Clinical trial NCT02558231: The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension
Official title: The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension: A Multi-center, Double-blind, Placebo-controlled, Phase 3b Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2015-09-23
Enrollment: 247
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

1. Signed informed consent prior to any study-mandated procedure.
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:

1. Any PAH-specific drug therapy at any time.
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.

Primary outcomes:
measure: Change From Baseline to Week 26 in Pulmonary Vascular Resistance (PVR)
timeFrame: Baseline, Week 26
Secondary outcomes:
measure: Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD)
timeFrame: Baseline, Week 26
measure: Change From Baseline to Week 26 in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Levels
timeFrame: Baseline, Week 26
measure: Percentage of Participants With Absence of Worsening From Baseline to Week 26 in World Health Organization (WHO) Functional Class (FC)
timeFrame: Week 26
measure: Change From Baseline to Week 26 in Mean Pulmonary Arterial Pressure (mPAP)
timeFrame: Baseline, Week 26
measure: Change From Baseline to Week 26 in Mean Right Atrial Pressure (mRAP)
timeFrame: Baseline, Week 26
measure: Change From Baseline to Week 26 in Total Pulmonary Resistance
timeFrame: Baseline, Week 26
measure: Change From Baseline to Week 26 in Cardiac Index
timeFrame: Baseline, Week 26
measure: Change From Baseline to Week 26 in Venous Oxygen Saturation (%)
timeFrame: Baseline, Week 26
measure: Number of Participants With Disease Progression Event
timeFrame: Week 26, Month 12, Month 18, Month 24, Month 30, and End of Analysis Period (up to 40 months)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Arizona Pulmonary Specialists, LTD
state: Arizona
city: La Jolla
country: United States
facility: UCSD Health Sciences
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Atlanta
country: United States
facility: Piedmont Pulmonary and Critical Care Research
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics
state: Iowa
city: Louisville
country: United States
facility: Kentuckiana Pulmonary Associates
state: Kentucky
city: New Orleans
country: United States
facility: LSU Health Sciences Center
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins School of Medicine
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Michigan
city: Albuquerque
country: United States
facility: University of New Mexico Hospital
state: New Mexico
city: Cincinnati
country: United States
facility: The Christ Hospital
state: Ohio
city: Pittsburgh
country: United States
facility: Allegheny General Hospital of Research
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Presbyterian
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Camperdown
country: Australia
facility: Royal Prince Albert Hospital
state: New South Wales
city: Darlinghurst
country: Australia
facility: St. Vincents Hospital Sydney
state: New South Wales
city: Graz
country: Austria
facility: LKH -Universität Klinkum Graz
city: Linz
country: Austria
facility: Krankenhaus der Elisabethinen Linz
city: Wien
country: Austria
facility: AKH Wien
city: Brussels
country: Belgium
facility: Hôpital Erasme
city: Leuven
country: Belgium
facility: UZ Leuven - Campus Gasthuisberg
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: London
country: Canada
facility: London Health Sciences Centre - Victoria Hospital
state: Ontario
city: Toronto
country: Canada
facility: University of Toronto
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Quebec City
country: Canada
facility: Institut Universitaire de Cardiologie et de Pneumologie de Québec
state: Quebec
city: Calgary
country: Canada
facility: University of Calgary
city: Ottawa
country: Canada
facility: University of Ottawa Heart Institute
city: Aarhus
country: Denmark
facility: Aarhus University Hospital Skejby
city: Copenhagen
country: Denmark
facility: Rigshospitalet Copenhagen
city: Le Kremlin-Bicêtre
country: France
facility: CHU de Bicêtre
city: Dresden
country: Germany
facility: Unversitätsklinikum Carl Gustav Carus
city: Giessen
country: Germany
facility: Universitätsklinikum Giessen
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Köln
country: Germany
facility: Universitätsklinikum Köln
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
city: Bologna
country: Italy
facility: Ospedale Sant'Orsola
city: Amsterdam
country: Netherlands
facility: VUmc Amsterdam
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Lund
country: Sweden
facility: Skånes universitetssjukhus Lund
city: Umeå
country: Sweden
facility: Norrlands universitetssjukhus
city: Uppsala
country: Sweden
facility: Kardiologkliniken
city: Zürich
country: Switzerland
facility: Universiätsspital Zürich
city: Clydebank
country: United Kingdom
facility: Golden Jubilee National Hospital
city: London
country: United Kingdom
facility: The Royal Free Hospital
city: London
country: United Kingdom
facility: Royal Brompton Hospital
city: London
country: United Kingdom
facility: Hammersmith Hospital
Study officials:
References:
citation: 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.