A Clinical Study to Investigate the Potential Interactions Between Food and ACT-541468 and Between ACT-541468 and Midazolam

A Single-center, Open-label Study to Investigate the Food Effect on the Pharmacokinetics of ACT-541468 and the Effect of Single- and Multiple-dose ACT-541468 on the Pharmacokinetics of Midazolam and Its Metabolite 1-Hydroxymidazolam in Healthy Male Subjects

The main objectives of this phase 1 trial are to evaluate the effect of food on the pharmacokinetics (i.e. how long and how much a compound is present in the blood) of ACT-541468 and to evaluate whether ACT-541468 can affect the pharmacokinetics of midazolam, a CYP3A4 substrate.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: Midazolam; Drug: ACT-541468

Detailed Description

Food effect will be assessed by comparing the pharmacokinetic (PK) parameters of a single dose of ACT-541468 under fasted (Treatment B) and fed (Treatment C) conditions.

Potential CYP3A4 inhibiting / inducing effects of ACT-541468 will be assessed by comparing the PK parameters of midazolam alone (Treatment A) and midazolam given with a single dose of ACT-541468 (Treatment B) or with multiple doses of ACT-541468 (Treatment D).

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Kiel, Germany, 24105
    • 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

Inclusion Criteria:

• Signed informed consent form
• Male subjects aged from 18 to 45 years (inclusive) at screening
• Body mass index (BMI) from 18.0 to 30.0 kg/m2 (inclusive) at screening
• Healthy on the basis of physical examination, cardiovascular assessments and laboratory tests

Exclusion Criteria:

• Any contraindication to the study treatments
• History or clinical evidence of any disease or medical / surgical 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 treatments
• History of narcolepsy or cataplexy or modified Swiss narcolepsy scale total score < 0
• 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: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Food effect and Drug-Drug interaction; Treatments will be given to all subjects in the same fixed sequence: Treatment A (Day 1, single dose of midazolam, fasted), Treatment B (Day 2, single dose of ACT-541468 followed by single dose of midazolam, fasted), Treatment C (Day 4, single dose ACT-541468, fed), Treatment D (multiple doses of ACT-541468 from Day 5 to Day 8 + single dose of midazolam on Day 8, fasted).

Drug: Midazolam; 2 mg/mL oral solution; Drug: ACT-541468; Hard gelatin capsules for oral use at a strength of 25 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum plasma concentration (Cmax) of ACT-541468	Cmax is directly determined from the plasma concentrations-time curves of ACT-541468	PK blood samples on Day 2, Day 4 and Day 8: before administration of ACT-541468 and up to 24 hours post-dose, and on Day 6 and Day 7: before ACT-541468 administration only
Time to reach Cmax (tmax) of ACT-541468	Tmax is directly determined from the plasma concentrations-time curves of ACT-541468	PK blood samples on Day 2, Day 4 and Day 8: before administration of ACT-541468 and up to 24 hours post-dose, and on Day 6 and Day 7: before ACT-541468 administration only
Area under the plasma concentration-time curve [AUC(0-24)] of ACT-541468	AUC is calculated from time zero to 24 hours post dose	PK blood samples on Day 2, Day 4 and Day 8: before administration of ACT-541468 and up to 24 hours post-dose, and on Day 6 and Day 7: before ACT-541468 administration only
Terminal half-life (t1/2) of ACT-541468	t1/2 is calculated from the plasma concentrations-time curves of ACT-541468	PK blood samples on Day 2, Day 4 and Day 8: before administration of ACT-541468 and up to 24 hours post-dose, and on Day 6 and Day 7: before ACT-541468 administration only
Maximum plasma concentration (Cmax) of midazolam	Cmax is directly obtained from the plasma concentrations-time curves of midazolam	PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose
Time to reach Cmax (tmax) of midazolam	Tmax is directly obtained from the plasma concentrations-time curves of midazolam	PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose
Area under the plasma concentration-time curve [AUC(0-24)] of midazolam	AUC is calculated from time zero to 24 hours post dose	PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose
Terminal half-life (t1/2) of midazolam	t1/2 is calculated from the plasma concentrations-time curves of midazolam	PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose
Maximum plasma concentration (Cmax) of 1-hydroxymidazolam	Cmax is directly determined from the plasma concentrations-time curves of 1-hydroxymidazolam	PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose
Time to reach Cmax (tmax) of 1-hydroxymidazolam	Tmax is directly determined from the plasma concentrations-time curves of 1-hydroxymidazolam	PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose
Area under the plasma concentration-time curve [AUC(0-24)] of 1-hydroxymidazolam	AUC is calculated from time zero to 24 hours post dose	PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose
Terminal half-life (t1/2) of 1-hydroxymidazolam	t1/2 is calculated from the plasma concentrations-time curves of 1-hydroxymidazolam	PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of subjects with treatment-emergent adverse events and serious adverse events	From baseline to end-of-study, i.e.,maximum 5 days after Day 8
Maximum plasma concentration (Cmax) of ACT-541468 metabolites	PK blood samples on Day 8, before administration of ACT-541468 and up to 24 hours post dose
Time to reach Cmax (tmax) of ACT-541468 metabolites	PK blood samples on Day 8, before administration of ACT-541468 and up to 24 hours post dose
Area under the plasma concentration-time curve [AUC(0-24)] of ACT-541468 metabolites	PK blood samples on Day 8, before administration of ACT-541468 and up to 24 hours post dose
Terminal half-life (t1/2) of ACT-541468 metabolites	PK blood samples on Day 8, before administration of ACT-541468 and up to 24 hours post dose

Collaborators and Investigators

• Sponsor: Idorsia Pharmaceuticals Ltd.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 1, 2017
• Primary Completion (ACTUAL): February 1, 2017
• Study Completion (ACTUAL): February 1, 2017

Study Registration Dates

• First Submitted: January 10, 2017
• First Submitted That Met QC Criteria: January 10, 2017
• First Posted (ESTIMATE): January 11, 2017

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

• Keywords: pharmacokinetics; drug-drug interaction; food-drug interaction
• 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; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: AC-078-104; 2016-003490-18 (EUDRACT_NUMBER)