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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a long-acting, once-a-month injectable form of buprenorphine is more effective than the usual daily sublingual buprenorphine with naloxone at keeping Veterans in treatment and off opioids. The study will also examine other factors such as the use of other substances, overdose rates, mental health, and quality of life. Veterans with opioid use disorder who have used opioids in the past month and are starting or already on buprenorphine treatment might be suitable candidates for this trial. As a Phase 4 trial, this research aims to understand how the already FDA-approved and effective treatment can benefit more patients.

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 is the safety track record for these treatments?

Earlier studies found that injectable subcutaneous buprenorphine, a long-lasting treatment, was generally well-tolerated. Most injection site side effects were mild to moderate, such as slight itching, with only one case of severe itching reported. However, a warning exists about the risk of serious harm or death if injected incorrectly into a vein. More than 350,000 people have used a similar injectable form, which helps reduce cravings and block the effects of other opioids.

Safety data from over 3,200 patients show that sublingual buprenorphine with naloxone is widely used and generally safe for treating opioid addiction. This treatment combines buprenorphine with naloxone to manage dependence by reducing withdrawal symptoms and cravings. Overall, earlier research has shown that both treatments in the study have been well-tolerated. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for opioid use disorder because they offer new delivery methods that could improve patient adherence and outcomes. The sublingual buprenorphine with naloxone is taken under the tongue and includes naloxone to deter misuse, providing a flexible dosing option that can be adjusted from 4 to 32mg. On the other hand, the injectable buprenorphine is administered as a subcutaneous shot that releases the medication steadily over 28 days, reducing the need for daily dosing and potentially enhancing compliance. Both treatments aim to provide effective management of opioid use disorder with distinct advantages over traditional oral medications.

What evidence suggests that this trial's treatments could be effective for opioid use disorder?

Research has shown that an injectable form of buprenorphine, effective for 28 days, holds promise for treating opioid use disorder (OUD). In this trial, some participants will receive this injectable form, which studies have found effective in helping patients maintain abstinence from opioids over time, with many sustaining their recovery. Other participants will receive daily sublingual buprenorphine with naloxone, which is also effective. This form is known to lower the risk of death and aid many patients in recovery. Both treatments benefit individuals with OUD, but the injectable form may offer advantages for long-term recovery. ^{6 7 8 9 10}

Who Is on the Research Team?

Ismene L. Petrakis, MD

Principal Investigator

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

Sandra Ann Springer, MD

Principal Investigator

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

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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 4-32mg that is standard practice. While the target dose is 4-32mg, occasionally patients may 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 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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. indivior.com indivior.com/en/media/press-releases/indivior-highlight-growing-body-of-data-on-sublocade

Press Release These data add to the growing body of evidence that SUBLOCADE can improve outcomes, such as abstinence, retention, and recovery in persons with OUD.

2. sciencedirect.com sciencedirect.com/science/article/pii/S2949875923002060

Integrated analysis of phase 3 studies Participants who received BUP-XR injections and stayed on treatment had improved opioid abstinence over time. After completing 18 injections, 90.4 % of all ...

3. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK546461/

Buprenorphine extended-release injection (Sublocade ... - NCBI Key Efficacy and Safety Outcomes for Buprenorphine Extended-Release Treatment Regimens and Placebo in Patients With Opioid Use Disorder in Study 13-0001. Go ...

4. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2820859

Extended-Release 7-Day Injectable Buprenorphine for ... Meaning Results of this study suggest that 7-day extended-release buprenorphine may be feasible in patients with opioid use disorder presenting ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0376871625002510

Extended-release injectable buprenorphine for the ... This prospective clinical cohort study found that among 25 patients with OUD at high risk of overdose who started XR-BUP in were followed in a low-barrier ...

6. sublocadehcp.com sublocadehcp.com/efficacy/clinical-safety

Safety | SUBLOCADE® (buprenorphine extended-release) HCP Most injection site-related adverse drug reactions were of mild to moderate severity, with 1 report of severe injection‐site pruritus.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2022/209819s010lbl.pdf

Sublocade - accessdata.fda.gov WARNING: RISK OF SERIOUS HARM OR DEATH WITH INTRAVENOUS. ADMINISTRATION; SUBLOCADE RISK EVALUATION AND MITIGATION. STRATEGY.

8. sublocade.com sublocade.com/

Patient Information for SUBLOCADE® (buprenorphine ... 350,000+ PEOPLE HAVE BEEN PRESCRIBED SUBLOCADE · Buprenorphine can reduce cravings and block the rewarding effects of other opioids, which can help break the ...

9. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39543001/

A Single-Dose Study to Evaluate the Relative ... This open-label pharmacokinetic study assessed three alternative injection locations (upper arm, thigh, buttocks) to offer additional flexibility.

10. brixadi.com brixadi.com/pdfs/brixadi-prescribing-information.pdf

HIGHLIGHTS OF PRESCRIBING INFORMATION ... The efficacy and safety of BRIXADI for the treatment of opioid use disorder was evaluated in a. Phase 3, 24-Week, randomized, double-blind, double-dummy ...