Multiple Dose Study of Blockade of Opioid Effects by Injections of Buprenorphine in Participants With Opioid Disorder

Multiple Dose Study of Blockade of Opioid Effects by Injections of Buprenorphine in Participants With Opioid Disorder

A Multiple-Dose Study of Blockade of Subjective Opioid Effects, Plasma Levels, and Safety of Subcutaneous Injections of Depot Buprenorphine (RBP-6000) in Subjects With Opioid Use Disorder

This is a multiple-dose study in non-treatment seeking male and female subjects with moderate to severe opioid use disorder who meet criteria from the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) to evaluate the effectiveness of RBP-6000 to block the effects of exogenous opioids. The primary objective of this study was to demonstrate that the "Drug Liking" visual analog scale (VAS) measured after challenge with 6 mg (Dose 1) and 18 mg (Dose 2) hydromorphone was noninferior to the "Drug Liking" visual analog scale (VAS) measured after challenge with placebo at Weeks 1-4 post first injection of subcutaneous buprenorphine 300 mg (RBP-6000).

For the hydromorphone challenge testing, subjects were randomized and assigned to 1 of 6 sequences during each week of hydromorphone challenge sessions. On Day -18, subjects who met initial eligibility criteria were admitted to the clinical facility for the baseline hydromorphone challenge. If the subject had acceptable hydromorphone responses to the hydromorphone challenge, they remained confined to the clinical facility for induction on SUBOXONE sublingual film. Once it was confirmed that a subject was experiencing opioid withdrawal, as evidenced by a Clinical Opiate Withdrawal Scale (COWS) score greater than 12, the subject was inducted on SUBOXONE sublingual film. Multiple doses were allowed while subjects were reaching a stable dose until Day -9 when subjects were stabilized on a dose of SUBOXONE 8 mg - 24 mg. SUBOXONE sublingual film was administered daily at approximately the same time of day (± 1 hour) once the dose was stabilised. There was a hydromorphone challenge conducted on days -3 to -1. The last day of SUBOXONE dosing was day -1. On Day 1, participants who met all inclusion/exclusion criteria and dosing criteria stopped receiving SUBOXONE sublingual film and received Injection 1 of RBP-6000 containing 300 mg buprenorphine. Participants returned in the evening of Days 4, 11, 18, and 25 to begin inpatient stays of 3 consecutive days (starting with Days 4-7 [and equivalent for subsequent weeks]). During these inpatient visits, subjects underwent randomised hydromorphone challenges, PK sample collection, Reinforcing Effects Tasks, and safety assessments. On Day 29, participants received the second injection of RBP-6000 containing 300 mg buprenorphine (Injection 2). Participants returned in the evening on Days 32, 39, 46, 53, 60, 67, 74, and 81 to begin inpatient states of 3 consecutive days (starting with days 32-35 [and equivalent for subsequent weeks]). During these inpatient visits, subjects underwent randomised hydromorphone challenges, pharmacokinetic (PK) samples collection, Reinforcing Effects Tasks, and safety assessments. A window of ± 1 day was allowed for all visits, except the Day 53-56 visit, which was required by the protocol to be completed on those days.

All subjects were dispensed the same 300 mg dose of the investigational drug, RBP-6000. They were all also exposed to 0 mg, 6 mg, and 18 mg of hydromorphone for challenges sequentially in a randomized manner.

The investigational drug, RBP-6000, was administered unblinded. The hydromorphone challenges used to measure the effectiveness of RBP-6000 were known and randomized in blinded fashion only to determine the order in which they were administered, with participant and clinical staff blinded to the order of dosing.

Participants were treated with RBP-6000 300-mg in a single subcutaneous injection on Days 1 and 29 following a prior 14 day stabilization period (day -14 to day -1) of buprenorphine and naloxone (SUBOXONE) . Challenges consist of participants receiving on three consecutive days intramuscular (IM) injections of hydromorphone 0 mg (placebo), 6 mg and 18 mg doses during weeks 1-12 in randomized sequential order.

A subcutaneous depot injection of buprenorphine 300 mg was delivered using the ATRIGEL® Delivery System on study days 1 and 29. As the depot degrades, buprenorphine is released into systemic circulation over an extended period of time.

Buprenorphine and naloxone (SUBOXONE® sublingual film) is given to participants on days -14 to day -1 (the SUBOXONE sublingual film stabilization period) or as soon as they start to experience withdrawal symptoms. SUBOXONE sublingual film may be initially administered several times daily until a stable dose between 8 mg and 24 mg daily is established.

Hydromorphone IM challenges are administered during the screening period (days -17 to -15), on days -3 to -1 during the buprenorphine and naloxone (SUBOXONE sublingual film) stabilization period, and weekly during the 12-week treatment period after administration of RBP-6000. Each challenge consists of 3 days during which participants are randomly administered 0 mg (placebo), 6 mg and 18 mg hydromorphone via intramuscular (IM) injection daily in varying blinded sequences. Additionally, hydromorphone can also be earned during the afternoon Reinforcing effects tasks sessions up to the same randomized dose received in the hydromorphone challenge that morning (or money can be chosen).

Opioid Blockade Following Administration of Hydromorphone Challenge As Measured Using the Subjective Opioid Effects Rating for the Question "Do You Like the Drug?" Visual Analog Scale (VAS) at Weeks 1-4 Analyzed by Mixed Model for Repeated Measures

The study's primary objective was to determine if the opioid blocking effect for the first injection of buprenorphine 300 mg (RBP-6000) on Day 1 was not inferior to placebo when challenged by hydromorphone. Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme liking of the drug 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone administration on the challenge days listed in the time frame field. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis.

This outcome reports observed values used in the "Change from Placebo....' endpoint that follows. Reinforcing Effects tasks began >= 5 hours after hydromorphone challenge. Participants made 12 choices between a preference for working for the amount of hydromorphone dosed that day or for money. The hydromorphone break point value is assigned to the highest level of hydromorphone units earned, with 1 unit having a breakpoint value of 5 and 12 units with a value of 2160. A repeated measures mixed-effects analysis of variance (ANOVA) was performed with the log transformed hydromorphone break point value as the dependent variable with period, hydromorphone sequence and hydromorphone dose as fixed effects, and subject nested within hydromorphone sequence as a random effect. Blockade is achieved if the upper bound of the 95% confidence interval is <= to the non-inferiority margin of 11.

Reinforcing Effects Of the Daily Randomized Hydromorphone Challenge as Measured by the Mean Hydromorphone Break Point Value at Weeks 1-12

The ability of RBP-6000 to reduce the reinforcing effects of hydromorphone used money as a choice alternative to hydromorphone. Reinforcing Effects Tasks began no earlier than 5 hours after randomised hydromorphone administration for each day. Each test consisted of the participant making 12 choices between a preference for working for the amount of hydromorphone dosed earlier that day or for money (each choice therefore has a scale of 0-12). The hydromorphone break point value is the ratio of the highest number of choices for hydromorphone to the highest number of choices for money. Hydromorphone breakpoint values were then analysed by week using a repeated measures mixed-effects model with period, hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect. Analyses were carried out on the log10 transformed hydromorphone breakpoint value.

Weeks 1 (Days 5-7), 2 (Days 12-14), 3 (Days 19-21), 4 (Days 26-28), 5 (Days 33-35), 6 (Days 40-42), 7 (Days 47-49), 8 (Days 53-56), 9 (Days 61-63), 10 (Days 68-70), 11 (Days 75-77), 12 (Days 82-84)

TEAE=any untoward medical occurrence that develops or worsens in severity after administration of 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 intervention to prevent one of the outcomes listed above. All adverse events that occurred between Day 1 to Day 91 are reported under the Depot Buprenorphine treatment arm. Adverse events that occurred on the day of a hydromorphone challenge are also reported under the appropriate hydromorphone challenge arm.

Depot Buprenorphine: Day 1 to Day 91. The three hydromorphone challenge levels were randomly assigned to one day in each of the three-day groupings spanning 12 weeks: Days 5-7, 11-14, 19-21, 26-28, 33-35, 40-42, 47-49, 54-56, 61-63, 68-70, 75-77, 82-84

PK Sampling Schedule: Day -17 to -15: before hydromorphone admin Day -4: before Suboxone admin Day 2: 24 hours after RBP-6000 admin Days 5-7, 12-14, 19-21 and 26-28: immediately before hydromorphone admin Days 29: before RBP-6000 admin Day 30: 24 hours after RBP-6000 admin Days 33-35, 40-42, 47-49, 54-56, 61-63, 68-70, 75-77, and 82-84: immediately before hydromorphone admin

A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to model the relationship between buprenorphine plasma concentrations and brain μORO based on 2 published clinical trials. This model used individual buprenorphine plasma concentrations measured to derive muORO individual predictions that were further described using summary statistics. The relationship between buprenorphine plasma concentration and μORO was best described by a maximal effect (Emax) model: µORO = E(max)*Cp / EC(50) + Cp Where Cp is the plasma concentration of buprenorphine, Emax is the maximal μORO, and EC50 is the plasma concentration of buprenorphine that is expected to achieve 50% of the maximal μORO. A direct (instantaneous) relationship between buprenorphine plasma concentration and µORO, i.e. without equilibration delay, was assumed. Row title format: Study Week: buprenorphine plasma concentrations for placebo/ 6 mg / 18 mg challenge dosages

Change From Placebo in Reinforcing Effects (Breakpoint) by Study Week and Simulated mu Opioid Receptor Occupancy (μORO)

This endpoint explores the correlation between the reinforcing effects of hydromorphone and simulated mu opioid receptor occupancy. Data are reported as change from placebo least square mean of Log10 transformed values for reinforcing effects. Reinforcing Effects tasks began >= 5 hours after hydromorphone challenge. Participants made 12 choices between a preference for working for the amount of hydromorphone dosed that day or for money. The hydromorphone break point value is assigned to the highest level of hydromorphone units earned, with 1 unit having a breakpoint value of 5 and 12 units with a value of 2160. Change from placebo was calculated as Active Challenge result - Placebo Challenge result. Values that approach 0 (implying little difference between the Active Challenge result and the Placebo Challenge result) indicate effectiveness of the opioid blockade. Row titles include Study Week: predicted mu opioid receptor occupancy for 6 mg / 18 mg challenge dosages

Visual Analog Scale (VAS) Score for "Do You Like the Drug?" by Study Week Analyzed by Mixed Model for Repeated Measures

This outcome reports observed values used in the "Change from Placebo....' endpoint that follows. Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme liking of the drug 30 minutes before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis. Blockade is achieved if the upper bound of the 95% confidence interval is <= to the non-inferiority margin of 11.

Change From Placebo in VAS Score for "Do You Like the Drug?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO)

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme liking of the drug 30 minutes before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis. Change from placebo was calculated as Active Challenge result - Placebo Challenge result. Values that approach 0 (implying little difference between the Active Challenge result and the Placebo Challenge result) indicate effectiveness of the opioid blockade. Row titles include Study Week: mean predicted mu opioid receptor occupancy for 6 mg / 18 mg challenge dosages

VAS Score for "How High Are You Right Now?" by Study Week Analyzed by Mixed Model for Repeated Measures

This outcome reports observed values used in the "Change from Placebo....' endpoint that follows. Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme high from the drug 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis. Blockade is achieved if the upper bound of the 95% confidence interval is <= to the non-inferiority margin of 11.

Change From Placebo in VAS Score for "How High Are You Right Now?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO)

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme high from the drug 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis. Change from placebo was calculated as Active Challenge result - Placebo Challenge result. Values that approach 0 (implying little difference between the Active Challenge result and the Placebo Challenge result) indicate effectiveness of the opioid blockade. Row titles include Study Week: mean predicted mu opioid receptor occupancy 6 mg / 18 mg

VAS Score for "Do You Feel Any Drug Effect?" by Study Week Analyzed by Mixed Model for Repeated Measures

This outcome reports observed values used in the "Change from Placebo....' endpoint that follows. Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme drug effect 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis. Blockade is achieved if the upper bound of the 95% confidence interval is <= to the non-inferiority margin of 11.

Change From Placebo in VAS Score for "Do You Feel Any Drug Effect?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO)

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme drug effect 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis. Change from placebo was calculated as Active Challenge result - Placebo Challenge result. Values that approach 0 (implying little difference between the Active Challenge result and the Placebo Challenge result) indicate effectiveness of the opioid blockade. Row titles include Study Week: mean predicted mu opioid receptor occupancy for 6 mg / 18 mg challenge dosages

VAS Score for "Does the Drug Have Any Good Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures

This outcome reports observed values used in the "Change from Placebo....' endpoint that follows. Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme good effect 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis. Blockade is achieved if the upper bound of the 95% confidence interval is <= to the non-inferiority margin of 11.

Change From Placebo in VAS Score for "Does the Drug Have Any Good Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO)

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme good effect 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis. Change from placebo was calculated as Active Challenge result - Placebo Challenge result. Values that approach 0 (implying little difference between the Active Challenge result and the Placebo Challenge result) indicate effectiveness of the opioid blockade. Row titles include Study Week: mean predicted mu opioid receptor occupancy for 6 mg / 18 mg challenge dosages

VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures

This outcome reports observed values used in the "Change from Placebo....' endpoint that follows. Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme bad effect 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis. Blockade is achieved if the upper bound of the 95% confidence interval is <= to the non-inferiority margin of 11.

Change From Placebo in VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO)

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme bad effect 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis. Change from placebo was calculated as Active Challenge result - Placebo Challenge result. Values that approach 0 (implying little difference between the Active Challenge result and the Placebo Challenge result) indicate effectiveness of the opioid blockade. Row titles include Study Week: mean predicted mu opioid receptor occupancy for 6 mg / 18 mg challenge dosages

This outcome reports observed values used in the "Change from Placebo....' endpoint that follows. Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme sedation 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis. Blockade is achieved if the upper bound of the 95% confidence interval is <= to the non-inferiority margin of 11.

Change From Placebo in VAS Score for "Do You Feel Sedated?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO)

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme sedation 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis. Change from placebo was calculated as Active Challenge result - Placebo Challenge result. Values that approach 0 (implying little difference between the Active Challenge result and the Placebo Challenge result) indicate effectiveness of the opioid blockade. Row titles include Study Week: mean predicted mu opioid receptor occupancy for 6 mg / 18 mg challenge dosages

Inclusion Criteria: Meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for moderate or severe opioid use disorder at screening and are not seeking opioid use disorder treatment Body mass index of >= 18.0 to <= 33.0 kg/m^2 Females - women of childbearing potential (defined as all women who are not surgically sterile or postmenopausal for at least 1 year prior to informed consent) must have negative pregnancy test prior to enrollment and must agree to use a medically acceptable means of contraception from screening through at least 3 months after the last dose of study drug Male subjects with female partners of child-bearing potential must agree to use medically acceptable contraception from screening through at least 3 months after the last dose of study drug Exclusion Criteria: Subjects with any current diagnosis requiring chronic opioid treatment Subjects who currently meet the criteria for diagnosis of moderate or severe substance use disorder by DSM-5 criteria for any substances other than opioids, caffeine, or nicotine. Subjects who have abused or used buprenorphine within 14 days prior to informed consent. Other protocol-defined criteria may apply.

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