Biased Opioid Agonists for Treatment of Opioid Withdrawal in OUD

Phase 2

Recruiting

• Conditions: Opioid-Use Disorder
• Interventions: Drug: TRV734; Other: Placebo

• Registration Number: NCT04316559
• Lead Sponsor: National Institute on Drug Abuse (NIDA)

Brief Summary

Background:

People with opioid-use disorder (OUD) might benefit from having more treatment drugs to choose from. A new drug, TRV734, could be used like methadone to treat OUD. It might not have as many side effects.

Objective:

To test if TRV734 relieves withdrawal symptoms and has fewer side effects than oxycodone in people with OUD.

Eligibility:

People ages 18-75 who have been receiving daily treatment with methadone for opioid use disorder for at least 3 months

Design:

Participants will be screened under Protocol 415. They will be screened with:

Medical, social, and psychiatric history

Physical exam

Electrocardiogram (ECG). For this, sticky pads will be placed on the participant s chest to monitor their heartbeat.

Blood and urine tests

Participants will stay in a residential unit for 13-21 days.

Most days, participants will receive their regular daily dose of methadone.

On 4 or 5 occasions, 3-4 days apart, participants will skip two doses of methadone in a row. About 4 hours after they skip the second dose, they will have an IV catheter inserted with a needle so that blood samples can be taken. They will take capsules of either oxycodone, a placebo, or the study drug. They will have an ECG. They will complete questionnaires. Their blood pressure, pupil size, and alertness will be tested. They will then take their usual dose of methadone.

Participants will give daily urine and breath samples.

Detailed Description

Background. Opioid-agonist medications (methadone and buprenorphine) are the most effective treatments available for opioid addiction. However, they are not effective in all cases, and with the vast number of people requiring treatment in the current crisis, even a modest increase in the percentage of people who respond to treatment would represent a substantial benefit in public health. Recent advances in neuropsychopharmacology have led to the discovery of a new class of opioid agonists that are functionally selective. That is, they are biased towards specific post-receptor pathways and in theory can produce therapeutic opioid effects (analgesia, withdrawal relief) while minimizing side effects (sedation, respiratory depression) that can lead people to discontinue treatment with methadone or buprenorphine.

Objective. Our goal is to assess the efficacy and tolerability of a biased opioid agonist for suppressing or reversing opioid withdrawal.

Participant population. Adults who are physically dependent on opioids and already receiving chronic daily methadone treatment (up to 64 enrolled; up to 30 completers, plus at least 3 to complete an initial unpowered dose-finding pilot). Target enrollment will include 40% women and 60% minorities (mostly African-American), reflecting the demographics of the relevant local population.

Experimental design. A double-blind within-subject randomized placebo-controlled experiment will be used to test whether a biased opioid agonist suppresses withdrawal when given about 52 hr after discontinuing methadone. TRV734 (capsule form), a biased opioid agonist with good oral bioavailability, will be compared to placebo and to oxycodone (positive control) in matching capsules. A signal of efficacy and safety in the proposed laboratory study will be our cue to embark on a larger clinical trial.

Methods. Participants in an unpowered dose-finding five-session pilot phase (up to 30 consecutive days, i.e., 29 consecutive nights) will receive placebo, oxycodone, and a range of doses of TRV734, starting on the high side of the analgesic dose range. The highest dose that relieves withdrawal symptoms with no appreciable adverse effects will be used as the higher of two doses for the participants in the main study. These participants will stay at the inpatient unit for up to 30 consecutive days to help ensure that participants use no additional opioids 52-76-hr prior to each test session.

Participants in the main phase will stay at the inpatient unit for up to 21 consecutive days (original timeline, likely to increase after the pilot is completed) to help ensure that participants use no additional opioids 52-76-hr prior to each test session. To help demonstrate that TRV734 s effects are dose-related, we will also select a lower dose with withdrawal-relief efficacy intermediate between placebo and the higher dose. For participants in the main study, there will be four experimental sessions: one each with placebo, oxycodone, and the two doses of TRV734. Safety and research measures will be collected before (baseline) and for 4 hours after administration of study drugs. The participant s usual methadone dose will be administered after each session.

Outcome measures: The primary outcome will be suppression of withdrawal symptoms, to be assessed by the SOWS (Subjective Opioid Withdrawal Scale). Secondary outcomes will include safety, specificity of effects (e.g., absence of psychomotor slowing), tolerability, and suppression of objective signs of withdrawal. Instruments used for these assessments will include the COWS (Clinical Opioid Withdrawal Scale), scales for opioid effects, psychomotor assessments, and differential dropout across sessions. We hypothesize that the higher dose of TRV734 will be superior to placebo in therapeutic effects and have lower adverse effects (including effects on alertness and psychomotor performance) compared to oxycodone.

Study Timeline

• Study First Submitted: 2020-03-19
• Study First Submitted QC: 2020-03-19
• Study First Posted: 2020-03-20
• Study Start: 2021-12-27
• Status Verified: 2024-10-04
• Last Update Submitted: 2024-10-17
• Last Update Posted: 2024-10-18
• Primary Completion: 2026-09-30
• Study Completion: 2026-09-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 64

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
TRV734	TRV734	TRV734 at different doses vs. oxycodone for withdrawal suppression
Placebo	Placebo	Placebo capsule

Primary Outcome Measures

Name	Time	Method
sows	within-session	Subjective Opioid Withdrawal Scale

Secondary Outcome Measures

Name	Time	Method
NIH Toolbox test battery	within-session	psychomotor tests
COWS	within-session	Clinical Opioid Withdrawal Scale

Trial Locations

Locations (1)

National Institute on Drug Abuse; 🇺🇸 Baltimore, Maryland, United States