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)
Condition: Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: FDC macitentan/tadalafil; Macitentan 10 mg; Tadalafil 40 mg; Placebo FDC; Placebo macitentan; Placebo tadalafil
Intervention description: Film-coated tablet with 10 mg macitentan and 40 mg tadalafil, to be administered orally once daily.; Film-coated tablet with 10 mg macitentan, to be administered orally once daily.; Film-coated tablet with 40 mg tadalafil (2 x 20 mg tablets), to be administered orally once daily.; Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.; Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.; Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.
Intervention MeSH terms: Tadalafil; Macitentan
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: In total, approximately 170 subjects are planned to be randomized into study to receive either FDC macitentan/tadalafil or macitentan 10 mg or tadalafil 40 mg given once daily and will also receive matching placebos for two other study treatments. Treatment allocation will be stratified based on prior PAH therapy (i.e., treatment-naïve or treated by an Endothelin receptor antagonist or a Phosphodiesterase type-5 inhibitor as a monotherapy) at baseline. Sample size will be re-estimated at interim analysis if study is not terminated early for efficacy/futility up to sample size of 150-250. After completion of double-blind treatment period, subjects will continue study in an open-label treatment (OLT) period for 24 months, which may be prolonged beyond 24 months until macitentan and tadalafil are accessible at required doses, through other options according to local regulations. All assessments at end of double-blind treatment must be completed before subject enters OLT period.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 187.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Pulmonary Arterial Hypertension; PAH; macitentan; tadalafil; fixed dose combination therapy

Summary:

      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.
    

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