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)

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.

Eligibility Criteria:
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 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

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 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
* 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
* 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