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Completed

NCT Number: NCT02206204

Study of Selexipag and Its Metabolite ACT-333679 on Cardiac Repolarization in Healthy Male and Female Subjects

This is a single-center, double-blind, randomized, placebo- and positive-controlled, double-dummy, parallel-group, multiple-dose, up-titration study with a nested cross-over comparison between moxifloxacin and placebo in healthy male and female subjects. The primary objective is to demonstrate that selexipag and its metabolite ACT-333679 do not have an effect on cardiac repolarization exceeding the threshold of regulatory concern, at two orally administered dose levels (800 and 1600 μg twice daily) in healthy male and female subjects. Moxifloxacin is included as a positive control.

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Key information

Conditions

Cardiodynamics Pharmacokinetics Safety Tolerability

Age range

18 year–45 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Covance Clinical Research Unit

Evansville, Indiana, 47710, United States

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Signed, dated written informed consent prior to any study procedure.
  • Ability to communicate well with the investigator in local language, and to understand and comply with the requirements of the study.
  • Women of childbearing potential must have had a negative serum pregnancy test at screening and a negative serum pregnancy test on Day -1. Women of childbearing potential must have consistently and correctly used a reliable method of contraception with a failure rate of < 1% per year, been sexually inactive, or have vasectomized partner.
  • Healthy based on medical history and assessments performed at screening and on Day -1.
  • Body mass index ≥ 18.5 and ≤ 32 kg/m^2 at screening. Body weight at least 50 kg.
  • Negative results from urine drug screen at screening and on Day -1 and negative urine alcohol test on Day -1.
  • Willing to refrain from alcohol consumption from at least 48 hours prior to clinic admission to the end of study.
  • Systolic blood pressure 90-145 mmHg, diastolic blood pressure 50-90 mmHg, and pulse rate 45-90 beats per minute, at screening and Day -1.
  • Hematology, blood chemistry, and urinalysis results not deviating from the normal range to a clinically relevant extent at screening and Day -1.

Exclusion criteria

  • Known hypersensitivity to selexipag, moxifloxacin, or excipients of the drug formulations used in this study.
  • Treatment with selexipag or an investigational drug prior to screening within 30 days or 6 half-lives, whichever was longer.
  • History or clinical evidence of any disease and/or the existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism, or excretion of selexipag and moxifloxacin.
  • Caffeine consumption of equal to or greater than 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.
  • History of clinical evidence of psychiatric disease, alcoholism, or drug abuse within the 3-year period prior to screening.
  • Smoking within the 3 months prior to screening and inability to refrain from smoking during the study.
  • Loss of 500 mL or more of blood within 56 days prior to screening.
  • Positive results from the hepatitis serology, except for vaccinated subjects at screening.
  • Positive results from human immunodeficiency virus serology at screening.
  • Previous treatment with any prescribed or over-the-counter medications, with the exception of contraceptives and hormone replacement therapy, within the 2 weeks prior to first study drug administration or 5 half-lives, whichever longer.
  • Excessive physical activities within 1 week prior to administration of study drug.
  • Any cardiac condition (including ECG abnormalities) or illness with a potential to increase the cardiac risk of the subject or that may affect QTc analysis.
  • QTc > 450 ms or > 470 ms for male or female subjects, respectively, at screening and Day -1.
  • Clinically relevant abnormalities on ECG, at screening and Day -1.
  • Personal or family history of long QT syndrome or hypokalemia.
  • Legal incapacity or limited legal capacity.
  • Veins unsuitable for intravenous puncture on either arm.
  • Any circumstances or conditions, which, in the opinion of the investigator, may affected the subject's participation in the study or compliance with the protocol.
  • Pregnant or nursing women.
  • Women who plan to become pregnant within 1 month of the end of study.

Treatment and study plan

Selexipag

Drug

placebo for selexipag

Drug

moxifloxacin

Drug

Moxifloxacin-matching placebo

Drug

Primary outcomes

  1. Baseline adjusted placebo corrected change in corrected QTc interval (time interval from beginning of the Q wave until end of the T wave) (ΔΔQTcI) at various time points

    Time frame: 24 days

    Electrocardiograms (ECGs) will be extracted in replicate at predefined timepoints from replicated 12-lead Holter ECGs. Cardiodynamic endpoints will be assessed at steady-state for 800 μg selexipag on Day 11 and at steady-state for 1600 μg selexipag on Day 23. Based on prospective criteria, QTcI will be the primary method for heart rate (HR) correction.

Secondary outcomes

  1. Baseline adjusted placebo corrected change in heart rate at various time points

    Time frame: 24 days

    Electrocardiograms (ECGs) will be extracted in replicate at predefined timepoints from replicated 12-lead Holter ECGs. Cardiodynamic endpoints will be assessed at steady-state for 800 μg selexipag on Day 11 and at steady-state for 1600 μg selexipag on Day 23.

  2. Baseline adjusted placebo corrected change in RR interval (interval from the peak of one QRS complex to the peak of the next) at various time points

    Time frame: 24 days

    Electrocardiograms (ECGs) will be extracted in replicate at predefined timepoints from replicated 12-lead Holter ECGs. Cardiodynamic endpoints will be assessed at steady-state for 800 μg selexipag on Day 11 and at steady-state for 1600 μg selexipag on Day 23.

  3. Baseline adjusted placebo corrected change in PR interval (time interval from the beginning of the P wave to the beginning of the QRS complex) at various time points

    Time frame: 24 days

    Electrocardiograms (ECGs) will be extracted in replicate at predefined timepoints from replicated 12-lead Holter ECGs. Cardiodynamic endpoints will be assessed at steady-state for 800 μg selexipag on Day 11 and at steady-state for 1600 μg selexipag on Day 23.

  4. Baseline adjusted placebo corrected change in QRS interval (time interval from the beginning of the Q wave to the end of the S wave) at various time points

    Time frame: 24 days

    Electrocardiograms (ECGs) will be extracted in replicate at predefined timepoints from replicated 12-lead Holter ECGs. Cardiodynamic endpoints will be assessed at steady-state for 800 μg selexipag on Day 11 and at steady-state for 1600 μg selexipag on Day 23.

  5. Number of time points at which T-wave morphology changes were observed

    Time frame: 24 days

    Electrocardiograms (ECGs) will be extracted in replicate at predefined timepoints from replicated 12-lead Holter ECGs. Cardiodynamic endpoints will be assessed at steady-state for 800 μg selexipag on Day 11 and at steady-state for 1600 μg selexipag on Day 23.

  6. Maximum plasma concentration (Cmax) for selexipag

    Time frame: 24 days

    Blood will be collected by direct venipuncture or via an intravenous catheter placed in a vein in the arm on Days 11 and 23. Samples will be collected immediately prior to morning dosing and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hours post-dosing. Selexipag concentrations will be quantified in plasma samples by liquid chromatography with tandem mass spectrometry. The measured individual plasma concentrations will be used to directly obtain Cmax

  7. Time to reach maximum plasma concentration (tmax) for selexipag

    Time frame: 24 days

    Blood will be collected by direct venipuncture or via an intravenous catheter placed in a vein in the arm on Days 11 and 23. Samples will be collected immediately prior to morning dosing and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hours post-dosing. Selexipag concentrations will be quantified in plasma samples by liquid chromatography with tandem mass spectrometry. The measured individual plasma concentrations will be used to directly obtain tmax

  8. Area under the plasma concentration-time curve (AUCt) for selexipag

    Time frame: 24 days

    Blood will be collected by direct venipuncture or via an intravenous catheter placed in a vein in the arm on Days 11 and 23. Samples will be collected immediately prior to morning dosing and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hours post-dosing. Selexipag concentrations will be quantified in plasma samples by liquid chromatography with tandem mass spectrometry. AUCt will be calculated according to the linear trapezoidal rule, using the measured concentration-time values above the limit of quantification during one dosing interval.

  9. Trough plasma concentration (Ctrough) for selexipag

    Time frame: 24 days

    Blood will be collected by direct venipuncture or via an intravenous catheter placed in a vein in the arm on Days 11 and 23. Samples will be collected immediately prior to morning dosing and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hours post-dosing. Selexipag concentrations will be quantified in plasma samples by liquid chromatography with tandem mass spectrometry. The measured individual plasma concentrations will be used to directly obtain Ctrough

  10. Maximum plasma concentration (Cmax) for ACT-333679

    Time frame: 24 days

    Blood will be collected by direct venipuncture or via an intravenous catheter placed in a vein in the arm on Days 11 and 23. Samples will be collected immediately prior to morning dosing and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hours post-dosing. ACT-333679 concentrations will be quantified in plasma samples by liquid chromatography with tandem mass spectrometry. The measured individual plasma concentrations will be used to directly obtain Cmax

  11. Time to reach maximum plasma concentration (tmax) for ACT-333679

    Time frame: 24 days

    Blood will be collected by direct venipuncture or via an intravenous catheter placed in a vein in the arm on Days 11 and 23. Samples will be collected immediately prior to morning dosing and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hours post-dosing. ACT-333679 concentrations will be quantified in plasma samples by liquid chromatography with tandem mass spectrometry. The measured individual plasma concentrations will be used to directly obtain tmax

  12. Area under the plasma concentration-time curve (AUCt) for ACT-333679

    Time frame: 24 days

    Blood will be collected by direct venipuncture or via an intravenous catheter placed in a vein in the arm on Days 11 and 23. Samples will be collected immediately prior to morning dosing and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hours post-dosing. ACT-333679 concentrations will be quantified in plasma samples by liquid chromatography with tandem mass spectrometry. AUCt will be calculated according to the linear trapezoidal rule, using the measured concentration-time values above the limit of quantification during one dosing interval.

  13. Trough plasma concentration (Ctrough) for ACT-333679

    Time frame: 24 days

    Blood will be collected by direct venipuncture or via an intravenous catheter placed in a vein in the arm on Days 11 and 23. Samples will be collected immediately prior to morning dosing and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hours post-dosing. ACT-333679 concentrations will be quantified in plasma samples by liquid chromatography with tandem mass spectrometry. The measured individual plasma concentrations will be used to directly obtain Ctrough

  14. Change in systolic blood pressure from baseline up to end of study

    Time frame: up to 29 days

    Blood pressure and pulse rate will be measured using an automatic oscillometric device, always on the dominant arm (i.e., dominant arm right = writing with right hand). Measurements will be recorded from the subject in the supine position after having rested for a 5-minute period.

  15. Change in diastolic blood pressure from baseline up to end of study

    Time frame: up to 29 days

    Blood pressure and pulse rate will be measured using an automatic oscillometric device, always on the dominant arm (i.e., dominant arm right = writing with right hand). Measurements will be recorded from the subject in the supine position after having rested for a 5-minute period.

  16. Change in pulse rate from baseline up to end of study

    Time frame: up to 29 days

    Blood pressure and pulse rate will be measured using an automatic oscillometric device, always on the dominant arm (i.e., dominant arm right = writing with right hand). Measurements will be recorded from the subject in the supine position after having rested for a 5-minute period.

  17. Change in body weight from baseline up to end of study

    Time frame: up to 29 days

    Body weight will be measured using weighing scales with a precision of at least 0.5 kg.

  18. Number of participants with treatment-related electrocardiogram abnormalities up to the end of study

    Time frame: up to 29 days

    Standard 12-lead electrocardiograms (ECGs) will be recorded at screening, on Day -1, Day 11, Day 23, and at end of study.

Sponsors and collaborators

Lead sponsor

Actelion

Industry

Registry information

Official study title

Single-center, Double-blind, Randomized, Placebo- and Positive-controlled, Parallel-group With Nested Cross-over, Multiple-dose, Up-titration Study of the Effects of Selexipag and Its Metabolite ACT-333679 on Cardiac Repolarization in Healthy Male and Female Subjects

Important dates

Study start
2012
Primary completion
2012
Study completion
2012
First posted
Aug 1, 2014
Registry last updated
Aug 1, 2014

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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