Biased Opioid Agonists for Treatment of Opioid Withdrawal in OUD

NCT04316559 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: 99992001420-DA-N014
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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 three (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.

Conditions

Opioid-Use Disorder

Keywords

Addiction; Psychomotor Testing; Substance-Use Disorder

Outcome Measures

Primary Outcomes (1)

• Withdrawal Symptoms Assessed by the Subjective Opioid Withdrawal Scale (SOWS)

  The subjective opioid withdrawal scale (SOWS) is a widely used measure for evaluating the intensity of opioid withdrawal symptoms. It consists of 16 items (such as "I feel nauseated" and "I am shaking"), each rated by participants on a 5-point scale of intensity from 0 (not at all) to 4 (extremely). The score is a sum of all item ratings; scores can range from 0 to 64, with standard cutoffs for mild withdrawal (1-10), moderate withdrawal (11-20), and severe withdrawal (21 or higher). Higher score indicates more severe withdrawal. Measurements were taken up to four hours during each study session--every 15 minutes for the first hour, decreasing to every 30 minutes as the session progressed. Analysis was done with Bayesian multilevel regression, to estimate marginal means and a 95% credible interval (CI) for each treatment as estimated by the regression.

  Up to four hours during each session, for a total of five noncontiguous session days

Secondary Outcomes (10)

• Withdrawal Signs Assessed by the Clinical Opioid Withdrawal Scale (COWS)

  Session baseline and up to four hours during each session, for a total of five noncontiguous session days

• Withdrawal Signs Assessed by Pupil Diameter

  Session baseline and up to four hours during each session, for a total of five noncontiguous session days

• Psychomotor Performance: Response Time in Four-Choice Reaction-Time Task

  Session baseline and up to four hours after each session, for a total of five noncontiguous session days

• Psychomotor Performance: Proportion of Correct Responses in Four-Choice Reaction-Time Task

  Session baseline and up to four hours after each session, for a total of five noncontiguous session days

• Psychomotor Performance: d-Prime (an Accuracy Measure) in Number-Vigilance Test

  Session baseline and up to four hours after each session, for a total of five noncontiguous session days

Study Arms (2)

Opioid Withdrawal Suppression Interventions: oxycodone, then placebo

EXPERIMENTAL

There were 5 noncontiguous session days, each conducted when the participant was in a state of mild to moderate withdrawal from methadone. All participants received oxycodone, placebo, and varying doses of the investigational drug TRV734. On session day 1, participants were randomized to receive a single dose of oxycodone 30mg orally. On session day 2, participants received whichever of the two interventions (oxycodone 30mg, or placebo) they had not received on day 1. On session days 3 to 5, participants received the investigational drug TRV734, orally, once per session day, starting with a dose intended to be minimally but detectably effective for withdrawal relief, and adjusted higher or lower on subsequent session days to identify partly effective and fully effective doses; dose for each session ranged from 65 to 175mg.

Other: Placebo; Drug: TRV734; Drug: Oxycodone

Opioid Withdrawal Suppression Interventions: placebo, then oxycodone

EXPERIMENTAL

There were 5 noncontiguous session days, each conducted when the participant was in a state of mild to moderate withdrawal from methadone. All participants received oxycodone, placebo, and varying doses of the investigational drug TRV734. On session day 1, participants were randomized to receive a single dose of placebo orally. On session day 2, participants received whichever of the two interventions (oxycodone 30mg, or placebo) they had not received on day 1. On session days 3 to 5, participants received the investigational drug TRV734, orally, once per session day, starting with a dose intended to be minimally but detectably effective for withdrawal relief, and adjusted higher or lower on subsequent session days to identify partly effective and fully effective doses; dose for each session ranged from 65 to 175mg.

Other: Placebo; Drug: TRV734; Drug: Oxycodone

Interventions

Placebo OTHER

Placebo capsule

Opioid Withdrawal Suppression Interventions: oxycodone, then placebo; Opioid Withdrawal Suppression Interventions: placebo, then oxycodone

TRV734 DRUG

biased opioid agonist

Opioid Withdrawal Suppression Interventions: oxycodone, then placebo; Opioid Withdrawal Suppression Interventions: placebo, then oxycodone

Oxycodone DRUG

Oxycodone tablet, 30mg

Opioid Withdrawal Suppression Interventions: oxycodone, then placebo; Opioid Withdrawal Suppression Interventions: placebo, then oxycodone

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age between 18 and 75.
• Currently receiving daily treatment with methadone (dose range 60-150 mg/day) for opioid use disorder (OUD) for at least 3 months prior to first study drug dose per participant's Opioid Treatment Program (OTP) and self-report. However, we will allow flexibility in the dose range during that 3-month period (such as an occasional missed methadone dose or a temporarily decreased methadone dose) if, in the judgement of the MAI, the candidate is stable on methadone overall and has not lost tolerance to methadone.
• Willing to miss two to three mornings' doses of methadone (without supplementing with other opioids), and reporting having done so in the past without severe withdrawal symptoms on the first day-with severe defined here as any of the following: repeated vomiting, repeated bouts of diarrhea, or any other symptoms so painful or uncomfortable that the participant would not want to experience them several times in this study.
• Willing to provide blood samples through an intravenous catheter to either upper extremity.
• For women of childbearing potential: must have a negative serum or urine pregnancy test within 72 hours prior to the first study drug dose (active or placebo) AND agree to use an adequate method of contraception to avoid pregnancy for a period of 3 months beginning from 30 days prior to first dose of study drug. Women of childbearing potential include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal.
• Standard NIH Clinical Center criteria for menopause:
• Women over age 55 who have not had a period for one year will be considered menopausal and do not need a pregnancy test, follicle stimulating hormone (FSH) test, or contraception.
• Women between 50-55, who have not had a period for one year, should have an FSH test. If their FSH level is more than 20, they will be considered menopausal and do not need pregnancy testing or contraception. If their FSH level is less than 20, they will need pregnancy testing and contraception as required by the protocol.
• Women between 45-50 who have not had a period for one year will need both an FSH test and a pregnancy test. If they are not pregnant and their FSH level is more than 20, they will be considered menopausal, and will not require contraception or additional pregnancy testing. If their FSH test is less than 20, they will need pregnancy testing and contraception as required by the protocol.
• For men, unless surgically sterilized (vasectomy with documentation of azoospermia), must agree to practice abstinence or use barrier contraception, and not donate sperm, for a period of 3 months beginning from first dose of study drug.
• Self-report of experiencing noticeable opioid withdrawal after missing just one or two days of methadone. This will be systematically assessed during screening.
• Participants must be able to speak, read, and understand English. Justification: This study uses scales and experimental procedures that are validated only in English. This includes the assessments conducted to test the primary and secondary outcomes and is therefore required to maintain the research integrity of the study.

You may not qualify if:

• Applicants will not be eligible if they meet any of the following criteria:
• A history of precipitated withdrawal after stopping opioid use and initiation onto buprenorphine or another partial or biased agonist, or self-reported prior inability to tolerate a moderate level of opioid withdrawal symptoms
• History of Diagnostic and Statistical Manual-5 (DSM-5) psychotic or bipolar disorder
• Current uncontrolled DSM-5 Major Depressive Disorder diagnosis.
• Current physical dependence on alcohol or sedative-hypnotic, e.g. benzodiazepine, to avoid the risk of physical withdrawal from them. Other DSM-5 criteria for substance use disorders (SUDs) involving alcohol or sedative-hypnotics are not automatically exclusory. The MAI will determine whether the clinical profile suggests a risk of physical withdrawal from alcohol or sedative-hypnotics.
• Inability to pass the National Institute on Drug Abuse (NIDA) Evaluation of Potential Research Participants Ability to Consent questionnaire (consent quiz) for 20-DA-N014.
• Any condition that interferes with urine or blood sampling.
• Clinically significant medical illness or medication use that, in the view of the investigators, would compromise safe participation in research, including but not limited to pulmonary disease, cirrhosis, nephrotic syndrome, thyroid disease, epilepsy, panhypopituitarism, adrenal insufficiency, ischemic heart disease, history of QTc prolongation, prolonged QTc on screening ECG (men, \>450ms; women, \>470ms, using the QTcF method), and potential causes of QTc prolongation (electrolyte abnormalities such as hypokalemia, hypomagnesemia, and hypocalcemia; medications such as certain antihistamines, antiemetics, antiarrhythmics, antidepressants, antibiotics, and antipsychotics; and structural or functional heart disease such as congenital long QT syndrome).
• Medications that could alter the effects of the opioid agonists being studied, including strong CYP3A4 inhibitors or inducers, or regular use of medications (such as alpha-2 agonists) that could attenuate signs or symptoms of opioid withdrawal.
• For women: pregnancy or breastfeeding.
• Any of the following lab values: Hb \< 10.5 g/dl; Cr \>2.0mg/dL; aspartate aminotransferase (AST) or alanine transaminase (ALT) \>3x upper limit of normal; total bilirubin \>2.0mg/dL.
• Any other medical reason or clinical condition that the MAI or designee considers unsafe for participation in the study.

Sponsors & Collaborators

• National Institute on Drug Abuse (NIDA): lead

Study Sites (1)

National Institute on Drug Abuse (NIDA)

Baltimore, Maryland, 21224, United States

Location

MeSH Terms

Conditions

Opioid-Related Disorders; Behavior, Addictive; Substance-Related Disorders

Interventions

Oxycodone

Condition Hierarchy (Ancestors)

Narcotic-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Compulsive Behavior; Impulsive Behavior; Behavior

Intervention Hierarchy (Ancestors)

Codeine; Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Limitations and Caveats

Data was only collected in the pilot phase before the study was terminated in 2025 because the drug was no longer being manufactured.

Results Point of Contact

• Title: Dr. David Epstein
• Organization: National Institute on Drug Abuse (NIDA)

david.epstein@nih.gov

667-312-5092

Study Officials

• David H Epstein, Ph.D.

  National Institute on Drug Abuse (NIDA)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 19, 2020
• First Posted: March 20, 2020
• Study Start: December 27, 2021
• Primary Completion: February 13, 2025
• Study Completion: February 14, 2025
• Last Updated: June 2, 2026
• Results First Posted: June 2, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: After publication of the main result
• Access Criteria: We will share some protocol data with our scientific research partners inside or outside the NIH. Research partners outside the NIH sign an agreement with the NIH to share data.

Locations

US (1)