A Study of Macitentan/Tadalafil Combination Administered a Fixed-dose Combination Formulation Compared to the Reference Free Combination of Macitentan and Tadalafil

A Single-center, Open-label, Single-dose, Randomized, 2-way Crossover Phase 1 Study in Healthy Adult Participants to Assess the Relative Oral Bioavailability of the Combination of Macitentan/Tadalafil (10 mg/20 mg) Administered a Fixed-dose Combination Formulation Compared to the Reference Free Combination of 10 mg Macitentan (Opsumit®) and 20 mg Tadalafil (Adcirca®)

The purpose of this study is to assess the rate and extent of absorption of macitentan and tadalafil following administration of a single oral dose of a fixed-dose combination (FDC) of 10 milligram (mg)/20 mg macitentan/tadalafil (test), compared to the coadministration as a free combination (reference) of 10 mg macitentan and 20 mg tadalafil under fasted conditions in healthy adult participants.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: FDC of macitentan/tadalafil (10 mg/20 mg); Drug: Macitentan 10 mg; Drug: Tadalafil 20 mg

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Merksem, Belgium, 2170
    • Clinical Pharmacology Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Must sign an informed consent form (ICF) indicating they understand the purpose of, and procedures required for, the study and are willing to participate in the study, before starting any screening activities
• Body mass index (BMI; weight [kg]/height^2 [m]^2) between 18.5 and 30.0 kilogram per meter square (kg/m^2) inclusive, and body weight not less than 50.0 kg at screening
• Healthy on the basis of physical examination, 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 millimeter of Mercury (mmHg) (inclusive) and diastolic blood pressure (DBP) between 50 and 90 mmHg (inclusive) at screening, preferably measured on the right arm, supine after 5 minutes of rest and standing after 3 minutes
• Twelve-lead electrocardiogram (ECG) with heart rate between 45 and 90 beats per minute (bpm) and without clinically relevant abnormalities, at the discretion of the investigator, measured after the participant is supine for at least 5 minutes, at screening
• During the study (from the day of first study drug intake onwards) and for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after the last study drug intake, a male participant must agree: (a) to wear a condom when engaging in any activity that allows for passage of ejaculate to another person (male participant should also be advised of the benefit for a female partner to use a highly effective method of contraception as condom may break or leak); (b) not to donate sperm for the purpose of reproduction.

Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for participants participating in clinical studies

Exclusion Criteria:

• Female participant who is breastfeeding at screening and/or plans to breastfeed throughout the study until 30 days after last study drug intake
• Known allergies, hypersensitivity, or intolerance to any active substance or drugs of the same class, or any excipient of the drug formulation(s)
• Values of hepatic aminotransferase (alanine aminotransferase and/or aspartate aminotransferase) greater than (>)1.5 * upper limit of normal at screening
• Any loss of vision (permanent or transient blindness in 1 or both eyes, including ophthalmic migraine, transient ischemic attack, retinal artery/vein thrombosis)
• Known hereditary degenerative retinal disorders, including retinitis pigmentosa

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Sequence AB; Participants will receive a single oral dose of fixed dose combination (FDC) of macitentan/tadalafil (10 milligram [mg]/20 mg) in fasted conditions (test) (Treatment A) in treatment period 1 followed by a single oral dose of a free combination of 10 mg macitentan and 20 mg tadalafil in fasted conditions (reference) (Treatment B) in treatment period 2 on Day 1. Study drug intake in subsequent treatment periods in an individual participant will be separated by a washout period of at least 10 days.	Drug: FDC of macitentan/tadalafil (10 mg/20 mg); FDC of macitentan/tadalafil (10 mg/20 mg) tablet will be administered orally as per assigned treatment sequence.; Other Names: Opsumit; Adcirca; Drug: Macitentan 10 mg; Macitentan 10 mg tablet will be administered orally as a free combination as per assigned treatment sequence.; Other Names: Opsumit; Drug: Tadalafil 20 mg; Tadalafil 20 mg tablet will be administered orally as a free combination as per assigned treatment sequence.; Other Names: Adcirca
Experimental: Treatment Sequence BA; Participants will receive Treatment B in treatment period 1 followed by Treatment A in treatment period 2 on Day 1. Study drug intake in subsequent treatment periods in an individual participant will be separated by a washout period of at least 10 days.	Drug: FDC of macitentan/tadalafil (10 mg/20 mg); FDC of macitentan/tadalafil (10 mg/20 mg) tablet will be administered orally as per assigned treatment sequence.; Other Names: Opsumit; Adcirca; Drug: Macitentan 10 mg; Macitentan 10 mg tablet will be administered orally as a free combination as per assigned treatment sequence.; Other Names: Opsumit; Drug: Tadalafil 20 mg; Tadalafil 20 mg tablet will be administered orally as a free combination as per assigned treatment sequence.; Other Names: Adcirca

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Analyte Concentration (Cmax) of Macitentan, its Metabolite ACT-132577, and Tadalafil	Cmax is defined as maximum observed plasma analyte concentration.	Predose and up to 216 hours post dose (Up to Day 10)
Area Under the Concentration-time Curve from Time Zero to the Last Quantifiable Concentration (AUC [0-last]) of Macitentan, its Metabolite ACT-132577, and Tadalafil	AUC(0-last) is the area under the plasma analyte concentration-time curve from time zero to time of the last quantifiable (non-below quantification limit [non-BQL]) concentration, calculated by linear-linear trapezoidal summation.	Predose and up to 216 hours post dose (Up to Day 10)
Area Under the Concentration-time Curve from Time Zero to Infinity (AUC [0-infinity]) of Macitentan, its Metabolite ACT-132577, and Tadalafil	AUC (0-infinity) is the area under the analyte concentration-time curve (AUC) from time zero to infinite time, calculated as the sum of AUC (0-last) and C(last)/lambda(z); wherein AUC (0-last) is area under the plasma concentration-time curve from time zero to last measurable concentration, C(last) is the last observed measurable (non-BQL) analyte concentration; and lambda(z) is apparent terminal elimination rate constant.	Predose and up to 216 hours post dose (Up to Day 10)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Adverse Events as a Measure of Safety and Tolerability	An AE is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.	Up to 8 weeks

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2021
• Primary Completion (Actual): August 8, 2021
• Study Completion (Actual): August 30, 2021

Study Registration Dates

• First Submitted: September 2, 2020
• First Submitted That Met QC Criteria: September 2, 2020
• First Posted (Actual): September 7, 2020

Study Record Updates

• Last Update Posted (Actual): September 14, 2022
• Last Update Submitted That Met QC Criteria: September 13, 2022
• Last Verified: September 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: CR108794; 2020-000566-42 (EudraCT Number); 67896062PAH1001 (Other Identifier: Janssen Research & Development, LLC)

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
• product manufactured in and exported from the U.S.: Yes