Combination Therapy in Pulmonary Arterial Hypertension

Inclusion criteria

• Signed informed consent prior to initiation of any study-mandated procedures.
• Males or females ≥ 12 years of age (females of child-bearing potential must have been surgically sterilized or use a reliable method of contraception).
• Symptomatic patients with the following types of PAH belonging to World Health Organization (WHO) Pulmonary Hypertension Classification Group I:

• Idiopathic (IPAH)
• Familial (FPAH)
• Associated with PAH (APAH):

• Collagen vascular disease
• Drugs and toxins
• Patients naïve to treatment with advanced PAH therapies (i.e., endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE-5) inhibitors or prostacyclins) with a right heart catheterization (RHC) showing all of the following:

• Mean pulmonary arterial pressure (mPAP) ≥ 25 mm Hg
• Pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg or left ventricular end diastolic pressure (LVEDP) ≤ 15 mm Hg when PCWP is not accurately obtained
• Pulmonary vascular resistance ≥ 3 Wood units
• 6-MWT distance ≥ 150 meters and < 360 meters.

Exclusion criteria

• Patients with Pulmonary Hypertension (PH) belonging to WHO Classification Group II-V.
• Patients with PAH (WHO PH Classification Group I) other than that listed in the Inclusion Criteria.
• Pregnant and/or nursing.
• Women of childbearing potential not using a reliable method of contraception.
• Patients with known human immunodeficiency virus (HIV) infection.
• Patients with significant vasoreactivity during right heart catheterization (i.e., a fall in mPAP to < 40 mm Hg with a decrease of ≥ 10 mm Hg and with a normal cardiac index ≥ 2.5 l/min.m^2).
• Patients with restrictive lung disease (i.e., total lung capacity (TLC) < 60% of normal predicted value).
• Patients with obstructive lung disease (i.e., forced expiratory volume/ forced vital capacity (FEV1/FVC) < 0.5).
• Patients with impaired left ventricular function (LVEF <50%) or diastolic dysfunction.
• Patients with portal hypertension, cirrhosis, moderate to severe liver impairment (Child-Pugh Class B or C), or liver enzymes (Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)) > 3.0 times the upper limit of normal range.
• Treatment with glibenclamide (glyburide) and calcineurin inhibitors (cyclosporine A, tacrolimus) sirolimus, everolimus up to 1 week prior to Baseline (Day 1).
• Patients currently receiving or predicted to require treatment, during the course of the study, with nitrates, protease inhibitors, or alpha-blockers.
• Patients with a hemoglobin concentration < 75 % of the lower limit of the normal range or < 8.5 g/dL.
• Patients currently receiving or predicted to require treatment with a prostanoid during the course of the study.
• Patients with systolic blood pressure < 85 mm Hg.
• Patients with body weight < 40 kg.
• Patients who have received any investigational product within 90 days prior to Baseline.
• Patients who previously received any advanced therapy for PAH (e.g., ERAs, PDE-5 inhibitors or prostacyclins).
• Patients with hypersensitivity to sildenafil or any excipients of its formulation.
• Patients with any contraindication to sildenafil treatment (i.e., nitrates).
• Patients with any recent medical condition limiting the ability to comply with the study requirements (i.e., stroke, myocardial infarction).
• Patients with unstable PAH whose disease state would prohibit the completion of study procedures, in the opinion of the investigator.
• Patients unable to complete a MRI scan (e.g., claustrophobia).
• Patients with permanent cardiac pacemakers, automatic internal cardioverter defibrillators (AICD's), neurostimulators, hearing aides, and other implanted metallic devices that are contraindicated during a MRI study.
• Patients with conditions that would interfere with proper cardiac gating during MRI, such as atrial fibrillation or multiple premature ventricular contractions (PVCs)/premature atrial contractions (PACs).
• Patients with conditions that prevent compliance with the protocol or the ability to adhere to therapy.