A Study to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/Recurrent Chronic Thromboembolic Pulmonary Hypertension (MACiTEPH)

A Prospective, Randomized, Double-blind, Multicenter, Placebo-controlled, Parallel Group, Adaptive Phase 3 Study With Open-label Extension to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/Recurrent Chronic Thromboembolic Pulmonary Hypertension

The purpose of the study is to evaluate the effect of macitentan 75 mg versus placebo on exercise capacity at Week 28 in participants with chronic thromboembolic pulmonary hypertension (CTEPH).

Study Overview

• Status: Terminated
• Conditions: Chronic Thromboembolic Pulmonary Hypertension
• Intervention / Treatment: Drug: Macitentan; Drug: Placebo

Detailed Description

CTEPH is one of the leading causes of severe pulmonary hypertension (PH), classified within World Health Organization (WHO) group 4 PH. It is a rare, progressive pulmonary vascular disease that if left untreated, leads to progressively increasing pulmonary vascular resistance (PVR) and eventually right ventricle failure and death. Histopathologic findings including endothelial cell dysfunction and distal pulmonary arterial remodeling are shared between PAH and CTEPH, and PH-specific therapies (that is, riociguat) have shown efficacy in inoperable and persistent/recurrent CTEPH. The endothelin receptor antagonist macitentan offers a different mode of action and addresses an important unmet medical need for an alternative treatment option in this indication. This study will assess the effect of macitentan 75 mg on exercise capacity in CTEPH. The total duration of the study is approximately 6 years. The study comprises of a screening period (at least 14 days and up to 60 days), a double-blind (DB) treatment period (28 weeks [minimum duration] up to 3.5 years), an open-label (OL) extension period (starts at end-of-DB-treatment [EODBT] and will end for all participants 104 weeks after the last participant has completed DB Week 28). The DB period consists of an 8-week up-titration phase and a maintenance phase. The maintenance phase is divided into a 28-week fixed duration part, at the end of which primary endpoint is assessed, and a variable duration part. The duration of the DB period for an individual participant depends on the timepoint of entry into the study and whether a CEC-confirmed clinical worsening event occurred. Participants who discontinue DB study intervention during the 28-week fixed duration part will be followed until Week 28 in a post-treatment observation period (PTOP).

• Study Type: Interventional
• Enrollment (Actual): 127
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1039AAO
    • Sanatorio de la Trinidad Mitre
  • C.a.b.a., Argentina, C1180AAX
    • Sanatorio Güemes
  • Ciudad Autonoma de Buenos Aires, Argentina, C1006ACC
    • Nexo Salud Investigacion Clinica
• Australia
  • Chermside, Australia, 4032
    • Queensland Lung Transplant Service
  • Darlinghurst, Australia, 2010
    • St Vincent's Hospital
• Austria
  • Graz, Austria, 8036
    • Lkh-Univ. Klinikum Graz
  • Linz, Austria, 4020
    • Ordensklinikum Linz GmbH Elisabethinen
  • Vienna, Austria, 1090
    • Medizinische Universitaet Wien
• Bulgaria
  • Sofia, Bulgaria, 1606
    • Military Medical Academy
  • Sofia, Bulgaria, 1750
    • University Multiprofile Hospital for Active Treatment- UMHAT Sveta Anna AD
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y 6J4
      • University of Calgary - Peter Lougheed Centre
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
  • Ontario
    • Toronto, Ontario, Canada, M5G 2N2
      • University Health Network - Toronto General Hospital
• China
  • Beijing, China, 100029
    • Beijing Anzhen Hospital
  • Beijing, China, 100038
    • Beijing Shijitan Hospital
  • Beijing, China, 100020
    • Beijing Chaoyang Hospital
  • Beijing, China, 100029
    • China Japan Friendship Hospital
  • Chongqing, China, 400016
    • The First Affiliated Hospital of Chongqing Medical University
  • Guangzhou, China, 510140
    • The First Affiliated Hospital of Guangzhou Medical University
  • Hangzhou, China, 310016
    • Sir Run Run Shaw Hospital Zhejiang University School of Medicine
  • Nanjing, China, 210009
    • Zhongda Hospital Southeast University
  • Qingdao, China, 266003
    • The Affiliated Hospital of Medical College Qingdao University
  • Shanghai, China, 200433
    • Shanghai Pulmonary Hospital
  • Shanghai, China
    • Zhongshan Hospital Fudan University
  • Shanghai, China, 200040
    • Huashan Hospital of Fudan University
  • Shenyang, China, 110000
    • The General Hospital of Northern Theater Command
  • Tian Jin, China, 300052
    • Tianjin Medical University General Hospital
  • Xi'An, China, 710061
    • The First Affiliated Hospital of Xian Jiaotong University
• Colombia
  • Bogota, Colombia, 1101131
    • Fundación Neumologica Colombiana
  • Bogota, Colombia, 85369
    • Fundación Abood Shaio
  • Cali, Colombia, 760042
    • Clínica Imbanaco S.A.S.
  • Medellin, Colombia, 681004
    • Centro Cardiovascular Colombiano Clínica Santa María
• Czechia
  • Praha 2, Czechia, 128 08
    • General University Hospital II.department of Internal Medicine-cardiology and angiology
• Denmark
  • Aarhus N, Denmark, 8200
    • Århus Universitetshospital, Skejby, Hjertemedicinsk Afdeling B
• France
  • Brest, France, 29200
    • CHU de Brest - Hopital de la Cavale Blanche
  • Grenoble Cedex 9, France, 38043
    • CHU de Grenoble Hopital Albert Michallon
  • Le Kremlin-Bicetre Cedex, France, 94275
    • Hopital Bicetre Aphp Hopitaux Universitaires Paris Sud
  • Lille Cedex, France, 59037
    • Hôpital Cardiologique - Chru Lille
  • Montpellier, France, 34295
    • CHU de Montpellier - Arnaud de Villeneuve
  • St Priest en Jarez Cedex, France, 42277
    • CHU Saint Etienne Hopital Nord
  • Toulouse Cedex 9, France
    • Hopital Larrey CHU de Toulouse
  • Vandoeuvre les Nancy Cedex, France, 54511
    • CHU de Nancy - Hopital de Brabois
• Germany
  • Bonn, Germany, 53127
    • Universitätsklinikum Bonn
  • Dresden, Germany, 01307
    • Medizinische Fakultaet Carl Gustav Carus Technische Universitaet Dresden
  • Giessen, Germany, 35392
    • Universitaetsklinikum Giessen
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg Eppendorf
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover Zentrum Innere Medizin Klinik für Pneumologie
  • Heidelberg, Germany, 69126
    • Thoraxklinik Heidelberg
  • Homburg, Germany, 66421
    • Universitaetsklinikum des Saarlandes
  • Jena, Germany, 07747
    • Universitätsklinikum Jena
  • München, Germany, 80639
    • Krankenhaus Neuwittelsbach
• Hungary
  • Budapest, Hungary, 1096
    • Gottsegen Gyorgy Orszagos Kardiovaszkularis Intezet Felnott kardiologiai osztaly
  • Szeged, Hungary, 6720
    • Szegedi Tudományegyetem, Általános Orvostudományi Kar, Családorvosi Intézet és rendelő
• Israel
  • Tel Aviv, Israel, 6423906
    • Tel Aviv Medical Center
  • Tel-Hashomer, Israel, 5265601
    • The Chaim Sheba Medical Center
• Italy
  • Chieti, Italy, 66100
    • Ospedale SS. Annunziata
  • Pavia, Italy, 27100
    • Fondazione IRCCS Policlinico San Matteo
  • Pisa, Italy, 56124
    • Fondazione Toscana Gabriele Monasterio CNR
  • Roma, Italy, 00168
    • Policlinico Gemelli Universita Cattolica
  • Torino, Italy, 10126
    • A.O.U. Città della Salute e della Scienza
• Japan
  • Bunkyo, Japan, 113-8655
    • The University of Tokyo Hospital
  • Fukuoka, Japan, 812 8582
    • Kyushu University Hospital
  • Hiroshima, Japan, 737-8505
    • Kure Kyosai Hospital
  • Kanagawa, Japan, 216 8511
    • St Marianna University Hospital
  • Kobe, Japan, 650 0017
    • Kobe University Hospital
  • Kyoto, Japan, 602-8566
    • University Hospital Kyoto Prefectural University of Medicine
  • Kyoto, Japan, 606 8507
    • Kyoto University Hospital
  • Matsumoto, Japan, 390 8621
    • Shinshu University Hospital
  • Meguro-ku, Japan, 153-8515
    • Toho University Medical Center, Ohashi Hospital
  • Mitaka, Japan, 181-8611
    • Kyorin University Hospital
  • Nagoya, Japan, 466 8560
    • Nagoya University Hospital
  • Okayama, Japan, 701-1192
    • National Hospital Organization Okayama Medical Center
  • Sapporo-shi, Japan, 060-8648
    • Hokkaido University Hospital
  • Suita-Shi, Japan, 564-8565
    • National Cerebral and Cardiovascular Center
  • Tokyo, Japan, 113-8431
    • Juntendo University Hospital
  • Tsukuba City, Japan, 305 8576
    • University of Tsukuba Hospital
• Korea, Republic of
  • Busan, Korea, Republic of, 49241
    • Pusan National University Hospital
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 06591
    • The Catholic University of Korea Seoul St Marys Hospital
• Lithuania
  • Kaunas, Lithuania, 50161
    • Lietuvos sveikatos mokslu universiteto ligonine Kauno klinik
  • Vilnius, Lithuania, LT-08661
    • Vilnius University Hospital Santariskiu Klinikos
• Mexico
  • Ciudad De México, Mexico, 14080
    • Instituto Nacional de Cardiologia Dr. Ignacio Chavez
  • Mexico, Mexico, 52787
    • Operadora de Hospitales Angeles SA de CV Hospital Angeles Lomas
  • Monterrey, Mexico, 64718
    • Unidad de Investigacion Clinica en Medicina S.C. (UDICEM)
  • Morelia, Mexico, 58260
    • Centro de Investigacion Clinica Chapultepec
  • Nuevo Leon, Mexico, 64060
    • CRI Centro Regiomontano de Investigacion SC
• Poland
  • Krakow, Poland, 31 202
    • Krakowski Szpital Specjalistyczny im Jana Pawla II
  • Lublin, Poland, 20 708
    • Wojewodzki Szpital Specjalistyczny im Stefana Kardynala Wyszynskiego PZOZ
  • Otwock, Poland, 05 400
    • Europejskie Centrum Zdrowia Otwock Sp z o o
• Portugal
  • Almada, Portugal, 2805 267
    • Uls Almada Seixal - Hosp. Garcia de Orta
• Romania
  • Bucuresti, Romania, 022328
    • Institutul de urgenta pentru Boli Cardiovasculare Prof. Dr. C.C. Iliescu
  • Tg. Mures, Romania, 540136
    • Spitalul Clinic Județean de Urgență
• Russian Federation
  • Kazan, Russian Federation, 420101
    • State Autonomous HealthCare Institution 'Interregional Clinical Diagnostic Center'
  • Moscow, Russian Federation, 121552
    • National Medical Research Center of Cardiology of MoH of Russian Federation
  • Moscow, Russian Federation, 121309
    • Moscow City Clinical Hospital No.51
  • Saint-Petersburg, Russian Federation, 197341
    • National medical Research Center n.a. V.A.Almazov of MoH of Russian Federation
  • Volgograd, Russian Federation, 400008
    • Volgograd Regional Clinical Cardiology Center
• Saudi Arabia
  • Riyadh, Saudi Arabia, 12713
    • King Faisal Specialist Hospital & Research Center
  • Riyadh, Saudi Arabia, 59046
    • King Fahad Medical City
• Serbia
  • Belgrade, Serbia, 11000
    • University Clinical Center of Serbia
  • Sremska Kamenica, Serbia, 21204
    • Institute for Pulmonary Disease of Vojvodina
• Singapore
  • Singapore, Singapore, 119228
    • National University Heart Centre, Singapore
  • Singapore, Singapore, 169609
    • National Heart Centre (NHC) Singapore
• Slovakia
  • Bratislava, Slovakia, 833 48
    • Narodny ustav srdcovych a cievnych chorob
• Spain
  • Barcelona, Spain, 08036
    • Hosp Clinic de Barcelona
  • Madrid, Spain, 28041
    • Hosp. Univ. 12 de Octubre
  • Madrid, Spain, 28046
    • Hosp. Univ. La Paz
  • Malaga, Spain, 29603
    • Hosp. Costa Del Sol
  • Málaga, Spain, 29010
    • Hosp Virgen de La Victoria
  • Toledo, Spain, 45007
    • Hosp. Gral. Univ. de Toledo
• Taiwan
  • Kaohsiung, Taiwan, 813
    • Kaohsiung Veterans General Hospital
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
  • Taipei, Taiwan, 112
    • Taipei Veterans General Hospital
  • Taoyuan, Taiwan, 333
    • Chang-Gung Memorial Hospital, LinKou Branch
• Thailand
  • Chiang Mai, Thailand, 50200
    • Maharaj Nakorn Chiang Mai Hospital
  • Khon Kaen, Thailand, 40002
    • Srinagarind Hospital, Khon Kaen University
  • Pathumthani, Thailand, 12120
    • Thammasat Hospital
• Turkey
  • Adana, Turkey, 01170
    • Adana City Hospital
  • Adana, Turkey, 01250
    • Cukurova University Medical Faculty
  • Ankara, Turkey, 06230
    • Hacettepe University Medical Faculty
  • Ankara, Turkey, 06800
    • Ankara Bilkent Sehir Hastanesi
  • Denizli, Turkey, 20070
    • Pamukkale University Medical Faculty
  • Eskisehir, Turkey, 26040
    • Eskisehir Osmangazi University Medical Faculty Hospital
  • Istanbul, Turkey, 34096
    • Istanbul University - Cerrahpasa Cardiology Institution
  • Istanbul, Turkey, 34899
    • Marmara University Medical Faculty
  • Istanbul, Turkey, 34668
    • Siyami Ersek Training and Research Hospital
  • Izmir, Turkey, 35100
    • Ege University Medical Faculty
  • Izmir, Turkey, 35340
    • Dokuz Eylul University Medical Faculty
  • Kartal Istanbul, Turkey, 34865
    • Kartal Koşuyolu Yüksek İhtisas Eğitim ve Araştirma Hastanesi
  • Mersin, Turkey, 33110
    • Mersin University Medical Faculty
• Ukraine
  • Cherkasy, Ukraine, 18009
    • CNE 'Cherkasy Regional Cardiological Center of Cherkasy Regional Council'
  • Dnipro, Ukraine, 49059
    • CE 'Dnipropetrovsk Regional Clinical Center of Cardiology and Cardiosurgery'
  • Kyiv, Ukraine, 03680
    • State Institute Of Phthisiology And Pulmonology N.A. F.G. Yanovskiy Of Ams Ukraine
  • Kyiv, Ukraine, 02000
    • SI National Scientific Center Institute of Cardiology of M.D. Strazhesko of NAMS of Ukraine
  • Lviv, Ukraine, 79010
    • Communal Noncommercial Enterprise of Lviv Regional Council 'Lviv Regional Clinical Hospital'
  • Ternopil, Ukraine, 46002
    • Municipal Non-commercial Enterprise Ternopil University Hospital of Ternopil Regional Council
• United Kingdom
  • Cambridge, United Kingdom, CB2 0AY
    • Papworth Hospital NHS Trust
  • Glasgow, United Kingdom, G81 4DY
    • National Waiting Times Centre Board Golden Jubilee National Hospital
  • London, United Kingdom, Nw3 2QG
    • Royal Free Hospital
  • London, United Kingdom, W12 0HS
    • Hammersmith Hospital
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
    • Freeman Hospital
  • Sheffield, United Kingdom, S10 2RX
    • Sheffield Teaching Hospitals NHS Foundation Trust Royal Hallamshire Hospital
• United States
  • California
    • La Jolla, California, United States, 92037
      • University of California San Diego Medical Center
    • Los Angeles, California, United States, 90033
      • Keck School of Medicine of USC
    • Sacramento, California, United States, 95817-2201
      • UC Davis Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anschutz Medical Campus
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale University School of Medicine
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida Health Jacksonville
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Piedmont Healthcare
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Feinberg School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 21118
      • Tufts Medical Center
  • Nebraska
    • Omaha, Nebraska, United States, 68198-2265
      • University of Nebraska Medical Center
  • Nevada
    • Reno, Nevada, United States, 89509
      • VA Sierra Nevada Health Care System
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico School of Medicine
  • New York
    • Syracuse, New York, United States, 13210
      • Syracuse VA Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Oregon
    • Portland, Oregon, United States, 97210
      • Legacy Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Texas
    • Plano, Texas, United States, 75093
      • Baylor Scott White - Plano
  • Utah
    • Murray, Utah, United States, 84107
      • Intermountain Medical Center
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Cardiovascular Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-2442
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Chronic thromboembolic pulmonary hypertension (CTEPH) (World Health Organization [WHO] Group 4) fulfilling one of the following criteria: a) inoperable due to the localization of the obstruction being surgically inaccessible (that is, distal disease), b) persistent/recurrent CTEPH after balloon pulmonary angioplasty (BPA), and deemed inoperable due to the localization of the obstruction being surgically inaccessible (that is, distal disease), c) persistent/recurrent CTEPH after rescue pulmonary endarterectomy (PEA)
• 6-minute walk distance (6MWD) greater than or equal to (>=) 100 meter (m) and less than or equal to (<=) 450 meters (m), documented by an eligibility and a baseline 6-minute walk test (6MWT). The baseline 6MWD must not differ by more than 15 percent (%) from the eligibility test
• World Health Organization functional class (WHO FC) >= II
• Participants are to receive riociguat as per local standard of care, unless it is contraindicated or unavailable

Exclusion Criteria:

• Acute pulmonary embolism within 3 months prior to or during Screening
• Planned balloon pulmonary angioplasty (BPA) during the fixed duration part of the double-blind period
• Significant obstructive and restrictive lung disease
• Acute or chronic conditions (other than dyspnea) that limit the ability to comply with study requirements, in particular with 6MWT (for example, intermittent claudication).
• Symptomatic coronary artery disease requiring an intervention within 3 months prior to or during Screening or anticipated during the fixed duration part of the study
• Decompensated cardiac failure if not under close supervision
• Known and documented life-threatening cardiac arrhythmias
• Acute myocardial infarction within 6 months prior to, or during Screening
• Cerebrovascular events (including transient ischemic attack) within 3 months prior to, or during Screening
• Known or suspicion of pulmonary veno-occlusive disease (PVOD)
• Administration of ERAs, intravenous prostacyclins / prostacyclin analogs, or investigational treatment within 90 days prior to Randomization
• Change in dose or initiation of Phosphodiesterase type-5 (PDE-5) inhibitors, oral, inhaled or subcutaneous (SC) prostacyclins / prostacyclin analogues, prostacyclin receptor agonists or riociguat, a) within 90 days prior to Randomization, or b) anticipated during the fixed duration part of the double-blind [DB] period
• Hypotension, that is, systolic blood pressure (SBP) less than (<) 90 millimeters of mercury (mmHg) or diastolic blood pressure (DBP) <50 mmHg at Screening.
• Severe renal dysfunction with an estimated Glomerular Filtration Rate <30 milliliters per minute per 1.73 meter square (mL/min/1.73 m^2) using the Chronic Kidney Disease Epidemiology Collaboration formula at Screening
• Known moderate to severe hepatic impairment, defined as Child-Pugh Class B or C, based on records that confirm documented medical history
• Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) greater than or equal to (>=) 1.5*upper limit of normal (ULN) at Screening
• Hemoglobin <100 g/L (<10 gram per deciliter [g/dL]) at Screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Macitentan; Participant will receive macitentan at a dose of 10 milligram (mg) once daily (OD) for 4 weeks, followed by a dose of macitentan 37.5 mg for another 4 weeks and continue with the target dose of macitentan 75 mg. Participants who have reached the target dose of 75 mg, completed the Double-blind (DB) period up to Week 28 (either on treatment or in Post-treatment observation period [PTOP]) at minimum, may be eligible for transitioning into the Open label (OL) extension period once all participants have completed the DB part of the study, or earlier if they experienced a Clinical event committee (CEC) confirmed clinical worsening event.	Drug: Macitentan; Participants will receive Macitentan film-coated tablets orally od.; Other Names: Opsumit; ACT-064992,
Experimental: Placebo; Participants will receive placebo tablets matching the macitentan 10 mg, macitentan 37.5mg and macitentan 75 mg tablets, respectively. Participants who completed the DB period as per protocol either on treatment or in PTOP are eligible for transitioning to the OL extension period and will receive macitentan 75 mg after an 8-week double-dummy uptitration (macitentan 10 mg for 4 weeks, followed by 37.5 mg for another 4 weeks).	Drug: Macitentan; Participants will receive Macitentan film-coated tablets orally od.; Other Names: Opsumit; ACT-064992,; Drug: Placebo; Participant will receive matching placebo tablets orally od.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in 6-minute Walk Distance (6MWD) at Week 28	Change from baseline in 6MWD as measured by 6-minute walk test (6MWT) at Week 28 was reported. The purpose of the 6MWT was to quantify exercise tolerance and capacity. This standardized test measured the distance an individual was able to walk over a total of six minutes on a hard, flat surface with no obstacles. The goal was for the individual to walk as far as possible in 6 minutes.	Baseline (Day 1), Week 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to First Clinical Event Committee (CEC) Confirmed Clinical Worsening up to End-of Double-blind-treatment (EODBT) Period	Time (months) to first CEC-confirmed clinical worsening up to EODBT were reported. Clinical worsening was defined as the occurrence of at least one of the following events: 1) All-cause death; 2) Heart and/or lung transplantation; 3) Unplanned pulmonary hypertension (PH)-related hospitalization; 4) PH-related deterioration from baseline identified by at least one of the following: a) Persistent increase in World Health Organization functional class (WHO FC) that could not be explained by another cause (for example, viral infection); b) Persistent deterioration by at least 15 percent (%) in exercise capacity; as measured by the 6MWD; c) New or worsened signs or symptoms of right heart failure; 5) Rescue pulmonary endarterectomy (PEA) and/or balloon pulmonary angioplasty (BPA) procedure due to worsening of PH.	From Baseline (Day 1) up to EODBT: median 24.5 weeks (min 3.9 weeks; max 160.4 weeks) for macitentan, median 44 weeks (min 4 weeks; max 147.9 weeks) for placebo
Number of Participants With Improvement in World Health Organization Functional Class (WHO FC) From Baseline to Week 28	Number of participants with improvement in WHO FC from baseline to Week 28 were reported. Improvement (decrease) in WHO FC from baseline to Week 28 was calculated for each participant. WHO FC test was used to assess disease severity. Four functional classes (FC) were defined from FC I (no limitation of physical activity) to FC IV (inability to carry out any physical activity without symptoms). For the analysis purpose, these WHO FC class values were transformed to a scale with scores ranged from 1 to 4; where a score of 1 corresponded to WHO FC Class I and a score of 4 corresponded to WHO FC Class IV. The higher scores indicate greater symptom severity or worse impact. Improvement was considered when a participant changed from a higher class to a lower class.	From Baseline (Day 1) up to Week 28
Change From Baseline to Week 28 in Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT) - Cardiopulmonary Symptom Domain Score	The cardiopulmonary symptoms domain consisted of 6 items: shortness of breath, fatigue, lack of energy, swelling in ankles or legs, swelling in stomach area and cough and were reported on a 5-point Likert scale from 0 (no symptom at all) to 4 (very severe symptoms), with higher score indicating more symptom. The symptoms part of the PAH-SYMPACT was administered daily over a 7-day period. The recall period of symptom items was the last 24 hours. The mean individual symptom item score was determined for each of the 6 items and a domain score was calculated by summing the mean individual symptom item scores and dividing by the number of items, ranged from 0=no cardiopulmonary symptoms to 4=severe cardiopulmonary symptoms. A higher score indicated more severe symptoms experienced.	From Baseline (Day 1) up to Week 28
Change From Baseline to Week 28 in PAH-SYMPACT - Cardiovascular Symptom Domain Score	The cardiovascular symptoms domain consisted of 5 items: heart palpitations (fluttering), rapid heartbeat, chest pain, chest tightness, and lightheadedness and were reported on a 5-point Likert scale ranged from 0 (no symptoms at al) to 4 (very severe symptoms), with high score indicating more symptom. The symptoms part of PAH-SYMPACT was administered daily over a 7-day period. The recall period of symptom items was the last 24 hours. An average Cardiovascular Symptoms domain score was determined based on the daily scores of the 5 items. The mean individual symptom item score was determined for each of the 5 items and a domain score was calculated by summing the mean individual symptom item scores and dividing by the number of items, ranged from 0=no cardiovascular symptoms to 4=severe cardiovascular symptoms. Higher score indicated more severe symptoms experienced.	From Baseline (Day 1) up to Week 28
Change From Baseline to Week 28 in Euro Quality of Life-5-Dimension-5-Level (EQ-5D-5L) Utility Score and Visual Analog Scale (VAS) Score	The EQ-5D-5L was a generic measure of health status. The EQ-5D-5L consisted of 2 parts: EQ-5D-5L utility score (descriptive system) and VAS score. EQ-5D-5L descriptive system consisted of 5-item questionnaire that assessed 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each questionnaire had 5 response levels: 1 =no problems, 2 =slight problems, 3 =moderate problems, 4 =severe problems and 5 =extreme problems. The scores for the 5 questionnaires were used to compute a single utility score which ranged from 0 to 1, where higher score indicated better health state and lower score indicated worse health state. EQ-5D-5L VAS rated current health state on a vertical scale with a score ranged from 0 (worst imaginable health state) to 100 (best imaginable health state), higher scores indicated a better health state.	From Baseline (Day 1) up to Week 28
Change From Baseline to Week 28 in Accelerometer-assessed Proportion of Time Spent in Moderate to Vigorous Physical Activity	Change from baseline to Week 28 in accelerometer-assessed proportion of time spent in moderate to vigorous physical activity were assessed. Daily life physical activity of participant was assessed using accelerometer which was provided to the participant at screening and was worn daily during waking hours up to Week 28. For each scheduled visit, the 14 days prior to the visit were considered as the assessment period for physical activity. To be considered evaluable for a given timepoint, actigraphy variables should have been measured for at least 7 complete days (consecutive or not). A complete day is defined as a record of at least 7 waking hours of data. Proportion of time spent in moderate to vigorous physical activity was the estimated number of minutes spent in moderate or higher physical activity as calculated using the Staudenmayer '15 technique as proportion of the total minutes of algorithmically detected wear time and excluding the minutes that fall within a sleep period.	From Baseline (Day 1) up to Week 28

Collaborators and Investigators

• Sponsor: Actelion
• Investigators: Study Director: Actelion Clinical Trial, Actelion

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2020
• Primary Completion (Actual): December 21, 2023
• Study Completion (Actual): December 21, 2023

Study Registration Dates

• First Submitted: February 13, 2020
• First Submitted That Met QC Criteria: February 13, 2020
• First Posted (Actual): February 17, 2020

Study Record Updates

• Last Update Posted (Actual): June 27, 2025
• Last Update Submitted That Met QC Criteria: June 19, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Endothelin A Receptor Antagonists; Endothelin Receptor Antagonists; Endothelin B Receptor Antagonists; Macitentan
• Other Study ID Numbers: CR108742; 2019-004131-24 (EudraCT Number); 67896062CTP3001 (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