GVHD) for BMT studies, if specified in the protocol. normal ≥2 - <3 mg/100 mL ≥3 - <6 mg/100 mL ≥6 - <15 mg/100 mL ≥15 mg/100 mL GGT (γ - Glutamyl transpeptidase) WNL >ULN - 2.5 x ULN >2.5 - 5.0 x ULN >5.0 - 20.0 x ULN >20.0 x ULN Hepatic enlargement absent - - present - Note: Grade Hepatic enlargement only for treatment related adverse event including Veno-Occlusive Disease. Hypoalbuminemia WNL <LLN - 3 g/dL ≥2 - <3 g/dL <2 g/dL - Liver dysfunction/ failure (clinical) normal - - asterixis encephalopathy or coma Portal vein flow normal - decreased portal vein flow reversal/retrograde portal vein flow - SGOT (AST) (serum glutamic oxaloacetic transaminase) WNL >ULN - 2.5 x ULN >2.5 - 5.0 x ULN >5.0 - 20.0 x ULN >20.0 x ULN SGPT (ALT) (serum glutamic pyruvic transaminase) WNL >ULN - 2.5 x ULN >2.5 - 5.0 x ULN >5.0 - 20.0 x ULN >20.0 x ULN Hepatic - Other (Specify, __________) none mild moderate severe life-threatening or disabling INFECTION/FEBRILE NEUTROPENIA Catheter-related infection none mild, no active treatment moderate, localized infection, requiring local or oral treatment severe, systemic infection, requiring IV antibiotic or antifungal treatment or hospitalization life-threatening sepsis (e.g., septic shock) Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 96 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 16 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infection) none - - Present Life-threatening sepsis (e.g., septic shock) (ANC <1.0 x 109/L, fever ≥38.5°C) Also consider Neutrophils. Note: Hypothermia instead of fever may be associated with neutropenia and is graded here. Infection (documented clinically or microbiologically) with grade 3 or 4 neutropenia none - - present life-threatening sepsis (e.g., septic shock) (ANC <1.0 x 109/L) Also consider Neutrophils. Notes: Hypothermia instead of fever may be associated with neutropenia and is graded here. In the absence of documented infection grade 3 or 4 neutropenia with fever is graded as Febrile neutropenia. Infection with unknown ANC none - - present life-threatening sepsis (e.g., septic shock) Note: This adverse event criterion is used in the rare case when ANC is unknown. Infection without neutropenia none mild, no active treatment moderate, localized infection, requiring local or oral treatment severe, systemic infection, requiring IV antibiotic or antifungal treatment, or hospitalization life-threatening sepsis (e.g., septic shock) Also consider Neutrophils. Wound-infectious is graded in the DERMATOLOGY/SKIN category. Infection/Febrile Neutropenia - Other (Specify, __________) none mild moderate severe life-threatening or disabling LYMPHATICS Lymphatics normal mild lymphedema moderate lymphedema requiring compression; lymphocyst severe lymphedema limiting function; lymphocyst requiring surgery severe lymphedema limiting function with ulceration Lymphatics - Other (Specify, __________) none mild moderate severe life-threatening or disabling METABOLIC/LABORATORY Acidosis (metabolic or respiratory) normal pH <normal, but ≥7.3 - pH <7.3 pH <7.3 with life- threatening physiologic consequences Alkalosis (metabolic or respiratory) normal pH >normal, but ≤7.5 - pH >7.5 pH >7.5 with life- threatening physiologic consequences Amylase WNL >ULN - 1.5 x ULN >1.5 - 2.0 x ULN >2.0 - 5.0 x ULN >5.0 x ULN Bicarbonate WNL <LLN - 16 mEq/dL 11 - 15 mEq/dL 8 - 10 mEq/dL <8 mEq/dL Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 97 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 17 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 CPK (creatine phosphokinase) WNL >ULN - 2.5 x ULN >2.5 - 5 x ULN >5 - 10 x ULN >10 x ULN Hypercalcemia WNL >ULN - 11.5 mg/dL >ULN - 2.9 mmol/L >11.5 - 12.5 mg/dL >2.9 - 3.1 mmol/L >12.5 - 13.5 mg/dL >3.1 - 3.4 mmol/L >13.5 mg/dL >3.4 mmol/L Hypercholesterolemia WNL >ULN - 300 mg/dL >ULN - 7.75 mmol/L >300 - 400 mg/dL >7.75 - 10.34 mmol/L >400 - 500 mg/dL >10.34 - 12.92 mmol/L >500 mg/dL >12.92 mmol/L Hyperglycemia WNL >ULN - 160 mg/dL >ULN - 8.9 mmol/L >160 - 250 mg/dL >8.9 - 13.9 mmol/L >250 - 500 mg/dL >13.9 - 27.8 mmol/L >500 mg/dL >27.8 mmol/L or acidosis Hyperkalemia WNL >ULN - 5.5 mmol/L >5.5 - 6.0 mmol/L >6.0 - 7.0 mmol/L >7.0 mmol/L Hypermagnesemia WNL >ULN - 3.0 mg/dL >ULN - 1.23 mmol/L - >3.0 - 8.0 mg/dL >1.23 - 3.30 mmol/L >8.0 mg/dL >3.30 mmol/L Hypernatremia WNL >ULN - 150 mmol/L >150 - 155 mmol/L >155 - 160 mmol/L >160 mmol/L Hypertriglyceridemia WNL >ULN - 2.5 x ULN >2.5 - 5.0 x ULN >5.0 - 10 x ULN >10 x ULN Hyperuricemia WNL >ULN - ≤10 mg/dL ≤0.59 mmol/L without physiologic consequences - >ULN - ≤10 mg/dL ≤0.59 mmol/L with physiologic consequences >10 mg/dL >0.59 mmol/L Also consider Tumor lysis syndrome, Renal failure, Creatinine, Hyperkalemia. Hypocalcemia WNL <LLN - 8.0 mg/dL <LLN - 2.0 mmol/L 7.0 - <8.0 mg/dL 1.75 - <2.0 mmol/L 6.0 - <7.0 mg/dL 1.5 - <1.75 mmol/L <6.0 mg/dL <1.5 mmol/L Hypoglycemia WNL <LLN - 55 mg/dL <LLN - 3.0 mmol/L 40 - <55 mg/dL 2.2 - <3.0 mmol/L 30 - <40 mg/dL 1.7 - <2.2 mmol/L <30 mg/dL <1.7 mmol/L Hypokalemia WNL <LLN - 3.0 mmol/L - 2.5 - <3.0 mmol/L <2.5 mmol/L Hypomagnesemia WNL <LLN - 1.2 mg/dL <LLN - 0.5 mmol/L 0.9 - <1.2 mg/dL 0.4 - <0.5 mmol/L 0.7 - <0.9 mg/dL 0.3 - <0.4 mmol/L <0.7 mg/dL <0.3 mmol/L Hyponatremia WNL <LLN - 130 mmol/L - 120 - <130 mmol/L <120 mmol/L Hypophosphatemia WNL <LLN -2.5 mg/dL <LLN - 0.8 mmol/L ≥2.0 - <2.5 mg/dL ≥0.6 - <0.8 mmol/L ≥1.0 - <2.0 mg/dL ≥0.3 - <0.6 mmol/L <1.0 mg/dL <0.3 mmol/L Hypothyroidism is graded in the ENDOCRINE category. Lipase WNL >ULN - 1.5 x ULN >1.5 - 2.0 x ULN >2.0 - 5.0 x ULN >5.0 x ULN Metabolic/Laboratory - Other (Specify, __________) none mild moderate severe life-threatening or disabling MUSCULOSKELETAL Arthralgia is graded in the PAIN category. Arthritis none mild pain with inflammation, erythema or joint swelling but not interfering with function moderate pain with inflammation, erythema, or joint swelling interfering with function, but not interfering with activities of daily living severe pain with inflammation, erythema, or joint swelling and interfering with activities of daily living disabling Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 98 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 18 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Muscle weakness (not due to neuropathy) normal asymptomatic with weakness on physical exam symptomatic and interfering with function, but not interfering with activities of daily living symptomatic and interfering with activities of daily living bedridden or disabling Myalgia [tenderness or pain in muscles] is graded in the PAIN category. Myositis (inflammation/damage of muscle) none mild pain, not interfering with function pain interfering with function, but not interfering with activities of daily living pain interfering with function and interfering with activities of daily living bedridden or disabling Also consider CPK. Note: Myositis implies muscle damage (i.e., elevated CPK). Osteonecrosis (avascular necrosis) none asymptomatic and detected by imaging only symptomatic and interfering with function, but not interfering with activities of daily living symptomatic and interfering with activities of daily living symptomatic; or disabling Musculoskeletal - Other (Specify, __________) none mild moderate severe life-threatening or disabling NEUROLOGY Aphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category. Arachnoiditis/meningismus/ radiculitis absent mild pain not interfering with function moderate pain interfering with function, but not interfering with activities of daily living severe pain interfering with activities of daily living unable to function or perform activities of daily living; bedridden; paraplegia Also consider Headache, Vomiting, Fever. Ataxia (incoordination) normal asymptomatic but abnormal on physical exam, and not interfering with function mild symptoms interfering with function, but not interfering with activities of daily living moderate symptoms interfering with activities of daily living bedridden or disabling CNS cerebrovascular ischemia none - - transient ischemic event or attack (TIA) permanent event (e.g., cerebral vascular accident) CNS hemorrhage/bleeding is graded in the HEMORRHAGE category. Cognitive disturbance/ learning problems none cognitive disability; not interfering with work/school performance; preservation of intelligence cognitive disability; interfering with work/school performance; decline of 1 SD (Standard Deviation) or loss of developmental milestones cognitive disability; resulting in significant impairment of work/school performance; cognitive decline >2 SD inability to work/frank mental retardation Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 99 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 19 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Confusion normal confusion or disorientation or attention deficit of brief duration; resolves spontaneously with no sequelae confusion or disorientation or attention deficit interfering with function, but not interfering with activities of daily living confusion or delirium interfering with activities of daily living harmful to others or self; requiring hospitalization Cranial neuropathy is graded in the NEUROLOGY category as Neuropathy-cranial. Delusions normal - - present toxic psychosis Depressed level of consciousness normal somnolence or sedation not interfering with function somnolence or sedation interfering with function, but not interfering with activities of daily living obtundation or stupor; difficult to arouse; interfering with activities of daily living coma Note: Syncope (fainting) is graded in the NEUROLOGY category. Dizziness/lightheadedness none not interfering with function interfering with function, but not interfering with activities of daily living interfering with activities of daily living bedridden or disabling Dysphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category. Extrapyramidal/ involuntary movement/ restlessness none mild involuntary movements not interfering with function moderate involuntary movements interfering with function, but not interfering with activities of daily living severe involuntary movements or torticollis interfering with activities of daily living bedridden or disabling Hallucinations normal - - present toxic psychosis Headache is graded in the PAIN category. Insomnia normal occasional difficulty sleeping not interfering with function difficulty sleeping interfering with function, but not interfering with activities of daily living frequent difficulty sleeping, interfering with activities of daily living - Note: This adverse event is graded when insomnia is related to treatment. If pain or other symptoms interfere with sleep do NOT grade as insomnia. Irritability (children <3 years of age) normal mild; easily consolable moderate; requiring increased attention severe; inconsolable - Leukoencephalopathy associated radiological findings none mild increase in SAS (subarachnoid space) and/or mild ventriculomegaly; and/or small (+/- multiple) focal T2 hyperintensities, involving periventricular white matter or <1/3 of susceptible areas of cerebrum moderate increase in SAS; and/or moderate ventriculomegaly; and/or focal T2 hyperintensities extending into centrum ovale; or involving 1/3 to 2/3 of susceptible areas of cerebrum severe increase in SAS; severe ventriculomegaly; near total white matter T2 hyperintensities or diffuse low attenuation (CT); focal white matter necrosis (cystic) severe increase in SAS; severe ventriculomegaly; diffuse low attenuation with calcification (CT); diffuse white matter necrosis (MRI) Memory loss normal memory loss not interfering with function memory loss interfering with function, but not interfering with activities of daily living memory loss interfering with activities of daily living amnesia Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 100 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 20 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Mood alteration-anxiety, agitation normal mild mood alteration not interfering with function moderate mood alteration interfering with function, but not interfering with activities of daily living severe mood alteration interfering with activities of daily living suicidal ideation or danger to self Mood alteration-depression normal mild mood alteration not interfering with function moderate mood alteration interfering with function, but not interfering with activities of daily living severe mood alteration interfering with activities of daily living suicidal ideation or danger to self Mood alteration-euphoria normal mild mood alteration not interfering with function moderate mood alteration interfering with function, but not interfering with activities of daily living severe mood alteration interfering with activities of daily living danger to self Neuropathic pain is graded in the PAIN category. Neuropathy-cranial absent - present, not interfering with activities of daily living present, interfering with activities of daily living life-threatening, disabling Neuropathy-motor normal subjective weakness but no objective findings mild objective weakness interfering with function, but not interfering with activities of daily living objective weakness interfering with activities of daily living paralysis Neuropathy-sensory normal loss of deep tendon reflexes or paresthesia (including tingling) but not interfering with function objective sensory loss or paresthesia (including tingling), interfering with function, but not interfering with activities of daily living sensory loss or paresthesia interfering with activities of daily living permanent sensory loss that interferes with function Nystagmus absent present - - - Also consider Vision-double vision. Personality/behavioral normal change, but not disruptive to patient or family disruptive to patient or family disruptive to patient and family; requiring mental health intervention harmful to others or self; requiring hospitalization Pyramidal tract dysfunction (e.g., ↑ tone, hyperreflexia, positive Babinski, ↓ fine motor coordination) normal asymptomatic with abnormality on physical examination symptomatic or interfering with function but not interfering with activities of daily living interfering with activities of daily living bedridden or disabling; paralysis Seizure(s) none - seizure(s) self-limited and consciousness is preserved seizure(s) in which consciousness is altered seizures of any type which are prolonged, repetitive, or difficult to control (e.g., status epilepticus, intractable epilepsy) Speech impairment (e.g., dysphasia or aphasia) normal - awareness of receptive or expressive dysphasia, not impairing ability to communicate receptive or expressive dysphasia, impairing ability to communicate inability to communicate Syncope (fainting) absent - - present - Also consider CARDIOVASCULAR (ARRHYTHMIA), Vasovagal episode, CNS cerebrovascular ischemia. Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 101 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 21 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Tremor none mild and brief or intermittent but not interfering with function moderate tremor interfering with function, but not interfering with activities of daily living severe tremor interfering with activities of daily living - Vertigo none not interfering with function interfering with function, but not interfering with activities of daily living interfering with activities of daily living bedridden or disabling Neurology - Other (Specify, __________) none mild moderate severe life-threatening or disabling OCULAR/VISUAL Cataract none asymptomatic symptomatic, partial visual loss symptomatic, visual loss requiring treatment or interfering with function - Conjunctivitis none abnormal ophthalmologic changes, but asymptomatic or symptomatic without visual impairment (i.e., pain and irritation) symptomatic and interfering with function, but not interfering with activities of daily living symptomatic and interfering with activities of daily living - Dry eye normal mild, not requiring treatment moderate or requiring artificial tears - - Glaucoma none increase in intraocular pressure but no visual loss increase in intraocular pressure with retinal changes visual impairment unilateral or bilateral loss of vision (blindness) Keratitis (corneal inflammation/ corneal ulceration) none abnormal ophthalmologic changes but asymptomatic or symptomatic without visual impairment (i.e., pain and irritation) symptomatic and interfering with function, but not interfering with activities of daily living symptomatic and interfering with activities of daily living unilateral or bilateral loss of vision (blindness) Tearing (watery eyes) none mild: not interfering with function moderate: interfering with function, but not interfering with activities of daily living interfering with activities of daily living - Vision-blurred vision normal - symptomatic and interfering with function, but not interfering with activities of daily living symptomatic and interfering with activities of daily living - Vision-double vision (diplopia) normal - symptomatic and interfering with function, but not interfering with activities of daily living symptomatic and interfering with activities of daily living - Vision-flashing lights/floaters normal mild, not interfering with function symptomatic and interfering with function, but not interfering with activities of daily living symptomatic and interfering with activities of daily living - Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 102 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 22 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Vision-night blindness (nyctalopia) normal abnormal electro- retinography but asymptomatic symptomatic and interfering with function, but not interfering with activities of daily living symptomatic and interfering with activities of daily living - Vision-photophobia normal - symptomatic and interfering with function, but not interfering with activities of daily living symptomatic and interfering with activities of daily living - Ocular/Visual - Other (Specify, __________) normal mild moderate severe unilateral or bilateral loss of vision (blindness) PAIN Abdominal pain or cramping none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling Arthralgia (joint pain) none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling Arthritis (joint pain with clinical signs of inflammation) is graded in the MUSCULOSKELETAL category. Bone pain none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling Chest pain (non-cardiac and non- pleuritic) none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling Dysmenorrhea none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling Dyspareunia none mild pain not interfering with function moderate pain interfering with sexual activity severe pain preventing sexual activity - Dysuria is graded in the RENAL/GENITOURINARY category. Earache (otalgia) none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling Headache none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 103 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 23 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Hepatic pain none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling Myalgia (muscle pain) none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling Neuropathic pain (e.g., jaw pain, neurologic pain, phantom limb pain, post-infectious neuralgia, or painful neuropathies) none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling Pain due to radiation none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling Pelvic pain none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling Pleuritic pain none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling Rectal or perirectal pain (proctalgia) none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling Tumor pain (onset or exacerbation of tumor pain due to treatment) none mild pain not interfering with function moderate pain: pain or analgesics interfering with function, but not interfering with activities of daily living severe pain: pain or analgesics severely interfering with activities of daily living disabling Tumor flare is graded in the SYNDROME category. Pain - Other (Specify, __________) none mild moderate severe disabling PULMONARY Adult Respiratory Distress Syndrome (ARDS) absent - - - present Apnea none - - present requiring intubation Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 104 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 24 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Carbon monoxide diffusion capacity (DLCO) ≥90% of pretreatment or normal value ≥75 - <90% of pretreatment or normal value ≥50 - <75% of pretreatment or normal value ≥25 - <50% of pretreatment or normal value <25% of pretreatment or normal value Cough absent mild, relieved by non- prescription medication requiring narcotic antitussive severe cough or coughing spasms, poorly controlled or unresponsive to treatment - Dyspnea (shortness of breath) normal - dyspnea on exertion dyspnea at normal level of activity dyspnea at rest or requiring ventilator support FEV1 ≥90% of pretreatment or normal value ≥75 - <90% of pretreatment or normal value ≥50 - <75% of pretreatment or normal value ≥25 - <50% of pretreatment or normal value <25% of pretreatment or normal value Hiccoughs (hiccups, singultus) none mild, not requiring treatment moderate, requiring treatment severe, prolonged, and refractory to treatment - Hypoxia normal - decreased O2 saturation with exercise decreased O2 saturation at rest, requiring supplemental oxygen decreased O2 saturation, requiring pressure support (CPAP) or assisted ventilation Pleural effusion (non-malignant) none asymptomatic and not requiring treatment symptomatic, requiring diuretics symptomatic, requiring O2 or therapeutic thoracentesis life-threatening (e.g., requiring intubation) Pleuritic pain is graded in the PAIN category. Pneumonitis/pulmonary infiltrates none radiographic changes but asymptomatic or symptoms not requiring steroids radiographic changes and requiring steroids or diuretics radiographic changes and requiring oxygen radiographic changes and requiring assisted ventilation Pneumothorax none no intervention required chest tube required sclerosis or surgery required life-threatening Pulmonary embolism is graded as Thrombosis/embolism in the CARDIOVASCULAR (GENERAL) category. Pulmonary fibrosis none radiographic changes, but asymptomatic or symptoms not requiring steroids requiring steroids or diuretics requiring oxygen requiring assisted ventilation Note: Radiation-related pulmonary fibrosis is graded in the RTOG/EORTC Late Radiation Morbidity Scoring Scheme-Lung. (See Appendix IV) Voice changes/stridor/larynx (e.g., hoarseness, loss of voice, laryngitis) normal mild or intermittent hoarseness persistent hoarseness, but able to vocalize; may have mild to moderate edema whispered speech, not able to vocalize; may have marked edema marked dyspnea/stridor requiring tracheostomy or intubation Notes: Cough from radiation is graded as cough in the PULMONARY category. Radiation-related hemoptysis from larynx/pharynx is graded as Grade 4 Mucositis due to radiation in the GASTROINTESTINAL category. Radiation- related hemoptysis from the thoracic cavity is graded as Grade 4 Hemoptysis in the HEMORRHAGE category. Pulmonary - Other (Specify, __________) none mild moderate severe life-threatening or disabling Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 105 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 25 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 RENAL/GENITOURINARY Bladder spasms absent mild symptoms, not requiring intervention symptoms requiring antispasmodic severe symptoms requiring narcotic - Creatinine WNL >ULN - 1.5 x ULN >1.5 - 3.0 x ULN >3.0 - 6.0 x ULN >6.0 x ULN Note: Adjust to age-appropriate levels for pediatric patients. Dysuria (painful urination) none mild symptoms requiring no intervention symptoms relieved with therapy symptoms not relieved despite therapy - Fistula or GU fistula (e.g., vaginal, vesicovaginal) none - - requiring intervention requiring surgery Hemoglobinuria - present - - - Hematuria (in the absence of vaginal bleeding) is graded in the HEMORRHAGE category. Incontinence none with coughing, sneezing, etc. spontaneous, some control no control (in the absence of fistula) - Operative injury to bladder and/or ureter none - injury of bladder with primary repair sepsis, fistula, or obstruction requiring secondary surgery; loss of one kidney; injury requiring anastomosis or re-implantation septic obstruction of both kidneys or vesicovaginal fistula requiring diversion Proteinuria normal or <0.15 g/24 hours 1+ or 0.15 - 1.0 g/24 hours 2+ to 3+ or 1.0 - 3.5 g/24 hours 4+ or >3.5 g/24 hours nephrotic syndrome Note: If there is an inconsistency between absolute value and dip stick reading, use the absolute value for grading. Renal failure none - - requiring dialysis, but reversible requiring dialysis and irreversible Ureteral obstruction none unilateral, not requiring surgery - bilateral, not requiring surgery stent, nephrostomy tube, or surgery Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) none asymptomatic, not requiring treatment mild, reversible and manageable with oral replacement reversible but requiring IV replacement irreversible, requiring continued replacement Also consider Acidosis, Bicarbonate, Hypocalcemia, Hypophosphatemia. Urinary frequency/urgency normal increase in frequency or nocturia up to 2 x normal increase >2 x normal but <hourly hourly or more with urgency, or requiring catheter - Urinary retention normal hesitancy or dribbling, but no significant residual urine; retention occurring during the immediate postoperative period hesitancy requiring medication or occasional in/out catheterization (<4 x per week), or operative bladder atony requiring indwelling catheter beyond immediate postoperative period but for <6 weeks requiring frequent in/out catheterization (≥4 x per week) or urological intervention (e.g., TURP, suprapubic tube, urethrotomy) bladder rupture Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 106 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 26 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Urine color change (not related to other dietary or physiologic cause e.g., bilirubin, concentrated urine, hematuria) normal asymptomatic, change in urine color - - - Vaginal bleeding is graded in the HEMORRHAGE category. Vaginitis (not due to infection) none mild, not requiring treatment moderate, relieved with treatment severe, not relieved with treatment, or ulceration not requiring surgery ulceration requiring surgery Renal/Genitourinary - Other (Specify, __________) none mild moderate severe life-threatening or disabling SECONDARY MALIGNANCY Secondary Malignancy - Other (Specify type, __________) excludes metastasis from initial primary none - - - present SEXUAL/REPRODUCTIVE FUNCTION Dyspareunia is graded in the PAIN category. Dysmenorrhea is graded in the PAIN category. Erectile impotence normal mild (erections impaired but satisfactory) moderate (erections impaired, unsatisfactory for intercourse) no erections - Female sterility normal - - sterile - Feminization of male is graded in the ENDOCRINE category. Irregular menses (change from baseline) normal occasionally irregular or lengthened interval, but continuing menstrual cycles very irregular, but continuing menstrual cycles persistent amenorrhea - Libido normal decrease in interest severe loss of interest - - Male infertility - - oligospermia (low sperm count) azoospermia (no sperm) - Masculinization of female is graded in the ENDOCRINE category. Vaginal dryness normal mild requiring treatment and/or interfering with sexual function, dyspareunia - - Sexual/Reproductive Function - Other (Specify, __________) none mild moderate severe disabling SYNDROMES (not included in previous categories) Acute vascular leak syndrome is graded in the CARDIOVASCULAR (GENERAL) category. ARDS (Adult Respiratory Distress Syndrome) is graded in the PULMONARY category. Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 107 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 27 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Grade Adverse Event 0 1 2 3 4 Autoimmune reactions are graded in the ALLERGY/IMMUNOLOGY category. DIC (disseminated intravascular coagulation) is graded in the COAGULATION category. Fanconi’s syndrome is graded as Urinary electrolyte wasting in the RENAL/GENITOURINARY category. Renal tubular acidosis is graded as Urinary electrolyte wasting in the RENAL/GENITOURINARY category. Stevens-Johnson syndrome (erythema multiforme) is graded in the DERMATOLOGY/SKIN category. SIADH (syndrome of inappropriate antidiuretic hormone) is graded in the ENDOCRINE category. Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura/TTP or hemolytic uremic syndrome/HUS) is graded in the COAGULATION category. Tumor flare none mild pain not interfering with function moderate pain; pain or analgesics interfering with function, but not interfering with activities of daily living severe pain; pain or analgesics interfering with function and interfering with activities of daily living Disabling Also consider Hypercalcemia. Note: Tumor flare is characterized by a constellation of symptoms and signs in direct relation to initiation of therapy (e.g., anti-estrogens/androgens or additional hormones). The symptoms/signs include tumor pain, inflammation of visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte disturbances. Tumor lysis syndrome absent - - present - Also consider Hyperkalemia, Creatinine. Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) is graded in the RENAL/GENITOURINARY category. Syndromes - Other (Specify, __________) none mild moderate severe life-threatening or disabling Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 108 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 28 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Appendix I Adverse Event Module To be implemented at the request of the study sponsor or principal investigator in the protocol or by protocol amendment when more detailed information is considered pertinent. Adverse Event: Date of Treatment: Course Number: Date of onset: Grade at onset: Date of first change in grade: Grade: Date of next change in grade: Grade: Date of next change in grade: Grade: Date of next change in grade: Grade: Date of next change in grade: Grade: Date of next change in grade: Grade: Did adverse event resolve? Yes______ No______ If so, date of resolution of adverse event: Date of last observation (if prior to recovery): Reason(s) observations stopped (if prior to recovery): Was patient retreated? Yes______ No______ If yes, was treatment delayed for recovery? Yes______ No______ Date of next treatment? Dose reduced for next treatment? Yes______ No______ Additional Comments: ________________________________________________________________________________________________________ ________________________________________________________________________________________________________ If module is being activated for new adverse event not currently in CTC, please provide definitions for adverse event grading: Grade 0 = ____________________________________________________________________ Grade 1 = ____________________________________________________________________ Grade 2 = ____________________________________________________________________ Grade 3 = ____________________________________________________________________ Grade 4 = ____________________________________________________________________ Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 109 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 29 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Appendix II Infection Module To be implemented at the request of the study sponsor or principal investigator in the protocol or by protocol amendment when more detailed information is considered pertinent. 1. Use the Common Toxicity Criteria definitions to grade the severity of the infection. 2. Specify type of infection from the following (CHOOSE ONE): BACTERIAL FUNGAL PROTOZOAL VIRAL UNKNOWN 3. Specify site of infection from the following (CHOOSE ALL THAT APPLY): BLOOD CULTURE POSITIVE BONE INFECTION CATHETER (intravenous) CATHETER (intravenous), tunnel infection CENTRAL NERVOUS SYSTEM INFECTION EAR INFECTION EYE INFECTION GASTROINTESTINAL INFECTION ORAL INFECTION PNEUMONIA SKIN INFECTION UPPER RESPIRATORY INFECTION URINARY TRACT INFECTION VAGINAL INFECTION INFECTION, not otherwise specified (Specify site, __________) 4. Specify organism, if known: _______________. 5. Prophylactic antibiotic, antifungal, or antiviral therapy administration Yes_______ No_______ If prophylaxis was given prior to infection, please specify below: Antibiotic prophylaxis _____________________________________________________ Antifungal prophylaxis ____________________________________________________ Antiviral prophylaxis ______________________________________________________ Other prophylaxis ________________________________________________________ Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 110 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 30 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Appendix III Performance Status Scales/Scores PERFORMANCE STATUS CRITERIA Karnofsky and Lansky performance scores are intended to be multiples of 10. ECOG (Zubrod) Karnofsky Lansky Score Description Score Description Score Description 100 Normal, no complaints, no evidence of disease. 100 Fully active, normal. 0 Fully active, able to carry on all pre-disease performance without restriction. 90 Able to carry on normal activity; minor signs or symptoms of disease. 90 Minor restrictions in physically strenuous activity. 80 Normal activity with effort; some signs or symptoms of disease. 80 Active, but tires more quickly 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. 70 Cares for self, unable to carry on normal activity or do active work. 70 Both greater restriction of and less time spent in play activity. 60 Requires occasional assistance, but is able to care for most of his/her needs. 60 Up and around, but minimal active play; keeps busy with quieter activities. 2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours. 50 Requires considerable assistance and frequent medical care. 50 Gets dressed, but lies around much of the day; no active play; able to participate in all quiet play and activities. 40 Disabled, requires special care and assistance. 40 Mostly in bed; participates in quiet activities. 3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. 30 Severely disabled, hospitalization indicated. Death not imminent. 30 In bed; needs assistance even for quiet play. 20 Very sick, hospitalization indicated. Death not imminent. 20 Often sleeping; play entirely limited to very passive activities. 4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair. 10 Moribund, fatal processes progressing rapidly. 10 No play; does not get out of bed. *The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 111 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 31 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Appendix IV RTOG/EORTC Late Radiation Morbidity Scoring Scheme Use for adverse event occurring greater than 90 days after radiation therapy. Grade Adverse Event 0 1 2 3 4 Bladder- Late RT Morbidity Scoring No change from baseline Slight epithelial atrophy/minor telangiectasia (microscopic hematuria) Moderate frequency/ generalized telangiectasia/ intermittent macroscopic hematuria Severe frequency and dysuria/severe generalized telangiectasia (often with petechiae); frequent hematuria; reduction in bladder capacity (<150 mL) Necrosis/contracted bladder (capacity <100 mL)/severe hemorrhagic cystitis Bone- Late RT Morbidity Scoring No change from baseline Asymptomatic; no growth retardation; reduced bone density Moderate pain or tenderness; growth retardation; irregular bone sclerosis Severe pain or tenderness; complete arrest of bone growth; dense bone sclerosis Necrosis/ spontaneous fracture Brain- Late RT Morbidity Scoring No change from baseline Mild headache; slight lethargy Moderate headache; great lethargy Severe headaches; severe CNS dysfunction (partial loss of power or dyskinesia) Seizures or paralysis; coma Esophagus- Late RT Morbidity Scoring No change from baseline Mild fibrosis; slight difficulty in swallowing solids; no pain on swallowing Unable to take solid food normally; swallowing semi-solid food; dilation may be indicated Severe fibrosis; able to swallow only liquids; may have pain on swallowing; dilation required Necrosis/ perforation; fistula Eye- Late RT Morbidity Scoring No change from baseline Asymptomatic cataract; minor corneal ulceration or keratitis Symptomatic cataract; moderate corneal ulceration; minor retinopathy or glaucoma Severe keratitis; severe retinopathy or detachment; severe glaucoma Panophthalmitis; blindness Heart- Late RT Morbidity Scoring No change from baseline Asymptomatic or mild symptoms; transient T wave inversion and ST changes; sinus tachycardia >110 (at rest) Moderate angina on effort; mild pericarditis; normal heart size; persistent abnormal T wave and ST changes; low QRS Severe angina; pericardial effusion; constrictive pericarditis; moderate heart failure; cardiac enlargement; EKG abnormalities Tamponade/severe heart failure/severe constrictive pericarditis Joint- Late RT Morbidity Scoring No change from baseline Mild joint stiffness; slight limitation of movement Moderate stiffness; intermittent or moderate joint pain; moderate limitation of movement Severe joint stiffness; pain with severe limitation of movement Necrosis/complete fixation Kidney- Late RT Morbidity Scoring No change from baseline Transient albuminuria; no hypertension; mild impairment of renal function; urea 25 - 35 mg%; creatinine 1.5 - 2.0 mg%; creatinine clearance >75% Persistent moderate albuminuria (2+); mild hypertension; no related anemia; moderate impairment of renal function; urea >36 - 60 mg%; creatinine clearance >50 - 74% Severe albuminuria; severe hypertension; persistent anemia (<10 g%); severe renal failure; urea >60 mg%; creatinine >4 mg%; creatinine clearance <50% Malignant hypertension; uremic coma/urea >100% Larynx- Late RT Morbidity Scoring No change from baseline Hoarseness; slight arytenoid edema Moderate arytenoid edema; chondritis Severe edema; severe chondritis Necrosis Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 112 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 32 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Appendix IV (continued) RTOG/EORTC Late Radiation Morbidity Scoring Scheme Use for adverse event occurring greater than 90 days after radiation therapy. Grade Adverse Event 0 1 2 3 4 Liver- Late RT Morbidity Scoring No change from baseline Mild lassitude; nausea; dyspepsia; slightly abnormal liver function Moderate symptoms; some abnormal liver function tests; serum albumin normal Disabling hepatic insufficiency; liver function tests grossly abnormal; low albumin; edema or ascites Necrosis/hepatic coma or encephalopathy Lung- Late RT Morbidity Scoring No change from baseline Asymptomatic or mild symptoms (dry cough); slight radiographic appearances Moderate symptomatic fibrosis or pneumonitis (severe cough); low grade fever; patchy radiographic appearances Severe symptomatic fibrosis or pneumonitis; dense radiographic changes Severe respiratory insufficiency/ continuous O2/assisted ventilation Mucous membrane- Late RT Morbidity Scoring No change from baseline Slight atrophy and dryness Moderate atrophy and telangiectasia; little mucus Marked atrophy with complete dryness; severe telangiectasia Ulceration Salivary glands- Late RT Morbidity Scoring No change from baseline Slight dryness of mouth; good response on stimulation Moderate dryness of mouth; poor response on stimulation Complete dryness of mouth; no response on stimulation Fibrosis Skin- Late RT Morbidity Scoring No change from baseline Slight atrophy; pigmentation change; some hair loss Patchy atrophy; moderate telangiectasia; total hair loss Marked atrophy; gross telangiectasia Ulceration Small/Large intestine- Late RT Morbidity Scoring No change from baseline Mild diarrhea; mild cramping; bowel movement 5 x daily; slight rectal discharge or bleeding Moderate diarrhea and colic; bowel movement >5 x daily; excessive rectal mucus or intermittent bleeding Obstruction or bleeding, requiring surgery Necrosis/perforation fistula Spinal cord- Late RT Morbidity Scoring No change from baseline Mild Lhermitte’s syndrome Severe Lhermitte’s syndrome Objective neurological findings at or below cord level treatment Mono-, para-, quadriplegia Subcutaneous tissue- Late RT Morbidity Scoring No change from baseline Slight induration (fibrosis) and loss of subcutaneous fat Moderate fibrosis but asymptomatic; slight field contracture; <10% linear reduction Severe induration and loss of subcutaneous tissue; field contracture >10% linear measurement Necrosis Radiation - Other (Specify, __________) None Mild Moderate Severe Life-threatening or disabling Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 113 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 33 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Appendix V BMT-Specific Adverse Events Summary of BMT-Specific Adverse Events that may be used if specified by the protocol. These differ from the standard CTC and may be more relevant to the transplant setting. They are listed here for the convenience of investigators writing transplant protocols. They are also included in the CTC document. Grade Adverse Event 0 1 2 3 4 Bilirubin associated with graft versus host disease for BMT studies . normal ≥2 - <3 mg/100 mL ≥3 - <6 mg/100 mL ≥6 - <15 mg/100 mL ≥15 mg/100 mL Diarrhea associated with graft versus host disease (GVHD) for BMT studies. none >500 - ≤1000mL of diarrhea/day >1000 - ≤1500mL of diarrhea/day >1500mL of diarrhea/day severe abdominal pain with or without ileus Diarrhea for pediatric BMT studies. >5 - ≤10 mL/kg of diarrhea/day >10 - ≤15 mL/kg of diarrhea/day >15 mL/kg of diarrhea/day - Hepatic enlargement absent - - present - Leukocytes (total WBC) for BMT studies. WNL ≥2.0 - <3.0 X 109 /L ≥2000 - <3000/mm3 ≥1.0 - <2.0 x 109 /L ≥1000 - <2000/mm3 ≥0.5 - <1.0 x 109 /L ≥500 - <1000/mm3 <0.5 x 109 /L <500/mm3 Leukocytes (total WBC) for pediatric BMT studies (using age, race and sex normal values). ≥75 - <100% LLN ≥50 - <75% LLN ≥25 - 50% LLN <25% LLN Lymphopenia for pediatric BMT studies (using age, race and sex normal values). mm3 ≥75-<100%LLN ≥50-<75%LLN ≥25-<50%LLN <25%LLN Neutrophils/granulocytes (ANC/AGC) for BMT studies. WNL ≥1.0 - <1.5 x 109 /L ≥1000 - <1500/mm3 ≥0.5 - <1.0 x 109 /L ≥500 - <1000/mm3 ≥0.1 - <0.5 x 109 /L ≥100 - <500/mm3 <0.1 x 109 /L <100/mm3 Platelets for BMT studies. WNL ≥50.0 - <75.0 x 109 /L ≥50,000 - <75,000/mm3 ≥20.0 - <50.0 x 109 /L ≥20,000 - <50,000/mm3 ≥10.0 - <20.0 x 109 /L ≥10,000 - <20,000/mm3 <10.0 x 109 /L <10,000/mm3 Rash/dermatitis associated with high-dose chemotherapy or BMT studies. none faint erythema or dry desquamation moderate to brisk erythema or a patchy moist desquamation, mostly confined to skin folds and creases; moderate edema confluent moist desquamation, ≥1.5 cm diameter, not confined to skin folds; pitting edema skin necrosis or ulceration of full thickness dermis; may include spontaneous bleeding not induced by minor trauma or abrasion Rash/desquamation associated with graft versus host disease (GVHD) for BMT studies. none macular or papular eruption or erythema covering <25% of body surface area without associated symptoms macular or papular eruption or erythema with pruritus or other associated symptoms covering ≥25 - <50% of body surface or localized desquamation or other lesions covering ≥25 - <50% of body surface area symptomatic generalized erythroderma or symptomatic macular, papular or vesicular eruption, with bullous formation, or desquamation covering ≥50% of body surface area generalized exfoliative dermatitis or ulcerative dermatitis or bullous formation Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 114 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 34 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Appendix V (Continued) BMT-Specific Adverse Events Summary of BMT-Specific Adverse Events that may be used if specified by the protocol. These differ from the standard CTC and may be more relevant to the transplant setting. They are listed here for the convenience of investigators writing transplant protocols. They are also included in the CTC document. Grade Adverse Event 0 1 2 3 4 Stomatitis/pharyngitis (oral/pharyngeal mucositis) for BMT studies. none painless ulcers, erythema, or mild soreness in the absence of lesions painful erythema, edema or ulcers but can swallow painful erythema, edema, or ulcers preventing swallowing or requiring hydration or parenteral (or enteral) nutritional support severe ulceration requiring prophylactic intubation or resulting in documented aspiration pneumonia Transfusion: Platelets for BMT studies. none 1 platelet transfusion in 24 hours 2 platelet transfusions in 24 hours ≥3 platelet transfusions in 24 hours platelet transfusions and other measures required to improve platelet increment; platelet transfusion refractoriness associated with life-threatening bleeding. (e.g., HLA or cross matched platelet transfusions) Transfusion: pRBCs for BMT studies. none ≤2 u pRBC in 24 hours elective or planned 3 u pRBC in 24 hours elective or planned ≥4 u pRBC in 24 hours hemorrhage or hemolysis associated with life-threatening anemia; medical intervention required to improve hemoglobin Transfusion: pRBCs for pediatric BMT studies. none ≤15mL/kg in 24 hours elective or planned >15 - ≤30mL/kg in 24 hours elective or planned >30mL/kg in 24 hours hemorrhage or hemolysis associated with life-threatening anemia; medical intervention required to improve hemoglobin Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura/TTP or hemolytic uremic syndrome/HUS) for BMT studies. - evidence of RBC destruction (schistocytosis) without clinical consequences evidence of RBC destruction with elevated creatinine (≤3 x ULN) evidence of RBC destruction with creatinine (>3 x ULN) not requiring dialysis evidence of RBC destruction with renal failure requiring dialysis and/or encephalopathy Weight gain associated with Veno-Occlusive Disease (VOD) for BMT studies. <2% ≥2 - <5% ≥5 - <10% ≥10% or as ascites ≥10% or fluid retention resulting in pulmonary failure Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 115 1.0 Approved 930010978 2.0 v CTC Version 2.0 Publish Date: April 30, 1999 Cancer Therapy Evaluation Program 35 Revised March 23, 1998 Common Toxicity Criteria, Version 2.0 DCTD, NCI, NIH, DHHS March 1998 Appendix VI BMT Complex/Multicomponent Events Grade Adverse Event 0 1 2 3 4 Note: The grading of Complex/Multicomponent Events in bone marrow transplant will be defined in the protocol. The grading scale must use the CTC criteria for grading the specific component events (adverse events). Failure to engraft absent mild moderate severe life-threatening Also consider Hemoglobin, Neutrophils/granulocytes (ANC/AGC), Neutrophils/granulocytes (ANC/AGC) for BMT studies, if specified in the protocol, Platelets, Platelets for BMT studies, if specified in the protocol Graft versus host disease absent mild moderate severe life-threatening Also consider Fatigue, Rash/desquamation, Rash/desquamation associated with graft versus host disease (GVHD) for BMT studies, if specified in the protocol, Diarrhea for patients without colostomy, Diarrhea for patients with colostomy, Diarrhea associated with graft versus host disease (GVHD) for BMT studies, if specified in the protocol, Diarrhea for pediatric BMT studies, if specified in the protocol, Bilirubin, Bilirubin associated with graft versus host disease (GVHD) for BMT studies, if specified in the protocol Stem cell infusion complications absent mild moderate severe life-threatening Also consider Allergic reaction/hypersensitivity, Conduction abnormality/Atrioventricular heart block, Nodal/junctional arrhythmia/dysrhythmia, Prolonged QTc interval (QTc >0.48 seconds), Sinus bradycardia, Sinus tachycardia, Supraventricular arrhythmias (SVT/atrial fibrillation/flutter), Vasovagal episode, Ventricular arrhythmia (PVCs/bigeminy/trigeminy/ventricular tachycardia), Cardiovascular/Arrhythmia - Other (Specify, ___________), Hypertension, Hypotension, Fever (in the absence of neutropenia, where neutropenia is defined as AGC <1.0 x 109/L), Rigors/chills, Sweating (diaphoresis), Rash/desquamation, Rash/desquamation associated with graft versus host disease (GVHD) for BMT studies, if specified in the protocol, Urticaria (hives, welts, wheals), Diarrhea for patients without colostomy, Diarrhea for patients with colostomy, Diarrhea associated with graft versus host disease (GVHD) for BMT studies, if specified in the protocol, Diarrhea for pediatric BMT studies, if specified in the protocol, Nausea, Vomiting, Hemorrhage/bleeding with grade 3 or 4 thrombocytopenia, Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia, Hemoptysis, Alkaline phosphatase, Bilirubin, Bilirubin associated with graft versus host disease (GVHD) for BMT studies, if specified in the protocol, GGT, SGOT (AST), SGPT (ALT), Infection (documented clinically or microbiologically) with grade 3 or 4 neutropenia (ANC <1.0 x 109/L), Infection without neutropenia, Hyperkalemia, Hypernatremia, Hypokalemia, Depressed level of consciousness, Seizures, Abdominal pain, Headache, Creatinine, Hemoglobinuria Veno-Occlusive Disease (VOD) absent mild moderate severe life-threatening Also consider Weight gain associated with Veno-Occlusive Disease (VOD) for BMT studies, if specified in the protocol, Bilirubin, Bilirubin associated with graft versus host disease (GVHD) for BMT studies, if specified in the protocol, Depressed level of consciousness, Hepatic pain, Renal failure, Hepatic enlargement Paclitaxel CA139387 BMS-181339 Clinical Protocol Date: 25-May-2005 116 1.0 Approved 930010978 2.0 v SAP_001.pdf: STATISTICAL ANALYSIS PLAN ROLLOVER STUDY OF WEEKLY PACLITAXEL (BMS-181339) IN PATIENTS WITH ADVANCED BREAST CANCER Protocol: CA139-387 NCT Number: NCT00971945 October 16, 2007 (Ver. 1.00) 1 Table of Contents Table of Contents 1 Introduction .................................................................................................................................................................................... 2 ........................................................................................................................................................................... 3 Study Objectives ............................................................................................................................................................................ 2 3.1 Primary Endpoint ................................................................................................................................................................. 2 3.2 Secondary Endpoint .............................................................................................................................................................. 2 4 Study Overview .............................................................................................................................................................................. 2 4.1 Study Design ........................................................................................................................................................................ 2 4.2 Study Population .................................................................................................................................................................. 2 4.3 Dose, Route, and Duration of Study Drug ............................................................................................................................ 2 4.4 Blinding and Unblinding ...................................................................................................................................................... 2 5 Criteria for Evaluation .................................................................................................................................................................... 2 5.1 Efficacy Evaluations ............................................................................................................................................................. 2 5.2 Safety Assessments ............................................................................................................................................................... 2 6 Sample Size Determination ............................................................................................................................................................ 3 7 Interim Review ............................................................................................................................................................................... 3 8 Data Sets Analyzed ........................................................................................................................................................................ 3 8.1 Enrolled Subjects .................................................................................................................................................................. 3 8.2 Treated subjects .................................................................................................................................................................... 3 9 Statistical Analysis ......................................................................................................................................................................... 3 9.1 Analysis Consideration ......................................................................................................................................................... 3 9.1.1 Subjects and Data Handling ............................................................................................................................................. 3 9.1.2 Data conversion ............................................................................................................................................................... 3 9.1.3 Adverse Event Coding ..................................................................................................................................................... 3 9.1.4 Review of Subgroup ........................................................................................................................................................ 3 9.1.5 Covariate Alignment ........................................................................................................................................................ 3 9.1.6 Multicenter Test ............................................................................................................................................................... 3 9.1.7 Multiplicity ...................................................................................................................................................................... 3 9.1.8 Significance Level ........................................................................................................................................................... 3 9.2 General Methods .................................................................................................................................................................. 4 9.3 Changes made to Statistical Analysis described in the Protocol ........................................................................................... 4 9.3.1 Additional points ............................................................................................................................................................. 4 9.3.2 Change ............................................................................................................................................................................. 4 9.4 Subject Disposition ............................................................................................................................................................... 4 9.4.1 Subject Disposition .......................................................................................................................................................... 4 9.4.2 Protocol Deviations ......................................................................................................................................................... 4 9.4.3 Baseline Subject Characteristics ...................................................................................................................................... 4 9.5 Drug Administration ............................................................................................................................................................. 4 9.5.1 Study Drug Administration .............................................................................................................................................. 4 9.6 Efficacy ................................................................................................................................................................................ 5 9.6.1 Response, Duration of Response ..................................................................................................................................... 5 9.7 Safety.................................................................................................................................................................................... 5 9.7.1 Subjective and objective adverse events .......................................................................................................................... 5 9.7.2 Peripheral neuropathies ................................................................................................................................................... 5 9.7.3 Nail Disorders .................................................................................................................................................................. 5 9.7.4 Allergic Reactions ........................................................................................................................................................... 5 9.7.5 Laboratory (Test) Abnormalities ...................................................................................................................................... 5 9.7.6 Laboratory Evaluations .................................................................................................................................................... 6 9.7.6.1 Myelosuppression ....................................................................................................................................................... 6 10 ............................................................................................................................................................................................................. 6 ...................................................................................................................................................................................... 2 1 Introduction The purpose of this document is to provide a detailed plan for the final analysis of rollover study of weekly Paclitaxel (BMS-181339) in patients with advanced breast cancer (Identification number: CA139-387). Attached materials show the table format to be used in the statistical analysis report. These tables and figures are referenced in the analysis section. Each figures and tables show the dataset (Analysis Sets) used for the analysis. 3 Study Objectives 3.1 Primary Endpoint The primary endpoint is the frequency and severity of adverse events (Subjective and objective findings and changes in laboratory (test) abnormalities) for the subjects in the study. 3.2 Secondary Endpoint Tumor response and duration of response. 4 Study Overview 4.1 Study Design This study is an extension study of weekly paclitaxel in subjects participating in the who require continued weekly paclitaxel due to lack of alternative treatment, and is an open-label clinical study by enrollment using the central multicenter method. The primary endpoint in this study will determine the frequency and severity of adverse events (Subjective and objective findings and changes in laboratory (test) abnormalities) in study subjects to evaluate the safety of continued paclitaxel treatment. In addition, the Safety Monitoring Board will be established as an advisory body to sponsor and the coordinating investigator to deliberate and report the preparation and revision of protocol, actions in the event of serious adverse event, and actions for situations requiring consideration of discontinuation of the entire study. 4.2 Study Population Among patients with advanced/recurrent breast cancer who meet the inclusion criteria and participated in the , those who are judged by the investigator ( ) to require continued administration of paclitaxel because there is no appropriate alternative therapy. 4.3 Dose, Route, and Duration of Study Drug Paclitaxel 100 mg / m2 is intravenously infused for 1 hour after premedication,. The first dose date of paclitaxel is Day 1, and the drug is administered at Day 8, 15, 22, 29, 36 (7-day intervals (± 1 day)), and then the drug is withdrawn until Day 49. One course is 49 days, and in principle, one or more courses are administered. For subjects who do not meet the discontinuation criteria, administration should be continued as much as possible within the study period at the discretion of the investigator. 4.4 Blinding and Unblinding Not applicable. 5 Criteria for Evaluation 5.1 Efficacy Evaluations Tumor response will be assessed using the Breast Cancer Treatment Code (Edited by the Japan Breast Cancer Society). Response Evaluation Criteria in Solid Tumors (RECIST) will be evaluated for reference. 5.2 Safety Assessments The safety endpoint will be adverse events (Subjective and objective findings and laboratory (test) abnormality), which will be graded according to the NCI Common Toxicity Criteria version 2 (JCOG Version). Final assessment of adverse events will be made by the Adjudication Committee for review outside the study site. Toxicities not included in CTC will be graded in accordance with the following criteria as "Other" toxicity of the applicable category, with specific descriptions. Grade 0: Normal, normal/within normal limits (WNL), none Grade 1: Mild/mild toxicity Grade 2: Moderate/moderate toxicity 3 Grade 3: Severe/severe toxicity Grade 4: Life-threatening or toxicity leading to inactivity Grade 5: Death due to toxicity 6 Sample Size Determination The number of subjects with this study will be determined by the number of subjects continuing from the preceding Currently, in Study , 9 subjects are continuing treatment, and therefore, it is expected that no more than 10 subjects will be enrolled in this study. 7 Interim Review No interim analysis will be performed in this study; however, an interim analysis will be performed if necessary to support the application for approval. 8 Data Sets Analyzed 8.1 Enrolled Subjects All subjects who are enroll to the study. 8.2 Treated subjects Subjects who entered the study and received at least one dose of investigational product. Safety and efficacy analyses will be performed. 9 Statistical Analysis This chapter is organized as follows. 9.1: Analysis Consideration 9.2: General methods 9.3 : Changes made to Statistical Analysis Described in the Protocol 9.4-9.7 : Detailed analysis method for analysis items. (Presentation formats for each analysis is provided in the attachment.) All analyses will be performed using SAS release 8.02. 9.1 Analysis Consideration 9.1.1 Subjects and Data Handling Handling of subjects and data will be specified separately before data lock as needed. 9.1.2 Data conversion No variables will be analyzed using converted values. However, this is not applicable to the case where an exploratory post-hoc analysis is performed. 9.1.3 Adverse Event Coding Adverse event terms/names of diseases described in case report form were coded to MedDRA terms to be used for reporting of analysis results. The most recent or one previous MedDRA version at the time of analysis will be used. 9.1.4 Review of Subgroup Subgroup will not be evaluated. 9.1.5 Covariate Alignment Analyses that would require adjustment by covariate will not be performed. 9.1.6 Multicenter Test Since the number of subjects per site is expected to be small, no investigation of inter-site differences will be conducted. 9.1.7 Multiplicity Multiplicity is not applicable because no statistical test will be performed. 9.1.8 Significance Level Significance level is not defined because no statistical test will be performed. 4 9.2 General Methods Baseline should be the most recent measurement or finding up to the start of the first dose in the parent study. Descriptive statistics will be used to summarize demographic factors, treatment status, and laboratory data. Categorical variables will be summarized using frequency tabulations. Adverse events for which the causal relationship is "related", "Probably related" or "possibly related" are defined as events for which the relationship with investigational product cannot be ruled out (adverse drug reaction). Events assessed as "not likely relarted" or "not related" to the study drug should be assessed as not related to investigational product. The same adverse event may occur more than once within a subject's scope as a MedDRA SOC, HLGT, or PT, and will be counted only once in the adverse event summary table. If the same adverse event is regarded as a single event, the most abnormal grade among them will be used for summary. Similarly, if multiple same adverse events are counted as 1 event, the most abnormal grade among the related events will be used for summary. The same handling as above will be applied to the total number of subjects with adverse events. For the outcome of adverse events, the final outcome by LLT in MedDRA is adopted as the outcome by PT in the order of priority of death > persistent > unknown > recovering > recovering, and the outcome in adverse drug reaction is handled in the same manner among related events. When frequency tabulations are prepared for adverse events and laboratory (test) abnormalities changes by symptom name, they should be presented in ascending order of SOC (HLGT) codes and in descending order of the number of applicable subjects. If the number of subjects in the same, display them in ascending order of PT code. The target of demographic analysis is data from the preceding study. Dosing and efficacy analyses will be summarized, including data from the subject's previous study. For the number of display digits to be used in the report, an appropriate number of digits should be selected according to the parameters, but rounding should be done as a rounded method unless otherwise specified. Proportion shows the first decimal places. 9.3 Changes made to Statistical Analysis described in the Protocol 9.3.1 Additional points Tabulation of exposure was added. 9.3.2 Change There were no changes. 9.4 Subject Disposition 9.4.1 Subject Disposition Subject composition (Table 1.1) – Study Drug administration – Primary reason for discontinuation One primary reason for discontinuation will be identified for each subject. Reasons for discontinuation by discontinuation course (Table 1.2) The discontinuation course is the sum of the administration courses in the preceding study. 9.4.2 Protocol Deviations Protocol deviations (Table 1.3) 9.4.3 Baseline Subject Characteristics Demographic characteristics (Table 2.1) – Age (years) – Body surface area (m 2) – P.S. (ECOG) The age should be accurately calculated from the date of informed consent and date of birth in years of age. 9.5 Drug Administration 9.5.1 Study Drug Administration In the following summaries, the number of courses plus the number of courses administered in the preceding study will be used. (For example, if a subject completed or discontinued 2 courses of the parent study and subsequently entered an extension study, the first course of the extension study will be counted as 3 courses.) Study Drug Administration (Table 3.1) – Number of administration courses 5 – Number of dose – Course interval (days) ・Course interval = first dose date in the course - last dose date in the previous course Dose delay (Table 3.2) Drug interruption (Table 3.3) Dose reduction (Table 3.4) 9.6 Efficacy 9.6.1 Response, Duration of Response In the following summary, the date will be specified based on the assessment by the attending physician and the data from the preceding study, and the period and cumulative dose will be calculated based on the date. Duration of response (Japan Breast Cancer Society) (Table 4.1) ・Duration of CR response = date of progression - date of CR ・Duration of PR response = date of progression - date of PR ・Overall response duration= date of progression - date of first dose The date of progression is defined as the earliest date among the date of progression of a lesion, the date of appearance of a new lesion, the date of initiation of subsequent treatment, or the date of death based on the evaluation criteria in the General Rules for Clinical Practice for Breast Cancer, and the date of the last measurement of a lesion in patients without progression. Duration of response (RECIST) (Table 4.2) ・Duration of complete response = date of progression - date of CR ・Overall response duration = date of progression - date of PR The date of progression is defined as the earliest date among the date of progression of lesion based on RECIST evaluation criteria, the date of appearance of new lesion, the date of initiation of subsequent treatment, or the date of death, and the date of the last measurement of lesion in patients without progression. 9.7 Safety The following summaries are based on events that are new or ongoing in the extension study. 9.7.1 Subjective and objective adverse events The number of subjects with subjective and objective adverse events will be summarized by SOC and PT. However, summaries by outcome will not be performed by SOC but only by PT. Subjective and objective adverse events: by worst grade (Table 5.1) Drug Related Subjective and objective adverse events: by worst grade (Table 5.2) Drug Related Subjective and objective adverse events by outcome (Table 5.3) 9.7.2 Peripheral neuropathies The number of subjects with peripheral neuropathy will be summarized by SOC and PT. Peripheral nerve disorders: by worst grade (Table 5.4) Peripheral nerve disorders- excluding "not related" and "not likely relarted" -: by worst grade (Table 5.5) 9.7.3 Nail Disorders The number of subjects with nail disorders will be summarized by SOC and PT. Nail disorders: by worst grade (Table 5.6) 9.7.4 Allergic Reactions The number of subjects with allergic reactions will be summarized by SOC and PT. In addition, the occurrence by dexamethasone dose will be summarized. Allergic reactions: by worst grade (Table 5.7) 9.7.5 Laboratory (Test) Abnormalities For laboratory (test) abnormalities changes, the number of subjects with each HLGT and each PT will be summarized. However, summaries by outcome will not be performed by HLGT but only by PT. Laboratory abnormalities: by worst grade (Table 6.1) Laboratory abnormalities (Drug Related): by worst grade (Table 6.2) Laboratory (test) abnormalities (Drug Related): Incidence by outcome (Table 6.3) 6 9.7.6 Laboratory Evaluations 9.7.6.1 Myelosuppression Worst grade, nadir, number of days to nadir, and number of days to recovery of white blood cell count decreased (Table 6.4 a) Worst grade of neutrophil count decreased, Nadir, number of days to Nadir, number of days to resolution (Table 6.4 b) Nadir (lowest value), number of days to Nadir and number of days to resolution will only be calculated for subjects who achieve Grade ≥ 2 in each course. The calculation method is as follows:.  Number of days to Nadir: date Nadir was reached - first dose date in each course + 1  Recovery date: Between the day of achievement of Nadir and before the start of the next course (Last measurement time point including follow-up data in the last course), the first day when the grade has recovered to ≤ 1 and has not subsequently worsened to ≥ 2.  Number of days to recovery: Recovery date - date Nadir was reached 10 List of Tables The following figures and tables will be included in the analysis report:. Table/table number Title Table 1.1 Subject Disposition Table 1.2 Reason for Discontinuation by Discontinuation Course Table 1.3 Protocol Deviations Table 2.1 Demographic Characteristics Table 3.1 Study Drug Administration - Including Prior Studies - Table 3.2 Dose Delay - Including Prior Studies - Table 3.3 Drug Interruption - Including Previous Studies - Table 3.4 Dose Reduction - Including Previous Studies - Table 4.1 Duration of Response (Japan Breast Cancer Society) - Including Prior Studies - Table 4.2 Duration of Response (RECIST) - Including Prior Studies - Table 5.1 Subjective and Objective Adverse Events Table 5.2 Drug Related Subjective and Objective Events Table 5.3 Drug Related Subjective and Objective Adverse Events by Outcome Table 5.4 Peripheral Nerve Disorders Table 5.5 Peripheral Neuropathies - excluding "not Related" "not Likely Related" - Table 5.6 Nail Disorders Table 5.7 Allergic Reactions Table 6.1 Laboratory Test Abnormalities Table 6.2 Laboratory Test Abnormalities (Drug Related) Table 6.3 Laboratory Test Abnormalities (Drug Related) by Onset Status/Outcome Table 6.4 a White Blood Cell Count Decreased Recovered to ≤ Grade 1 Table 6.4 b Neutrophil Count Decreased Recovered to ≤ Grade 1 . 7 Document History Date Edition Number Person who created/updated Remarks 2007/01/10 Draft Initiation of draft preparation 2007/08/06 0.00 Completion of draft statistical analysis plan Submit to Reviewers 2007/09/07 0.50 Reflected the review results. Resubmission to Reviewers 2007/09/28 0.60 Reflected the results of the meeting with Clinical Strategy Department Resubmission to Reviewers 2007/10/16 1.00 Reflected the review results, and prepared the approval document.	1	arm 1: None	[ 0 ]	1	[ 0 ]	intervention 1: Solution, I.V., 100 mg/m2, Weekly for 6 of 7 weeks, Until disease progression or unacceptable toxicity became apparent	intervention 1: Paclitaxel	4	Nagoya \| Aichi-ken \| Japan \| 136.90641 \| 35.18147 Hiroshima \| Hiroshima \| Japan \| 132.45 \| 34.4 Kagoshima \| Kagoshima-ken \| Japan \| 130.55 \| 31.56667 Toshima-ku \| Tokyo \| Japan \| N/A \| N/A	6	0	0	0	NCT00971945	1COMPLETED	2008-03-31	2005-06-30	Bristol-Myers Squibb	4INDUSTRY	true	true	false	https://cdn.clinicaltrials.gov/large-docs/45/NCT00971945/Prot_000.pdf https://cdn.clinicaltrials.gov/large-docs/45/NCT00971945/SAP_001.pdf	0	0	0	0	0
[ 3 ]	387	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	false	The purpose of this study is assess the effects of the investigational drug dasatinib on participants who are in chronic phase Philadelphia chromosome chronic myeloid leukemia and who are either resistant to or intolerant of imatinib. Other purposes of the study are to identify any side effects the drug may produce and to study the level of dasatanib in the blood and assess the efficacy of dasatanib in the treatment of leukemia.	null	Chronic Myeloid Leukemia Philadelphia-Positive Myeloid Leukemia	Chronic phase Philadelphia chromosome chronic myeloid leukemia (Ph+CML)	null	1	arm 1: Dasatanib, 70 mg twice daily (BID), with dose escalation to 90 mg BID was allowed for participants who showed evidence of progression or lack of response. Up to 2 dose reductions were allowed for intolerance.	[ 0 ]	1	[ 0 ]	intervention 1: Tablets; oral; 70 mg BID, depending on response	intervention 1: Dasatinib	85	Anaheim \| California \| United States \| -117.9145 \| 33.83529 Loma Linda \| California \| United States \| -117.26115 \| 34.04835 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Stanford \| California \| United States \| -122.16608 \| 37.42411 Vallejo \| California \| United States \| -122.25664 \| 38.10409 Hartford \| Connecticut \| United States \| -72.68509 \| 41.76371 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 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 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 Detroit \| Michigan \| United States \| -83.04575 \| 42.33143 Kansas City \| Missouri \| United States \| -94.57857 \| 39.09973 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Omaha \| Nebraska \| United States \| -95.94043 \| 41.25626 Hackensack \| New Jersey \| United States \| -74.04347 \| 40.88593 New Brunswick \| New Jersey \| United States \| -74.45182 \| 40.48622 New York \| New York \| United States \| -74.00597 \| 40.71427 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Greenville \| South Carolina \| United States \| -82.39401 \| 34.85262 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 Spokane \| Washington \| United States \| -117.42908 \| 47.65966 St Leonards \| New South Wales \| Australia \| 151.19836 \| -33.82344 South Brisbane \| Queensland \| Australia \| 153.02049 \| -27.48034 Adelaide \| South Australia \| Australia \| 138.59863 \| -34.92866 East Mebourne \| Victoria \| Australia \| N/A \| N/A Parkville \| Victoria \| Australia \| 144.95 \| -37.78333 Wein \| N/A \| Austria \| N/A \| N/A B-Leuven \| N/A \| Belgium \| N/A \| N/A Brussels \| N/A \| Belgium \| 4.34878 \| 50.85045 Edegem \| N/A \| Belgium \| 4.44504 \| 51.15662 Yvoir \| N/A \| Belgium \| 4.88059 \| 50.3279 Vancouver \| British Columbia \| Canada \| -123.11934 \| 49.24966 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884 Aarhus \| N/A \| Denmark \| 10.21076 \| 56.15674 Helsinki \| N/A \| Finland \| 24.93545 \| 60.16952 Lille \| N/A \| France \| 3.05858 \| 50.63297 Lyon \| N/A \| France \| 4.84671 \| 45.74846 Nantes \| N/A \| France \| -1.55336 \| 47.21725 Paris \| N/A \| France \| 2.3488 \| 48.85341 Pessac \| N/A \| France \| -0.6324 \| 44.80565 Poitiers \| N/A \| France \| 0.34348 \| 46.58261 Strasbourg \| N/A \| France \| 7.74553 \| 48.58392 Hamburg \| N/A \| Germany \| 9.99302 \| 53.55073 Leipzig \| N/A \| Germany \| 12.37129 \| 51.33962 Mainz \| N/A \| Germany \| 8.2791 \| 49.98419 Mannheim \| N/A \| Germany \| 8.46694 \| 49.4891 Co Galway \| Galway \| Ireland \| N/A \| N/A Dublin \| N/A \| Ireland \| -6.24889 \| 53.33306 Ramat Gan \| N/A \| Israel \| 34.81065 \| 32.08227 Bari \| N/A \| Italy \| 16.86982 \| 41.12066 Bologna \| N/A \| Italy \| 11.33875 \| 44.49381 Milan \| N/A \| Italy \| 12.59836 \| 42.78235 Napoli \| N/A \| Italy \| 14.5195 \| 40.87618 Orbassano \| N/A \| Italy \| 7.53813 \| 45.00547 Roma \| N/A \| Italy \| 11.10642 \| 44.99364 Nijmegen \| N/A \| Netherlands \| 5.85278 \| 51.8425 Rotterdam \| N/A \| Netherlands \| 4.47917 \| 51.9225 Trondheim \| N/A \| Norway \| 10.39506 \| 63.43049 Lima \| Lima Province \| Peru \| -77.02824 \| -12.04318 Singapore \| N/A \| Singapore \| 103.85007 \| 1.28967 Parktown \| Gauteng \| South Africa \| 28.02671 \| -26.18205 Soweto \| Gauteng \| South Africa \| 27.85849 \| -26.26781 Kyunggi-Do \| N/A \| South Korea \| N/A \| N/A Barcelona \| N/A \| Spain \| 2.15899 \| 41.38879 Madrid \| N/A \| Spain \| -3.70256 \| 40.4165 Gothenburg \| N/A \| Sweden \| 11.96679 \| 57.70716 Lund \| N/A \| Sweden \| 13.19321 \| 55.70584 Stockholm \| N/A \| Sweden \| 18.06871 \| 59.32938 Umeå \| N/A \| Sweden \| 20.25972 \| 63.82842 Uppsala \| N/A \| Sweden \| 17.63889 \| 59.85882 Basel \| N/A \| Switzerland \| 7.57327 \| 47.55839 Glasgow \| Central \| United Kingdom \| -4.25763 \| 55.86515 London \| Greater London \| United Kingdom \| -0.12574 \| 51.50853	387	2	0.005168	1	NCT00101660	1COMPLETED	2008-04-01	2005-02-01	Bristol-Myers Squibb	4INDUSTRY	false	false	false	null	1	0	0	1	0.001418
[ 2 ]	41	NON_RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	null	The purpose of this study is to characterize the safety and tolerability of AMG 706 plus panitumumab when administered with gemcitabine and cisplatin chemotherapy. This is a Phase 1b clinical study.	null	Lung Cancer Pancreatic Cancer Esophageal Cancer	Advanced Cancer AMG 706 Panitumumab Gemcitabine-Cisplatin	null	6	arm 1: Panitumumab 9 mg/kg intravenously on Day 1 + gemcitabine (gem) 1250 mg/m\^2 on Day 1 and Day 8, and cisplatin (cis) 75 mg/m\^2 on Day 1 of each 3-week cycle. arm 2: AMG 706 50 mg administered orally once daily (QD) + panitumumab 9 mg/kg intravenously on Day 1 + gemcitabine (gem) 1250 mg/m\^2 on Day 1 and Day 8, and cisplatin (cis) 75 mg/m\^2 on Day 1 of each 3-week cycle. arm 3: AMG 706 75 mg administered orally once daily (QD) + panitumumab 9 mg/kg intravenously on Day 1 + gemcitabine (gem) 1250 mg/m\^2 on Day 1 and Day 8, and cisplatin (cis) 75 mg/m\^2 on Day 1 of each 3-week cycle. arm 4: AMG 706 100 mg administered orally once daily (QD) + panitumumab 9 mg/kg intravenously on Day 1 + gemcitabine (gem) 1250 mg/m\^2 on Day 1 and Day 8, and cisplatin (cis) 75 mg/m\^2 on Day 1 of each 3-week cycle. arm 5: AMG 706 125 mg administered orally once daily (QD) + panitumumab 9 mg/kg intravenously on Day 1 + gemcitabine (gem) 1250 mg/m\^2 on Day 1 and Day 8, and cisplatin (cis) 75 mg/m\^2 on Day 1 of each 3-week cycle. arm 6: AMG 706 75 mg administered orally twice daily (BID) + panitumumab 9 mg/kg intravenously on Day 1 + gemcitabine (gem) 1250 mg/m\^2 on Day 1 and Day 8, and cisplatin (cis) 75 mg/m\^2 on Day 1 of each 3-week cycle.	[ 0, 0, 0, 0, 0, 0 ]	4	[ 0, 2, 0, 0 ]	intervention 1: AMG 706 will be provided as 25-mg and 100-mg tablets and will be continuously self-administered orally once or twice daily based on cohort assignment starting on day 1 of Cycle 1. intervention 2: Panitumumab will be administered by intravenous (IV) infusion at a dose of 9 mg/kg on Day 1 of each 3-week cycle. intervention 3: Gemcitabine will be administered intravenously on Day 1 and Day 8 of each 21-day cycle at a dose of 1250 mg/m\^2. intervention 4: Cisplatin will be administered intravenously on Day 1 of each 3-week cycle at a dose of 75 mg/m\^2.	intervention 1: AMG 706 intervention 2: Panitumumab intervention 3: Gemcitabine intervention 4: Cisplatin	0	null	41	1	0.02439	1	NCT00101907	6TERMINATED	2008-04-01	2004-12-01	Amgen	4INDUSTRY	false	false	false	null	0	0	0	1	0.004319
[ 3 ]	184	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	true	The purpose of this multicenter, double-blind, placebo-controlled study is to evaluate the efficacy and safety of Lenalidomide in adult subjects with Complex Regional Pain Syndrome (CRPS) Type 1.	This is a multicenter, double-blind, placebo-controlled study in adult subjects with Complex Regional Pain Syndrome (CRPS) Type 1. One hundred eighty (180) subjects diagnosed with unilateral CRPS Type 1 will be enrolled and randomized to receive orally either 10 mg/day of lenalidomide or placebo (90 subjects per treatment arm). For each subject, the study consists of three phases: Pre-randomization Phase (2 weeks), Treatment Phase (12 weeks) and Extension Phase where subjects have the opportunity to receive lenalidomide treatment as long as a benefit is derived from the drug. Subjects who complete all 12 weeks of the treatment phase may be eligible to receive lenalidomide in the extension phase. Subject may continue in the extension phase as long as a benefit is derived from the drug.	Complex Regional Pain Syndrome, Type I	CRPS RSDS Pain CC-5013 Revlimid Complex Regional Pain Syndrome Reflex Sympathy Dystrophy Syndrome Lenalidomide CRPS Type I Celgene	null	2	arm 1: 10 mg/day lenalidomide orally for up to 12 weeks in the double-blind treatment period. Participants who completed double-blind treatment had the option of continuing on lenalidomide in the open-label extension period for as long as benefit was derived from the drug or until study closure. arm 2: Placebo orally for up to 12 weeks in the double-blind treatment period. Participants who completed double-blind treatment had the option of crossing over to lenalidomide 10mg in the open-label extension period for as long as benefit was derived from the drug or until study closure.	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: Two 5 mg capsules taken one time per day intervention 2: Two placebo capsules taken one time per day	intervention 1: lenalidomide intervention 2: Placebo	27	Peoria \| Arizona \| United States \| -112.23738 \| 33.5806 La Jolla \| California \| United States \| -117.2742 \| 32.84727 Loma Linda \| California \| United States \| -117.26115 \| 34.04835 Palm Bay \| Florida \| United States \| -80.58866 \| 28.03446 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 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Springfield \| Massachusetts \| United States \| -72.58981 \| 42.10148 Rochester \| Minnesota \| United States \| -92.4699 \| 44.02163 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 New York \| New York \| United States \| -74.00597 \| 40.71427 Rochester \| New York \| United States \| -77.61556 \| 43.15478 Chapel Hill \| North Carolina \| United States \| -79.05584 \| 35.9132 Durham \| North Carolina \| United States \| -78.89862 \| 35.99403 Fort Bragg \| North Carolina \| United States \| -79.00603 \| 35.139 Winston-Salem \| North Carolina \| United States \| -80.24422 \| 36.09986 Dayton \| Ohio \| United States \| -84.19161 \| 39.75895 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Allentown \| Pennsylvania \| United States \| -75.49018 \| 40.60843 Fort Washington \| Pennsylvania \| United States \| -75.20906 \| 40.14178 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Dallas \| Texas \| United States \| -96.80667 \| 32.78306 Lubbock \| Texas \| United States \| -101.85517 \| 33.57786 Charlottesville \| Virginia \| United States \| -78.47668 \| 38.02931 Seattle \| Washington \| United States \| -122.33207 \| 47.60621	180	1	0.005556	1	NCT00109772	6TERMINATED	2008-04-01	2005-02-01	Celgene Corporation	4INDUSTRY	false	false	false	null	1	0	0	0	0.000981
[ 4 ]	1,850	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	null	The primary objective is to determine whether candesartan, compared to placebo reduces the progression of diabetic retinopathy in normotensive, normoalbuminuric type 1 diabetic patients with retinopathy. The secondary objective is to determine whether candesartan, compared to placebo, reduces the incidence of clinically significant macular oedema (CSME) and/or proliferative diabetic retinopathy (PDR) and beneficially influences the rate of change in urinary albumin excretion rate (UAER). This study is part of the DIRECT Programme also including a primary prevention study of diabetic retinopathy in type 1 diabetes and a secondary prevention study in type 2 diabetes. The primary objective for all three pooled studies is to determine whether candesartan, compared to placebo, reduces the incidence of microalbuminuria in type 1 and type 2 diabetic patients.	null	Type 1 Diabetes	Diabetes mellitus type 1	null	2	arm 1: candesartan cilexetil 32 mg once daily arm 2: control	[ 0, 4 ]	1	[ 0 ]	intervention 1: 32 mg oral tablet	intervention 1: candesartan	0	null	1,902	5	0.002629	1	NCT00252720	1COMPLETED	2008-04-01	2001-08-01	AstraZeneca	4INDUSTRY	false	false	false	null	1	0	1	3	0.001123
[ 4 ]	5,238	RANDOMIZED	PARALLEL	0TREATMENT	4QUADRUPLE	false	0ALL	null	The primary objective is to determine whether candesartan, compared to placebo reduces the incidence of diabetic retinopathy in normotensive, normoalbuminuric type 1 diabetic patients without retinopathy. The secondary objective is to determine whether candesartan, compared to placebo, beneficially influences the rate of change in urinary albumin excretion rate (UAER). This study is part of the DIRECT Programme also including secondary prevention studies of diabetic retinopathy in both type 1 and type 2 diabetes. The primary objective for all three pooled studies is to determine whether candesartan, compared to placebo, reduces the incidence of microalbuminuria in type 1 and type 2 diabetic patients.	null	Type 1 Diabetes	Diabetes Mellitus, Insulin-Dependent	null	2	arm 1: Placebo arm 2: candesartan cilexetil	[ 4, 0 ]	1	[ 0 ]	intervention 1: 32 mg once daily oral tablet given over 60 months	intervention 1: candesartan cilexetil	3	Herston \| N/A \| Australia \| 153.01852 \| -27.44453 Perth \| N/A \| Australia \| 115.8614 \| -31.95224 Odense \| N/A \| Denmark \| 10.38831 \| 55.39594	1,420	1	0.000704	1	NCT00252733	1COMPLETED	2008-04-01	2001-06-01	AstraZeneca	4INDUSTRY	false	false	false	null	0	0	0	1	0.000124
[ 4 ]	504	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	The purpose of this study is to compare the effectiveness and safety of sustained- release hydromorphone, formulated to release slowly over time, taken once daily, and controlled- release oxycodone taken twice daily, in patients with chronic non-cancer pain. The study will also determine the dose of sustained-release hydromorphone that provides a level of pain control that is equal to the pain control provided by control-released oxycodone (equi-analgesic dosage).	Conventional immediate-release forms of hydromorphone and oxycodone have a relatively short duration of action that require dosing every 4 to 6 hours. To counterbalance the drawback of repeated opioid intake, sustained-release formulations of oxycodone and hydromorphone were developed that allow twice-daily dosing. Subsequently, a novel, once-daily, extended-release hydromorphone formulation was developed to further enhance ease of treatment and improve effectiveness in the treatment of severe pain. This is a randomized, open-label, comparative, parallel-group, 24-week flexible-dose study in patients with chronic noncancer pain severe enough to require continuous opioid therapy. Patients will receive either 8 mg of sustained-release hydromorphone, taken once daily or 10 mg of controlled-release oxycodone, taken twice daily. Individual adjustments in dosing will be performed to achieve satisfactory pain control, up to a maximum daily dosage of 32 mg for hydromorphone and 80 mg for oxycodone. The primary efficacy outcome will be the determination of the dose of hydromorphone that produces a level of pain control that is equal to the pain control provided by oxycodone (equi-analgesic dose). Safety will be monitored throughout the study. The study hypothesis is that sustained-release hydromorphone taken once daily is well tolerated and is not inferior with regard to pain control to controlled-release oxycodone taken twice daily. Amendment: Amendment was made to the duration of the study from duration of '24 weeks' to '52 weeks' in order to collect long-term safety and efficacy data. OROS hydromorphone 8, 16, or 32 mg tablets QD or SR oxycodone 10, 20, or 40 mg tablets BID. Individual adjustments in dosing performed to achieve satisfactory pain control over 24 weeks. Amendment: treatment duration was extended to 52 weeks.	Pain	chronic noncancer pain pain analgesia analgesic opioid oxycodone hydromorphone	null	2	arm 1: None arm 2: None	[ 1, 0 ]	2	[ 0, 0 ]	intervention 1: 8 to 32 mg once daily for 52 weeks (flexible dosing) intervention 2: 10, 20, or 40 mg twice a day for 52 weeks (flexible dosing)	intervention 1: OROS hydromorphone HCl intervention 2: Oxycodone	52	Brno \| N/A \| Czechia \| 16.60796 \| 49.19522 Pilsen \| N/A \| Czechia \| 13.37759 \| 49.74747 Prague \| N/A \| Czechia \| 14.42076 \| 50.08804 Copenhagen \| N/A \| Denmark \| 12.56553 \| 55.67594 Esbjerg \| N/A \| Denmark \| 8.45187 \| 55.47028 Nyborg \| N/A \| Denmark \| 10.78964 \| 55.31274 Svendborg \| N/A \| Denmark \| 10.60677 \| 55.05982 Vejle \| N/A \| Denmark \| 9.5357 \| 55.70927 Amiens \| N/A \| France \| 2.3 \| 49.9 Bois-Guillaume \| N/A \| France \| 1.12219 \| 49.4602 Lille \| N/A \| France \| 3.05858 \| 50.63297 Paris \| N/A \| France \| 2.3488 \| 48.85341 Berlin \| N/A \| Germany \| 13.41053 \| 52.52437 Drensteinfurt \| N/A \| Germany \| 7.73815 \| 51.79535 Dresden \| N/A \| Germany \| 13.73832 \| 51.05089 Duderstadt \| N/A \| Germany \| 10.25951 \| 51.51312 Frankfurt \| N/A \| Germany \| 10.53333 \| 49.68333 Giessen \| N/A \| Germany \| 8.67554 \| 50.58727 Göppingen \| N/A \| Germany \| 9.65209 \| 48.70354 Hamburg \| N/A \| Germany \| 9.99302 \| 53.55073 Herne \| N/A \| Germany \| 7.22572 \| 51.5388 Jena \| N/A \| Germany \| 11.5899 \| 50.92878 Kiel \| N/A \| Germany \| 10.13489 \| 54.32133 Kÿln \| N/A \| Germany \| N/A \| N/A Ludwigshafen \| N/A \| Germany \| 9.06138 \| 47.81663 Mannheim \| N/A \| Germany \| 8.46694 \| 49.4891 Nuremberg \| N/A \| Germany \| 11.07752 \| 49.45421 Regensburg \| N/A \| Germany \| 12.10161 \| 49.01513 Rodgau \| N/A \| Germany \| 8.88588 \| 50.02627 Wiesbaden \| N/A \| Germany \| 8.24932 \| 50.08258 Bodø \| N/A \| Norway \| 14.37513 \| 67.28267 Lørenskog \| N/A \| Norway \| N/A \| N/A Oslo \| N/A \| Norway \| 10.74609 \| 59.91273 Gdansk \| N/A \| Poland \| 18.64912 \| 54.35227 Krakow \| N/A \| Poland \| 19.93658 \| 50.06143 Lublin \| N/A \| Poland \| 22.56667 \| 51.25 Warsaw \| N/A \| Poland \| 21.01178 \| 52.22977 Wroclaw \| N/A \| Poland \| 17.03333 \| 51.1 Banská Bystrica \| N/A \| Slovakia \| 19.15349 \| 48.73946 Bratislava \| N/A \| Slovakia \| 17.10674 \| 48.14816 Martin \| N/A \| Slovakia \| 18.92399 \| 49.06651 Prešov \| N/A \| Slovakia \| 21.23393 \| 48.99839 Ljubljana \| N/A \| Slovenia \| 14.50513 \| 46.05108 Maribor \| N/A \| Slovenia \| 15.64667 \| 46.55472 Slovenj Gradec \| N/A \| Slovenia \| 15.08056 \| 46.51028 Gothenburg \| N/A \| Sweden \| 11.96679 \| 57.70716 Jönköping \| N/A \| Sweden \| 14.15618 \| 57.78145 Kristianstad \| N/A \| Sweden \| 14.15242 \| 56.03129 Linköping \| N/A \| Sweden \| 15.62157 \| 58.41086 Aarau \| N/A \| Switzerland \| 8.04422 \| 47.39254 Basel \| N/A \| Switzerland \| 7.57327 \| 47.55839 Lausanne \| N/A \| Switzerland \| 6.63282 \| 46.516	504	1	0.001984	1	NCT00261495	1COMPLETED	2008-04-01	2006-03-01	Janssen Pharmaceutica N.V., Belgium	4INDUSTRY	false	false	false	null	0	0	0	1	0.00035
[ 4 ]	1,053	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	This is an open-label, international, two-arm, parallel, randomized, Phase 3 study evaluating the efficacy and safety of S-1/cisplatin versus 5-FU/cisplatin in patients with advanced gastric cancer previously untreated with chemotherapy for advanced disease. Patients will be randomly assigned (1:1) to S-1/cisplatin (experimental arm) or 5-FU/cisplatin (control arm). Patients will be stratified by number of metastatic sites (one vs. more than one), locally advanced or metastatic disease, prior adjuvant therapy (yes or no), measurable or non-measurable disease, and center.	null	Gastric Cancer	Gastric Cancer	null	2	arm 1: In Arm A, S-1 25 mg/m² was administered orally BID from Day 1 through Day 21 followed by a recovery period from Days 22 through Day 28. On Day 1, the morning dose of S-1 was administered before cisplatin 75 mg/m2 administration as a 1- to 3-hour IV infusion. This regimen was repeated every 4 weeks. S-1 was administered one hour before or one hour after a meal with a glass of water (approximately 100 mL). arm 2: In Arm B, 5-FU 1000 mg/m2/24 hours was administered by continuous intravenous infusion (CIV) over 120 hours (on Days 1 through 5). This regimen was repeated every 4 weeks. 5-FU CIV followed cisplatin infusion on Day 1. All 5-FU used in this study was commercially available product.	[ 1, 1 ]	2	[ 0, 0 ]	intervention 1: In Arm A, S-1 25 mg/m2 was taken orally two times daily for 21 days followed by a 7-day recovery period. The patient was instructed to have nothing by mouth (NPO 1 hour prior to and 1 hour after S-1 administration. S-1 was taken with approximately 8 ounces of water and prior to cisplatin infusion on Day 1. Cisplatin 75 mg/m2 was administered as a 1- to 3-hour IV infusion after the morning dose of S-1 on Day 1 of each cycle. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment for cisplatin. intervention 2: In Arm B, 5-FU 1000 mg/m2/24 hours was administered CIV on Days 1 through 5 following cisplatin 100 mg/m2 administered IV as a 1- to 3-hour infusion on Day 1. This regimen was repeated every 4 weeks with a maximum of 6 cycles of treatment for cisplatin.	intervention 1: S-1/Cisplatin intervention 2: 5-FU/cisplatin	33	Huntsville \| Alabama \| United States \| -86.58594 \| 34.7304 Burbank \| California \| United States \| -118.30897 \| 34.18084 Gilroy \| California \| United States \| -121.56828 \| 37.00578 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 Palm Springs \| California \| United States \| -116.54529 \| 33.8303 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Santa Monica \| California \| United States \| -118.49138 \| 34.01949 Lakewood \| Colorado \| United States \| -105.08137 \| 39.70471 Fort Lauderdale \| Florida \| United States \| -80.14338 \| 26.12231 Tampa \| Florida \| United States \| -82.45843 \| 27.94752 West Palm Beach \| Florida \| United States \| -80.05337 \| 26.71534 Honolulu \| Hawaii \| United States \| -157.85833 \| 21.30694 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Metairie \| Louisiana \| United States \| -90.15285 \| 29.98409 Duluth \| Minnesota \| United States \| -92.10658 \| 46.78327 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 Las Vegas \| Nevada \| United States \| -115.13722 \| 36.17497 Albuquerque \| New Mexico \| United States \| -106.65114 \| 35.08449 Albuquerque \| New Mexico \| United States \| -106.65114 \| 35.08449 Albuquerque \| New Mexico \| United States \| -106.65114 \| 35.08449 Hawthorne \| New York \| United States \| -73.79597 \| 41.10732 New City \| New York \| United States \| -73.98931 \| 41.1476 New Bern \| North Carolina \| United States \| -77.04411 \| 35.10849 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Philadelphia \| Pennsylvania \| United States \| -75.16362 \| 39.95238 Charleston \| South Carolina \| United States \| -79.93275 \| 32.77632 Chattanooga \| Tennessee \| United States \| -85.30968 \| 35.04563 Chattanooga \| Tennessee \| United States \| -85.30968 \| 35.04563 Houston \| Texas \| United States \| -95.36327 \| 29.76328 Madison \| Wisconsin \| United States \| -89.40123 \| 43.07305 Montreal \| Quebec \| Canada \| -73.58781 \| 45.50884	1,029	1	0.000972	1	NCT00400179	1COMPLETED	2008-04-01	2005-05-01	Taiho Oncology, Inc.	4INDUSTRY	false	false	false	null	0	1	0	0	0.000172
[ 3 ]	4	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	1FEMALE	true	Lymphangioleiomyomatosis (LAM), a disease primarily of women of child-bearing age, is characterized by cystic lung disease and abdominal tumors (e.g., angiomyolipomas). Within the LAM patient population is a subset of patients who develop chylous effusions and lymphangioleiomyomas. Treatment of many of these symptoms has been ineffective. Previous studies with somatostatin and octreotide in other clinical settings have shown reduction in chylous effusions. This study assesses the effectiveness of octreotide in symptomatic patients with LAM, lymphangioleiomyomas and/or chylous effusions/ascites, peripheral lymphedema and chyluria.	Lymphangioleiomyomatosis (LAM), a disease primarily of women of child-bearing age, is characterized by cystic lung disease and abdominal tumors (e.g., angiomyolipomas). Within the LAM patient population is a subset of patients who develop chylous ascites, chylous pleural effusions, chyluria, peripheral lymphedema, and/or lymphangioleiomyomas. Lymphangioleiomyomas are believed to result from a proliferation of abnormal smooth muscle cells within the lymphatic system, which appears to obstruct fluid outflow, leading to fluid accumulation and an increase in size. The lymphangioleiomyomas may occur anywhere along the axial lymphatic chain. In patients with LAM, they occur most frequently in the thorax, abdomen and pelvis and may give rise to a myriad of symptoms (e.g., paresthesias, palpitations, peripheral edema). In some patients, treatment of many of these symptoms, i.e., elevation of lower extremities, paracentesis, thoracentesis, diuretics, and/or surgery, has been ineffective. Previous studies with somatostatin and octreotide in other clinical settings (e.g., traumatic damage to the lymphatics) have shown a successful reduction in chylous effusions, chyluria, ascites, and peripheral lymphedema, when other therapies were less effective. This study will assess the effectiveness of octreotide in symptomatic patients with LAM, lymphangioleiomyomas and/or chylous effusions/ascites, peripheral lymphedema and chyluria. The dose of octreotide starts at 50 micrograms (ug) by the subcutaneous route twice a day. After two weeks the dose will be increased to 200 ug per day and two weeks later to 400 ug/day. Maximal dose is 400 ug twice a day.	Lymphangioleiomyomatosis Lymphangiomyomas Pleural Effusions Ascites	Chylous Ascites Chylous Pleural Effusion Inhibitory Effects Lymphangioleiomyoma Somatostatin Lymphangioleiomyomatosis (LAM)	null	1	arm 1: Patients with lymphangioleiomyomatosis and lymphatic tumors, ascites or pleural effusions who are symptomatic will receive subcutaneous injections of octreotide starting at a dose of 100 micrograms per day. Doses will be gradually increased to a maximum of 800 micrograms per day, two months after enrollment, if there is no response to lower doses.	[ 0 ]	1	[ 0 ]	intervention 1: Treatment with octreotide starts at a dose of 50 micrograms(ug) twice a day which is increased to 100 ug twice a day after two weeks and to 200 ug twice a day two weeks later. After two months, if there is no response the dose shall be increased to 400 ug twice a day.	intervention 1: Octreotide	1	Bethesda \| Maryland \| United States \| -77.10026 \| 38.98067	4	0	0	0	NCT00005906	1COMPLETED	2008-04-01	2000-06-01	National Heart, Lung, and Blood Institute (NHLBI)	0NIH	false	false	false	null	0	0	0	0	0
[ 2, 3 ]	49	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. PURPOSE: Phase I/II trial to study the effectiveness of temozolomide and vinorelbine in treating patients who have recurrent brain metastases.	OBJECTIVES: * Determine the maximum tolerated dose of vinorelbine when administered in combination with temozolomide in patients with recurrent brain metastases (phase I accrual completed). * Determine the safety and feasibility of this treatment regimen in these patients. * Determine the efficacy of this treatment regimen, in terms of objective radiographic response and overall and progression-free survival, in these patients. OUTLINE: This is a dose-escalation study of vinorelbine. Patients receive vinorelbine IV over 5-10 minutes on days 1 and 8 and oral temozolomide once daily on days 1-7 and 15-21. Courses repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of vinorelbine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 6 patients experience dose-limiting toxicity. Once the MTD is determined, an additional 20-35 patients will be treated at that dose level. Patients are followed every 3-4 months. PROJECTED ACCRUAL: A minimum of 3 patients will be accrued for the phase I portion of this study and 20-35 patients will be accrued for the phase II portion of this study within 2 years.	Metastatic Cancer	tumors metastatic to brain	null	1	arm 1: Patients will be treated with vinorelbine on days 1 and 8 of each cycle; temozolomide will be administered on days 1 to 7 and 15 to 21 of each cycle. The dose level of temozolomide will be given at a dose of 150 mg/m2/day. A cycle will be defined as 28 days of treatment.	[ 0 ]	2	[ 0, 0 ]	intervention 1: None intervention 2: None	intervention 1: temozolomide intervention 2: vinorelbine tartrate	2	Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 New York \| New York \| United States \| -74.00597 \| 40.71427	49	0	0	0	NCT00026494	1COMPLETED	2008-04-01	2001-07-01	Memorial Sloan Kettering Cancer Center	7OTHER	false	false	false	null	0	0	0	0	0
[ 4 ]	29	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	0ALL	null	The purpose of this study is to test whether long-term treatment with oral acyclovir improves the outcome for infants with herpes simplex virus (HSV) disease of the skin, eyes, and mouth (SEM). Study participants will include infants in the United States and Canada who have HSV disease of the skin, eyes, and mouth, with no central nervous system disease present. Initially, all subjects will be treated with acyclovir administered through IV access (through the vein) for 14 days while hospitalized. Participants will then be placed in one of two groups, acyclovir given by mouth or a placebo (substance with no medication present). The participant and the study site will not know to which group the subject is assigned. All children will be followed at 6, 12, 24, 36, 48, and 60 months of age. During the follow up visits, physicals, hearing assessments, eye assessments, and neurological assessments will be completed.	Neonatal herpes simplex virus (HSV) disease complicates approximately one in every 3,000 births in the United States. This study will be a placebo-controlled Phase III evaluation of suppressive therapy with oral Acyclovir suspension following neonatal HSV infections limited to the skin, eyes, and mouth (SEM). This study will evaluate the efficacy of long-term suppressive therapy with oral acyclovir in infants with SEM disease. It will determine if suppressive oral acyclovir therapy improves neurological outcome in infants following SEM disease. Only infants with SEM disease will qualify for this study. After qualifying for the study and obtaining informed consent, the infant will complete 14 days of intravenous (IV) Acyclovir (20 mg/kg/dose given every 8 hours). Patients will be randomized to receive suppressive oral Acyclovir versus placebo only if they continue to meet all study inclusion criteria at the completion of the IV therapy. This study will be double-blinded and placebo controlled. At the time of randomization, the patient will be placed in 1 of 2 groups (oral suppressive Acyclovir versus placebo). If a patient in either group has a cutaneous HSV recurrence, open-label oral Acyclovir (80 mg/kg/day divided into 4 doses per day) will be provided for 5 days. During the time of administration of open-label oral Acyclovir, study drug will be withheld. All children will be followed at 6, 12, 24, 36, 48, and 60 months of age. Physical examination, hearing assessment, and retinal examination will be performed at each follow up visit. Standardized neurologic evaluation will be performed at 12, 24, 36, 48, and 60 months of age.	Herpes Simplex	Herpes Simplex, Acyclovir, Infants	null	2	arm 1: None arm 2: None	[ 2, 0 ]	2	[ 0, 0 ]	intervention 1: Oral suspension 300 mg/m\^2/dose, 3 times per day (TID), for 6 months. intervention 2: Placebo identical to oral acyclovir suspension in appearance and taste.	intervention 1: Acyclovir intervention 2: Placebo	28	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 San Diego \| California \| United States \| -117.16472 \| 32.71571 Stanford \| California \| United States \| -122.16608 \| 37.42411 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Louisville \| Kentucky \| United States \| -85.75941 \| 38.25424 New Orleans \| Louisiana \| United States \| -90.07507 \| 29.95465 Portland \| Maine \| United States \| -70.2589 \| 43.65737 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Detroit \| Michigan \| United States \| -83.04575 \| 42.33143 Jackson \| Mississippi \| United States \| -90.18481 \| 32.29876 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 New York \| New York \| United States \| -74.00597 \| 40.71427 Syracuse \| New York \| United States \| -76.14742 \| 43.04812 Charlotte \| North Carolina \| United States \| -80.84313 \| 35.22709 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Columbus \| Ohio \| United States \| -82.99879 \| 39.96118 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Providence \| Rhode Island \| United States \| -71.41283 \| 41.82399 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 Fort Worth \| Texas \| United States \| -97.32085 \| 32.72541 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Seattle \| Washington \| United States \| -122.33207 \| 47.60621 Edmonton \| Alberta \| Canada \| -113.46871 \| 53.55014	29	0	0	0	NCT00031447	1COMPLETED	2008-04-01	1999-08-01	National Institute of Allergy and Infectious Diseases (NIAID)	0NIH	false	false	false	null	0	0	0	0	0
[ 4 ]	46	RANDOMIZED	PARALLEL	0TREATMENT	3TRIPLE	false	0ALL	null	The purpose of this study is to test whether long term treatment with acyclovir given orally (by mouth) improves the outcome for infants with herpes simplex virus infection of the brain or spinal cord (known as the central nervous system \[CNS\]). Infants with herpes viral infection of the CNS that has or has not spread to other parts of the body will be enrolled in this study. All participants will receive treatment in a hospital for 21 days with acyclovir, given intravenously (by a needle inserted into a vein). Participants will then be divided into two groups: those with CNS disease that has or has not spread to the skin, and those whose viral infection has spread and involves the CNS. Both groups will be randomly assigned to receive either oral acyclovir or placebo (inactive substance) for 6 months. Infants in the US and Canada will participate for 5 years. A physical exam, hearing exam, eye exam, and an evaluation of the nervous system will be performed throughout the study.	Neonatal herpes simplex virus (HSV) disease complicates approximately 1 in every 3,000 deliveries in the United States, resulting in an estimated 1, 500 cases annually in this country. HSV-1 and HSV-2 infections in the neonate can manifest as: disseminated disease; central nervous system (CNS) disease; or disease limited to the skin, eyes, and mouth (SEM disease). This study will evaluate the efficacy of long term suppressive therapy with oral acyclovir in infants with CNS disease, with or without evidence of dissemination to other organs (including the skin). It will determine if suppressive oral acyclovir therapy improves neurologic outcome in infants following HSV disease with CNS involvement and address the significance of a positive cerebral spinal fluid (CSF) polymerase chain reaction (PCR) result when all other CSF parameters either remain normal or show improvement. Comparisons will be made between groups with respect to post-randomization time to first positive CSF PCR result during the initial 12 months of life, and results will be correlated with clinical neurological assessments. It will determine if continuous administration of oral acyclovir suspension suppresses recurrent skin lesions in infants following HSV disease with CNS involvement, and it will confirm the safety of long-term administration of oral acyclovir therapy in a cohort of infants with HSV disease with CNS involvement. Finally, the effects of suppressive acyclovir therapy on issues of pharmacoeconomics and family infrastructure will be assessed and quantitated. Infants with CNS disease (with or without evidence of viral dissemination to other organs, such as the skin, liver, and lungs) will qualify for this study. Following a 21 day course of treatment with intravenous (IV) acyclovir, infants with CNS disease, with or without cutaneous involvement, will be randomized to either continuous oral acyclovir or placebo (CNS Sub-Study). Similarly, infants with disseminated disease with CNS involvement will be randomized to either continuous oral acyclovir or placebo (Disseminated with CNS Involvement Sub-Study). The subset of infants with CNS disease (with or without dissemination) who do not clear their acute infection in 21 days of IV acyclovir therapy will be eligible for enrollment in a Pilot Sub-Study. This group is expected to be of insufficient number to be able to obtain statistical significance for establishing efficacy. Per protocol amendment dated 19-Nov-1998, 66 subjects will be recruited into each sub-study. Subjects will begin oral drug therapy 8 hours after the final IV acyclovir dose and oral drug therapy will be administered for 6 months. Whole blood (1.0 cubic centimeter) will be obtained at study enrollment and at completion of IV antiviral therapy for HSV PCR analysis, per protocol amendment dated 4-May-1998. This amendment replaces the obtaining of serum for HSV PCR analysis. In the event that whole blood is not available, serum will be provided instead. All children will be followed at 6, 12, 24, 36, 48, and 60 months of age. Physical examination, hearing assessment, and retinal examination will be performed at each follow-up visit. Standardized neurological evaluations will be performed at 12, 24, 36, 48, and 60 months. The primary study endpoint will evaluate neurological impairment at 12 months of life. The secondary endpoints will evaluate post-randomization detection of HSV DNA in CSF by PCR at any time during the initial 12 months of life and 2 or fewer episodes post-randomization of cutaneous recurrence of HSV disease during the initial 12 months of life.	Herpes Simplex	acyclovir, central nervous system, Herpes Simplex Virus	null	2	arm 1: None arm 2: None	[ 0, 2 ]	2	[ 0, 0 ]	intervention 1: Oral banana flavored acyclovir suspension: 300 mg/m\^2/dose three times a day (TID), to be given at least 6 to 8 hours apart for 6 months. Dosage adjustments will be made monthly to compensate for increases in body surface area. intervention 2: Oral banana flavored placebo suspension: to be given at least 6 to 8 hours apart for 6 months. Dosage adjustments will be made monthly to compensate for increases in body surface area.	intervention 1: Acyclovir intervention 2: Placebo	29	Birmingham \| Alabama \| United States \| -86.80249 \| 33.52066 Little Rock \| Arkansas \| United States \| -92.28959 \| 34.74648 Los Angeles \| California \| United States \| -118.24368 \| 34.05223 San Diego \| California \| United States \| -117.16472 \| 32.71571 Stanford \| California \| United States \| -122.16608 \| 37.42411 Jacksonville \| Florida \| United States \| -81.65565 \| 30.33218 Chicago \| Illinois \| United States \| -87.65005 \| 41.85003 Louisville \| Kentucky \| United States \| -85.75941 \| 38.25424 New Orleans \| Louisiana \| United States \| -90.07507 \| 29.95465 Portland \| Maine \| United States \| -70.2589 \| 43.65737 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 Detroit \| Michigan \| United States \| -83.04575 \| 42.33143 Jackson \| Mississippi \| United States \| -90.18481 \| 32.29876 St Louis \| Missouri \| United States \| -90.19789 \| 38.62727 New York \| New York \| United States \| -74.00597 \| 40.71427 Syracuse \| New York \| United States \| -76.14742 \| 43.04812 Charlotte \| North Carolina \| United States \| -80.84313 \| 35.22709 Cincinnati \| Ohio \| United States \| -84.51439 \| 39.12711 Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995 Columbus \| Ohio \| United States \| -82.99879 \| 39.96118 Portland \| Oregon \| United States \| -122.67621 \| 45.52345 Providence \| Rhode Island \| United States \| -71.41283 \| 41.82399 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 Fort Worth \| Texas \| United States \| -97.32085 \| 32.72541 San Antonio \| Texas \| United States \| -98.49363 \| 29.42412 Seattle \| Washington \| United States \| -122.33207 \| 47.60621 Edmonton \| Alberta \| Canada \| -113.46871 \| 53.55014	45	0	0	0	NCT00031460	1COMPLETED	2008-04-01	1997-12-01	National Institute of Allergy and Infectious Diseases (NIAID)	0NIH	false	false	false	null	0	0	0	0	0
[ 3 ]	21	NA	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	null	Drugs used in chemotherapy, such as rebeccamycin analog, work in different ways to stop tumor cells from dividing so they stop growing or die. This phase II trial is studying how well rebeccamycin analog works as second-line therapy in treating patients with limited-stage or extensive-stage small cell lung cancer that has relapsed after previous first-line chemotherapy.	OBJECTIVES: I. Determine the objective response rate in patients with limited or extensive stage small cell lung cancer that relapsed after prior first-line chemotherapy when treated with rebeccamycin analogue as second-line therapy. II. Determine the duration of remission and survival of patients treated with this drug. III. Determine the toxicity of this drug in these patients. OUTLINE: This is a multicenter study. Patients receive rebeccamycin analogue IV over 1 hour on days 1-5. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients are followed annually. PROJECTED ACCRUAL: A total of 20-39 patients will be accrued for this study within 15 months.	Extensive Stage Small Cell Lung Cancer Limited Stage Small Cell Lung Cancer Recurrent Small Cell Lung Cancer		null	1	arm 1: Patients receive rebeccamycin analogue IV over 1 hour on days 1-5. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.	[ 0 ]	1	[ 0 ]	intervention 1: Given IV	intervention 1: becatecarin	1	Cleveland \| Ohio \| United States \| -81.69541 \| 41.4995	20	0	0	0	NCT00084487	6TERMINATED	2008-04-01	2004-04-01	National Cancer Institute (NCI)	0NIH	false	false	false	null	0	0	0	0	0
[ 3, 4 ]	77	RANDOMIZED	FACTORIAL	0TREATMENT	4QUADRUPLE	false	1FEMALE	true	Women with Anorexia Nervosa have been found to have low bone density. The study will determine whether administration of low doses of a natural hormone, testosterone and/or risedronate, a medication to help prevent bone breakdown will improve or prevent bone loss in this condition.	II. SPECIFIC AIMS Severe osteopenia is a prevalent complication of anorexia nervosa (AN), affecting over half of all women with this disease. Loss of 25-50% of total bone mass occurs frequently and is often permanent. Although anorexia nervosa affects from 0.5-1.0% of college age women, no successful therapeutic interventions have been developed for osteoporosis in this population. Bone loss in anorexia nervosa is characterized by reduced bone formation coupled with increased bone resorption. Anorexia nervosa results in a deficiency of testosterone. Testosterone administration reduces bone resorption and data suggest that low-dose testosterone replacement therapy can increase surrogate markers of bone formation. Bisphosphonates are now well established to decrease bone resorption and improve bone density in severely osteopenic postmenopausal women. However, there are few data regarding the use of this antiresorptive therapy in women with severe pre-menopausal bone loss. Our preliminary data demonstrate that administration of a bisphosphonate decreases bone resorption and increases bone mass in women with AN after 6 and 9 months. These are the first data to demonstrate a striking increase in bone density in such women. We will test the hypothesis that a combined strategy to increase bone formation and decrease bone resorption by combining testosterone with a bisphosphonate will increase bone mass in anorexia nervosa. The following hypotheses will be tested: Specific Aim 1. Testosterone, a nutritionally dependent bone trophic factor, is a critical determinant of decreased bone formation in anorexia nervosa, and administration of physiologic testosterone will increase bone formation and lean body mass in this disease We will investigate in women with anorexia nervosa whether: A. Bone formation is reduced in association with low serum testosterone B. Testosterone deficiency is due to a combination of ovarian and adrenal defects resulting from undernutrition C. Testosterone administration reverses testosterone deficiency leading to an acute and sustained increase in bone formation and a decrease in bone resorption D. Administration of physiologic testosterone replacement stimulates increases in IGF-I levels in women with anorexia nervosa, a mechanism for increased bone formation and bone density E. Administration of physiologic testosterone replacement increases lean body mass, a major determinant of bone density Specific Aim 2. Long-term (12 months) physiologic testosterone administration combined with a bisphosphonate increases bone density by a dual anabolic and anti-resorptive strategy We will investigate in women with anorexia nervosa whether: A. Physiologic testosterone administration increases bone density B. Administration of a bisphosphonate decreases the excessive state of bone resorption and increases bone density C. Co-administration of physiologic testosterone replacement and a bisphosphonate increases bone density to a greater degree than testosterone or a bisphosphonate alone by increasing bone formation and decreasing bone resorption	Anorexia Nervosa	Eating Disorders Osteopenia	null	4	arm 1: Placebo Actonel (risedronate) and active testosterone patch arm 2: Active Actonel (risedronate) and active testosterone patch arm 3: Active Actonel (risedronate) and placebo testosterone arm 4: Placebo testosterone patch and placebo Actonel (risedronate)	[ 1, 1, 1, 2 ]	4	[ 0, 0, 0, 0 ]	intervention 1: Testosterone patch 150mcg daily intervention 2: Actonel (risedronate) 35mg PO one time weekly intervention 3: Placebo tablet identical in appearance to active Actonel (risedronate) tablet intervention 4: Placebo patch identical in appearance to testosterone patch	intervention 1: Testosterone intervention 2: Actonel (risedronate) intervention 3: Placebo Actonel (risedronate) intervention 4: Placebo testosterone	1	Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843	77	0	0	0	NCT00089843	1COMPLETED	2008-04-01	2003-06-01	Massachusetts General Hospital	7OTHER	false	false	false	null	0	0	0	0	-0
[ 3 ]	32	NON_RANDOMIZED	SINGLE_GROUP	0TREATMENT	0NONE	false	0ALL	true	This is a Phase 2 study being conducted at multiple centers in the United States and France. Patients having melanoma that has spread to other parts of the body (i.e., metastatic) are eligible to participate. Patients must have disease that has been treated with no more than 1 prior treatment for metastatic disease (prior adjuvant treatment for localized disease does not count as prior treatment for metastatic disease). The purpose of the study is to test whether the angiogenesis inhibitor AG-013736 is an effective treatment for metastatic melanoma as shown by the number of patients in the study who experience significant and durable tumor shrinkage.	null	Melanoma Skin Neoplasms	melanoma antiangiogenesis	null	1	arm 1: None	[ 0 ]	1	[ 0 ]	intervention 1: VEGFR \[vascular endothelial growth factor Receptor\] and PDGFR \[Platelet-Derived Growth Factor Receptor\] inhibitor: Single agent AG-013736 starting dose 5 mg BID +/- 20% according to toxicity. Treatment until progression or unacceptable toxicity occurs.	intervention 1: Axitinib [AG-013736]	12	Orange \| California \| United States \| -117.85311 \| 33.78779 Miami Beach \| Florida \| United States \| -80.13005 \| 25.79065 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Clairton \| Pennsylvania \| United States \| -79.88171 \| 40.29229 Greensburg \| Pennsylvania \| United States \| -79.53893 \| 40.30146 Johnstown \| Pennsylvania \| United States \| -78.92197 \| 40.32674 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Pittsburgh \| Pennsylvania \| United States \| -79.99589 \| 40.44062 Wexford \| Pennsylvania \| United States \| -80.05589 \| 40.62646 Paris \| N/A \| France \| 2.3488 \| 48.85341	32	0	0	0	NCT00094107	1COMPLETED	2008-04-01	2004-12-01	Pfizer	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 4 ]	69	RANDOMIZED	PARALLEL	0TREATMENT	0NONE	false	0ALL	false	The purpose of this study is to evaluate antiviral activity and efficacy of entecavir (ETV) compared to adefovir in adults with chronic hepatitis B who have not been treated yet with an antiviral medicine.	null	Hepatitis B Chronic Disease	chronic hepatitis B infection	null	2	arm 1: None arm 2: None	[ 1, 1 ]	2	[ 0, 0 ]	intervention 1: Tablets, Oral, ETV 0.5 mg, once daily, up to 96 weeks intervention 2: Tablets, Oral, ADV 10 mg, once daily, up to 96 weeks	intervention 1: entecavir intervention 2: adefovir	24	San Diego \| California \| United States \| -117.16472 \| 32.71571 San Francisco \| California \| United States \| -122.41942 \| 37.77493 Torrance \| California \| United States \| -118.34063 \| 33.83585 Miami \| Florida \| United States \| -80.19366 \| 25.77427 North Miami Beach \| Florida \| United States \| -80.16255 \| 25.93315 Baltimore \| Maryland \| United States \| -76.61219 \| 39.29038 New York \| New York \| United States \| -74.00597 \| 40.71427 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 Galveston \| Texas \| United States \| -94.7977 \| 29.30135 Edmonton \| Alberta \| Canada \| -113.46871 \| 53.55014 Vancouver \| British Columbia \| Canada \| -123.11934 \| 49.24966 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643 Chai Wan \| N/A \| Hong Kong \| 114.24051 \| 22.26718 Pokfulham \| N/A \| Hong Kong \| N/A \| N/A Tai Po \| N/A \| Hong Kong \| 114.16877 \| 22.45007 Jakarta \| N/A \| Indonesia \| 106.84513 \| -6.21462 Cebu \| N/A \| Philippines \| 121.5961 \| 16.75187 Manila \| N/A \| Philippines \| 120.9822 \| 14.6042 Singapore \| N/A \| Singapore \| 103.85007 \| 1.28967 Taichung \| N/A \| Taiwan \| 120.6839 \| 24.1469 Taoyan \| N/A \| Taiwan \| N/A \| N/A Bangkok \| N/A \| Thailand \| 100.50144 \| 13.75398	69	0	0	0	NCT00096785	1COMPLETED	2008-04-01	2004-12-01	Bristol-Myers Squibb	4INDUSTRY	false	false	false	null	0	0	0	0	0
[ 3 ]	126	RANDOMIZED	PARALLEL	9OTHER	3TRIPLE	false	0ALL	true	The objective of this study is to identify immune intervention strategies that will preserve residual beta cell function at the onset of type 1 diabetes. Scientific evidence developed over the last 10 - 20 years suggests that type 1 diabetes is a chronic, slowly progressive autoimmune disease and that clinical symptoms do not develop until at least 80% - 90% of beta cell mass has been destroyed as a result of the autoimmune process. It is now recognized that preservation of remaining beta cells is clinically important as the ability to secrete, even small amounts of insulin, can make the disease easier to control and help minimize complications associated with having years of inadequate glycemic control. This clinical trial is the first in a series of studies to be launched by the TrialNet Study Group to test various interventions for preserving residual beta cell function in new onset type 1 diabetes. Specifically, this study is designed to determine the ability of Mycophenolate Mofetil (MMF/CellCept) used alone, or in combination with Daclizumab (DZB/Zenapax) to see if it is possible to stop the immune system from destroying beta cells in new onset type 1 diabetes patients (within 3 months of diagnosis.) Researchers have made great strides in understanding how the immune system works and in changing the activity of immune cells with medicines called immunotherapies. Some immunotherapies work by making the immune system less active. Scientists have discovered that key immune cells, called T cells, help to cause type 1 diabetes. These T cells are largely responsible for attacking the beta cells that produce insulin. Doctors have found medicines that slow or suppress the activity of T cells. It is hoped that these immunosuppressive medicines can help treat type 1 diabetes by stopping T cells before they destroy all of the beta cells. Medicines that make the immune system less active have been developed and studied for other diseases. Mycophenolate mofetil (MMF) and Daclizumab (DZB) are two of these medicines. Their effects on the immune system are well understood. Researchers believe these medicines may lessen the immune system's destruction of beta cells that leads to type 1 diabetes. In addition, researchers hope the effect of these medicines will last longer than other therapies. The goal of this study is to find out if two medicines are able to stop the ongoing destruction of beta cells which are still functioning at the time type 1 diabetes is diagnosed. The two immunosuppressive medications being tested are Mycophenolate mofetil (MMF/CellCept®) and Daclizumab (DZB/Zenapax®). They work by making the immune system less active. TrialNet researchers hope that these medications will help maintain insulin secretion from remaining beta cells and thus help to maintain better glycemic control. Even if the medications work, study participants will still need to take insulin injections but it may make it easier to control normal blood sugar levels which can help reduce long-term complications of diabetes such as blindness, kidney failure, nerve damage, heart attack and stroke. The aim is to arrest beta cell destruction in newly diabetic subjects because immune modulation may not work well alone once the autoimmune process has progressed to complete or near complete destruction of beta cells. The study's rationale is to demonstrate a meaningful preservation of islet function with minimal immune system side effects over the 4-year course of this study. The data from this clinical trial could serve as the basis for a larger trial if the results are sufficiently positive, or they could suggest other combined intervention trials that might achieve either better efficacy or potentially preserve C-peptide without the need for continued immunosuppression.	Design of Study: The study is a multi-center, three-arm, randomized, double-masked, placebo-controlled clinical trial. Comparisons will be made among the three groups, which are: * Mycophenolate mofetil active drug with Daclizumab (DZB) placebo IV * Mycophenolate mofetil active drug with active Daclizumab IV * Mycophenolate mofetil placebo with Daclizumab placebo IV Participants that agree to enroll in the study will be asked to take study medications for two years. MMF is given by mouth twice a day. DZB is given by an intravenous infusion twice, once at the time of enrollment and again two weeks later. Both these medications are approved by the U.S. Food and Drug Administration and are used by people who have received an organ transplant. This study is testing a new use of these medications to preserve insulin secretion by delaying or stopping further destruction of insulin-secreting cells in people with newly diagnosed type 1 diabetes. Both MMF and DZB make the immune system less active. Participants will be monitored closely for any possible side effects that can occur from taking either DZB and/or MMF due to decreased activity of the immune system. Participants will need to go to the Clinical Center for visits and tests. For the first month participants will come in every week; then participants will come in at month 2 and month 3. After the month 3 visit, visits will occur about every three months. At most visits, blood will be drawn and participants will meet with a study physician to review their overall diabetes management, and be monitored for any possible side-effects from the study medication. Participants will be asked to do a longer test called a Mixed Meal Tolerance Test (MMTT) at the initial visit and at five additional visits while taking the assigned study medication. The MMTT involves drinking a special drink which has a controlled amount of carbohydrates, protein, and fat to measure residual insulin secretion. The test requires having an IV inserted into the arm and having blood samples taken from the IV over a period of 2 to 4 hours. After completing the two year period of taking the study medication, participants will be asked to return every 3-6 months for an additional 1-2 years to evaluate their ability to secrete insulin after discontinuing the study medication.	Diabetes Mellitus, Type 1	immunosuppressive therapy Type 1 Diabetes TrialNet TrialNet POPPII POPPII-1	null	3	arm 1: DZB given by intravenous infusion (1 mg/kg)at baseline and 2 weeks later, and MMF given orally at dose of 600 mg/m2 (2000 mg/day maximum) in 2-3 divided doses for 2 years. arm 2: MMF given orally at dose of 600 mg/m2 (2000 mg/day maximum) in 2-3 divided doses for 2 years and saline intravenous infusions given at baseline and two weeks later. arm 3: Placebo pills given daily for two years and saline intravenous infusions given at baseline and two weeks later.	[ 0, 0, 2 ]	4	[ 0, 0, 0, 0 ]	intervention 1: None intervention 2: None intervention 3: Placebo pills taken orally intervention 4: saline intravenous infusions	intervention 1: Mycophenolate mofeteil (MMF) intervention 2: Daclizumab (DZB) intervention 3: Placebo control for Mycophenolate mofeteil (MMF) intervention 4: Placebo control for Daclizumab (DZB)	11	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 Denver \| Colorado \| United States \| -104.9847 \| 39.73915 Gainesville \| Florida \| United States \| -82.32483 \| 29.65163 Indianapolis \| Indiana \| United States \| -86.15804 \| 39.76838 Boston \| Massachusetts \| United States \| -71.05977 \| 42.35843 Minneapolis \| Minnesota \| United States \| -93.26384 \| 44.97997 New York \| New York \| United States \| -74.00597 \| 40.71427 Seattle \| Washington \| United States \| -122.33207 \| 47.60621 Toronto \| Ontario \| Canada \| -79.39864 \| 43.70643	114	0	0	0	NCT00100178	1COMPLETED	2008-04-01	2004-05-01	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	0NIH	false	false	false	null	0	0	0	0	0

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