Biased Opioid Agonists for Treatment of Opioid Withdrawal in OUD
Biased Opioid Agonists for Treatment of Opioid Withdrawal in OUD
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.
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.
-  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.