Clinical trial NCT02050802: Study to Assess the Effect of Macitentan on the Electrocardiogram (ECG) in Healthy Male and Female Subjects
Official title: A Double-blind, Randomized, Placebo-controlled, Four-way Crossover Phase 1 Study Including an Open-label Positive Control (Moxifloxacin) to Assess the Effect of Repeated Daily Doses of 10 mg and 30 mg Macitentan on the QT/QTc Interval of the ECG in Healthy Male and Female Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Macitentan
Pharmacokinetics
Pharmacodynamics
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2014-01-31
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: The study is intended to demonstrate that macitentan does not have an effect on cardiac repolarization exceeding the threshold of regulatory concern after repeated administration of daily oral doses of 10 and 30 mg to healthy male and female subjects.


Eligibility criteria: Inclusion Criteria:

* Ability to communicate well with the investigator in the local language, and to understand and comply with the requirements of the study.
* Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice and the local legislation.
* Males and females aged ≥ 18 and ≤ 55 years at screening.
* Women of childbearing potential must have had a negative pre-treatment serum pregnancy test and used consistently and correctly 2 methods of contraception at the same time from screening and up to 30 days after study treatment discontinuation. Abstinence was not considered a reliable method of contraception.
* Healthy on the basis of medical history and the assessments performed at screening.
* Physical examination without clinically relevant abnormalities at screening.
* Body mass index (BMI) ≥ 18.0 and ≤ 28.0 kg/m\^2 at screening. Body weight at least 50.0 kg.
* Negative results from urine drug screen and alcohol test at screening.
* Willing and able to refrain from alcohol consumption from study start to the end of the study.
* Negative human immunodeficiency virus (HIV) serology and hepatitis serology at screening.
* Systolic blood pressure (SBP) 100-145 mmHg, diastolic blood pressure (DBP) 50-90 mmHg, and heart rate (HR) 45-90 bpm (all inclusive), measured on the dominant arm (dominant arm = writing arm).
* 12-lead ECG without clinically relevant abnormalities at screening and on Day 1 prior to drug administration.
* Hematology, blood chemistry, and urinalysis results not deviating from the normal range to a clinically relevant extent at screening and on Day 1 prior to drug administration.

Exclusion Criteria:

* Known hypersensitivity to any excipients of the drug formulations.
* Treatment with macitentan or another investigational drug in the 3 months prior to screening.
* History or clinical evidence of any disease and/or the existence of any surgical or medical condition, which might have interfered with the absorption, distribution, metabolism, or excretion of macitentan and moxifloxacin (except appendectomy and herniotomy).
* History or clinical evidence of drug abuse, alcoholism, or psychiatric disease within the 3 year period prior to screening.
* Caffeine consumption ≥ 800 mg per day at screening.
* History of fainting, collapse, syncope, blackouts, orthostatic hypotension, or vasovagal reactions.
* Chronic or relevant acute infections.
* History of relevant allergy/hypersensitivity.
* Previous treatment with any prescribed or over-the-counter medications or herbal remedies (including herbal medicines such as St John's Wort) within 2 weeks prior to first dosing or during the trial.
* Smoking and use of tobacco substitutes or nicotine substitutes.
* Loss of 250 mL or more blood in the 3 months prior to dosing (including blood donation).
* Positive results from the hepatitis serology at screening, except for vaccinated subjects.
* Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) above the upper limit of normal prior to randomization.
* Excessive physical activities within 1 week prior to randomization.
* Any cardiac condition (including ECG abnormalities) or illness with a potential to increase the cardiac risk of the subject or that might affect the corrected QT analysis (QTc).
* QTc \> 450 ms or \> 470 ms (using the ECG machine heart rate-correction method) before randomization for male or female subjects, respectively.
* Subjects with personal or family history of long-QT syndrome or hypokalemia.
* Legal incapacity or limited legal capacity at screening.
* Veins unsuitable for intravenous (i.v.) puncture on either arm (e.g., veins that are difficult to locate, access or puncture; veins with a tendency to rupture during or after puncture).
* Vulnerable subjects (e.g., persons kept in detention).
* Employee of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, as well as family members of the employees or the investigator.

Primary outcomes:
measure: Baseline-adjusted placebo-corrected QT interval according to Fridericia's correction (QTcF)
timeFrame: Day 8
Secondary outcomes:
measure: Placebo corrected change from baseline in heart rate on Day 8
timeFrame: Day 8
measure: Placebo corrected change from baseline in RR interval (the interval from the onset of one QRS complex to the onset of the next QRS complex) on Day 8
timeFrame: Day 8
measure: Placebo corrected change from baseline in PR interval (time interval from the beginning of the P wave to the beginning of the QRS complex) on Day 8
timeFrame: Day 8
measure: Placebo corrected change from baseline in QRS interval (time interval from the beginning of the Q wave to the end of the S wave) on Day 8
timeFrame: Day 8
measure: Number of participants with treatment emergent ECG abnormalities
timeFrame: 8 Days
measure: Maximum plasma concentration (Cmax) of macitentan on Day 8
timeFrame: Day 8
measure: Maximum plasma concentration (Cmax) of the macitentan metabolite ACT-132577 on Day 8
timeFrame: Day 8
measure: Time to reach maximum plasma concentration (tmax) of macitentan on Day 8
timeFrame: Day 8
measure: Time to reach maximum plasma concentration (tmax) of the macitentan metabolite ACT-132577 on Day 8
timeFrame: Day 8
measure: Area under the plasma concentration-time curve over a dosing interval (AUCτ) of macitentan on Day 8
timeFrame: Day 8
measure: Area under the plasma concentration-time curve over a dosing interval (AUCτ) of the macitentan metabolite ACT-132577 on Day 8
timeFrame: Day 8
measure: Change from baseline to Day 8 in systolic blood pressure (SBP)
timeFrame: 8 days
measure: Change from baseline to Day 8 in diastolic blood pressure (DBP)
timeFrame: 8 days
measure: Change from baseline to Day 8 in heart rate
timeFrame: 8 days
measure: Change from baseline to Day 8 in body weight
timeFrame: 8 days
Other outcomes:
Locations:
Study officials:
affiliation: Actelion
name: Nicolas Lindegger, PhD
role: STUDY_DIRECTOR
References: