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)

Completed · Phase 3 · Has a placebo group

Conditions studied: Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)

In brief

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.

Key facts

Study ID: NCT03904693
Run by: Actelion
People needed: 187
Starts: 2019-07-29
Expected to finish: 2024-09-27
Last updated by the study team: 2025-12-19

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

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
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

You may not qualify if…

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
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

Where it is running

University of Southern California — Los Angeles, California, United States
Piedmont Healthcare — Atlanta, Georgia, United States
WellStar Health System — Marietta, Georgia, United States
OSF HealthCare Cardiovascular Institute — Peoria, Illinois, United States
University of Iowa Hospitals and Clinics — Iowa City, Iowa, United States
Norton Healthcare — Louisville, Kentucky, United States
Sparrow Clinical Research Institute — Lansing, Michigan, United States
Minneapolis Heart Institute Foundation — Minneapolis, Minnesota, United States
Washington University School Of Medicine — St Louis, Missouri, United States
VA Sierra Nevada Health Care System — Reno, Nevada, United States
The University of North Carolina at Chapel Hill — Chapel Hill, North Carolina, United States
Pitt County Memorial Hospital d/b/a Vidant Medical Center — Greenville, North Carolina, United States
Sanford Health — Fargo, North Dakota, United States
University of Cincinnati — Cincinnati, Ohio, United States
St. Elizabeth Hospital Mercy Bon Secors — Youngstown, Ohio, United States
Legacy Hospital — Portland, Oregon, United States
Oregon Health and Science University — Portland, Oregon, United States
Thomas Jefferson University Hospital — Philadelphia, Pennsylvania, United States
University of Pittsburgh Medical Center — Pittsburgh, Pennsylvania, United States
Sanford Health — Sioux Falls, South Dakota, United States
University of Texas Southwestern Medical Center — Dallas, Texas, United States
Baylor Scott White - Plano — Plano, Texas, United States
WVU Health Sciences Center — Morgantown, West Virginia, United States
University of Wisconsin At Madison — Madison, Wisconsin, United States
Providence Medical Foundation — Fullerton, California, United States

Full record on ClinicalTrials.gov

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