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

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 60days) during the current treatment episode, be taking ≥ the recommended target dosefor transmucosal BUP (or equivalent for extended-release), and have documentation ofreceiving BUP, including dose and the start date of the current treatment episode,from their BUP provider, and, for participants prescribed transmucosal BUP, have atleast one UDS positive for buprenorphine/norbuprenorphine;

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

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

6. Must not be breastfeeding; if of child bearing potential, must test negative on thestudy-administered pregnancy test(s), and if of childbearing potential and engaging /planning to engage in sexual intercourse must agree to effective contraception forthe duration of the trial through 30 days after the trial; effective contraceptionis 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 barriermethod (e.g., condoms, etc.).

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

1. infertile due to surgical sterilization (hysterectomy, bilateraloophorectomy, tubal implants, or tubal ligation), congenital anomaly suchas Mullerian agenesis; are
2. post-menopausal defined as ≥ 55 years old not on hormone therapy, who hashad at least 12 months of spontaneous amenorrhea;
3. ≥ 55 years old with a diagnosis of menopause prior to starting hormonereplacement therapy; or
4. ≥ 40 years old with an intact uterus, not on hormone therapy, who hascessation of menses for at least 1 year without an alternative medicalcause, AND a follicle-stimulating hormone ≥ 40 mIU/mL; participants inthis category must test negative on the study-administered pregnancytest(s).

Exclusion Criteria:

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

2. have a BMI <23.0 kg/m²;

3. have any of the following cardiovascular conditions within 90 days prior to signingconsent: acute myocardial infarction, cerebrovascular accident (stroke), unstableangina, 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, orother severe gastrointestinal disease;

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

6. have previously taken tirzepatide, have taken any GLP-1 analogue within the 6 monthsbefore consent, or have a known history of prior hypersensitivity reaction to anyGLP-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 tostart during the course of the trial:

9. 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;

10. systemic steroids including prednisone, hydrocortisone, dexamethasone;

11. have a history of suicide attempts in the prior year or significant active suicidalideation as assessed by a qualified study clinician;

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

13. have current status as a prisoner OR be currently in jail, prison, or any inpatientovernight facility as required by court of law or have pending legal action or othersituation (e.g., unstable living arrangements) that, in the judgement of the siteinvestigator, could prevent participation in the study or in any study activities.