Combination Therapy in Pulmonary Arterial Hypertension
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: Bosentan; Sildenafil
Intervention description: Oral bosentan 62.5 mg BID first 4 weeks followed by 24 weeks of 125 mg BID if the 62.5 mg BID dose was well tolerated; Oral sildenafil 20 mg TID in patients who do not reach the 6-MWT distance threshold at Week 16
Intervention MeSH terms: Bosentan; Sildenafil Citrate
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 100.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: pulmonary arterial hypertension; bosentan; sildenafil; combination therapy; Compass 3

Summary:

      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.
    

Eligibility criteria:

        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.