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

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.

Time frame: Weeks 1 (Days 5-7), 2 (Days 12-14), 3 (Days 19-21), 4 (Days 26-28)

Population: The intent-to-treat (ITT) population included all subjects who received at least 1 dose of RBP-6000 and had at least 1 complete sequence (i.e., 0 mg \[placebo\], 6 mg and 18 mg hydromorphone in the randomised order) of hydromorphone challenges following administration of RBP-6000.

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

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT population.

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

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT population.

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

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT population.

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

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT population.

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

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT population.

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

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT population.

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

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT population.

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.

Time frame: 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

Population: Safety; one participant was administered the first RBP-6000 injection but no hydromorphone challenges. Investigators did not assess AEs for potential relatedness to hydromorphone.

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

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT

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

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT population

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.

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT population.

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.

Time frame: 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)

Population: Intent to treat population

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.

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT population.

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.

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT population.

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.

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT population.

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.

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT population.

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.

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT population.

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.

Time frame: Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)

Population: ITT population.