INDV-2000 First in Human

Study Overview
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Brief Summary
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This study is a single ascending dose (SAD) study conducted to identify the maximum tolerated dose (MTD) of INDV-2000. After completion of the SAD portion of the study and acceptable safety evaluation, a food-interaction, single-dose study under fed and fasted conditions will be conducted.

Official Title
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A Phase I, Double-blind, Placebo-controlled, Randomized, Single Ascending Dose Study to Assess the Safety, Tolerability and Pharmacokinetics of INDV-2000 (C4X_3256) Under Fasting and Fed Conditions in Healthy Volunteers

Conditions
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Opioid Dependence

Intervention / Treatment
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* Drug: INDV-2000
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be able to verbalize understanding the consent form, able to provide written informed consent, and verbalize willingness to complete study procedures, and be able to comply with protocol requirements, rules and regulations of the study site, and be likely to complete all the study interventions. Must be considered a healthy male or non-childbearing female for Part I For Part II, must be a healthy male who did not participate in Part I and willing to consume a high-fat meal. Body mass index (BMI) within 18.0 to 30.0 kg/m^2, inclusive (minimum weight of at least 50.0 kg at Screening) 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 time of screening until 90 days after last dose of Investigational Medicinal Product (IMP). Additionally, male subjects must agree to not donate sperm during the study and for at least 90 days from last dose of IMP. Exclusion Criteria: Have a medical history of clinically significant neurological, cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, or psychiatric disorder as judged by an Investigator, Have clinically significant abnormal biochemistry, hematology or urinalysis results as judged by an Investigator, Have a history of narcolepsy or other significant sleep disorders Have disorders that may interfere with drug absorption, distribution, metabolism and excretion (ADME) processes, Positive test results for human immunodeficiency virus (HIV)-1/HIV-2 antibodies, hepatitis B surface antigen (HBsAg) or hepatitis C antibody (HCVAb). Serious cardiac illness or other medical condition including, but not limited to: Uncontrolled arrhythmias; History of congestive heart failure (CHF); myocardial infarction < 6 months from receipt of first dose of IMP; uncontrolled symptomatic angina; corrected QT value (QTcF) > 450 msec for males and > 470 msec for females or history of prolonged QT syndrome; Have a blood pressure reading outside of the following range: systolic < 86 or > 149 mmHg; diastolic < 50 or > 94 mmHg Current active hepatic or biliary disease. Subjects with cholecystectomy < 90 days prior to screening. 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). Positive test result for alcohol and/or drugs of abuse at screening or prior to the first IMP administration. 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. Concurrent treatment or treatment with an investigational drug within 30 days prior to the first dose. Blood donation of approximately 500 mL within 56 days or plasma donation within 7 days of screening. Subjects who are taking, or have taken, any prescribed or over-the-counter drugs (other than 2 g per day acetaminophen, hormone replacement therapy, 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. Any consumption of food or drink containing poppy seeds, grapefruit or Seville oranges within 7 days prior to the IMP administration 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. Known allergy or hypersensitivity to IMP or its excipients. Any condition that, in the opinion of an Investigator, would interfere with evaluation of the IMP or interpretation of subject safety or study results. 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. Subjects who are unable, in the opinion of an Investigator, to comply fully with the study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part I - sequential escalating dose cohorts; within each dose cohort participants will be randomized to INDV-2000 or matching placebo in a 3:1 ratio. Part II - single cohort crossover study in which participants will receive INDV-2000 on 2 occasions separated by a 1-week washout period, once under fasting conditions and once after a standard high-fat breakfast.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I: INDV-2000<br>Participants will receive a single dose of INDV-2000. The starting dose is 1 mg with dose escalation dependent upon observed clinical safety, tolerability and pharmacokinetics. | Drug: INDV-2000<br>* INDV-2000 will be administered as either powder in solution or powder in capsule, depending on dose administered.<br>* Other names: C4X_3256;|
| Placebo Comparator: Part I: Placebo<br>Participants will receive a single dose of matching placebo. | Drug: Placebo<br>* Placebo will be administered as either powder in solution or powder in capsule, depending on dose administered.<br>|
| Experimental: Part II: INDV-2000 Fasted/Fed<br>Participants will receive a single dose of INDV-2000 orally on Day 1 under fasted conditions and a single dose of INDV-2000 after a high-fat breakfast on Day 8. Dose to be determined based on a well-tolerated dose studied in Part I. | Drug: INDV-2000<br>* INDV-2000 will be administered as either powder in solution or powder in capsule, depending on dose administered.<br>* Other names: C4X_3256;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) was considered related to study drug if it could not reasonably be explained by other factors. A serious AE is any event that met any of the following criteria: Death Life-threatening In-patient hospitalization or prolongation of existing hospitalization Persistent or significant disability/incapacity Congenital anomaly/birth defect Other important medical event that may have jeopardized the participant or required an intervention to prevent an above outcome. A severe AE describes the intensity of an AE, defined as causing marked limitation in activity; medical intervention or therapy or hospitalization required. For vital sign and laboratory abnormalities assessed as AEs, intensity was graded in accordance with the Food and Drug Administration Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, where Grade 3 = serious and Grade 4 = potentially life-threatening. | From first dose of study drug to end of study participation for each cohort; 11 days in Part 1 and 7 days in Part II, Period 1 (fasted conditions) and 10 days in Part II, Period 2 (fed conditions). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinically Significant Laboratory Findings | The investigator assessed abnormal laboratory values to determine clinical significance. | From first dose of study drug to end of study participation for each cohort; 11 days in Part I and 7 days in Part II, Period 1 (fasted conditions) and 10 days in Part II, Period 2 (fed conditions). | 
| Number of Participants With Clinically Significant Changes in Vital Signs | The investigator assessed changes in vital signs (including including blood pressure, respiratory rate, heart rate and temperature) to determine clinical significance. | From first dose of study drug to end of study participation for each cohort; 11 days in Part 1 and 7 days in Part II, Period 1 (fasted conditions) and 10 days in Part II, Period 2 (fed conditions). | 
| Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings | The investigator assessed abnormal ECG values to determine clinical significance. | From first dose of study drug to end of study participation for each cohort; 11 days in Part I and 7 days in Part II, Period 1 (fasted conditions) and 10 days in Part II, Period 2 (fed conditions). | 
| Number of Participants With Clinically Significant Physical Examination Findings | Any clinically significant abnormalities observed during physical examination, including changes from baseline, were recorded as adverse events on the adverse event (AE) case report form (CRF) and are reported in the adverse events section of results below. However, these events were not recorded as physical examination findings. Therefore, clinically significant physical examination findings can not be reported separately. | From first dose of study drug to end of study participation for each cohort; 11 days in Part I and 7 days in Part II, Period 1 (fasted conditions) and 10 days in Part II, Period 2 (fed conditions). | 
| Part I: Maximum Observed Plasma Concentration (Cmax) of INDV-2000 After a Single Dose | Concentrations of INDV-2000 were measured using a validated high-performance liquid chromatography with electrospray tandem Mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters based on the actual sample collection times were derived using standard non-compartmental methods. | Day 1 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part I: Time to Maximum Observed Plasma Concentration (Tmax) of INDV-2000 After a Single Dose |  | Day 1 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part I: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUC0-last) of INDV-2000 After A Single Dose |  | Day 1 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part I: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of INDV-2000 After A Single Dose |  | Day 1 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part I: Apparent Plasma Clearance (CL/F) of INDV-2000 After a Single Dose |  | Day 1 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part I: Plasma Terminal Half-life of INDV-2000 After a Single Dose |  | Day 1 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part I: Maximum Observed Plasma Concentration (Cmax) of M12 After a Single Dose of INDV-2000 | Concentrations of INDV-2000 metabolite M12 were measured using a validated high-performance liquid chromatography with electrospray tandem Mass spectrometry (LC-MS/MS) method. | Day 1 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part I: Time to Maximum Observed Plasma Concentration (Tmax) of M12 After a Single Dose of INDV-2000 |  | Day 1 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part I: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration of M12 After A Single Dose of INDV-2000 |  | Day 1 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part I: Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of M12 After A Single Dose of INDV-2000 |  | Day 1 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part I: Plasma Terminal Half-life of M12 After a Single Dose of INDV-2000 |  | Day 1 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part II: Cmax of INDV-2000 After a Single Dose Under Fasting and Fed Conditions |  | Day 1 and Day 8 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part II: Tmax of INDV-2000 After a Single Dose Under Fasting and Fed Conditions |  | Day 1 and Day 8 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part II: AUC0-last of INDV-2000 After a Single Dose Under Fasting and Fed Conditions |  | Day 1 and Day 8 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part II: AUC0-inf of INDV-2000 After a Single Dose Under Fasting and Fed Conditions |  | Day 1 and Day 8 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part II: Apparent Clearance of INDV-2000 After a Single Dose Under Fasting and Fed Conditions |  | Day 1 and Day 8 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part II: Plasma Terminal Half-life of INDV-2000 After a Single Dose Under Fasting and Fed Conditions |  | Day 1 and Day 8 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part II: Cmax of M12 After a Single Dose of INDV-2000 Under Fasting and Fed Conditions |  | Day 1 and Day 8 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part II: Tmax of M12 After a Single Dose of INDV-2000 Under Fasting and Fed Conditions |  | Day 1 and Day 8 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part II: AUC0-last of M12 After a Single Dose of INDV-2000 Under Fasting and Fed Conditions |  | Day 1 and Day 8 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part II: AUC0-inf of M12 After a Single Dose of INDV-2000 Under Fasting and Fed Conditions |  | Day 1 and Day 8 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose | 
| Part II: Plasma Terminal Half-life of M12 After a Single Dose of INDV-2000 Under Fasting and Fed Conditions |  | Day 1 and Day 8 pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose |