A Single Ascending Dose Study of ACT-541468 in Healthy Male Subjects

Study Overview
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Brief Summary
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The main objectives of this first-into-man study were to investigate the safety, tolerability and the pharmacokinetic profile of single oral doses of ACT-541468 in healthy male adults. Pharmacodynamic effects (through a battery of Central Nervous System tests) were also assessed.

Detailed Description
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The study consisted of ascending dose groups; each dose group was investigated in a new group of 8 healthy male subjects (6 on active drug and 2 on placebo). In addition, the study included a biocomparison part (dose group 2), an absolute bioavailability part (dose group 4), and a mass balance / metabolism part (dose group 3).

Official Title
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Double-blind, Placebo-controlled, Randomized, Single Ascending Dose Study to Investigate the Tolerability, Safety, Pharmacokinetics, Pharmacodynamics, Absolute Bioavailability, Mass Balance, and Metabolism of ACT-541468 in Healthy Male Subjects

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: ACT-541468 (Formulation A)
* Drug: ACT-541468 (Formulation B)
* Drug: Placebo (Formulation A)
* Drug: Placebo (Formulation B)
* Drug: 14C-labeled ACT-541468
* Drug: Placebo tracer


Participation Criteria
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Eligibility Criteria
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Key inclusion Criteria: Signed informed consent prior to any study-mandated procedure. Males aged from 18 to 45 years (inclusive) at screening. Body mass index (BMI) between 18.0 and 30.0 kg/m2 (inclusive) at screening. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate (PR) between 100-145 mmHg, 50-90 mmHg and 45-90 bpm (all inclusive) at screening, respectively. Healthy on the basis of physical examination,electrocardiogram and laboratory tests. Key exclusion Criteria: Known hypersensitivity to any excipients of the drug formulations. History or presence of any disease or condition or treatment, which may put the subject at risk of participation in the study or may interfere with the absorption, distribution, metabolism or excretion of the study drugs. History of narcolepsy or cataplexy or modified Swiss narcolepsy scale total score < 0 at screening. Any circumstances or conditions, which, in the opinion of the investigator, may affect the subject's full participation in the study or compliance with the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

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: Dose group 1<br>Six subjects received 5 mg of ACT-541468 (formulation A) as a single oral dose and two subjects received the matching placebo. | Drug: ACT-541468 (Formulation A)<br>* Hard gelatin capsules for oral administration formulated at strengths of 5 mg, 25 mg and 100 mg<br>Drug: Placebo (Formulation A)<br>* Hard capsules matching ACT-541468 Formulation A<br>|
| Experimental: Dose group 2<br>Three subjects received a single oral dose (25 mg) of ACT-541468 formulation A during Period 1 and a single oral dose (25 mg) of ACT-541468 formulation B during Period 2. Three other subjects Subjects received ACT-541468 formulation B during Period 1 and ACT-541468 formulation A during Period 2. Two additional subjects received the matching placebos in both treatment periods. | Drug: ACT-541468 (Formulation A)<br>* Hard gelatin capsules for oral administration formulated at strengths of 5 mg, 25 mg and 100 mg<br>Drug: ACT-541468 (Formulation B)<br>* Soft gelatin capsules for oral administration formulated at the strength of 25 mg<br>Drug: Placebo (Formulation A)<br>* Hard capsules matching ACT-541468 Formulation A<br>Drug: Placebo (Formulation B)<br>* Soft capsules matching ACT-541468 Formulation B<br>|
| Experimental: Dose group 3<br>Six subjects received 50 mg of ACT-541468 (formulation A) as a single oral dose in combination with a [14C]-ACT-541468 oral tracer for the mass balance and metabolism analyses. Two other subjects received the matching placebos. | Drug: ACT-541468 (Formulation A)<br>* Hard gelatin capsules for oral administration formulated at strengths of 5 mg, 25 mg and 100 mg<br>Drug: Placebo (Formulation A)<br>* Hard capsules matching ACT-541468 Formulation A<br>Drug: 14C-labeled ACT-541468<br>* Tracer at a nominal dose of 250 nCi (corresponding to 2.02 µg ACT-541468) administered either orally or intravenously<br>Drug: Placebo tracer<br>* Sterile NaCl 0.9% was used as placebo matching the tracer for oral and i.v. administration.<br>|
| Experimental: Dose group 4<br>Six subjects received 100 mg of ACT-541468 (formulation A) as a single oral dose in combination with a [14C]-ACT-541468 intravenous tracer for the absolute bioavailability assessment. Two other subjects received the matching placebos. | Drug: ACT-541468 (Formulation A)<br>* Hard gelatin capsules for oral administration formulated at strengths of 5 mg, 25 mg and 100 mg<br>Drug: Placebo (Formulation A)<br>* Hard capsules matching ACT-541468 Formulation A<br>Drug: 14C-labeled ACT-541468<br>* Tracer at a nominal dose of 250 nCi (corresponding to 2.02 µg ACT-541468) administered either orally or intravenously<br>Drug: Placebo tracer<br>* Sterile NaCl 0.9% was used as placebo matching the tracer for oral and i.v. administration.<br>|
| Experimental: Dose group 5<br>Six subjects received 200 mg of ACT-541468 (formulation A) as a single oral dose and two subjects received the matching placebo. | Drug: ACT-541468 (Formulation A)<br>* Hard gelatin capsules for oral administration formulated at strengths of 5 mg, 25 mg and 100 mg<br>Drug: Placebo (Formulation A)<br>* Hard capsules matching ACT-541468 Formulation A<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with treatment-emergent adverse events and serious adverse events | Collection of any adverse event at each dose level | Day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) of ACT-541468 | Cmax was directly derived from the observed plasma concentrations of ACT-541468 for each dose level | From pre-dose up to 168 hours post-dose | 
| Time to reach Cmax (tmax) of ACT-541468 | tmax was directly derived from the observed plasma concentrations of ACT-541468 for each dose level | From pre-dose up to 168 hours post-dose | 
| Terminal half-life (t1/2) of ACT-541468 | t1/2 was calculated from the terminal rate constant obtained from the plasma concentrations-time curves of ACT-541468, at each dose level | From pre-dose up to 168 hours post-dose | 
| Area under the plasma concentration-time curves [AUC(0-inf)] of ACT-541468 | AUC(0-inf) is the area under the plasma concentration-time curves of ACT-541468, calculated from time 0 (pre-dose) to extrapolated infinite time, at each dose level | From pre-dose up to 168 hours post-dose | 
| Percentage of dose excreted in feces and urine | Percentage of oral dose of 14C-labeled ACT-541468 excreted in feces (FPE), urine (UPE) and both, as determined in the dose group 3 | From pre-dose up to 168 hours post-dose | 
| Absolute bioavailability (F) of ACT-541468 | Absolute bioavailability was determined for dose group 4 and defined as the ratio of AUC(0-inf) after oral administration of ACT-541468 and after intravenous infusion of 14C-labeled ACT-541468 (tracer) | Up to 96 hours post-dose |