Treatment Seeking Participants With Opioid Use Disorders Assessing Tolerability of Depot Injections of Buprenorphine

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo controlled, multicenter study in male and female participants who are seeking treatment for opioid use disorder.

Detailed Description
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After completing an up to 2-week screening period, subjects entered an open-label run-in induction phase with SUBOXONE (buprenorphine/naloxone) sublingual film for 3 days followed by a 4- to 11-day SUBOXONE sublingual film open-label run-in dose-adjustment period to achieve buprenorphine dosages ranging from 8 to 24 mg according to the SUBOXONE sublingual film prescribing information. This is a 24-week non-residential study with participants being randomized after meeting randomization criteria. On Day 1 and Day 29 (± 2 days) participants will receive subcutaneous injections of 300 mg RBP-6000 or placebo. Thereafter, participants will receive 4 injections (once every 28 days ± 2 days) of either 300 mg or 100 mg RBP-6000 doses or placebo.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study To Assess the Efficacy, Safety, and Tolerability of Multiple Subcutaneous Injections of Depot Buprenorphine (RBP-6000 [100 mg and 300 mg]) Over 24 Weeks in Treatment-Seeking Subjects With Opioid Use Disorder

Conditions
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Opioid Dependence, Opioid Related Disorders

Intervention / Treatment
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* Drug: SUBOXONE
* Drug: RBP-6000
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Currently meets Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for moderate or severe opioid use disorder By medical history has met DSM-5 criteria for moderate or severe opioid use disorder for the 3 months immediately prior to signing the informed consent form Is seeking medication-assisted treatment for opioid use disorder Is an appropriate candidate for opioid partial-agonist medication-assisted treatment in the opinion of the investigator or medically responsible physician Body mass index (BMI) of ≥ 18.0 to ≤ 35.0 kg/m^2 Exclusion Criteria: Current diagnosis other than opioid use disorder requiring chronic opioid treatment Current substance use disorder as defined by DSM-5 criteria with regard to any substances other than opioids, cocaine, cannabis, tobacco, or alcohol. Positive urine drug screen (UDS) result at screening for cocaine or cannabis AND meets DSM-5 criteria for either moderate or severe cocaine or cannabis use disorder, respectively Meets DSM-5 criteria for moderate or severe alcohol use disorder Received medication-assisted treatment for opioid use disorder (e.g., methadone, buprenorphine) in the 90 days prior to providing written informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RBP-6000 300mg/100mg<br>During the Run-In Period, participants are inducted onto SUBOXONE sublingual film (SL) followed by a 4- to 11-day SUBOXONE sublingual film open-label run-in dose-adjustment period to achieve buprenorphine dosages ranging from 8 to 24 mg according to the SUBOXONE sublingual film prescribing information. Participants are then randomized. As of protocol Amendment 2 (21 August 2015) SUBOXONE use is tapered from 6 mg to 2 mg from Days 1-5 and then discontinued. Participants in this treatment arm are given RBP-6000 300 mg injections on Days 1 and 29. Injections 3-6 are separated by 28 days (Day 57-Day 141) and contain RBP-6000 100 mg. In addition, participants received individual drug counseling (IDC) at least once a week. | Drug: SUBOXONE<br>* SUBOXONE (buprenorphine sublingual film) is used for induction therapy. Participants take sublingual film for 3 days according to the sublingual film prescribing information; they then complete a 4-to-11 day sublingual film dose adjustment at doses ranging from 8 mg to 24 mg sublingual film prior to randomization. Following randomization, SUBOXONE use is tapered from 6 mg to 2 mg from Days 1-5 and then discontinued.<br>* Other names: Sublingual Film;Drug: RBP-6000<br>* Six injections administered subcutaneously every 28 days on alternate sides of participant's abdomen at either 300 mg or 100 mg dose.<br>* Other names: Buprenorphine;|
| Experimental: RBP-6000 300mg/300mg<br>During the Run-In Period, participants are inducted onto SUBOXONE sublingual film (SL) followed by a 4- to 11-day SUBOXONE sublingual film open-label run-in dose-adjustment period to achieve buprenorphine dosages ranging from 8 to 24 mg according to the SUBOXONE sublingual film prescribing information. Participants are then randomized. As of protocol Amendment 2 (21 August 2015) SUBOXONE use is tapered from 6 mg to 2 mg from Days 1-5 and then discontinued. Participants in this treatment arm are given six RBP-6000 300 mg injections on Days 1 to 141 with injections separated by 28 days. In addition, participants received individual drug counseling (IDC) at least once a week. | Drug: SUBOXONE<br>* SUBOXONE (buprenorphine sublingual film) is used for induction therapy. Participants take sublingual film for 3 days according to the sublingual film prescribing information; they then complete a 4-to-11 day sublingual film dose adjustment at doses ranging from 8 mg to 24 mg sublingual film prior to randomization. Following randomization, SUBOXONE use is tapered from 6 mg to 2 mg from Days 1-5 and then discontinued.<br>* Other names: Sublingual Film;Drug: RBP-6000<br>* Six injections administered subcutaneously every 28 days on alternate sides of participant's abdomen at either 300 mg or 100 mg dose.<br>* Other names: Buprenorphine;|
| Placebo Comparator: Placebo Matching 300 mg/100 mg RBP-6000<br>During the Run-In Period, participants are inducted onto SUBOXONE sublingual film (SL) followed by a 4- to 11-day SUBOXONE sublingual film open-label run-in dose-adjustment period to achieve buprenorphine dosages ranging from 8 to 24 mg according to the SUBOXONE sublingual film prescribing information. Participants are then randomized. As of protocol Amendment 2 (21 August 2015) SUBOXONE use is tapered from 6 mg to 2 mg from Days 1-5 and then discontinued. Participants in this treatment arm are given placebo injections on Days 1 and 29 (matching the RBP-6000 300 mg dose volume). Injections 3-6 are separated by 28 days (Day 57-Day 141) and also contain placebo (matching the RBP-6000 100 mg volume). In addition, participants received individual drug counseling (IDC) at least once a week. | Drug: SUBOXONE<br>* SUBOXONE (buprenorphine sublingual film) is used for induction therapy. Participants take sublingual film for 3 days according to the sublingual film prescribing information; they then complete a 4-to-11 day sublingual film dose adjustment at doses ranging from 8 mg to 24 mg sublingual film prior to randomization. Following randomization, SUBOXONE use is tapered from 6 mg to 2 mg from Days 1-5 and then discontinued.<br>* Other names: Sublingual Film;Drug: Placebo<br>* Six injections of placebo administered subcutaneously every 28 days on alternate sides of participant's abdomen at volumes matching the experimental drug.<br>* Other names: Volume-matched placebo;|
| Placebo Comparator: Placebo Matching 300 mg RBP-6000<br>During the Run-In Period, participants are inducted onto SUBOXONE sublingual film (SL) followed by a 4- to 11-day SUBOXONE sublingual film open-label run-in dose-adjustment period to achieve buprenorphine dosages ranging from 8 to 24 mg according to the SUBOXONE sublingual film prescribing information. Participants are then randomized. As of protocol Amendment 2 (21 August 2015) SUBOXONE use is tapered from 6 mg to 2 mg from Days 1-5 and then discontinued. Participants in this treatment arm are given six placebo injections (volume-matched to RBP-6000 300 mg dose) on Days 1 to 141 with injections separated by 28 days. In addition, participants received individual drug counseling (IDC) at least once a week. | Drug: SUBOXONE<br>* SUBOXONE (buprenorphine sublingual film) is used for induction therapy. Participants take sublingual film for 3 days according to the sublingual film prescribing information; they then complete a 4-to-11 day sublingual film dose adjustment at doses ranging from 8 mg to 24 mg sublingual film prior to randomization. Following randomization, SUBOXONE use is tapered from 6 mg to 2 mg from Days 1-5 and then discontinued.<br>* Other names: Sublingual Film;Drug: Placebo<br>* Six injections of placebo administered subcutaneously every 28 days on alternate sides of participant's abdomen at volumes matching the experimental drug.<br>* Other names: Volume-matched placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Distribution Function (CDF) of the Percentage of Urine Samples Negative for Opioids Combined With Self-Reports Negative for Illicit Opioid Use Collected From Week 5 Through Week 24 | Data represent the count of participants at various percentage abstinence levels. Abstinence was defined as urine samples being negative for opioids AND negative self-reports (obtained from Timeline Followback (TLFB) interviews) for illicit opioid use. The primary endpoint was based on visits in which paired urine samples and self-reports were expected for each subject as specified in the schedule of events. Missing urine drug screen(s) (UDS) samples and/or self-reports were considered as non-negative. | Weekly from Weeks 5-24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Considered A Treatment Success | Treatment success is defined as a participant having ≥80% of urine samples negative for opioids combined with self-reports negative for illicit opioid use between weeks 5-24. | Weeks 5-24 | 
| Cumulative Distribution Function (CDF) of the Percentage of Urine Samples Negative for Opioids From Week 5 Through Week 24 | Data represent the count of participants at various percentage levels in which urine samples tested negative for opioids. All missing reports for urine samples were considered non-negative. | Weekly from Weeks 5-24 | 
| Cumulative Distribution Function (CDF) of the Percentage of Self-Reports Negative for Illicit Opioid Use From Week 5 Through Week 24 | Data represent the count of participants at various percentage levels in which self-reports were negative for illicit use of opioids. Self-reports were obtained from Timeline Followback (TLFB) interviews. All missing self-reports were considered non-negative. | Weekly from Weeks 5-24 | 
| Change From Baseline in the Opioid Craving Visual Analog Scale (VAS) Prior to Injections From Week 5 Through Week 24 Analyzed by Mixed Model for Repeated Measures | The opioid craving scale was a 100 mm scale with 0= 'no craving' on the left end and 100= 'strongest craving ever' on the right end of the scale. Participants marked where along the scale reflected their craving for opioids. The full range of the change from baseline scale was therefore 100 (no craving at baseline, strongest craving during study) to -100 (strongest craving at baseline, no craving during study). Baseline was defined as the last non-missing value prior to subcutaneous injection on Day 1. The opioid craving VAS was completed each week; measurements were taken prior to dosing on weeks 5, 9, 13, 17 and 21. Negative change from baseline values indicate a lessening of craving symptoms. Change from baseline was analyzed using a mixed model for repeated measures (MMRM) with terms for treatment, visit, and treatment-by-visit interaction as factors and baseline value as a covariate. Center was included in the model as a random effect. | Baseline: Day 1 (prior to dosing), Weeks 5-24 | 
| Participants Who Complete the Week 24 Visit (Completers) | A completer was defined as a participant who completed either the urine drug screen (UDS) or Timeline Followback (TLFB) assessment at the Week 24 visit. | Week 24 | 
| Participants Who Are Abstinent at Week 24 | Participants with both a negative urine sample and negative self-report for illicit opioid use at Week 24. | Week 24 | 
| Change From Baseline in the Clinical Global Impression - Improvement Scale (CGI-I) Prior to Injections From Week 5 Through Week 24 Analyzed by Mixed Model for Repeated Measures | The CGI-I was used to rate the change in clinical status since the start of the treatment on an ordinal scale ranging from 1 (very much improved; nearly all better; good level of functioning; minimal symptoms; represents a very substantial change) to 7 (very much worse; severe exacerbation of symptoms and loss of functioning). Baseline was defined as the last non-missing value prior to subcutaneous injection on Day 1. Measurements taken during the treatment period were taken at the end of each 28 day treatment and prior to dosing of the next treatment. Negative change from baseline values indicate an improved clinical global impression. Change from baseline was analyzed using a mixed model for repeated measures (MMRM) with terms for treatment, visit, and treatment-by-visit interaction as factors and baseline value as a covariate. Center was included in the model as a random effect. | Baseline: Day 1 (prior to dosing), Days 29, 57, 85, 113, 141, 169 | 
| Change From Baseline in the Clinical Global Impression - Severity Scale (CGI-S) Prior to Injections From Week 5 Through Week 24 Analyzed by Mixed Model for Repeated Measures | The CGI-S was an assessment completed by the clinician to rate the severity of symptoms on an ordinal scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill subjects; pathology drastically interferes in many life functions). Baseline was defined as the last non-missing value prior to subcutaneous injection on Day 1. Measurements taken during the treatment period were taken at the end of each 28 day treatment and prior to dosing of the next treatment. Negative change from baseline values indicate an improvement in the severity of symptoms. Change from baseline was analyzed using a mixed model for repeated measures (MMRM) with terms for treatment, visit, and treatment-by-visit interaction as factors and baseline value as a covariate. Center was included in the model as a random effect. | Baseline: Day 1 (prior to dosing), Days 29, 57, 85, 113, 141, 169 | 
| Change From Baseline in the Clinical Opiate Withdrawal Scale (COWS) Through Week 24 Analyzed by Mixed Model for Repeated Measures | COWS is an 11-item instrument used to assess signs and symptoms of opioid withdrawal (Wesson et al., 1999). The score is the sum of the responses for a total range of 0-48. The COWS is commonly used by clinicians treating patients with buprenorphine to monitor the severity of withdrawal. COWS scores below 5 are considered not indicative of withdrawal. Scores from 5 to 12 are considered mild withdrawal; from 13 to 24 moderate withdrawal; 25 to 36 moderately severe withdrawal, and 37-48 severe withdrawal. Negative change from baseline values indicate a lessening of withdrawal symptoms. Baseline was defined as the last non-missing value prior to subcutaneous injection on Day 1. The COWS was completed each week; measurements were taken prior to dosing on weeks 5, 9, 13, 17 and 21. Change from baseline was analyzed using a mixed model for repeated measures (MMRM) with terms for treatment, visit, and treatment-by-visit interaction as factors and baseline value as a covariate. | Baseline: Day 1 (prior to dosing), Baseline: Day 1 (prior to dosing), Days 2, 8, 5, 22, 29, 30, 36, 43, 50, 57, 58, 64, 71, 78, 85, 86, 92, 99, 106, 113, 114, 120, 127, 134, 141, 142, 148, 155, 162, 169 | 
| Change From Baseline in the Subjective Opiate Withdrawal Scale (SOWS) Through Week 24 Analyzed by Mixed Model for Repeated Measures | The Subjective Opiate Withdrawal Scale (SOWS) contains 16 symptoms whose intensity the participant rates on a scale of 0 (not at all) to 4 (extremely) for a full scale of 0 (no withdrawal symptoms) to 64 (extreme withdrawal symptoms). Negative change from baseline values indicate a lessening of withdrawal symptoms. Baseline was defined as the last non-missing value prior to subcutaneous injection on Day 1. The SOWS was completed each week; measurements were taken prior to dosing on weeks 5, 9, 13, 17 and 21. Change from baseline was analyzed using a mixed model for repeated measures (MMRM) with terms for treatment, visit, and treatment-by-visit interaction as factors and baseline value as a covariate. | Baseline: Day 1 (prior to dosing), Baseline: Day 1 (prior to dosing), Days 2, 8, 5, 22, 29, 30, 36, 43, 50, 57, 58, 64, 71, 78, 85, 86, 92, 99, 106, 113, 114, 120, 127, 134, 141, 142, 148, 155, 162, 169 | 
| Total Number of Weeks of Abstinence as Assessed From Urine Samples Negative for Opioids Combined With Self-Reports Negative for Illicit Opioid Use Collected From Week 5 Through Week 24 | The total number of weeks of abstinence was assessed from urine samples negative for opioids combined with self-reports negative for illicit opioid use collected from week 5 through week 24. All missing reports for opioids were considered non-negative. | Weeks 5 through 24 | 
| Participants With Adverse Events During the Treatment Period | Treatment-emergent adverse event (TEAE) = any untoward medical occurrence that develops or worsens in severity after dispensation of the study drug and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= a marked limitation in activity. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent one of the outcomes listed in this definition. | Day 1 through Week 24 | 
| Worst Injection Site Pain From Injections 1-6 as Measured by Participant-Reported Visual Analog Scale (VAS) | Injection site pain as measured by participant-reported VAS The participant-reported VAS for injection site pain was measured on a 100 mm scale with 'no pain' on the left end and 'strongest pain ever' on the right end of the scale (total scale of 0-100). Participants marked where along the scale reflected their localized injection pain. The injection site pain VAS scores were obtained (after the completion of the injection) within 1 minute and at 5, 10, 15, 30, 60 and 120 minutes (+- 5 minutes). The timing of the injection site pain VAS should have been measured from the end of the injection. Data represents the worst pain recorded for each participant across all 6 injections and all VAS records. The mean value is presented. | Days 1, 29, 57, 85, 113, 141 | 
| Suicidality Using the Columbia Suicide Severity Rating Scale (C-SSRS) From Week 2 - 24 | The C-SSRS asks questions of study participants regarding whether they had suicidal ideation and/or suicidal behavior since the last visit using the electronic version of the scale. The C-SSRS was completed each week; measurements were taken prior to dosing on weeks 5, 9, 13, 17 and 21. | Weekly - Week 2 through Week 24 |