Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH) (A DUE)

Prospective, Multi-center, Double-blind, Randomized, Active-controlled, Triple-dummy, Parallel-group, Group-sequential, Adaptive Phase 3 Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed Dose Combination in Subjects With Pulmonary Arterial Hypertension (PAH), Followed by an Open-label Treatment Period With Macitentan and Tadalafil Fixed Dose Combination Therapy

Combination therapy in pulmonary arterial hypertension (PAH) has been the subject of active investigation for more than a decade, with the benefit of targeting different pathways known to be involved in the pathogenesis of the disease. Adherence to prescribed therapy has an impact on clinical outcomes. Reducing the pill/tablet count and frequency has a major impact on patients' adherence to therapies and therefore the observed clinical outcomes. One way to simplify treatment is to use fixed-dose combination (FDC) products that combine multiple treatments targeting different pathways into a single tablet.

This study aims to demonstrate that the FDC of macitentan and tadalafil is more effective than therapy with 10 mg of macitentan alone or 40 mg of tadalafil alone. This phase 3 study will evaluate the efficacy and safety at 16 weeks of an FDC (macitentan 10 mg and tadalafil 40 mg) against these two PAH-approved therapies given as monotherapy to further confirm the added value of the FDC.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)
• Intervention / Treatment: Drug: FDC macitentan/tadalafil; Drug: Placebo macitentan; Drug: Placebo tadalafil; Drug: Macitentan 10 mg; Drug: Placebo FDC; Drug: Tadalafil 40 mg

Detailed Description

PAH is characterized by a progressive increase in pulmonary arterial pressure (PAP) and in pulmonary vascular resistance (PVR) potentially leading to right heart failure and death. Current PAH-specific therapeutic options include treatments that target the three pathways (endothelin, nitric oxide, and prostacyclin pathways). While combination treatment is common, FDC pills or tablets that combine two or more PAH-specific therapies are not available, thereby requiring participants to take multiple pills/tablets daily. An FDC is an attractive option for PAH participants because it simplifies the treatment regimen by combining two therapies (which would otherwise involve a total of three tablets: one macitentan 10 mg tablet and two tadalafil 20 mg tablets) into a single tablet. Macitentan is an orally active, non-peptide, potent dual endothelin receptor A and B antagonist. Tadalafil is a selective inhibitor of phosphodiesterase type-5 (PDE-5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). This study comprises the following consecutive periods: Screening period (lasts up to 30 days), Double-blind treatment period (consists of the titration phase [the first 2 weeks] and the maintenance phase [Week 3 through Week 16]), Open-label treatment period, End-of-Treatment (EOT), Safety follow-up (S-FU) period, and End of Study (EOS). The total study duration for a participant will be up to 30 months. Study assessments like physical examinations, vital signs, right heart catheterization, 6-minute walk test will be performed. Safety will be assessed throughout the study.

• Study Type: Interventional
• Enrollment (Actual): 187
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Royal Adelaide Hospital
  • Hobart, Australia, 7000
    • Pulmonary Arterial Hypertension Clinic
  • Milton, Australia, 4064
    • Core Research Group
• Brazil
  • Belo Horizonte, Brazil, 30441-070
    • Instituto das Pequenas Missionárias de Maria Imaculada - Hospital Madre Teresa
  • Belo Horizonte, Brazil, 30130-100
    • Universidade Federal De Minas Gerais - Hospital das Clínicas
  • Botucatu, Brazil, 18618-686
    • Fundacao para o Desenvolvimento Medico Hospitalar (UNESP Botucatu)
  • Fortaleza, Brazil, 60840-285
    • Secretaria da Saude do Estado do Ceara - Hospital Doutor Carlos Alberto Studart Gomes
  • Goiânia, Brazil, 74605-020
    • Universidade Federal de Goias - Hospital das Clinicas da UFG
  • Porto Alegre, Brazil, 90035-007
    • Hospital das Clinicas de Porto Alegre
  • Porto Alegre, Brazil, 90035-074
    • Irmandade Santa Casa de Misericordia de Porto Alegre
  • Porto Alegre, Brazil, 90610-000
    • Uniao Brasileira de Educaçao e Assistência Hospital São Lucas da PUCRS
  • São Paulo, Brazil, 05403-000
    • Hospital das Clinicas da Faculdade de Medicina da USP
  • São Paulo, Brazil, 04024-002
    • SPDM - Associacao Paulista para o Desenvolvimento da Medicina - Hospital Sao Paulo
• Bulgaria
  • Sofia, Bulgaria, 1309
    • National Heart Hospital
  • Sofia, Bulgaria, 1750
    • University Multiprofile Hospital for Active Treatment- UMHAT Sveta Anna AD
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y 6J4
      • Alberta Health Services
    • Edmonton, Alberta, Canada, T6G 2G3
      • University of Alberta
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver General Hospital
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Centre
• China
  • Beijing, China, 100029
    • Beijing Anzhen Hospital
  • Changsha, China, 410011
    • The Second Xiangya Hospital of Central South Hospital
  • Guangzhou, China, 510120
    • The First Affiliated Hospital of Guangzhou Medical University
  • Nanjing, China
    • Jiangsu Province Hospital
  • Shanghai, China, 200433
    • Shanghai Pulmonary Hospital
  • Shenyang, China, 110000
    • The General Hospital of Northern Theater Command
  • Tianjin, China, 300052
    • Tianjin Medical University General Hospital
  • Xi'an, China, 710061
    • The First Affiliated Hospital of Xian Jiaotong University
• Czechia
  • Prague, Czechia, 128 08
    • General University Hospital II.department of Internal Medicine-cardiology and angiology
• Germany
  • Bonn, Germany, 53105
    • Universitätsklinikum Bonn
  • Dresden, Germany, 01307
    • Universitätsklinikum Carl Gustav Carus Dresden
  • Giessen, Germany, 35392
    • Universitaetsklinikum Giessen
  • Greifswald, Germany, 17475
    • Universitat Greifswald
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg Eppendorf
  • Heidelberg, Germany, 69126
    • Thoraxklinik am Universitatsklinikum Heidelberg
  • Papenburg, Germany, 26871
    • Kardiologische Praxis Papenburg
  • Regensburg, Germany, 93053
    • Universitaetsklinikum Regensburg
  • Würzburg, Germany, 97074
    • Klinikum Würzburg Mitte gGmbH Standort Missioklinik
• Hungary
  • Budapest, Hungary, 1096
    • Gottsegen Gyorgy Orszagos Kardiologiai Intezet, Felnott kardiologiai osztaly
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem,Pulmonológiai Klinika
  • Pécs, Hungary, 7624
    • Pecsi Tudomanyegyetem Klinikai Kozpont
  • Szeged, Hungary, 6725
    • Szegedi Tudomanyegyetem
• Italy
  • Bari, Italy, 70124
    • Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari
  • Brescia, Italy, 25123
    • Cardiologia c/o Spedali Civili
  • Milan, Italy, 20122
    • Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
  • Monza, Italy, 20090
    • Azienda Ospedaliera San Gerardo
  • Nuoro, Italy, 08100
    • Ospedale San Francesco
  • Pavia, Italy, 27100
    • Irccs Policlinico San Matteo, Universita Degli Studi Di Pavi
  • Roma, Italy, 00161
    • Policlinico Umberto I
• Japan
  • Bunkyō City, Japan, 113-8655
    • The University of Tokyo Hospital
  • Chiba, Japan, 260 8677
    • Chiba University Hospital
  • Fukuoka, Japan, 812 8582
    • Kyushu University Hospital
  • Fukushima, Japan, 960 1295
    • Fukushima Medical University Hospital
  • Gunma, Japan, 371-0034
    • Gunma University Hospital
  • Hiroshima, Japan, 737-8505
    • Kure Kyosai Hospital
  • Isehara, Japan, 259-1193
    • Tokai University Hospital
  • Kagoshima, Japan, 890-8544
    • Kagoshima University Hospital
  • Kanazawa, Japan, 920 8641
    • Kanazawa University Hospital
  • Kobe, Japan, 650 0017
    • Kobe University Hospital
  • Kumamoto, Japan, 860-8556
    • Kumamoto University Hospital
  • Kurume, Japan, 830-0011
    • Kurume 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
  • Mitaka, Japan, 181-8611
    • Kyorin University Hospital
  • Nagasaki, Japan, 852-8501
    • Nagasaki University Hospital
  • Okayama, Japan, 701-1192
    • National Hospital Organization Okayama Medical Center
  • Okayama, Japan, 700 8558
    • Okayama University Hospital
  • Sapporo, Japan, 060-8648
    • Hokkaido University Hospital
  • Sapporo, Japan, 060-8543
    • Sapporo Medical University Hospital
  • Sendai, Japan, 980 8574
    • Tohoku University Hospital
  • Suita-Shi, Japan, 564-8565
    • National Cerebral and Cardiovascular Center
  • Tokyo, Japan, 113-8431
    • Juntendo University Hospital
  • Tsu, Japan, 514 8507
    • Mie University Hospital
  • Tsukuba, Japan, 305 8576
    • University of Tsukuba Hospital
• Malaysia
  • Kuala Lumpur, Malaysia, 50400
    • Institut Jantung Negara (National Heart Institute)
  • Kuching, Malaysia, 94300
    • Sarawak Heart Center
• Mexico
  • Monterrey, Mexico, 64718
    • Unidad de Investigacion Clinica en Medicina S.C. (UDICEM)
  • México, Mexico, 14080
    • Instituto Nacional de Cardiologia Dr. Ignacio Chavez
• Poland
  • Bialystok, Poland, 15 276
    • Klinika Kardiologii Z Oddzialem Intensywnego Nadzoru Kardiologicznego UM W Bialymstoku
  • Bydgoszcz, Poland, 85-168
    • Szpital Uniwersytecki nr 2 im dr Jana Biziela w Bydgoszczy, Klinika Kardiologii
  • Gdansk, Poland, 80 214
    • Uniwersyteckie Centrum Kliniczne
  • Katowice, Poland, 40 635
    • GCM SUM I Oddzial Kardiologii
  • Lodz, Poland, 91 347
    • Oddzial Kardiologii Wojewodzki Szpital Specjalistyczny im W Bieganskiego
  • Lublin, Poland, 20-718
    • Wojewodzki Szpital Specjalistyczny im. Stefana Kardynala Wyszynskiego SPZOZ, Oddzial Kardiologii
  • Otwock, Poland, 05-400
    • ECZ Otwock Klinika Kardiologii Klinika Krazenia Plucnego Chorob Zakrzepowo Zatorowych i Kardiologii
  • Szczecin, Poland, 70 111
    • Uniwersytecki Szpital Kliniczny nr 2 PUM Klinika Kardiologii
  • Wroclaw, Poland, 51 124
    • Wojewodzki Szpital Specjalistyczny Oddzial Kardiologiczny
• Russia
  • Barnaul, Russia, 656055
    • Altay Regional Cardiological Dispensary
  • Kemerovo, Russia, 650002
    • Scientific and Research Institution of Cardiovascular Diseases Complex Problems
  • Moscow, Russia, 121552
    • National Medical Research Center of Cardiology of MoH of Russian Federation
  • Moscva, Russia, 129090
    • GU Moscow Regional Research Clinical Institute n.a. M.F.Vla
  • Saint Petersburg, Russia, 197341
    • National medical Research Center n.a. V.A.Almazov of MoH of Russian Federation
  • Samara, Russia, 443070
    • Samara Regional Clinical Cardiological Dispensary
• South Africa
  • Durban, South Africa, 4001
    • Abdullah, IA
  • Lenasia, South Africa, 1820
    • Dr Kalla
• Spain
  • Barcelona, Spain, 08036
    • Hosp Clinic de Barcelona
  • Barcelona, Spain, 8035
    • Hosp Univ Vall D Hebron
  • Madrid, Spain, 28034
    • Hosp. Univ. Ramon Y Cajal
  • Madrid, Spain, 28046
    • Hosp. Univ. La Paz
  • Madrid, Spain, 28040
    • Hosp Univ Fund Jimenez Diaz
  • Salamanca, Spain, 37007
    • Hosp Clinico Univ de Salamanca
  • Santander, Spain, 39011
    • Hosp. Univ. Marques de Valdecilla
  • Toledo, Spain, 45004
    • Hosp. Virgen de La Salud
  • Valencia, Spain, 46014
    • Hosp. Gral. Univ. Valencia
• Taiwan
  • Kaohsiung City, Taiwan, 813
    • Kaohsiung Veterans General Hospital
  • Tainan, Taiwan, 704
    • National Cheng Kung University Hospital
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
  • Taipei, Taiwan, 10449
    • Mackay Memorial Hospital
  • Taipei, Taiwan, 112
    • Taipei Veterans General Hospital
  • Taoyuan District, Taiwan, 333
    • Chang-Gung Memorial Hospital, Linkou Branch
• Turkey (Türkiye)
  • Adana, Turkey (Türkiye), 01790
    • Cukurova University Medical Faculty
  • Ankara, Turkey (Türkiye), 6100
    • Hacettepe University Medical Faculty
  • Ankara, Turkey (Türkiye), 6500
    • Ankara University Medical Faculty
  • Bursa, Turkey (Türkiye), 16310
    • Bursa Yuksek Ihtisas Training and Research Hospital
  • Istanbul, Turkey (Türkiye), 34096
    • Istanbul University Cerrahpasa Medical Faculty
  • Istanbul, Turkey (Türkiye), 34899
    • Marmara University Medical Faculty
  • Istanbul, Turkey (Türkiye), 34096
    • Istanbul University - Cerrahpasa Cardiology Institution
  • Izmir, Turkey (Türkiye), 35100
    • Ege University School of Medicine
  • Izmir, Turkey (Türkiye), 35340
    • Dokuz Eylul University Hospital
  • Kartal Istanbul, Turkey (Türkiye), 34865
    • Kartal Koşuyolu Yüksek İhtisas Eğitim ve Araştirma Hastanesi
  • Konya, Turkey (Türkiye), 42131
    • Konya Selcuk University Medical Faculty
  • Mersin, Turkey (Türkiye), 33110
    • Mersin University Medical Faculty
• United States
  • California
    • Fullerton, California, United States, 92835
      • Providence Medical Foundation
    • Los Angeles, California, United States, 90033
      • University of Southern California
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Piedmont Healthcare
    • Marietta, Georgia, United States, 30060
      • Wellstar Health System
  • Illinois
    • Peoria, Illinois, United States, 61614
      • OSF HealthCare Cardiovascular Institute
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kentucky
    • Louisville, Kentucky, United States, 40202-1332
      • Norton Healthcare
  • Michigan
    • Lansing, Michigan, United States, 48912
      • Sparrow Clinical Research Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Minneapolis Heart Institute Foundation
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nevada
    • Reno, Nevada, United States, 89509
      • VA Sierra Nevada Health Care System
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • The University of North Carolina at Chapel Hill
    • Greenville, North Carolina, United States, 27835
      • Pitt County Memorial Hospital d/b/a Vidant Medical Center
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • Sanford Health
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Youngstown, Ohio, United States, 44503
      • St. Elizabeth Hospital Mercy Bon Secors
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97210
      • Legacy Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • University Of Pittsburgh Medical Center
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Sanford Health
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Plano, Texas, United States, 75093
      • Baylor Scott White - Plano
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • WVU Health Sciences Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin At Madison
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin Froedtert Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Signed and dated informed consent form (ICF)
• Confirmed diagnosis of symptomatic PAH in WHO FC II or III

• Symptomatic PAH belonging to one of the following subgroups of WHO Group 1 pulmonary hypertension:

  • Idiopathic
  • Heritable
  • Drug- or toxin-induced
  • Associated with connective tissue disease, HIV infection, portal hypertension or congenital heart disease with simple systemic-to-pulmonary shunt with persistent pulmonary hypertension documented by a right heart catheterization (RHC) ≥ 1 year after surgical repair

• PAH diagnosis confirmed by hemodynamic evaluation at rest (through central reading), evaluated within 5 weeks prior to randomization:

  • Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, AND
  • Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg, AND
  • Pulmonary vascular resistance (PVR) ≥ 3 WU (i.e., ≥ 240 dyn∙sec∙cm-5)
• Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH. (Participants for whom no vasoreactivity test was performed at diagnosis can be eligible if currently treated with PAH therapy for more than 3 months and PAH diagnosis confirmed by hemodynamic evaluation at least 3 months after introduction of their PAH therapy).
• Currently receiving a stable dose of ERA or PDE-5i monotherapy for at least 3 months prior to baseline RHC, within the prespecified doses in the study protocol or no history of PAH-specific treatment
• Participant able to perform the 6MWT with a minimum distance of 100 m and maximum distance of 450 m at Screening

• A woman of childbearing potential must:

  • have negative serum pregnancy test at Screening and a negative urine pregnancy test at Randomization
  • agree to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation
  • agree to follow the contraception scheme from Screening up to at least 30 days after study treatment discontinuation

Exclusion Criteria:

• Treatment with a soluble guanylate cyclase stimulator, L-arginine, any form of prostanoids or prostacyclin-receptor agonists (including oral, inhaled, or infused routes) in the 3-month period prior to start of treatment
• Treatment with combination therapy of ERA and PDE-5i in the 3-month period prior to start of treatment or history of intolerance to ERA and PDE-5i combination therapy
• Hypersensitivity to any of the study treatments or any excipient of their formulations
• Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer in the 1-month period prior to start of treatment
• Treatment with a strong CYP3A4 inhibitor or a moderate dual CYP3A4/CYP2C9 inhibitor or co-administration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors in the 1-month period prior to start of treatment
• Treatment with doxazosin
• Treatment with any form of organic nitrate, either regularly or intermittently
• Diuretic treatment initiated or dose changed within 1 week prior to the RHC or start of treatment
• Treatment with another investigational drug in the 3-month period prior to start of treatment
• Body mass index (BMI) > 40 kg/m2 at Screening

• Known presence of three or more of the following risk factors for heart failure with preserved ejection fraction at Screening:

  • BMI > 30 kg/m2
  • Diabetes mellitus of any type
  • Essential hypertension (even if well controlled)
  • Coronary artery disease, i.e. history of stable angina or known more than 50% stenosis in a coronary artery or history of myocardial infarction or history of or planned coronary artery bypass grafting and/or coronary artery stenting
• Known presence of moderate or severe obstructive lung disease any time prior to Screening as specified in study protocol
• Known presence of moderate or severe restrictive lung disease any time prior to Screening as specified in study protocol
• Clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or congestive left-sided cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular dysfunction; or left ventricular outflow obstruction, in the opinion of the investigator
• Known permanent atrial fibrillation, in the opinion of the investigator
• Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism)
• Documented pulmonary veno-occlusive disease
• Hemoglobin < 100 g/L (<10 g/dL) at Screening
• Known severe hepatic impairment as specified in study protocol
• Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 × upper limit of normal (ULN) at Screening
• Severe renal impairment at Screening as specified in study protocol
• Systemic hypotension at Screening or Randomization and systemic hypertension at Screening as specified in study protocol
• Acute myocardial infarction or cerebrovascular event (e.g., stroke) within the last 26 weeks prior to Screening
• Known bleeding disorder, in the opinion of the investigator
• Loss of vision in one or both eyes because of non-arteritic anterior ischemic optic neuropathy
• Hereditary degenerative retinal disorders, including retinitis pigmentosa
• History of priapism, conditions that predispose to priapism (example, sickle cell anemia, multiple myeloma, or leukemia) or anatomical deformation of the penis (example, angulation, cavernosal fibrosis, or Peyronie's disease)
• Difficulty swallowing large pills/tablets that would interfere with the ability to comply with study treatment regimen
• Any planned surgical intervention (including organ transplant) during the double-blind treatment period, except minor interventions
• Exercise training program for cardiopulmonary rehabilitation in the 12-week period prior to start of treatment, or planned to be started during the double-blind period of the study
• Pregnant, planning to become pregnant or lactating
• Any known factor or disease that might interfere with treatment adherence, full participation in the study or interpretation of the results as judged by the investigator (e.g., drug or alcohol dependence etc.)
• Known concomitant life-threatening disease with a life expectancy less than (<) 12 months
• Calcium channel blocker treatment initiated, or dose changed within 3 months prior to right heart catheterization (RHC) at screening

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FDC therapy + Placebo macitentan + Placebo tadalafil; Subjects to receive FDC macitentan/tadalafil (macitentan 10 mg and tadalafil 40 mg) plus matching placebos for the two other study treatments.	Drug: FDC macitentan/tadalafil; Film-coated tablet with 10 mg macitentan and 40 mg tadalafil, to be administered orally once daily.; Other Names: ACT-064992D; Drug: Placebo macitentan; Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.; Drug: Placebo tadalafil; Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.
Active Comparator: Macitentan mono-therapy + Placebo tadalafil + Placebo FDC; Subjects to receive macitentan 10 mg plus matching placebos for the two other study treatments.	Drug: Placebo tadalafil; Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.; Drug: Macitentan 10 mg; Film-coated tablet with 10 mg macitentan, to be administered orally once daily.; Other Names: ACT-064992; Drug: Placebo FDC; Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.
Active Comparator: Tadalafil mono-therapy + Placebo macitentan + Placebo FDC; Subjects to receive tadalafil 40 mg (2 x 20 mg) plus matching placebos for the two other study treatments.	Drug: Placebo macitentan; Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.; Drug: Placebo FDC; Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.; Drug: Tadalafil 40 mg; Film-coated tablet with 40 mg tadalafil (2 x 20 mg tablets), to be administered orally once daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline	Change in PVR expressed as the ratio of geometric means of EDBT to baseline were reported.	Baseline, EDBT (up to 16 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to EDBT in 6-minutes Walking Distance (6MWD)	Change from baseline to EDBT in 6MWD were reported. 6MWD was measured by 6-minute walk test (6MWT). The 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, EDBT (Week 16)
Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT	Change from baseline in PAH-SYMPACT in cardiopulmonary symptom domain scores to EDBT were reported. PAH-SYMPACT was a pulmonary arterial hypertension (PAH)-specific patient-reported outcomes questionnaire that consists of 11 symptoms items, 11 impacts items and 1 item on oxygen use. The symptom items were divided into cardiopulmonary and cardiovascular domains, and the impact items were divided into physical and emotional/cognitive domains. Cardiopulmonary symptoms contain 6 items; shortness of breath, fatigue, lack of energy, swelling in ankles or legs, swelling in stomach area, and cough. Scores for the individual items were reported on a 5-point Likert scale, ranging from 0 (no symptom at all) to 4 (very severe symptoms), with higher scores indicated greater symptom severity.	Baseline, EDBT (Week 16)
Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT	Change from baseline in PAH-SYMPACT in cardiovascular symptom domain scores to EDBT were reported. PAH-SYMPACT is a PAH-specific patient-reported outcomes questionnaire that consists of 11 symptoms items, 11 impacts items and 1 item on oxygen use. The symptom items were divided into cardiopulmonary and cardiovascular domains, and the impact items were divided into physical and emotional/cognitive domains. Cardiovascular symptoms contain 5 items; heart palpitations (heart fluttering), rapid heartbeat, chest pain, chest tightness, and lightheadedness. Scores for the individual items were reported on a 5-point Likert scale, ranging from 0 (no symptom at all) to 4 (very severe symptom), with higher scores indicated greater symptom severity.	Baseline, EDBT (Week 16)
Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT	Percentage of participants with absence of worsening in FC from baseline to EDBT were reported. The study was adaptive with two stages: Stage 1 and Stage 2. WHO functional classification (FC), PAH range from Class I (no limitation in physical activity, no dyspnea or fatigue, chest pain, or near syncope with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity), Class IV (cannot perform a physical activity without any symptoms, dyspnea and/or fatigue at rest).	At Week 16 (EDBT)

Collaborators and Investigators

• Sponsor: Actelion
• Investigators: Study Director: Hany Rofael, MD, Janssen, LP

Publications and helpful links

General Publications

• Grunig E, Jansa P, Fan F, Hauser JA, Pannaux M, Morganti A, Rofael H, Chin KM. Randomized Trial of Macitentan/Tadalafil Single-Tablet Combination Therapy for Pulmonary Arterial Hypertension. J Am Coll Cardiol. 2024 Jan 30;83(4):473-484. doi: 10.1016/j.jacc.2023.10.045.
• Fan F, Sun L, Yang Z, Wang L, Wang Q, Li J, Gu H, Xie W, Zhang N, Bin J, Rofael H, Friberg M, Hauser JA. Macitentan Plus Tadalafil Single-Tablet Combination Therapy in Chinese Patients With Pulmonary Arterial Hypertension: A Subgroup Analysis of the A DUE Study. Pulm Circ. 2025 Nov 16;15(4):e70194. doi: 10.1002/pul2.70194. eCollection 2025 Oct.

Helpful Links

• RRF KOM slides

Study record dates

Study Major Dates

• Study Start (Actual): July 29, 2019
• Primary Completion (Actual): August 23, 2022
• Study Completion (Actual): September 27, 2024

Study Registration Dates

• First Submitted: April 4, 2019
• First Submitted That Met QC Criteria: April 4, 2019
• First Posted (Actual): April 5, 2019

Study Record Updates

• Last Update Posted (Estimated): December 19, 2025
• Last Update Submitted That Met QC Criteria: December 4, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Pulmonary Arterial Hypertension; PAH; macitentan; tadalafil; fixed dose combination therapy
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indoles; Indole Alkaloids; Heterocyclic Compounds, 3-Ring; Carbolines; Tadalafil; macitentan
• Other Study ID Numbers: AC-077A301 (Other Identifier: Actelion Pharmaceuticals Ltd); 2014-004786-25 (EudraCT Number)

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