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

NCT02050802 | Completed Phase 1

• 1 other identifier: AC-055-114
• Study Type: interventional
• Target: 64
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Healthy

Keywords

Macitentan; Pharmacokinetics; Pharmacodynamics

Outcome Measures

Primary Outcomes (1)

• Baseline-adjusted placebo-corrected QT interval according to Fridericia's correction (QTcF)

  The QTcF interval was obtained directly from the Holter ECG monitoring.Triplicate ECG recordings were obtained from a 12-lead Holter recording device at various time points on Day 8. Baseline data were obtained from the pre-dose recording on Day 1 (from about 45 to 15 minutes prior to the morning dose). The QTcF interval is the QT interval (interval from beginning of the Q wave until end of the T wave) corrected for heart rate with Fridericia's formula (QTcF = QT/RR\^0.33 where RR is 60/heart rate)

  Day 8

Secondary Outcomes (15)

• Placebo corrected change from baseline in heart rate on Day 8

  Day 8

• 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

  Day 8

• 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

  Day 8

• 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

  Day 8

• Number of participants with treatment emergent ECG abnormalities

  8 Days

Study Arms (8)

Treatment sequence BCAD

EXPERIMENTAL

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.

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

Treatment sequence ABDC

EXPERIMENTAL

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.

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

Treatment sequence DACB

EXPERIMENTAL

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.

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

Treatment sequence CDBA

EXPERIMENTAL

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.

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

Treatment sequence DBAC

EXPERIMENTAL

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.

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

Treatment sequence ADCB

EXPERIMENTAL

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.

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

Treatment sequence CABD

EXPERIMENTAL

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.

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

Treatment sequence BCDA

EXPERIMENTAL

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.

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

Interventions

Moxifloxacin 400 mg DRUG

Treatment sequence ABDC; Treatment sequence ADCB; Treatment sequence BCAD; Treatment sequence BCDA; Treatment sequence CABD; Treatment sequence CDBA; Treatment sequence DACB; Treatment sequence DBAC

Macitentan 10 mg DRUG

Also known as: Opsumit

Treatment sequence ABDC; Treatment sequence ADCB; Treatment sequence BCAD; Treatment sequence BCDA; Treatment sequence CABD; Treatment sequence CDBA; Treatment sequence DACB; Treatment sequence DBAC

Macitentan 30 mg DRUG

Also known as: Opsumit

Treatment sequence ABDC; Treatment sequence ADCB; Treatment sequence BCAD; Treatment sequence BCDA; Treatment sequence CABD; Treatment sequence CDBA; Treatment sequence DACB; Treatment sequence DBAC

Placebo OTHER

Treatment sequence ABDC; Treatment sequence ADCB; Treatment sequence BCAD; Treatment sequence BCDA; Treatment sequence CABD; Treatment sequence CDBA; Treatment sequence DACB; Treatment sequence DBAC

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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).
• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Actelion: lead

MeSH Terms

Interventions

Moxifloxacin; macitentan

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Nicolas Lindegger, PhD

  Actelion

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2014
• First Posted: January 31, 2014
• Study Start: August 1, 2011
• Primary Completion: November 1, 2011
• Study Completion: November 1, 2011
• Last Updated: February 3, 2025

Record last verified: 2025-01