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

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

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

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: ACT-709478; Drug: Placebo; Drug: Midazolam; Drug: ACT-709478 combined with midazolam

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 14050
    • Parexel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ACT-709478; 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; Hard gelatine capsules for oral administration
Placebo Comparator: Placebo; Matched placebo administered accordingly	Drug: Placebo; Placebo capsules matching ACT-709478 capsules
Other: Midazolam; 4 mg taken by mouth on Day 1 of the corresponding cohort	Drug: Midazolam; Midazolam oral solution (2 mg/mL) applied with a syringe
Experimental: ACT-709478 combined with Midazolam; 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; Hard gelatine capsules for oral administration (ACT-709478) to be taken first followed by Midazolam oral solution (2 mg/mL) applied with a syringe

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Idorsia Pharmaceuticals Ltd.

Publications and helpful links

General Publications

• Richard M, Kaufmann P, Ort M, Kornberger R, Dingemanse J. Multiple-Ascending Dose Study in Healthy Subjects to Assess the Pharmacokinetics, Tolerability, and CYP3A4 Interaction Potential of the T-Type Calcium Channel Blocker ACT-709478, A Potential New Antiepileptic Drug. CNS Drugs. 2020 Mar;34(3):311-323. doi: 10.1007/s40263-019-00697-1.

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2017
• Primary Completion (Actual): November 15, 2018
• Study Completion (Actual): December 28, 2018

Study Registration Dates

• First Submitted: May 23, 2017
• First Submitted That Met QC Criteria: May 23, 2017
• First Posted (Actual): May 24, 2017

Study Record Updates

• Last Update Posted (Actual): December 24, 2019
• Last Update Submitted That Met QC Criteria: December 20, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: tolerability; safety
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Midazolam; ACT-709478
• Other Study ID Numbers: AC-083-102; 2017-000336-34 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No