The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension

NCT02558231 | Completed Phase 3 Results DMC

• 1 other identifier: AC-065A308
• Study Type: interventional
• Target: 247
• Locations: 14 countries
• Sites: 55

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.

Conditions

Pulmonary Arterial Hypertension

Outcome Measures

Primary Outcomes (1)

• Change From Baseline to Week 26 in Pulmonary Vascular Resistance (PVR)

  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.

  Baseline, Week 26

Secondary Outcomes (9)

• Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD)

  Baseline, Week 26

• Change From Baseline to Week 26 in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) Levels

  Baseline, Week 26

• Percentage of Participants With Absence of Worsening From Baseline to Week 26 in World Health Organization (WHO) Functional Class (FC)

  Week 26

• Change From Baseline to Week 26 in Mean Pulmonary Arterial Pressure (mPAP)

  Baseline, Week 26

• Change From Baseline to Week 26 in Mean Right Atrial Pressure (mRAP)

  Baseline, Week 26

Study Arms (2)

Triple oral combination treatment

EXPERIMENTAL

Macitentan, tadalafil, and selexipag

Drug: Macitentan; Drug: Tadalafil; Drug: Selexipag

Dual oral combination treatment

PLACEBO COMPARATOR

Macitentan, tadalafil, and placebo

Drug: Macitentan; Drug: Tadalafil

Interventions

Macitentan DRUG

Used open-label in both arms, 10 mg tablet, 1 tablet u.i.d.

Dual oral combination treatment; Triple oral combination treatment

Tadalafil DRUG

Used open-label in both arms, 20 mg tablet, 1-2 tablets u.i.d.

Dual oral combination treatment; Triple oral combination treatment

Selexipag DRUG

Used double-blind in the triple oral treatment arm, 200 microgram tablet, 1-8 tablets b.i.d.

Triple oral combination treatment

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent prior to any study-mandated procedure.
• Male or female ≥ 18 and ≤ 75 years of age at screening.
• Initial PAH diagnosis \< 6 months prior to enrollment.
• 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.
• minute walk distance (6MWD) ≥ 50 m at screening.
• Women of childbearing potential must not be pregnant, must perform regular pregnancy tests, and use reliable contraception.

You may not qualify if:

• Any PAH-specific drug therapy at any time.
• Cardio pulmonary rehabilitation program based on exercise (planned, or started ≤ 12 weeks prior to Day 1).
• Body mass index (BMI) \> 40 kg/m2 at screening.
• 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.
• Acute myocardial infarction ≤ 12 weeks prior to screening.
• Stroke ≤ 12 weeks prior to screening.
• Known permanent atrial fibrillation.

Sponsors & Collaborators

• Actelion: lead

Study Sites (58)

Arizona Pulmonary Specialists, LTD

Phoenix, Arizona, 85012, United States

Location

UCSD Health Sciences

La Jolla, California, 92093, United States

Location

UCLA Medical Center

Los Angeles, California, 90095, United States

Location

Mayo Clinic Jacksonville

Jacksonville, Florida, 32224, United States

Location

Cleveland Clinic Florida

Weston, Florida, 33331, United States

Location

Piedmont Pulmonary and Critical Care Research

Atlanta, Georgia, 30309, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Iowa Hospitals & Clinics

Iowa City, Iowa, 52242, United States

Location

Kentuckiana Pulmonary Associates

Louisville, Kentucky, 40202, United States

Location

LSU Health Sciences Center

New Orleans, Louisiana, 70112, United States

Location

Johns Hopkins School of Medicine

Baltimore, Maryland, 21205, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111-1552, United States

Location

Boston University Medical Center

Boston, Massachusetts, 02118-2526, United States

Location

Washington University School of Medicine

Saint Louis, Michigan, 63110, United States

Location

University of New Mexico Hospital

Albuquerque, New Mexico, 87106, United States

Location

The Christ Hospital

Cincinnati, Ohio, 45219-2906, United States

Location

Allegheny General Hospital of Research

Pittsburgh, Pennsylvania, 15212, United States

Location

UPMC Presbyterian

Pittsburgh, Pennsylvania, 15213, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390-8550, United States

Location

Houston Methodist Hospital

Houston, Texas, 77030, United States

Location

Royal Prince Albert Hospital

Camperdown, New South Wales, 2050, Australia

Location

St. Vincents Hospital Sydney

Darlinghurst, New South Wales, 2010, Australia

Location

LKH -Universität Klinkum Graz

Graz, 8036, Austria

Location

Krankenhaus der Elisabethinen Linz

Linz, 4020, Austria

Location

AKH Wien

Vienna, 1090, Austria

Location

Hôpital Erasme

Brussels, 1070, Belgium

Location

UZ Leuven - Campus Gasthuisberg

Leuven, 3000, Belgium

Location

Vancouver General Hospital

Vancouver, British Columbia, V5Z 1M9, Canada

Location

London Health Sciences Centre - Victoria Hospital

London, Ontario, N6A 5W9, Canada

Location

University of Toronto

Toronto, Ontario, M5G 2N2, Canada

Location

Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

Institut Universitaire de Cardiologie et de Pneumologie de Québec

Québec, Quebec, G1V 4G5, Canada

Location

University of Calgary

Calgary, T1Y 6J4, Canada

Location

University of Ottawa Heart Institute

Ottawa, K1Y 4W7, Canada

Location

Aarhus University Hospital Skejby

Aarhus, 8200, Denmark

Location

Rigshospitalet Copenhagen

Copenhagen, 2100, Denmark

Location

CHU de Bicêtre

Le Kremlin-Bicêtre, 94270, France

Location

Universitätsklinikum Köln

Cologne, 50924, Germany

Location

Unversitätsklinikum Carl Gustav Carus

Dresden, 01307, Germany

Location

Universitätsklinikum Giessen

Giessen, 35392, Germany

Location

Universitätsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Medizinische Hochschule Hannover

Hanover, 30625, Germany

Location

Universitätsklinikum Heidelberg

Heidelberg, 69126, Germany

Location

Universitätsklinikum Regensburg

Regensburg, 93053, Germany

Location

Mater Misericordiae University Hospital

Dublin, D07 R2WY, Ireland

Location

Ospedale Sant'Orsola

Bologna, 40138, Italy

Location

VUmc Amsterdam

Amsterdam, 1081 HV, Netherlands

Location

Maastricht University Medical Center

Maastricht, 6229 HX, Netherlands

Location

Hospital Clinic de Barcelona

Barcelona, 08036, Spain

Location

Hospital 12 de Octubre

Madrid, 28041, Spain

Location

Skånes universitetssjukhus Lund

Lund, 221 85, Sweden

Location

Norrlands universitetssjukhus

Umeå, 901 85, Sweden

Location

Kardiologkliniken

Uppsala, 751 85, Sweden

Location

Universiätsspital Zürich

Zurich, 8091, Switzerland

Location

Golden Jubilee National Hospital

Clydebank, G81 4DY, United Kingdom

Location

The Royal Free Hospital

London, NW3 2QG, United Kingdom

Location

Royal Brompton Hospital

London, SW3 6NP, United Kingdom

Location

Hammersmith Hospital

London, W12 0HS, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 34593120 DERIVED

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Interventions

macitentan; Tadalafil; selexipag

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Carbolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring

Limitations and Caveats

The main limitation of the sponsor's findings was that analyses of disease progression and mortality were exploratory due to the testing hierarchy and the post hoc nature of the analyses. The study was not powered to show significant differences for the disease progression related endpoint. Another limitation was the availability of hemodynamic assessments only for Week 26 timepoint.

Results Point of Contact

• Title: Principal Clinical Scientist
• Organization: Actelion Pharmaceuticals Ltd.

ClinicalTrialDisclosure@its.jnj.com

844-434-4210

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: September 22, 2015
• First Posted: September 23, 2015
• Study Start: May 1, 2016
• Primary Completion: August 29, 2019
• Study Completion: April 20, 2020
• Last Updated: March 30, 2025
• Results First Posted: September 11, 2020

Record last verified: 2025-03

Locations

IE (1); IT (1); DE (7); BE (2); NL (2); SE (3); US (20); CH (1); ES (2); CA (7); GB (4); AU (2); DK (2); FR (1)