Biased Opioid Agonists for Treatment of Opioid Withdrawal in OUD

Phase 2TerminatedNCT04316559

National Institute on Drug Abuse (NIDA)5 enrolled

Overview

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.

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 hours 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-hours 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-hours 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 Subjective Opioid Withdrawal Scale (SOWS). 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 Clinical Opioid Withdrawal Scale (COWS), 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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

* INCLUSION CRITERIA: Participants will be eligible for inclusion in the study if they meet the following criteria: * 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. * Adequate methods of contraception for sexually active women are those who have a male sexual partner(s) who is surgically sterilized prior to inclusion; have a sexual partner(s) who is/are exclusively female; is using oral contraceptives (either combined or progesterone only) WITH a single-barrier method of contraception consisting of spermicide and condom or diaphragm; is using double-barrier contraception, specifically, a condom plus spermicide AND a female diaphragm or cervical cap; or is using an approved intrauterine device (IUD) with established efficacy. 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. EXCLUSION CRITERIA: 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.

Outcomes

Primary Outcomes

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.

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

Secondary Outcomes

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

The clinical opioid withdrawal scale (COWS) is a widely used measure for evaluating the intensity of both signs and symptoms of opioid withdrawal. Signs are assessed by an observed; symptoms are assessed by asking the participant to rate them. Each of 11 COWS items item is scored on a 3, 4, or 5 point scale to reflect the severity of the symptom, with a maximum score of 48. Standard cutoffs are: mild withdrawal (5-12), moderate withdrawal (13-24), moderately severe withdrawal (25-36), and severe withdrawal (36 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 binomial regression to estimate probability of moderate withdrawal (versus mild withdrawal) with 95% credible interval (CI) for each treatment as estimated by the regression.

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

Withdrawal Signs Assessed by Pupil Diameter

Pupil diameter is a commonly used indicator of opioid withdrawal; wider diameters suggest more severe withdrawal, though there are no specific cutoffs, and clinical judgment must be used to assess pupil diameter relative to ambient light. Measurements were taken with a pupillometer 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.

Time frame: 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

The Four-Choice Reaction-Time task was one of two tasks used to assess psychomotor performance; this outcome measure was one of two main measures derived from the task. Participants performed the task on a laptop computer, and task response time was measured in milliseconds. Measurements were taken once per hour, up to four hours after each treatment. 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.

Time frame: 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

The Four-Choice Reaction-Time task was one of two tasks used to assess psychomotor performance; this outcome measure was the second of two main measures derived from the task. Participants performed the task on a laptop computer, and proportion of correct responses was assessed. Measurements were taken once per hour, up to four hours after each treatment. 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.

Time frame: 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

The Number-Vigilance test was used to assess psychomotor performance, specifically sustained attention and reaction time. Participants performed the task on a computer, responding when the number on the screen changed. Measurements were taken once per hour, up to four hours after each treatment. Sensitivity index was calculated by the testing software as the standardized difference between the hit rate (correct detection of the stimulus change) and the false alarm rate (incorrect responding in the absence of a stimulus change). Higher scores indicate better performance, with 0 indicating performance no better than chance and values over 3 indicating near perfect performance. 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.

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

Visual Analog Scales (VAS): Perceived Bad Effects From Study Drug

This item on a Visual Analog Scale (VAS) was a participant self-rating of perceived bad effects from the the study pill. The prompt was "Do you feel any bad effects from the study pill?"; the response scale was a 100-mm horizontal line on which the participant marked a point at or between two labeled extremes: 0 ("Not at all or never had any") and 100 ("Extremely"). 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.

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

Visual Analog Scales (VAS): Opioid Craving

This item on a Visual Analog Scale (VAS) was a participant self-rating of severity of opioid craving. The prompt was a "Do you crave more opioids (like heroin or oxycodone) right now?"; the response scale was 100-mm horizontal line on which the participant marked a point at or between two labeled extremes: 0 ("Not at all") and 100 ("Extremely"). 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.

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

Visual Analog Scales (VAS): Global Self-rating of Opioid Withdrawal Symptoms

This item on a Visual Analog Scale (VAS) was a participant self-rating of severity of opioid withdrawal symptoms, intended to complement the score from the multi-item SOWS. The prompt was "Are you feeling withdrawal symptoms right now?"; the response scale was a 100-mm horizontal line on which the participant marked a point at or between two labeled extremes: 0 ("Not at all") and 100 ("Extremely"). 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.

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

Visual Analog Scales (VAS): Perceived High From Study Drug

This item on a Visual Analog Scale (VAS) was a participant self-rating of perceived high from the the study pill. The prompt was "Do you feel high from the study pill?"; the response scale was a 100-mm horizontal line on which the participant marked a point at or between two labeled extremes: 0 ("Not at all or never had any") and 100 ("Extremely"). 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.

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

Visual Analog Scales (VAS): Perceived Relief of Opioid Withdrawal Symptoms by Study Drug

This item on a Visual Analog Scale (VAS) was a participant self-rating of perceived withdrawal relief attributed to the study pill. The prompt was "Is the study pill relieving your withdrawal symptoms?"; the response scale was a 100-mm horizontal line on which the participant marked a point at or between two labeled extremes: 0 ("Not at all or never had any") and 100 ("Completely"). 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.

Time frame: Up to four hours after each session, for a total of five noncontiguous session days

Biased Opioid Agonists for Treatment of Opioid Withdrawal in OUD

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes