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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Macitentan 10 mg; Drug: Tadalafil 20 mg; Drug: Macitentan 10 mg/Tadalafil 20mg FDC

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84124
      • PRAHS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Sequence ABC; 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; Macitentan 10mg tablet will be administered orally as per assigned treatment sequence.; Other Names: Opsumit; JNJ-67896062; Drug: Tadalafil 20 mg; Tadalafil 20mg tablet will be administered orally as per assigned treatment sequence.; Other Names: Adcirca; JNJ-10291697; Drug: Macitentan 10 mg/Tadalafil 20mg FDC; FDC of Macitentan 10 mg/Tadalafil 20 mg will be administered orally as single dose tablets.; Other Names: ACT-064992D
Experimental: Treatment Sequence BCA; 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; Macitentan 10mg tablet will be administered orally as per assigned treatment sequence.; Other Names: Opsumit; JNJ-67896062; Drug: Tadalafil 20 mg; Tadalafil 20mg tablet will be administered orally as per assigned treatment sequence.; Other Names: Adcirca; JNJ-10291697; Drug: Macitentan 10 mg/Tadalafil 20mg FDC; FDC of Macitentan 10 mg/Tadalafil 20 mg will be administered orally as single dose tablets.; Other Names: ACT-064992D
Experimental: Treatment Sequence CAB; 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; Macitentan 10mg tablet will be administered orally as per assigned treatment sequence.; Other Names: Opsumit; JNJ-67896062; Drug: Tadalafil 20 mg; Tadalafil 20mg tablet will be administered orally as per assigned treatment sequence.; Other Names: Adcirca; JNJ-10291697; Drug: Macitentan 10 mg/Tadalafil 20mg FDC; FDC of Macitentan 10 mg/Tadalafil 20 mg will be administered orally as single dose tablets.; Other Names: ACT-064992D
Experimental: Treatment Sequence ACB; 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; Macitentan 10mg tablet will be administered orally as per assigned treatment sequence.; Other Names: Opsumit; JNJ-67896062; Drug: Tadalafil 20 mg; Tadalafil 20mg tablet will be administered orally as per assigned treatment sequence.; Other Names: Adcirca; JNJ-10291697; Drug: Macitentan 10 mg/Tadalafil 20mg FDC; FDC of Macitentan 10 mg/Tadalafil 20 mg will be administered orally as single dose tablets.; Other Names: ACT-064992D
Experimental: Treatment Sequence CBA; 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; Macitentan 10mg tablet will be administered orally as per assigned treatment sequence.; Other Names: Opsumit; JNJ-67896062; Drug: Tadalafil 20 mg; Tadalafil 20mg tablet will be administered orally as per assigned treatment sequence.; Other Names: Adcirca; JNJ-10291697; Drug: Macitentan 10 mg/Tadalafil 20mg FDC; FDC of Macitentan 10 mg/Tadalafil 20 mg will be administered orally as single dose tablets.; Other Names: ACT-064992D
Experimental: Treatment Sequence BAC; 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; Macitentan 10mg tablet will be administered orally as per assigned treatment sequence.; Other Names: Opsumit; JNJ-67896062; Drug: Tadalafil 20 mg; Tadalafil 20mg tablet will be administered orally as per assigned treatment sequence.; Other Names: Adcirca; JNJ-10291697; Drug: Macitentan 10 mg/Tadalafil 20mg FDC; FDC of Macitentan 10 mg/Tadalafil 20 mg will be administered orally as single dose tablets.; Other Names: ACT-064992D

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Actelion

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2022
• Primary Completion (Actual): May 13, 2022
• Study Completion (Actual): May 14, 2022

Study Registration Dates

• First Submitted: February 2, 2022
• First Submitted That Met QC Criteria: February 2, 2022
• First Posted (Actual): February 11, 2022

Study Record Updates

• Last Update Posted (Actual): May 25, 2022
• Last Update Submitted That Met QC Criteria: May 24, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Endothelin Receptor Antagonists; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Tadalafil; Macitentan
• Other Study ID Numbers: CR109140; 67896062PAH1002 (Other Identifier: Actelion)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No