The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension
- Conditions
- Pulmonary Arterial Hypertension
- Interventions
- Registration Number
- NCT02558231
- Lead Sponsor
- Actelion
- Brief Summary
The objective of this clinical trial is to compare the efficacy and safety of an initial triple oral treatment regimen (macitentan, tadalafil, selexipag) versus an initial dual oral treatment regimen (macitentan, tadalafil, placebo) in newly diagnosed, treatment-naïve patients with pulmonary arterial hypertension.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 247
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Signed informed consent prior to any study-mandated procedure.
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Male or female ≥ 18 and ≤ 75 years of age at screening.
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Initial PAH diagnosis < 6 months prior to enrollment.
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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).
-
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.
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6-minute walk distance (6MWD) ≥ 50 m at screening.
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Women of childbearing potential must not be pregnant, must perform regular pregnancy tests, and use reliable contraception.
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Any PAH-specific drug therapy at any time.
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Cardio pulmonary rehabilitation program based on exercise (planned, or started ≤ 12 weeks prior to Day 1).
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Body mass index (BMI) > 40 kg/m2 at screening.
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Presence of three or more of the following risk factors for heart failure with preserved ejection fraction at screening:
-
BMI > 30 kg/m2.
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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.
-
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Acute myocardial infarction ≤ 12 weeks prior to screening.
-
Stroke ≤ 12 weeks prior to screening.
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Known permanent atrial fibrillation.
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SBP < 90 mmHg at screening or Day 1.
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Ongoing or planned treatment with organic nitrates and/or doxazosin.
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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.
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Known or suspected pulmonary veno-occlusive disease (PVOD).
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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.
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Serum AST and/or alanine aminotransferase (ALT) > 3 × ULN (assessed by central laboratory at screening).
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Severe renal impairment (estimated creatinine clearance ≤ 30 mL/min/1.73 m2) assessed by central laboratory at screening.
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Ongoing or planned dialysis.
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Hemoglobin < 100 g/L assessed by central laboratory at screening.
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Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).
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Loss of vision in one or both eyes because of non-arteritic ischemic optic neuropathy (NAION).
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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.
-
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.
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Treatment with another investigational drug (planned, or taken ≤ 12 weeks prior to Day 1).
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Hypersensitivity to any of the 3 study treatments or any excipient of their formulations.
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Pregnancy, breastfeeding, or intention to become pregnant during the study.
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Concomitant life-threatening disease with a life expectancy < 12 months.
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Alcohol abuse.
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Any factor or condition likely to affect protocol compliance of the subject, as judged by the investigator.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Triple oral combination treatment Macitentan Macitentan, tadalafil, and selexipag Triple oral combination treatment Tadalafil Macitentan, tadalafil, and selexipag Triple oral combination treatment Selexipag Macitentan, tadalafil, and selexipag Dual oral combination treatment Tadalafil Macitentan, tadalafil, and placebo Dual oral combination treatment Macitentan Macitentan, tadalafil, and placebo
- Primary Outcome Measures
Name Time Method Change From Baseline to Week 26 in Pulmonary Vascular Resistance (PVR) Baseline, Week 26 Change from baseline to Week 26 in PVR was expressed as the ratio of Week 26 to baseline PVR value (Week 26 divided by baseline) using re-calculated PVR. PVR was determined by right heart catheterization (RHC). A geometric least square mean ratio of Week 26 to baseline PVR less than (\<) 1 corresponds to a reduction in PVR from baseline. Missing values were imputed using a last observation carried forward (LOCF) approach.
- Secondary Outcome Measures
Name Time Method Change From Baseline to Week 26 in Mean Pulmonary Arterial Pressure (mPAP) Baseline, Week 26 Change from baseline to Week 26 in mean Pulmonary Arterial Pressure (mPAP) was measured. The pulmonary artery pressure is a measure of the blood pressure found in the main pulmonary artery. Missing values were imputed using a LOCF approach.
Change From Baseline to Week 26 in Venous Oxygen Saturation (%) Baseline, Week 26 Change from baseline to Week 26 in venous oxygen saturation was measured. Missing values were imputed using a LOCF approach.
Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) Baseline, Week 26 The change from baseline to Week 26 in 6MWD was calculated as Week 26 minus baseline. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. Missing values were imputed using a LOCF approach.
Number of Participants With Disease Progression Event Week 26, Month 12, Month 18, Month 24, Month 30, and End of Analysis Period (up to 40 months) Number of participants with disease progression event were reported. Disease progression event as adjudicated by the CEC, defined as any of the following: a. Death (all causes; adjudicated for PAH relationship); b. Hospitalization for worsening PAH; c. Initiation of prostacyclin, a prostacyclin analog, or a prostacyclin receptor agonist for worsening PAH; d. Clinical worsening defined as a post-baseline decrease in 6MWD by more than (\>) 15 percent (%) from the highest 6MWD obtained at or after baseline, accompanied by WHO FC III or IV (both conditions confirmed at two consecutive post-baseline visits separated by 1-21 days).
Change From Baseline to Week 26 in Total Pulmonary Resistance Baseline, Week 26 Change from baseline to Week 26 in total pulmonary resistance was measured. Total pulmonary resistance was calculated as mPAP/CO\*80, where CO is cardiac output. Re-calculated values were used for analysis and missing values were imputed using a LOCF approach.
Change From Baseline to Week 26 in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Levels Baseline, Week 26 The change from baseline to Week 26 in NT-proBNP was expressed as the ratio of Week 26 to baseline NT-proBNP (Week 26 divided by baseline). A geometric least square mean ratio of Week 26 to baseline NT-proBNP \<1 corresponds to a reduction in NT-proBNP from baseline. Missing values were imputed using a LOCF approach.
Percentage of Participants With Absence of Worsening From Baseline to Week 26 in World Health Organization (WHO) Functional Class (FC) Week 26 WHO FC is a classification graded from Class I to IV which reflects disease severity based on symptoms. Worsening was defined as death or hospitalization due to PAH. Class I: No limitation of activity; Class II: slight limitation with ordinary activities; Class III: may not have symptoms at rest but greatly limited activities; Class IV: symptoms at rest and inability to carry out any physical activity without symptoms. Missing values were imputed using a LOCF approach.
Change From Baseline to Week 26 in Mean Right Atrial Pressure (mRAP) Baseline, Week 26 Change from baseline to Week 26 in mean Right Atrial Pressure (mRAP) was measured. Missing values were imputed using a LOCF approach.
Change From Baseline to Week 26 in Cardiac Index Baseline, Week 26 Change from baseline to Week 26 in cardiac index was measured. Cardiac index is the amount of blood pumped by the heart, per minute, per meter square of body surface area. Re-calculated values were used for analysis and missing values were imputed using a LOCF approach.
Trial Locations
- Locations (58)
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Boston University Medical Center
🇺🇸Boston, Massachusetts, United States
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Johns Hopkins School of Medicine
🇺🇸Baltimore, Maryland, United States
St. Vincents Hospital Sydney
🇦🇺Darlinghurst, New South Wales, Australia
Vancouver General Hospital
🇨🇦Vancouver, British Columbia, Canada
The Christ Hospital
🇺🇸Cincinnati, Ohio, United States
Rigshospitalet Copenhagen
🇩🇰Copenhagen, Denmark
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
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
University of New Mexico Hospital
🇺🇸Albuquerque, New Mexico, United States
UPMC Presbyterian
🇺🇸Pittsburgh, Pennsylvania, United States
Royal Prince Albert Hospital
🇦🇺Camperdown, New South Wales, Australia
Houston Methodist Hospital
🇺🇸Houston, Texas, United States
LKH -Universität Klinkum Graz
🇦🇹Graz, Austria
Krankenhaus der Elisabethinen Linz
🇦🇹Linz, Austria
Hôpital Erasme
🇧🇪Brussels, Belgium
UZ Leuven - Campus Gasthuisberg
🇧🇪Leuven, Belgium
University of Toronto
🇨🇦Toronto, Ontario, Canada
London Health Sciences Centre - Victoria Hospital
🇨🇦London, Ontario, Canada
University of Calgary
🇨🇦Calgary, Canada
Institut Universitaire de Cardiologie et de Pneumologie de Québec
🇨🇦Quebec City, Quebec, Canada
University of Ottawa Heart Institute
🇨🇦Ottawa, Canada
Aarhus University Hospital Skejby
🇩🇰Aarhus, Denmark
CHU de Bicêtre
🇫🇷Le Kremlin-Bicêtre, France
Medizinische Hochschule Hannover
🇩🇪Hannover, Germany
Unversitätsklinikum Carl Gustav Carus
🇩🇪Dresden, Germany
Universitätsklinikum Giessen
🇩🇪Giessen, Germany
Universitätsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Universitätsklinikum Heidelberg
🇩🇪Heidelberg, Germany
Ospedale Sant'Orsola
🇮🇹Bologna, Italy
Universitätsklinikum Köln
🇩🇪Köln, Germany
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Skånes universitetssjukhus Lund
🇸🇪Lund, Sweden
Norrlands universitetssjukhus
🇸🇪Umeå, Sweden
Hospital 12 de Octubre
🇪🇸Madrid, Spain
Kardiologkliniken
🇸🇪Uppsala, Sweden
Universiätsspital Zürich
🇨🇭Zürich, Switzerland
Hammersmith Hospital
🇬🇧London, United Kingdom
The Royal Free Hospital
🇬🇧London, United Kingdom
Golden Jubilee National Hospital
🇬🇧Clydebank, United Kingdom
Allegheny General Hospital of Research
🇺🇸Pittsburgh, Pennsylvania, United States
Universitätsklinikum Regensburg
🇩🇪Regensburg, Germany
Washington University School of Medicine
🇺🇸Saint Louis, Michigan, United States
AKH Wien
🇦🇹Wien, Austria
Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
Maastricht University Medical Center
🇳🇱Maastricht, Netherlands
VUmc Amsterdam
🇳🇱Amsterdam, Netherlands
Arizona Pulmonary Specialists, LTD
🇺🇸Phoenix, Arizona, United States
Mater Misericordiae University Hospital
🇮🇪Dublin, Ireland
Royal Brompton Hospital
🇬🇧London, United Kingdom