ClinicalTrials.gov

History of Changes for Study: NCT04316559
Biased Opioid Agonists for Treatment of Opioid Withdrawal in OUD
Latest version (submitted September 13, 2022) on ClinicalTrials.gov
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Study Record Versions
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1 March 19, 2020 None (earliest Version on record)
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Study NCT04316559
Submitted Date:  March 19, 2020 (v1)

Open or close this module Study Identification
Unique Protocol ID: 999920014
Brief Title: Biased Opioid Agonists for Treatment of Opioid Withdrawal in OUD
Official Title: Biased Opioid Agonists for Treatment of Opioid Withdrawal in OUD: A Dose-Finding Pilot and Within-Subject Randomized Inpatient Trial
Secondary IDs: 20-DA-N014
Open or close this module Study Status
Record Verification: March 12, 2020
Overall Status: Not yet recruiting
Study Start: March 25, 2020
Primary Completion: September 30, 2022 [Anticipated]
Study Completion: September 30, 2022 [Anticipated]
First Submitted: March 19, 2020
First Submitted that
Met QC Criteria:
March 19, 2020
First Posted: March 20, 2020 [Actual]
Last Update Submitted that
Met QC Criteria:
March 19, 2020
Last Update Posted: March 20, 2020 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: National Institute on Drug Abuse (NIDA)
Responsible Party: Sponsor
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug: Yes
U.S. FDA-regulated Device: No
Data Monitoring:
Open or close this module Study Description
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 13-26 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 53 enrolled; up to 30 completers, plus three to run in 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 h 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 will stay at the inpatient unit for 13-21 consecutive nights to help ensure that participants use no additional opioids during a 52-hr opioid abstinence period prior to each test session. The first three participants will be enrolled in an unpowered dose-finding five-session pilot study (18-26 consecutive nights) to test 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. 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.

Open or close this module Conditions
Conditions: Opioid-Use Disorder
Keywords: Addiction
Psychomotor Testing
Substance Use Disorders
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 2
Interventional Study Model: Sequential Assignment
Number of Arms: 2
Masking: Triple (Participant, Care Provider, Investigator)
Allocation: Randomized
Enrollment: 53 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Placebo Comparator: Placebo
Placebo capsule
Placebo
Placebo capsule
Experimental: TRV734
TRV734 at different doses vs. oxycodone for withdrawal suppression
Drug: TRV734
biased agonist at muopioid receptors
Open or close this module Outcome Measures
Primary Outcome Measures:
1. sows
[ Time Frame: within-session ]

Subjective Opioid Withdrawal Scale
Secondary Outcome Measures:
1. NIH Toolbox test battery
[ Time Frame: within-session ]

psychomotor tests
2. COWS
[ Time Frame: within-session ]

Clinical Opioid Withdrawal Scale
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age: 75 Years
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:
  • 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 75-120 mg/day) for opioid-use disorder (OUD) for at least 3 months.
  • Willing to miss a dose 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.
  • For women of childbearing potential: must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the first study drug dose (active or placebo) AND agree to use an adequate method of contraception (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.) 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 1 year will be considered menopausal and do not need a pregnancy test, FSH test, or contraception.
  • Women between 50-55, who have not had a period for 1 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 1 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.

      (6) Self-report of experiencing noticeable opioid withdrawal after missing just one or two days of methadone; this will be operationalized with the screening question: How many days of methadone do you have to miss before you have withdrawal symptoms such as runny nose, nausea, aches, chills, or anxiety?

EXCLUSION CRITERIA:

Applicants will not be eligible if they meet any of the following criteria:

  • History of DSM-5 psychotic or bipolar disorder; current DSM-5 Major Depressive Disorder.
  • Current DSM-5 dependence on alcohol or sedative-hypnotic, e.g. benzodiazepine.
  • cognitive impairment severe enough to preclude informed consent or valid self-report.
  • any condition that interferes with urine or blood sampling.
  • medical illness or medications that, in the view of the investigators, would compromise participation in research, including but not limited to pulmonary disease, cirrhosis, nephrotic syndrome, thyroid disease, epilepsy, panhypopituatarism, adrenal insufficiency, ischemic heart disease, history of QTc prolongation, prolonged QT on screening ECG (men, >450ms; women, > 470ms), 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 CYP3A4 inhibitors or inducers.
  • For women: pregnancy or breastfeeding.
  • Any of the following lab values: Hb < 10; Cr >2.0; AST or ALT >3x upper limit of normal; total bilirubin >2.0.
  • Any other medical reason or clinical condition that the study physician considers unsafe for participation in the study.
Open or close this module Contacts/Locations
Central Contact Person: Shannon M Pfistner
Telephone: (443) 740-2283
Email: pfistners@mail.nih.gov
Study Officials: David H Epstein, Ph.D.
Principal Investigator
National Institute on Drug Abuse (NIDA)
Locations: United States, Maryland
National Institute on Drug Abuse
Baltimore, Maryland, United States, 21224
Contact:Contact: For more information contact Mathew's Media Group Recruiting 800-535-8254 researchstudies@mail.nih.gov
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Citations:
Links:
Available IPD/Information:

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