Proof of Concept and Dose-ranging Study of INDV-2000 in Individuals With Moderate to Severe Opioid Use Disorder

From Day 1 to Day 7, TM buprenorphine and randomized INDV-2000/Placebo will be administered, INDV-2000/Placebo will be administered alone from Day 8 onward. The randomized treatment period starts when the participant receives randomized treatment (at Day 1) and ends at his/her last study visit, if on INDV-2000/Placebo alone, or ends when starting buprenorphine rescue therapy.

Inclusion criteria

• Participants are eligible to be included in the study only if all of the following criteria apply:

• Participant must be 18 or the legal age of consent in the jurisdiction in which the study is taking place to 65 years of age inclusive, at the time of signing the informed consent.
• Able to verbalize understanding of the consent form, able to provide written informed consent, and verbalize willingness to complete study procedures, be able to comply with protocol requirements, rules and regulations of study site, and be likely to complete all the study interventions.
• Males or females with moderate or severe opioid use disorder (OUD) by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria who are looking to transition from daily short-term opioid agonist treatment (medically supervised withdrawal) to non-opioid treatment.
• Have not been on medication for opioid use for 3 months prior to the current treatment episode, and satisfies either a or b below.

• The participant will initiate, or is undergoing medically supervised withdrawal, and

• In the opinion of the investigator, the participant is able to achieve a stable dose of transmucosal (TM) buprenorphine between ≤24 mg inclusive prior to randomization.
• Current opioid agonist treatment does not exceed 35 days from the start of TM buprenorphine to the end of Screening window.
• The participant recently completed medically supervised withdrawal outside of the study, and

• Time elapsed between last dose of TM buprenorphine or other withdrawal medication and Study Day 1/randomization does not exceed 21 calendar days.
• Recently completed opioid agonist treatment does not exceed 35 days of TM buprenorphine dosing days inclusive of medically assisted withdrawal dosing.
• Male participants who are sexually active with individuals who are of childbearing potential must agree to use a medically acceptable forms of contraception from Screening until at least 90 days after the last dose of study medication. The following methods of contraception are considered to be medically acceptable: established use of oral, injected or implanted hormonal contraception; placement of an intrauterine device or intrauterine system; or use of a double barrier method of contraception (condom or occlusive cap with use of a spermicide), or abstinence.
• A female participant of non-childbearing potential, or a male of childbearing potential if

• She agrees to use a medically acceptable form of contraception from Screening until at least 90 days after the last dose of study medication. The following methods of contraception are considered to be medically acceptable: abstinence; established use or oral, injected or implanted hormonal contraception; placement of an intrauterine device or intrauterine system; or use of a double barrier method of contraception (condom or occlusive cap with use of a spermicide).
• She is not pregnant as confirmed by a negative serum screening and or urine human chorionic gonadotrophin test on Study Day 1.
• She is not lactating.
• Body mass index (BMI) within 18.0 to 40.0 kg/m2 (inclusive)

Exclusion criteria

• Participants are excluded from the study if any of the following criteria apply:

• Have a current diagnosis, other than OUD, requiring chronic opioid treatment.
• Have a concurrent primary substance use disorder, as defined by DSM-5 criteria, other than opioid, tobacco, cannabis or alcohol use disorders.
• Meet DSM-5 criteria for severe substance use disorder other than opioids.
• Have a medical history of clinically significant neurological, cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, or psychiatric disorder that would impact participation in the study as judged by an Investigator or medically responsible physician.
• Had an opioid overdose event within the 6 months prior to the Screening Visit.
• Uses any substance of abuse via the injection route more than 2 times per week over the last 3 months prior to Screening.
• Have clinically significant abnormal biochemistry, hematology or urinalysis results that would impact participation in the study as judged by an Investigator or medically responsible physician.
• Have a history of narcolepsy, cataplexy, obstructive or central sleep apnea.
• Have disorders that may interfere with drug absorption, distribution, metabolism and excretion processes.
• History of suicidal ideation within 30 days prior to providing written informed consent as evidenced by answering "yes" to questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) completed at the Screening Visit or history of a suicide attempt (per the C-SSRS) in the 6 months prior to informed consent.
• Serious cardiac illness or other cardiac assessments including, but not limited to:

• Uncontrolled arrhythmias.
• History of congestive heart failure.
• Myocardial infarction <6 months from receipt of first dose of investigational medicinal product (IMP)
• Uncontrolled symptomatic angina
• QT interval corrected with Fridericia's formula (QTcF) >450 msec for males and >470 msec for females or history of prolonged QT syndrome.
• Have any combination of the following at screening:

• Total bilirubin ≥1.5×upper limit of normal (ULN) (with direct bilirubin >1.3 mg/dL),
• Alanine aminotransferase (ALT) ≥3×ULN
• Aspartate aminotransferase (AST) ≥3×ULN
• International normalized ratio (INR) >1.2 for participants not receiving anticoagulation therapy, >3.0 for participants on conventional coagulation therapy, >3.5 for participants on intensive anticoagulation, or
• Estimated glomerular filtration rate <60 mL/min by Cockroft-Gault formula.
• Current symptomatic hepatic or biliary disease, including participants with cholecystectomy <90 days prior to Screening.
• Use of a long-acting buprenorphine or naltrexone treatment for OUD within 2 years or 1 year of the screening visit, respectively.
• Concurrent treatment or treatment with an investigational drug, or participation in any other clinical study within 30 days prior to the signing the informed consent form.
• Blood or platelets donation of greater than 500 mL within 56 days or plasma donation within 7 days of screening; clinically significant anemia or low hemoglobin (<11 g/dL for females, <12 g/dL for males).
• Known allergy or hypersensitivity to IMP or its excipients.
• Any condition that, in the opinion of an Investigator or medically responsible physician, would interfere with evaluation of the IMP or interpretation of participant safety or study results.
• Is a member of site staff, has a financial interest in Indivior, or is an immediate family member of anyone directly involved in the study (ie, site staff, Indivior, or Clinical Research Organization [CRO] employee).
• Participants who are unable, in the opinion of an Investigator or medically responsible physician, to comply fully with the study requirements, including prohibited concomitant therapies.
• Current incarceration, treatment for OUD required by court order, or pending incarceration/legal action that could prevent participation or compliance in the study.