Study in Healthy Male Subjects to Demonstrate Bioequivalence of 1600 μg Selexipag Administered as Eight Tablets of 200 μg or as Single Tablet of 1600 μg

Bioequivalence Clinical Trial

Official title:

A Single-center, Open-label, Randomized, Two-period, Two-treatment, Crossover Study in Healthy Male Subjects to Demonstrate Bioequivalence of 1600 μg Selexipag Administered as Eight Tablets of 200 μg (Reference Drug) or as Single Tablet of 1600 μg (Test Drug)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02206295
• Other study ID #: AC-065-108
• Status: Completed
• Phase: Phase 1
• First received: July 30, 2014
• Last updated: July 30, 2014
• Start date: September 2012
• Est. completion date: December 2012

Study information

• Verified date: July 2014
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

The primary aim of this study is to demonstrate bioequivalence in the rate and extent of absorption between 1600 μg selexipag test drug (administered orally as film-coated tablets of 1600 μg, twice a day (b.i.d.) and 1600 μg selexipag reference drug (administered orally as 8 film-coated tablets of 200 μg b.i.d.) at steady-state in healthy male subjects following a multiple-dose up-titration scheme.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: December 2012
• Est. primary completion date: December 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Signed informed consent in the local language prior to any study-mandated procedure.

• Healthy male subjects aged between 18 and 55 years (inclusive) at Screening.

• No clinically significant findings on the physical examination at Screening.

• Body mass index of 18.0 to 30.0 kg/m^2 (inclusive) at Screening.

• Systolic blood pressure 100-145 mmHg, diastolic blood pressure 50-90 mmHg, and pulse rate 45-90 beats per minute (all inclusive), measured at Screening.

• 12-lead electrocardiogram without clinically relevant abnormalities, measured at Screening.

• Hematology, clinical chemistry, and urinalysis test results not deviating from the normal range to a clinically relevant extent at Screening.

• Negative results from urine drug screen and alcohol breath test at Screening.

• Ability to communicate well with the investigator, in the local language, and to understand and comply with the requirements of the study.

Exclusion Criteria:

• Known allergic reactions or hypersensitivity to selexipag or any excipient of the drug formulation used in this study.

• History or clinical evidence of any disease and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism, or excretion of selexipag.

• Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.

• Veins unsuitable for intravenous 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).

• Treatment with selexipag or another investigational drug within 1 month prior to Screening or 5 half-lives, whichever is longer.

• History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to Screening.

• Excessive caffeine consumption at Screening.

• Smoking within 3 months prior to Screening and inability to refrain from smoking during the course of the study.

• Previous treatment with any prescribed medications (including vaccines) or over-the-counter medications within 2 weeks prior to first study drug administration.

• Loss of 500 mL or more of blood within 3 months prior to Screening.

• Positive results from the hepatitis serology (hepatitis B antigen and hepatitis C antibodies), except for vaccinated subjects or subjects with past but resolved hepatitis, at Screening.

• Positive results from the human immunodeficiency virus serology at Screening.

• Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.

• Legal incapacity or limited legal capacity at Screening.

Study Design

Allocation: Randomized, Endpoint Classification: Bio-equivalence Study, Intervention Model: Crossover Assignment, Masking: Open Label

Related Conditions & MeSH terms

• Bioequivalence

Intervention

Drug:
• selexipag

Locations

Country	Name	City	State
Netherlands	QPS	Groningen

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area under the plasma concentration-time curve (AUCt) for selexipag	Blood will be collected by direct venipuncture or via an intravenous catheter placed in an arm vein after 4.5 days' treatment with 1600 µg selexipag b.i.d. during Treatments A and B. Selexipag will be quantified in plasma samples using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay. 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.	23 days	No
Primary	Maximum plasma concentration at steady state (Cmax,ss) for selexipag	Blood will be collected by direct venipuncture or via an intravenous catheter placed in an arm vein after 4.5 days' treatment with 1600 µg selexipag b.i.d. during Treatments A and B. Selexipag will be quantified in plasma samples using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay. The measured individual plasma concentrations of selexipag will be used to directly obtain Cmax,ss.	23 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 an arm vein after 4.5 days' treatment with 1600 µg selexipag b.i.d. during Treatments A and B. ACT-333679 will be quantified in plasma samples using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay. 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.	23 days	No
Secondary	Maximum plasma concentration at steady state (Cmax,ss) for ACT-333679	Blood will be collected by direct venipuncture or via an intravenous catheter placed in an arm vein after 4.5 days' treatment with 1600 µg selexipag b.i.d. during Treatments A and B. ACT-333679 will be quantified in plasma samples using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay. The measured individual plasma concentrations of ACT-333679 will be used to directly obtain Cmax,ss.	23 days	No
Secondary	Time to reach maximum plasma concentration at steady state (tmax,ss) for selexipag	Blood will be collected by direct venipuncture or via an intravenous catheter placed in an arm vein after 4.5 days' treatment with 1600 µg selexipag b.i.d. during Treatments A and B. Selexipag will be quantified in plasma samples using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay. The measured individual plasma concentrations of selexipag will be used to directly obtain tmax,ss.	23 days	No
Secondary	Trough plasma concentration at the end of one dose interval (Ctrough) for selexipag	Blood will be collected by direct venipuncture or via an intravenous catheter placed in an arm vein after 4.5 days' treatment with 1600 µg selexipag b.i.d. during Treatments A and B. Selexipag will be quantified in plasma samples using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay. The measured individual plasma concentrations of selexipag will be used to directly obtain Ctrough.	23 days	No
Secondary	Trough plasma concentration at the end of one dose interval (Ctrough) for ACT-333679	Blood will be collected by direct venipuncture or via an intravenous catheter placed in an arm vein after 4.5 days' treatment with 1600 µg selexipag b.i.d. during Treatments A and B. ACT-333679 will be quantified in plasma samples using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay. The measured individual plasma concentrations of ACT-333679 will be used to directly obtain Ctrough.	23 days	No
Secondary	Trough plasma concentration at steady state (Ctrough,ss) for selexipag	Blood will be collected by direct venipuncture or via an intravenous catheter placed in an arm vein after 4.5 days' treatment with 1600 µg selexipag b.i.d. during Treatments A and B. Selexipag will be quantified in plasma samples using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay. The measured individual plasma concentrations of selexipag will be used to directly obtain Ctrough,ss.	23 days	No
Secondary	Trough plasma concentration (Ctrough,ss) for ACT-333679	Blood will be collected by direct venipuncture or via an intravenous catheter placed in an arm vein after 4.5 days' treatment with 1600 µg selexipag b.i.d. during Treatments A and B. ACT-333679 will be quantified in plasma samples using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay. The measured individual plasma concentrations of ACT-333679 will be used to directly obtain Ctrough,ss.	23 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).	up to 28 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).	up to 28 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).	up to 28 days	Yes
Secondary	Change in body weight 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).	up to 28 days	Yes
Secondary	Change in heart rate from baseline up to end of study	Heart rate will be measured using standard 12-lead electrocardiography recorded at rest with the subject in the supine position for a 5 minute period.	up to 28 days	Yes
Secondary	Change in PQ/PR interval (time interval from the beginning of the P wave to the beginning of the QRS complex) from baseline up to end of study	PQ/PR interval will be measured using standard 12-lead electrocardiography recorded at rest with the subject in the supine position for a 5 minute period.	up to 28 days	Yes
Secondary	Change in QRS interval (time interval from the beginning of the Q wave to the end of the S wave) from baseline up to end of study	QRS interval will be measured using standard 12-lead electrocardiography recorded at rest with the subject in the supine position for a 5 minute period.	up to 28 days	Yes
Secondary	Change in QT interval (time interval from beginning of the Q wave until end of the T wave) from baseline up to end of study	QT interval will be measured using standard 12-lead electrocardiography recorded at rest with the subject in the supine position for a 5 minute period.	up to 28 days	Yes
Secondary	Change in QTcB interval (time interval from beginning of the Q wave until end of the T wave, according to Bazett's correction) from baseline up to end of study	QT interval will be measured using standard 12-lead electrocardiography recorded at rest with the subject in the supine position for a 5 minute period. QTcB will be calculated according to the following formula (QTcB = QT/RR^0.5 where RR is 60/heart rate).	up to 28 days	Yes
Secondary	Change in QTcF interval (time interval from beginning of the Q wave until end of the T wave, according to Fridericia's correction) from baseline up to end of study	QT interval will be measured using standard 12-lead electrocardiography recorded at rest with the subject in the supine position for a 5 minute period. QTcF will be calculated according to the following formula (QTcF = QT/RR^0.33 where RR is 60/heart rate).	up to 28 days	Yes
Secondary	Number of treatment-emergent electrocardiogram abnormalities from baseline up to end of study	Electrocardiogram abnormalities will be measured using standard 12-lead electrocardiography recorded at rest with the subject in the supine position for a 5 minute period.	up to 28 days	Yes
Secondary	Number of participants with adverse events leading to discontinuation of study treatment	Adverse events will be considered as any adverse change from the subject's baseline condition that occurred during the course of the study. The subjects will be required to report any adverse events spontaneously. In addition, each subject will be assessed by the investigator at any measurement timepoint as well as at the end of observation and whenever necessary as deemed by the investigator.	up to 28 days	Yes