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) (A DUE)

  • End date
    Sep 24, 2024
  • participants needed
  • sponsor
Updated on 5 June 2022


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.


PAH is characterized by a progressive increase in pulmonary arterial pressure (PAP) and in pulmonary vascular resistance (PVR) potentially leading to right heart failure and death. Current PAH-specific therapeutic options include treatments that target the three pathways (endothelin, nitric oxide, and prostacyclin pathways). While combination treatment is common, FDC pills or tablets that combine two or more PAH-specific therapies are not available, thereby requiring participants to take multiple pills/tablets daily. An FDC is an attractive option for PAH participants because it simplifies the treatment regimen by combining two therapies (which would otherwise involve a total of three tablets: one macitentan 10 mg tablet and two tadalafil 20 mg tablets) into a single tablet. Macitentan is an orally active, non-peptide, potent dual endothelin receptor A and B antagonist. Tadalafil is a selective inhibitor of phosphodiesterase type-5 (PDE-5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). This study comprises the following consecutive periods: Screening period (lasts up to 30 days), Double-blind treatment period (consists of the titration phase [the first 2 weeks] and the maintenance phase [Week 3 through Week 16]), Open-label treatment period, End-of-Treatment (EOT), Safety follow-up (S-FU) period, and End of Study (EOS). The total study duration for a participant will be up to 30 months. Study assessments like physical examinations, vital signs, right heart catheterization, 6-minute walk test will be performed. Safety will be assessed throughout the study.

Condition Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)
Treatment Macitentan 10 mg, FDC macitentan/tadalafil, Tadalafil 40 mg, Placebo FDC, Placebo macitentan, Placebo tadalafil
Clinical Study IdentifierNCT03904693
Last Modified on5 June 2022


Yes No Not Sure

Inclusion Criteria

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
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)
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
Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH
Participant able to perform the 6MWT with a minimum distance of 100 m and maximum distance of 450 m at Screening
(Participants for whom no vasoreactivity test was performed at diagnosis can
A woman of childbearing potential must
be eligible if currently treated with PAH therapy for more than 3 months and
have negative serum pregnancy test at Screening and a negative urine pregnancy test at Randomization
PAH diagnosis confirmed by hemodynamic evaluation at least 3 months after
agree to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation
introduction of their PAH therapy)
agree to follow the contraception scheme from Screening up to at least 30 days after study treatment discontinuation

Exclusion Criteria

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 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)
Known presence of moderate or severe obstructive lung disease any time prior to
Documented pulmonary veno-occlusive disease
Screening as specified in study protocol
Hemoglobin < 100 g/L (<10 g/dL) at Screening
Known severe hepatic impairment as specified in study protocol
Severe renal impairment at Screening as specified in study protocol
Systemic hypotension at Screening or Randomization and systemic hypertension at Screening as specified in study protocol
Acute myocardial infarction or cerebrovascular event (e.g., stroke) within the last 26 weeks prior to Screening
Known bleeding disorder, in the opinion of the investigator
Loss of vision in one or both eyes because of non-arteritic anterior ischemic optic neuropathy
Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 × upper limit of normal (ULN) at Screening
Hereditary degenerative retinal disorders, including retinitis pigmentosa
History of priapism, conditions that predispose to priapism (example, sickle cell anemia, multiple myeloma, or leukemia) or anatomical deformation of the penis (example, angulation, cavernosal fibrosis, or Peyronie's disease)
Difficulty swallowing large pills/tablets that would interfere with the ability to comply with study treatment regimen
Any planned surgical intervention (including organ transplant) during the double-blind treatment period, except minor interventions
Exercise training program for cardiopulmonary rehabilitation in the 12-week period prior to start of treatment, or planned to be started during the double-blind period of the study
Pregnant, planning to become pregnant or lactating
Any known factor or disease that might interfere with treatment adherence, full participation in the study or interpretation of the results as judged by the investigator (e.g., drug or alcohol dependence etc.)
Known concomitant life-threatening disease with a life expectancy less than (<) 12 months
Calcium channel blocker treatment initiated, or dose changed within 3 months prior to right heart catheterization (RHC) at screening
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