Safety and Tolerability Study of Depot Buprenorphine in Treatment Seeking Subjects With Opioid Use Disorder

Study Overview
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Brief Summary
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A multi-center, open-label, long-term safety study in which approximately 600 subjects diagnosed with opioid use disorder will be enrolled. Following a screening period, all subjects will receive run in SUBOXONE sublingual film followed by an initial injection of open-label high dose (300 mg) RBP-6000. The RBP-6000 monthly injection dose can be adjusted to low dose (100 mg), and back to high dose, based on the medical judgment of the Investigator. Subjects will participate in the study for either 6 or 12 months.

Detailed Description
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Approximately 600 subjects diagnosed with opioid use disorder will be enrolled; approximately 300 subjects who completed the randomized,double-blind, placebo-controlled study NCT02357901 (RB-US-13-0001) ('roll-over' participants), and approximately 300 subjects who did not participate in study RB-US-13-0001 ('de novo' participants). Following informed consent and completion of screening procedures, all subjects will receive SUBOXONE sublingual film, titrated to response. After 4-14 days of SUBOXONE sublingual film treatment, subjects will be evaluated for enrollment into the study. Eligible subjects will receive 300 mg RBP-6000 as an initial dose, followed by monthly injections of 100 mg or 300 mg RBP-6000, based on the medical judgment of the investigator. Subjects who participated in study RB-US-13-0001 ('roll-over' participants) will receive monthly injections for up to 6 months. Subjects who did not participate in study RB-US-13-0001 ('de novo' participants) will receive monthly injections for up to12 months. At all injection visits continuous electrocardiogram recordings and pulse oximetry will be collected prior to injection and at least 4 hours after injection. Subjects will return to the clinic every 1-4 weeks for laboratory tests, complete study questionnaires, adverse event and injection site assessments.

Official Title
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An Open-Label, Long-Term Safety and Tolerability Study of Depot Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With Opioid Use Disorder

Conditions
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Opioid Use Disorder, Opioid-related Disorders

Intervention / Treatment
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* Drug: SUBOXONE sublingual film
* Drug: RBP-6000


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: De novo subjects: Seeking treatment for opioid use disorder (OUD) and for the previous 3 months meet the Diagnostic and Statistical Manual 5 (DSM-5) criteria for moderate or severe OUD Appropriate candidate for opioid partial-agonist treatment BMI between 18 and 35, inclusive Roll-over subjects: Completed RB-US-13-0001 Exclusion Criteria: De novo subjects: Current diagnosis, other than OUD, requiring chronic opioid treatment Current substance use disorder with regard to substances other than opioids, cocaine, cannabis, tobacco or alcohol Received medication-assisted treatment for OUD in the 90 days prior to informed consent Use (within past 30 days prior to informed consent) or positive urine drug screen (UDS) at screening for barbiturates, benzodiazepines,methadone or buprenorphine Treatment for OUD required by court order History of recent suicidal ideation or attempt Roll over subjects: Experienced major protocol deviations or adverse events in RB-US-13-0001 which could potentially compromise subject safety Discontinued early from study RB-US-13-0001

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Roll-over Subjects<br>Subjects who completed RB-US-13-0001 received SUBOXONE sublingual film during the Run-In period, followed by an initial open-label injection of 300 mg RBP-6000. Participants continued with monthly injections of either 300 mg or 100 mg (based on judgement of the Investigator) for a total of 6 months in the Treatment period. | Drug: SUBOXONE sublingual film<br>* SUBOXONE (buprenorphine sublingual film) is used for induction therapy on Days -14 to -12. Participants then complete a 4-to-11 day sublingual film dose adjustment at doses ranging from 8 mg to 24 mg sublingual film prior to starting the Treatment Period.<br>* Other names: buprenorphine;Drug: RBP-6000<br>* Injections administered subcutaneously every 28 days on alternate sides of participant's abdomen starting at 300 mg. Subsequent doses of RBP-6000 could be adjusted down to 100 mg with the possibility of adjusting back up to 300 mg based on the medical judgment of the investigator. De novo subjects receive up to 12 injections and roll-over subjects receive up to 6 injections.<br>* Other names: Atrigel buprenorphine;|
| Experimental: De Novo Subjects<br>Subjects who did not participate in RB-US-13-0001 received SUBOXONE sublingual film during the Run-In period, followed by an initial open-label injection of 300 mg RBP-6000. Participants continued with monthly injections of either 300 mg or 100 mg (based on judgement of the Investigator) for a total of 12 months in the Treatment period. | Drug: SUBOXONE sublingual film<br>* SUBOXONE (buprenorphine sublingual film) is used for induction therapy on Days -14 to -12. Participants then complete a 4-to-11 day sublingual film dose adjustment at doses ranging from 8 mg to 24 mg sublingual film prior to starting the Treatment Period.<br>* Other names: buprenorphine;Drug: RBP-6000<br>* Injections administered subcutaneously every 28 days on alternate sides of participant's abdomen starting at 300 mg. Subsequent doses of RBP-6000 could be adjusted down to 100 mg with the possibility of adjusting back up to 300 mg based on the medical judgment of the investigator. De novo subjects receive up to 12 injections and roll-over subjects receive up to 6 injections.<br>* Other names: Atrigel buprenorphine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Treatment-Emergent Adverse Events (TEAE) During the Treatment Period | 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 to Week 49 (De novo arm); Day 1 to Week 25 (Roll-over arm) | 
| Percentage Change From Baseline to End of Study (Weeks 25 and 49) in Vital Signs | Vital signs include systolic blood pressure (mmHg) diastolic blood pressure (mmHg) respiratory rate (breaths/minute) weight (kg) body mass index (kg/m^2) waist-to-hip ratio Baseline is defined as the last non-missing value prior to subcutaneous injection of RBP-6000 on Day 1. | Baseline (Day 1 predose) End of Study: Week 49 (De novo arm); Week 25 (Roll-over arm) | 
| Shifts in Suicidality Using the Columbia Suicide Severity Rating Scale (C-SSRS) From Baseline to Most Severe Assessment During the Treatment Period | 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. Only the most severe assessment is reported in this summary. Participants who experienced suicidal ideation and suicidal behavior are only summarized in the suicidal behavior since behavior is more severe than ideation. C-SSRS baseline version was completed during the screening visit. C-SSRS 'since-last-visit' version was completed weekly for the first month and at least every month until the end of the study. Shift table category titles are structured as: baseline category/treatment category. The category 'No Suicidal Ideation or Behaviour' has been abbreviated as 'No Suicidal I or B'. | Baseline (Screening visit, days -21 to -15), End of Study: Week 49 (De novo arm); Week 25 (Roll-over arm) | 
| Worst Local Injection Site Pain From Injections 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' at 0 mm and 'strongest pain ever' at 100 mm (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 and 60 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 injections and all VAS records. The mean value is presented. De Novo subjects were given injections on Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281 and 309. Roll-over subjects were given injections on Days 1, 29, 57, 85, 113, 141. | De Novo Subjects: Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281 and 309 Roll-over Subjects: Days 1, 29, 57, 85, 113, 141 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Clinical Opiate Withdrawal Scale (COWS) at End of Study (Weeks 25 and 49) | COWS is an 11-item instrument used to assess signs and symptoms of opioid withdrawal. 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. Baseline value is reported as an observed actual value. Weeks 25 and 49 represent change from baseline values. | Baseline (Day 1 predose), End of Study: Week 49 (De novo arm); Week 25 (Roll-over arm) | 
| Change From Baseline in the Subjective Opiate Withdrawal Scale (SOWS) at End of Study (Weeks 25 and 49) | 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. Baseline value is reported as an observed actual value. Weeks 25 and 49 represent change from baseline values. | Baseline (Day 1 predose), End of Study: Week 49 (De novo arm); Week 25 (Roll-over arm) | 
| Change From Baseline in the Opioid Craving Visual Analog Scale (VAS) at End of Study (Weeks 25 and 49) | The opioid craving scale was a 100 mm scale with 'no craving' indicated by 0 mm and 'strongest craving ever' indicated by 100 mm. Participants marked where along the scale reflected their craving for opioids. Baseline was defined as the last non-missing value prior to subcutaneous injection on Day 1. Baseline value is reported as an observed actual value. Weeks 25 and 49 represent change from baseline values. | Baseline (Day 1 predose), End of Study: Week 49 (De novo arm); Week 25 (Roll-over arm) | 
| Cumulative Distribution Function (CDF) of the Percentage Abstinence Collected From Week 1 Through End of Study (Weeks 25 and 49) | Participants' self-reported illicit opioid drug use from the timeline followback (TLFB) interview and results from the urine drug screens (UDS) for opioids were combined into a single endpoint. Opioids assessed included codeine, hydrocodone, hydromorphone, methadone, morphine, opiates, oxycodone, and oxymorphone (by UDS) and amphetamine/methadone, buprenorphine, methadone, and opioids in the TLFB. 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 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. All missing reports for opioids were considered nonnegative. | Weekly during Month 1, Every other week from Month 2-6, Monthly from Month 7-12. De novo arm stopped at Week 49. Roll-over arm stopped at Week 25 |