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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: ACT-541468 (Formulation A); Drug: Placebo (Formulation A); Drug: ACT-541468 (Formulation B); Drug: Placebo (Formulation B); Drug: 14C-labeled ACT-541468; Drug: Placebo tracer

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Leiden, Netherlands, 2333 CL
    • Investigator site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Dose group 1; 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); Hard gelatin capsules for oral administration formulated at strengths of 5 mg, 25 mg and 100 mg; Drug: Placebo (Formulation A); Hard capsules matching ACT-541468 Formulation A
EXPERIMENTAL: Dose group 2; 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); Hard gelatin capsules for oral administration formulated at strengths of 5 mg, 25 mg and 100 mg; Drug: Placebo (Formulation A); Hard capsules matching ACT-541468 Formulation A; Drug: ACT-541468 (Formulation B); Soft gelatin capsules for oral administration formulated at the strength of 25 mg; Drug: Placebo (Formulation B); Soft capsules matching ACT-541468 Formulation B
EXPERIMENTAL: Dose group 3; 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); Hard gelatin capsules for oral administration formulated at strengths of 5 mg, 25 mg and 100 mg; Drug: Placebo (Formulation A); Hard capsules matching ACT-541468 Formulation A; Drug: 14C-labeled ACT-541468; Tracer at a nominal dose of 250 nCi (corresponding to 2.02 µg ACT-541468) administered either orally or intravenously; Drug: Placebo tracer; Sterile NaCl 0.9% was used as placebo matching the tracer for oral and i.v. administration.
EXPERIMENTAL: Dose group 4; 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); Hard gelatin capsules for oral administration formulated at strengths of 5 mg, 25 mg and 100 mg; Drug: Placebo (Formulation A); Hard capsules matching ACT-541468 Formulation A; Drug: 14C-labeled ACT-541468; Tracer at a nominal dose of 250 nCi (corresponding to 2.02 µg ACT-541468) administered either orally or intravenously; Drug: Placebo tracer; Sterile NaCl 0.9% was used as placebo matching the tracer for oral and i.v. administration.
EXPERIMENTAL: Dose group 5; 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); Hard gelatin capsules for oral administration formulated at strengths of 5 mg, 25 mg and 100 mg; Drug: Placebo (Formulation A); Hard capsules matching ACT-541468 Formulation A

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Time Frame
Change from baseline in saccadic peak velocity (SPV)	At baseline till 10 hours after study drug administration
Change from baseline in body sway	At baseline till 10 hours after study drug administration
Change from baseline in adaptive tracking	At baseline till 10 hours after study drug administration
Chnage from baseline in Bond and Lader visual analog scale (B&L VAS)l	At baseline till 10 hours after study drug administration

Collaborators and Investigators

• Sponsor: Idorsia Pharmaceuticals Ltd.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 1, 2015
• Primary Completion (ACTUAL): May 1, 2015
• Study Completion (ACTUAL): May 1, 2015

Study Registration Dates

• First Submitted: September 28, 2016
• First Submitted That Met QC Criteria: September 28, 2016
• First Posted (ESTIMATE): September 29, 2016

Study Record Updates

• Last Update Posted (ACTUAL): July 10, 2018
• Last Update Submitted That Met QC Criteria: July 6, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Other Study ID Numbers: AC-078-101; 2014-003129-16 (EUDRACT_NUMBER)