Combination Therapy in Pulmonary Arterial Hypertension
Combination Therapy in Pulmonary Arterial Hypertension
An open label, non-comparative study design is appropriate for this Phase 4 study designed to
 assess whether a core therapy of bosentan, either as monotherapy or with the addition of
 sildenafil, enables patients with pulmonary arterial hypertension (PAH) to achieve a 6-minute
 walk distance (6 MWD) of ≥380 meters after 28 weeks of therapy This design is also
 appropriate to pioneer the utility of cardiac MRI in assessing improved functional capacity
 in PAH and exploring its correlation with other parameters.
Inclusion Criteria:

 1. Signed informed consent prior to initiation of any study-mandated procedures.

 2. Males or females ≥ 12 years of age (females of child-bearing potential must have been
 surgically sterilized or use a reliable method of contraception).

 3. 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

 4. 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

 5. 6-MWT distance ≥ 150 meters and < 360 meters.

 Exclusion Criteria:

 1. Patients with Pulmonary Hypertension (PH) belonging to WHO Classification Group II-V.

 2. Patients with PAH (WHO PH Classification Group I) other than that listed in the
 Inclusion Criteria.

 3. Pregnant and/or nursing.

 4. Women of childbearing potential not using a reliable method of contraception.

 5. Patients with known human immunodeficiency virus (HIV) infection.

 6. 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).

 7. Patients with restrictive lung disease (i.e., total lung capacity (TLC) < 60% of
 normal predicted value).

 8. Patients with obstructive lung disease (i.e., forced expiratory volume/ forced vital
 capacity (FEV1/FVC) < 0.5).

 9. Patients with impaired left ventricular function (LVEF <50%) or diastolic dysfunction.

 10. 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.

 11. Treatment with glibenclamide (glyburide) and calcineurin inhibitors (cyclosporine A,
 tacrolimus) sirolimus, everolimus up to 1 week prior to Baseline (Day 1).

 12. Patients currently receiving or predicted to require treatment, during the course of
 the study, with nitrates, protease inhibitors, or alpha-blockers.

 13. Patients with a hemoglobin concentration < 75 % of the lower limit of the normal range
 or < 8.5 g/dL.

 14. Patients currently receiving or predicted to require treatment with a prostanoid
 during the course of the study.

 15. Patients with systolic blood pressure < 85 mm Hg.

 16. Patients with body weight < 40 kg.

 17. Patients who have received any investigational product within 90 days prior to
 Baseline.

 18. Patients who previously received any advanced therapy for PAH (e.g., ERAs, PDE-5
 inhibitors or prostacyclins).

 19. Patients with hypersensitivity to sildenafil or any excipients of its formulation.

 20. Patients with any contraindication to sildenafil treatment (i.e., nitrates).

 21. Patients with any recent medical condition limiting the ability to comply with the
 study requirements (i.e., stroke, myocardial infarction).

 22. Patients with unstable PAH whose disease state would prohibit the completion of study
 procedures, in the opinion of the investigator.

 23. Patients unable to complete a MRI scan (e.g., claustrophobia).

 24. 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.

 25. 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).

 26. Patients with conditions that prevent compliance with the protocol or the ability to
 adhere to therapy.