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

Chronic Thromboembolic Pulmonary Hypertension Clinical Trial

— MACiTEPH  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04271475
• Other study ID #: CR108742
• Secondary ID: 2019-004131-2467
• Status: Terminated
• Phase: Phase 3
• Start date: July 7, 2020
• Est. completion date: December 21, 2023

Study information

• Verified date: February 2024
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 127
• Est. completion date: December 21, 2023
• Est. primary completion date: December 21, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Chronic Thromboembolic Pulmonary Hypertension
• Hypertension
• Hypertension, Pulmonary

Intervention

Drug:
• Macitentan
Participants will receive Macitentan film-coated tablets orally od.
• Placebo
Participant will receive matching placebo tablets orally od.

Locations

Country	Name	City	State
Argentina	Sanatorio de la Trinidad Mitre	Buenos Aires
Argentina	Sanatorio Guemes	C.a.b.a.
Argentina	Nexo Salud Investigacion Clinica	Ciudad Autonoma de Buenos Aires
Australia	Queensland Lung Transplant Service	Chermside
Australia	St Vincent's hospital	Darlinghurst
Austria	LKH-Univ. Klinikum Graz	Graz
Austria	Ordensklinikum Linz GmbH Elisabethinen	Linz
Austria	Medizinische Universität Wien	Vienna
Bulgaria	Military Medical Academy	Sofia
Bulgaria	University Multiprofile Hospital for Active Treatment- UMHAT Sveta Anna AD	Sofia
Canada	University Of Calgary - Peter Lougheed Centre	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	University Health Network - Toronto General Hospital	Toronto	Ontario
China	Beijing Anzhen Hospital	Beijing
China	Beijing Chaoyang Hospital	Beijing
China	Beijing Shijitan Hospital	Beijing
China	China-Japan Friendship 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	Tian Jin
China	The First Affiliated Hospital of Xian Jiaotong University	Xi'An
Colombia	Fundación Abood Shaio	Bogota
Colombia	Fundacion Neumologica Colombiana	Bogota
Colombia	Clínica Imbanaco S.A.S.	Cali
Colombia	Centro Cardiovascular Colombiano Clínica Santa María	Medellin
Czechia	General University Hospital II.department of Internal Medicine-cardiology and angiology	Praha 2
Denmark	Århus Universitetshospital, Skejby, Hjertemedicinsk Afdeling B	Aarhus N
France	CHU de Brest - Hôpital de la Cavale Blanche	Brest
France	CHU de Grenoble Hopital Albert Michallon	Grenoble Cedex 9
France	Hopital Bicêtre - Aphp Hôpitaux Universitaires Paris-Sud	Le Kremlin-Bicetre Cedex
France	Hôpital Cardiologique - Chru Lille	Lille Cedex
France	CHU de Montpellier - Arnaud de Villeneuve	Montpellier
France	CHU Saint-Etienne - Hopital Nord	St Priest en Jarez Cedex
France	Hopital Larrey CHU de Toulouse	Toulouse Cedex 9
France	CHU de Nancy - Hopital de Brabois	Vandoeuvre les Nancy Cedex
Germany	Universitatsklinikum Bonn	Bonn
Germany	Medizinische Fakultat Carl Gustav Carus Technische Universitat Dresden	Dresden
Germany	Universitaetsklinikum Giessen	Giessen
Germany	Universitaetsklinikum Hamburg Eppendorf	Hamburg
Germany	Medizinische Hochschule Hannover Zentrum Innere Medizin Klinik für Pneumologie	Hannover
Germany	Thoraxklinik Heidelberg	Heidelberg
Germany	Universitaetsklinikum des Saarlandes	Homburg
Germany	Universitätsklinikum Jena	Jena
Germany	Krankenhaus Neuwittelsbach	München
Hungary	Gottsegen György Országos Kardiológiai Intézet, Felnott kardiológiai osztály	Budapest
Hungary	Szegedi Tudományegyetem, Általános Orvostudományi Kar, Családorvosi Intézet és rendelo	Szeged
Israel	Tel Aviv Medical Center	Tel Aviv
Israel	The Chaim Sheba Medical Center	Tel-Hashomer
Italy	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
Japan	The University of Tokyo Hospital	Bunkyo
Japan	Kyushu University Hospital	Fukuoka
Japan	Kure Kyosai Hospital	Hiroshima
Japan	St.Marianna University Hospital	Kanagawa
Japan	Kobe University Hospital	Kobe
Japan	Kyoto University Hospital	Kyoto
Japan	University Hospital Kyoto Perfectural University of Medicine	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-shi
Japan	National Cerebral and Cardiovascular Center	Suita-Shi
Japan	Juntendo University Hospital	Tokyo
Japan	University of Tsukuba Hospital	Tsukuba-City
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	The Catholic University of Korea Seoul St. Mary's Hospital	Seoul
Lithuania	Lietuvos sveikatos mokslu universiteto ligonine Kauno klinik	Kaunas
Lithuania	Vilnius University Hospital Santariskiu Klinikos	Vilnius
Mexico	Instituto Nacional de Cardiologia Dr. Ignacio Chavez	Ciudad De México
Mexico	Operadora de Hospitales Angeles SA de CV Hospital Angeles Lomas	Mexico
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 Leon
Poland	Krakowski Szpital Specjalistyczny im Jana Pawla II	Kraków
Poland	Wojewódzki Szpital Specjalistyczny im. Stefana Kardynala Wyszynskiego, PZOZ	Lublin
Poland	Europejskie Centrum Zdrowia Otwock Sp. z o.o	Otwock
Portugal	Hosp. Garcia de Orta	Almada
Romania	Institutul de urgenta pentru Boli Cardiovasculare Prof. Dr. C.C. Iliescu	Bucuresti
Romania	Spitalul Clinic Judetean de Urgenta	Tg. Mures
Russian Federation	State Autonomous HealthCare Institution 'Interregional Clinical Diagnostic Center'	Kazan
Russian Federation	Moscow City Clinical Hospital No.51	Moscow
Russian Federation	National Medical Research Center of Cardiology of MoH of Russian Federation	Moscow
Russian Federation	National medical Research Center n.a. V.A.Almazov of MoH of Russian Federation	Saint-Petersburg
Russian Federation	Volgograd Regional Clinical Cardiology Center	Volgograd
Saudi Arabia	King Fahad Medical City	Riyadh
Saudi Arabia	King Faisal Specialist Hospital & Research Center	Riyadh
Serbia	University Clinical Center of Serbia	Belgrade
Serbia	Institute for Pulmonary Disease of Vojvodina	Sremska Kamenica
Singapore	National Heart Centre (NHC) Singapore	Singapore
Singapore	National University Heart Centre, Singapore	Singapore
Slovakia	Narodny ustav srdcovych a cievnych chorob	Bratislava
Spain	Hosp. Clinic de Barcelona	Barcelona
Spain	Hosp. Univ. 12 de Octubre	Madrid
Spain	Hosp. Virgen de La Victoria	Málaga
Spain	Hosp. Gral. Univ. de Toledo	Toledo
Taiwan	Kaohsiung Veterans General Hospital	Kaohsiung
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Chang-Gung Memorial Hospital, LinKou Branch	Taoyuan
Thailand	Maharaj Nakorn Chiang Mai Hospital	Chiang Mai
Thailand	Srinagarind Hospital, Khon Kaen University	Khon Kaen
Thailand	Thammasat Hospital	Pathumthani
Turkey	Adana City Hospital	Adana
Turkey	Cukurova University Medical Faculty	Adana
Turkey	Ankara Bilkent Sehir Hastanesi	Ankara
Turkey	Hacettepe University Medical Faculty	Ankara
Turkey	Pamukkale University Medical Faculty	Denizli
Turkey	Eskisehir Osmangazi University Medical Faculty Hospital	Eskisehir
Turkey	Istanbul University - Cerrahpasa Cardiology Institution	Istanbul
Turkey	Marmara University Medical Faculty	Istanbul
Turkey	Siyami Ersek Training and Research Hospital	Istanbul
Turkey	Dokuz Eylul University Medical Faculty	Izmir
Turkey	Ege University Medical Faculty	Izmir
Turkey	Kartal Kosuyolu Yuksek Ihtisas Egitim Ve Arastirma Hastanesi	Kartal Istanbul
Turkey	Mersin University Medical Faculty	Mersin
Ukraine	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
United Kingdom	Papworth Hospital NHS Trust	Cambridge
United Kingdom	National Waiting Times Centre Board Golden Jubilee National Hospital	Glasgow
United Kingdom	Hammersmith Hospital	London
United Kingdom	Royal Free Hospital	London
United Kingdom	Freeman Hospital	Newcastle Upon Tyne
United Kingdom	Sheffield Teaching Hospitals NHS Foundation Trust Royal Hallamshire Hospital	Sheffield
United States	University of New Mexico School of Medicine	Albuquerque	New Mexico
United States	Piedmont Healthcare	Atlanta	Georgia
United States	University of Colorado - Anschutz Medical Campus	Aurora	Colorado
United States	University of Maryland	Baltimore	Maryland
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	University of Florida Health Jacksonville	Gainesville	Florida
United States	Indiana University	Indianapolis	Indiana
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of California San Diego Medical Center	La Jolla	California
United States	Keck School of Medicine of USC	Los Angeles	California
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Intermountain Medical Center	Murray	Utah
United States	Yale University School Of Medicine	New Haven	Connecticut
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Baylor Scott White - Plano	Plano	Texas
United States	Legacy Hospital	Portland	Oregon
United States	VA Sierra Nevada Health Care System	Reno	Nevada
United States	UC Davis Medical Center	Sacramento	California
United States	University of Utah Cardiovascular Center	Salt Lake City	Utah
United States	Syracuse VA Medical Center	Syracuse	New York

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Bulgaria,  Canada,  China,  Colombia,  Czechia,  Denmark,  France,  Germany,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Lithuania,  Mexico,  Poland,  Portugal,  Romania,  Russian Federation,  Saudi Arabia,  Serbia,  Singapore,  Slovakia,  Spain,  Taiwan,  Thailand,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline to Week 28 in 6- minute Walk Distance [6MWD]	Change from baseline to week 28 in 6MWD as measured by 6-minute walk test [6MWT]) will be reported. The purpose of the six-minute walk test (6MWT) is to quantify exercise tolerance and capacity. This standardized test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in 6 minutes.	Baseline up to Week 28
Secondary	Time to Clinical Worsening up to End-of double-blind-treatment (EODBT) Period	Time to first Clinical Event Committee (CEC) confirmed clinical worsening up to EODBT will be reported. Clinical worsening is 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 cannot 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 worsening signs or symptoms of right heart failure; 5) Rescue pulmonary endarterectomy (PEA) and/or balloon pulmonary angioplasty (BPA) procedure due to worsening of PH.	Up to EODBT (variable duration per participant, up to 3.5 years)
Secondary	Number of Participants with Improvement in WHO Functional Class (WHO FC) From Baseline to Week 28	Improvement in WHO FC from baseline to Week 28 will be calculated for each participant. WHO FC test is used to assess disease severity. Four functional classes (FC) are defined from FC I (no limitation of physical activity) to FC IV (inability to carry out any physical activity without symptoms). Improvement is considered when a participant changes from a higher class to a lower class.	Baseline up to Week 28
Secondary	Change From Baseline to Week 28 in Pulmonary Arterial Hypertension - Symptoms Based on (PAH-SYMPACT) - Cardiopulmonary Symptom Domain Score	The Cardiopulmonary Symptoms domain consists of 6 items (shortness of breath, fatigue, lack of energy, swelling in ankles or legs, swelling in stomach area and cough) reported on a 5-point Likert scale (from 0 to 4). The value 0 means "no symptom" and value 4 corresponds to "very severe symptoms". The symptoms part of the PAH-SYMPACT will be administered daily over a 7-day period. The recall period of symptom items is the last 24 hours. An average Cardiopulmonary Symptoms domain score is determined based on the daily scores of the 6 items. Questionnaires to be completed at site at screening for training purpose. PAH-SYMPACT to be performed at home, during the 7-day period prior to the scheduled visit.	Baseline up to Week 28
Secondary	Change from Baseline to Week 28 in PAH-SYMPACT - Cardiovascular Symptom Domain Score	The Cardiovascular Symptoms domain consists of 5 items (heart palpitations [fluttering], rapid heartbeat, chest pain, chest tightness, and lightheadedness) reported on a 5-point Likert scale (from 0 to 4). The value 0 corresponds to "no symptoms" and value 4 corresponds to "very severe symptoms". The symptoms part of the PAH-SYMPACT will be administered daily over a 7-day period. The recall period of symptom items is the last 24 hours. An average Cardiovascular Symptoms domain score is determined based on the daily scores of the 5 items. Questionnaires to be completed at site at screening for training purpose. PAH-SYMPACT to be performed at home, during the 7-day period prior to the scheduled visit.	Baseline up to Week 28
Secondary	Change from baseline to Week 28 in Euro Quality of life-5-Dimension-5-Level (EQ-5D-5L) Utility Score	The EQ-5D-5L is a generic measure of health status. The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating "health today" with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).	Baseline up to Week 28
Secondary	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 will be assessed.	Baseline up to Week 28