A Study of Two Different Test Formulations Compared to the Reference Formulation of Macitentan in Healthy Adult Participants

Phase 1

Completed

• Conditions: Healthy
• Interventions: Drug: Macitentan

• Registration Number: NCT05392530
• Lead Sponsor: Actelion

Brief Summary

The purpose of this study is to assess the rate and extent of absorption of a single oral dose of macitentan given as 2 test formulations compared to the reference formulation under fed conditions in healthy adult participants.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2022-05-23
• Study First Submitted QC: 2022-05-23
• Study Start: 2022-05-25
• Study First Posted: 2022-05-26
• Primary Completion: 2022-08-30
• Study Completion: 2022-09-14
• Status Verified: 2022-11
• Last Update Submitted: 2022-11-08
• Last Update Posted: 2022-11-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 23

Inclusion Criteria

• Healthy on the basis of physical examination and medical and surgical history, performed at screening. If there are abnormalities, the participant may be included only if the investigator judges the abnormalities to be not clinically significant. This determination must be recorded in the participant's source documents and initialed by the investigator
• Systolic blood pressure (SBP) between 100 and 145 millimeters of mercury (mmHg) (inclusive), diastolic blood pressure (DBP) between 50 and 90 mmHg (inclusive), and pulse rate between 45 and 90 beats per minute (inclusive), within 3 minutes after standing up and after the participant is supine for at least 5 minutes, at screening
• Twelve-lead electrocardiogram (ECG) without clinically relevant abnormalities, at the discretion of the investigator, measured after the participant is supine for at least 5 minutes, at screening
• Body weight not less than 50 kilograms (Kg) and body mass index (BMI; weight/height^2) within the range 18.5 -30 kg per meter square (kg/m^2) (inclusive)at screening
• All women must have a negative highly sensitive serum (beta-human chorionic gonadotropin [beta-hCG]) pregnancy test at screening and a negative urine pregnancy test on Day -1 of the first treatment period

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Exclusion Criteria

• Known allergies, hypersensitivity, or intolerance to any active substance or drugs of the same class, or any excipient of the drug formulation(s)
• 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 the study intervention(s) (appendectomy and herniotomy allowed, cholecystectomy not allowed)
• A history of repeated fainting due to cardiac cause, collapse, syncope, orthostatic hypotension, or vasovagal reactions
• Female participant who is breastfeeding at screening and plans to breastfeed throughout the study
• Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (example, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Treatment Sequence BAC	Macitentan	Participants will receive Treatment B in Treatment Period 1 followed by Treatment A in treatment period 2, and then Treatment C in Treatment Period 3 on Day 1. The study intervention administrations will be separated by at least 14 days to allow adequate washout duration following the single doses.
Treatment Sequence BCA	Macitentan	Participants will receive Treatment B in Treatment Period 1 followed by Treatment C in Treatment Period 2, and then Treatment A in Treatment Period 3 on Day 1. The study intervention administrations will be separated by at least 14 days to allow adequate washout duration following the single doses.
Treatment Sequence CAB	Macitentan	Participants will receive Treatment C in Treatment Period 1 followed by Treatment A in Treatment Period 2, and then Treatment B in Treatment Period 3 on Day 1. The study intervention administrations will be separated by at least 14 days to allow adequate washout duration following the single doses.
Treatment Sequence ABC	Macitentan	Participants will receive single oral dose of final marketing image (FMI) candidate #1 of macitentan (Treatment A \[test\]) under fed condition in Treatment Period 1, followed by single oral dose of FMI candidate #2 of macitentan (Treatment B \[test\]) under fed conditions in Treatment Period 2, and then single oral dose of the reference formulation of macitentan (Treatment C) under fed conditions in Treatment Period 3. The study intervention administrations will be separated by at least 14 days to allow adequate washout duration following the single doses.
Treatment Sequence CBA	Macitentan	Participants will receive Treatment C in Treatment Period 1 followed by Treatment B in Treatment Period 2, and then Treatment A in Treatment Period 3 on Day 1. The study intervention administrations will be separated by at least 14 days to allow adequate washout duration following the single doses.
Treatment Sequence ACB	Macitentan	Participants will receive Treatment A in Treatment Period 1 followed by Treatment C in Treatment Period 2, and then Treatment B in Treatment Period 3 on Day 1. The study intervention administrations will be separated by at least 14 days to allow adequate washout duration following the single doses.

Primary Outcome Measures

Name	Time	Method
Maximum Observed Plasma Analyte Concentration (Cmax) of Macitentan	Predose, up to 336 hours post dose (up to Day 15)	Cmax is defined as maximum observed plasma analyte concentration of macitentan.
Area Under the Plasma Analyte Concentration-time Curve from Time Zero to Time of the Last Quantifiable Concentration of Macitentan (AUC[0-last])	Predose, up to 336 hours post dose (up to Day 15)	AUC(0-last) is defined as area under the plasma analyte concentration-time curve of macitentan from time zero to time of the last quantifiable (non-below quantification limit \[BQL\]) concentration.
Area Under the Plasma Analyte Concentration-time Curve from Time Zero to Infinite Time (AUC[0-infinity]) of Macitentan	Predose, up to 336 hours post dose (up to Day 15)	AUC(0-infinity) is defined as area under the plasma analyte concentration-time curve of macitentan from time zero to infinite time.

Secondary Outcome Measures

Name	Time	Method
Number of Participants with Serious Adverse Events (SAEs)	Up to 13 weeks	Number of Participants with Serious Adverse Events (SAEs) will be reported SAE is any untoward medical occurrence that at any dose may results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via a medicinal product.
Last Observed Measurable Plasma Analyte Concentration (Clast) of Macitentan and its Metabolite Aprocitentan	Predose, up to 336 hours post dose (up to Day 15)	Clast is defined as last observed measurable plasma analyte concentration of macitentan and its metabolite aprocitentan.
Area Under the Plasma Analyte Concentration-time Curve of Macitentan and its Metabolite Aprocitentan from Time Zero to 72 Hours Post dose (AUC[0-72 Hours])	Predose, up to 336 hours post dose (up to Day 15)	AUC(0-72 hours) is defined as area under the plasma analyte concentration-time curve of macitentan and its metabolite aprocitentan from time zero to 72 hours post dose, calculated by linear-linear trapezoidal summation.
Area Under the Plasma Analyte Concentration-Time Curve from Time Zero to Time of the Last Quantifiable Concentration of Aprocitentan (AUC[0-last])	Predose, up to 336 hours post dose (up to Day 15)	AUC(0-last) of metabolite Aprocitentan is defined as area under the plasma analyte concentration-time curve from time zero to time of the last quantifiable (BQL) concentration, calculated by linear-linear trapezoidal summation.
Maximum Observed Plasma Analyte Concentration (Cmax) of Aprocitentan	Predose, up to 336 hours post dose (up to Day 15)	Cmax is defined as maximum observed plasma analyte concentration of metabolite aprocitentan.
Apparent Terminal Elimination Half-life (t1/2) of Macitentan and its Metabolite Aprocitentan	Predose, up to 336 hours post dose (up to Day 15)	t1/2 is defined as apparent terminal elimination half-life of macitentan and its metabolite aprocitentan.
Apparent Terminal Elimination Rate Constant (Lambda[z]) of Macitentan and its Metabolite Aprocitentan	Predose, up to 336 hours post dose (up to Day 15)	Lambda(z) is defined as apparent terminal elimination rate constant of macitentan and its metabolite aprocitentan, estimated by linear regression using the terminal log-linear phase of the log transformed concentration versus time curve.
Actual Sampling Time to Reach the Maximum Observed Plasma Analyte Concentration (Tmax) of Macitentan and its Metabolite Aprocitentan	Predose, up to 336 hours post dose (up to Day 15)	Tmax is defined as actual sampling time to reach the maximum observed plasma analyte concentration of macitentan and its metabolite aprocitentan.
Total Apparent Oral Clearance (CL/F) of Macitentan	Predose, up to 336 hours post dose (up to Day 15)	CL/F of macitentan is defined as total apparent oral clearance, calculated as dose/AUC (0-infinity).
Apparent Volume of Distribution (Vdz/F) of Macitentan	Predose, up to 336 hours post dose (up to Day 15)	Vdz/F of macitentan is defined as apparent volume of distribution, calculated as dose/(Lambda\[z\]\*AUC \[0-infinity\]).
Number of Participants with Abnormalities in Vital Signs	Up to Day 15	Number of participants with abnormalities in vital signs (including temperature \[tympanic\], pulse rate, and blood pressure) will be reported.
Area Under the Plasma Analyte Concentration-Time Curve of Aprocitentan from Time Zero to Infinity (AUC[0-infinity])	Predose, up to 336 hours post dose (up to Day 15)	AUC(0-infinity) is defined as area under the plasma analyte concentration-time curve of metabolite aprocitentan from time zero to infinite time.
Number of Participants with Adverse Events (AEs)	Up to 13 weeks	Number of participants with AEs will be reported. An AE is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non investigational) product.
Number of Participants with Abnormalities in Clinical Laboratory Tests	Up to Day 15	Number of participants with abnormalities in clinical laboratory tests (including serum chemistry, hematology, and urinalysis) will be reported.
Number of Participants with Abnormalities in Physical Examination	Up to Day 15	Number of participants with abnormalities in physical examination (including general appearance, respiratory, neurological, eyes, ear/nose/throat, thyroid, cardiovascular, abdominal/gastrointestinal, hepatic, musculoskeletal, and dermatologic) will be reported.
Number of Participants with Abnormalities in Electrocardiograms (ECGs)	Up to Day 15	Number of participants with abnormalities in ECGs will be reported.

Trial Locations

Locations (1)

SGS Belgium NV; 🇧🇪 Edegem, Belgium