Study to Assess Repeated Doses of INDV-2000 in Healthy Volunteers and in Treatment Seeking Individuals With Opioid Use Disorder

A Phase I Double-Blind, Placebo-Controlled Randomized Study to Assess Repeated Doses of INDV-2000 (C4X_3256) up to 28 Days in Healthy Volunteers, and an Open-Label Study of INDV-2000 up to 11 Days in Treatment Seeking Individuals With Opioid Use Disorder

The primary objectives for the study are:

• Part I and Part II: Assess safety and tolerability of repeated doses of INDV-2000 in healthy volunteers.
• Part III: Assess the safety and tolerability of repeated doses of INDV-2000 administered alone and with SUBOXONE sublingual (SL) film in an opioid use disorder (OUD) treatment seeking population.

The study will be conducted in 3 parts:

Part I: Double-blind, placebo-controlled, randomized, multiple ascending dose study for 7 days of dosing with INDV-2000 in healthy volunteers.

Part II: Double-blind, placebo-controlled, randomized, multiple ascending dose study for 28 days of dosing with INDV-2000 in healthy volunteers.

Part III: This part is an open-label study in OUD treatment seeking individuals.

Inclusion Criteria:

1. 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.

2. Female subjects of child-bearing potential who are sexually active with males must use, with their partner, a condom plus an approved method of effective contraception from the time of screening until 30 days after the last dose of Investigational Medicinal Product (IMP). The impact of IMP on the efficacy of hormonal contraceptives is unknown. Male subjects who are sexually active with female partners of child-bearing potential must use, with their partner, a condom plus an approved method of effective contraception from the time of screening until 90 days after the last dose of IMP and agree to not donate sperm over this time period. Effective methods of contraception are:

   1. Combined (estrogen and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal
   2. Progestogen-only hormonal contraception: oral, injectable/implantable, or intrauterine hormone-releasing system (IUD)
   3. Implantable intrauterine device (IUS)
   4. Surgical sterilization (for example, vasectomy or bilateral tubal ligation)
   5. Male condom with spermicidal gel/foam or with female cap or diaphragm (double barrier)
   6. abstinence from heterosexual intercourse as a conscious choice and established pattern of lifestyle

   Part I and II only:

3. Healthy male or female.

4. Between 18 and 55 years of age inclusive.

5. Body mass index (BMI) within 18.0 to 32.0 kg/m^2, inclusive (minimum weight of at least 50.0 kg at Screening).

   Part III only:

6. Male or female seeking treatment for OUD with a diagnosis of moderate or severe OUD by Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria.

7. Between 18 and 65 years of age inclusive.

8. BMI within 18.0 to 35.0 kg/m^2, inclusive (minimum weight of at least 50.0 kg at Screening).

Exclusion Criteria:

1. Have a medical history of clinically significant neurological, cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, or psychiatric disorder as judged by an Investigator.

2. Have clinically significant abnormal biochemistry, hematology or urinalysis results as judged by an Investigator or medically responsible physician.

3. Have a history of narcolepsy or other significant sleep disorders.

4. Have disorders that may interfere with drug absorption, distribution, metabolism and excretion (ADME) processes.

5. Positive test results for human immunodeficiency virus (HIV)-1/HIV-2 antibodies, hepatitis B surface antigen (HBsAg) or hepatitis C antibody (HCVAb).

6. Serious cardiac illness or other cardiac assessments including, but not limited to:

   1. Uncontrolled arrhythmias.
   2. History of congestive heart failure (CHF).
   3. Myocardial infarction <6 months from receipt of first dose of IMP
   4. Uncontrolled symptomatic angina
   5. QTcF > 450 msec for males and > 470 msec for females or history of prolonged QT syndrome.

7. Current active hepatic or biliary disease, including subjects with cholecystectomy <90 days prior to Screening.

8. Concurrent treatment or treatment with an investigational drug within 30 days prior to the first dose of any study drug.

9. 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.

10. Pregnant or lactating females.

11. Any consumption of food or drink containing poppy seeds, grapefruit or Seville oranges within 7 days prior to the IMP administration.

12. Treatment with any known drugs that are moderate or strong inhibitors/inducers of cytochrome P450 (CYP) 3A4 within 30 days prior to first dose of IMP.

13. Known allergy or hypersensitivity to IMP or its excipients.

14. Any condition that, in the opinion of an Investigator or medically responsible physician, would interfere with evaluation of the IMP or interpretation of subject safety or study results.

15. Affiliated with, or a family member of, site staff directly involved in the study, or anyone with a financial interest in the outcome of the study.

16. Subjects who are unable, in the opinion of an Investigator or medically responsible physician, to comply fully with the study requirements.

17. Participation in any other clinical study within 30 days prior to signing the informed consent form.

18. Current incarceration or pending incarceration/legal action that could prevent participation or compliance in the study.

    Part I and II only:

19. Regular alcohol consumption in males > 21 units per week and females > 14 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine).

20. Positive test result for alcohol and/or any drugs of abuse at screening

21. Have a blood pressure reading outside of the following range: Systolic < 86 or > 149 mmHg; Diastolic < 50 or > 94 mmHg

22. Current smokers and those who have smoked within the last 90 days. Current users of e-cigarettes and nicotine replacement products, and those who have used these products within the last 90 days.

23. Blood 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).

24. Healthy volunteers who are taking, or have taken, any prescribed or over-the-counter drugs (other than 2 g per day acetaminophen, hormone replacement therapy [HRT], hormonal contraception) or herbal remedies in the 14 days before IMP administration. Exceptions may apply on a case by case basis if considered not to interfere with the objectives of the study, as agreed by an Investigator and Sponsor's Medical Monitor.

    Part III only:

25. Regular alcohol consumption in males > 27 units per week and females > 20 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine).

26. Current substance use disorder, as defined by DSM-5 criteria, with any substances other than opioids, tobacco, cannabis, or alcohol, or dependence with any substance that would interfere with the completion of the study by judgment of the Investigator or medically responsible physician.

27. Current history of alcohol withdrawal within one year prior to screening.

28. Blood donation of greater than 500 mL within 56 days or plasma donation within 7 days of screening; clinically significant anemia or low hemoglobin (< 10 g/dL for females, < 12 g/dL for males).

29. Have a blood pressure reading outside of the following range: Systolic < 86 or > 159 mmHg; Diastolic < 50 or > 99 mmHg. Investigator should rule out acute changes resulting from opioid withdrawal.

30. Has 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, serum creatinine > 2 × ULN, or international normalized ratio (INR) > 1.5 × ULN at Screening).

31. Received medication-assisted treatment for OUD (e.g., methadone, buprenorphine) in the 30 days prior to providing written informed consent.

32. Received any prior treatment with a buprenorphine implant or injection.

33. Treatment for OUD required by court order.