Buprenorphine + XR-Naltrexone for Opioid Use Disorder

(COMBO Trial)

Recruiting at 1 trial location

Overseen By Adam Bisaga, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: New York State Psychiatric Institute

Must be taking: XR-naltrexone

Must not be taking: Methadone, Buprenorphine

Disqualifiers: Severe mental disorder, Severe alcohol use, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 24 weeks

180 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will evaluate the effectiveness of a new pharmacological approach to increase efficacy of treatment with extended release naltrexone (XR-naltrexone) for individuals with opioid use disorder by combining it with buprenorphine-naloxone. This is a two arm, double-blind, placebo-controlled study to examine whether addition of buprenorphine-naloxone will improve treatment retention, reduce opioid craving, and improve mood over 24 weeks of treatment with extended release naltrexone (XR-naltrexone) administered every four weeks for a total of 6 injections. The NYSPI site, which provides study oversight (no direct participant involvement) is currently paused and has been paused since an institutional pause on human subjects research began in June, 2023. The U.S. Department of Health and Human Services (HHS) Office of Human Research Protections (OHRP) issued an FWA restriction on NYSPI research that also included a pause of human subjects research as of June 23, 2023.

Do I have to stop taking my current medications for the trial?

The trial requires that you stop taking methadone and limit buprenorphine use before starting the treatment. If you are on methadone, you must stop at least two weeks before starting, and if you use buprenorphine, you must limit it to no more than 8 mg per day for three days a week before starting.

What data supports the effectiveness of the drug Buprenorphine/naloxone for opioid use disorder?

Research shows that both buprenorphine-naloxone and extended-release naltrexone are effective in reducing opioid relapse in people with opioid use disorder. Additionally, buprenorphine-naloxone has been shown to improve outcomes for individuals seeking treatment for opioid use disorder, although adherence to the medication can be a challenge. ^{1 2 3 4 5}

Is the combination of Buprenorphine and XR-Naltrexone safe for humans?

Buprenorphine, often combined with naloxone, has a high safety profile and is well-tolerated in treating opioid dependence, though it has been subject to misuse. Extended-release naltrexone (XR-NTX) is considered similarly safe to sublingual buprenorphine-naloxone for opioid use disorder, but it can be difficult to start due to detoxification requirements. ^{4 6 7 8 9}

How is the drug Buprenorphine/naloxone unique for treating opioid use disorder?

Buprenorphine/naloxone is unique because it combines a long-acting partial agonist (which activates opioid receptors) and an antagonist (which blocks opioid effects), offering higher bioavailability and faster dissolve time compared to other formulations, potentially improving patient adherence and reducing the risk of misuse. ^{3 8 10 11 12}

Research Team

Adam Bisaga, MD

Principal Investigator

New York State Psychiatric Institute

Eligibility Criteria

Adults aged 18-65 with opioid use disorder for at least six months, confirmed by tests or recent detox treatment, and in good health based on medical exams. They must understand the difference between agonist and antagonist treatments and be interested in antagonist-based relapse prevention without severe alcohol or sedative use, significant liver issues, suicidal tendencies, pregnancy, or certain medication allergies.

Inclusion Criteria

I have completed detox and received an XR-NTX shot within the last 2 weeks.

I have been diagnosed with opioid addiction for at least 6 months.

Voluntarily seeking treatment for opioid use disorder

Exclusion Criteria

I am over 60 and may have early cognitive decline, as shown by my MMSE score.

I do not have a severe addiction to alcohol or sedatives that would complicate medical detox.

- Suicidal or homicidal

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Detoxification

Participants undergo detoxification and receive the first XR-Naltrexone injection if they consent

1-2 weeks

Treatment

Participants receive XR-naltrexone injections every four weeks for 24 weeks, with adjunctive buprenorphine-naloxone or placebo

24 weeks

6 visits (in-person) for injections, weekly medication management visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Buprenorphine/naloxone
• Placebo

Trial Overview The trial is testing if combining buprenorphine-naloxone with extended-release naltrexone (XR-naltrexone) improves treatment retention and mood over 24 weeks compared to a placebo. Participants will receive XR-naltrexone injections every four weeks for a total of six doses in this double-blind study.

Participant Groups

Group I: Buprenorphine-naloxone Experimental Treatment 1 Intervention

Buprenorphine/naloxone 5.7 mg /1.4 mg/day sub-lingual tablets

Group II: Placebo Placebo Group 1 Intervention

placebo sub-lingual tablet

Buprenorphine/naloxone is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Suboxone for:

• Opioid dependence
• Opioid use disorder

Approved in United States as Suboxone for:

• Opioid dependence
• Opioid use disorder

Approved in Canada as Suboxone for:

• Opioid dependence
• Opioid use disorder

Who Is Running the Clinical Trial?

New York State Psychiatric Institute

Lead Sponsor

Trials

481

Recruited

154,000+

National Institute on Drug Abuse (NIDA) (DA038095)

Collaborator

Trials

2

Recruited

190+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Findings from Research

The study will involve 280 adults with opioid use disorder and aims to improve adherence to buprenorphine-naloxone treatment through two psychological interventions: contingency management (CM) and brief motivational interviewing plus substance-free activities and mindfulness (BSM).

The primary goal is to assess which intervention is more effective in promoting medication adherence, measured by attendance at physician appointments and the presence of buprenorphine in urine toxicology, with follow-up occurring 8 months after randomization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of a sequential multiple assignment randomized trial to test contingency management and an integrated behavioral economic and mindfulness intervention for buprenorphine-naloxone medication adherence for opioid use disorder. Peter, SC., Murphy, JG., Witkiewitz, K., et al.[2023]

In a study of 533 participants over 18 months after stopping extended-release buprenorphine injection (BUP-XR), 47% reported sustained opioid abstinence, with higher rates of abstinence linked to longer treatment durations.

More than 60% of participants showed stable or improved outcomes in health-related quality of life and mental health scores, indicating that BUP-XR has a long-term positive impact on recovery from opioid use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Continued Posttrial Benefits of Buprenorphine Extended Release: RECOVER Study Findings. Boyett, B., Nadipelli, VR., Solem, CT., et al.[2023]

In the X:BOT trial involving 474 participants with opioid use disorder, both extended-release naltrexone (XR-NTX) and buprenorphine-naloxone (BUP-NX) effectively reduced drinking behaviors, but neither treatment was superior in this regard.

Only a small portion of the participants had alcohol use disorder (AUD), which limited the ability to detect significant differences in drinking outcomes between the two treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is extended release naltrexone superior to buprenorphine-naloxone to reduce drinking among outpatients receiving treatment for opioid use disorder? A secondary analysis of the CTN X:BOT trial. Roache, JD., Pavlicova, M., Campbell, A., et al.[2023]

In a study involving 302 participants with cocaine dependence and a history of opioid dependence, buprenorphine + naloxone (BUP) combined with extended-release injectable naltrexone (XR-NTX) showed a significant reduction in cocaine use for those receiving 16 mg/day of BUP compared to placebo, indicating its potential effectiveness in this population.

However, no significant differences were observed in the primary outcome for the 4 mg/day BUP group compared to placebo, suggesting that higher doses may be necessary for efficacy, while adherence, retention, and adverse events were similar across all groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine + naloxone plus naltrexone for the treatment of cocaine dependence: the Cocaine Use Reduction with Buprenorphine (CURB) study. Ling, W., Hillhouse, MP., Saxon, AJ., et al.[2018]

In a study involving 570 adults with opioid use disorder, buprenorphine-naloxone was found to be more cost-effective than extended-release naltrexone, being preferred in 97% of cases at 24 weeks and 85% at 36 weeks based on quality-adjusted life-years (QALYs).

The analysis suggests that buprenorphine-naloxone is the better first-line treatment option, especially for patients needing detoxification before starting extended-release naltrexone, although the study had limitations such as a relatively short follow-up period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness of Buprenorphine-Naloxone Versus Extended-Release Naltrexone to Prevent Opioid Relapse. Murphy, SM., McCollister, KE., Leff, JA., et al.[2020]

A 12-month study involving 384 opioid-dependent patients in Germany showed that buprenorphine-naloxone is highly effective and safe, with low rates of serious adverse events (1.2%) and no reported deaths.

The treatment led to significant improvements in mental health and quality of life, with a 57.1% retention rate, and 96.7% of patients who remained in treatment continued with buprenorphine-naloxone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, effectiveness and tolerance of buprenorphine-naloxone in the treatment of opioid dependence: results from a nationwide non-interventional study in routine care. Apelt, SM., Scherbaum, N., Gölz, J., et al.[2015]

In a study of 26 high-risk patients receiving Buprenorphine Extended-Release (BUP-XR), 81% maintained treatment with six or more monthly injections, indicating strong retention in a challenging population.

BUP-XR was associated with significant reductions in emergency department visits, hospitalization days, non-prescribed opioid use, and homelessness, suggesting it effectively supports patients with opioid use disorder despite a high mortality risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended-release buprenorphine outcomes among treatment resistant veterans. Cotton, AJ., Lo, K., Kurtz, FB., et al.[2022]

In a study involving adults with moderate-to-severe opioid use disorder (OUD), the 300-mg maintenance dose of BUP-XR (SUBLOCADE®) was found to be more effective than the 100-mg dose for opioid-injecting participants, leading to better treatment retention and higher rates of opioid abstinence.

Both the 100-mg and 300-mg doses of BUP-XR had similar safety profiles, indicating that increasing the dose for injecting participants does not compromise safety while enhancing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Examining the benefit of a higher maintenance dose of extended-release buprenorphine in opioid-injecting participants treated for opioid use disorder. Greenwald, MK., Wiest, KL., Haight, BR., et al.[2023]

Extended-release naltrexone (XR-NTX) is viewed positively by patients for its once-monthly dosing and lack of physical dependence, but barriers such as ambivalence and unfamiliarity with antagonist treatment hinder initiation, especially in the context of opioid detoxification.

Once patients initiate XR-NTX, they report it as an effective treatment for opioid use disorder (OUD), with high satisfaction and sustained abstinence, indicating its potential as a viable long-term solution for managing OUD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patients' perspectives on initiating treatment with extended-release naltrexone (XR-NTX). Gauthier, P., Greco, P., Meyers-Ohki, S., et al.[2022]

The new sublingual buprenorphine/naloxone tablet (Zubsolv®) has higher bioavailability and better taste, which may improve patient adherence and reduce the risk of misuse compared to the reference product (Suboxone®).

In large phase III trials lasting up to 28 days, Zubsolv® demonstrated high treatment retention rates and effectively reduced opioid cravings and withdrawal symptoms, making it a viable option for treating opioid dependence in adults and adolescents over 15 years old.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine/Naloxone (Zubsolv®): A Review in Opioid Dependence. Heo, YA., Scott, LJ.[2021]

In a study of 37 hospitalized patients with opioid use disorder (OUD), monthly subcutaneous injectable buprenorphine (XR-Bup) was successfully administered at discharge, addressing adherence issues associated with sublingual buprenorphine.

The treatment showed promise, with 64% of patients attending follow-up appointments and 55% receiving a second dose, indicating that XR-Bup can provide effective coverage for over 30 days post-discharge.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended-release Buprenorphine Administered at Discharge in Hospitalized Persons With Opioid Use Disorder: A Case Series. Hansen, ER., South, AM., Lofwall, MR., et al.[2023]

Monthly extended-release injectable naltrexone (XR-NTX) is as effective as daily sublingual buprenorphine-naloxone (BUP-NX) in treating opioid use disorder, based on two good-quality randomized controlled trials.

Both treatments do not lead to an increase in serious adverse events or fatal overdoses, indicating that XR-NTX is a safe alternative for managing opioid use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does XR injectable naltrexone prevent relapse as effectively as daily sublingual buprenorphine-naloxone? Roe, M., Wilson, CG., Fusco, CW., et al.[2021]

References

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

Use of a sequential multiple assignment randomized trial to test contingency management and an integrated behavioral economic and mindfulness intervention for buprenorphine-naloxone medication adherence for opioid use disorder. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Continued Posttrial Benefits of Buprenorphine Extended Release: RECOVER Study Findings. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Is extended release naltrexone superior to buprenorphine-naloxone to reduce drinking among outpatients receiving treatment for opioid use disorder? A secondary analysis of the CTN X:BOT trial. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Buprenorphine + naloxone plus naltrexone for the treatment of cocaine dependence: the Cocaine Use Reduction with Buprenorphine (CURB) study. [2018]

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

Cost-Effectiveness of Buprenorphine-Naloxone Versus Extended-Release Naltrexone to Prevent Opioid Relapse. [2020]

6. Germany pubmed.ncbi.nlm.nih.gov

Safety, effectiveness and tolerance of buprenorphine-naloxone in the treatment of opioid dependence: results from a nationwide non-interventional study in routine care. [2015]

7. England pubmed.ncbi.nlm.nih.gov

Extended-release buprenorphine outcomes among treatment resistant veterans. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Examining the benefit of a higher maintenance dose of extended-release buprenorphine in opioid-injecting participants treated for opioid use disorder. [2023]

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

Patients' perspectives on initiating treatment with extended-release naltrexone (XR-NTX). [2022]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Buprenorphine/Naloxone (Zubsolv®): A Review in Opioid Dependence. [2021]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Extended-release Buprenorphine Administered at Discharge in Hospitalized Persons With Opioid Use Disorder: A Case Series. [2023]

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

Does XR injectable naltrexone prevent relapse as effectively as daily sublingual buprenorphine-naloxone? [2021]