Buprenorphine Forms for Opioid Use Disorder

(VA-BRAVE Trial)

Recruiting in Palo Alto (17 mi)

+20 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: VA Office of Research and Development

Must be taking: Sublingual buprenorphine

Must not be taking: Methadone, Buprenorphine, XR-NTX

Disqualifiers: Pregnancy, Suicidal ideation, Sedative use, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

VA-BRAVE will determine whether a 28-day long-acting injectable sub-cutaneous (in the belly area) formulation of buprenorphine at a target dose of 300mg is superior in retaining Veterans in opioid treatment and in sustaining opioid abstinence compared to the daily sublingual (under the tongue) buprenorphine formulation at a target dose of 16-32 mg (standard of care). This is an open-label, randomized, controlled trial including 952 Veterans with opioid use disorder (OUD) recruited over 3 years and followed actively for 52 weeks. There are a number of secondary objectives that will be studied as well and include: comorbid substance use, both non-fatal and fatal opioid overdose, HIV and Hepatitis B (HBV) and C (HCV) testing results and risk behaviors, incarceration, quality of life, psychiatric symptoms of depression and posttraumatic stress disorder, housing status, dental health and utilization, and cost-effectiveness.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those who have been on certain opioid treatments like methadone or buprenorphine for more than 30 days before joining. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of this drug for opioid use disorder?

Research shows that sublingual buprenorphine is effective for maintaining treatment in opioid dependence, and the addition of naloxone helps reduce misuse. Long-acting forms like Sublocade and Probuphine are also available, offering effective options for managing opioid use disorder.

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How does the drug Buprenorphine differ from other treatments for opioid use disorder?

Buprenorphine is unique because it is available in long-acting formulations like monthly injections (Sublocade) and implants (Probuphine), which reduce the need for daily dosing and help prevent misuse. It acts as a partial agonist at mu receptors, providing a safer profile with a lower risk of overdose compared to full agonists like methadone.

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Eligibility Criteria

This trial is for Veterans with moderate to severe opioid use disorder who have used opioids within the last 30 days. They must be seeking treatment and open to 'partial-agonist-based' therapy. Exclusions include inability to consent, pending felony charges, certain medical or psychiatric conditions, recent suicidal ideation requiring hospitalization, and those already on medication-assisted treatment for over a month.

Inclusion Criteria

I have used opioids in the last 30 days or just before entering a supervised setting.

You have a moderate to severe opioid use disorder (OUD) based on a special interview called the Mini-International Neuropsychiatric Interview.

I am seeking treatment for opioid use disorder and open to partial-agonist therapy.

Exclusion Criteria

I am a Veteran and under 18 years old.

Is determined unsuitable for study participation based on the clinical judgement of the LSI or Co-I given results of a CIWA-Ar, physical exam, Liver function tests, kidney function tests, and CBC

I have been on prescribed medication-assisted treatment for over 30 days.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Participants are inducted on daily SL buprenorphine using SAMHSA guidelines and dosed upward for a target dose of 16-32 mg for 3 days

3-30 days

1 visit (in-person)

Randomization and Treatment

Participants are randomized to receive either a 28-day supply of SL buprenorphine or injectable sub-cutaneous buprenorphine administered in the clinic

52 weeks

Biweekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment using administrative data

Up to 10 years

Participant Groups

The study compares two forms of buprenorphine: a monthly injectable dose (300mg) versus daily sublingual doses (16-24mg). It aims to see which is better at keeping patients in treatment and abstinent from opioids over a year-long period among 952 Veteran participants.

Group I: Sublingual Arm Experimental Treatment 1 Intervention

The sublingual buprenorphine contains naloxone in a ratio of 4:1 and will be prescribed. Consistent with the SAMHSA guidelines, before SL-BUP/NLX is prescribed, participants will be evaluated for recent (within 24 hours) drug use and associated symptoms. The randomization dose will be determined based on the maintenance dose identified during the induction period, with a target dose of 16-32mg that is standard practice. While the target dose is 16-32mg, doses may go as low as 8mg as occasionally patients prefer lower doses. SL-BUP/NLX will be prescribed at the randomization visit (28-day supply), then every 4 weeks through week 48.

Group II: Injectable Arm Experimental Treatment 1 Intervention

Injectable buprenorphine consists of a depot injectable formulation in polymeric solution and releases buprenorphine over a 28-day (4-week) period by diffusion as the polymer biodegrades. The injection will be administered subcutaneously in the abdomen at each 28-day visit. The target dose is 300mg, there is the option to use 100mg dose. The final study dose of injectable buprenorphine will be given at Week 48.

Injectable subcutaneous buprenorphine is already approved in United States, European Union, Canada for the following indications:

🇺🇸 Approved in United States as Buprenorphine for:

• Opioid use disorder
• Severe pain

🇪🇺 Approved in European Union as Buprenorphine for:

• Opioid dependence
• Severe pain

🇨🇦 Approved in Canada as Buprenorphine for:

• Opioid use disorder
• Severe pain

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Wilmington VA Medical Center, Wilmington, DE Wilmington, DE

Dayton VA Medical Center, Dayton, OH Dayton, OH

North Florida/South Georgia Veterans Health System, Gainesville, FL Gainesville, FL

Bay Pines VA Healthcare System, Pay Pines, FL Bay Pines, FL

More Trial Locations

Who Is Running the Clinical Trial?

VA Office of Research and Development Lead Sponsor

References

1. England pubmed.ncbi.nlm.nih.gov

Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusers. [2022] Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomized, double-blind, cross-over study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine-maintained injection drug users (IDUs).

2. United States pubmed.ncbi.nlm.nih.gov

Recent advances in the treatment of opioid use disorders-focus on long-acting buprenorphine formulations. [2021] Oral methadone or sublingual buprenorphine are first-line medications for pharmacotherapy of opioid use disorders (OUDs). Three long-acting buprenorphine depot or implant formulations are currently available for the treatment of OUDs: (1) CAM 2038 (Buvidal) for subcutaneous weekly and monthly application; (2) RBP-6000 (Sublocade™) as a monthly depot formulation; and (3) A six-month buprenorphine implant [Probuphine™]. The pharmacology, clinical efficacy and prospects of these medications are discussed.

3. United States pubmed.ncbi.nlm.nih.gov

Subcutaneous Extended-Release Buprenorphine Use in Pregnancy. [2022] Opioid use disorder (OUD) in pregnancy is managed by medication-assisted treatment. Sublingual buprenorphine is one option, but subcutaneous extended-release buprenorphine (Sublocade®) is an alternate form administered in monthly injections. Through an extensive literature search, we did not find any prior publication on the use of Sublocade in pregnancy.

4. United States pubmed.ncbi.nlm.nih.gov

Preference for buprenorphine/naloxone and buprenorphine among patients receiving buprenorphine maintenance therapy in France: a prospective, multicenter study. [2015] Maintenance treatment with buprenorphine tablets (Subutex) has been associated with reductions in heroin use; however, concerns for intravenous misuse exist. A buprenorphine/naloxone formulation (Suboxone) was designed to reduce this misuse risk while retaining buprenorphine's efficacy and safety. This prospective, open-label, multicenter trial compared preferences for buprenorphine and buprenorphine/naloxone in 53 opioid-dependent patients stabilized on buprenorphine. Buprenorphine was first administered at the patient's current dose (Days 1-2), followed by a direct switch to buprenorphine/naloxone (Days 3-5). Global satisfaction rates were high and similar between buprenorphine and buprenorphine/naloxone; however, patients preferred the tablet taste, size, and sublingual dissolution time of buprenorphine/naloxone. At the end of the study, 54% of patients preferred buprenorphine/naloxone, 31% preferred buprenorphine, and 15% had no preference; most patients (71%) wished to continue treatment with buprenorphine/naloxone. This study did not identify any impediments to a direct buprenorphine-to-buprenorphine/naloxone switch and revealed some characteristics that may facilitate treatment with buprenorphine/naloxone.

5. Netherlands pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and pharmaceutical properties of a novel buprenorphine/naloxone sublingual tablet for opioid substitution therapy versus conventional buprenorphine/naloxone sublingual tablet in healthy volunteers. [2018] A novel sublingual buprenorphine/naloxone rapidly-dissolving tablet (BNX-RDT) for opioid substitution therapy has been developed for improved bioavailability, rapid disintegration and improved taste masking. We compared the bioavailability and pharmaceutical properties of BNX-RDT with conventional buprenorphine/naloxone sublingual tablets (BNX).

6. France pubmed.ncbi.nlm.nih.gov

[Prolonged-release buprenorphine formulations: Perspectives for clinical practice]. [2022] Buprenorphine and methadone are the two main opioids agonist treatments approved for opioid use disorder. Buprenorphine is a partial agonist of the mu-opioid receptors, which has been merely available through sublingual form until now. In practice, the use of buprenorphine is smoother than that of methadone, and it induces reduced risks of overdose. However, sublingual buprenorphine also exposes to risks (e.g., withdrawal, misuse) and constraints (e.g., daily intake). Three new galenic formulations of prolonged-release buprenorphine (PRB) are being commercialized and should allow some improvements in patients' comfort and safety. This narrative review aims to describe the main technical features and efficacy and safety data of these PRBs, as well as patients' and professionals' expectancies and concerns, using data of the scientific literature and the regulatory texts. PRBs consist of one subcutaneous implant and two subcutaneous injection depots. Sixmo®/Probuphine® is a six-month-long implant which needs to be surgically placed and removed and is approved for subjects previously treated with a maximum daily dose of 8mg of sublingual buprenorphine, and can be used only for two successive periods of six months before the subject needs to be switched back to sublingual form. Sublocade® is a one-month-long depot formulation that is indicated in switch from sublingual buprenorphine, and which proposes only two dose schemes, i.e., 100 and 300mg monthly. Buvidal®/Brixadi® is a one-week- or one-month-long depot formulation with multiple dosages, which can be used in initiation or in switched from sublingual formulations. While opioid users report some concerns with a risk of coercive use of long-acting forms of buprenorphine, both users and professionals deem that these new specialties could be particularly appreciated in stabilized patients bothered with the daily intake of the treatments, or specific situations at risk of treatment dropout (e.g., following hospital discharge or prison release).

7. United States pubmed.ncbi.nlm.nih.gov

Buprenorphine and its formulations: a comprehensive review. [2022] Buprenorphine, a novel long-acting analgesic, was developed with the intention of two purposes: analgesia and opioid use disorder. Regarding its pharmacodynamics, it is a partial agonist at mu receptors, an inverse agonist at kappa receptors, and an antagonist at delta receptors. For the purpose of analgesia, three formulations of buprenorphine were developed: IV/IM injectable formulation (Buprenex®), transdermal patch formulation (Butrans®), and buccal film formulation (Belbuca®). Related to opioid dependence, the formulations developed were subcutaneous extended release (Sublocade®), subdermal implant (Probuphine®), and sublingual tablets (Subutex®). Lastly, in order to avoid misuse of buprenorphine for opioid dependence, two combination formulations paired with naloxone were developed: film formulation (Suboxone®) and tablet formulation (Zubsolv®). In this review, we present details of each formulation along with their similarities and differences between each other and clinical considerations.