Clinical Study to Investigate Safety and Effects on Heart Rate, Blood Pressure, and Pharmacokinetic Interactions of ACT-334441

Study Overview
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Brief Summary
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The aim of the study is to investigate the safety of the concomitant administration of ACT-334441 with cardiovascular drugs.

Detailed Description
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The study will consist of two parts: a pilot part (Part A) that will be completed prior to the start of the main part (Part B). The Subjects who will participate in Part A are excluded from Part B.

Official Title
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Single-center, Open-label, Randomized, Multiple-dose, Parallel-group Study to Investigate Safety and Effects on Heart Rate, Blood Pressure, and Pharmacokinetic Interactions of ACT-334441 Combined With Calcium-channel Blocker (Diltiazem) or Beta-blocker (Atenolol) Treatment in Healthy Subjects

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: ACT-334441 2 mg
* Drug: ACT-334441 4 mg
* Drug: Placebo
* Drug: Atenolol
* Drug: Diltiazem ER


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Body mass index (BMI) between 18.0 and 30.0 kg/m2 (inclusive) at screening. Women of childbearing potential must have a negative pregnancy test and they must use reliable methods of contraception Healthy on the basis of physical examination,cardiovascular assessments and laboratory tests Exclusion Criteria: Pregnant or lactating women Any contraindication to the study drugs 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 Any clinically significant abnormalities in laboratory tests, vital signs, ECG variables and pulmonary variables 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: 25 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A ACT-334441 + atenolol<br>4 subjects will receive 50 mg of atenolol once daily for 6 days, and a concomitant single administration of ACT-334441 2 mg on Day 6 | Drug: ACT-334441 2 mg<br>* capsule containing ACT-334441 at a strength of 2 mg<br>Drug: Atenolol<br>* film-coated tablet containing atenolol at a strength of 50 mg<br>* Other names: Tenormine;|
| Experimental: Part A ACT-334441 + diltiazem<br>4 subjects will receive 240 mg of diltiazem once daily for 6 days, and a concomitant single administration of ACT-334441 2 mg on Day 6 | Drug: ACT-334441 2 mg<br>* capsule containing ACT-334441 at a strength of 2 mg<br>Drug: Diltiazem ER<br>* film-coated tablet containing diltiazem at a strength of of 120 mg<br>* Other names: Bi-tildiem;|
| Experimental: Part B ACT-334441 + atenolol<br>12 subjects will receive 50 mg of atenolol (once daily) from day 1 to day 15, placebo once on day 6, and ACT-334441 4 mg (once daily) from day 8 to day 15 | Drug: ACT-334441 4 mg<br>* capsule containing ACT-334441 at a strength of 4 mg<br>Drug: Placebo<br>* ACT-33441-matching placebo<br>Drug: Atenolol<br>* film-coated tablet containing atenolol at a strength of 50 mg<br>* Other names: Tenormine;|
| Experimental: Part B ACT-334441 + diltiazem<br>12 subjects will receive 240 mg of diltiazem (once daily) from day 1 to day 15, placebo once on day 6, and ACT-334441 4 mg (once daily) from day 8 to day 15 | Drug: ACT-334441 4 mg<br>* capsule containing ACT-334441 at a strength of 4 mg<br>Drug: Placebo<br>* ACT-33441-matching placebo<br>Drug: Diltiazem ER<br>* film-coated tablet containing diltiazem at a strength of of 120 mg<br>* Other names: Bi-tildiem;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PR intervals measured by 12-lead ECG (Part A + Part B) | Absolute PR intervals and corresponding changes from baseline at the different days of measurement | Days 1 and 6 (Part A); Days 1, 6, 8, 9, 15, and 16 (Part B) | 
| Heart rate (HR) measured by 12-lead ECG (PArt A + Part B) | Absolute heart rates at the different days of measurement | Days 1 and 6 (Part A); Days 1, 6, 8, 9, 15, and 16 (Part B) | 
| Hourly mean heart rate (HR) measured by 24-hour Holter ECG | Absolute and change from baseline in hourly mean HR on each day of measurement | Days 1 and 6 (Part A); Days 1, 6, 8, 9, 15, and 16 (Part B | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Areas under the plasma concentration-time curves (AUC) for ACT-334441, diltiazem and atenolol (Part B) | AUCs will be calculated will be calculated according to the linear trapezoidal rule for the following periods: from zero to time t of the last measured concentration above the limit of quantification, from zero to 24h after study drug administration, from zero to infinity) | Blood samples from Day 1 to Day 20 for the PK profile of diltiazem and atenolol, and from Day 8 to Day 21 for the PK profile of ACT-334441. | 
| Maximum plasma concentration (Cmax) for ACT-334441, diltiazem and atenolol (Part B) | The measured individual concentrations of ACT-334441, diltiazem and atenolol will be used to obtain their respective Cmax | From Day 1 to Day 20 for diltiazem and atenolol; from Day 8 to Day 21 for ACT-33444. | 
| Time to reach the maximum plasma concentration (tmax) for ACT-334441, diltiazem and atenolol (Part B) | The measured individual concentrations of ACT-334441, diltiazem and atenolol will be used to obtain their respective tmax | From Day 1 to Day 20 for diltiazem and atenolol; from Day 8 to Day 21 for ACT-33444 | 
| Terminal half-life [t(1/2)] of ACT-334441, diltiazem and atenolol (Part B) | Time required for the plasma concentration of a drug to decrease by 50% in the final stage of its elimination | From Day 1 to Day 20 for diltiazem and atenolol; from Day 8 to Day 21 for ACT-33444 | 
| Trough plasma levels (Ctrough) of of ACT-334441, diltiazem and atenolol (Part B) | Ctrough will be used to determine the attainment of steady state conditions | From Day 1 to Day 15 for diltiazem and atenolol; from Day 8 to Day 15 for ACT-33444 | 
| Number of subjects with adverse events as a measure of safety | An AE is defined as any unfavorable and unintended sign, including an abnormal laboratory finding, symptom or disease, that occurs during the course of the study, whether or not considered related to the study drug | From baseline to end of study [Day 20-23 (Part A), Day 556-59 (Part B)] | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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safety, heart rate, pharmacokinetics