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

Study Overview
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Brief Summary
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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.

Official Title
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A Single-center, Open-label, Single-dose, Randomized, 3-way Crossover Phase 1 Study in Healthy Adult Participants to Assess the Relative Oral Bioavailability of Macitentan 75 mg as Two Different Test Formulations Compared to the Reference Formulation

Conditions
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Healthy

Intervention / Treatment
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* Drug: Macitentan


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Sequence ABC<br>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. | Drug: Macitentan<br>* Macitentan film coated tablets will be administered orally as per assigned treatment sequence.<br>* Other names: Opsumit;|
| Experimental: Treatment Sequence BCA<br>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. | Drug: Macitentan<br>* Macitentan film coated tablets will be administered orally as per assigned treatment sequence.<br>* Other names: Opsumit;|
| Experimental: Treatment Sequence CAB<br>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. | Drug: Macitentan<br>* Macitentan film coated tablets will be administered orally as per assigned treatment sequence.<br>* Other names: Opsumit;|
| Experimental: Treatment Sequence ACB<br>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. | Drug: Macitentan<br>* Macitentan film coated tablets will be administered orally as per assigned treatment sequence.<br>* Other names: Opsumit;|
| Experimental: Treatment Sequence CBA<br>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. | Drug: Macitentan<br>* Macitentan film coated tablets will be administered orally as per assigned treatment sequence.<br>* Other names: Opsumit;|
| Experimental: Treatment Sequence BAC<br>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. | Drug: Macitentan<br>* Macitentan film coated tablets will be administered orally as per assigned treatment sequence.<br>* Other names: Opsumit;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Analyte Concentration (Cmax) of Macitentan | Cmax is defined as maximum observed plasma analyte concentration of macitentan. | Predose, up to 336 hours post dose (up to Day 15) | 
| Area Under the Plasma Analyte Concentration-time Curve from Time Zero to Time of the Last Quantifiable Concentration of Macitentan (AUC[0-last]) | 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. | Predose, up to 336 hours post dose (up to Day 15) | 
| Area Under the Plasma Analyte Concentration-time Curve from Time Zero to Infinite Time (AUC[0-infinity]) of Macitentan | AUC(0-infinity) is defined as area under the plasma analyte concentration-time curve of macitentan from time zero to infinite time. | Predose, up to 336 hours post dose (up to Day 15) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Actual Sampling Time to Reach the Maximum Observed Plasma Analyte Concentration (Tmax) of Macitentan and its Metabolite Aprocitentan | Tmax is defined as actual sampling time to reach the maximum observed plasma analyte concentration of macitentan and its metabolite aprocitentan. | Predose, up to 336 hours post dose (up to Day 15) | 
| Last Observed Measurable Plasma Analyte Concentration (Clast) of Macitentan and its Metabolite Aprocitentan | Clast is defined as last observed measurable plasma analyte concentration of macitentan and its metabolite aprocitentan. | Predose, up to 336 hours post dose (up to Day 15) | 
| 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]) | 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. | Predose, up to 336 hours post dose (up to Day 15) | 
| Apparent Terminal Elimination Half-life (t1/2) of Macitentan and its Metabolite Aprocitentan | t1/2 is defined as apparent terminal elimination half-life of macitentan and its metabolite aprocitentan. | Predose, up to 336 hours post dose (up to Day 15) | 
| Apparent Terminal Elimination Rate Constant (Lambda[z]) of Macitentan and its Metabolite Aprocitentan | 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. | Predose, up to 336 hours post dose (up to Day 15) | 
| Total Apparent Oral Clearance (CL/F) of Macitentan | CL/F of macitentan is defined as total apparent oral clearance, calculated as dose/AUC (0-infinity). | Predose, up to 336 hours post dose (up to Day 15) | 
| Apparent Volume of Distribution (Vdz/F) of Macitentan | Vdz/F of macitentan is defined as apparent volume of distribution, calculated as dose/(Lambda[z]*AUC [0-infinity]). | Predose, up to 336 hours post dose (up to Day 15) | 
| Maximum Observed Plasma Analyte Concentration (Cmax) of Aprocitentan | Cmax is defined as maximum observed plasma analyte concentration of metabolite aprocitentan. | Predose, up to 336 hours post dose (up to Day 15) | 
| Area Under the Plasma Analyte Concentration-Time Curve from Time Zero to Time of the Last Quantifiable Concentration of Aprocitentan (AUC[0-last]) | 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. | Predose, up to 336 hours post dose (up to Day 15) | 
| Area Under the Plasma Analyte Concentration-Time Curve of Aprocitentan from Time Zero to Infinity (AUC[0-infinity]) | AUC(0-infinity) is defined as area under the plasma analyte concentration-time curve of metabolite aprocitentan from time zero to infinite time. | Predose, up to 336 hours post dose (up to Day 15) | 
| Number of Participants with Serious Adverse Events (SAEs) | 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. | Up to 13 weeks | 
| Number of Participants with Adverse Events (AEs) | 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. | Up to 13 weeks | 
| Number of Participants with Abnormalities in Physical Examination | 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. | Up to Day 15 | 
| Number of Participants with Abnormalities in Vital Signs | Number of participants with abnormalities in vital signs (including temperature [tympanic], pulse rate, and blood pressure) will be reported. | Up to Day 15 | 
| Number of Participants with Abnormalities in Electrocardiograms (ECGs) | Number of participants with abnormalities in ECGs will be reported. | Up to Day 15 | 
| Number of Participants with Abnormalities in Clinical Laboratory Tests | Number of participants with abnormalities in clinical laboratory tests (including serum chemistry, hematology, and urinalysis) will be reported. | Up to Day 15 |