Buprenorphine Forms for Opioid Use Disorder

(VA-BRAVE Trial)

Recruiting at 20 trial locations

Overseen By Avron Spiro, PhD MS

Age: 18+

Sex: Any

Trial Phase: Phase 4

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 All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

952 Participants Needed

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 7 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. ^{1 2 3 4 5}

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. ^{1 2 3 6 7}

Research Team

Sandra Ann Springer, MD

Principal Investigator

VA Connecticut Healthcare System West Haven Campus, West Haven, CT

Ismene L. Petrakis, MD

Principal Investigator

VA Connecticut Healthcare System West Haven Campus, West Haven, CT

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.

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

Treatment Details

Interventions

• Injectable subcutaneous buprenorphine
• Sublingual buprenorphine with naloxone

Trial Overview 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.

Participant Groups

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

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Findings from Research

In a study involving 12 intravenous heroin users, buprenorphine/naloxone was self-administered significantly less often than buprenorphine or heroin, indicating a lower potential for misuse.

Participants reported lower 'drug liking' and 'desire to take the drug again' for buprenorphine/naloxone compared to buprenorphine alone, suggesting that this combination may be a safer option for treating opioid dependence while reducing the risk of misuse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusers. Comer, SD., Sullivan, MA., Vosburg, SK., et al.[2022]

Long-acting buprenorphine formulations, including CAM 2038 (Buvidal), RBP-6000 (Sublocade™), and Probuphine™, provide effective options for treating opioid use disorders (OUDs) with varying administration schedules, such as weekly, monthly, or every six months.

These depot and implant formulations enhance patient adherence to treatment by reducing the frequency of dosing compared to traditional oral or sublingual medications, potentially improving overall outcomes in managing OUDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent advances in the treatment of opioid use disorders-focus on long-acting buprenorphine formulations. Soyka, M., Franke, AG.[2021]

Two case studies of pregnant patients with opioid use disorder (OUD) who switched from sublingual buprenorphine to monthly injections of Sublocade® showed no adverse outcomes for either the mothers or their babies, suggesting potential safety in this treatment during pregnancy.

Both patients maintained positive urine drug screens for buprenorphine throughout their pregnancies without experiencing withdrawal symptoms or birth anomalies, indicating that Sublocade may be a viable option for managing OUD in pregnant women, although further research is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous Extended-Release Buprenorphine Use in Pregnancy. Towers, CV., Deisher, H.[2022]

A study involving 53 opioid-dependent patients showed that switching from buprenorphine to buprenorphine/naloxone was well-tolerated, with no significant issues reported during the transition.

Patients expressed a preference for buprenorphine/naloxone over buprenorphine, with 54% favoring the combination formulation due to its taste and ease of use, indicating it may be a more acceptable option for maintenance treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preference for buprenorphine/naloxone and buprenorphine among patients receiving buprenorphine maintenance therapy in France: a prospective, multicenter study. Daulouède, JP., Caer, Y., Galland, P., et al.[2015]

The novel sublingual buprenorphine/naloxone rapidly-dissolving tablet (BNX-RDT) demonstrated equivalent absorption of buprenorphine and naloxone compared to conventional tablets at higher doses, while showing improved dose proportionality and faster dissolve times.

Participants preferred the taste and mouthfeel of BNX-RDT over conventional tablets, with 78% indicating a preference for the new formulation, highlighting its potential for better patient compliance in opioid substitution therapy.

NCBI (Pubmed)

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. Jönsson, M., Mundin, G., Sumner, M.[2018]

New prolonged-release formulations of buprenorphine, including a six-month implant and two subcutaneous injection depots, aim to improve patient comfort and safety by reducing the need for daily intake and minimizing risks associated with sublingual forms.

These formulations have shown promise in addressing concerns about treatment adherence, particularly for stabilized patients, while also raising some apprehensions about potential coercive use among opioid users.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Prolonged-release buprenorphine formulations: Perspectives for clinical practice]. Chappuy, M., Trojak, B., Nubukpo, P., et al.[2022]

Buprenorphine is a versatile medication designed for both pain relief and treatment of opioid use disorder, acting as a partial agonist at mu receptors and an antagonist at delta receptors, which helps manage pain while reducing the risk of misuse.

Various formulations of buprenorphine, including injectable, transdermal, and sublingual options, have been developed to cater to different patient needs, with specific combinations like Suboxone® including naloxone to deter misuse in opioid dependence treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine and its formulations: a comprehensive review. Poliwoda, S., Noor, N., Jenkins, JS., et al.[2022]

References

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

Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusers. [2022]

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

Recent advances in the treatment of opioid use disorders-focus on long-acting buprenorphine formulations. [2021]

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

Subcutaneous Extended-Release Buprenorphine Use in Pregnancy. [2022]

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]

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]

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

[Prolonged-release buprenorphine formulations: Perspectives for clinical practice]. [2022]

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

Buprenorphine and its formulations: a comprehensive review. [2022]