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

Pharmacokinetics Clinical Trial

Official 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02206204
• Other study ID #: AC-065-106
• Status: Completed
• Phase: Phase 1
• First received: July 30, 2014
• Last updated: July 30, 2014
• Start date: June 2012
• Est. completion date: November 2012

Study information

• Verified date: July 2014
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 159
• Est. completion date: November 2012
• Est. primary completion date: November 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 45 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor)

Related Conditions & MeSH terms

• Cardiodynamics
• Pharmacokinetics
• Safety
• Tolerability

Intervention

Drug:
• selexipag

• placebo for selexipag

• moxifloxacin

• moxifloxacin-matching placebo

Locations

Country	Name	City	State
United States	Covance Clinical Research Unit	Evansville	Indiana

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Baseline adjusted placebo corrected change in corrected QTc interval (time interval from beginning of the Q wave until end of the T wave) (??QTcI) at various time points	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.	24 days	Yes
Secondary	Baseline adjusted placebo corrected change in heart rate at various time points	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.	24 days	Yes
Secondary	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	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.	24 days	Yes
Secondary	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	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.	24 days	Yes
Secondary	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	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.	24 days	Yes
Secondary	Number of time points at which T-wave morphology changes were observed	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.	24 days	Yes
Secondary	Maximum plasma concentration (Cmax) for selexipag	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	24 days	No
Secondary	Time to reach maximum plasma concentration (tmax) for selexipag	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	24 days	No
Secondary	Area under the plasma concentration-time curve (AUCt) for selexipag	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.	24 days	No
Secondary	Trough plasma concentration (Ctrough) for selexipag	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	24 days	No
Secondary	Maximum plasma concentration (Cmax) for ACT-333679	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	24 days	No
Secondary	Time to reach maximum plasma concentration (tmax) for ACT-333679	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	24 days	No
Secondary	Area under the plasma concentration-time curve (AUCt) for ACT-333679	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.	24 days	No
Secondary	Trough plasma concentration (Ctrough) for ACT-333679	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	24 days	No
Secondary	Change in systolic blood pressure from baseline up to end of study	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.	up to 29 days	Yes
Secondary	Change in diastolic blood pressure from baseline up to end of study	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.	up to 29 days	Yes
Secondary	Change in pulse rate from baseline up to end of study	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.	up to 29 days	Yes
Secondary	Change in body weight from baseline up to end of study	Body weight will be measured using weighing scales with a precision of at least 0.5 kg.	up to 29 days	Yes
Secondary	Number of participants with treatment-related electrocardiogram abnormalities up to the end of study	Standard 12-lead electrocardiograms (ECGs) will be recorded at screening, on Day -1, Day 11, Day 23, and at end of study.	up to 29 days	Yes