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

NCT02044094 | Completed Phase 2 Results

• 1 other identifier: RB-US-13-0002
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Opioid Use Disorder

Keywords

Opioid dependent; Buprenorphine; Suboxone Film; Opioid blockade; Hydromorphone challenge

Outcome Measures

Primary Outcomes (1)

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

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

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

Secondary Outcomes (18)

• Reinforcing Effects (Breakpoint) by Study Week Analyzed by Mixed Model for Repeated Measures

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

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

  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)

• Participants With Treatment-Emergent Adverse Events (TEAE)

  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

• Plasma Concentrations of Buprenorphine Summarized by Study Week

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

• Predicted mu Opioid Receptor Occupancy (μORO) by Mean Buprenorphine Concentrations and Study Week

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

Study Arms (1)

depot buprenorphine

EXPERIMENTAL

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

Drug: Buprenorphine; Drug: buprenorphine and naloxone; Drug: hydromorphone; Drug: placebo

Interventions

Buprenorphine DRUG

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

Also known as: RBP-6000, Subcutaneous buprenorphine

depot buprenorphine

buprenorphine and naloxone DRUG

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

Also known as: SUBOXONE® sublingual film

depot buprenorphine

hydromorphone DRUG

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

Also known as: dihydromorphinone

depot buprenorphine

placebo DRUG

Placebo for hydromorphone administered via intramuscular injection during each challenge.

Also known as: 0.45% normal saline

depot buprenorphine

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for moderate or severe opioid use disorder at screening and are not seeking opioid use disorder treatment
• Body mass index of \>= 18.0 to \<= 33.0 kg/m\^2
• Females - women of childbearing potential (defined as all women who are not surgically sterile or postmenopausal for at least 1 year prior to informed consent) must have negative pregnancy test prior to enrollment and must agree to use a medically acceptable means of contraception from screening through at least 3 months after the last dose of study drug
• Male subjects with female partners of child-bearing potential must agree to use medically acceptable contraception from screening through at least 3 months after the last dose of study drug

You may not qualify if:

• Subjects with any current diagnosis requiring chronic opioid treatment
• Subjects who currently meet the criteria for diagnosis of moderate or severe substance use disorder by DSM-5 criteria for any substances other than opioids, caffeine, or nicotine.
• Subjects who have abused or used buprenorphine within 14 days prior to informed consent.
• Other protocol-defined criteria may apply.

Sponsors & Collaborators

• Indivior Inc.: lead

Study Sites (1)

Vince & Associates Clinical Research

Overland Park, Kansas, 66212, United States

Location

Related Publications (4)

• Greenwald MK, Johanson CE, Moody DE, Woods JH, Kilbourn MR, Koeppe RA, Schuster CR, Zubieta JK. Effects of buprenorphine maintenance dose on mu-opioid receptor availability, plasma concentrations, and antagonist blockade in heroin-dependent volunteers. Neuropsychopharmacology. 2003 Nov;28(11):2000-9. doi: 10.1038/sj.npp.1300251.

  PMID: 12902992 BACKGROUND

• Greenwald M, Johanson CE, Bueller J, Chang Y, Moody DE, Kilbourn M, Koeppe R, Zubieta JK. Buprenorphine duration of action: mu-opioid receptor availability and pharmacokinetic and behavioral indices. Biol Psychiatry. 2007 Jan 1;61(1):101-10. doi: 10.1016/j.biopsych.2006.04.043. Epub 2006 Sep 1.

  PMID: 16950210 BACKGROUND

• Nasser AF, Greenwald MK, Vince B, Fudala PJ, Twumasi-Ankrah P, Liu Y, Jones JP 3rd, Heidbreder C. Sustained-Release Buprenorphine (RBP-6000) Blocks the Effects of Opioid Challenge With Hydromorphone in Subjects With Opioid Use Disorder. J Clin Psychopharmacol. 2016 Feb;36(1):18-26. doi: 10.1097/JCP.0000000000000434.

  PMID: 26650971 RESULT

• Laffont CM, Ngaimisi E, Gopalakrishnan M, Ivaturi V, Young M, Greenwald MK, Heidbreder C. Buprenorphine exposure levels to optimize treatment outcomes in opioid use disorder. Front Pharmacol. 2022 Nov 18;13:1052113. doi: 10.3389/fphar.2022.1052113. eCollection 2022.

  PMID: 36467036 DERIVED

MeSH Terms

Conditions

Opioid-Related Disorders

Interventions

Buprenorphine; Buprenorphine, Naloxone Drug Combination; Hydromorphone; Saline Solution

Condition Hierarchy (Ancestors)

Narcotic-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Naloxone; Drug Combinations; Pharmaceutical Preparations; Morphine Derivatives; Crystalloid Solutions; Isotonic Solutions; Solutions

Results Point of Contact

• Title: Global Director, Clinical Development
• Organization: Indivior, Inc.

804-379-1090

Study Officials

• Clinical Development Manager

  Indivior Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Masking Details: The investigational drug, RBP-6000, was administered unblinded. The hydromorphone challenges used to measure the effectiveness of RBP-6000 were known and randomized in blinded fashion only to determine the order in which they were administered, with participant and clinical staff blinded to the order of dosing.
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

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

Study Record Dates

• First Submitted: January 21, 2014
• First Posted: January 23, 2014
• Study Start: November 1, 2013
• Primary Completion: July 1, 2014
• Study Completion: July 1, 2014
• Last Updated: April 24, 2018
• Results First Posted: April 24, 2018

Record last verified: 2018-04

Locations

US (1)