AzTrials
AzTrials

Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)Phase 3A DUENCT03904693

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 Phase 3 study testing FDC macitentan/tadalafil, Macitentan 10 mg and Tadalafil 40 mg in people with Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH), run by Actelion at 148 sites in 19 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
FDC macitentan/tadalafil, Macitentan 10 mg and Tadalafil 40 mg
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
187 participants
Where
148 sitesin 19 countries
Study dates
29 Jul 2019to 27 Sep 2024
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 18Show fewer
  • 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

Who cannot join

  • 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
Show all 38Show fewer
  • 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

Trial locations and contacts

148 sites in 19 countries.

148 sites in 19 countries

United States26 sites

  • Piedmont Healthcare

    Atlanta, Georgia, 30309

  • The University of North Carolina at Chapel Hill

    Chapel Hill, North Carolina, 27514

  • University of Cincinnati

    Cincinnati, Ohio, 45267

  • University of Texas Southwestern Medical Center

    Dallas, Texas, 75390

  • Sanford Health

    Fargo, North Dakota, 58122

  • Providence Medical Foundation

    Fullerton, California, 92835

  • Pitt County Memorial Hospital d/b/a Vidant Medical Center

    Greenville, North Carolina, 27835

  • University of Iowa Hospitals and Clinics

    Iowa City, Iowa, 52242

  • Sparrow Clinical Research Institute

    Lansing, Michigan, 48912

  • University of Southern California

    Los Angeles, California, 90033

  • Norton Healthcare

    Louisville, Kentucky, 40202-1332

  • University of Wisconsin At Madison

    Madison, Wisconsin, 53792

  • WellStar Health System

    Marietta, Georgia, 30060

  • Medical College of Wisconsin Froedtert Hospital

    Milwaukee, Wisconsin, 53226

  • Minneapolis Heart Institute Foundation

    Minneapolis, Minnesota, 55407

  • WVU Health Sciences Center

    Morgantown, West Virginia, 26506

  • OSF HealthCare Cardiovascular Institute

    Peoria, Illinois, 61614

  • Thomas Jefferson University Hospital

    Philadelphia, Pennsylvania, 19107

  • University of Pittsburgh Medical Center

    Pittsburgh, Pennsylvania, 15213

  • Baylor Scott White - Plano

    Plano, Texas, 75093

  • Legacy Hospital

    Portland, Oregon, 97210

  • Oregon Health and Science University

    Portland, Oregon, 97239

  • VA Sierra Nevada Health Care System

    Reno, Nevada, 89509

  • Sanford Health

    Sioux Falls, South Dakota, 57105

  • Washington University School Of Medicine

    St Louis, Missouri, 63110

  • St. Elizabeth Hospital Mercy Bon Secors

    Youngstown, Ohio, 44503

Other trials in United States

Japan26 sites

  • The University of Tokyo Hospital

    Bunkyō City, 113-8655

  • Chiba University Hospital

    Chiba, 260 8677

  • Kyushu University Hospital

    Fukuoka, 812 8582

  • Fukushima Medical University Hospital

    Fukushima, 960 1295

  • Gunma University Hospital

    Gunma, 371-0034

  • Kure Kyosai Hospital

    Hiroshima, 737-8505

  • Tokai University Hospital

    Isehara, 259-1193

  • Kagoshima University Hospital

    Kagoshima, 890-8544

  • Kanazawa University Hospital

    Kanazawa, 920 8641

  • Kobe University Hospital

    Kobe, 650 0017

  • Kumamoto University Hospital

    Kumamoto, 860-8556

  • Kurume University Hospital

    Kurume, 830-0011

  • University Hospital Kyoto Prefectural University of Medicine

    Kyoto, 602-8566

  • Kyoto University Hospital

    Kyoto, 606 8507

  • Shinshu University Hospital

    Matsumoto, 390 8621

  • Kyorin University Hospital

    Mitaka, 181-8611

  • Nagasaki University Hospital

    Nagasaki, 852-8501

  • Okayama University Hospital

    Okayama, 700 8558

  • National Hospital Organization Okayama Medical Center

    Okayama, 701-1192

  • Sapporo Medical University Hospital

    Sapporo, 060-8543

  • Hokkaido University Hospital

    Sapporo, 060-8648

  • Tohoku University Hospital

    Sendai, 980 8574

  • National Cerebral and Cardiovascular Center

    Suita-Shi, 564-8565

  • Juntendo University Hospital

    Tokyo, 113-8431

  • Mie University Hospital

    Tsu, 514 8507

  • University of Tsukuba Hospital

    Tsukuba, 305 8576

Other trials in Japan

Turkey (Türkiye)12 sites

  • Cukurova University Medical Faculty

    Adana, 01790

  • Hacettepe University Medical Faculty

    Ankara, 6100

  • Ankara University Medical Faculty

    Ankara, 6500

  • Bursa Yuksek Ihtisas Training and Research Hospital

    Bursa, 16310

  • Istanbul University - Cerrahpasa Cardiology Institution

    Istanbul, 34096

  • Istanbul University Cerrahpasa Medical Faculty

    Istanbul, 34096

  • Marmara University Medical Faculty

    Istanbul, 34899

  • Ege University School of Medicine

    Izmir, 35100

  • Dokuz Eylul University Hospital

    Izmir, 35340

  • Kartal Kosuyolu Yuksek Ihtisas Egitim Ve Arastirma Hastanesi

    Kartal Istanbul, 34865

  • Konya Selcuk University Medical Faculty

    Konya, 42131

  • Mersin University Medical Faculty

    Mersin, 33110

Other trials in Turkey (Türkiye)

Brazil10 sites

  • Universidade Federal De Minas Gerais - Hospital das Clínicas

    Belo Horizonte, 30130-100

  • Instituto das Pequenas Missionárias de Maria Imaculada - Hospital Madre Teresa

    Belo Horizonte, 30441-070

  • Fundacao para o Desenvolvimento Medico Hospitalar (UNESP Botucatu)

    Botucatu, 18618-686

  • Secretaria da Saude do Estado do Ceara - Hospital Doutor Carlos Alberto Studart Gomes

    Fortaleza, 60840-285

  • Universidade Federal de Goias - Hospital das Clinicas da UFG

    Goiânia, 74605-020

  • Hospital das Clinicas de Porto Alegre

    Porto Alegre, 90035-007

  • Irmandade Santa Casa de Misericordia de Porto Alegre

    Porto Alegre, 90035-074

  • Uniao Brasileira de Educacao e Assistencia Hospital Sao Lucas da PUCRS

    Porto Alegre, 90610-000

  • SPDM - Associacao Paulista para o Desenvolvimento da Medicina - Hospital Sao Paulo

    São Paulo, 04024-002

  • Hospital Das Clinicas Da Faculdade De Medicina Da USP

    São Paulo, 05403-000

Other trials in Brazil

Germany9 sites

  • Universitatsklinikum Bonn

    Bonn, 53105

  • Universitatsklinikum Carl Gustav Carus Dresden

    Dresden, 01307

  • Universitaetsklinikum Giessen

    Giessen, 35392

  • Universitat Greifswald

    Greifswald, 17475

  • Universitaetsklinikum Hamburg Eppendorf

    Hamburg, 20246

  • Thoraxklinik am Universitatsklinikum Heidelberg

    Heidelberg, 69126

  • Kardiologische Praxis Papenburg

    Papenburg, 26871

  • Universitaetsklinikum Regensburg

    Regensburg, 93053

  • Klinikum Würzburg Mitte gGmbH Standort Missioklinik

    Würzburg, 97074

Other trials in Germany

Poland9 sites

  • Klinika Kardiologii Z Oddzialem Intensywnego Nadzoru Kardiologicznego UM W Bialymstoku

    Bialystok, 15 276

  • Szpital Uniwersytecki nr 2 im dr Jana Biziela w Bydgoszczy, Klinika Kardiologii

    Bydgoszcz, 85-168

  • Uniwersyteckie Centrum Kliniczne

    Gdansk, 80 214

  • GCM SUM I Oddzial Kardiologii

    Katowice, 40 635

  • Oddzial Kardiologii Wojewodzki Szpital Specjalistyczny im W Bieganskiego

    Lodz, 91 347

  • Wojewodzki Szpital Specjalistyczny im. Stefana Kardynala Wyszynskiego SPZOZ, Oddzial Kardiologii

    Lublin, 20-718

  • ECZ Otwock Klinika Kardiologii Klinika Krazenia Plucnego Chorob Zakrzepowo Zatorowych i Kardiologii

    Otwock, 05-400

  • Uniwersytecki Szpital Kliniczny nr 2 PUM Klinika Kardiologii

    Szczecin, 70 111

  • Wojewodzki Szpital Specjalistyczny Oddzial Kardiologiczny

    Wroclaw, 51 124

Other trials in Poland

Spain9 sites

  • Hosp Clinic de Barcelona

    Barcelona, 08036

  • Hosp Univ Vall D Hebron

    Barcelona, 8035

  • Hosp. Univ. Ramon Y Cajal

    Madrid, 28034

  • Hosp Univ Fund Jimenez Diaz

    Madrid, 28040

  • Hosp. Univ. La Paz

    Madrid, 28046

  • Hosp Clinico Univ de Salamanca

    Salamanca, 37007

  • Hosp. Univ. Marques de Valdecilla

    Santander, 39011

  • Hosp. Virgen de La Salud

    Toledo, 45004

  • Hosp. Gral. Univ. Valencia

    Valencia, 46014

Other trials in Spain

China8 sites

  • Beijing Anzhen Hospital

    Beijing, 100029

  • The Second Xiangya Hospital of Central South Hospital

    Changsha, 410011

  • The First Affiliated Hospital of Guangzhou Medical University

    Guangzhou, 510120

  • Jiangsu Province Hospital

    Nanjing

  • Shanghai Pulmonary Hospital

    Shanghai, 200433

  • The General Hospital of Northern Theater Command

    Shenyang, 110000

  • Tianjin Medical University General Hospital

    Tianjin, 300052

  • The First Affiliated Hospital of Xian Jiaotong University

    Xi'an, 710061

Other trials in China

Italy7 sites

  • Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari

    Bari, 70124

  • Cardiologia c/o Spedali Civili

    Brescia, 25123

  • Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico

    Milan, 20122

  • Azienda Ospedaliera San Gerardo

    Monza, 20090

  • Ospedale San Francesco

    Nuoro, 08100

  • IRCCS Policlinico San Matteo, Università degli studi di Pavi

    Pavia, 27100

  • Policlinico Umberto I

    Roma, 00161

Other trials in Italy

Russia6 sites

  • Altay Regional Cardiological Dispensary

    Barnaul, 656055

  • Scientific and Research Institution of Cardiovascular Diseases Complex Problems

    Kemerovo, 650002

  • National Medical Research Center of Cardiology of MoH of Russian Federation

    Moscow, 121552

  • GU Moscow Regional Research Clinical Institute n.a. M.F.Vla

    Moscva, 129090

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

    Saint Petersburg, 197341

  • Samara Regional Clinical Cardiological Dispensary

    Samara, 443070

Other trials in Russia

Taiwan6 sites

  • Kaohsiung Veterans General Hospital

    Kaohsiung City, 813

  • National Cheng Kung University Hospital

    Tainan, 704

  • National Taiwan University Hospital

    Taipei, 10002

  • Mackay Memorial Hospital

    Taipei, 10449

  • Taipei Veterans General Hospital

    Taipei, 112

  • Chang-Gung Memorial Hospital, LinKou Branch

    Taoyuan, 333

Other trials in Taiwan

Canada4 sites

  • Alberta Health Services

    Calgary, Alberta, T1Y 6J4

  • University of Alberta

    Edmonton, Alberta, T6G 2G3

  • London Health Sciences Centre

    London, Ontario, N6A 5W9

  • Vancouver General Hospital

    Vancouver, British Columbia, V5Z 1M9

Other trials in Canada

Hungary4 sites

  • Semmelweis Egyetem,Pulmonológiai Klinika

    Budapest, 1083

  • Gottsegen György Országos Kardiológiai Intézet, Felnőtt kardiológiai osztály

    Budapest, 1096

  • Pecsi Tudomanyegyetem Klinikai Kozpont

    Pécs, 7624

  • Szegedi Tudomanyegyetem

    Szeged, 6725

Other trials in Hungary

Australia3 sites

  • Royal Adelaide Hospital

    Adelaide, 5000

  • Pulmonary Arterial Hypertension Clinic

    Hobart, 7000

  • Core Research Group

    Milton, 4064

Other trials in Australia

Bulgaria2 sites

  • National Heart Hospital

    Sofia, 1309

  • University Multiprofile Hospital for Active Treatment- UMHAT Sveta Anna AD

    Sofia, 1750

Other trials in Bulgaria

Malaysia2 sites

  • Institut Jantung Negara (National Heart Institute)

    Kuala Lumpur, 50400

  • Sarawak Heart Center

    Kuching, 94300

Other trials in Malaysia

Mexico2 sites

  • Instituto Nacional de Cardiologia Dr. Ignacio Chavez

    México, 14080

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

    Monterrey, 64718

Other trials in Mexico

South Africa2 sites

  • Abdullah, IA

    Durban, 4001

  • Dr Kalla

    Lenasia, 1820

Other trials in South Africa

Czechia1 site

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

    Prague, 128 08

Other trials in Czechia

About this study

Official title: 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.

Read the 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.

Being tested
FDC macitentan/tadalafil, Macitentan 10 mg, Tadalafil 40 mg, Placebo FDC, Placebo macitentan
Keywords
Pulmonary Arterial Hypertension, PAH, macitentan, tadalafil, fixed dose combination therapy
Medical subject headings
Pulmonary Arterial Hypertension

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • FDC macitentan/tadalafilDrug

    Also called ACT-064992D

    Film-coated tablet with 10 mg macitentan and 40 mg tadalafil, to be administered orally once daily.

  • Macitentan 10 mgDrug

    Also called ACT-064992

    Film-coated tablet with 10 mg macitentan, to be administered orally once daily.

  • Tadalafil 40 mgDrug

    Film-coated tablet with 40 mg tadalafil (2 x 20 mg tablets), to be administered orally once daily.

  • Placebo FDCDrug

    Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.

  • Placebo macitentanDrug

    Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.

  • Placebo tadalafilDrug

    Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.

Study groups in NCT03904693
Study groupRoleWhat they receive
FDC therapy + Placebo macitentan + Placebo tadalafilExperimentalSubjects to receive FDC macitentan/tadalafil (macitentan 10 mg and tadalafil 40 mg) plus matching placebos for the two other study treatments.
Receives: Drug: FDC macitentan/tadalafil; Drug: Placebo macitentan; Drug: Placebo tadalafil
Macitentan mono-therapy + Placebo tadalafil + Placebo FDCActive comparatorSubjects to receive macitentan 10 mg plus matching placebos for the two other study treatments.
Receives: Drug: Macitentan 10 mg; Drug: Placebo FDC; Drug: Placebo tadalafil
Tadalafil mono-therapy + Placebo macitentan + Placebo FDCActive comparatorSubjects to receive tadalafil 40 mg (2 x 20 mg) plus matching placebos for the two other study treatments.
Receives: Drug: Tadalafil 40 mg; Drug: Placebo FDC; Drug: Placebo macitentan

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Baseline, EDBT (up to 16 weeks)

Secondary outcomes (4)

  1. 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.

    Measured: Baseline, EDBT (Week 16)

  2. 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.

    Measured: Baseline, EDBT (Week 16)

  3. 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.

    Measured: Baseline, EDBT (Week 16)

  4. 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).

    Measured: At Week 16 (EDBT)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Apr 2019
  2. Study start29 Jul 2019
  3. Primary completion23 Aug 2022
  4. Study completion27 Sep 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
In total, approximately 170 subjects are planned to be randomized into study to receive either FDC macitentan/tadalafil or macitentan 10 mg or tadalafil 40 mg given once daily and will also receive matching placebos for two other study treatments. Treatment allocation will be stratified based on prior PAH therapy (i.e., treatment-naïve or treated by an Endothelin receptor antagonist or a Phosphodiesterase type-5 inhibitor as a monotherapy) at baseline. Sample size will be re-estimated at interim analysis if study is not terminated early for efficacy/futility up to sample size of 150-250. After completion of double-blind treatment period, subjects will continue study in an open-label treatment (OLT) period for 24 months, which may be prolonged beyond 24 months until macitentan and tadalafil are accessible at required doses, through other options according to local regulations. All assessments at end of double-blind treatment must be completed before subject enters OLT period.
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
187 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03904693
Sponsor's protocol ID
AC-077A301
Other IDs
2014-004786-25, AC-077A301, 2014
Acronym
A DUE
Status last verified
Dec 2025
First submitted
4 Apr 2019
Last updated
19 Dec 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: 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.

Publications

  • 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 May;43(5):2106-2124. doi: 10.1007/s12325-026-03525-3. Epub 2026 Mar 12.

    PubMed 41820779

  • 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.

    PubMed 41250682

  • 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.

    PubMed 38267108

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing FDC macitentan/tadalafil, Macitentan 10 mg and Tadalafil 40 mg in people with Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH), run by Actelion at 148 sites in 19 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 18 inclusion and 38 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 148 sites in United States, Japan, Turkey (Türkiye), Brazil, Germany and 14 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 Nov 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline (time frame: Baseline, EDBT (up to 16 weeks)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03904693, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Dec 2025.

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