Trial Outcomes & Findings for Multiple Dose Study of Blockade of Opioid Effects by Injections of Buprenorphine in Participants With Opioid Disorder (NCT NCT02044094)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

39 participants

Primary outcome timeframe

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

Results posted on

2018-04-24

Participant Flow

A total of 342 subjects signed an informed consent with 39 subjects being enrolled and randomized to the sequential order of hydromorphone challenges to be received. The most common reason for not being randomized was due to the study exclusion criteria being met.

Participant milestones

Participant milestones
Measure	Depot Buprenorphine Participants were treated with RBP-6000 300-mg in a single subcutaneous injection on Days 1 and 29. Challenges consist of participants receiving on three consecutive days intramuscular (IM) injections of hydromorphone randomly assigned at 0 mg (placebo), 6 mg and 18 mg doses during weeks 1-12.
RBP-6000 Injection 1 (Day 1 to Day 28) STARTED	39
RBP-6000 Injection 1 (Day 1 to Day 28) Intent to Treat Population	38
RBP-6000 Injection 1 (Day 1 to Day 28) Completers Population	30
RBP-6000 Injection 1 (Day 1 to Day 28) COMPLETED	30
RBP-6000 Injection 1 (Day 1 to Day 28) NOT COMPLETED	9
RBP-6000 Injection 2 (Day 29 to Week 12) STARTED	30
RBP-6000 Injection 2 (Day 29 to Week 12) COMPLETED	17
RBP-6000 Injection 2 (Day 29 to Week 12) NOT COMPLETED	13

Reasons for withdrawal

Reasons for withdrawal
Measure	Depot Buprenorphine Participants were treated with RBP-6000 300-mg in a single subcutaneous injection on Days 1 and 29. Challenges consist of participants receiving on three consecutive days intramuscular (IM) injections of hydromorphone randomly assigned at 0 mg (placebo), 6 mg and 18 mg doses during weeks 1-12.
RBP-6000 Injection 1 (Day 1 to Day 28) Lost to Follow-up	3
RBP-6000 Injection 1 (Day 1 to Day 28) Physician Decision	3
RBP-6000 Injection 1 (Day 1 to Day 28) Withdrawal by Subject	3
RBP-6000 Injection 2 (Day 29 to Week 12) Adverse Event	4
RBP-6000 Injection 2 (Day 29 to Week 12) Lost to Follow-up	5
RBP-6000 Injection 2 (Day 29 to Week 12) Withdrawal by Subject	2
RBP-6000 Injection 2 (Day 29 to Week 12) Physician Decision	1
RBP-6000 Injection 2 (Day 29 to Week 12) Noncompliance	1

Baseline Characteristics

36 of 39 participants had a smoking history.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Depot Buprenorphine n=39 Participants Participants were treated with RBP-6000 300-mg in a single subcutaneous injection on Days 1 and 29. Challenges consist of participants receiving on three consecutive days intramuscular (IM) injections of hydromorphone randomly assigned at 0 mg (placebo), 6 mg and 18 mg doses during weeks 1-12.
Age, Continuous	34.6 years STANDARD_DEVIATION 8.93 • n=39 Participants
Sex: Female, Male Female	4 Participants n=39 Participants
Sex: Female, Male Male	35 Participants n=39 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=39 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	38 Participants n=39 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=39 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=39 Participants
Race (NIH/OMB) Asian	2 Participants n=39 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=39 Participants
Race (NIH/OMB) Black or African American	12 Participants n=39 Participants
Race (NIH/OMB) White	25 Participants n=39 Participants
Race (NIH/OMB) More than one race	0 Participants n=39 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=39 Participants
Weight	79.55 kg STANDARD_DEVIATION 11.178 • n=39 Participants
Height	176.99 cm STANDARD_DEVIATION 6.421 • n=39 Participants
Body Mass Index	25.35 kg/m^2 STANDARD_DEVIATION 3.017 • n=39 Participants
Smoking History (Nicotine Use)	19.03 years STANDARD_DEVIATION 8.962 • n=36 Participants • 36 of 39 participants had a smoking history.

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
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 Week 1	1.447 units on a scale Standard Error 1.638	5.103 units on a scale Standard Error 1.639	8.374 units on a scale Standard Error 1.638	—
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 Week 2	1.850 units on a scale Standard Error 1.216	2.436 units on a scale Standard Error 1.200	4.750 units on a scale Standard Error 1.200	—
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 Week 3	1.320 units on a scale Standard Error 1.476	2.183 units on a scale Standard Error 1.476	6.246 units on a scale Standard Error 1.475	—
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 Week 4	0.534 units on a scale Standard Error 2.214	3.849 units on a scale Standard Error 2.214	7.211 units on a scale Standard Error 2.214	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
Reinforcing Effects (Breakpoint) by Study Week Analyzed by Mixed Model for Repeated Measures Baseline Week -1	4.984 units on a scale Interval 4.443 to 5.525	7.121 units on a scale Interval 6.746 to 7.497	7.042 units on a scale Interval 6.666 to 7.418	—
Reinforcing Effects (Breakpoint) by Study Week Analyzed by Mixed Model for Repeated Measures Week 1	4.767 units on a scale Interval 4.147 to 5.388	5.379 units on a scale Interval 4.784 to 5.975	5.708 units on a scale Interval 5.148 to 6.267	—
Reinforcing Effects (Breakpoint) by Study Week Analyzed by Mixed Model for Repeated Measures Week 2	4.036 units on a scale Interval 3.229 to 4.842	4.779 units on a scale Interval 4.011 to 5.546	5.496 units on a scale Interval 4.835 to 6.157	—
Reinforcing Effects (Breakpoint) by Study Week Analyzed by Mixed Model for Repeated Measures Week 3	4.760 units on a scale Interval 4.049 to 5.471	5.706 units on a scale Interval 5.024 to 6.388	5.669 units on a scale Interval 5.014 to 6.324	—
Reinforcing Effects (Breakpoint) by Study Week Analyzed by Mixed Model for Repeated Measures Week 4	4.144 units on a scale Interval 3.382 to 4.907	5.533 units on a scale Interval 4.799 to 6.268	6.030 units on a scale Interval 5.326 to 6.733	—
Reinforcing Effects (Breakpoint) by Study Week Analyzed by Mixed Model for Repeated Measures Week 5	4.564 units on a scale Interval 3.549 to 5.578	4.470 units on a scale Interval 3.517 to 5.424	4.936 units on a scale Interval 4.037 to 5.835	—
Reinforcing Effects (Breakpoint) by Study Week Analyzed by Mixed Model for Repeated Measures Week 6	4.303 units on a scale Interval 3.21 to 5.396	4.419 units on a scale Interval 3.357 to 5.48	5.282 units on a scale Interval 4.291 to 6.273	—
Reinforcing Effects (Breakpoint) by Study Week Analyzed by Mixed Model for Repeated Measures Week 7	5.092 units on a scale Interval 3.745 to 6.44	5.808 units on a scale Interval 4.455 to 7.161	5.965 units on a scale Interval 4.628 to 7.303	—
Reinforcing Effects (Breakpoint) by Study Week Analyzed by Mixed Model for Repeated Measures Week 8	3.899 units on a scale Interval 2.78 to 5.019	4.418 units on a scale Interval 3.341 to 5.494	4.747 units on a scale Interval 3.646 to 5.849	—
Reinforcing Effects (Breakpoint) by Study Week Analyzed by Mixed Model for Repeated Measures Week 9	4.342 units on a scale Interval 3.116 to 5.568	4.432 units on a scale Interval 3.383 to 5.481	5.437 units on a scale Interval 4.506 to 6.368	—
Reinforcing Effects (Breakpoint) by Study Week Analyzed by Mixed Model for Repeated Measures Week 10	4.546 units on a scale Interval 2.97 to 6.122	4.578 units on a scale Interval 2.995 to 6.161	4.997 units on a scale Interval 3.444 to 6.551	—
Reinforcing Effects (Breakpoint) by Study Week Analyzed by Mixed Model for Repeated Measures Week 11	4.330 units on a scale Interval 2.958 to 5.702	4.114 units on a scale Interval 2.865 to 5.364	5.076 units on a scale Interval 3.906 to 6.247	—
Reinforcing Effects (Breakpoint) by Study Week Analyzed by Mixed Model for Repeated Measures Week 12	4.029 units on a scale Interval 3.151 to 4.906	4.623 units on a scale Interval 3.588 to 5.659	5.615 units on a scale Interval 4.726 to 6.503	—

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
Reinforcing Effects Of the Daily Randomized Hydromorphone Challenge as Measured by the Mean Hydromorphone Break Point Value at Weeks 1-12 Week 1	2.070 log10 transformed ratio Standard Error 0.134	2.336 log10 transformed ratio Standard Error 0.129	2.479 log10 transformed ratio Standard Error 0.120	—
Reinforcing Effects Of the Daily Randomized Hydromorphone Challenge as Measured by the Mean Hydromorphone Break Point Value at Weeks 1-12 Week 2	1.753 log10 transformed ratio Standard Error 0.175	2.075 log10 transformed ratio Standard Error 0.166	2.387 log10 transformed ratio Standard Error 0.142	—
Reinforcing Effects Of the Daily Randomized Hydromorphone Challenge as Measured by the Mean Hydromorphone Break Point Value at Weeks 1-12 Week 3	2.067 log10 transformed ratio Standard Error 0.153	2.478 log10 transformed ratio Standard Error 0.146	2.462 log10 transformed ratio Standard Error 0.140	—
Reinforcing Effects Of the Daily Randomized Hydromorphone Challenge as Measured by the Mean Hydromorphone Break Point Value at Weeks 1-12 Week 4	1.800 log10 transformed ratio Standard Error 0.164	2.403 log10 transformed ratio Standard Error 0.158	2.619 log10 transformed ratio Standard Error 0.151	—
Reinforcing Effects Of the Daily Randomized Hydromorphone Challenge as Measured by the Mean Hydromorphone Break Point Value at Weeks 1-12 Week 5	1.982 log10 transformed ratio Standard Error 0.217	1.941 log10 transformed ratio Standard Error 0.203	2.144 log10 transformed ratio Standard Error 0.190	—
Reinforcing Effects Of the Daily Randomized Hydromorphone Challenge as Measured by the Mean Hydromorphone Break Point Value at Weeks 1-12 Week 6	1.869 log10 transformed ratio Standard Error 0.232	1.919 log10 transformed ratio Standard Error 9.224	2.294 log10 transformed ratio Standard Error 0.208	—
Reinforcing Effects Of the Daily Randomized Hydromorphone Challenge as Measured by the Mean Hydromorphone Break Point Value at Weeks 1-12 Week 7	2.212 log10 transformed ratio Standard Error 0.277	2.522 log10 transformed ratio Standard Error 0.278	2.591 log10 transformed ratio Standard Error 0.274	—
Reinforcing Effects Of the Daily Randomized Hydromorphone Challenge as Measured by the Mean Hydromorphone Break Point Value at Weeks 1-12 Week 8	1.694 log10 transformed ratio Standard Error 0.232	1.919 log10 transformed ratio Standard Error 0.220	2.062 log10 transformed ratio Standard Error 0.227	—
Reinforcing Effects Of the Daily Randomized Hydromorphone Challenge as Measured by the Mean Hydromorphone Break Point Value at Weeks 1-12 Week 9	1.886 log10 transformed ratio Standard Error 0.262	1.925 log10 transformed ratio Standard Error 0.224	2.361 log10 transformed ratio Standard Error 0.197	—
Reinforcing Effects Of the Daily Randomized Hydromorphone Challenge as Measured by the Mean Hydromorphone Break Point Value at Weeks 1-12 Week 10	1.974 log10 transformed ratio Standard Error 0.310	1.988 log10 transformed ratio Standard Error 0.313	2.170 log10 transformed ratio Standard Error 0.302	—
Reinforcing Effects Of the Daily Randomized Hydromorphone Challenge as Measured by the Mean Hydromorphone Break Point Value at Weeks 1-12 Week 11	1.880 log10 transformed ratio Standard Error 0.289	1.787 log10 transformed ratio Standard Error 0.261	2.205 log10 transformed ratio Standard Error 0.242	—
Reinforcing Effects Of the Daily Randomized Hydromorphone Challenge as Measured by the Mean Hydromorphone Break Point Value at Weeks 1-12 Week 12	1.750 log10 transformed ratio Standard Error 0.180	2.008 log10 transformed ratio Standard Error 0.217	2.438 log10 transformed ratio Standard Error 0.183	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo n=39 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge n=38 Participants Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
Participants With Treatment-Emergent Adverse Events (TEAE) >=1 TEAE	39 Participants	29 Participants	26 Participants	25 Participants
Participants With Treatment-Emergent Adverse Events (TEAE) >=1 TEAE related to study drug	25 Participants	—	—	—
Participants With Treatment-Emergent Adverse Events (TEAE) >=1 Severe TEAE	0 Participants	0 Participants	0 Participants	0 Participants
Participants With Treatment-Emergent Adverse Events (TEAE) Deaths	0 Participants	0 Participants	0 Participants	0 Participants
Participants With Treatment-Emergent Adverse Events (TEAE) >=1 SAE other than death	0 Participants	0 Participants	0 Participants	0 Participants
Participants With Treatment-Emergent Adverse Events (TEAE) Withdrew from study due to a TEAE	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

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

Population: ITT

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

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
Plasma Concentrations of Buprenorphine Summarized by Study Week Week 3	1.933 ng/mL Standard Deviation 0.657	1.882 ng/mL Standard Deviation 0.663	1.916 ng/mL Standard Deviation 0.606	—
Plasma Concentrations of Buprenorphine Summarized by Study Week Week 4	1.722 ng/mL Standard Deviation 0.648	1.776 ng/mL Standard Deviation 0.602	1.812 ng/mL Standard Deviation 0.633	—
Plasma Concentrations of Buprenorphine Summarized by Study Week Week 5	3.684 ng/mL Standard Deviation 1.174	3.649 ng/mL Standard Deviation 1.122	3.667 ng/mL Standard Deviation 1.035	—
Plasma Concentrations of Buprenorphine Summarized by Study Week Week 6	3.423 ng/mL Standard Deviation 1.082	3.530 ng/mL Standard Deviation 1.104	3.521 ng/mL Standard Deviation 1.181	—
Plasma Concentrations of Buprenorphine Summarized by Study Week Week 7	3.427 ng/mL Standard Deviation 1.121	3.495 ng/mL Standard Deviation 1.107	3.466 ng/mL Standard Deviation 1.136	—
Plasma Concentrations of Buprenorphine Summarized by Study Week Week -1	0.000 ng/mL Standard Deviation 0.000	0.000 ng/mL Standard Deviation 0.000	0.000 ng/mL Standard Deviation 0.000	—
Plasma Concentrations of Buprenorphine Summarized by Study Week Week 1	2.030 ng/mL Standard Deviation 0.717	2.164 ng/mL Standard Deviation 0.882	2.042 ng/mL Standard Deviation 0.765	—
Plasma Concentrations of Buprenorphine Summarized by Study Week Week 2	1.892 ng/mL Standard Deviation 0.637	1.874 ng/mL Standard Deviation 0.605	1.970 ng/mL Standard Deviation 0.764	—
Plasma Concentrations of Buprenorphine Summarized by Study Week Week 8	3.326 ng/mL Standard Deviation 1.217	3.365 ng/mL Standard Deviation 1.160	3.497 ng/mL Standard Deviation 1.304	—
Plasma Concentrations of Buprenorphine Summarized by Study Week Week 9	3.156 ng/mL Standard Deviation 1.103	3.122 ng/mL Standard Deviation 1.030	3.210 ng/mL Standard Deviation 1.200	—
Plasma Concentrations of Buprenorphine Summarized by Study Week Week 10	2.985 ng/mL Standard Deviation 1.074	3.039 ng/mL Standard Deviation 3.193	1.150 ng/mL Standard Deviation 1.136	—
Plasma Concentrations of Buprenorphine Summarized by Study Week Week 11	3.117 ng/mL Standard Deviation 1.257	2.985 ng/mL Standard Deviation 3.081	1.083 ng/mL Standard Deviation 1.124	—
Plasma Concentrations of Buprenorphine Summarized by Study Week Week 12	2.626 ng/mL Standard Deviation 0.956	2.646 ng/mL Standard Deviation 1.039	2.624 ng/mL Standard Deviation 0.945	—

SECONDARY outcome

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

Population: ITT population

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

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
Predicted mu Opioid Receptor Occupancy (μORO) by Mean Buprenorphine Concentrations and Study Week Baseline Week -1: 0.00/0.00/0.00	0.000 percentage receptor occupancy Standard Deviation 0.000	0.000 percentage receptor occupancy Standard Deviation 0.000	0.000 percentage receptor occupancy Standard Deviation 0.000	—
Predicted mu Opioid Receptor Occupancy (μORO) by Mean Buprenorphine Concentrations and Study Week Week 1: 2.03/2.16/2.04	67.077 percentage receptor occupancy Standard Deviation 6.675	67.875 percentage receptor occupancy Standard Deviation 6.806	67.089 percentage receptor occupancy Standard Deviation 6.591	—
Predicted mu Opioid Receptor Occupancy (μORO) by Mean Buprenorphine Concentrations and Study Week Week 2: 1.89/1.87/1.97	66.071 percentage receptor occupancy Standard Deviation 6.240	66.059 percentage receptor occupancy Standard Deviation 5.692	66.485 percentage receptor occupancy Standard Deviation 6.670	—
Predicted mu Opioid Receptor Occupancy (μORO) by Mean Buprenorphine Concentrations and Study Week Week 3: 1.93/1.88/1.92	66.442 percentage receptor occupancy Standard Deviation 6.108	66.000 percentage receptor occupancy Standard Deviation 6.010	66.438 percentage receptor occupancy Standard Deviation 5.934	—
Predicted mu Opioid Receptor Occupancy (μORO) by Mean Buprenorphine Concentrations and Study Week Week 4: 1.72/1.78/1.81	64.270 percentage receptor occupancy Standard Deviation 6.116	65.108 percentage receptor occupancy Standard Deviation 5.534	65.349 percentage receptor occupancy Standard Deviation 5.848	—
Predicted mu Opioid Receptor Occupancy (μORO) by Mean Buprenorphine Concentrations and Study Week Week 5: 3.68/3.65/3.67	76.346 percentage receptor occupancy Standard Deviation 4.031	76.285 percentage receptor occupancy Standard Deviation 3.938	76.417 percentage receptor occupancy Standard Deviation 3.856	—
Predicted mu Opioid Receptor Occupancy (μORO) by Mean Buprenorphine Concentrations and Study Week Week 6: 3.42/3.53/3.52	75.432 percentage receptor occupancy Standard Deviation 4.156	75.699 percentage receptor occupancy Standard Deviation 4.685	75.686 percentage receptor occupancy Standard Deviation 4.366	—
Predicted mu Opioid Receptor Occupancy (μORO) by Mean Buprenorphine Concentrations and Study Week Week 7: 3.43/3.50/3.47	75.351 percentage receptor occupancy Standard Deviation 4.347	75.641 percentage receptor occupancy Standard Deviation 4.373	75.429 percentage receptor occupancy Standard Deviation 4.601	—
Predicted mu Opioid Receptor Occupancy (μORO) by Mean Buprenorphine Concentrations and Study Week Week 8: 3.33/3.37/3.50	74.544 percentage receptor occupancy Standard Deviation 5.419	74.792 percentage receptor occupancy Standard Deviation 5.495	75.179 percentage receptor occupancy Standard Deviation 5.302	—
Predicted mu Opioid Receptor Occupancy (μORO) by Mean Buprenorphine Concentrations and Study Week Week 9: 3.16/3.12/3.21	74.000 percentage receptor occupancy Standard Deviation 5.314	73.970 percentage receptor occupancy Standard Deviation 5.131	74.036 percentage receptor occupancy Standard Deviation 5.692	—
Predicted mu Opioid Receptor Occupancy (μORO) by Mean Buprenorphine Concentrations and Study Week Week 10: 2.99/3.04/3.19	73.002 percentage receptor occupancy Standard Deviation 6.288	73.075 percentage receptor occupancy Standard Deviation 6.579	74.179 percentage receptor occupancy Standard Deviation 5.355	—
Predicted mu Opioid Receptor Occupancy (μORO) by Mean Buprenorphine Concentrations and Study Week Week 11: 3.12/2.99/3.08	73.385 percentage receptor occupancy Standard Deviation 6.382	73.054 percentage receptor occupancy Standard Deviation 6.099	73.507 percentage receptor occupancy Standard Deviation 5.904	—
Predicted mu Opioid Receptor Occupancy (μORO) by Mean Buprenorphine Concentrations and Study Week Week 12: 2.63/2.65/2.62	71.274 percentage receptor occupancy Standard Deviation 5.946	71.313 percentage receptor occupancy Standard Deviation 5.933	71.303 percentage receptor occupancy Standard Deviation 5.863	—

SECONDARY outcome

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

Population: ITT population.

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

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
Change From Placebo in Reinforcing Effects (Breakpoint) by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Baseline Week -1: 0.00/0.00 %	0.93 log10 transformed ratio Interval 0.67 to 1.18	0.89 log10 transformed ratio Interval 0.64 to 1.17	—	—
Change From Placebo in Reinforcing Effects (Breakpoint) by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 1: 67.88/67.09 %	0.27 log10 transformed ratio Interval -0.001 to 0.53	0.41 log10 transformed ratio Interval 0.15 to 0.67	—	—
Change From Placebo in Reinforcing Effects (Breakpoint) by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 2: 66.06/66.49 %	0.32 log10 transformed ratio Interval -0.05 to 0.7	0.63 log10 transformed ratio Interval 0.28 to 0.99	—	—
Change From Placebo in Reinforcing Effects (Breakpoint) by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 3: 66.00/66.44 %	0.41 log10 transformed ratio Interval 0.14 to 0.69	0.40 log10 transformed ratio Interval 0.13 to 0.66	—	—
Change From Placebo in Reinforcing Effects (Breakpoint) by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 4: 65.11/65.35 %	0.60 log10 transformed ratio Interval 0.31 to 0.9	0.82 log10 transformed ratio Interval 0.53 to 1.11	—	—
Change From Placebo in Reinforcing Effects (Breakpoint) by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 5: 76.29/76.42 %	-0.04 log10 transformed ratio Interval -0.47 to 0.39	0.16 log10 transformed ratio Interval -0.24 to 0.56	—	—
Change From Placebo in Reinforcing Effects (Breakpoint) by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 6: 75.70/75.69 %	0.05 log10 transformed ratio Interval -0.41 to 0.51	0.43 log10 transformed ratio Interval -0.03 to 0.88	—	—
Change From Placebo in Reinforcing Effects (Breakpoint) by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 7: 75.64/75.43 %	0.31 log10 transformed ratio Interval -0.004 to 0.63	0.38 log10 transformed ratio Interval 0.043 to 0.72	—	—
Change From Placebo in Reinforcing Effects (Breakpoint) by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 8: 74.79/75.18 %	0.23 log10 transformed ratio Interval -0.16 to 0.61	0.37 log10 transformed ratio Interval -0.05 to 0.79	—	—
Change From Placebo in Reinforcing Effects (Breakpoint) by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 9: 73.97/74.04 %	0.04 log10 transformed ratio Interval -0.61 to 0.69	0.48 log10 transformed ratio Interval -0.14 to 1.09	—	—
Change From Placebo in Reinforcing Effects (Breakpoint) by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 10: 73.08/74.18 %	0.01 log10 transformed ratio Interval -0.41 to 0.44	0.20 log10 transformed ratio Interval -0.22 to 0.61	—	—
Change From Placebo in Reinforcing Effects (Breakpoint) by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 11: 73.05/73.51 %	-0.09 log10 transformed ratio Interval -0.73 to 0.55	0.32 log10 transformed ratio Interval -0.29 to 0.94	—	—
Change From Placebo in Reinforcing Effects (Breakpoint) by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 12: 71.31/71.30 %	0.26 log10 transformed ratio Interval -0.25 to 0.77	0.69 log10 transformed ratio Interval 0.22 to 1.16	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
Visual Analog Scale (VAS) Score for "Do You Like the Drug?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 1	1.447 units on a scale Interval -1.813 to 4.707	5.103 units on a scale Interval 1.84 to 8.366	8.374 units on a scale Interval 5.113 to 11.636	—
Visual Analog Scale (VAS) Score for "Do You Like the Drug?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 2	1.850 units on a scale Interval -0.578 to 4.279	2.436 units on a scale Interval 0.038 to 4.835	4.750 units on a scale Interval 2.351 to 7.148	—
Visual Analog Scale (VAS) Score for "Do You Like the Drug?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 3	1.320 units on a scale Interval -1.615 to 4.255	2.183 units on a scale Interval -0.752 to 5.118	6.246 units on a scale Interval 3.314 to 9.179	—
Visual Analog Scale (VAS) Score for "Do You Like the Drug?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 4	0.534 units on a scale Interval -3.906 to 4.973	3.849 units on a scale Interval -0.59 to 8.289	7.211 units on a scale Interval 2.771 to 11.65	—
Visual Analog Scale (VAS) Score for "Do You Like the Drug?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 5	1.048 units on a scale Interval -0.495 to 2.59	1.785 units on a scale Interval 0.22 to 3.349	2.258 units on a scale Interval 0.733 to 3.783	—
Visual Analog Scale (VAS) Score for "Do You Like the Drug?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 6	0.440 units on a scale Interval -2.495 to 3.375	0.789 units on a scale Interval -2.146 to 3.723	3.600 units on a scale Interval 0.68 to 6.542	—
Visual Analog Scale (VAS) Score for "Do You Like the Drug?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 7	0.672 units on a scale Interval -0.839 to 2.183	0.521 units on a scale Interval -1.021 to 2.063	2.550 units on a scale Interval 1.04 to 4.061	—
Visual Analog Scale (VAS) Score for "Do You Like the Drug?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 8	1.270 units on a scale Interval -2.052 to 4.592	0.225 units on a scale Interval -3.09 to 3.54	3.203 units on a scale Interval -0.112 to 6.518	—
Visual Analog Scale (VAS) Score for "Do You Like the Drug?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 9	0.451 units on a scale Interval -3.982 to 4.884	0.328 units on a scale Interval -4.122 to 4.777	4.616 units on a scale Interval 0.2 to 9.032	—
Visual Analog Scale (VAS) Score for "Do You Like the Drug?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 10	0.596 units on a scale Interval -0.153 to 1.345	0.507 units on a scale Interval -0.253 to 1.268	0.722 units on a scale Interval -0.041 to 1.485	—
Visual Analog Scale (VAS) Score for "Do You Like the Drug?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 11	1.471 units on a scale Interval -1.135 to 4.076	1.154 units on a scale Interval -1.451 to 3.76	4.709 units on a scale Interval 2.135 to 7.283	—
Visual Analog Scale (VAS) Score for "Do You Like the Drug?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 12	0.973 units on a scale Interval -0.644 to 2.589	0.939 units on a scale Interval -0.722 to 2.599	3.756 units on a scale Interval 2.085 to 5.427	—
Visual Analog Scale (VAS) Score for "Do You Like the Drug?" by Study Week Analyzed by Mixed Model for Repeated Measures Baseline Week -1	2.892 units on a scale Interval -5.079 to 10.862	48.252 units on a scale Interval 40.223 to 56.281	63.503 units on a scale Interval 55.443 to 71.562	—

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
Change From Placebo in VAS Score for "Do You Like the Drug?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Baseline Week -1: 0.00/0.00 %	45.36 units on a scale Interval 37.16 to 53.56	60.61 units on a scale Interval 52.32 to 68.9	—	—
Change From Placebo in VAS Score for "Do You Like the Drug?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 1: 67.88/67.09 %	3.66 units on a scale Interval -0.03 to 7.34	6.93 units on a scale Interval 3.24 to 10.61	—	—
Change From Placebo in VAS Score for "Do You Like the Drug?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 2: 66.06/66.49 %	0.59 units on a scale Interval -1.98 to 3.15	2.90 units on a scale Interval 0.33 to 5.47	—	—
Change From Placebo in VAS Score for "Do You Like the Drug?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 3: 66.00/66.44 %	0.86 units on a scale Interval -3.05 to 4.78	4.93 units on a scale Interval 1.02 to 8.84	—	—
Change From Placebo in VAS Score for "Do You Like the Drug?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 4: 65.11/65.35 %	3.32 units on a scale Interval -1.43 to 8.06	6.68 units on a scale Interval 1.94 to 11.42	—	—
Change From Placebo in VAS Score for "Do You Like the Drug?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 5: 76.29/76.42 %	0.74 units on a scale Interval -0.94 to 2.42	1.21 units on a scale Interval -0.43 to 2.85	—	—
Change From Placebo in VAS Score for "Do You Like the Drug?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 6: 75.70/75.69 %	0.35 units on a scale Interval -3.62 to 4.32	3.16 units on a scale Interval -0.83 to 7.15	—	—
Change From Placebo in VAS Score for "Do You Like the Drug?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 7: 75.64/75.43 %	-0.15 units on a scale Interval -2.16 to 1.86	1.88 units on a scale Interval -0.11 to 3.87	—	—
Change From Placebo in VAS Score for "Do You Like the Drug?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 8: 74.79/75.18 %	-1.05 units on a scale Interval -4.77 to 2.68	1.93 units on a scale Interval -1.79 to 5.66	—	—
Change From Placebo in VAS Score for "Do You Like the Drug?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 9: 73.97/74.04 %	-0.12 units on a scale Interval -6.2 to 5.96	4.17 units on a scale Interval -1.84 to 10.17	—	—
Change From Placebo in VAS Score for "Do You Like the Drug?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 10: 73.08/74.18 %	-0.09 units on a scale Interval -0.69 to 0.51	0.13 units on a scale Interval -0.5 to 0.76	—	—
Change From Placebo in VAS Score for "Do You Like the Drug?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 11: 73.05/73.51 %	-0.32 units on a scale Interval -3.97 to 3.34	3.24 units on a scale Interval -0.35 to 6.83	—	—
Change From Placebo in VAS Score for "Do You Like the Drug?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 12: 71.31/71.30 %	-0.03 units on a scale Interval -2.19 to 2.12	2.78 units on a scale Interval 0.61 to 4.96	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
VAS Score for "How High Are You Right Now?" by Study Week Analyzed by Mixed Model for Repeated Measures Baseline Week -1	2.654 units on a scale Interval -4.624 to 9.932	33.052 units on a scale Interval 25.722 to 40.382	53.597 units on a scale Interval 46.239 to 60.954	—
VAS Score for "How High Are You Right Now?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 1	1.386 units on a scale Interval -1.261 to 4.034	4.444 units on a scale Interval 1.795 to 7.093	6.240 units on a scale Interval 3.592 to 8.889	—
VAS Score for "How High Are You Right Now?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 2	2.020 units on a scale Interval -0.639 to 4.679	2.539 units on a scale Interval -0.089 to 5.167	5.173 units on a scale Interval 2.545 to 7.801	—
VAS Score for "How High Are You Right Now?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 3	1.362 units on a scale Interval -1.38 to 4.103	3.028 units on a scale Interval 0.286 to 5.769	5.731 units on a scale Interval 2.991 to 8.471	—
VAS Score for "How High Are You Right Now?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 4	0.595 units on a scale Interval -3.818 to 5.007	4.251 units on a scale Interval -0.161 to 8.663	7.737 units on a scale Interval 3.325 to 12.149	—
VAS Score for "How High Are You Right Now?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 5	0.860 units on a scale Interval -0.8 to 2.521	2.406 units on a scale Interval 0.726 to 4.085	2.304 units on a scale Interval 0.66 to 3.948	—
VAS Score for "How High Are You Right Now?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 6	0.463 units on a scale Interval -1.426 to 2.351	0.878 units on a scale Interval -1.01 to 2.767	2.555 units on a scale Interval 0.662 to 4.448	—
VAS Score for "How High Are You Right Now?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 7	0.661 units on a scale Interval -0.777 to 2.099	0.540 units on a scale Interval -0.927 to 2.008	2.481 units on a scale Interval 1.043 to 3.919	—
VAS Score for "How High Are You Right Now?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 8	1.431 units on a scale Interval -1.947 to 4.81	0.261 units on a scale Interval -3.111 to 3.633	3.277 units on a scale Interval -0.095 to 6.649	—
VAS Score for "How High Are You Right Now?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 9	0.519 units on a scale Interval -3.869 to 4.906	0.265 units on a scale Interval -4.139 to 4.669	4.534 units on a scale Interval 0.163 to 8.905	—
VAS Score for "How High Are You Right Now?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 10	0.644 units on a scale Interval 0.011 to 1.277	0.417 units on a scale Interval -0.221 to 1.056	0.624 units on a scale Interval -0.016 to 1.263	—
VAS Score for "How High Are You Right Now?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 11	0.950 units on a scale Interval 0.023 to 1.877	0.987 units on a scale Interval 0.06 to 1.914	2.460 units on a scale Interval 1.54 to 3.379	—
VAS Score for "How High Are You Right Now?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 12	0.289 units on a scale Interval -0.847 to 1.426	0.458 units on a scale Interval -0.68 to 1.597	0.994 units on a scale Interval -0.145 to 2.133	—

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
Change From Placebo in VAS Score for "How High Are You Right Now?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Baseline Week -1: 0.00/0.00 %	30.40 units on a scale Interval 22.99 to 37.81	50.94 units on a scale Interval 43.45 to 58.43	—	—
Change From Placebo in VAS Score for "How High Are You Right Now?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 1: 67.88/67.09 %	3.06 units on a scale Interval 0.35 to 5.76	4.85 units on a scale Interval 2.15 to 7.56	—	—
Change From Placebo in VAS Score for "How High Are You Right Now?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 2: 66.06/66.49 %	0.52 units on a scale Interval -2.2 to 3.23	3.15 units on a scale Interval 0.44 to 5.87	—	—
Change From Placebo in VAS Score for "How High Are You Right Now?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 3: 66.00/66.44 %	1.67 units on a scale Interval -1.78 to 5.11	4.37 units on a scale Interval 0.93 to 7.81	—	—
Change From Placebo in VAS Score for "How High Are You Right Now?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 4: 65.11/65.35 %	3.66 units on a scale Interval -1.21 to 8.52	7.14 units on a scale Interval 2.28 to 12.01	—	—
Change From Placebo in VAS Score for "How High Are You Right Now?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 5: 76.29/76.42 %	1.55 units on a scale Interval -0.08 to 3.18	1.44 units on a scale Interval -0.15 to 3.03	—	—
Change From Placebo in VAS Score for "How High Are You Right Now?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 6: 75.70/75.69 %	0.42 units on a scale Interval -2.01 to 2.84	2.09 units on a scale Interval -0.35 to 4.53	—	—
Change From Placebo in VAS Score for "How High Are You Right Now?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 7: 75.64/75.43 %	-0.12 units on a scale Interval -2.01 to 1.77	1.82 units on a scale Interval -0.05 to 3.69	—	—
Change From Placebo in VAS Score for "How High Are You Right Now?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 8: 74.79/75.18 %	-1.17 units on a scale Interval -4.88 to 2.54	1.85 units on a scale Interval -1.87 to 5.56	—	—
Change From Placebo in VAS Score for "How High Are You Right Now?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 9: 73.97/74.04 %	-0.25 units on a scale Interval -6.29 to 5.78	4.02 units on a scale Interval -1.94 to 9.97	—	—
Change From Placebo in VAS Score for "How High Are You Right Now?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 10: 73.08/74.18 %	-0.23 units on a scale Interval -0.6 to 0.14	-0.02 units on a scale Interval -0.41 to 0.37	—	—
Change From Placebo in VAS Score for "How High Are You Right Now?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 11: 73.05/73.51 %	0.04 units on a scale Interval -1.07 to 1.14	1.51 units on a scale Interval 0.43 to 2.59	—	—
Change From Placebo in VAS Score for "How High Are You Right Now?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 12: 71.31/71.30 %	0.17 units on a scale Interval -0.29 to 0.63	0.71 units on a scale Interval 0.24 to 1.17	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
VAS Score for "Do You Feel Any Drug Effect?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 12	0.285 units on a scale Interval -0.809 to 1.379	0.524 units on a scale Interval -0.573 to 1.621	1.269 units on a scale Interval 0.172 to 2.367	—
VAS Score for "Do You Feel Any Drug Effect?" by Study Week Analyzed by Mixed Model for Repeated Measures Baseline Week -1	3.274 units on a scale Interval -3.844 to 10.391	39.047 units on a scale Interval 31.88 to 46.213	58.912 units on a scale Interval 51.72 to 66.105	—
VAS Score for "Do You Feel Any Drug Effect?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 1	1.200 units on a scale Interval -1.172 to 3.572	4.214 units on a scale Interval 1.84 to 6.588	6.433 units on a scale Interval 4.06 to 8.806	—
VAS Score for "Do You Feel Any Drug Effect?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 2	1.775 units on a scale Interval -0.751 to 4.302	2.787 units on a scale Interval 0.29 to 5.284	5.466 units on a scale Interval 2.969 to 7.962	—
VAS Score for "Do You Feel Any Drug Effect?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 3	1.193 units on a scale Interval -1.605 to 3.992	2.933 units on a scale Interval 0.135 to 5.732	6.046 units on a scale Interval 3.249 to 8.842	—
VAS Score for "Do You Feel Any Drug Effect?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 4	0.514 units on a scale Interval -4.058 to 5.086	4.491 units on a scale Interval -0.081 to 9.063	8.269 units on a scale Interval 3.697 to 12.841	—
VAS Score for "Do You Feel Any Drug Effect?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 5	0.933 units on a scale Interval -0.798 to 2.665	2.497 units on a scale Interval 0.746 to 4.247	2.388 units on a scale Interval 0.673 to 4.103	—
VAS Score for "Do You Feel Any Drug Effect?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 6	0.673 units on a scale Interval -0.154 to 1.5	0.872 units on a scale Interval 0.045 to 1.699	1.364 units on a scale Interval 0.536 to 2.191	—
VAS Score for "Do You Feel Any Drug Effect?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 7	0.625 units on a scale Interval -0.688 to 1.939	0.533 units on a scale Interval -0.808 to 1.874	2.269 units on a scale Interval 0.955 to 3.583	—
VAS Score for "Do You Feel Any Drug Effect?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 8	1.297 units on a scale Interval -2.011 to 4.604	0.329 units on a scale Interval -2.971 to 3.63	3.240 units on a scale Interval -0.061 to 6.54	—
VAS Score for "Do You Feel Any Drug Effect?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 9	0.522 units on a scale Interval -3.864 to 4.907	0.305 units on a scale Interval -4.098 to 4.708	5.033 units on a scale Interval 0.665 to 9.402	—
VAS Score for "Do You Feel Any Drug Effect?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 10	0.654 units on a scale Interval -0.083 to 1.39	0.491 units on a scale Interval -0.256 to 1.238	0.709 units on a scale Interval -0.04 to 1.457	—
VAS Score for "Do You Feel Any Drug Effect?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 11	0.993 units on a scale Interval -0.05 to 2.037	1.118 units on a scale Interval 0.074 to 2.162	2.935 units on a scale Interval 1.903 to 3.966	—

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
Change From Placebo in VAS Score for "Do You Feel Any Drug Effect?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Baseline Week -1: 0.00/0.00 %	35.77 units on a scale Interval 28.66 to 42.89	55.64 units on a scale Interval 48.45 to 62.83	—	—
Change From Placebo in VAS Score for "Do You Feel Any Drug Effect?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 1: 67.88/67.09 %	3.01 units on a scale Interval 0.44 to 5.58	5.23 units on a scale Interval 2.67 to 7.8	—	—
Change From Placebo in VAS Score for "Do You Feel Any Drug Effect?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 2: 66.06/66.49 %	1.01 units on a scale Interval -1.6 to 3.62	3.69 units on a scale Interval 1.08 to 6.3	—	—
Change From Placebo in VAS Score for "Do You Feel Any Drug Effect?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 3: 66.00/66.44 %	1.74 units on a scale Interval -1.75 to 5.23	4.85 units on a scale Interval 1.37 to 8.34	—	—
Change From Placebo in VAS Score for "Do You Feel Any Drug Effect?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 4: 65.11/65.35 %	3.98 units on a scale Interval -1.01 to 8.97	7.76 units on a scale Interval 2.77 to 12.74	—	—
Change From Placebo in VAS Score for "Do You Feel Any Drug Effect?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 5: 76.29/76.42 %	1.56 units on a scale Interval -0.09 to 3.22	1.46 units on a scale Interval -0.16 to 3.07	—	—
Change From Placebo in VAS Score for "Do You Feel Any Drug Effect?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 6: 75.70/75.69 %	0.20 units on a scale Interval -0.7 to 1.1	0.69 units on a scale Interval -0.21 to 1.59	—	—
Change From Placebo in VAS Score for "Do You Feel Any Drug Effect?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 7: 75.64/75.43 %	-0.09 units on a scale Interval -1.82 to 1.64	1.64 units on a scale Interval -0.07 to 3.35	—	—
Change From Placebo in VAS Score for "Do You Feel Any Drug Effect?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 8: 74.79/75.18 %	-0.97 units on a scale Interval -4.7 to 2.76	1.94 units on a scale Interval -1.79 to 5.67	—	—
Change From Placebo in VAS Score for "Do You Feel Any Drug Effect?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 9: 73.97/74.04 %	-0.22 units on a scale Interval -6.32 to 5.89	4.51 units on a scale Interval -1.52 to 10.54	—	—
Change From Placebo in VAS Score for "Do You Feel Any Drug Effect?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 10: 73.08/74.18 %	-0.16 units on a scale Interval -0.71 to 0.39	0.06 units on a scale Interval -0.52 to 0.63	—	—
Change From Placebo in VAS Score for "Do You Feel Any Drug Effect?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 11: 73.05/73.51 %	0.13 units on a scale Interval -1.34 to 1.59	1.94 units on a scale Interval 0.5 to 3.38	—	—
Change From Placebo in VAS Score for "Do You Feel Any Drug Effect?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 12: 71.31/71.30 %	0.24 units on a scale Interval -0.28 to 0.76	0.98 units on a scale Interval 0.46 to 1.51	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
VAS Score for "Does the Drug Have Any Good Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Baseline Week -1	3.131 units on a scale Interval -4.201 to 10.464	43.888 units on a scale Interval 36.5 to 51.276	61.640 units on a scale Interval 54.223 to 69.057	—
VAS Score for "Does the Drug Have Any Good Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 1	1.239 units on a scale Interval -1.658 to 4.135	4.252 units on a scale Interval 1.352 to 7.151	7.072 units on a scale Interval 4.174 to 9.97	—
VAS Score for "Does the Drug Have Any Good Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 2	1.768 units on a scale Interval -0.82 to 4.356	2.364 units on a scale Interval -0.193 to 4.922	5.263 units on a scale Interval 2.706 to 7.821	—
VAS Score for "Does the Drug Have Any Good Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 3	1.221 units on a scale Interval -2.599 to 5.041	2.930 units on a scale Interval -0.89 to 6.75	7.395 units on a scale Interval 3.578 to 11.212	—
VAS Score for "Does the Drug Have Any Good Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 4	0.476 units on a scale Interval -4.098 to 5.05	4.508 units on a scale Interval -0.066 to 9.082	8.130 units on a scale Interval 3.556 to 12.704	—
VAS Score for "Does the Drug Have Any Good Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 5	0.863 units on a scale Interval -0.813 to 2.538	2.264 units on a scale Interval 0.569 to 3.959	2.270 units on a scale Interval 0.612 to 3.929	—
VAS Score for "Does the Drug Have Any Good Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 6	0.410 units on a scale Interval -0.377 to 1.197	0.761 units on a scale Interval -0.026 to 1.548	1.164 units on a scale Interval 0.376 to 1.952	—
VAS Score for "Does the Drug Have Any Good Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 7	0.574 units on a scale Interval -0.755 to 1.902	0.504 units on a scale Interval -0.852 to 1.861	2.225 units on a scale Interval 0.896 to 3.554	—
VAS Score for "Does the Drug Have Any Good Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 8	1.289 units on a scale Interval -2.063 to 4.641	0.188 units on a scale Interval -3.157 to 3.533	3.146 units on a scale Interval -0.199 to 6.491	—
VAS Score for "Does the Drug Have Any Good Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 9	0.399 units on a scale Interval -4.028 to 4.825	0.270 units on a scale Interval -4.173 to 4.714	4.815 units on a scale Interval 0.405 to 9.225	—
VAS Score for "Does the Drug Have Any Good Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 10	0.536 units on a scale Interval -0.155 to 1.226	0.564 units on a scale Interval -0.137 to 1.265	0.681 units on a scale Interval -0.022 to 1.384	—
VAS Score for "Does the Drug Have Any Good Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 11	1.149 units on a scale Interval -0.679 to 2.978	1.023 units on a scale Interval -0.805 to 2.851	3.712 units on a scale Interval 1.906 to 5.518	—
VAS Score for "Does the Drug Have Any Good Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 12	0.550 units on a scale Interval -0.616 to 1.716	0.681 units on a scale Interval -0.498 to 1.86	2.251 units on a scale Interval 1.069 to 3.433	—

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
Change From Placebo in VAS Score for "Does the Drug Have Any Good Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Baseline Week -1: 0.00/0.00 %	40.76 units on a scale Interval 33.1 to 48.42	58.51 units on a scale Interval 50.76 to 66.26	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Good Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 1: 67.88/67.09 %	3.01 units on a scale Interval -0.28 to 6.3	5.83 units on a scale Interval 2.55 to 9.12	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Good Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 2: 66.06/66.49 %	0.60 units on a scale Interval -2.08 to 3.27	3.50 units on a scale Interval 0.82 to 6.17	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Good Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 3: 66.00/66.44 %	1.71 units on a scale Interval -3.36 to 6.78	6.17 units on a scale Interval 1.11 to 11.24	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Good Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 4: 65.11/65.35 %	4.03 units on a scale Interval -0.82 to 8.88	7.65 units on a scale Interval 2.81 to 12.5	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Good Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 5: 76.29/76.42 %	1.40 units on a scale Interval -0.27 to 3.07	1.41 units on a scale Interval -0.22 to 3.03	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Good Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 6: 75.70/75.69 %	0.35 units on a scale Interval -0.45 to 1.15	0.75 units on a scale Interval -0.05 to 1.55	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Good Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 7: 75.64/75.43 %	-0.07 units on a scale Interval -1.84 to 1.7	1.65 units on a scale Interval -0.1 to 3.4	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Good Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 8: 74.79/75.18 %	-1.10 units on a scale Interval -4.86 to 2.66	1.86 units on a scale Interval -1.9 to 5.62	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Good Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 9: 73.97/74.04 %	-0.13 units on a scale Interval -6.23 to 5.98	4.42 units on a scale Interval -1.61 to 10.45	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Good Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 10: 73.08/74.18 %	0.03 units on a scale Interval -0.51 to 0.57	0.15 units on a scale Interval -0.42 to 0.71	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Good Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 11: 73.05/73.51 %	-0.13 units on a scale Interval -2.69 to 2.44	2.56 units on a scale Interval 0.04 to 5.08	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Good Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 12: 71.31/71.30 %	0.13 units on a scale Interval -0.96 to 1.22	1.70 units on a scale Interval 0.6 to 2.8	—	—

SECONDARY outcome

Timeframe: 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 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.

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Baseline Week -1	4.797 units on a scale Interval 0.69 to 8.904	7.145 units on a scale Interval 3.027 to 11.262	11.046 units on a scale Interval 6.909 to 15.183	—
VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 1	1.117 units on a scale Interval 0.595 to 1.638	1.159 units on a scale Interval 0.638 to 1.681	1.107 units on a scale Interval 0.586 to 1.629	—
VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 2	0.980 units on a scale Interval 0.282 to 1.677	1.120 units on a scale Interval 0.43 to 1.81	1.507 units on a scale Interval 0.817 to 2.197	—
VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 3	0.842 units on a scale Interval 0.237 to 1.447	0.926 units on a scale Interval 0.321 to 1.531	1.228 units on a scale Interval 0.623 to 1.833	—
VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 4	0.691 units on a scale Interval 0.146 to 1.235	0.663 units on a scale Interval 0.118 to 1.208	1.117 units on a scale Interval 0.572 to 1.662	—
VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 5	0.785 units on a scale Interval 0.45 to 1.119	0.817 units on a scale Interval 0.481 to 1.152	0.690 units on a scale Interval 0.356 to 1.024	—
VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 6	0.494 units on a scale Interval 0.116 to 0.872	0.521 units on a scale Interval 0.143 to 0.899	0.525 units on a scale Interval 0.147 to 0.903	—
VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 7	0.760 units on a scale Interval 0.411 to 1.11	0.666 units on a scale Interval 0.316 to 1.016	0.642 units on a scale Interval 0.292 to 0.992	—
VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 8	0.544 units on a scale Interval 0.101 to 0.987	0.553 units on a scale Interval 0.11 to 0.996	0.508 units on a scale Interval 0.065 to 0.951	—
VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 9	0.376 units on a scale Interval -0.088 to 0.839	0.395 units on a scale Interval -0.068 to 0.858	0.434 units on a scale Interval -0.029 to 0.897	—
VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 10	0.504 units on a scale Interval -0.037 to 1.046	0.420 units on a scale Interval -0.122 to 0.962	0.403 units on a scale Interval -0.139 to 0.945	—
VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 11	0.523 units on a scale Interval -0.006 to 1.051	0.629 units on a scale Interval 0.101 to 1.157	0.569 units on a scale Interval 0.041 to 1.097	—
VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 12	0.393 units on a scale Interval -0.415 to 1.201	0.387 units on a scale Interval -0.421 to 1.195	0.368 units on a scale Interval -0.44 to 1.176	—

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
Change From Placebo in VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Baseline Week -1: 0.00/0.00 %	2.35 units on a scale Interval -1.19 to 5.88	6.25 units on a scale Interval 2.64 to 9.85	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 1: 67.88/67.09 %	0.04 units on a scale Interval -0.16 to 0.25	-0.01 units on a scale Interval -0.21 to 0.19	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 2: 66.06/66.49 %	0.14 units on a scale Interval -0.55 to 0.83	0.53 units on a scale Interval -0.16 to 1.22	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 3: 66.00/66.44 %	0.08 units on a scale Interval -0.54 to 0.71	0.39 units on a scale Interval -0.24 to 1.01	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 4: 65.11/65.35 %	-0.03 units on a scale Interval -0.52 to 0.47	0.43 units on a scale Interval -0.07 to 0.92	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 5: 76.29/76.42 %	0.03 units on a scale Interval -0.13 to 0.19	-0.10 units on a scale Interval -0.25 to 0.06	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 6: 75.70/75.69 %	0.03 units on a scale Interval -0.14 to 0.2	0.03 units on a scale Interval -0.14 to 0.2	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 7: 75.64/75.43 %	-0.09 units on a scale Interval -0.25 to 0.06	-0.12 units on a scale Interval -0.27 to 0.03	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 8: 74.79/75.18 %	0.01 units on a scale Interval -0.11 to 0.13	-0.04 units on a scale Interval -0.16 to 0.09	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 9: 73.97/74.04 %	0.02 units on a scale Interval -0.08 to 0.12	0.06 units on a scale Interval -0.04 to 0.16	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 10: 73.08/74.18 %	-0.08 units on a scale Interval -0.2 to 0.03	-0.10 units on a scale Interval -0.22 to 0.02	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 11: 73.05/73.51 %	0.11 units on a scale Interval -0.04 to 0.25	0.05 units on a scale Interval -0.1 to 0.19	—	—
Change From Placebo in VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 12: 71.31/71.30 %	-0.01 units on a scale Interval -0.11 to 0.1	-0.02 units on a scale Interval -0.13 to 0.08	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
VAS Score for "Do You Feel Sedated?" by Study Week Analyzed by Mixed Model for Repeated Measures Baseline Week -1	3.399 units on a scale Interval -3.436 to 10.235	14.504 units on a scale Interval 7.64 to 21.367	30.979 units on a scale Interval 24.068 to 37.89	—
VAS Score for "Do You Feel Sedated?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 1	1.199 units on a scale Interval -1.859 to 4.256	3.979 units on a scale Interval 0.92 to 7.038	5.401 units on a scale Interval 2.344 to 8.457	—
VAS Score for "Do You Feel Sedated?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 2	3.126 units on a scale Interval -0.702 to 6.954	3.508 units on a scale Interval -0.296 to 7.312	7.048 units on a scale Interval 3.245 to 10.852	—
VAS Score for "Do You Feel Sedated?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 3	1.135 units on a scale Interval -1.565 to 3.835	1.975 units on a scale Interval -0.725 to 4.675	4.897 units on a scale Interval 2.199 to 7.594	—
VAS Score for "Do You Feel Sedated?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 4	0.661 units on a scale Interval -3.518 to 4.839	3.462 units on a scale Interval -0.717 to 7.64	5.774 units on a scale Interval 1.596 to 9.952	—
VAS Score for "Do You Feel Sedated?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 5	1.110 units on a scale Interval -1.15 to 3.369	2.873 units on a scale Interval 0.588 to 5.158	2.445 units on a scale Interval 0.207 to 4.682	—
VAS Score for "Do You Feel Sedated?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 6	1.152 units on a scale Interval -1.488 to 3.793	0.923 units on a scale Interval -1.718 to 3.563	3.354 units on a scale Interval 0.708 to 6.0	—
VAS Score for "Do You Feel Sedated?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 7	2.348 units on a scale Interval -1.871 to 6.567	2.233 units on a scale Interval -2.001 to 6.468	3.894 units on a scale Interval -0.325 to 8.113	—
VAS Score for "Do You Feel Sedated?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 8	1.787 units on a scale Interval -2.647 to 6.22	1.142 units on a scale Interval -3.286 to 5.571	3.395 units on a scale Interval -1.033 to 7.824	—
VAS Score for "Do You Feel Sedated?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 9	0.506 units on a scale Interval -4.077 to 5.088	1.041 units on a scale Interval -3.557 to 5.639	4.996 units on a scale Interval 0.429 to 9.564	—
VAS Score for "Do You Feel Sedated?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 10	1.155 units on a scale Interval -0.144 to 2.454	0.567 units on a scale Interval -0.766 to 1.9	1.032 units on a scale Interval -0.312 to 2.375	—
VAS Score for "Do You Feel Sedated?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 11	0.858 units on a scale Interval -1.372 to 3.088	1.403 units on a scale Interval -0.827 to 3.633	3.299 units on a scale Interval 1.085 to 5.512	—
VAS Score for "Do You Feel Sedated?" by Study Week Analyzed by Mixed Model for Repeated Measures Week 12	0.344 units on a scale Interval -2.035 to 2.723	2.408 units on a scale Interval -0.024 to 4.841	0.086 units on a scale Interval -2.36 to 2.532	—

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Placebo n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.	Hydromorphone 6 mg n=38 Participants During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.	Hydromorphone 18 mg During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.	Hydromorphone 18 mg Challenge Participants received three hydromorphone challenges each week, one challenge on each of three consecutive days/week in this 12 week study. Participants and clinical facility staff were blinded to the specific dose of hydromorphone being administered during each challenge. The hydromorphone 18 mg challenge consisted of an intramuscular injection of 18 mg hydromorphone.
Change From Placebo in VAS Score for "Do You Feel Sedated?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Baseline Week -1: 0.00/0.00 %	11.10 units on a scale Interval 3.99 to 18.22	27.58 units on a scale Interval 20.32 to 34.84	—	—
Change From Placebo in VAS Score for "Do You Feel Sedated?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 1: 67.88/67.09 %	2.78 units on a scale Interval -0.001 to 5.56	4.20 units on a scale Interval 1.43 to 6.97	—	—
Change From Placebo in VAS Score for "Do You Feel Sedated?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 2: 66.06/66.49 %	0.38 units on a scale Interval -2.52 to 3.28	3.92 units on a scale Interval 1.02 to 6.83	—	—
Change From Placebo in VAS Score for "Do You Feel Sedated?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 3: 66.00/66.44 %	0.84 units on a scale Interval -2.71 to 4.39	3.76 units on a scale Interval 0.22 to 7.31	—	—
Change From Placebo in VAS Score for "Do You Feel Sedated?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 4: 65.11/65.35 %	2.80 units on a scale Interval -1.54 to 7.14	5.11 units on a scale Interval 0.78 to 9.45	—	—
Change From Placebo in VAS Score for "Do You Feel Sedated?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 5: 76.29/76.42 %	1.76 units on a scale Interval -0.44 to 3.97	1.34 units on a scale Interval -0.82 to 3.49	—	—
Change From Placebo in VAS Score for "Do You Feel Sedated?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 6: 75.70/75.69 %	-0.23 units on a scale Interval -3.59 to 3.13	2.20 units on a scale Interval -1.17 to 5.58	—	—
Change From Placebo in VAS Score for "Do You Feel Sedated?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 7: 75.64/75.43 %	-0.12 units on a scale Interval -2.35 to 2.12	1.55 units on a scale Interval -0.66 to 3.75	—	—
Change From Placebo in VAS Score for "Do You Feel Sedated?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 8: 74.79/75.18 %	-0.64 units on a scale Interval -4.51 to 3.22	1.61 units on a scale Interval -2.26 to 5.47	—	—
Change From Placebo in VAS Score for "Do You Feel Sedated?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 9: 73.97/74.04 %	0.54 units on a scale Interval -5.39 to 6.46	4.49 units on a scale Interval -1.36 to 10.34	—	—
Change From Placebo in VAS Score for "Do You Feel Sedated?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 10: 73.08/74.18 %	-0.59 units on a scale Interval -2.01 to 0.84	-0.12 units on a scale Interval -1.61 to 1.36	—	—
Change From Placebo in VAS Score for "Do You Feel Sedated?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 11: 73.05/73.51 %	0.55 units on a scale Interval -2.0 to 3.1	2.44 units on a scale Interval -0.06 to 4.94	—	—
Change From Placebo in VAS Score for "Do You Feel Sedated?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO) Week 12: 71.31/71.30 %	2.06 units on a scale Interval -0.93 to 5.06	-0.26 units on a scale Interval -3.29 to 2.77	—	—

Adverse Events

Depot Buprenorphine

Serious events: 0 serious events

Other events: 34 other events

Deaths: 0 deaths

Placebo Challenge

Serious events: 0 serious events

Other events: 23 other events

Deaths: 0 deaths

Hydromorphone 6 mg Challenge

Serious events: 0 serious events

Other events: 18 other events

Deaths: 0 deaths

Hydromorphone 18 mg Challenge

Serious events: 0 serious events

Other events: 19 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Global Director, Clinical Development

Indivior, Inc.

Phone: 804-379-1090

Results disclosure agreements

Principal investigator is a sponsor employee Proposed publications shall be submitted to Sponsor 30 days prior to submission for publication, and may be withheld for an additional period, up to 90 days, to allow Sponsor to file patent applications. If a multi-center publication isn't submitted for publication within 12 months of the conclusion of the Study at all sites, or is published in a shorter period, the results from the institution's site may be published individually.
Publication restrictions are in place

Restriction type: OTHER