Study to Assess the Effect of Macitentan on the Electrocardiogram (ECG) in Healthy Male and Female Subjects

Actelion Pharmaceuticals

Status and phase: Completed; Phase 1

Conditions: Healthy

Treatments: Drug: Moxifloxacin 400 mg; Other: Placebo; Drug: Macitentan 30 mg; Drug: Macitentan 10 mg

Study type: Interventional

Funder types: Industry

Identifiers

NCT02050802

AC-055-114

Details and patient eligibility

About

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.

Enrollment: 64 patients

Sex: All

Ages: 18 to 55 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

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64 participants in 8 patient groups

Treatment sequence BCAD

Experimental group

Description:

Subjects received study medication in the sequence BCAD. Treatment A: moxifloxacin positive control (3 placebo tablets once daily on Days 1-7, and on Day 8 moxifloxacin 400 mg tablet and 2 macitentan-matching placebo tablets). Treatment B: macitentan 10 mg (1 macitentan 10 mg tablet and 2 placebo tablets once daily on Days 1-8). Treatment C: macitentan 30 mg (3 macitentan 10 mg tablets once daily on Days 1-8). Treatment D: placebo (3 placebo tablets on Days 1-8). There was a wash-out period of at least 10 days between the last study drug administration of the previous treatment and the first study drug administration of the following treatment.

Treatment:

Drug: Macitentan 10 mg

Drug: Macitentan 30 mg

Other: Placebo

Drug: Moxifloxacin 400 mg

Treatment sequence ABDC

Experimental group

Description:

Subjects received study medication in the sequence ABDC. Treatment A: moxifloxacin positive control (3 placebo tablets once daily on Days 1-7, and on Day 8 moxifloxacin 400 mg tablet and 2 macitentan-matching placebo tablets). Treatment B: macitentan 10 mg (1 macitentan 10 mg tablet and 2 placebo tablets once daily on Days 1-8). Treatment C: macitentan 30 mg (3 macitentan 10 mg tablets once daily on Days 1-8). Treatment D: placebo (3 placebo tablets on Days 1-8). There was a wash-out period of at least 10 days between the last study drug administration of the previous treatment and the first study drug administration of the following treatment.

Treatment:

Drug: Macitentan 10 mg

Drug: Macitentan 30 mg

Other: Placebo

Drug: Moxifloxacin 400 mg

Treatment sequence DACB

Experimental group

Description:

Subjects received study medication in the sequence DACB. Treatment A: moxifloxacin positive control (3 placebo tablets once daily on Days 1-7, and on Day 8 moxifloxacin 400 mg tablet and 2 macitentan-matching placebo tablets). Treatment B: macitentan 10 mg (1 macitentan 10 mg tablet and 2 placebo tablets once daily on Days 1-8). Treatment C: macitentan 30 mg (3 macitentan 10 mg tablets once daily on Days 1-8). Treatment D: placebo (3 placebo tablets on Days 1-8). There was a wash-out period of at least 10 days between the last study drug administration of the previous treatment and the first study drug administration of the following treatment.

Treatment:

Drug: Macitentan 10 mg

Drug: Macitentan 30 mg

Other: Placebo

Drug: Moxifloxacin 400 mg

Treatment sequence CDBA

Experimental group

Description:

Subjects received study medication in the sequence CDBA. Treatment A: moxifloxacin positive control (3 placebo tablets once daily on Days 1-7, and on Day 8 moxifloxacin 400 mg tablet and 2 macitentan-matching placebo tablets). Treatment B: macitentan 10 mg (1 macitentan 10 mg tablet and 2 placebo tablets once daily on Days 1-8). Treatment C: macitentan 30 mg (3 macitentan 10 mg tablets once daily on Days 1-8). Treatment D: placebo (3 placebo tablets on Days 1-8). There was a wash-out period of at least 10 days between the last study drug administration of the previous treatment and the first study drug administration of the following treatment.

Treatment:

Drug: Macitentan 10 mg

Drug: Macitentan 30 mg

Other: Placebo

Drug: Moxifloxacin 400 mg

Treatment sequence DBAC

Experimental group

Description:

Subjects received study medication in the sequence DBAC. Treatment A: moxifloxacin positive control (3 placebo tablets once daily on Days 1-7, and on Day 8 moxifloxacin 400 mg tablet and 2 macitentan-matching placebo tablets). Treatment B: macitentan 10 mg (1 macitentan 10 mg tablet and 2 placebo tablets once daily on Days 1-8). Treatment C: macitentan 30 mg (3 macitentan 10 mg tablets once daily on Days 1-8). Treatment D: placebo (3 placebo tablets on Days 1-8). There was a wash-out period of at least 10 days between the last study drug administration of the previous treatment and the first study drug administration of the following treatment.

Treatment:

Drug: Macitentan 10 mg

Drug: Macitentan 30 mg

Other: Placebo

Drug: Moxifloxacin 400 mg

Treatment sequence ADCB

Experimental group

Description:

Subjects received study medication in the sequence ADCB. Treatment A: moxifloxacin positive control (3 placebo tablets once daily on Days 1-7, and on Day 8 moxifloxacin 400 mg tablet and 2 macitentan-matching placebo tablets). Treatment B: macitentan 10 mg (1 macitentan 10 mg tablet and 2 placebo tablets once daily on Days 1-8). Treatment C: macitentan 30 mg (3 macitentan 10 mg tablets once daily on Days 1-8). Treatment D: placebo (3 placebo tablets on Days 1-8). There was a wash-out period of at least 10 days between the last study drug administration of the previous treatment and the first study drug administration of the following treatment.

Treatment:

Drug: Macitentan 10 mg

Drug: Macitentan 30 mg

Other: Placebo

Drug: Moxifloxacin 400 mg

Treatment sequence CABD

Experimental group

Description:

Subjects received study medication in the sequence CABD . Treatment A: moxifloxacin positive control (3 placebo tablets once daily on Days 1-7, and on Day 8 moxifloxacin 400 mg tablet and 2 macitentan-matching placebo tablets). Treatment B: macitentan 10 mg (1 macitentan 10 mg tablet and 2 placebo tablets once daily on Days 1-8). Treatment C: macitentan 30 mg (3 macitentan 10 mg tablets once daily on Days 1-8). Treatment D: placebo (3 placebo tablets on Days 1-8). There was a wash-out period of at least 10 days between the last study drug administration of the previous treatment and the first study drug administration of the following treatment.

Treatment:

Drug: Macitentan 10 mg

Drug: Macitentan 30 mg

Other: Placebo

Drug: Moxifloxacin 400 mg

Treatment sequence BCDA

Experimental group

Description:

Subjects received study medication in the sequence BCDA. Treatment A: moxifloxacin positive control (3 placebo tablets once daily on Days 1-7, and on Day 8 moxifloxacin 400 mg tablet and 2 macitentan-matching placebo tablets). Treatment B: macitentan 10 mg (1 macitentan 10 mg tablet and 2 placebo tablets once daily on Days 1-8). Treatment C: macitentan 30 mg (3 macitentan 10 mg tablets once daily on Days 1-8). Treatment D: placebo (3 placebo tablets on Days 1-8). There was a wash-out period of at least 10 days between the last study drug administration of the previous treatment and the first study drug administration of the following treatment.

Treatment:

Drug: Macitentan 10 mg

Drug: Macitentan 30 mg

Other: Placebo

Drug: Moxifloxacin 400 mg