The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension
NCT ID: NCT02558231
Last Updated: 2025-03-30
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
247 participants
INTERVENTIONAL
2016-05-01
2020-04-20
Brief Summary
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Triple oral combination treatment
Macitentan, tadalafil, and selexipag
Macitentan
Used open-label in both arms, 10 mg tablet, 1 tablet u.i.d.
Tadalafil
Used open-label in both arms, 20 mg tablet, 1-2 tablets u.i.d.
Selexipag
Used double-blind in the triple oral treatment arm, 200 microgram tablet, 1-8 tablets b.i.d.
Dual oral combination treatment
Macitentan, tadalafil, and placebo
Macitentan
Used open-label in both arms, 10 mg tablet, 1 tablet u.i.d.
Tadalafil
Used open-label in both arms, 20 mg tablet, 1-2 tablets u.i.d.
Interventions
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Macitentan
Used open-label in both arms, 10 mg tablet, 1 tablet u.i.d.
Tadalafil
Used open-label in both arms, 20 mg tablet, 1-2 tablets u.i.d.
Selexipag
Used double-blind in the triple oral treatment arm, 200 microgram tablet, 1-8 tablets b.i.d.
Eligibility Criteria
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Inclusion Criteria
2. Male or female ≥ 18 and ≤ 75 years of age at screening.
3. Initial PAH diagnosis \< 6 months prior to enrollment.
4. RHC performed between Day -28 and Day 1, meeting all the following criteria:
* Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg.
* Pulmonary artery wedge pressure or left ventricular end-diastolic pressure ≤ 15 mmHg.
* PVR ≥ 480 dyn•sec/cm5 (≥ 6 Wood Units).
* Negative vasoreactivity test mandatory in idiopathic, heritable, and drug/toxin induced PAH (at this or a previous RHC).
5. Symptomatic PAH belonging to one of the following subgroups:
* Idiopathic.
* Heritable.
* Drug or toxin induced.
* Associated with one of the following: connective tissue disease; HIV infection; congenital heart disease.
6. 6-minute walk distance (6MWD) ≥ 50 m at screening.
7. Women of childbearing potential must not be pregnant, must perform regular pregnancy tests, and use reliable contraception.
Exclusion Criteria
2. Cardio pulmonary rehabilitation program based on exercise (planned, or started ≤ 12 weeks prior to Day 1).
3. Body mass index (BMI) \> 40 kg/m2 at screening.
4. 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.
* Coronary artery disease, i.e., any of the following:
* History of stable angina or
* More than 50% stenosis in a coronary artery (by coronary angiography) or
* History of myocardial infarction or
* History of or planned coronary artery bypass grafting and/or coronary artery stenting.
5. Acute myocardial infarction ≤ 12 weeks prior to screening.
6. Stroke ≤ 12 weeks prior to screening.
7. Known permanent atrial fibrillation.
8. SBP \< 90 mmHg at screening or Day 1.
9. Ongoing or planned treatment with organic nitrates and/or doxazosin.
10. Presence of one or more of the following signs of relevant lung disease at any time up to screening:
* Diffusing capacity of the lung for carbon monoxide (DLCO) \< 40% of predicted (eligible only if no or mild interstitial lung disease on computed tomography).
* Forced vital capacity (FVC) \< 60% of predicted.
* Forced expiratory volume in one second (FEV1) \< 60% of predicted.
11. Known or suspected pulmonary veno-occlusive disease (PVOD).
12. Documented severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin \> 3 × upper limit of the normal range (ULN) accompanied by aspartate aminotransferase (AST) \> ULN (assessed by central laboratory at screening); and/or Child-Pugh Class C.
13. Serum AST and/or alanine aminotransferase (ALT) \> 3 × ULN (assessed by central laboratory at screening).
14. Severe renal impairment (estimated creatinine clearance ≤ 30 mL/min/1.73 m2) assessed by central laboratory at screening.
15. Ongoing or planned dialysis.
16. Hemoglobin \< 100 g/L assessed by central laboratory at screening.
17. Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).
18. Loss of vision in one or both eyes because of non-arteritic ischemic optic neuropathy (NAION).
19. Treatment with strong inducers of cytochrome P450 3A4 (CYP3A4; e.g., carbamazepine, rifampin, rifampicin, rifabutin, rifapentin, phenobarbital, phenytoin, and St. John's wort) ≤ 28 days prior to Day 1.
20. Treatment with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) and/or strong inhibitors of CYP2C8 (e.g., gemfibrozil) ≤ 28 days prior to Day 1.
21. Treatment with another investigational drug (planned, or taken ≤ 12 weeks prior to Day 1).
22. Hypersensitivity to any of the 3 study treatments or any excipient of their formulations.
23. Pregnancy, breastfeeding, or intention to become pregnant during the study.
24. Concomitant life-threatening disease with a life expectancy \< 12 months.
25. Alcohol abuse.
26. Any factor or condition likely to affect protocol compliance of the subject, as judged by the investigator.
18 Years
75 Years
ALL
No
Sponsors
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Actelion
INDUSTRY
Responsible Party
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Locations
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Arizona Pulmonary Specialists, LTD
Phoenix, Arizona, United States
UCSD Health Sciences
La Jolla, California, United States
UCLA Medical Center
Los Angeles, California, United States
Mayo Clinic Jacksonville
Jacksonville, Florida, United States
Cleveland Clinic Florida
Weston, Florida, United States
Piedmont Pulmonary and Critical Care Research
Atlanta, Georgia, United States
Northwestern University
Chicago, Illinois, United States
University of Iowa Hospitals & Clinics
Iowa City, Iowa, United States
Kentuckiana Pulmonary Associates
Louisville, Kentucky, United States
LSU Health Sciences Center
New Orleans, Louisiana, United States
Johns Hopkins School of Medicine
Baltimore, Maryland, United States
Tufts Medical Center
Boston, Massachusetts, United States
Boston University Medical Center
Boston, Massachusetts, United States
Washington University School of Medicine
Saint Louis, Michigan, United States
University of New Mexico Hospital
Albuquerque, New Mexico, United States
The Christ Hospital
Cincinnati, Ohio, United States
Allegheny General Hospital of Research
Pittsburgh, Pennsylvania, United States
UPMC Presbyterian
Pittsburgh, Pennsylvania, United States
University of Texas Southwestern Medical Center
Dallas, Texas, United States
Houston Methodist Hospital
Houston, Texas, United States
Royal Prince Albert Hospital
Camperdown, New South Wales, Australia
St. Vincents Hospital Sydney
Darlinghurst, New South Wales, Australia
LKH -Universität Klinkum Graz
Graz, , Austria
Krankenhaus der Elisabethinen Linz
Linz, , Austria
AKH Wien
Vienna, , Austria
Hôpital Erasme
Brussels, , Belgium
UZ Leuven - Campus Gasthuisberg
Leuven, , Belgium
Vancouver General Hospital
Vancouver, British Columbia, Canada
London Health Sciences Centre - Victoria Hospital
London, Ontario, Canada
University of Toronto
Toronto, Ontario, Canada
Jewish General Hospital
Montreal, Quebec, Canada
Institut Universitaire de Cardiologie et de Pneumologie de Québec
Québec, Quebec, Canada
University of Calgary
Calgary, , Canada
University of Ottawa Heart Institute
Ottawa, , Canada
Aarhus University Hospital Skejby
Aarhus, , Denmark
Rigshospitalet Copenhagen
Copenhagen, , Denmark
CHU de Bicêtre
Le Kremlin-Bicêtre, , France
Universitätsklinikum Köln
Cologne, , Germany
Unversitätsklinikum Carl Gustav Carus
Dresden, , Germany
Universitätsklinikum Giessen
Giessen, , Germany
Universitätsklinikum Hamburg-Eppendorf
Hamburg, , Germany
Medizinische Hochschule Hannover
Hanover, , Germany
Universitätsklinikum Heidelberg
Heidelberg, , Germany
Universitätsklinikum Regensburg
Regensburg, , Germany
Mater Misericordiae University Hospital
Dublin, , Ireland
Ospedale Sant'Orsola
Bologna, , Italy
VUmc Amsterdam
Amsterdam, , Netherlands
Maastricht University Medical Center
Maastricht, , Netherlands
Hospital Clinic de Barcelona
Barcelona, , Spain
Hospital 12 de Octubre
Madrid, , Spain
Skånes universitetssjukhus Lund
Lund, , Sweden
Norrlands universitetssjukhus
Umeå, , Sweden
Kardiologkliniken
Uppsala, , Sweden
Universiätsspital Zürich
Zurich, , Switzerland
Golden Jubilee National Hospital
Clydebank, , United Kingdom
The Royal Free Hospital
London, , United Kingdom
Royal Brompton Hospital
London, , United Kingdom
Hammersmith Hospital
London, , United Kingdom
Countries
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References
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Chin KM, Sitbon O, Doelberg M, Feldman J, Gibbs JSR, Grunig E, Hoeper MM, Martin N, Mathai SC, McLaughlin VV, Perchenet L, Poch D, Saggar R, Simonneau G, Galie N. Three- Versus Two-Drug Therapy for Patients With Newly Diagnosed Pulmonary Arterial Hypertension. J Am Coll Cardiol. 2021 Oct 5;78(14):1393-1403. doi: 10.1016/j.jacc.2021.07.057.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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AC-065A308
Identifier Type: -
Identifier Source: org_study_id
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