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

NCT ID: NCT04271475

Last Updated: 2025-06-27

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 127 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-07
• Study Completion Date: 2023-12-21

Brief Summary

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).

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).

Conditions

Chronic Thromboembolic Pulmonary Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: EXPERIMENTAL

Macitentan

Intervention Type: DRUG

Participants will receive Macitentan film-coated tablets orally od.

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).

Group Type: EXPERIMENTAL

Macitentan

Intervention Type: DRUG

Participants will receive Macitentan film-coated tablets orally od.

Placebo

Intervention Type: DRUG

Participant will receive matching placebo tablets orally od.

Interventions

Macitentan

Participants will receive Macitentan film-coated tablets orally od.

Intervention Type: DRUG

Placebo

Participant will receive matching placebo tablets orally od.

Intervention Type: DRUG

Other Intervention Names

ACT-064992,; Opsumit

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Actelion

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Actelion Clinical Trial

Role: STUDY_DIRECTOR

Actelion

Locations

University of California San Diego Medical Center

La Jolla, California, United States

Keck School of Medicine of USC

Los Angeles, California, United States

UC Davis Medical Center

Sacramento, California, United States

University of Colorado Anschutz Medical Campus

Aurora, Colorado, United States

Yale University School Of Medicine

New Haven, Connecticut, United States

University of Florida Health Jacksonville

Gainesville, Florida, United States

Piedmont Healthcare

Atlanta, Georgia, United States

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States

Indiana University

Indianapolis, Indiana, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

University of Maryland

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Tufts Medical Center

Boston, Massachusetts, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

VA Sierra Nevada Health Care System

Reno, Nevada, United States

University of New Mexico School of Medicine

Albuquerque, New Mexico, United States

Syracuse VA Medical Center

Syracuse, New York, United States

Cleveland Clinic

Cleveland, Ohio, United States

Legacy Hospital

Portland, Oregon, United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Baylor Scott White - Plano

Plano, Texas, United States

Intermountain Medical Center

Murray, Utah, United States

University of Utah Cardiovascular Center

Salt Lake City, Utah, United States

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, United States

Nexo Salud Investigacion Clinica

Buenos Aires, , Argentina

Sanatorio de la Trinidad Mitre

Buenos Aires, , Argentina

Sanatorio Guemes

C.a.b.a., , Argentina

Queensland Lung Transplant Service

Chermside, , Australia

St Vincent's hospital

Darlinghurst, , Australia

LKH-Univ. Klinikum Graz

Graz, , Austria

Ordensklinikum Linz GmbH Elisabethinen

Linz, , Austria

Medizinische Universitaet Wien

Vienna, , Austria

Military Medical Academy

Sofia, , Bulgaria

University Multiprofile Hospital for Active Treatment- UMHAT Sveta Anna AD

Sofia, , Bulgaria

University Of Calgary - Peter Lougheed Centre

Calgary, Alberta, Canada

University of Alberta Hospital

Edmonton, Alberta, Canada

University Health Network - Toronto General Hospital

Toronto, Ontario, Canada

Beijing Chaoyang Hospital

Beijing, , China

Beijing Anzhen Hospital

Beijing, , China

China Japan Friendship Hospital

Beijing, , China

Beijing Shijitan Hospital

Beijing, , China

The First Affiliated Hospital of Chongqing Medical University

Chongqing, , China

The First Affiliated Hospital of Guangzhou Medical University

Guangzhou, , China

Sir Run Run Shaw Hospital Zhejiang University School of Medicine

Hangzhou, , China

Zhongda Hospital Southeast University

Nanjing, , China

The Affiliated Hospital of Medical College Qingdao University

Qingdao, , China

Huashan Hospital of Fudan University

Shanghai, , China

Shanghai Pulmonary Hospital

Shanghai, , China

Zhongshan Hospital Fudan University

Shanghai, , China

The General Hospital of Northern Theater Command

Shenyang, , China

Tianjin Medical University General Hospital

Tianjin, , China

The First Affiliated Hospital of Xian Jiaotong University

Xi'an, , China

Fundacion Neumologica Colombiana

Bogotá, , Colombia

Fundación Abood Shaio

Bogotá, , Colombia

Clínica Imbanaco S.A.S.

Cali, , Colombia

Centro Cardiovascular Colombiano Clínica Santa María

Medellín, , Colombia

General University Hospital II.department of Internal Medicine-cardiology and angiology

Prague, , Czechia

Århus Universitetshospital, Skejby, Hjertemedicinsk Afdeling B

Aarhus N, , Denmark

CHU de Brest - Hopital de la Cavale Blanche

Brest, , France

CHU de Grenoble Hopital Albert Michallon

Grenoble, , France

Hopital Bicetre Aphp Hopitaux Universitaires Paris Sud

Le Kremlin-Bicêtre, , France

Hôpital Cardiologique - Chru Lille

Lille, , France

CHU de Montpellier - Arnaud de Villeneuve

Montpellier, , France

CHU Saint Etienne Hopital Nord

Saint-Priest-en-Jarez, , France

Hopital Larrey CHU de Toulouse

Toulouse, , France

CHU de Nancy - Hopital de Brabois

Vandœuvre-lès-Nancy, , France

Universitatsklinikum Bonn

Bonn, , Germany

Medizinische Fakultaet Carl Gustav Carus Technische Universitaet Dresden

Dresden, , Germany

Universitaetsklinikum Giessen

Giessen, , Germany

Universitaetsklinikum Hamburg Eppendorf

Hamburg, , Germany

Medizinische Hochschule Hannover Zentrum Innere Medizin Klinik für Pneumologie

Hanover, , Germany

Thoraxklinik Heidelberg

Heidelberg, , Germany

Universitaetsklinikum des Saarlandes

Homburg, , Germany

Universitatsklinikum Jena

Jena, , Germany

Krankenhaus Neuwittelsbach

München, , Germany

Gottsegen Gyorgy Orszagos Kardiovaszkularis Intezet Felnott kardiologiai osztaly

Budapest, , Hungary

Szegedi Tudományegyetem, Általános Orvostudományi Kar, Családorvosi Intézet és rendelő

Szeged, , Hungary

Tel Aviv Medical Center

Tel Aviv, , Israel

The Chaim Sheba Medical Center

Tel Litwinsky, , Israel

Ospedale SS. Annunziata

Chieti, , Italy

Fondazione IRCCS Policlinico San Matteo

Pavia, , Italy

Fondazione Toscana Gabriele Monasterio CNR

Pisa, , Italy

Policlinico Gemelli Universita Cattolica

Roma, , Italy

A.O.U. Città della Salute e della Scienza

Torino, , Italy

The University of Tokyo Hospital

Bunkyō City, , Japan

Kyushu University Hospital

Fukuoka, , Japan

Kure Kyosai Hospital

Hiroshima, , Japan

St Marianna University Hospital

Kanagawa, , Japan

Kobe University Hospital

Kobe, , Japan

University Hospital Kyoto Prefectural University of Medicine

Kyoto, , Japan

Kyoto University Hospital

Kyoto, , Japan

Shinshu University Hospital

Matsumoto, , Japan

Toho University Medical Center, Ohashi Hospital

Meguro-ku, , Japan

Kyorin University Hospital

Mitaka, , Japan

Nagoya University Hospital

Nagoya, , Japan

National Hospital Organization Okayama Medical Center

Okayama, , Japan

Hokkaido University Hospital

Sapporo, , Japan

National Cerebral and Cardiovascular Center

Suita-Shi, , Japan

Juntendo University Hospital

Tokyo, , Japan

University of Tsukuba Hospital

Tsukuba, , Japan

Lietuvos sveikatos mokslų universiteto ligoninė Kauno klinik

Kaunas, , Lithuania

Vilnius University Hospital Santariskiu Klinikos

Vilnius, , Lithuania

Instituto Nacional de Cardiologia Dr. Ignacio Chavez

Mexico City, , Mexico

Operadora de Hospitales Angeles SA de CV Hospital Angeles Lomas

México, , Mexico

Unidad de Investigacion Clinica en Medicina S.C. (UDICEM)

Monterrey, , Mexico

Centro de Investigacion Clinica Chapultepec

Morelia, , Mexico

CRI Centro Regiomontano de Investigacion SC

Nuevo León, , Mexico

Krakowski Szpital Specjalistyczny im Jana Pawla II

Krakow, , Poland

Wojewodzki Szpital Specjalistyczny im Stefana Kardynala Wyszynskiego PZOZ

Lublin, , Poland

Europejskie Centrum Zdrowia Otwock Sp z o o

Otwock, , Poland

Uls Almada Seixal - Hosp. Garcia de Orta

Almada, , Portugal

Institutul de urgenta pentru Boli Cardiovasculare Prof. Dr. C.C. Iliescu

Bucharest, , Romania

Spitalul Clinic Judetean de Urgenta

Tg. Mures, , Romania

State Autonomous HealthCare Institution 'Interregional Clinical Diagnostic Center'

Kazan', , Russia

Moscow City Clinical Hospital No.51

Moscow, , Russia

National Medical Research Center of Cardiology of MoH of Russian Federation

Moscow, , Russia

National medical Research Center n.a. V.A.Almazov of MoH of Russian Federation

Saint Petersburg, , Russia

Volgograd Regional Clinical Cardiology Center

Volgograd, , Russia

King Faisal Specialist Hospital & Research Center

Riyadh, , Saudi Arabia

King Fahad Medical City

Riyadh, , Saudi Arabia

University Clinical Center of Serbia

Belgrade, , Serbia

Institute for Pulmonary Disease of Vojvodina

Kamenitz, , Serbia

National University Heart Centre, Singapore

Singapore, , Singapore

National Heart Centre (NHC) Singapore

Singapore, , Singapore

Narodny ustav srdcovych a cievnych chorob

Bratislava, , Slovakia

Pusan National University Hospital

Busan, , South Korea

Seoul National University Hospital

Seoul, , South Korea

Asan Medical Center

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

The Catholic University of Korea Seoul St Marys Hospital

Seoul, , South Korea

Hosp Clinic de Barcelona

Barcelona, , Spain

Hosp. Univ. 12 de Octubre

Madrid, , Spain

Hosp. Univ. La Paz

Madrid, , Spain

Hosp Virgen de La Victoria

Málaga, , Spain

Hosp. Costa Del Sol

Málaga, , Spain

Hosp. Gral. Univ. de Toledo

Toledo, , Spain

Kaohsiung Veterans General Hospital

Kaohsiung City, , Taiwan

National Taiwan University Hospital

Taipei, , Taiwan

Taipei Veterans General Hospital

Taipei, , Taiwan

Chang-Gung Memorial Hospital, LinKou Branch

Taoyuan District, , Taiwan

Maharaj Nakorn Chiang Mai Hospital

Chiang Mai, , Thailand

Srinagarind Hospital, Khon Kaen University

Khon Kaen, , Thailand

Thammasat Hospital

Pathum Thani, , Thailand

Adana City Hospital

Adana, , Turkey (Türkiye)

Cukurova University Medical Faculty

Adana, , Turkey (Türkiye)

Hacettepe University Medical Faculty

Ankara, , Turkey (Türkiye)

Ankara Bilkent Sehir Hastanesi

Ankara, , Turkey (Türkiye)

Pamukkale University Medical Faculty

Denizli, , Turkey (Türkiye)

Eskisehir Osmangazi University Medical Faculty Hospital

Eskişehir, , Turkey (Türkiye)

Istanbul University - Cerrahpasa Cardiology Institution

Istanbul, , Turkey (Türkiye)

Siyami Ersek Training and Research Hospital

Istanbul, , Turkey (Türkiye)

Marmara University Medical Faculty

Istanbul, , Turkey (Türkiye)

Ege University Medical Faculty

Izmir, , Turkey (Türkiye)

Dokuz Eylul University Medical Faculty

Izmir, , Turkey (Türkiye)

Kartal Kosuyolu Yuksek Ihtisas Egitim Ve Arastirma Hastanesi

Kartal Istanbul, , Turkey (Türkiye)

Mersin University Medical Faculty

Mersin, , Turkey (Türkiye)

CNE 'Cherkasy Regional Cardiological Center of Cherkasy Regional Council'

Cherkasy, , Ukraine

CE 'Dnipropetrovsk Regional Clinical Center of Cardiology and Cardiosurgery'

Dnipro, , Ukraine

SI National Scientific Center Institute of Cardiology of M.D. Strazhesko of NAMS of Ukraine

Kyiv, , Ukraine

State Institute Of Phthisiology And Pulmonology N.A. F.G. Yanovskiy Of Ams Ukraine

Kyiv, , Ukraine

Communal Noncommercial Enterprise of Lviv Regional Council 'Lviv Regional Clinical Hospital'

Lviv, , Ukraine

Municipal Non-commercial Enterprise Ternopil University Hospital of Ternopil Regional Council

Ternopil, , Ukraine

Papworth Hospital NHS Trust

Cambridge, , United Kingdom

National Waiting Times Centre Board Golden Jubilee National Hospital

Glasgow, , United Kingdom

Royal Free Hospital

London, , United Kingdom

Hammersmith Hospital

London, , United Kingdom

Freeman Hospital

Newcastle upon Tyne, , United Kingdom

Sheffield Teaching Hospitals NHS Foundation Trust Royal Hallamshire Hospital

Sheffield, , United Kingdom

Countries

United States; Argentina; Australia; Austria; Bulgaria; Canada; China; Colombia; Czechia; Denmark; France; Germany; Hungary; Israel; Italy; Japan; Lithuania; Mexico; Poland; Portugal; Romania; Russia; Saudi Arabia; Serbia; Singapore; Slovakia; South Korea; Spain; Taiwan; Thailand; Turkey (Türkiye); Ukraine; United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

67896062CTP3001

Identifier Type: OTHER

Identifier Source: secondary_id

2019-004131-24

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CR108742

Identifier Type: -

Identifier Source: org_study_id