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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether combining two medications, buprenorphine (used to treat opioid use disorder) and extended-release naltrexone, helps individuals with opioid use disorder adhere to their treatment and improve their well-being. The study includes two groups: one receives buprenorphine with naltrexone, while the other receives a placebo (a pill with no active medicine). Researchers aim to determine if this combination reduces cravings and improves mood over 24 weeks. Individuals who have struggled with opioid use for at least six months and seek help with naltrexone treatment might be suitable for this trial. As a Phase 2 trial, this study measures the treatment's effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that buprenorphine-naloxone is generally safe and effective for treating opioid use disorder. Studies have found that it reduces the risk of death and improves recovery chances. Safety reports include data from hundreds of people who have used this medication in similar situations.

Buprenorphine can cause a mild high or slow breathing at low doses, but these effects are usually less intense than with other opioids. Some people might stop using buprenorphine-naloxone more often than other treatments like methadone, yet the overall results remain similar.

The FDA has approved this treatment for opioid use disorder, supporting its safety. However, individual experiences can differ, so discussing any concerns with a healthcare provider is always advisable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Buprenorphine/naloxone is unique because it combines two active ingredients that target opioid use disorder differently. Buprenorphine helps reduce withdrawal symptoms and cravings, while naloxone is an opioid antagonist that blocks the effects of opioids, reducing the risk of misuse. Unlike traditional treatments that often involve methadone or standalone buprenorphine, this combination aims to provide a more comprehensive approach to managing the disorder. Researchers are excited about this treatment because it offers a potentially safer and more effective method, with the convenience of sub-lingual tablets, which could improve adherence and outcomes.

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

Research has shown that a combination of buprenorphine and naloxone effectively treats opioid addiction. In this trial, some participants will receive this combination treatment, which studies have found helps more people stay healthy and reduces their cravings for opioids. It also significantly lowers the risk of death from overdoses. Overall, these medications can greatly improve the lives of those dealing with opioid addiction. ^{1 4 5 6 7}

Who Is on the Research Team?

Adam Bisaga, MD

Principal Investigator

New York State Psychiatric Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11610725/

Buprenorphine-Naloxone for Opioid Use Disorder Buprenorphine-naloxone was associated with significantly reduced mortality and increased remission rates for patients with opioid use disorder.

2. nih.gov nih.gov/news-events/news-releases/higher-doses-buprenorphine-may-improve-treatment-outcomes-people-opioid-use-disorder

Higher doses of buprenorphine may improve treatment ... Those taking daily doses of more than 24 mg of buprenorphine went 50% longer before having a subsequent emergency or inpatient health care visit ...

3. jamanetwork.com jamanetwork.com/journals/jama/fullarticle/2825088

Buprenorphine/Naloxone vs Methadone for the Treatment ... The risk of treatment discontinuation was higher among recipients of buprenorphine/naloxone compared with methadone (88.8% vs 81.5% within 24 months).

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2949875923002606

Evaluation of opioid use disorder treatment outcomes in ... In this study, patients receiving once daily buprenorphine-naloxone had similar treatment outcomes to patients receiving split dosing.

5. cdc.gov cdc.gov/mmwr/volumes/73/wr/mm7325a1.htm

Treatment for Opioid Use Disorder: Population Estimates Medications for opioid use disorder (OUD), particularly buprenorphine and methadone, substantially reduce overdose-related and overall mortality ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2025/204242s031lbl.pdf

Reference ID: 5593165 - accessdata.fda.gov In total, safety data were available for 538 opioid-dependent subjects exposed to ZUBSOLV. (buprenorphine/naloxone) sublingual tablets when used for initial ...

7. samhsa.gov samhsa.gov/substance-use/treatment/options/buprenorphine

What is Buprenorphine? Side Effects, Treatment & Use It produces effects such as euphoria or respiratory depression at low to moderate doses. With buprenorphine, however, these effects are weaker ...