Clinical trial NCT04271475: A Study to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/Recurrent Chronic Thromboembolic Pulmonary Hypertension
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Chronic Thromboembolic Pulmonary Hypertension
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2020-02-17
Enrollment: 127
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: Change From Baseline in 6-minute Walk Distance (6MWD) at Week 28
timeFrame: Baseline (Day 1), Week 28
Secondary outcomes:
measure: Time to First Clinical Event Committee (CEC) Confirmed Clinical Worsening up to End-of Double-blind-treatment (EODBT) Period
timeFrame: 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
measure: Number of Participants With Improvement in World Health Organization Functional Class (WHO FC) From Baseline to Week 28
timeFrame: From Baseline (Day 1) up to Week 28
measure: Change From Baseline to Week 28 in Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT) - Cardiopulmonary Symptom Domain Score
timeFrame: From Baseline (Day 1) up to Week 28
measure: Change From Baseline to Week 28 in PAH-SYMPACT - Cardiovascular Symptom Domain Score
timeFrame: From Baseline (Day 1) up to Week 28
measure: 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
timeFrame: From Baseline (Day 1) up to Week 28
measure: Change From Baseline to Week 28 in Accelerometer-assessed Proportion of Time Spent in Moderate to Vigorous Physical Activity
timeFrame: From Baseline (Day 1) up to Week 28
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California San Diego Medical Center
state: California
city: Los Angeles
country: United States
facility: Keck School of Medicine of USC
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Anschutz Medical Campus
state: Colorado
city: New Haven
country: United States
facility: Yale University School Of Medicine
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida Health Jacksonville
state: Florida
city: Atlanta
country: United States
facility: Piedmont Healthcare
state: Georgia
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Reno
country: United States
facility: VA Sierra Nevada Health Care System
state: Nevada
city: Albuquerque
country: United States
facility: University of New Mexico School of Medicine
state: New Mexico
city: Syracuse
country: United States
facility: Syracuse VA Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Legacy Hospital
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Plano
country: United States
facility: Baylor Scott White - Plano
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah Cardiovascular Center
state: Utah
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Sanatorio de la Trinidad Mitre
city: C.a.b.a.
country: Argentina
facility: Sanatorio Guemes
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Nexo Salud Investigacion Clinica
city: Chermside
country: Australia
facility: Queensland Lung Transplant Service
city: Darlinghurst
country: Australia
facility: St Vincent's hospital
city: Graz
country: Austria
facility: LKH-Univ. Klinikum Graz
city: Linz
country: Austria
facility: Ordensklinikum Linz GmbH Elisabethinen
city: Vienna
country: Austria
facility: Medizinische Universitat Wien
city: Sofia
country: Bulgaria
facility: Military Medical Academy
city: Sofia
country: Bulgaria
facility: University Multiprofile Hospital for Active Treatment- UMHAT Sveta Anna AD
city: Calgary
country: Canada
facility: University Of Calgary - Peter Lougheed Centre
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Toronto
country: Canada
facility: University Health Network - Toronto General Hospital
state: Ontario
city: Beijing
country: China
facility: Beijing Chaoyang Hospital
city: Beijing
country: China
facility: Beijing Anzhen Hospital
city: Beijing
country: China
facility: China Japan Friendship Hospital
city: Beijing
country: China
facility: Beijing Shijitan Hospital
city: Chongqing
country: China
facility: The First Affiliated Hospital of Chongqing Medical University
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Guangzhou Medical University
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital Zhejiang University School of Medicine
city: Nanjing
country: China
facility: Zhongda Hospital Southeast University
city: Qingdao
country: China
facility: The Affiliated Hospital of Medical College Qingdao University
city: Shanghai
country: China
facility: Huashan Hospital of Fudan University
city: Shanghai
country: China
facility: Shanghai Pulmonary Hospital
city: Shanghai
country: China
facility: Zhongshan Hospital Fudan University
city: Shenyang
country: China
facility: The General Hospital of Northern Theater Command
city: Tian Jin
country: China
facility: Tianjin Medical University General Hospital
city: Xi'An
country: China
facility: The First Affiliated Hospital of Xian Jiaotong University
city: Bogota
country: Colombia
facility: Fundacion Neumologica Colombiana
city: Bogota
country: Colombia
facility: Fundación Abood Shaio
city: Cali
country: Colombia
facility: Clínica Imbanaco S.A.S.
city: Medellin
country: Colombia
facility: Centro Cardiovascular Colombiano Clínica Santa María
city: Praha 2
country: Czechia
facility: General University Hospital II.department of Internal Medicine-cardiology and angiology
city: Aarhus N
country: Denmark
facility: Århus Universitetshospital, Skejby, Hjertemedicinsk Afdeling B
city: Brest
country: France
facility: CHU de Brest - Hopital de la Cavale Blanche
city: Grenoble Cedex 9
country: France
facility: CHU de Grenoble Hopital Albert Michallon
city: Le Kremlin-Bicetre Cedex
country: France
facility: Hopital Bicetre Aphp Hopitaux Universitaires Paris Sud
city: Lille Cedex
country: France
facility: Hôpital Cardiologique - Chru Lille
city: Montpellier
country: France
facility: CHU de Montpellier - Arnaud de Villeneuve
city: St Priest en Jarez Cedex
country: France
facility: CHU Saint Etienne Hopital Nord
city: Toulouse Cedex 9
country: France
facility: Hopital Larrey CHU de Toulouse
city: Vandoeuvre les Nancy Cedex
country: France
facility: CHU de Nancy - Hopital de Brabois
city: Bonn
country: Germany
facility: Universitatsklinikum Bonn
city: Dresden
country: Germany
facility: Medizinische Fakultaet Carl Gustav Carus Technische Universitaet Dresden
city: Giessen
country: Germany
facility: Universitaetsklinikum Giessen
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover Zentrum Innere Medizin Klinik für Pneumologie
city: Heidelberg
country: Germany
facility: Thoraxklinik Heidelberg
city: Homburg
country: Germany
facility: Universitaetsklinikum des Saarlandes
city: Jena
country: Germany
facility: Universitatsklinikum Jena
city: München
country: Germany
facility: Krankenhaus Neuwittelsbach
city: Budapest
country: Hungary
facility: Gottsegen Gyorgy Orszagos Kardiovaszkularis Intezet Felnott kardiologiai osztaly
city: Szeged
country: Hungary
facility: Szegedi Tudományegyetem, Általános Orvostudományi Kar, Családorvosi Intézet és rendelő
city: Tel Aviv
country: Israel
facility: Tel Aviv Medical Center
city: Tel-Hashomer
country: Israel
facility: The Chaim Sheba Medical Center
city: Chieti
country: Italy
facility: Ospedale SS. Annunziata
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Pisa
country: Italy
facility: Fondazione Toscana Gabriele Monasterio CNR
city: Roma
country: Italy
facility: Policlinico Gemelli Universita Cattolica
city: Torino
country: Italy
facility: A.O.U. Città della Salute e della Scienza
city: Bunkyo
country: Japan
facility: The University of Tokyo Hospital
city: Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Hiroshima
country: Japan
facility: Kure Kyosai Hospital
city: Kanagawa
country: Japan
facility: St Marianna University Hospital
city: Kobe
country: Japan
facility: Kobe University Hospital
city: Kyoto
country: Japan
facility: University Hospital Kyoto Prefectural University of Medicine
city: Kyoto
country: Japan
facility: Kyoto University Hospital
city: Matsumoto
country: Japan
facility: Shinshu University Hospital
city: Meguro-ku
country: Japan
facility: Toho University Medical Center, Ohashi Hospital
city: Mitaka
country: Japan
facility: Kyorin University Hospital
city: Nagoya
country: Japan
facility: Nagoya University Hospital
city: Okayama
country: Japan
facility: National Hospital Organization Okayama Medical Center
city: Sapporo-shi
country: Japan
facility: Hokkaido University Hospital
city: Suita-Shi
country: Japan
facility: National Cerebral and Cardiovascular Center
city: Tokyo
country: Japan
facility: Juntendo University Hospital
city: Tsukuba City
country: Japan
facility: University of Tsukuba Hospital
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea Seoul St Marys Hospital
city: Kaunas
country: Lithuania
facility: Lietuvos sveikatos mokslų universiteto ligoninė Kauno klinik
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santariskiu Klinikos
city: Ciudad De México
country: Mexico
facility: Instituto Nacional de Cardiologia Dr. Ignacio Chavez
city: Mexico
country: Mexico
facility: Operadora de Hospitales Angeles SA de CV Hospital Angeles Lomas
city: Monterrey
country: Mexico
facility: Unidad de Investigacion Clinica en Medicina S.C. (UDICEM)
city: Morelia
country: Mexico
facility: Centro de Investigacion Clinica Chapultepec
city: Nuevo Leon
country: Mexico
facility: CRI Centro Regiomontano de Investigacion SC
city: Krakow
country: Poland
facility: Krakowski Szpital Specjalistyczny im Jana Pawla II
city: Lublin
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im Stefana Kardynala Wyszynskiego PZOZ
city: Otwock
country: Poland
facility: Europejskie Centrum Zdrowia Otwock Sp z o o
city: Almada
country: Portugal
facility: Uls Almada Seixal - Hosp. Garcia de Orta
city: Bucuresti
country: Romania
facility: Institutul de urgenta pentru Boli Cardiovasculare Prof. Dr. C.C. Iliescu
city: Tg. Mures
country: Romania
facility: Spitalul Clinic Judetean de Urgenta
city: Kazan
country: Russian Federation
facility: State Autonomous HealthCare Institution 'Interregional Clinical Diagnostic Center'
city: Moscow
country: Russian Federation
facility: Moscow City Clinical Hospital No.51
city: Moscow
country: Russian Federation
facility: National Medical Research Center of Cardiology of MoH of Russian Federation
city: Saint-Petersburg
country: Russian Federation
facility: National medical Research Center n.a. V.A.Almazov of MoH of Russian Federation
city: Volgograd
country: Russian Federation
facility: Volgograd Regional Clinical Cardiology Center
city: Riyadh
country: Saudi Arabia
facility: King Faisal Specialist Hospital & Research Center
city: Riyadh
country: Saudi Arabia
facility: King Fahad Medical City
city: Belgrade
country: Serbia
facility: University Clinical Center of Serbia
city: Sremska Kamenica
country: Serbia
facility: Institute for Pulmonary Disease of Vojvodina
city: Singapore
country: Singapore
facility: National University Heart Centre, Singapore
city: Singapore
country: Singapore
facility: National Heart Centre (NHC) Singapore
city: Bratislava
country: Slovakia
facility: Narodny ustav srdcovych a cievnych chorob
city: Barcelona
country: Spain
facility: Hosp Clinic de Barcelona
city: Madrid
country: Spain
facility: Hosp. Univ. 12 de Octubre
city: Madrid
country: Spain
facility: Hosp. Univ. La Paz
city: Malaga
country: Spain
facility: Hosp. Costa Del Sol
city: Málaga
country: Spain
facility: Hosp Virgen de La Victoria
city: Toledo
country: Spain
facility: Hosp. Gral. Univ. de Toledo
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Veterans General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taoyuan
country: Taiwan
facility: Chang-Gung Memorial Hospital, LinKou Branch
city: Chiang Mai
country: Thailand
facility: Maharaj Nakorn Chiang Mai Hospital
city: Khon Kaen
country: Thailand
facility: Srinagarind Hospital, Khon Kaen University
city: Pathumthani
country: Thailand
facility: Thammasat Hospital
city: Adana
country: Turkey
facility: Adana City Hospital
city: Adana
country: Turkey
facility: Cukurova University Medical Faculty
city: Ankara
country: Turkey
facility: Hacettepe University Medical Faculty
city: Ankara
country: Turkey
facility: Ankara Bilkent Sehir Hastanesi
city: Denizli
country: Turkey
facility: Pamukkale University Medical Faculty
city: Eskisehir
country: Turkey
facility: Eskisehir Osmangazi University Medical Faculty Hospital
city: Istanbul
country: Turkey
facility: Istanbul University - Cerrahpasa Cardiology Institution
city: Istanbul
country: Turkey
facility: Siyami Ersek Training and Research Hospital
city: Istanbul
country: Turkey
facility: Marmara University Medical Faculty
city: Izmir
country: Turkey
facility: Ege University Medical Faculty
city: Izmir
country: Turkey
facility: Dokuz Eylul University Medical Faculty
city: Kartal Istanbul
country: Turkey
facility: Kartal Kosuyolu Yuksek Ihtisas Egitim Ve Arastirma Hastanesi
city: Mersin
country: Turkey
facility: Mersin University Medical Faculty
city: Cherkasy
country: Ukraine
facility: CNE 'Cherkasy Regional Cardiological Center of Cherkasy Regional Council'
city: Dnipro
country: Ukraine
facility: CE 'Dnipropetrovsk Regional Clinical Center of Cardiology and Cardiosurgery'
city: Kyiv
country: Ukraine
facility: SI National Scientific Center Institute of Cardiology of M.D. Strazhesko of NAMS of Ukraine
city: Kyiv
country: Ukraine
facility: State Institute Of Phthisiology And Pulmonology N.A. F.G. Yanovskiy Of Ams Ukraine
city: Lviv
country: Ukraine
facility: Communal Noncommercial Enterprise of Lviv Regional Council 'Lviv Regional Clinical Hospital'
city: Ternopil
country: Ukraine
facility: Municipal Non-commercial Enterprise Ternopil University Hospital of Ternopil Regional Council
city: Cambridge
country: United Kingdom
facility: Papworth Hospital NHS Trust
city: Glasgow
country: United Kingdom
facility: National Waiting Times Centre Board Golden Jubilee National Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS Foundation Trust Royal Hallamshire Hospital
Study officials:
affiliation: Actelion
name: Actelion Clinical Trial
role: STUDY_DIRECTOR
References: