A Study of Fixed Dose Combination of Macitentan/Tadalafil (10 mg/20 mg) Compared to the Reference Free Combination of Macitentan and Tadalafil in Healthy Adult Participants

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate bioequivalence on the primary pharmacokinetic (PK) parameters between macitentan and tadalafil administered as a fixed dose combination (FDC) (test) of macitentan/tadalafil and the co- administered free combination (reference) of macitentan (Opsumit) and tadalafil (Adcirca) in fasted conditions in healthy adult participants; and to evaluate the effect of food on the primary PK parameters of macitentan and tadalafil administered as an FDC of macitentan/tadalafil in fed versus fasted 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 Bioequivalence of the Combination of Macitentan/Tadalafil (10 mg/20 mg) Administered as a Fixed Dose Combination Formulation Compared to the Reference Free Combination of 10 mg Macitentan (Opsumit®) and 20 mg Tadalafil (Adcirca®) as Well as the Food Effect of the Fixed-dose Combination Formulation

Conditions
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Healthy

Intervention / Treatment
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* Drug: Macitentan 10 mg
* Drug: Tadalafil 20 mg
* Drug: Macitentan 10 mg/Tadalafil 20mg FDC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy on the basis of physical examination and medical history, performed at screening. If there are any abnormalities, they must be considered not clinically relevant and 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 (mm Hg) (inclusive), diastolic blood pressure (DBP) between 50 and 90 mm Hg (inclusive), and pulse rate between 45 and 90 beats per minute (inclusive) at screening, supine for at least 5 minutes and after 3 minutes of standing 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 A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for a period of 30 days after the last study intervention intake Willing and able to adhere to the lifestyle restrictions specified in this protocol Exclusion Criteria: Known allergies, hypersensitivity, or intolerance to macitentan, tadalafil, or drug of the same class, or its excipients 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) Veins unsuitable for intravenous puncture on either arm (example, veins that are difficult to locate, access, or puncture, and veins with a tendency to rupture during or after puncture) Known hereditary degenerative retinal disorders, including retinitis pigmentosa

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 fixed dose combination (FDC) of macitentan/tadalafil under fasting conditions in (test) (Treatment A) Treatment Period 1 followed by single oral dose of FDC of macitentan/tadalafil under fed conditions (test) (Treatment B) in Treatment Period 2 and then single oral dose of macitentan/tadalafil under fasting conditions (reference) (Treatment C) in Treatment Period 3 on Day 1 of each Treatment Period. There will be a wash-out period of at least 12 days between Day 1 of subsequent treatment period. | Drug: Macitentan 10 mg<br>* Macitentan 10mg tablet will be administered orally as per assigned treatment sequence.<br>* Other names: JNJ-67896062;Drug: Tadalafil 20 mg<br>* Tadalafil 20mg tablet will be administered orally as per assigned treatment sequence.<br>* Other names: JNJ-10291697;Drug: Macitentan 10 mg/Tadalafil 20mg FDC<br>* FDC of Macitentan 10 mg/Tadalafil 20 mg will be administered orally as single dose tablets.<br>* Other names: ACT-064992D;|
| Experimental: Treatment Sequence BCA<br>Participants will receive Treatment B in Treatment Period 1 followed by Treatment C in Treatment Period 2 and Treatment A in Treatment Period 3. There will be a wash-out period of at least 12 days between Day 1 of subsequent treatment period. | Drug: Macitentan 10 mg<br>* Macitentan 10mg tablet will be administered orally as per assigned treatment sequence.<br>* Other names: JNJ-67896062;Drug: Tadalafil 20 mg<br>* Tadalafil 20mg tablet will be administered orally as per assigned treatment sequence.<br>* Other names: JNJ-10291697;Drug: Macitentan 10 mg/Tadalafil 20mg FDC<br>* FDC of Macitentan 10 mg/Tadalafil 20 mg will be administered orally as single dose tablets.<br>* Other names: ACT-064992D;|
| Experimental: Treatment Sequence CAB<br>Participants will receive Treatment C in Treatment Period 1 followed by Treatment A in Treatment Period 2 and Treatment B in Treatment Period 3. There will be a wash-out period of at least 12 days between Day 1 of subsequent treatment period. | Drug: Macitentan 10 mg<br>* Macitentan 10mg tablet will be administered orally as per assigned treatment sequence.<br>* Other names: JNJ-67896062;Drug: Tadalafil 20 mg<br>* Tadalafil 20mg tablet will be administered orally as per assigned treatment sequence.<br>* Other names: JNJ-10291697;Drug: Macitentan 10 mg/Tadalafil 20mg FDC<br>* FDC of Macitentan 10 mg/Tadalafil 20 mg will be administered orally as single dose tablets.<br>* Other names: ACT-064992D;|
| Experimental: Treatment Sequence ACB<br>Participants will receive Treatment A in Treatment Period 1 followed by Treatment C in Treatment Period 2 and Treatment B in Treatment Period 3. There will be a wash-out period of at least 12 days between Day 1 of subsequent treatment period. | Drug: Macitentan 10 mg<br>* Macitentan 10mg tablet will be administered orally as per assigned treatment sequence.<br>* Other names: JNJ-67896062;Drug: Tadalafil 20 mg<br>* Tadalafil 20mg tablet will be administered orally as per assigned treatment sequence.<br>* Other names: JNJ-10291697;Drug: Macitentan 10 mg/Tadalafil 20mg FDC<br>* FDC of Macitentan 10 mg/Tadalafil 20 mg will be administered orally as single dose tablets.<br>* Other names: ACT-064992D;|
| Experimental: Treatment Sequence CBA<br>Participants will receive Treatment C in Treatment Period 1 followed by Treatment B in Treatment Period 2 and Treatment A in Treatment Period 3. There will be a wash-out period of at least 12 days between Day 1 of subsequent treatment period. | Drug: Macitentan 10 mg<br>* Macitentan 10mg tablet will be administered orally as per assigned treatment sequence.<br>* Other names: JNJ-67896062;Drug: Tadalafil 20 mg<br>* Tadalafil 20mg tablet will be administered orally as per assigned treatment sequence.<br>* Other names: JNJ-10291697;Drug: Macitentan 10 mg/Tadalafil 20mg FDC<br>* FDC of Macitentan 10 mg/Tadalafil 20 mg will be administered orally as single dose tablets.<br>* Other names: ACT-064992D;|
| Experimental: Treatment Sequence BAC<br>Participants will receive Treatment B in Treatment Period 1 followed by Treatment A in Treatment Period 2 and Treatment C in Treatment Period 3. There will be a wash-out period of at least 12 days between Day 1 of subsequent treatment period. | Drug: Macitentan 10 mg<br>* Macitentan 10mg tablet will be administered orally as per assigned treatment sequence.<br>* Other names: JNJ-67896062;Drug: Tadalafil 20 mg<br>* Tadalafil 20mg tablet will be administered orally as per assigned treatment sequence.<br>* Other names: JNJ-10291697;Drug: Macitentan 10 mg/Tadalafil 20mg FDC<br>* FDC of Macitentan 10 mg/Tadalafil 20 mg will be administered orally as single dose tablets.<br>* Other names: ACT-064992D;|

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 and its Metabolite JNJ-68212820, and Tadalafil. | Cmax is defined as the maximum observed plasma analyte concentration. | Predose up to 216 hours (up to Day 10) | 
| Area Under the Plasma Analyte Concentration Time Curve of Macitentan, its Metabolite JNJ-68212820, and Tadalafil from Time Zero to Time of the Last Quantifiable Concentration (AUC [0-Last]) | AUC (0-last) is defined as area under the plasma analyte concentration time curve of macitentan, its metabolite JNJ-68212820 and tadalafil from time 0 to the time of the last quantifiable (non-below quantification limit [non-BQL]) concentrations. | Predose up to 216 hours (up to Day 10) | 
| Area Under the Plasma Concentration Time Curve of Macitentan and its Metabolite JNJ-68212820, and Tadalafil from Time Zero to Infinite time (AUC [0-Infinity]) | AUC (0-infinity) is defined as area under the plasma concentration-time curve of macitentan and its metabolite JNJ-68212820, and tadalafil from time 0 to infinite time, calculated as the sum of AUC (0-last) and C(last)/lambda(z) where C(last) is the last observed measurable (non-BQL) plasma analyte concentration. | Predose up to 216 hours (up to Day 10) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach Maximum Observed Plasma Analyte Concentration (Tmax) of Macitentan and its Metabolite JNJ-68212820, Tadalafil | Tmax is defined as actual sampling time to reach the maximum observed plasma analyte concentration. | Predose up to 216 hours (up to Day 10) | 
| Area Under the Plasma Concentration Versus Time Curve of Macitentan and its Metabolite JNJ-68212820, Tadalafil From Time Zero up to 72 Hours Post Dosing (AUC72h) | (AUC 0-72h) is defined as the area under the plasma concentration-time curve of macitentan and its metabolite JNJ-68212820, tadalafil from time 0 to 72 hours postdose, calculated by linear-linear trapezoidal summation. | Predose up to 216 hours (up to Day 10) | 
| Apparent Elimination Half-Life (t1/2) of Macitentan and its Metabolite JNJ-68212820, Tadalafil | t1/2 is defined as apparent elimination half-life calculated as 0.693/lambda(z). | Predose up to 216 hours (up to Day 10) | 
| Apparent Terminal Elimination Rate Constant (lambda z) of Macitentan and its Metabolite JNJ-68212820, Tadalafil | Apparent terminal elimination rate constant is estimated by linear regression using the terminal log-linear phase of the log-transformed concentration versus time curve. | Predose up to 216 hours (up to Day 10) | 
| Total Apparent Oral Clearance (CL/F) of Macitentan and its Metabolite JNJ-68212820, Tadalafil | CL/F is defined as total apparent oral clearance calculated as dose/AUC(0-infinity). | Predose up to 216 hours (up to Day 10) | 
| Apparent Volume of Distribution (Vd/F) of Macitentan and its Metabolite JNJ-68212820, Tadalafil | Vd/F is defined as apparent volume of distribution calculated as dose/(lambda(z) *AUC (0 to infinity). | Predose up to 216 hours (up to Day 10) | 
| Last Observed Measurable Plasma Concentration (Clast) of Macitentan and its Metabolite JNJ-68212820, Tadalafil | Clast is defined as the last observed measurable (non-BQL) plasma concentration of macitentan and its metabolite JNJ-68212820, Tadalafil. | Predose up to 216 hours (up to Day 10) |