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
2 other identifiers
interventional
187
19 countries
148
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_3
Started Jul 2019
Longer than P75 for phase_3
148 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
April 4, 2019
CompletedFirst Posted
Study publicly available on registry
April 5, 2019
CompletedStudy Start
First participant enrolled
July 29, 2019
CompletedPrimary Completion
Last participant's last visit for primary outcome
August 23, 2022
CompletedResults Posted
Study results publicly available
November 13, 2023
CompletedStudy Completion
Last participant's last visit for all outcomes
September 27, 2024
CompletedDecember 19, 2025
December 1, 2025
3.1 years
April 4, 2019
October 19, 2023
December 4, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
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 Outcomes (4)
Change From Baseline to EDBT in 6-minutes Walking Distance (6MWD)
Baseline, EDBT (Week 16)
Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT
Baseline, EDBT (Week 16)
Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT
Baseline, EDBT (Week 16)
Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT
At Week 16 (EDBT)
Study Arms (3)
FDC therapy + Placebo macitentan + Placebo tadalafil
EXPERIMENTALSubjects to receive FDC macitentan/tadalafil (macitentan 10 mg and tadalafil 40 mg) plus matching placebos for the two other study treatments.
Macitentan mono-therapy + Placebo tadalafil + Placebo FDC
ACTIVE COMPARATORSubjects to receive macitentan 10 mg plus matching placebos for the two other study treatments.
Tadalafil mono-therapy + Placebo macitentan + Placebo FDC
ACTIVE COMPARATORSubjects to receive tadalafil 40 mg (2 x 20 mg) plus matching placebos for the two other study treatments.
Interventions
Film-coated tablet with 40 mg tadalafil (2 x 20 mg tablets), to be administered orally once daily.
Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.
Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.
Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.
Film-coated tablet with 10 mg macitentan and 40 mg tadalafil, to be administered orally once daily.
Film-coated tablet with 10 mg macitentan, to be administered orally once daily.
Eligibility Criteria
You may qualify if:
- 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:
- +3 more criteria
You may not qualify if:
- 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
- +23 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Actelionlead
Study Sites (148)
Providence Medical Foundation
Fullerton, California, 92835, United States
University of Southern California
Los Angeles, California, 90033, United States
Piedmont Healthcare
Atlanta, Georgia, 30309, United States
WellStar Health System
Marietta, Georgia, 30060, United States
OSF HealthCare Cardiovascular Institute
Peoria, Illinois, 61614, United States
University of Iowa Hospitals and Clinics
Iowa City, Iowa, 52242, United States
Norton Healthcare
Louisville, Kentucky, 40202-1332, United States
Sparrow Clinical Research Institute
Lansing, Michigan, 48912, United States
Minneapolis Heart Institute Foundation
Minneapolis, Minnesota, 55407, United States
Washington University School Of Medicine
St Louis, Missouri, 63110, United States
VA Sierra Nevada Health Care System
Reno, Nevada, 89509, United States
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27514, United States
Pitt County Memorial Hospital d/b/a Vidant Medical Center
Greenville, North Carolina, 27835, United States
Sanford Health
Fargo, North Dakota, 58122, United States
University of Cincinnati
Cincinnati, Ohio, 45267, United States
St. Elizabeth Hospital Mercy Bon Secors
Youngstown, Ohio, 44503, United States
Legacy Hospital
Portland, Oregon, 97210, United States
Oregon Health and Science University
Portland, Oregon, 97239, United States
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, 19107, United States
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, 15213, United States
Sanford Health
Sioux Falls, South Dakota, 57105, United States
University of Texas Southwestern Medical Center
Dallas, Texas, 75390, United States
Baylor Scott White - Plano
Plano, Texas, 75093, United States
WVU Health Sciences Center
Morgantown, West Virginia, 26506, United States
University of Wisconsin At Madison
Madison, Wisconsin, 53792, United States
Medical College of Wisconsin Froedtert Hospital
Milwaukee, Wisconsin, 53226, United States
Royal Adelaide Hospital
Adelaide, 5000, Australia
Pulmonary Arterial Hypertension Clinic
Hobart, 7000, Australia
Core Research Group
Milton, 4064, Australia
Universidade Federal De Minas Gerais - Hospital das Clínicas
Belo Horizonte, 30130-100, Brazil
Instituto das Pequenas Missionárias de Maria Imaculada - Hospital Madre Teresa
Belo Horizonte, 30441-070, Brazil
Fundacao para o Desenvolvimento Medico Hospitalar (UNESP Botucatu)
Botucatu, 18618-686, Brazil
Secretaria da Saude do Estado do Ceara - Hospital Doutor Carlos Alberto Studart Gomes
Fortaleza, 60840-285, Brazil
Universidade Federal de Goias - Hospital das Clinicas da UFG
Goiânia, 74605-020, Brazil
Hospital das Clinicas de Porto Alegre
Porto Alegre, 90035-007, Brazil
Irmandade Santa Casa de Misericordia de Porto Alegre
Porto Alegre, 90035-074, Brazil
Uniao Brasileira de Educacao e Assistencia Hospital Sao Lucas da PUCRS
Porto Alegre, 90610-000, Brazil
SPDM - Associacao Paulista para o Desenvolvimento da Medicina - Hospital Sao Paulo
São Paulo, 04024-002, Brazil
Hospital Das Clinicas Da Faculdade De Medicina Da USP
São Paulo, 05403-000, Brazil
National Heart Hospital
Sofia, 1309, Bulgaria
University Multiprofile Hospital for Active Treatment- UMHAT Sveta Anna AD
Sofia, 1750, Bulgaria
Alberta Health Services
Calgary, Alberta, T1Y 6J4, Canada
University of Alberta
Edmonton, Alberta, T6G 2G3, Canada
Vancouver General Hospital
Vancouver, British Columbia, V5Z 1M9, Canada
London Health Sciences Centre
London, Ontario, N6A 5W9, Canada
Beijing Anzhen Hospital
Beijing, 100029, China
The Second Xiangya Hospital of Central South Hospital
Changsha, 410011, China
The First Affiliated Hospital of Guangzhou Medical University
Guangzhou, 510120, China
Jiangsu Province Hospital
Nanjing, China
Shanghai Pulmonary Hospital
Shanghai, 200433, China
The General Hospital of Northern Theater Command
Shenyang, 110000, China
Tianjin Medical University General Hospital
Tianjin, 300052, China
The First Affiliated Hospital of Xian Jiaotong University
Xi'an, 710061, China
General University Hospital II.department of Internal Medicine-cardiology and angiology
Prague, 128 08, Czechia
Universitatsklinikum Bonn
Bonn, 53105, Germany
Universitatsklinikum Carl Gustav Carus Dresden
Dresden, 01307, Germany
Universitaetsklinikum Giessen
Giessen, 35392, Germany
Universitat Greifswald
Greifswald, 17475, Germany
Universitaetsklinikum Hamburg Eppendorf
Hamburg, 20246, Germany
Thoraxklinik am Universitatsklinikum Heidelberg
Heidelberg, 69126, Germany
Kardiologische Praxis Papenburg
Papenburg, 26871, Germany
Universitaetsklinikum Regensburg
Regensburg, 93053, Germany
Klinikum Würzburg Mitte gGmbH Standort Missioklinik
Würzburg, 97074, Germany
Semmelweis Egyetem,Pulmonológiai Klinika
Budapest, 1083, Hungary
Gottsegen György Országos Kardiológiai Intézet, Felnőtt kardiológiai osztály
Budapest, 1096, Hungary
Pecsi Tudomanyegyetem Klinikai Kozpont
Pécs, 7624, Hungary
Szegedi Tudomanyegyetem
Szeged, 6725, Hungary
Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari
Bari, 70124, Italy
Cardiologia c/o Spedali Civili
Brescia, 25123, Italy
Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
Milan, 20122, Italy
Azienda Ospedaliera San Gerardo
Monza, 20090, Italy
Ospedale San Francesco
Nuoro, 08100, Italy
IRCCS Policlinico San Matteo, Università degli studi di Pavi
Pavia, 27100, Italy
Policlinico Umberto I
Roma, 00161, Italy
The University of Tokyo Hospital
Bunkyō City, 113-8655, Japan
Chiba University Hospital
Chiba, 260 8677, Japan
Kyushu University Hospital
Fukuoka, 812 8582, Japan
Fukushima Medical University Hospital
Fukushima, 960 1295, Japan
Gunma University Hospital
Gunma, 371-0034, Japan
Kure Kyosai Hospital
Hiroshima, 737-8505, Japan
Tokai University Hospital
Isehara, 259-1193, Japan
Kagoshima University Hospital
Kagoshima, 890-8544, Japan
Kanazawa University Hospital
Kanazawa, 920 8641, Japan
Kobe University Hospital
Kobe, 650 0017, Japan
Kumamoto University Hospital
Kumamoto, 860-8556, Japan
Kurume University Hospital
Kurume, 830-0011, Japan
University Hospital Kyoto Prefectural University of Medicine
Kyoto, 602-8566, Japan
Kyoto University Hospital
Kyoto, 606 8507, Japan
Shinshu University Hospital
Matsumoto, 390 8621, Japan
Kyorin University Hospital
Mitaka, 181-8611, Japan
Nagasaki University Hospital
Nagasaki, 852-8501, Japan
Okayama University Hospital
Okayama, 700 8558, Japan
National Hospital Organization Okayama Medical Center
Okayama, 701-1192, Japan
Sapporo Medical University Hospital
Sapporo, 060-8543, Japan
Hokkaido University Hospital
Sapporo, 060-8648, Japan
Tohoku University Hospital
Sendai, 980 8574, Japan
National Cerebral and Cardiovascular Center
Suita-Shi, 564-8565, Japan
Juntendo University Hospital
Tokyo, 113-8431, Japan
Mie University Hospital
Tsu, 514 8507, Japan
University of Tsukuba Hospital
Tsukuba, 305 8576, Japan
Institut Jantung Negara (National Heart Institute)
Kuala Lumpur, 50400, Malaysia
Sarawak Heart Center
Kuching, 94300, Malaysia
Instituto Nacional de Cardiologia Dr. Ignacio Chavez
México, 14080, Mexico
Unidad de Investigacion Clinica en Medicina S.C. (UDICEM)
Monterrey, 64718, Mexico
Klinika Kardiologii Z Oddzialem Intensywnego Nadzoru Kardiologicznego UM W Bialymstoku
Bialystok, 15 276, Poland
Szpital Uniwersytecki nr 2 im dr Jana Biziela w Bydgoszczy, Klinika Kardiologii
Bydgoszcz, 85-168, Poland
Uniwersyteckie Centrum Kliniczne
Gdansk, 80 214, Poland
GCM SUM I Oddzial Kardiologii
Katowice, 40 635, Poland
Oddzial Kardiologii Wojewodzki Szpital Specjalistyczny im W Bieganskiego
Lodz, 91 347, Poland
Wojewodzki Szpital Specjalistyczny im. Stefana Kardynala Wyszynskiego SPZOZ, Oddzial Kardiologii
Lublin, 20-718, Poland
ECZ Otwock Klinika Kardiologii Klinika Krazenia Plucnego Chorob Zakrzepowo Zatorowych i Kardiologii
Otwock, 05-400, Poland
Uniwersytecki Szpital Kliniczny nr 2 PUM Klinika Kardiologii
Szczecin, 70 111, Poland
Wojewodzki Szpital Specjalistyczny Oddzial Kardiologiczny
Wroclaw, 51 124, Poland
Altay Regional Cardiological Dispensary
Barnaul, 656055, Russia
Scientific and Research Institution of Cardiovascular Diseases Complex Problems
Kemerovo, 650002, Russia
National Medical Research Center of Cardiology of MoH of Russian Federation
Moscow, 121552, Russia
GU Moscow Regional Research Clinical Institute n.a. M.F.Vla
Moscva, 129090, Russia
National medical Research Center n.a. V.A.Almazov of MoH of Russian Federation
Saint Petersburg, 197341, Russia
Samara Regional Clinical Cardiological Dispensary
Samara, 443070, Russia
Abdullah, IA
Durban, 4001, South Africa
Dr Kalla
Lenasia, 1820, South Africa
Hosp Clinic de Barcelona
Barcelona, 08036, Spain
Hosp Univ Vall D Hebron
Barcelona, 8035, Spain
Hosp. Univ. Ramon Y Cajal
Madrid, 28034, Spain
Hosp Univ Fund Jimenez Diaz
Madrid, 28040, Spain
Hosp. Univ. La Paz
Madrid, 28046, Spain
Hosp Clinico Univ de Salamanca
Salamanca, 37007, Spain
Hosp. Univ. Marques de Valdecilla
Santander, 39011, Spain
Hosp. Virgen de La Salud
Toledo, 45004, Spain
Hosp. Gral. Univ. Valencia
Valencia, 46014, Spain
Kaohsiung Veterans General Hospital
Kaohsiung City, 813, Taiwan
National Cheng Kung University Hospital
Tainan, 704, Taiwan
National Taiwan University Hospital
Taipei, 10002, Taiwan
Mackay Memorial Hospital
Taipei, 10449, Taiwan
Taipei Veterans General Hospital
Taipei, 112, Taiwan
Chang-Gung Memorial Hospital, LinKou Branch
Taoyuan District, 333, Taiwan
Cukurova University Medical Faculty
Adana, 01790, Turkey (Türkiye)
Hacettepe University Medical Faculty
Ankara, 6100, Turkey (Türkiye)
Ankara University Medical Faculty
Ankara, 6500, Turkey (Türkiye)
Bursa Yuksek Ihtisas Training and Research Hospital
Bursa, 16310, Turkey (Türkiye)
Istanbul University - Cerrahpasa Cardiology Institution
Istanbul, 34096, Turkey (Türkiye)
Istanbul University Cerrahpasa Medical Faculty
Istanbul, 34096, Turkey (Türkiye)
Marmara University Medical Faculty
Istanbul, 34899, Turkey (Türkiye)
Ege University School of Medicine
Izmir, 35100, Turkey (Türkiye)
Dokuz Eylul University Hospital
Izmir, 35340, Turkey (Türkiye)
Kartal Kosuyolu Yuksek Ihtisas Egitim Ve Arastirma Hastanesi
Kartal Istanbul, 34865, Turkey (Türkiye)
Konya Selcuk University Medical Faculty
Konya, 42131, Turkey (Türkiye)
Mersin University Medical Faculty
Mersin, 33110, Turkey (Türkiye)
Related Publications (3)
Ford HJ, Chin KM, Fan F, Friberg M, Grunig E, Hauser JA, Pannaux M, Rofael H, Jansa P. Long-Term Treatment with Single-Tablet Combination of Macitentan and Tadalafil in Pulmonary Arterial Hypertension: Results from A DUE and Its Open-Label Period. Adv Ther. 2026 Mar 12. doi: 10.1007/s12325-026-03525-3. Online ahead of print.
PMID: 41820779DERIVEDFan 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.
PMID: 41250682DERIVEDGrunig 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.
PMID: 38267108DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Clinical Scientific Leader
- Organization
- Actelion Pharmaceuticals Ltd.
Study Officials
- STUDY DIRECTOR
Hany Rofael, MD
Janssen, LP
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- OTHER
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- INDUSTRY
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
April 4, 2019
First Posted
April 5, 2019
Study Start
July 29, 2019
Primary Completion
August 23, 2022
Study Completion
September 27, 2024
Last Updated
December 19, 2025
Results First Posted
November 13, 2023
Record last verified: 2025-12
Data Sharing
- IPD Sharing
- Will share
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.