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

NCT ID: NCT02044094

Last Updated: 2018-04-24

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 39 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-11-30
• Study Completion Date: 2014-07-31

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).

Detailed Description

For the hydromorphone challenge testing, subjects were randomized and assigned to 1 of 6 sequences during each week of hydromorphone challenge sessions.

On Day -18, subjects who met initial eligibility criteria were admitted to the clinical facility for the baseline hydromorphone challenge. If the subject had acceptable hydromorphone responses to the hydromorphone challenge, they remained confined to the clinical facility for induction on SUBOXONE sublingual film. Once it was confirmed that a subject was experiencing opioid withdrawal, as evidenced by a Clinical Opiate Withdrawal Scale (COWS) score greater than 12, the subject was inducted on SUBOXONE sublingual film. Multiple doses were allowed while subjects were reaching a stable dose until Day -9 when subjects were stabilized on a dose of SUBOXONE 8 mg - 24 mg. SUBOXONE sublingual film was administered daily at approximately the same time of day (± 1 hour) once the dose was stabilised. There was a hydromorphone challenge conducted on days -3 to -1. The last day of SUBOXONE dosing was day -1.

On Day 1, participants who met all inclusion/exclusion criteria and dosing criteria stopped receiving SUBOXONE sublingual film and received Injection 1 of RBP-6000 containing 300 mg buprenorphine. Participants returned in the evening of Days 4, 11, 18, and 25 to begin inpatient stays of 3 consecutive days (starting with Days 4-7 [and equivalent for subsequent weeks]). During these inpatient visits, subjects underwent randomised hydromorphone challenges, PK sample collection, Reinforcing Effects Tasks, and safety assessments.

On Day 29, participants received the second injection of RBP-6000 containing 300 mg buprenorphine (Injection 2). Participants returned in the evening on Days 32, 39, 46, 53, 60, 67, 74, and 81 to begin inpatient states of 3 consecutive days (starting with days 32-35 [and equivalent for subsequent weeks]). During these inpatient visits, subjects underwent randomised hydromorphone challenges, pharmacokinetic (PK) samples collection, Reinforcing Effects Tasks, and safety assessments. A window of ± 1 day was allowed for all visits, except the Day 53-56 visit, which was required by the protocol to be completed on those days.

Conditions

Opioid Use Disorder

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

depot buprenorphine

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.

Group Type: EXPERIMENTAL

Buprenorphine

Intervention Type: 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.

buprenorphine and naloxone

Intervention Type: 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.

hydromorphone

Intervention Type: 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).

placebo

Intervention Type: DRUG

Placebo for hydromorphone administered via intramuscular injection during each challenge.

Interventions

Buprenorphine

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.

Intervention Type: DRUG

buprenorphine and naloxone

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.

Intervention Type: DRUG

hydromorphone

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).

Intervention Type: DRUG

placebo

Placebo for hydromorphone administered via intramuscular injection during each challenge.

Intervention Type: DRUG

Other Intervention Names

RBP-6000; Subcutaneous buprenorphine; SUBOXONE® sublingual film; dihydromorphinone; 0.45% normal saline

Eligibility Criteria

Inclusion Criteria

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

Exclusion Criteria

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

Other protocol-defined criteria may apply.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Indivior Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Development Manager

Role: STUDY_DIRECTOR

Indivior Inc.

Locations

Vince & Associates Clinical Research

Overland Park, Kansas, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 12902992 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16950210 (View on PubMed)

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.

Reference Type: RESULT

PMID: 26650971 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36467036 (View on PubMed)

Other Identifiers

RB-US-13-0002

Identifier Type: -

Identifier Source: org_study_id