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Trial record 95 of 186 for:    BUPRENORPHINE AND NALOXONE

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

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ClinicalTrials.gov Identifier: NCT02044094
Recruitment Status : Completed
First Posted : January 23, 2014
Results First Posted : April 24, 2018
Last Update Posted : April 24, 2018
Sponsor:
Information provided by (Responsible Party):
Indivior Inc.

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Opioid Use Disorder
Interventions Drug: Buprenorphine
Drug: buprenorphine and naloxone
Drug: hydromorphone
Drug: placebo
Enrollment 39
Recruitment Details  
Pre-assignment Details 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.
Arm/Group Title Depot Buprenorphine
Hide Arm/Group Description 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.
Period Title: RBP-6000 Injection 1 (Day 1 to Day 28)
Started 39
Intent to Treat Population 38 [1]
Completers Population 30 [2]
Completed 30
Not Completed 9
Reason Not Completed
Lost to Follow-up             3
Physician Decision             3
Withdrawal by Subject             3
[1]
Subjects who receive >=1 dose of RBP-6000 and have >=1 complete sequence of hydromorphone challenges
[2]
Subjects that reached Day 28 + completed all challenges at Week 4 were considered study completers.
Period Title: RBP-6000 Injection 2 (Day 29 to Week 12)
Started 30
Completed 17
Not Completed 13
Reason Not Completed
Adverse Event             4
Lost to Follow-up             5
Withdrawal by Subject             2
Physician Decision             1
Noncompliance             1
Arm/Group Title Depot Buprenorphine
Hide Arm/Group Description 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.
Overall Number of Baseline Participants 39
Hide Baseline Analysis Population Description
Safety population
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 39 participants
34.6  (8.93)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 39 participants
Female
4
  10.3%
Male
35
  89.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 39 participants
Hispanic or Latino
1
   2.6%
Not Hispanic or Latino
38
  97.4%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 39 participants
American Indian or Alaska Native
0
   0.0%
Asian
2
   5.1%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
12
  30.8%
White
25
  64.1%
More than one race
0
   0.0%
Unknown or Not Reported
0
   0.0%
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 39 participants
79.55  (11.178)
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 39 participants
176.99  (6.421)
Body Mass Index  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 39 participants
25.35  (3.017)
Smoking History (Nicotine Use)   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 36 participants
19.03  (8.962)
[1]
Measure Analysis Population Description: 36 of 39 participants had a smoking history.
1.Primary Outcome
Title 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
Hide Description

The study's primary objective was to determine if the opioid blocking effect for the first injection of buprenorphine 300 mg (RBP-6000) on Day 1 was not inferior to placebo when challenged by hydromorphone.

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme liking of the drug 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone administration on the challenge days listed in the time frame field. The drug in question was hydromorphone (6 or 18 mg) or placebo.

For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis.

Time Frame Weeks 1 (Days 5-7), 2 (Days 12-14), 3 (Days 19-21), 4 (Days 26-28)
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Placebo Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38 38
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
Week 1 Number Analyzed 38 participants 38 participants 38 participants
1.447  (1.638) 5.103  (1.639) 8.374  (1.638)
Week 2 Number Analyzed 34 participants 35 participants 35 participants
1.850  (1.216) 2.436  (1.200) 4.750  (1.200)
Week 3 Number Analyzed 33 participants 33 participants 33 participants
1.320  (1.476) 2.183  (1.476) 6.246  (1.475)
Week 4 Number Analyzed 30 participants 30 participants 30 participants
0.534  (2.214) 3.849  (2.214) 7.211  (2.214)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Hydromorphone 6 mg
Comments

Week 1

Complete hydromorphone blockade was claimed for RBP-6000 if blockade was achieved for both hydromorphone doses (6 mg and 18 mg) during each week of testing for the 4 weeks after the first dose of RBP-6000. Each test was performed at a 2-sided α = 0.05.

Type of Statistical Test Non-Inferiority
Comments Blockade was achieved if the upper bound of the 95% confidence interval was <= the non-inferiority margin of 11.
Method of Estimation Estimation Parameter LSM difference
Estimated Value 3.656
Confidence Interval (2-Sided) 95%
-0.032 to 7.344
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.850
Estimation Comments Hydromorphone - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Hydromorphone 18 mg
Comments Week 1 Complete hydromorphone blockade was claimed for RBP-6000 if blockade was achieved for both hydromorphone doses (6 mg and 18 mg) during each week of testing for the 4 weeks after the first dose of RBP-6000. Each test was performed at a 2-sided α = 0.05.
Type of Statistical Test Non-Inferiority
Comments Blockade was achieved if the upper bound of the 95% confidence interval was <= the non-inferiority margin of 11.
Method of Estimation Estimation Parameter LSM difference
Estimated Value 6.927
Confidence Interval (2-Sided) 95%
3.243 to 10.612
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.848
Estimation Comments Hydromorphone - Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Hydromorphone 6 mg
Comments

Week 2

Complete hydromorphone blockade was claimed for RBP-6000 if blockade was achieved for both hydromorphone doses (6 mg and 18 mg) during each week of testing for the 4 weeks after the first dose of RBP-6000. Each test was performed at a 2-sided α = 0.05.

Type of Statistical Test Non-Inferiority
Comments Blockade was achieved if the upper bound of the 95% confidence interval was <= the non-inferiority margin of 11.
Method of Estimation Estimation Parameter LSM difference
Estimated Value 0.586
Confidence Interval (2-Sided) 95%
-1.977 to 3.149
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.283
Estimation Comments Hydromorphone - Placebo
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Hydromorphone 18 mg
Comments

Week 2

Complete hydromorphone blockade was claimed for RBP-6000 if blockade was achieved for both hydromorphone doses (6 mg and 18 mg) during each week of testing for the 4 weeks after the first dose of RBP-6000. Each test was performed at a 2-sided α = 0.05.

Type of Statistical Test Non-Inferiority
Comments Blockade was achieved if the upper bound of the 95% confidence interval was <= the non-inferiority margin of 11.
Method of Estimation Estimation Parameter LSM difference
Estimated Value 2.899
Confidence Interval (2-Sided) 95%
0.333 to 5.465
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.285
Estimation Comments Hydromorphone - Placebo
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Hydromorphone 6 mg
Comments

Week 3

Complete hydromorphone blockade was claimed for RBP-6000 if blockade was achieved for both hydromorphone doses (6 mg and 18 mg) during each week of testing for the 4 weeks after the first dose of RBP-6000. Each test was performed at a 2-sided α = 0.05.

Type of Statistical Test Non-Inferiority
Comments Blockade was achieved if the upper bound of the 95% confidence interval was <= the non-inferiority margin of 11.
Method of Estimation Estimation Parameter LSM difference
Estimated Value 0.863
Confidence Interval (2-Sided) 95%
-3.053 to 4.778
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.959
Estimation Comments Hydromorphone - Placebo
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Placebo, Hydromorphone 18 mg
Comments

Week 3

Complete hydromorphone blockade was claimed for RBP-6000 if blockade was achieved for both hydromorphone doses (6 mg and 18 mg) during each week of testing for the 4 weeks after the first dose of RBP-6000. Each test was performed at a 2-sided α = 0.05.

Type of Statistical Test Non-Inferiority
Comments Blockade was achieved if the upper bound of the 95% confidence interval was <= the non-inferiority margin of 11.
Method of Estimation Estimation Parameter LSM difference
Estimated Value 4.926
Confidence Interval (2-Sided) 95%
1.016 to 8.837
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.956
Estimation Comments Hydromorphone - Placebo
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Placebo, Hydromorphone 6 mg
Comments

Week 4

Complete hydromorphone blockade was claimed for RBP-6000 if blockade was achieved for both hydromorphone doses (6 mg and 18 mg) during each week of testing for the 4 weeks after the first dose of RBP-6000. Each test was performed at a 2-sided α = 0.05.

Type of Statistical Test Non-Inferiority
Comments Blockade was achieved if the upper bound of the 95% confidence interval was <= the non-inferiority margin of 11.
Method of Estimation Estimation Parameter LSM difference
Estimated Value 3.316
Confidence Interval (2-Sided) 95%
-1.425 to 8.025
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.367
Estimation Comments Hydromorphone - Placebo
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Placebo, Hydromorphone 18 mg
Comments

Week 4

Complete hydromorphone blockade was claimed for RBP-6000 if blockade was achieved for both hydromorphone doses (6 mg and 18 mg) during each week of testing for the 4 weeks after the first dose of RBP-6000. Each test was performed at a 2-sided α = 0.05.

Type of Statistical Test Non-Inferiority
Comments Blockade was achieved if the upper bound of the 95% confidence interval was <= the non-inferiority margin of 11.
Method of Estimation Estimation Parameter LSM difference
Estimated Value 6.677
Confidence Interval (2-Sided) 95%
1.936 to 11.418
Parameter Dispersion
Type: Standard Error of the Mean
Value: 2.367
Estimation Comments Hydromorphone - Placebo
2.Secondary Outcome
Title Reinforcing Effects (Breakpoint) by Study Week Analyzed by Mixed Model for Repeated Measures
Hide Description

This outcome reports observed values used in the "Change from Placebo....' endpoint that follows.

Reinforcing Effects tasks began >= 5 hours after hydromorphone challenge. Participants made 12 choices between a preference for working for the amount of hydromorphone dosed that day or for money. The hydromorphone break point value is assigned to the highest level of hydromorphone units earned, with 1 unit having a breakpoint value of 5 and 12 units with a value of 2160.

A repeated measures mixed-effects analysis of variance (ANOVA) was performed with the log transformed hydromorphone break point value as the dependent variable with period, hydromorphone sequence and hydromorphone dose as fixed effects, and subject nested within hydromorphone sequence as a random effect.

Blockade is achieved if the upper bound of the 95% confidence interval is <= to the non-inferiority margin of 11.

Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38 38
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Baseline Week -1 Number Analyzed 38 participants 38 participants 38 participants
4.984
(4.443 to 5.525)
7.121
(6.746 to 7.497)
7.042
(6.666 to 7.418)
Week 1 Number Analyzed 38 participants 38 participants 38 participants
4.767
(4.147 to 5.388)
5.379
(4.784 to 5.975)
5.708
(5.148 to 6.267)
Week 2 Number Analyzed 34 participants 35 participants 35 participants
4.036
(3.229 to 4.842)
4.779
(4.011 to 5.546)
5.496
(4.835 to 6.157)
Week 3 Number Analyzed 33 participants 33 participants 33 participants
4.760
(4.049 to 5.471)
5.706
(5.024 to 6.388)
5.669
(5.014 to 6.324)
Week 4 Number Analyzed 30 participants 30 participants 30 participants
4.144
(3.382 to 4.907)
5.533
(4.799 to 6.268)
6.030
(5.326 to 6.733)
Week 5 Number Analyzed 29 participants 28 participants 30 participants
4.564
(3.549 to 5.578)
4.470
(3.517 to 5.424)
4.936
(4.037 to 5.835)
Week 6 Number Analyzed 27 participants 27 participants 27 participants
4.303
(3.210 to 5.396)
4.419
(3.357 to 5.480)
5.282
(4.291 to 6.273)
Week 7 Number Analyzed 27 participants 26 participants 27 participants
5.092
(3.745 to 6.440)
5.808
(4.455 to 7.161)
5.965
(4.628 to 7.303)
Week 8 Number Analyzed 24 participants 24 participants 24 participants
3.899
(2.780 to 5.019)
4.418
(3.341 to 5.494)
4.747
(3.646 to 5.849)
Week 9 Number Analyzed 22 participants 22 participants 22 participants
4.342
(3.116 to 5.568)
4.432
(3.383 to 5.481)
5.437
(4.506 to 6.368)
Week 10 Number Analyzed 20 participants 19 participants 19 participants
4.546
(2.970 to 6.122)
4.578
(2.995 to 6.161)
4.997
(3.444 to 6.551)
Week 11 Number Analyzed 18 participants 18 participants 18 participants
4.330
(2.958 to 5.702)
4.114
(2.865 to 5.364)
5.076
(3.906 to 6.247)
Week 12 Number Analyzed 17 participants 17 participants 17 participants
4.029
(3.151 to 4.906)
4.623
(3.588 to 5.659)
5.615
(4.726 to 6.503)
3.Secondary Outcome
Title Reinforcing Effects Of the Daily Randomized Hydromorphone Challenge as Measured by the Mean Hydromorphone Break Point Value at Weeks 1-12
Hide Description

The ability of RBP-6000 to reduce the reinforcing effects of hydromorphone used money as a choice alternative to hydromorphone.

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

Time Frame Weeks 1 (Days 5-7), 2 (Days 12-14), 3 (Days 19-21), 4 (Days 26-28), 5 (Days 33-35), 6 (Days 40-42), 7 (Days 47-49), 8 (Days 53-56), 9 (Days 61-63), 10 (Days 68-70), 11 (Days 75-77), 12 (Days 82-84)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent to treat population
Arm/Group Title Placebo Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38 38
Least Squares Mean (Standard Error)
Unit of Measure: log10 transformed ratio
Week 1 Number Analyzed 38 participants 38 participants 38 participants
2.070  (0.134) 2.336  (0.129) 2.479  (0.120)
Week 2 Number Analyzed 34 participants 35 participants 35 participants
1.753  (0.175) 2.075  (0.166) 2.387  (0.142)
Week 3 Number Analyzed 33 participants 33 participants 33 participants
2.067  (0.153) 2.478  (0.146) 2.462  (0.140)
Week 4 Number Analyzed 30 participants 30 participants 30 participants
1.800  (0.164) 2.403  (0.158) 2.619  (0.151)
Week 5 Number Analyzed 29 participants 28 participants 30 participants
1.982  (0.217) 1.941  (0.203) 2.144  (0.190)
Week 6 Number Analyzed 27 participants 27 participants 27 participants
1.869  (0.232) 1.919  (9.224) 2.294  (0.208)
Week 7 Number Analyzed 27 participants 26 participants 27 participants
2.212  (0.277) 2.522  (0.278) 2.591  (0.274)
Week 8 Number Analyzed 24 participants 24 participants 24 participants
1.694  (0.232) 1.919  (0.220) 2.062  (0.227)
Week 9 Number Analyzed 22 participants 22 participants 22 participants
1.886  (0.262) 1.925  (0.224) 2.361  (0.197)
Week 10 Number Analyzed 20 participants 19 participants 19 participants
1.974  (0.310) 1.988  (0.313) 2.170  (0.302)
Week 11 Number Analyzed 18 participants 18 participants 18 participants
1.880  (0.289) 1.787  (0.261) 2.205  (0.242)
Week 12 Number Analyzed 17 participants 17 participants 17 participants
1.750  (0.180) 2.008  (0.217) 2.438  (0.183)
4.Secondary Outcome
Title Participants With Treatment-Emergent Adverse Events (TEAE)
Hide Description

TEAE=any untoward medical occurrence that develops or worsens in severity after administration of study drug and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= a marked limitation in activity. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required intervention to prevent one of the outcomes listed above.

All adverse events that occurred between Day 1 to Day 91 are reported under the Depot Buprenorphine treatment arm.

Adverse events that occurred on the day of a hydromorphone challenge are also reported under the appropriate hydromorphone challenge arm.

Time Frame Depot Buprenorphine: Day 1 to Day 91. The three hydromorphone challenge levels were randomly assigned to one day in each of the three-day groupings spanning 12 weeks: Days 5-7, 11-14, 19-21, 26-28, 33-35, 40-42, 47-49, 54-56, 61-63, 68-70, 75-77, 82-84
Hide Outcome Measure Data
Hide Analysis Population Description
Safety; one participant was administered the first RBP-6000 injection but no hydromorphone challenges. Investigators did not assess AEs for potential relatedness to hydromorphone.
Arm/Group Title Depot Buprenorphine Placebo Challenge Hydromorphone 6 mg Challenge Hydromorphone 18 mg Challenge
Hide Arm/Group Description:
Participants were treated with RBP-6000 300-mg in a single subcutaneous injection on Days 1 and 29.

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 placebo challenge consisted of an intramuscular injection of placebo (hydromorphone 0mg).

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 6 mg challenge consisted of an intramuscular injection of 6 mg hydromorphone.

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.

Overall Number of Participants Analyzed 39 38 38 38
Measure Type: Count of Participants
Unit of Measure: Participants
>=1 TEAE Number Analyzed 39 participants 38 participants 38 participants 38 participants
39
 100.0%
29
  76.3%
26
  68.4%
25
  65.8%
>=1 TEAE related to study drug Number Analyzed 39 participants 0 participants 0 participants 0 participants
25
  64.1%
>=1 Severe TEAE Number Analyzed 39 participants 38 participants 38 participants 38 participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Deaths Number Analyzed 39 participants 38 participants 38 participants 38 participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
>=1 SAE other than death Number Analyzed 39 participants 38 participants 38 participants 38 participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Withdrew from study due to a TEAE Number Analyzed 39 participants 38 participants 38 participants 38 participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
5.Secondary Outcome
Title Plasma Concentrations of Buprenorphine Summarized by Study Week
Hide Description

PK Sampling Schedule:

  • Day -17 to -15: before hydromorphone admin
  • Day -4: before Suboxone admin
  • Day 2: 24 hours after RBP-6000 admin
  • Days 5-7, 12-14, 19-21 and 26-28: immediately before hydromorphone admin
  • Days 29: before RBP-6000 admin
  • Day 30: 24 hours after RBP-6000 admin
  • Days 33-35, 40-42, 47-49, 54-56, 61-63, 68-70, 75-77, and 82-84: immediately before hydromorphone admin
Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT
Arm/Group Title Placebo Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38 38
Mean (Standard Deviation)
Unit of Measure: ng/mL
Week -1 Number Analyzed 38 participants 38 participants 38 participants
0.000  (0.000) 0.000  (0.000) 0.000  (0.000)
Week 1 Number Analyzed 38 participants 38 participants 38 participants
2.030  (0.717) 2.164  (0.882) 2.042  (0.765)
Week 2 Number Analyzed 34 participants 35 participants 35 participants
1.892  (0.637) 1.874  (0.605) 1.970  (0.764)
Week 3 Number Analyzed 33 participants 33 participants 33 participants
1.933  (0.657) 1.882  (0.663) 1.916  (0.606)
Week 4 Number Analyzed 30 participants 30 participants 30 participants
1.722  (0.648) 1.776  (0.602) 1.812  (0.633)
Week 5 Number Analyzed 29 participants 28 participants 30 participants
3.684  (1.174) 3.649  (1.122) 3.667  (1.035)
Week 6 Number Analyzed 27 participants 27 participants 27 participants
3.423  (1.082) 3.530  (1.104) 3.521  (1.181)
Week 7 Number Analyzed 27 participants 26 participants 27 participants
3.427  (1.121) 3.495  (1.107) 3.466  (1.136)
Week 8 Number Analyzed 24 participants 24 participants 24 participants
3.326  (1.217) 3.365  (1.160) 3.497  (1.304)
Week 9 Number Analyzed 22 participants 22 participants 22 participants
3.156  (1.103) 3.122  (1.030) 3.210  (1.200)
Week 10 Number Analyzed 20 participants 19 participants 19 participants
2.985  (1.074) 3.039  (3.193) 1.150  (1.136)
Week 11 Number Analyzed 18 participants 18 participants 18 participants
3.117  (1.257) 2.985  (3.081) 1.083  (1.124)
Week 12 Number Analyzed 17 participants 17 participants 17 participants
2.626  (0.956) 2.646  (1.039) 2.624  (0.945)
6.Secondary Outcome
Title Predicted mu Opioid Receptor Occupancy (μORO) by Mean Buprenorphine Concentrations and Study Week
Hide Description

A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to model the relationship between buprenorphine plasma concentrations and brain μORO based on 2 published clinical trials. This model used individual buprenorphine plasma concentrations measured to derive muORO individual predictions that were further described using summary statistics. The relationship between buprenorphine plasma concentration and μORO was best described by a maximal effect (Emax) model:

µORO = E(max)*Cp / EC(50) + Cp

Where Cp is the plasma concentration of buprenorphine, Emax is the maximal μORO, and EC50 is the plasma concentration of buprenorphine that is expected to achieve 50% of the maximal μORO. A direct (instantaneous) relationship between buprenorphine plasma concentration and µORO, i.e. without equilibration delay, was assumed.

Row title format: Study Week: buprenorphine plasma concentrations for placebo/ 6 mg / 18 mg challenge dosages

Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population
Arm/Group Title Placebo Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38 38
Mean (Standard Deviation)
Unit of Measure: percentage receptor occupancy
Baseline Week -1: 0.00/0.00/0.00 Number Analyzed 38 participants 38 participants 38 participants
0.000  (0.000) 0.000  (0.000) 0.000  (0.000)
Week 1: 2.03/2.16/2.04 Number Analyzed 38 participants 38 participants 38 participants
67.077  (6.675) 67.875  (6.806) 67.089  (6.591)
Week 2: 1.89/1.87/1.97 Number Analyzed 34 participants 35 participants 35 participants
66.071  (6.240) 66.059  (5.692) 66.485  (6.670)
Week 3: 1.93/1.88/1.92 Number Analyzed 33 participants 33 participants 33 participants
66.442  (6.108) 66.000  (6.010) 66.438  (5.934)
Week 4: 1.72/1.78/1.81 Number Analyzed 30 participants 30 participants 30 participants
64.270  (6.116) 65.108  (5.534) 65.349  (5.848)
Week 5: 3.68/3.65/3.67 Number Analyzed 29 participants 28 participants 30 participants
76.346  (4.031) 76.285  (3.938) 76.417  (3.856)
Week 6: 3.42/3.53/3.52 Number Analyzed 27 participants 27 participants 27 participants
75.432  (4.156) 75.699  (4.685) 75.686  (4.366)
Week 7: 3.43/3.50/3.47 Number Analyzed 27 participants 26 participants 27 participants
75.351  (4.347) 75.641  (4.373) 75.429  (4.601)
Week 8: 3.33/3.37/3.50 Number Analyzed 24 participants 24 participants 24 participants
74.544  (5.419) 74.792  (5.495) 75.179  (5.302)
Week 9: 3.16/3.12/3.21 Number Analyzed 22 participants 22 participants 22 participants
74.000  (5.314) 73.970  (5.131) 74.036  (5.692)
Week 10: 2.99/3.04/3.19 Number Analyzed 20 participants 19 participants 19 participants
73.002  (6.288) 73.075  (6.579) 74.179  (5.355)
Week 11: 3.12/2.99/3.08 Number Analyzed 18 participants 18 participants 18 participants
73.385  (6.382) 73.054  (6.099) 73.507  (5.904)
Week 12: 2.63/2.65/2.62 Number Analyzed 17 participants 17 participants 17 participants
71.274  (5.946) 71.313  (5.933) 71.303  (5.863)
7.Secondary Outcome
Title Change From Placebo in Reinforcing Effects (Breakpoint) by Study Week and Simulated mu Opioid Receptor Occupancy (μORO)
Hide Description

This endpoint explores the correlation between the reinforcing effects of hydromorphone and simulated mu opioid receptor occupancy.

Data are reported as change from placebo least square mean of Log10 transformed values for reinforcing effects. Reinforcing Effects tasks began >= 5 hours after hydromorphone challenge. Participants made 12 choices between a preference for working for the amount of hydromorphone dosed that day or for money. The hydromorphone break point value is assigned to the highest level of hydromorphone units earned, with 1 unit having a breakpoint value of 5 and 12 units with a value of 2160.

Change from placebo was calculated as Active Challenge result - Placebo Challenge result. Values that approach 0 (implying little difference between the Active Challenge result and the Placebo Challenge result) indicate effectiveness of the opioid blockade.

Row titles include Study Week: predicted mu opioid receptor occupancy for 6 mg / 18 mg challenge dosages

Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38
Least Squares Mean (95% Confidence Interval)
Unit of Measure: log10 transformed ratio
Baseline Week -1: 0.00/0.00 % Number Analyzed 38 participants 38 participants
0.93
(0.67 to 1.18)
0.89
(0.64 to 1.17)
Week 1: 67.88/67.09 % Number Analyzed 38 participants 38 participants
0.27
(-0.001 to 0.53)
0.41
(0.15 to 0.67)
Week 2: 66.06/66.49 % Number Analyzed 35 participants 35 participants
0.32
(-0.05 to 0.70)
0.63
(0.28 to 0.99)
Week 3: 66.00/66.44 % Number Analyzed 33 participants 33 participants
0.41
(0.14 to 0.69)
0.40
(0.13 to 0.66)
Week 4: 65.11/65.35 % Number Analyzed 30 participants 30 participants
0.60
(0.31 to 0.90)
0.82
(0.53 to 1.11)
Week 5: 76.29/76.42 % Number Analyzed 28 participants 30 participants
-0.04
(-0.47 to 0.39)
0.16
(-0.24 to 0.56)
Week 6: 75.70/75.69 % Number Analyzed 27 participants 27 participants
0.05
(-0.41 to 0.51)
0.43
(-0.03 to 0.88)
Week 7: 75.64/75.43 % Number Analyzed 26 participants 27 participants
0.31
(-0.004 to 0.63)
0.38
(0.043 to 0.72)
Week 8: 74.79/75.18 % Number Analyzed 24 participants 24 participants
0.23
(-0.16 to 0.61)
0.37
(-0.05 to 0.79)
Week 9: 73.97/74.04 % Number Analyzed 22 participants 22 participants
0.04
(-0.61 to 0.69)
0.48
(-0.14 to 1.09)
Week 10: 73.08/74.18 % Number Analyzed 19 participants 19 participants
0.01
(-0.41 to 0.44)
0.20
(-0.22 to 0.61)
Week 11: 73.05/73.51 % Number Analyzed 18 participants 18 participants
-0.09
(-0.73 to 0.55)
0.32
(-0.29 to 0.94)
Week 12: 71.31/71.30 % Number Analyzed 17 participants 17 participants
0.26
(-0.25 to 0.77)
0.69
(0.22 to 1.16)
8.Secondary Outcome
Title Visual Analog Scale (VAS) Score for "Do You Like the Drug?" by Study Week Analyzed by Mixed Model for Repeated Measures
Hide Description

This outcome reports observed values used in the "Change from Placebo....' endpoint that follows.

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme liking of the drug 30 minutes before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo.

For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis.

Blockade is achieved if the upper bound of the 95% confidence interval is <= to the non-inferiority margin of 11.

Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38 38
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Baseline Week -1 Number Analyzed 38 participants 38 participants 38 participants
2.892
(-5.079 to 10.862)
48.252
(40.223 to 56.281)
63.503
(55.443 to 71.562)
Week 1 Number Analyzed 38 participants 38 participants 38 participants
1.447
(-1.813 to 4.707)
5.103
(1.840 to 8.366)
8.374
(5.113 to 11.636)
Week 2 Number Analyzed 34 participants 35 participants 35 participants
1.850
(-0.578 to 4.279)
2.436
(0.038 to 4.835)
4.750
(2.351 to 7.148)
Week 3 Number Analyzed 33 participants 33 participants 33 participants
1.320
(-1.615 to 4.255)
2.183
(-0.752 to 5.118)
6.246
(3.314 to 9.179)
Week 4 Number Analyzed 30 participants 30 participants 30 participants
0.534
(-3.906 to 4.973)
3.849
(-0.590 to 8.289)
7.211
(2.771 to 11.650)
Week 5 Number Analyzed 29 participants 28 participants 30 participants
1.048
(-0.495 to 2.590)
1.785
(0.220 to 3.349)
2.258
(0.733 to 3.783)
Week 6 Number Analyzed 27 participants 27 participants 27 participants
0.440
(-2.495 to 3.375)
0.789
(-2.146 to 3.723)
3.600
(0.68 to 6.542)
Week 7 Number Analyzed 27 participants 26 participants 27 participants
0.672
(-0.839 to 2.183)
0.521
(-1.021 to 2.063)
2.550
(1.040 to 4.061)
Week 8 Number Analyzed 24 participants 24 participants 24 participants
1.270
(-2.052 to 4.592)
0.225
(-3.090 to 3.540)
3.203
(-0.112 to 6.518)
Week 9 Number Analyzed 22 participants 22 participants 22 participants
0.451
(-3.982 to 4.884)
0.328
(-4.122 to 4.777)
4.616
(0.200 to 9.032)
Week 10 Number Analyzed 20 participants 19 participants 19 participants
0.596
(-0.153 to 1.345)
0.507
(-0.253 to 1.268)
0.722
(-0.041 to 1.485)
Week 11 Number Analyzed 18 participants 18 participants 18 participants
1.471
(-1.135 to 4.076)
1.154
(-1.451 to 3.760)
4.709
(2.135 to 7.283)
Week 12 Number Analyzed 17 participants 17 participants 17 participants
0.973
(-0.644 to 2.589)
0.939
(-0.722 to 2.599)
3.756
(2.085 to 5.427)
9.Secondary Outcome
Title Change From Placebo in VAS Score for "Do You Like the Drug?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO)
Hide Description

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme liking of the drug 30 minutes before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis.

Change from placebo was calculated as Active Challenge result - Placebo Challenge result. Values that approach 0 (implying little difference between the Active Challenge result and the Placebo Challenge result) indicate effectiveness of the opioid blockade.

Row titles include Study Week: mean predicted mu opioid receptor occupancy for 6 mg / 18 mg challenge dosages

Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Baseline Week -1: 0.00/0.00 % Number Analyzed 38 participants 38 participants
45.36
(37.16 to 53.56)
60.61
(52.32 to 68.90)
Week 1: 67.88/67.09 % Number Analyzed 38 participants 38 participants
3.66
(-0.03 to 7.34)
6.93
(3.24 to 10.61)
Week 2: 66.06/66.49 % Number Analyzed 35 participants 35 participants
0.59
(-1.98 to 3.15)
2.90
(0.33 to 5.47)
Week 3: 66.00/66.44 % Number Analyzed 33 participants 33 participants
0.86
(-3.05 to 4.78)
4.93
(1.02 to 8.84)
Week 4: 65.11/65.35 % Number Analyzed 30 participants 30 participants
3.32
(-1.43 to 8.06)
6.68
(1.94 to 11.42)
Week 5: 76.29/76.42 % Number Analyzed 28 participants 30 participants
0.74
(-0.94 to 2.42)
1.21
(-0.43 to 2.85)
Week 6: 75.70/75.69 % Number Analyzed 27 participants 27 participants
0.35
(-3.62 to 4.32)
3.16
(-0.83 to 7.15)
Week 7: 75.64/75.43 % Number Analyzed 26 participants 27 participants
-0.15
(-2.16 to 1.86)
1.88
(-0.11 to 3.87)
Week 8: 74.79/75.18 % Number Analyzed 24 participants 24 participants
-1.05
(-4.77 to 2.68)
1.93
(-1.79 to 5.66)
Week 9: 73.97/74.04 % Number Analyzed 22 participants 22 participants
-0.12
(-6.20 to 5.96)
4.17
(-1.84 to 10.17)
Week 10: 73.08/74.18 % Number Analyzed 19 participants 19 participants
-0.09
(-0.69 to 0.51)
0.13
(-0.50 to 0.76)
Week 11: 73.05/73.51 % Number Analyzed 18 participants 18 participants
-0.32
(-3.97 to 3.34)
3.24
(-0.35 to 6.83)
Week 12: 71.31/71.30 % Number Analyzed 17 participants 17 participants
-0.03
(-2.19 to 2.12)
2.78
(0.61 to 4.96)
10.Secondary Outcome
Title VAS Score for "How High Are You Right Now?" by Study Week Analyzed by Mixed Model for Repeated Measures
Hide Description

This outcome reports observed values used in the "Change from Placebo....' endpoint that follows.

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme high from the drug 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo.

For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis.

Blockade is achieved if the upper bound of the 95% confidence interval is <= to the non-inferiority margin of 11.

Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38 38
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Baseline Week -1 Number Analyzed 38 participants 38 participants 38 participants
2.654
(-4.624 to 9.932)
33.052
(25.722 to 40.382)
53.597
(46.239 to 60.954)
Week 1 Number Analyzed 38 participants 38 participants 38 participants
1.386
(-1.261 to 4.034)
4.444
(1.795 to 7.093)
6.240
(3.592 to 8.889)
Week 2 Number Analyzed 34 participants 35 participants 35 participants
2.020
(-0.639 to 4.679)
2.539
(-0.089 to 5.167)
5.173
(2.545 to 7.801)
Week 3 Number Analyzed 33 participants 33 participants 33 participants
1.362
(-1.380 to 4.103)
3.028
(0.286 to 5.769)
5.731
(2.991 to 8.471)
Week 4 Number Analyzed 30 participants 30 participants 30 participants
0.595
(-3.818 to 5.007)
4.251
(-0.161 to 8.663)
7.737
(3.325 to 12.149)
Week 5 Number Analyzed 29 participants 28 participants 30 participants
0.860
(-0.800 to 2.521)
2.406
(0.726 to 4.085)
2.304
(0.660 to 3.948)
Week 6 Number Analyzed 27 participants 27 participants 27 participants
0.463
(-1.426 to 2.351)
0.878
(-1.010 to 2.767)
2.555
(0.662 to 4.448)
Week 7 Number Analyzed 27 participants 26 participants 27 participants
0.661
(-0.777 to 2.099)
0.540
(-0.927 to 2.008)
2.481
(1.043 to 3.919)
Week 8 Number Analyzed 24 participants 24 participants 24 participants
1.431
(-1.947 to 4.810)
0.261
(-3.111 to 3.633)
3.277
(-0.095 to 6.649)
Week 9 Number Analyzed 22 participants 22 participants 22 participants
0.519
(-3.869 to 4.906)
0.265
(-4.139 to 4.669)
4.534
(0.163 to 8.905)
Week 10 Number Analyzed 20 participants 19 participants 19 participants
0.644
(0.011 to 1.277)
0.417
(-0.221 to 1.056)
0.624
(-0.016 to 1.263)
Week 11 Number Analyzed 18 participants 18 participants 18 participants
0.950
(0.023 to 1.877)
0.987
(0.060 to 1.914)
2.460
(1.540 to 3.379)
Week 12 Number Analyzed 17 participants 17 participants 17 participants
0.289
(-0.847 to 1.426)
0.458
(-0.680 to 1.597)
0.994
(-0.145 to 2.133)
11.Secondary Outcome
Title Change From Placebo in VAS Score for "How High Are You Right Now?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO)
Hide Description

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme high from the drug 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis.

Change from placebo was calculated as Active Challenge result - Placebo Challenge result. Values that approach 0 (implying little difference between the Active Challenge result and the Placebo Challenge result) indicate effectiveness of the opioid blockade.

Row titles include Study Week: mean predicted mu opioid receptor occupancy 6 mg / 18 mg

Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Baseline Week -1: 0.00/0.00 % Number Analyzed 38 participants 38 participants
30.40
(22.99 to 37.81)
50.94
(43.45 to 58.43)
Week 1: 67.88/67.09 % Number Analyzed 38 participants 38 participants
3.06
(0.35 to 5.76)
4.85
(2.15 to 7.56)
Week 2: 66.06/66.49 % Number Analyzed 35 participants 35 participants
0.52
(-2.20 to 3.23)
3.15
(0.44 to 5.87)
Week 3: 66.00/66.44 % Number Analyzed 33 participants 33 participants
1.67
(-1.78 to 5.11)
4.37
(0.93 to 7.81)
Week 4: 65.11/65.35 % Number Analyzed 30 participants 30 participants
3.66
(-1.21 to 8.52)
7.14
(2.28 to 12.01)
Week 5: 76.29/76.42 % Number Analyzed 28 participants 30 participants
1.55
(-0.08 to 3.18)
1.44
(-0.15 to 3.03)
Week 6: 75.70/75.69 % Number Analyzed 27 participants 27 participants
0.42
(-2.01 to 2.84)
2.09
(-0.35 to 4.53)
Week 7: 75.64/75.43 % Number Analyzed 26 participants 27 participants
-0.12
(-2.01 to 1.77)
1.82
(-0.05 to 3.69)
Week 8: 74.79/75.18 % Number Analyzed 24 participants 24 participants
-1.17
(-4.88 to 2.54)
1.85
(-1.87 to 5.56)
Week 9: 73.97/74.04 % Number Analyzed 22 participants 22 participants
-0.25
(-6.29 to 5.78)
4.02
(-1.94 to 9.97)
Week 10: 73.08/74.18 % Number Analyzed 19 participants 19 participants
-0.23
(-0.60 to 0.14)
-0.02
(-0.41 to 0.37)
Week 11: 73.05/73.51 % Number Analyzed 18 participants 18 participants
0.04
(-1.07 to 1.14)
1.51
(0.43 to 2.59)
Week 12: 71.31/71.30 % Number Analyzed 17 participants 17 participants
0.17
(-0.29 to 0.63)
0.71
(0.24 to 1.17)
12.Secondary Outcome
Title VAS Score for "Do You Feel Any Drug Effect?" by Study Week Analyzed by Mixed Model for Repeated Measures
Hide Description

This outcome reports observed values used in the "Change from Placebo....' endpoint that follows.

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme drug effect 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo.

For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis.

Blockade is achieved if the upper bound of the 95% confidence interval is <= to the non-inferiority margin of 11.

Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38 38
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Baseline Week -1 Number Analyzed 38 participants 38 participants 38 participants
3.274
(-3.844 to 10.391)
39.047
(31.880 to 46.213)
58.912
(51.720 to 66.105)
Week 1 Number Analyzed 38 participants 38 participants 38 participants
1.200
(-1.172 to 3.572)
4.214
(1.840 to 6.588)
6.433
(4.060 to 8.806)
Week 2 Number Analyzed 34 participants 35 participants 35 participants
1.775
(-0.751 to 4.302)
2.787
(0.290 to 5.284)
5.466
(2.969 to 7.962)
Week 3 Number Analyzed 33 participants 33 participants 33 participants
1.193
(-1.605 to 3.992)
2.933
(0.135 to 5.732)
6.046
(3.249 to 8.842)
Week 4 Number Analyzed 30 participants 30 participants 30 participants
0.514
(-4.058 to 5.086)
4.491
(-0.081 to 9.063)
8.269
(3.697 to 12.841)
Week 5 Number Analyzed 29 participants 28 participants 30 participants
0.933
(-0.798 to 2.665)
2.497
(0.746 to 4.247)
2.388
(0.673 to 4.103)
Week 6 Number Analyzed 27 participants 27 participants 27 participants
0.673
(-0.154 to 1.500)
0.872
(0.045 to 1.699)
1.364
(0.536 to 2.191)
Week 7 Number Analyzed 27 participants 26 participants 27 participants
0.625
(-0.688 to 1.939)
0.533
(-0.808 to 1.874)
2.269
(0.955 to 3.583)
Week 8 Number Analyzed 24 participants 24 participants 24 participants
1.297
(-2.011 to 4.604)
0.329
(-2.971 to 3.630)
3.240
(-0.061 to 6.540)
Week 9 Number Analyzed 22 participants 22 participants 22 participants
0.522
(-3.864 to 4.907)
0.305
(-4.098 to 4.708)
5.033
(0.665 to 9.402)
Week 10 Number Analyzed 20 participants 19 participants 19 participants
0.654
(-0.083 to 1.390)
0.491
(-0.256 to 1.238)
0.709
(-0.040 to 1.457)
Week 11 Number Analyzed 18 participants 18 participants 18 participants
0.993
(-0.050 to 2.037)
1.118
(0.074 to 2.162)
2.935
(1.903 to 3.966)
Week 12 Number Analyzed 17 participants 17 participants 17 participants
0.285
(-0.809 to 1.379)
0.524
(-0.573 to 1.621)
1.269
(0.172 to 2.367)
13.Secondary Outcome
Title Change From Placebo in VAS Score for "Do You Feel Any Drug Effect?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO)
Hide Description

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme drug effect 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis.

Change from placebo was calculated as Active Challenge result - Placebo Challenge result. Values that approach 0 (implying little difference between the Active Challenge result and the Placebo Challenge result) indicate effectiveness of the opioid blockade.

Row titles include Study Week: mean predicted mu opioid receptor occupancy for 6 mg / 18 mg challenge dosages

Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Baseline Week -1: 0.00/0.00 % Number Analyzed 38 participants 38 participants
35.77
(28.66 to 42.89)
55.64
(48.45 to 62.83)
Week 1: 67.88/67.09 % Number Analyzed 38 participants 38 participants
3.01
(0.44 to 5.58)
5.23
(2.67 to 7.80)
Week 2: 66.06/66.49 % Number Analyzed 35 participants 35 participants
1.01
(-1.60 to 3.62)
3.69
(1.08 to 6.30)
Week 3: 66.00/66.44 % Number Analyzed 33 participants 33 participants
1.74
(-1.75 to 5.23)
4.85
(1.37 to 8.34)
Week 4: 65.11/65.35 % Number Analyzed 30 participants 30 participants
3.98
(-1.01 to 8.97)
7.76
(2.77 to 12.74)
Week 5: 76.29/76.42 % Number Analyzed 28 participants 30 participants
1.56
(-0.09 to 3.22)
1.46
(-0.16 to 3.07)
Week 6: 75.70/75.69 % Number Analyzed 27 participants 27 participants
0.20
(-0.70 to 1.10)
0.69
(-0.21 to 1.59)
Week 7: 75.64/75.43 % Number Analyzed 26 participants 27 participants
-0.09
(-1.82 to 1.64)
1.64
(-0.07 to 3.35)
Week 8: 74.79/75.18 % Number Analyzed 24 participants 24 participants
-0.97
(-4.70 to 2.76)
1.94
(-1.79 to 5.67)
Week 9: 73.97/74.04 % Number Analyzed 22 participants 22 participants
-0.22
(-6.32 to 5.89)
4.51
(-1.52 to 10.54)
Week 10: 73.08/74.18 % Number Analyzed 19 participants 19 participants
-0.16
(-0.71 to 0.39)
0.06
(-0.52 to 0.63)
Week 11: 73.05/73.51 % Number Analyzed 18 participants 18 participants
0.13
(-1.34 to 1.59)
1.94
(0.50 to 3.38)
Week 12: 71.31/71.30 % Number Analyzed 17 participants 17 participants
0.24
(-0.28 to 0.76)
0.98
(0.46 to 1.51)
14.Secondary Outcome
Title VAS Score for "Does the Drug Have Any Good Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures
Hide Description

This outcome reports observed values used in the "Change from Placebo....' endpoint that follows.

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme good effect 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo.

For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis.

Blockade is achieved if the upper bound of the 95% confidence interval is <= to the non-inferiority margin of 11.

Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38 38
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Baseline Week -1 Number Analyzed 38 participants 38 participants 38 participants
3.131
(-4.201 to 10.464)
43.888
(36.500 to 51.276)
61.640
(54.223 to 69.057)
Week 1 Number Analyzed 38 participants 38 participants 38 participants
1.239
(-1.658 to 4.135)
4.252
(1.352 to 7.151)
7.072
(4.174 to 9.970)
Week 2 Number Analyzed 34 participants 35 participants 35 participants
1.768
(-0.820 to 4.356)
2.364
(-0.193 to 4.922)
5.263
(2.706 to 7.821)
Week 3 Number Analyzed 33 participants 33 participants 33 participants
1.221
(-2.599 to 5.041)
2.930
(-0.890 to 6.750)
7.395
(3.578 to 11.212)
Week 4 Number Analyzed 30 participants 30 participants 30 participants
0.476
(-4.098 to 5.050)
4.508
(-0.066 to 9.082)
8.130
(3.556 to 12.704)
Week 5 Number Analyzed 29 participants 28 participants 30 participants
0.863
(-0.813 to 2.538)
2.264
(0.569 to 3.959)
2.270
(0.612 to 3.929)
Week 6 Number Analyzed 27 participants 27 participants 27 participants
0.410
(-0.377 to 1.197)
0.761
(-0.026 to 1.548)
1.164
(0.376 to 1.952)
Week 7 Number Analyzed 27 participants 26 participants 27 participants
0.574
(-0.755 to 1.902)
0.504
(-0.852 to 1.861)
2.225
(0.896 to 3.554)
Week 8 Number Analyzed 24 participants 24 participants 24 participants
1.289
(-2.063 to 4.641)
0.188
(-3.157 to 3.533)
3.146
(-0.199 to 6.491)
Week 9 Number Analyzed 22 participants 22 participants 22 participants
0.399
(-4.028 to 4.825)
0.270
(-4.173 to 4.714)
4.815
(0.405 to 9.225)
Week 10 Number Analyzed 20 participants 19 participants 19 participants
0.536
(-0.155 to 1.226)
0.564
(-0.137 to 1.265)
0.681
(-0.022 to 1.384)
Week 11 Number Analyzed 18 participants 18 participants 18 participants
1.149
(-0.679 to 2.978)
1.023
(-0.805 to 2.851)
3.712
(1.906 to 5.518)
Week 12 Number Analyzed 17 participants 17 participants 17 participants
0.550
(-0.616 to 1.716)
0.681
(-0.498 to 1.860)
2.251
(1.069 to 3.433)
15.Secondary Outcome
Title Change From Placebo in VAS Score for "Does the Drug Have Any Good Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO)
Hide Description

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme good effect 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis.

Change from placebo was calculated as Active Challenge result - Placebo Challenge result. Values that approach 0 (implying little difference between the Active Challenge result and the Placebo Challenge result) indicate effectiveness of the opioid blockade.

Row titles include Study Week: mean predicted mu opioid receptor occupancy for 6 mg / 18 mg challenge dosages

Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Baseline Week -1: 0.00/0.00 % Number Analyzed 38 participants 38 participants
40.76
(33.10 to 48.42)
58.51
(50.76 to 66.26)
Week 1: 67.88/67.09 % Number Analyzed 38 participants 38 participants
3.01
(-0.28 to 6.30)
5.83
(2.55 to 9.12)
Week 2: 66.06/66.49 % Number Analyzed 35 participants 35 participants
0.60
(-2.08 to 3.27)
3.50
(0.82 to 6.17)
Week 3: 66.00/66.44 % Number Analyzed 33 participants 33 participants
1.71
(-3.36 to 6.78)
6.17
(1.11 to 11.24)
Week 4: 65.11/65.35 % Number Analyzed 30 participants 30 participants
4.03
(-0.82 to 8.88)
7.65
(2.81 to 12.50)
Week 5: 76.29/76.42 % Number Analyzed 28 participants 30 participants
1.40
(-0.27 to 3.07)
1.41
(-0.22 to 3.03)
Week 6: 75.70/75.69 % Number Analyzed 27 participants 27 participants
0.35
(-0.45 to 1.15)
0.75
(-0.05 to 1.55)
Week 7: 75.64/75.43 % Number Analyzed 26 participants 27 participants
-0.07
(-1.84 to 1.70)
1.65
(-0.10 to 3.40)
Week 8: 74.79/75.18 % Number Analyzed 24 participants 24 participants
-1.10
(-4.86 to 2.66)
1.86
(-1.90 to 5.62)
Week 9: 73.97/74.04 % Number Analyzed 22 participants 22 participants
-0.13
(-6.23 to 5.98)
4.42
(-1.61 to 10.45)
Week 10: 73.08/74.18 % Number Analyzed 19 participants 19 participants
0.03
(-0.51 to 0.57)
0.15
(-0.42 to 0.71)
Week 11: 73.05/73.51 % Number Analyzed 18 participants 18 participants
-0.13
(-2.69 to 2.44)
2.56
(0.04 to 5.08)
Week 12: 71.31/71.30 % Number Analyzed 17 participants 17 participants
0.13
(-0.96 to 1.22)
1.70
(0.60 to 2.80)
16.Secondary Outcome
Title VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week Analyzed by Mixed Model for Repeated Measures
Hide Description

This outcome reports observed values used in the "Change from Placebo....' endpoint that follows.

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme bad effect 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo.

For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis.

Blockade is achieved if the upper bound of the 95% confidence interval is <= to the non-inferiority margin of 11.

Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38 38
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Baseline Week -1 Number Analyzed 38 participants 38 participants 38 participants
4.797
(0.690 to 8.904)
7.145
(3.027 to 11.262)
11.046
(6.909 to 15.183)
Week 1 Number Analyzed 38 participants 38 participants 38 participants
1.117
(0.595 to 1.638)
1.159
(0.638 to 1.681)
1.107
(0.586 to 1.629)
Week 2 Number Analyzed 34 participants 35 participants 35 participants
0.980
(0.282 to 1.677)
1.120
(0.430 to 1.810)
1.507
(0.817 to 2.197)
Week 3 Number Analyzed 33 participants 33 participants 33 participants
0.842
(0.237 to 1.447)
0.926
(0.321 to 1.531)
1.228
(0.623 to 1.833)
Week 4 Number Analyzed 30 participants 30 participants 30 participants
0.691
(0.146 to 1.235)
0.663
(0.118 to 1.208)
1.117
(0.572 to 1.662)
Week 5 Number Analyzed 29 participants 28 participants 30 participants
0.785
(0.450 to 1.119)
0.817
(0.481 to 1.152)
0.690
(0.356 to 1.024)
Week 6 Number Analyzed 27 participants 27 participants 27 participants
0.494
(0.116 to 0.872)
0.521
(0.143 to 0.899)
0.525
(0.147 to 0.903)
Week 7 Number Analyzed 27 participants 26 participants 27 participants
0.760
(0.411 to 1.110)
0.666
(0.316 to 1.016)
0.642
(0.292 to 0.992)
Week 8 Number Analyzed 24 participants 24 participants 24 participants
0.544
(0.101 to 0.987)
0.553
(0.110 to 0.996)
0.508
(0.065 to 0.951)
Week 9 Number Analyzed 22 participants 22 participants 22 participants
0.376
(-0.088 to 0.839)
0.395
(-0.068 to 0.858)
0.434
(-0.029 to 0.897)
Week 10 Number Analyzed 20 participants 19 participants 19 participants
0.504
(-0.037 to 1.046)
0.420
(-0.122 to 0.962)
0.403
(-0.139 to 0.945)
Week 11 Number Analyzed 18 participants 18 participants 18 participants
0.523
(-0.006 to 1.051)
0.629
(0.101 to 1.157)
0.569
(0.041 to 1.097)
Week 12 Number Analyzed 17 participants 17 participants 17 participants
0.393
(-0.415 to 1.201)
0.387
(-0.421 to 1.195)
0.368
(-0.440 to 1.176)
17.Secondary Outcome
Title Change From Placebo in VAS Score for "Does the Drug Have Any Bad Effects?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO)
Hide Description

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme bad effect 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis.

Change from placebo was calculated as Active Challenge result - Placebo Challenge result. Values that approach 0 (implying little difference between the Active Challenge result and the Placebo Challenge result) indicate effectiveness of the opioid blockade.

Row titles include Study Week: mean predicted mu opioid receptor occupancy for 6 mg / 18 mg challenge dosages

Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Baseline Week -1: 0.00/0.00 % Number Analyzed 38 participants 38 participants
2.35
(-1.19 to 5.88)
6.25
(2.64 to 9.85)
Week 1: 67.88/67.09 % Number Analyzed 38 participants 38 participants
0.04
(-0.16 to 0.25)
-0.01
(-0.21 to 0.19)
Week 2: 66.06/66.49 % Number Analyzed 35 participants 35 participants
0.14
(-0.55 to 0.83)
0.53
(-0.16 to 1.22)
Week 3: 66.00/66.44 % Number Analyzed 33 participants 33 participants
0.08
(-0.54 to 0.71)
0.39
(-0.24 to 1.01)
Week 4: 65.11/65.35 % Number Analyzed 30 participants 30 participants
-0.03
(-0.52 to 0.47)
0.43
(-0.07 to 0.92)
Week 5: 76.29/76.42 % Number Analyzed 28 participants 30 participants
0.03
(-0.13 to 0.19)
-0.10
(-0.25 to 0.06)
Week 6: 75.70/75.69 % Number Analyzed 27 participants 27 participants
0.03
(-0.14 to 0.20)
0.03
(-0.14 to 0.20)
Week 7: 75.64/75.43 % Number Analyzed 26 participants 27 participants
-0.09
(-0.25 to 0.06)
-0.12
(-0.27 to 0.03)
Week 8: 74.79/75.18 % Number Analyzed 24 participants 24 participants
0.01
(-0.11 to 0.13)
-0.04
(-0.16 to 0.09)
Week 9: 73.97/74.04 % Number Analyzed 22 participants 22 participants
0.02
(-0.08 to 0.12)
0.06
(-0.04 to 0.16)
Week 10: 73.08/74.18 % Number Analyzed 19 participants 19 participants
-0.08
(-0.20 to 0.03)
-0.10
(-0.22 to 0.02)
Week 11: 73.05/73.51 % Number Analyzed 18 participants 18 participants
0.11
(-0.04 to 0.25)
0.05
(-0.10 to 0.19)
Week 12: 71.31/71.30 % Number Analyzed 17 participants 17 participants
-0.01
(-0.11 to 0.10)
-0.02
(-0.13 to 0.08)
18.Secondary Outcome
Title VAS Score for "Do You Feel Sedated?" by Study Week Analyzed by Mixed Model for Repeated Measures
Hide Description

This outcome reports observed values used in the "Change from Placebo....' endpoint that follows.

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme sedation 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo.

For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis.

Blockade is achieved if the upper bound of the 95% confidence interval is <= to the non-inferiority margin of 11.

Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of placebo.
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38 38
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Baseline Week -1 Number Analyzed 38 participants 38 participants 38 participants
3.399
(-3.436 to 10.235)
14.504
(7.640 to 21.367)
30.979
(24.068 to 37.890)
Week 1 Number Analyzed 38 participants 38 participants 38 participants
1.199
(-1.859 to 4.256)
3.979
(0.920 to 7.038)
5.401
(2.344 to 8.457)
Week 2 Number Analyzed 34 participants 35 participants 35 participants
3.126
(-0.702 to 6.954)
3.508
(-0.296 to 7.312)
7.048
(3.245 to 10.852)
Week 3 Number Analyzed 33 participants 33 participants 33 participants
1.135
(-1.565 to 3.835)
1.975
(-0.725 to 4.675)
4.897
(2.199 to 7.594)
Week 4 Number Analyzed 30 participants 30 participants 30 participants
0.661
(-3.518 to 4.839)
3.462
(-0.717 to 7.640)
5.774
(1.596 to 9.952)
Week 5 Number Analyzed 29 participants 28 participants 30 participants
1.110
(-1.150 to 3.369)
2.873
(0.588 to 5.158)
2.445
(0.207 to 4.682)
Week 6 Number Analyzed 27 participants 27 participants 27 participants
1.152
(-1.488 to 3.793)
0.923
(-1.718 to 3.563)
3.354
(0.708 to 6.000)
Week 7 Number Analyzed 27 participants 26 participants 27 participants
2.348
(-1.871 to 6.567)
2.233
(-2.001 to 6.468)
3.894
(-0.325 to 8.113)
Week 8 Number Analyzed 24 participants 24 participants 24 participants
1.787
(-2.647 to 6.220)
1.142
(-3.286 to 5.571)
3.395
(-1.033 to 7.824)
Week 9 Number Analyzed 22 participants 22 participants 22 participants
0.506
(-4.077 to 5.088)
1.041
(-3.557 to 5.639)
4.996
(0.429 to 9.564)
Week 10 Number Analyzed 20 participants 19 participants 19 participants
1.155
(-0.144 to 2.454)
0.567
(-0.766 to 1.900)
1.032
(-0.312 to 2.375)
Week 11 Number Analyzed 18 participants 18 participants 18 participants
0.858
(-1.372 to 3.088)
1.403
(-0.827 to 3.633)
3.299
(1.085 to 5.512)
Week 12 Number Analyzed 17 participants 17 participants 17 participants
0.344
(-2.035 to 2.723)
2.408
(-0.024 to 4.841)
0.086
(-2.360 to 2.532)
19.Secondary Outcome
Title Change From Placebo in VAS Score for "Do You Feel Sedated?" by Study Week and Simulated mu Opioid Receptor Occupancy (μORO)
Hide Description

Participants completed a visual analog scale (VAS) that ranged from 0 - 100, with 0 meaning not at all, and 100 meaning the most extreme sedation 30 minutes (± 5 minutes) before and 15, 30 , 45, 60, 75, 90, 120, 150, 180, 210, 240, 270, and 300 minutes (± 5 minutes) after hydromorphone challenge. The drug in question was hydromorphone (6 or 18 mg) or placebo. For each hydromorphone challenge week, a mixed-effects model with period (where period is day), hydromorphone sequence, and hydromorphone dose as fixed effects and subject nested within hydromorphone sequence as a random effect were used for analysis.

Change from placebo was calculated as Active Challenge result - Placebo Challenge result. Values that approach 0 (implying little difference between the Active Challenge result and the Placebo Challenge result) indicate effectiveness of the opioid blockade.

Row titles include Study Week: mean predicted mu opioid receptor occupancy for 6 mg / 18 mg challenge dosages

Time Frame Baseline (Week -1), Weeks 1-12 (RBP-6000 admin on Weeks 1 and 5)
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Hide Analysis Population Description
ITT population.
Arm/Group Title Hydromorphone 6 mg Hydromorphone 18 mg
Hide Arm/Group Description:
During hydromorphone challenges, participants received intramuscular (IM) injections of 6 mg hydromorphone.
During hydromorphone challenges, participants received intramuscular (IM) injections of 18 mg hydromorphone.
Overall Number of Participants Analyzed 38 38
Least Squares Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Baseline Week -1: 0.00/0.00 % Number Analyzed 38 participants 38 participants
11.10
(3.99 to 18.22)
27.58
(20.32 to 34.84)
Week 1: 67.88/67.09 % Number Analyzed 38 participants 38 participants
2.78
(-0.001 to 5.56)
4.20
(1.43 to 6.97)
Week 2: 66.06/66.49 % Number Analyzed 35 participants 35 participants
0.38
(-2.52 to 3.28)
3.92
(1.02 to 6.83)
Week 3: 66.00/66.44 % Number Analyzed 33 participants 33 participants
0.84
(-2.71 to 4.39)
3.76
(0.22 to 7.31)
Week 4: 65.11/65.35 % Number Analyzed 30 participants 30 participants
2.80
(-1.54 to 7.14)
5.11
(0.78 to 9.45)
Week 5: 76.29/76.42 % Number Analyzed 28 participants 30 participants
1.76
(-0.44 to 3.97)
1.34
(-0.82 to 3.49)
Week 6: 75.70/75.69 % Number Analyzed 27 participants 27 participants
-0.23
(-3.59 to 3.13)
2.20
(-1.17 to 5.58)
Week 7: 75.64/75.43 % Number Analyzed 26 participants 27 participants
-0.12
(-2.35 to 2.12)
1.55
(-0.66 to 3.75)
Week 8: 74.79/75.18 % Number Analyzed 24 participants 24 participants
-0.64
(-4.51 to 3.22)
1.61
(-2.26 to 5.47)
Week 9: 73.97/74.04 % Number Analyzed 22 participants 22 participants
0.54
(-5.39 to 6.46)
4.49
(-1.36 to 10.34)
Week 10: 73.08/74.18 % Number Analyzed 19 participants 19 participants
-0.59
(-2.01 to 0.84)
-0.12
(-1.61 to 1.36)
Week 11: 73.05/73.51 % Number Analyzed 18 participants 18 participants
0.55
(-2.00 to 3.10)
2.44
(-0.06 to 4.94)
Week 12: 71.31/71.30 % Number Analyzed 17 participants 17 participants
2.06
(-0.93 to 5.06)
-0.26
(-3.29 to 2.77)
Time Frame Depot Buprenorphine: Day 1 to Day 91. Hydromorphone Challenges: the three hydromorphone challenge levels (0 mg, 6 mg and 18 mg) 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, and 82-84.
Adverse Event Reporting Description

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 treatment arm.

 
Arm/Group Title Depot Buprenorphine Placebo Challenge Hydromorphone 6 mg Challenge Hydromorphone 18 mg Challenge
Hide Arm/Group Description Participants were treated with RBP-6000 300 mg in a single subcutaneous injection on Days 1 and 29.

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 placebo challenge consisted of an intramuscular injection of placebo (hydromorphone 0mg).

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 6 mg challenge consisted of an intramuscular injection of 6 mg hydromorphone.

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.

All-Cause Mortality
Depot Buprenorphine Placebo Challenge Hydromorphone 6 mg Challenge Hydromorphone 18 mg Challenge
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/39 (0.00%)   0/38 (0.00%)   0/38 (0.00%)   0/38 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Depot Buprenorphine Placebo Challenge Hydromorphone 6 mg Challenge Hydromorphone 18 mg Challenge
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/39 (0.00%)   0/38 (0.00%)   0/38 (0.00%)   0/38 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Depot Buprenorphine Placebo Challenge Hydromorphone 6 mg Challenge Hydromorphone 18 mg Challenge
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   34/39 (87.18%)   23/38 (60.53%)   18/38 (47.37%)   19/38 (50.00%) 
Cardiac disorders         
Tachycardia  1  2/39 (5.13%)  0/38 (0.00%)  0/38 (0.00%)  0/38 (0.00%) 
Gastrointestinal disorders         
Constipation  1  12/39 (30.77%)  0/38 (0.00%)  1/38 (2.63%)  2/38 (5.26%) 
Nausea  1  11/39 (28.21%)  3/38 (7.89%)  2/38 (5.26%)  1/38 (2.63%) 
Vomiting  1  9/39 (23.08%)  1/38 (2.63%)  1/38 (2.63%)  3/38 (7.89%) 
Diarrhoea  1  4/39 (10.26%)  0/38 (0.00%)  2/38 (5.26%)  0/38 (0.00%) 
Toothache  1  6/39 (15.38%)  2/38 (5.26%)  1/38 (2.63%)  2/38 (5.26%) 
General disorders         
Injection site erythema  1  2/39 (5.13%)  0/38 (0.00%)  0/38 (0.00%)  0/38 (0.00%) 
Injection site pruritis  1  2/39 (5.13%)  0/38 (0.00%)  0/38 (0.00%)  1/38 (2.63%) 
Local swelling  1  2/39 (5.13%)  0/38 (0.00%)  0/38 (0.00%)  0/38 (0.00%) 
Infections and infestations         
Upper respiratory tract infection  1  4/39 (10.26%)  0/38 (0.00%)  0/38 (0.00%)  1/38 (2.63%) 
Gastroenteritis  1  2/39 (5.13%)  0/38 (0.00%)  0/38 (0.00%)  0/38 (0.00%) 
Investigations         
Weight decreased  1  4/39 (10.26%)  0/38 (0.00%)  0/38 (0.00%)  0/38 (0.00%) 
Musculoskeletal and connective tissue disorders         
Musculoskeletal pain  1  11/39 (28.21%)  2/38 (5.26%)  2/38 (5.26%)  1/38 (2.63%) 
Back pain  1  2/39 (5.13%)  0/38 (0.00%)  0/38 (0.00%)  0/38 (0.00%) 
Nervous system disorders         
Headache  1  20/39 (51.28%)  8/38 (21.05%)  9/38 (23.68%)  10/38 (26.32%) 
Sedation  1  9/39 (23.08%)  3/38 (7.89%)  4/38 (10.53%)  2/38 (5.26%) 
Dizziness  1  2/39 (5.13%)  0/38 (0.00%)  0/38 (0.00%)  0/38 (0.00%) 
Paraesthesia  1  2/39 (5.13%)  0/38 (0.00%)  0/38 (0.00%)  0/38 (0.00%) 
Psychiatric disorders         
Anxiety  1  12/39 (30.77%)  2/38 (5.26%)  2/38 (5.26%)  3/38 (7.89%) 
Abnormal dreams  1  4/39 (10.26%)  0/38 (0.00%)  0/38 (0.00%)  0/38 (0.00%) 
Renal and urinary disorders         
Leukocyturia  1  2/39 (5.13%)  0/38 (0.00%)  0/38 (0.00%)  0/38 (0.00%) 
Skin and subcutaneous tissue disorders         
Dermatitis contact  1  3/39 (7.69%)  2/38 (5.26%)  0/38 (0.00%)  1/38 (2.63%) 
Vascular disorders         
Hypotension  1  3/39 (7.69%)  1/38 (2.63%)  2/38 (5.26%)  0/38 (0.00%) 
Hot flush  1  2/39 (5.13%)  0/38 (0.00%)  0/38 (0.00%)  0/38 (0.00%) 
1
Term from vocabulary, MedDRA (16.1)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
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Name/Title: Global Director, Clinical Development
Organization: Indivior, Inc.
Phone: 804-379-1090
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Responsible Party: Indivior Inc.
ClinicalTrials.gov Identifier: NCT02044094     History of Changes
Other Study ID Numbers: RB-US-13-0002
First Submitted: January 21, 2014
First Posted: January 23, 2014
Results First Submitted: December 29, 2017
Results First Posted: April 24, 2018
Last Update Posted: April 24, 2018