A Study to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/Recurrent Chronic Thromboembolic Pulmonary Hypertension (MACiTEPH)
Chronic Thromboembolic Pulmonary Hypertension
About this trial
This is an interventional treatment trial for Chronic Thromboembolic Pulmonary Hypertension
Eligibility Criteria
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
Sites / Locations
- University of California San Diego Medical Center
- Keck School of Medicine of USC
- UC Davis Medical Center
- University of Colorado - Anschutz Medical Campus
- Yale University School Of Medicine
- University of Florida Health Jacksonville
- Piedmont Healthcare
- Northwestern University Feinberg School of Medicine
- Indiana University
- University of Kansas Medical Center
- University of Maryland
- Massachusetts General Hospital
- Tufts Medical Center
- University of Nebraska Medical Center
- VA Sierra Nevada Health Care System
- University of New Mexico School of Medicine
- Syracuse VA Medical Center
- Cleveland Clinic
- Legacy Hospital
- University of Pittsburgh Medical Center
- Baylor Scott White - Plano
- Intermountain Medical Center
- University of Utah Cardiovascular Center
- University of Wisconsin Hospital and Clinics
- Sanatorio de la Trinidad Mitre
- Sanatorio Guemes
- Nexo Salud Investigacion Clinica
- Queensland Lung Transplant Service
- St Vincent's hospital
- LKH-Univ. Klinikum Graz
- Ordensklinikum Linz GmbH Elisabethinen
- Medizinische Universität Wien
- Military Medical Academy
- University Multiprofile Hospital for Active Treatment- UMHAT Sveta Anna AD
- University Of Calgary - Peter Lougheed Centre
- University of Alberta Hospital
- University Health Network - Toronto General Hospital
- Beijing Chaoyang Hospital
- Beijing Anzhen Hospital
- China-Japan Friendship Hospital
- Beijing Shijitan Hospital
- The First Affiliated Hospital of Chongqing Medical University
- The First Affiliated Hospital of Guangzhou Medical University
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
- Zhongda Hospital,Southeast University
- The Affiliated Hospital of Medical College Qingdao University
- Huashan Hospital of Fudan University
- Shanghai Pulmonary Hospital
- Zhongshan Hospital,Fudan University
- The General Hospital of Northern Theater Command
- Tianjin Medical University General Hospital
- The First Affiliated Hospital of Xi'an Jiaotong University
- Fundacion Neumologica Colombiana
- Fundación Abood Shaio
- Clínica Imbanaco S.A.S.
- Centro Cardiovascular Colombiano Clínica Santa María
- General University Hospital II.department of Internal Medicine-cardiology and angiology
- Århus Universitetshospital, Skejby, Hjertemedicinsk Afdeling B
- CHU de Brest - Hôpital de la Cavale Blanche
- CHU de Grenoble - Hopital Albert Michallon
- Hopital Bicêtre - Aphp Hôpitaux Universitaires Paris-Sud
- Hôpital Cardiologique - Chru Lille
- CHU de Montpellier - Arnaud de Villeneuve
- CHU Saint-Etienne - Hôpital Nord
- Hopital Larrey CHU de Toulouse
- CHU de Nancy - Hôpital de Brabois
- Universitatsklinikum Bonn
- Medizinische Fakultat Carl Gustav Carus Technische Universitat Dresden
- Universitaetsklinikum Giessen
- Universitaetsklinikum Hamburg Eppendorf
- Medizinische Hochschule Hannover Zentrum Innere Medizin Klinik für Pneumologie
- Thoraxklinik Heidelberg
- Universitaetsklinikum des Saarlandes
- Universitätsklinikum Jena
- Krankenhaus Neuwittelsbach
- Gottsegen György Országos Kardiológiai Intézet, Felnőtt kardiológiai osztály
- Szegedi Tudományegyetem, Általános Orvostudományi Kar, Családorvosi Intézet és rendelő
- Tel Aviv Medical Center
- The Chaim Sheba Medical Center
- Ospedale SS. Annunziata
- Fondazione IRCCS Policlinico San Matteo
- Fondazione Toscana Gabriele Monasterio CNR
- Policlinico Gemelli Universita Cattolica
- A.O.U. Città della Salute e della Scienza
- The University of Tokyo Hospital
- Kyushu University Hospital
- Kure Kyosai Hospital
- St.Marianna University Hospital
- Kobe University Hospital
- University Hospital Kyoto Perfectural University of Medicine
- Kyoto University Hospital
- Shinshu University Hospital
- Toho University Medical Center, Ohashi Hospital
- Kyorin University Hospital
- Nagoya University Hospital
- National Hospital Organization Okayama Medical Center
- Hokkaido University Hospital
- National Cerebral and Cardiovascular Center
- Juntendo University Hospital
- University of Tsukuba Hospital
- Pusan National University Hospital
- Seoul National University Hospital
- Asan Medical Center
- Samsung Medical Center
- The Catholic University of Korea Seoul St. Mary's Hospital
- Lietuvos sveikatos mokslų universiteto ligoninė Kauno klinik
- Vilnius University Hospital Santariskiu Klinikos
- Instituto Nacional de Cardiologia Dr. Ignacio Chavez
- Operadora de Hospitales Angeles SA de CV Hospital Angeles Lomas
- Unidad de Investigacion Clinica en Medicina S.C. (UDICEM)
- Centro de Investigacion Clinica Chapultepec
- CRI Centro Regiomontano de Investigacion SC
- Krakowski Szpital Specjalistyczny im Jana Pawla II
- Wojewódzki Szpital Specjalistyczny im. Stefana Kardynała Wyszyńskiego, PZOZ
- Europejskie Centrum Zdrowia Otwock Sp. z o.o
- Hosp. Garcia de Orta
- Institutul de urgenta pentru Boli Cardiovasculare Prof. Dr. C.C. Iliescu Sectia cardiologie III
- Spitalul Clinic Judetean de Urgenta
- State Autonomous HealthCare Institution 'Interregional Clinical Diagnostic Center'
- Moscow City Clinical Hospital No.51
- National Medical Research Center of Cardiology of MoH of Russian Federation
- National medical Research Center n.a. V.A.Almazov of MoH of Russian Federation
- Volgograd Regional Clinical Cardiology Center
- King Faisal Specialist Hospital & Research Center
- King Fahad Medical City
- University Clinical Center of Serbia
- Institute for Pulmonary Disease of Vojvodina
- National University Heart Centre, Singapore
- National Heart Centre (NHC) Singapore
- Narodny ustav srdcovych a cievnych chorob
- Hosp. Clinic I Provincial de Barcelona
- Hosp. Univ. 12 de Octubre
- Hosp. Univ. La Paz
- Hosp. Costa Del Sol
- Hosp. Virgen de La Victoria
- Hosp. Gral. Univ. de Toledo
- Kaohsiung Veterans General Hospital
- National Taiwan University Hospital
- Taipei Veterans General Hospital
- Chang-Gung Memorial Hospital, LinKou Branch
- Maharaj Nakorn Chiang Mai Hospital
- Srinagarind Hospital, Khon Kaen University
- Thammasat Hospital
- Adana City Hospital
- Cukurova University Medical Faculty
- Hacettepe University Medical Faculty
- Ankara Bilkent Sehir Hastanesi
- Pamukkale University Medical Faculty
- Eskisehir Osmangazi University Medical Faculty Hospital
- Istanbul University - Cerrahpasa Cardiology Institution
- Siyami Ersek Training and Research Hospital
- Marmara University Medical Faculty
- Ege University Medical Faculty
- Dokuz Eylul University Medical Faculty
- Kartal Kosuyolu Yuksek Ihtisas Egitim Ve Arastirma Hastanesi
- Mersin University Medical Faculty
- CNE 'Cherkasy Regional Cardiological Center of Cherkasy Regional Council'
- CE 'Dnipropetrovsk Regional Clinical Center of Cardiology and Cardiosurgery'
- SI National Scientific Center Institute of Cardiology of M.D. Strazhesko of NAMS of Ukraine
- State Institute Of Phthisiology And Pulmonology N.A. F.G. Yanovskiy Of Ams Ukraine
- Communal Noncommercial Enterprise of Lviv Regional Council 'Lviv Regional Clinical Hospital'
- Municipal Non-commercial Enterprise Ternopil University Hospital of Ternopil Regional Council
- Papworth Hospital NHS Trust
- National Waiting Times Centre Board Golden Jubilee National Hospital
- Royal Free Hospital
- Hammersmith Hospital
- Freeman Hospital
- Sheffield Teaching Hospitals NHS Foundation Trust Royal Hallamshire Hospital
Arms of the Study
Arm 1
Arm 2
Experimental
Experimental
Macitentan
Placebo
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.
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).