TV1380-COA-201

Teva Pharmaceutical Industries Ltd.

5 Bazel Street, Petach Tikva, Israel,

Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc, 01 215-591-3000, ustevatrials@tevapharm.com

Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc, 01 215-591-3000, ustevatrials@tevapharm.com

No

No

No

Final

20 Jul 2015

No

Yes

09 Jun 2014

No

The primary objective of this study is to assess the efficacy and safety of TV-1380 in facilitating abstinence in cocaine-dependent subjects.

Before this study starts, the protocol will be submitted to the national/local health authorities and to each IEC/IRB for review. As required, the study will not start at a given investigational center before the IEC/IRB and health authority (where applicable) for the center give written approval or a favorable opinion. The investigator, or a qualified person designated by the investigator, should fully inform the subject of all pertinent aspects of the study, including the written information approved by the IRB/IEC. Written informed consent will be obtained from each subject before any study-specific procedures or assessments are done and after the aims, methods, anticipated benefits, and potential hazards are explained, according to the IRB/IEC requirements. The subject’s willingness to participate in the study will be documented in writing in a consent form, which will be signed and personally dated by the subject. The investigator will keep the original consent forms, and copies will be given to the subjects. It will also be explained to the subjects that they are free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Written and oral information about the study in a language understood by the subject will be given to all subjects. Each investigator must assure that the privacy of the subjects, including their identity and all personal medical information, is maintained at all times. In CRFs and other documents/images submitted to the sponsor, subjects will be identified not by their names, but by an identification code (e.g., initials and identification number). Personal medical information will always be treated as confidential.

28 Jun 2013

No

Yes

Spain: 12

United States: 196

208

12

0

0

0

0

0

0

208

0

0

Overall trial (overall period)

Randomised - controlled

- A transparent colored tape was wrapped around each TV-1380 or placebo subject syringe because the two solutions were not identical in color. - An unblinded pharmacist or health care professional (independent of the study) prepared the study drug syringe and blinded it prior to administration. - The injection volume of 3.0 mL was the same for all treatments. The TV-1380 150 mg treatment arm was a mix of 1.5 mL TV-1380 plus 1.5 mL placebo.

Yes

Placebo

Solution for injection

Intramuscular use

Subjects randomly assigned to placebo received one IM injection of 3ml QW over 12 weeks (Week 1-Week 12). The placebo injection was administered into the buttock (gluteus maximus muscle).

TV-1380

Solution for injection

Intramuscular use

Subjects randomly assigned to TV-1380, 150 or 300 mg, were administered one intra-muscular (IM) injection of 150 or 300 mg once weekly (QW) over 12 weeks (week 1-week 12) into the buttock (gluteus maximus muscle). TV-1380 drug product was provided as a lyophilized cake which can deliver 100 mg of TV-1380 in 1 mL of formulation buffer. All study injections were 3 mL. Therefore the 150 mg/week treatment consisted of 1.5 mL TV-1380 and 1.5 mL placebo.

TV-1380

Solution for injection

Intramuscular use

Subjects randomly assigned to TV-1380, 150 or 300 mg, were administered one intra-muscular (IM) injection of 150 or 300 mg once weekly (QW) over 12 weeks (week 1-week 12) into the buttock (gluteus maximus muscle). TV-1380 drug product was provided as a lyophilized cake which can deliver 100 mg of TV-1380 in 1 mL of formulation buffer. All study injections were 3 mL.

Placebo

TV-1380 150 mg/week

TV-1380 300 mg/week

Placebo

TV-1380 150 mg/week

TV-1380 300 mg/week

FAS - Placebo

Subjects randomly assigned to the Placebo treatment arm were administered one intra-muscular (IM) injection of placebo over 12 weeks (week 1-week 12) into the buttock (gluteus maximus muscle). The full analysis set (FAS) included all subjects in the ITT population who receive at least 1 dose of study drug.

FAS - TV-1380 150 mg/week

Subjects randomly assigned to TV-1380 150 mg/week treatment arm were administered one intramuscular (IM) injection of 150 mg once weekly (QW) over 12 weeks (week 1-week 12) into the buttock (gluteus maximus muscle). The full analysis set (FAS) included all subjects in the ITT population who receive at least 1 dose of study drug.

FAS - TV-1380 300 mg/week

Subjects randomly assigned to TV-1380 300 mg/week treatment arm were administered one intramuscular (IM) injection of 300 mg once weekly (QW) over 12 weeks (week 1-week 12) into the buttock (gluteus maximus muscle). The full analysis set (FAS) included all subjects in the ITT population who receive at least 1 dose of study drug.

Completers - Placebo

Subjects randomly assigned to the Placebo treatment arm were administered one intra-muscular (IM) injection of placebo over 12 weeks (week 1-week 12) into the buttock (gluteus maximus muscle). The completers analysis set includes all subjects in the ITT population who took the study drug according to protocol.

Completers - TV-1380 150 mg/week

Subjects randomly assigned to TV-1380 150 mg/week treatment arm were administered one intramuscular (IM) injection of 150 mg once weekly (QW) over 12 weeks (week 1-week 12) into the buttock (gluteus maximus muscle). The completers analysis set included all subjects in the ITT population who took the study drug according to protocol.

Completers - TV-1380 300 mg/week

Subjects randomly assigned to TV-1380 300 mg/week treatment arm were administered one intramuscular (IM) injection of 300 mg once weekly (QW) over 12 weeks (week 1-week 12) into the buttock (gluteus maximus muscle). The completers analysis set included all subjects in the ITT population who took the study drug according to protocol.

Safety - Placebo

Subjects randomly assigned to the Placebo treatment arm were administered one intra-muscular (IM) injection of placebo over 12 weeks (week 1-week 12) into the buttock (gluteus maximus muscle). The safety population included all randomized subjects who receive at least 1 dose of study drug. In this analysis set, treatment was assigned based upon the treatment subjects actually receive, regardless of the treatment to which they were randomized.

Safety - TV-1380 150 mg/week

Subjects randomly assigned to TV-1380 150 mg/week treatment arm were administered one intramuscular (IM) injection of 150 mg once weekly (QW) over 12 weeks (week 1-week 12) into the buttock (gluteus maximus muscle). The safety population included all randomized subjects who receive at least 1 dose of study drug. In this analysis set, treatment was assigned based upon the treatment subjects actually receive, regardless of the treatment to which they were randomized.

Safety - TV-1380 300 mg/week

Subjects randomly assigned to TV-1380 300 mg/week treatment arm were administered one intramuscular (IM) injection of 300 mg once weekly (QW) over 12 weeks (week 1-week 12) into the buttock (gluteus maximus muscle). The safety population included all randomized subjects who receive at least 1 dose of study drug. In this analysis set, treatment was assigned based upon the treatment subjects actually receive, regardless of the treatment to which they were randomized.

Abstinence from cocaine during the last three weeks of the treatment phase (weeks 10-12) was based on daily self-report of no use confirmed by urine samples considered negative for cocaine metabolites. In order to consider a subject as abstinent during weeks 10-12, the following criteria was met: 1. Self-report of no use during each whole week 2. At least one analyzable urine sample is available during each of the above weeks (usually collected thrice weekly) 3. All urine samples provided during each of the above weeks were considered negative for cocaine metabolites (BE<150 ng/ml and EME<15 ng/ml). In case no urine sample was provided or no analyzable urine sample was available during a single week (week 10, 11 or 12), it was considered that cocaine has been used for that specific week regardless of the information from self-report.

Primary

Weeks 10-12

The odds ratios (active vs placebo), confidence intervals, and p-values were calculated from a logistic regression analysis stratified by country with the following effects: treatment group, alcohol dependence or non-dependence, route of cocaine administration, and positive or negative last urine cocaine screening prior to randomization. 95% CI value of 999 = infinity

FAS - Placebo v FAS - TV-1380 150 mg/week

137

Pre-specified

3.66

2-sided

The odds ratios (active vs placebo), confidence intervals, and p-values were calculated from a logistic regression analysis stratified by country with the following effects: treatment group, alcohol dependence or non-dependence, route of cocaine administration, and positive or negative last urine cocaine screening prior to randomization. 95% CI value of 999 = infinity

FAS - Placebo v FAS - TV-1380 300 mg/week

135

Pre-specified

4.48

2-sided

Abstinence from cocaine during the last three weeks of the treatment phase (weeks 10-12) was based on daily self-report of no use confirmed by urine samples considered negative for cocaine metabolites. In order to consider a subject as abstinent during weeks 10-12, the following criteria was met: 1. Self-report of no use during each whole week 2. At least one analyzable urine sample is available during each of the above weeks (usually collected thrice weekly) 3. All urine samples provided during each of the above weeks were considered negative for cocaine metabolites (BE<150 ng/ml and EME<15 ng/ml). In case no urine sample was provided or no analyzable urine sample was available during a single week (week 10, 11 or 12), it was considered that cocaine has been used for that specific week regardless of the information from self-report.

Primary

Weeks 10-12

The odds ratios (active vs placebo), confidence intervals, and p-values were calculated from a logistic regression analysis stratified by country with the following effects: treatment group, alcohol dependence or non-dependence, route of cocaine administration, and positive or negative last urine cocaine screening prior to randomization. 95% CI value of 999 = infinity

Completers - TV-1380 150 mg/week v Completers - Placebo

110

Pre-specified

6.13

2-sided

The odds ratios (active vs placebo), confidence intervals, and p-values were calculated from a logistic regression analysis stratified by country with the following effects: treatment group, alcohol dependence or non-dependence, route of cocaine administration, and positive or negative last urine cocaine screening prior to randomization. 95% CI value of 999 = infinity

Completers - Placebo v Completers - TV-1380 300 mg/week

111

Pre-specified

4.86

2-sided

The secondary efficacy endpoint for this study was defined as the percent of urine samples that were considered negative for cocaine metabolites (BE<150 ng/ml and EME<15 ng/ml) out of all planned urine samples during the last 8 weeks of the treatment phase (weeks 5-12).

Secondary

Weeks 5-12

An analysis of covariance (ANCOVA) model was used to compare the LS means percent of urine samples per subject that are considered negative for cocaine metabolites during week 5-week 12 (study days 29-84). The model included the following effects: treatment group, pooled center, alcohol dependence or non-dependence, route of cocaine administration, and positive or negative last urine cocaine at screening prior to randomization.

FAS - Placebo v FAS - TV-1380 150 mg/week

130

Pre-specified

3.41

2-sided

Standard error of the mean

3.717

An analysis of covariance (ANCOVA) model was used to compare the LS means percent of urine samples per subject that are considered negative for cocaine metabolites during week 5-week 12 (study days 29-84). The model included the following effects: treatment group, pooled center, alcohol dependence or non-dependence, route of cocaine administration, and positive or negative last urine cocaine at screening prior to randomization.

FAS - Placebo v FAS - TV-1380 300 mg/week

129

Pre-specified

8.39

2-sided

Standard error of the mean

3.759

An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product, regardless of whether it has a causal relationship with this treatment. AEs summarized are those that began or worsened after treatment with study drug. The relationship to study drug treatment and study procedures, and the severity and seriousness of each adverse event was judged by the investigator. Severity was graded as 1) Mild: No limitation of usual activities 2) Moderate: Some limitation of usual activities or 3) Severe: Inability to carry out usual activities. Relationship was considered as not related, or there was a reasonable possibility of relation to study drug. A serious AE includes death, a life-threatening AE, in-patient hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event requiring intervention to prevent one of the aforementioned.

Secondary

Day 1 to Week 12

Clinically significant criteria: Sodium: >=147 mmol/L Potassium Low: <=3.3 mmol/L Potassium High: >=5.4 mmol/L Glucose Low: <=55 mmol/L Glucose High: >=200 mmol/L Creatinine: >=2 μmol/L Phosphorus: <=2 mmol/L AST: >=3x upper limit of normal ALT: >=3x upper limit of normal GGT: >=3x upper limit of normal Total bilirubin: >=1.5x upper limit of normal

Secondary

Day 1 to Week 12

Clinically Significant Criteria: Hemoglobin - males: <=115 g/L Hemoglobin - females: <=100 g/L WBC count: <=3 * 10^9/L Platelet count: >=600 * 10^9/L

Secondary

Day 1 to week 12

Clinically Significant Criteria: Pulse High: >=120 bpm and increase >=15 Pulse Low: <=45 bpm and decrease >=1538.3 Sitting Systolic BP High: >=180 mmHg and increase >=20 Sitting Systolic BP Low: <=90 mmHg and decrease >=20 Sitting Diastolic BP High: >=100 mmHg and increase >=15 Sitting Diastolic BP Low: <=50 mmHg and decrease >=15 Body Temperature Low: <=35.5 ºC Body Temperature High: >=38.3 ºC and increase from baseline of >=2 ºC Respiratory rate: <=10 breaths/min Height: <=147 cm Weight: >=137 kg

Secondary

Day 1 to Week 12

Includes only subjects with both baseline and postbaseline electrocardiograms. A subject is considered to have a newly diagnosed finding when the baseline finding is normal and there is an abnormal postbaseline finding. For the Overall Total, the worst postbaseline finding, i.e. the abnormal finding if there are both normal and abnormal findings, are counted for each subject. Endpoint is end of study.

Secondary

Day 1 to Week 12

Day 1 to Week 12

16.0

PLACEBO

TV-1380 150 mg/week

TV-1380 300 mg/week