Evaluation of Tirzepatide as an Adjunct to Buprenorphine for the Treatment of Opioid Use Disorder

Phase 2

Not yet recruiting

• Conditions: Opioid Use Disorder; Opioid Use Disorder, Moderate; Opioid Use Disorder, Severe
• Interventions: Drug: Tirzepatide; Other: Placebo

• Registration Number: NCT06651177
• Lead Sponsor: T. John Winhusen, PhD

Brief Summary

The primary objective of this research study is to evaluate the effect of tirzepatide, relative to placebo, as an adjunct to BUP on retention, substance use, and sleep outcomes in individuals with OUD.

Detailed Description

This is a Phase 2, pragmatic, multi-site, double-blind, randomized, placebo-controlled, intent-to-treat trial. The selection of placebo as the comparator is considered the gold standard for medication trials. Eligible participants will be randomized in a 1:1 ratio to tirzepatide or placebo, balancing on site and buprenorphine (BUP) formulation (transmucosal vs extended-release).

Participants will receive tirzepatide or placebo based on randomized assignment, with "dose escalation" of placebo following the schedule for tirzepatide and tirzepatide dosing being consistent with prescribing guidelines. Participants will be administered a subcutaneous (SQ) study medication injection weekly and attend weekly research visits through 26 weeks post-randomization with longer research visits at 1, 3, and 6 months post-randomization. A follow-up visit for final safety measures will be completed at week 30, which takes into account tirzepatide's long half-life.

Duration of participation will be approximately 31 weeks for study participants. Participants will be administered study medication and attend weekly research visits through 6 months post-randomization with longer research visits at 1-, 3-, and 6-months post-randomization. Participants will be provided with a Fitbit to measure sleep. BUP is not a study medication; participants will receive BUP through their clinical provider. A follow-up visit for final safety measures will be completed at week 30.

Study Timeline

• Study First Submitted: 2024-10-17
• Study First Submitted QC: 2024-10-18
• Study First Posted: 2024-10-21
• Status Verified: 2025-08
• Last Update Submitted: 2025-08-11
• Last Update Posted: 2025-08-14
• Study Start: 2025-11-19
• Primary Completion: 2027-06-30
• Study Completion: 2027-06-30

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 310

Inclusion Criteria

1. Must be ≥18 years of age;

2. Must have moderate to severe OUD;

3. Must, at the time of randomization, be newly initiated on BUP (i.e., within 7 to 28 days) during the current treatment episode, be taking ≥ the recommended target dose for transmucosal BUP (or equivalent for extended-release), and have documentation of receiving BUP, including dose and the start date of the current treatment episode, from their BUP provider;

4. Must be willing to be randomized to tirzepatide or placebo and to comply with study procedures, including weekly visits for 6 months;

5. Must be able to understand the study, and having understood, provide written informed consent in English;

6. Must not be breastfeeding; if of child bearing potential, must test negative on the study-administered pregnancy test(s), and if of childbearing potential and engaging /planning to engage in sexual intercourse must agree to effective contraception for the duration of the trial through 30 days after the trial; effective contraception is defined as using: a) birth control injection, an intrauterine device, or implant; or b) two birth control methods - for example birth control pills with a barrier method (e.g., condoms, etc.).

   • If ever of childbearing potential, a participant is considered to not be of childbearing potential for the study if they are:

     1. infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, tubal implants, or tubal ligation), congenital anomaly such as Mullerian agenesis; are
     2. post-menopausal defined as ≥ 55 years old not on hormone therapy, who has had at least 12 months of spontaneous amenorrhea;
     3. ≥ 55 years old with a diagnosis of menopause prior to starting hormone replacement therapy; or
     4. ≥ 40 years old with an intact uterus, not on hormone therapy, who has cessation of menses for at least 1 year without an alternative medical cause, AND a follicle-stimulating hormone ≥ 40 mIU/mL; participants in this category must test negative on the study-administered pregnancy test(s).

Exclusion Criteria

1. have a history of type 1 or type 2 diabetes mellitus (other than pregnancy-related diabetes);

2. have a BMI <25.0;

3. have any of the following cardiovascular conditions within 90 days prior to signing consent: acute myocardial infarction, cerebrovascular accident (stroke), unstable angina, or hospitalization due to congestive heart failure (CHF);

4. have a known history of chronic or acute pancreatitis, gallbladder disease, gastroparesis, gastric emptying abnormality, gastroesophageal reflux disease, or other severe gastrointestinal disease;

5. have a personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2);

6. have previously taken tirzepatide, have taken any GLP-1 analogue within the 6 months before consent, or have a known history of prior hypersensitivity reaction to any GLP-1 analogue;

7. have renal impairment defined as an estimated glomerular filtration rate (eGFR) value of < 15 mL/min/1.73 m2 or requiring dialysis;

8. have a current, or within the 30 days prior to signing consent, use of, or plan to start during the course of the trial:

   1. medications with glucose lowering properties: GLP-1 analogs, sulfonylurea, insulin, metformin, thiazolidinediones, dipeptidyl peptidase-4 (DPP-IV) inhibitors, sodium-glucose cotransporter-2 (SGLT-2) inhibitors;
   2. systemic steroids including prednisone, hydrocortisone, dexamethasone;

9. have a history of suicide attempts or significant active suicidal ideation as assessed by a qualified study clinician;

10. have a psychiatric or medical condition that, in the judgment of the site medical clinician (BMC or UMC), would make study participation unsafe or which would make treatment compliance difficult;

11. have current status as a prisoner OR be currently in jail, prison, or any inpatient overnight facility as required by court of law or have pending legal action or other situation (e.g., unstable living arrangements) that, in the judgement of the site investigator, could prevent participation in the study or in any study activities.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tirzepatide	Tirzepatide	The tirzepatide pen is a pre-filled, disposable, injection device designed for subcutaneous administration. Each pen is pre-filled with a single dose of tirzepatide and is available in six doses: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg/0.5 mL. An unblinded study MC (UMC) will administer the once-weekly SQ dose of tirzepatide. Consistent with tirzepatide's prescribing guidelines, participants will be initiated at a once-weekly SQ dose of 2.5 mg/week with a dose increase to 5mg/week at week 5. Consistent with tirzepatide's prescribing information, once the participant has received 5 mg/week for 4 weeks they are eligible for a dose increase if needed.
Placebo	Placebo	Saline administered subcutaneously with a syringe will be used as the placebo for the trial. The placebo which will be administered by a study UMC. The process for deciding on "dose increases" will be the same for placebo and tirzepatide.

Primary Outcome Measures

Name	Time	Method
6-month medication for opioid use disorder (MOUD) retention rate - Timeline Follow-Back (TLFB)	6 months	MOUD is defined as buprenorphine (BUP) or methadone. The receipt of MOUD will be assessed by self-report collected through a TLFB procedure.
6-month medication for opioid use disorder (MOUD) retention rate - Urine Drug Screen (UDS)	6 months	MOUD is defined as BUP. This will be measured by UDS results for BUP.

Secondary Outcome Measures

Name	Time	Method
Opioid Cravings	6 months	Craving will be assessed with the Opioid Craving Scale, which was utilized in CTN-0030 and shown to have predictive validity. The total score is calculated by averaging the scores from three visual analogue scales which assess craving, cue-induced craving, and likelihood of using.
Treatment Effectiveness	6 months	Treatment Effectiveness will be measured by the Treatment Effectiveness Assessment (TEA). The TEA is a patient-oriented instrument that assesses the participant's perceived improvements in substance use, health, ability to fulfill adult obligations, and to be a good community member. The TEA includes four items, each rated on a 1-10-point scale (from none to much better) yielding a total score of 4-40.
Substance Use Days	6 months	Days of illicit-opioid, other drug, alcohol, and nicotine use during the 26 week active treatment phase will be assessed with the Timeline Follow-back (TLFB).
Proportion of illicit opioid-negative urine samples during the 6-month active treatment phase	6 Months	A rapid Urine Drug Screen (UDS)UDS system will be used to analyze the urine samples. Urine samples will be tested for: buprenorphine/ norbuprenorphine and fentanyl.
Proportion of urine samples negative for other substances of abuse during the 6-month active treatment phase	6 months	Nicotine abstinence will be assessed with cotinine, alcohol abstinence will be assessed with ethyl glucuronide, and drug abstinence will be assessed based on the other substances (other than buprenorphine/ norbuprenorphine) assessed for by the UDS system.
Days of Substance Bingeing	6 months	Days of bingeing of illicit opioids and/or other drugs during the 26 week active treatment phase will be assessed with the Timeline Follow-back (TLFB).
Opioid Withdrawal Symptoms	6 months	The Short Opiate Withdrawal Scale (SOWS)-Gossop will be used to measure opioid withdrawal symptoms. The SOWS-Gossop, which is a self-administered scale that includes 10 items, rated on a scale of 0 (none) to 3 (severe), is a validated instrument with good reliability.
Non-Opioid Drug and Alcohol Craving	6 months	Non-Opioid Drug and Alcohol Craving will be measured by the Non-Opioid Drug and Alcohol Craving Scale. The 3-item craving scale, which assesses craving for drugs and alcohol, will be modified to ask about substances other than opioids.
The Modified Patient-Reported Outcomes Measurement Information System (PROMIS)-based Opioid Use Monitor	6 months	The PROMIS-based Opioid Use Monitor (OUM) was adapted from the PROMIS substance use measure by replacing "drugs" with "opioids" and changing the timeframe from the past 3 months to the past 2 weeks. For the present trial, a modified version of the OUM (M-OUM) will be used as an outcome measure and for use in determining whether a dose increase is needed. The M-OUM includes seven items that are each rated on a 0-4-point scale ("0-never" to "4-almost always") yielding a total score of 0-28.
Sleep Quality - The Pittsburgh Sleep Quality Index (PSQI)	6 months	Participant perceived sleep quality will be assessed using the PSQI, which is a relatively brief, validated instrument that measures sleep quality.
Self-reported control of opioid/stimulant use and craving -	6 months	The PROMIS-based Opioid Use Monitor (OUM) was adapted from the PROMIS substance use measure by replacing "drugs" with "opioids" and changing the timeframe from the past 3 months to the past 2 weeks. A modified version of the OUM (M-OUM) will be used as an outcome measure and for use in helping to determine whether a dose increase should be offered.
Sleep Quality - Fitbit Charge 6™ (FBC-6)	6 months	An objective measure of the impact of tirzepatide, relative to placebo, on sleep will be obtained using the Fitbit Charge 6™ (FBC-6). A comparison of an earlier version of the device (Fitbit Charge 4™) to polysomnography found no significant differences in the measures of total sleep time and waking after sleep onset. Each participant will be provided with a Fitbit Charge 6™ when they are deemed eligible for randomization and asked to wear it every night (or whenever they have their longer period of intended sleep) through the final study visit. Data from the Fitbit Charge 6™ will be downloaded at the weekly research visits. Total sleep time is the main outcome of interest.

Trial Locations

Locations (10)

Tarzana Treatment Centers; 🇺🇸 Tarzana, California, United States

Gateway Community Services; 🇺🇸 Jacksonville, Florida, United States

IBIS Behavioral Health; 🇺🇸 Tampa, Florida, United States

Ruth M. Rothstein CORE Center; 🇺🇸 Chicago, Illinois, United States

The Gibson Center for Behavioral Change; 🇺🇸 Cape Girardeau, Missouri, United States

Prisma Health; 🇺🇸 Greenville, South Carolina, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

University of Utah; 🇺🇸 Salt Lake City, Utah, United States

Marshall Health; 🇺🇸 Huntington, West Virginia, United States

Healthy Minds/Chestnut Ridge; 🇺🇸 Morgantown, West Virginia, United States