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

Study Overview
=================
Brief Summary
-----------------
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.

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).

Official Title
-----------------
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

Conditions
-----------------
Healthy Subjects

Intervention / Treatment
-----------------
* Drug: Midazolam
* Drug: ACT-541468


Participation Criteria
=================
Eligibility Criteria
-----------------
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

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

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Food effect and Drug-Drug interaction<br>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<br>* 2 mg/mL oral solution<br>Drug: ACT-541468<br>* Hard gelatin capsules for oral use at a strength of 25 mg<br>|

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 | Measure Description | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
food-drug interaction, drug-drug interaction, pharmacokinetics