Study to Evaluate Safety and Tolerability of ACT-709478 in Healthy Subjects

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the safety and tolerability of ascending multiple doses of ACT-709478 in healthy male and female subjects

Official Title
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A Single-center, Double-blind, Parallel-group, Randomized, Placebo-controlled, Multiple-ascending Oral Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-709478 in Healthy Subjects

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: ACT-709478
* Drug: Placebo
* Drug: Midazolam
* Drug: ACT-709478 combined with midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent form Healthy male and female subjects aged between 18 and 55 years (inclusive) at screening Negative serum pregnancy tests at screening and negative urine pregnancy test at Day -1 for women and agreement to use 2 reliable methods of contraception for at least 3 months after last study drug administration Body mass index of 18.0 to 29.9 kg/m2 (inclusive) at screening Systolic blood pressure 100-140 mmHg, diastolic blood pressure 50-90 mmHg, and pulse rate 50-90 bpm (inclusive), measured after 5 minutes in the supine position at screening and on Day -1 Healthy on the basis of physical examination, cardiovascular, ophthalmological, neurological assessments and laboratory tests Exclusion Criteria: Known hypersensitivity to ACT-709478 or drugs of the same class, or any of their excipients History or clinical evidence of any disease and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism, or excretion of the study treatments QT interval corrected with Fridericia's formula (QTcF) > 450 ms (using the ECG machine HR correction method) at screening and on Day -1 Treatment with another investigational treatment within 2 months or 5 t1/2 (whichever is the longest) prior to screening or participation in more than four investigational treatment studies within 1 year prior to screening Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ACT-709478<br>40 subjects will receive multiple doses of ACT-709478 at the planned dose levels of 30, 60, 100, and 200 mg. Each dose level will be investigated in a new cohort of 10 healthy male and female subjects (4 male subjects on active drug and 1 on placebo, 4 female subjects on active drug and 1 on placebo) undergoing one treatment period with a once daily dosing scheme. | Drug: ACT-709478<br>* Hard gelatine capsules for oral administration<br>|
| Placebo Comparator: Placebo<br>Matched placebo administered accordingly | Drug: Placebo<br>* Placebo capsules matching ACT-709478 capsules<br>|
| Other: Midazolam<br>4 mg taken by mouth on Day 1 of the corresponding cohort | Drug: Midazolam<br>* Midazolam oral solution (2 mg/mL) applied with a syringe<br>|
| Experimental: ACT-709478 combined with Midazolam<br>On Day 22 and Day 30, midazolam (4 mg) and ACT-709478 (60 mg or 100 mg) to be co-administered. | Drug: ACT-709478 combined with midazolam<br>* Hard gelatine capsules for oral administration (ACT-709478) to be taken first followed by Midazolam oral solution (2 mg/mL) applied with a syringe<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events | The percentage of subjects with treatment-emergent adverse events will be reported | up to Day 23 | 
| Changes from baseline in vital signs | Vital signs include diastolic and systolic blood pressure and pulse rate | up to Day 23 | 
| Incidence of any clinical relevant findings in ECG variables | The number of subjects with any treatment-emergent electrocardiogram (ECG) abnormalities will be reported | up to Day 23 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) of ACT-709478 | Cmax is derived from the observed plasma concentration-time curves | up to Day 23 | 
| Time to reach Cmax (tmax) of ACT-709478 | tmax is directly derived from the observed plasma concentrations | up to Day 23 | 
| Terminal half-life (t1/2) of ACT-709478 | t1/2 is calculated from the terminal rate constant obtained from the plasma concentrations-time curves | up to Day 23 | 
| Area under the plasma concentration-time curve AUC(tau) of ACT-709478 | AUCtau is defined as the area under the plasma concentration-time curve during one dosing interval | up to Day 23 | 
| Area under the plasma concentration-time curve AUC(tau) of midazolam | AUCtau is defined as the area under the plasma concentration-time curve during one dosing interval | 24 hours after dosing on Day 1, Day 22 and Day 30 | 
| Time to reach Cmax (tmax) | tmax is directly derived from the observed plasma concentrations | 24 hours after dosing on Day 1, Day 22 and Day 30 | 
| Maximum plasma concentration (Cmax) of ACT-709478 | Cmax is derived from the observed plasma concentration-time curves | 24 hours after dosing on Day 1, Day 22 and Day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tolerability, safety