A Study to Evaluate if AC-084 is Safe, Its Fate in the Body as Well as Its Potential Effects on the Body in Healthy Subjects

Study Overview
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Brief Summary
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The primary purpose of this first-in-man study is to investigate whether AC-084 is safe and well-tolerated when orally administered at single- and multiple-ascending dose to healthy adults

Detailed Description
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The study is designed in three parts, A, B and C Part A: single-center, double-blind, randomized, placebo-controlled, single ascending dose Part B: single-center, double-blind, randomized, placebo-controlled, multiple ascending dose Part C: single-center, open-label, single dose in CYP2C9 poor metabolizers

Official Title
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A Three-part Single-center, Phase 1 Study to Assess the Tolerability, Safety, Pharmacokinetics (Including Food Interaction), and Pharmacodynamics of Ascending Single and Multiple Doses of AC-084 in Healthy Subjects and to Investigate the Pharmacokinetics of a Single Dose of AC-084 in Healthy CYP2C9 Poor Metabolizers

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: AC-084
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent in the local language prior to any study-mandated procedure Healthy male subjects for Part A, healthy male and female subjects for Part B and Part C aged between 18 and 55 years (inclusive) at screening No clinically significant findings on physical examination at screening Body mass index (BMI) of 18.0 to 28.0 kg/m2 (inclusive) at screening CYP2C9 poor metabolizers (Part C) Exclusion Criteria: History or clinical evidence of any disease and/or existence of any surgical or medical condition that might interfere with the absorption, distribution, metabolism or excretion of the study treatment (appendectomy and herniotomy allowed, cholecystectomy not allowed) Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions Treatment or substances known to induce CYP enzyme drug metabolism within 30 days prior to first study treatment administration Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol Known allergic reactions or hypersensitivity to the study treatment or drugs of the same class, or any of their excipients For Part A and Part B, CYP2C9 poor metabolizers enrolled in a cohort to be dosed with single or multiple dose of 500 mg or higher of ACT-774312 (confirmed by genotyping before enrollment)

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AC-084, single ascending dose (Part A)<br>AC-084 administered at different single dose levels in a sequential manner, and in a maximum of 7 dose levels starting from 1 mg (number of cohorts and dose levels will depend on the safety and pharmacokinetic results of the previous cohort). Each dose level will be investigated in a new group of at least 8 healthy male subjects (6 on active drug and 2 on placebo) | Drug: AC-084<br>* Hard gelatin capsules for oral administration formulated in strengths of 1 mg, 10 mg, and 100 mg<br>|
| Placebo Comparator: Placebo,single ascending dose (Part A)<br>Matched placebo administered as single ascending doses in parallel to AC-084 | Drug: Placebo<br>* Placebo capsules matching AC-084 capsules<br>|
| Experimental: AC-084, multiple ascending dose (Part B)<br>AC-084 administered in a twice daily (b.i.d.) dosing regimen at multiple dose levels. The starting dose will be between 1 and 30 mg and will be selected on the basis of the safety and pharmacokinetic results of the part A. Each dose level will be investigated in a new group of at least 8 healthy male subjects (6 on active drug and 2 on placebo) | Drug: AC-084<br>* Hard gelatin capsules for oral administration formulated in strengths of 1 mg, 10 mg, and 100 mg<br>|
| Placebo Comparator: Placebo,multiple ascending dose (Part B)<br>Matched placebo administered as multiple ascending doses in parallel to AC-084 | Drug: Placebo<br>* Placebo capsules matching AC-084 capsules<br>|
| Experimental: AC-084, single dose (Part C)<br>Up to 6 subjects in part C will receive AC-084 administered at a single dose (foreseen to be 100 mg) | Drug: AC-084<br>* Hard gelatin capsules for oral administration formulated in strengths of 1 mg, 10 mg, and 100 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) (Part A) | Treatment-emergent AEs and treatment-emergent serious AEs | From dosing until day 4 | 
| Number of participants with adverse events (AEs) (Part B) | Treatment-emergent AEs and treatment-emergent serious AEs | From dosing until day 8 | 
| Number of participants with adverse events (AEs) (Part C) | Treatment-emergent AEs and treatment-emergent serious AEs | From dosing until day 6 | 
| Incidence of safety events of interest (Part A) | Events of interest are any abnormalities in ECG, vital signs or laboratory test results | From dosing until day 4 | 
| Incidence of safety events of interest (Part B) | Events of interest are any abnormalities in ECG, vital signs or laboratory test results | From dosing until day 8 | 
| Incidence of safety events of interest (Part C) | Events of interest are any abnormalities in ECG, vital signs or laboratory test results | From dosing until day 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) following single oral ascending doses (Part A) | Cmax is derived from the observed plasma concentration-time curves | From dosing until day 4 | 
| Maximum plasma concentration (Cmax) following single oral ascending doses (Part B) | Cmax is derived from the observed plasma concentration-time curves | From dosing until day 8 | 
| Maximum plasma concentration (Cmax) following single oral ascending doses (Part C) | Cmax is derived from the observed plasma concentration-time curves | From dosing until day 6 | 
| Time to reach Cmax (tmax) following single oral ascending doses (Part A) | Tmax is derived from the observed plasma concentration-time curves | From dosing until day 4 | 
| Time to reach Cmax (tmax) following single oral ascending doses (Part B) | Tmax is derived from the observed plasma concentration-time curves | From dosing until day 8 | 
| Time to reach Cmax (tmax) following single oral ascending doses (Part C) | Tmax is derived from the observed plasma concentration-time curves | From dosing until day 6 | 
| Terminal half-life [t(1/2)] following single oral ascending doses (Part A) |  | From dosing until day 4 | 
| Terminal half-life [t(1/2)] following single oral ascending doses (Part B) |  | From dosing until day 8 | 
| Terminal half-life [t(1/2)] following single oral ascending doses (Part C) |  | From dosing until day 6 | 
| Area under the plasma concentration-time curve (AUC) following single oral ascending doses (Part A) | AUC is defined for the time intervals from zero to time t of the last measured concentration above the limit of quantification and from zero to infinity | From dosing until day 4 | 
| Area under the plasma concentration-time curve (AUC) following single oral ascending doses (Part B) | AUC is defined for the time intervals from zero to time t of the last measured concentration above the limit of quantification and from zero to infinity | From dosing until day 8 | 
| Area under the plasma concentration-time curve (AUC) following single oral ascending doses (Part C) | AUC is defined for the time intervals from zero to time t of the last measured concentration above the limit of quantification and from zero to infinity | From dosing until day 6 |