A 2-part Study to Investigate the Effect of Macitentan in Healthy Male Participants

A Single-center, Open-label, Single-sequence, 2-part Study to Investigate the Effect of 75 mg Macitentan Once Daily at Steady State on the Pharmacokinetics of Riociguat, Sildenafil, Rosuvastatin and Tadalafil in Healthy Male Subjects

The purpose of this study is to evaluate the effect of macitentan at steady state on the pharmacokinetic (PK) of a single dose of riociguat and sildenafil (Part A); and rosuvastatin (Part B) when co-administered to healthy male participants under fasted conditions.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Macitentan; Drug: Sildenafil; Drug: Riociguat; Drug: Rosuvastatin

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Male (according to their reproductive organs and functions assigned by chromosomal complement)
• Healthy on the basis of physical examination, medical history, and 12 lead electrocardiogram (ECG) performed at screening. This determination must be recorded in the participant's source documents and initialed by the investigator
• Body mass index (BMI; weight per height^2) between 18.0 and 30.0 kilogram (kg)/meter square (m^2) (inclusive), and body weight not less than 50.0 kg at screening and on Day -5
• Blood pressure (after the participant is supine for 5 minutes) between 100 and 140 millimeters of mercury (mmHg) systolic blood pressure (SBP), inclusive, and between 60 and 90 mmHg Diastolic blood pressure (DBP), inclusive, at screening and on Day -5. If blood pressure is out of range, up to 2 repeated assessments are permitted
• Heart rate between 45 and 90 beats per minute (bpm, inclusive) at screening and on Day -5

Exclusion Criteria:

• History of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin and carcinoma in situ of the cervix, or malignancy, which is considered cured with minimal risk of recurrence)
• Use of any prescription or nonprescription medication (including vitamins and herbal supplements), except for paracetamol (acetaminophen) within 14 days before the first dose of the study drug is scheduled until completion of the study
• A participant who has been on a known cytochrome P450 (CYP) inhibitor or inducer or transport inhibitor or inducer should be excluded from the study based upon the duration of the inhibitor or inductive effect and also at least 5 terminal half-lives of the drug, vitamin or herbal supplements
• Orthostatic hypotension (greater than [>] 20 mmHg decrease in SBP or >10 mmHg decrease in DBP after 2 minutes of standing compared to supine blood pressure)
• One or more of the following lab abnormalities at screening, defined as grade 1 or more by the World Health Organisation (WHO) Toxicity Grading Scale for Determining the Severity of Adverse Events, February 2003: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than or equal to (>=) 1.25 * upper limit of normal (ULN), total bilirubin >=1.25 * ULN, and Hemoglobin less than or equal to (<=) 10.5 gram per deciliter (g/dL)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: Macitentan + Substrate Drug (Sildenafil/Riociguat); Participants will receive a single dose of film-coated tablet of sildenafil under fasted condition (Treatment A1), then riociguat under fasted condition (Treatment A2) followed by macitentan under fed condition (Treatment B1), then riociguat along with macitentan under fasted conditions followed by macitentan under fed conditions (Treatment B2) and then sildenafil along with macitentan under fasted condition (Treatment B3). Macitentan will be administered in an up-titration regimen.	Drug: Macitentan; Macitentan will be administrated as film-coated tablet in Part A and Part B.; Other Names: JNJ-67896062-AAA; Drug: Sildenafil; Sildenafil will be administrated as film-coated tablet in Part A.; Other Names: Revatio; Drug: Riociguat; Riociguat will be administrated as film-coated tablet in Part A.; Other Names: Adempas
Experimental: Part B: Macitentan + Substrate Drug (Rosuvastatin); Participants will receive a single dose of film-coated tablet of rosuvastatin under fasted condition (Treatment A1), then macitentan under fed condition (Treatment B1) followed by rosuvastatin along with macitentan under fasted condition followed by macitentan under fed condition (Treatment B2). Macitentan will be administered in an up-titration regimen. Part B of the study will be conducted depending on the results of Part A and feedback from Health Authorities.	Drug: Macitentan; Macitentan will be administrated as film-coated tablet in Part A and Part B.; Other Names: JNJ-67896062-AAA; Drug: Rosuvastatin; Rosuvastatin will be administrated as film-coated tablet in Part B.; Other Names: Crestor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A and Part B: Area Under the Plasma Analyte Concentration-time Curve from Time Zero to Infinite Time (AUC[0-infinity]) of Sildenafil, Riociguat, Rosuvastatin	AUC(0-infinity) is defined as area under the plasma analyte concentration-time curve from time 0 to infinite time.	Up to 25 days
Part A and Part B: Maximum Observed Plasma Analyte Concentration (Cmax) of Sildenafil, Riociguat, Rosuvastatin	Cmax is defined as the maximum observed plasma analyte concentration.	Up to 25 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Area Under the Plasma Analyte Concentration-time Curve from Time Zero to Infinite Time (AUC[0-infinity]) of Desmethyl-sildenafil, M1 (Metabolite of Riociguat) and ACT-132577 (Metabolite of Macitentan)	AUC(0-infinity) is defined as area under the plasma analyte concentration-time curve from time 0 to infinite time.	Up to 25 days
Part A: Maximum Observed Plasma Analyte Concentration (Cmax) of Desmethyl-sildenafil, M1 and ACT-132577	Cmax is defined as the maximum observed plasma analyte concentration.	Up to 25 days
Part A and Part B: Area Under the Plasma Analyte Concentration-time Curve from 0 to Time t of the Last Measured Concentration (AUC[0-t]) of Sildenafil, Desmethyl-sildenafil, Riociguat, M1, Macitentan, ACT-132577, Rosuvastatin	AUC(0-t) is defined as area under the plasma analyte concentration-time curve from time 0 to time t of the last measured concentration above the lower limit of quantification (LLOQ), calculated according to the linear trapezoidal rule, using the measured concentration-time values above the LLOQ.	Up to 25 days
Part A and Part B: Time to Reach Maximum Observed Plasma Analyte Concentration (Tmax) of Sildenafil, Desmethyl-sildenafil, Riociguat, M1, Macitentan, ACT-132577, Rosuvastatin	Tmax is defined as actual sampling time to reach maximum observed plasma analyte concentration.	Up to 25 days
Part A and Part B: Apparent Elimination Half-life (t1/2) of Sildenafil, Desmethyl-sildenafil, Riociguat, M1, Macitentan, ACT-132577, Rosuvastatin	t1/2 is defined as the time measured for the plasma concentration to decrease by 1 half of its original concentration. It is associated with the terminal slope of the semilogarithmic drug concentration-time curve, calculated as t1/2=0.693/ lambda(z).	Up to 25 days
Part A and Part B: Trough Plasma Concentration (Ctrough) of Macitentan and ACT-132577	Ctrough is defined as the observed plasma concentration before dosing or at the end of the dosing interval.	Up to 25 days
Part B: Number of Participants with Adverse Event as a Measure of Safety and Tolerability	An adverse event 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 Day 45

Collaborators and Investigators

• Sponsor: Actelion

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2020
• Primary Completion (Actual): April 19, 2021
• Study Completion (Actual): April 19, 2021

Study Registration Dates

• First Submitted: December 23, 2019
• First Submitted That Met QC Criteria: December 23, 2019
• First Posted (Actual): December 26, 2019

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; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Enzyme Activators; Endothelin Receptor Antagonists; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Rosuvastatin Calcium; Sildenafil Citrate; Macitentan; Riociguat
• Other Study ID Numbers: CR108727; 2019-004001-27 (EudraCT Number); 67896062PAH1003 (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: No
• Studies a U.S. FDA-regulated device product: No