A Study to Compare the Macitentan-tadalafil Fixed Dose Combination Tablet Relative to the Concomitant Administration of the Reference Tablets of Macitentan and Tadalafil in Healthy Subjects

Study Overview
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Brief Summary
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The primary objective of this study is to demonstrate that macitentan and tadalafil administered as a fixed combination is bioequivalent to both compounds given as separate tablets given at the same doses as in the fixed combination (i.e. whether the amounts of macitentan and tadalfil which reach the blood are comparable).

Official Title
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Single-center, Open-label, Single-dose, Two-period, Randomized, Crossover, Phase I Study to Demonstrate Bioequivalence Between a Fixed Dose Combination Product Formulation of Macitentan/Tadalafil (10 mg/40 mg) and the Free Combination of 10 mg Macitentan (Opsumit®) and 40 mg Tadalafil (Adcirca®) in Healthy Male and Female Subjects

Conditions
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Healthy Subjects

Intervention / Treatment
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* Combination Product: Macitentan / tadalafil FDC
* Drug: Macitentan (Opsumit®)
* Drug: Tadalafil (Adcirca®)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Signed informed consent Male and female subjects aged between 18 and 55 years (inclusive) at screening Healthy on the basis of the physical examination, vital signs, 12-lead ECG, and laboratory tests performed at screening Women must have a negative serum pregnancy test at screening and a negative urine pregnancy test on Day-1 or must be of non-childbearing potential. Body mass index (BMI) of 18.0 to 30.0 kg/m2 (inclusive) at screening Systolic blood pressure 100-145 mmHg, diastolic blood pressure 50-90 mmHg, and pulse rate 45-90 bpm (inclusive) Key Exclusion Criteria: Known hypersensitivity to any active substance or drugs of the same class, or any excipients 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 treatment(s) Values of hepatic aminotransferase (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) > 3 X upper limit of normal at screening Loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy Known hereditary degenerative retinal disorders, including retinitis pigmentosa Priapism and anatomical deformation of the penis Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions Treatment with another investigational drug within 3 months prior to screening or participation in more than 4 investigational drug studies within 1 year prior to screening Excessive caffeine consumption, defined as > or = 800 mg per day at screening. Nicotine intake (e.g., smoking, nicotine patch, nicotine chewing gum, or electronic cigarettes) within 3 months prior to screening and inability to refrain from nicotine intake from screening until end-of-study (EOS; washout period included) Previous treatment with any prescribed medications (including vaccines) or over the counter (OTC) medications within 3 weeks prior to first study treatment administration. Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.

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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence A/B<br>Subjects receive one tablet of macitentan / tadalafil FDC (fixed dose combination) during Period 1, then after a washout period of at least 7 days they receive one tablet of macitentan (Opsumit®) and two tablets of tadalafil (Adcirca®) during Period 2 | Combination Product: Macitentan / tadalafil FDC<br>* Tablets for oral administration containing 10 mg of macitentan and 40 mg of tadalafil<br>Drug: Macitentan (Opsumit®)<br>* Film-coated tablets for oral administration formulated at a strength of 10 mg<br>* Other names: ACT-064992;Drug: Tadalafil (Adcirca®)<br>* Film-coated tablets for oral administration formulated at a strength of 20 mg<br>|
| Experimental: Sequence B/A<br>Subjects receive one tablet of macitentan (Opsumit®) and two tablets of tadalafil (Adcirca®) during Period 1, then after a washout period of at least 7 days, they receive one tablet of macitentan / tadalafil FDC (fixed dose combination) during Period 2 | Combination Product: Macitentan / tadalafil FDC<br>* Tablets for oral administration containing 10 mg of macitentan and 40 mg of tadalafil<br>Drug: Macitentan (Opsumit®)<br>* Film-coated tablets for oral administration formulated at a strength of 10 mg<br>* Other names: ACT-064992;Drug: Tadalafil (Adcirca®)<br>* Film-coated tablets for oral administration formulated at a strength of 20 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) of macitentan and tadalafil | The measured individual plasma concentrations of macitentan and tadalafil are used to directly obtain Cmax | Blood samples for pharmacokinetic evaluations are collected at selected time points from Baseline (pre-dose) to 216 hours post-dose of each study period | 
| Area under the plasma concentration-time curve from 0 to time t [AUC(0-t)] of macitentan and tadalafil | AUC(0-t) is the area calculated from the concentration-time profile of macitentan and tadalafil, from time 0 to to time t of the last measured concentration above the limit of quantification | Blood samples for pharmacokinetic evaluations are collected at selected time points from Baseline (pre-dose) to 216 hours post-dose of each study period | 
| Area under the plasma concentration-time curve to infinitiy [AUC(0-inf)] of macitentan and tadalafil | AUC(0-inf) is the area calculated from the concentration-time profile of macitentan and tadalafil, from time 0 to extrapolated infinite time | Blood samples for pharmacokinetic evaluations are collected at selected time points from Baseline (pre-dose) to 216 hours post-dose of each study period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| maximal plasma concentration (Cmax) of ACT-132577 | Cmax of the active metabolite of macitentan, ACT-132577, is measured directly from the plasma concentrations of ACT-132577 | Blood samples for pharmacokinetic evaluations are collected at selected time points from Baseline (pre-dose) to 216 hours post-dose of each study period | 
| Area under the plasma concentration-time curve from 0 to time t [AUC(0-t)] of ACT-132577 | AUC(0-t) of the active metabolite of macitentan, ACT-132577, is calculated from the concentration-time profile of ACT-132577 from time 0 to time t of the last measured concentration above the limit of quantification | Blood samples for pharmacokinetic evaluations are collected at selected time points from Baseline (pre-dose) to 216 hours post-dose of each study period | 
| Area under the plasma concentration-time curve to infinity [AUC(0-inf)] of ACT-132577 | AUC(0-inf) of the active metabolite of macitentan, ACT-132577, is calculated from the concentration-time profile of ACT-132577 from time 0 to extrapolated infinite time | Blood samples for pharmacokinetic evaluations are collected at selected time points from Baseline (pre-dose) to 216 hours post-dose of each study period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bioequivalence