A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis

Inclusion Criteria

• A right heart catheterization done at baseline with a mean pulmonary artery pressure (mPAP) ≥ 25mmHg, pulmonary artery wedge pressure (PAWP) ≤ 15mmHg, and pulmonary vascular resistance (PVR) ≥3 Woods units.
• Scleroderma defined as systemic sclerosis with diffuse or limited scleroderma meeting the American College of Rheumatology (ACR) criteria (33). Cases will be included if they meet clinical features that satisfy ACR criteria for a diagnosis of scleroderma or the presence of three of five features of the CREST syndrome are identified; or there is the presence of definite Raynaud's phenomenon, abnormal nail fold capillaries typical of scleroderma and the presence of a specific scleroderma related auto-antibody. Limited skin involvement is defined as skin tightening distal to elbows and knees with or without facial involvement; and diffuse skin involvement, tightening proximal to these joints or truncal involvement.
• Subjects will be older than 18 years of age with a diagnosis of PAH-SSc.
• Subjects will be NYHA functional class II or III.
• 6 minute walk distance ≥ 100 meters and ≤ 500 meters at screening and baseline.
• Negative urine pregnancy test for women of childbearing age at screening and baseline visits.
• Ability and willingness to provide written informed consent

Exclusion Criteria

• Right heart catheterization reveals evidence of pulmonary venous hypertension (pulmonary capillary wedge pressure > 15 mm Hg).
• Significant chronic obstructive: Forced expiratory volume in 1 second to forced expiratory volume ratio 3 times the upper limit of normal at screening or at baseline) or chronic liver disease.
• Advanced kidney failure (GFR < 30 ml/min at screening or at baseline).
• Acute decompensation of underlying illness or hospitalization for pulmonary hypertension within 4 weeks prior to enrollment.
• Prior chronic therapy with an endothelin-receptor antagonist, PDE V inhibitor, or a prostacyclin analogue.
• History of hypersensitivity reaction or adverse effect related to ambrisentan or tadalafil.
• History of implantable permanent pacemaker or any metallic objects in the body.
• Participation in a clinical study involving an investigational drug or device within four weeks before the screening visit.
• Pregnant or lactating women.
• Concomitant use of nitrates (any form) either regularly or intermittently
• Concomitant use of potent Cytochrome P3A (CYP3A) inhibitors (eg, ritonavir, ketoconazole, itraconazole)
• Any additional contraindications and precautions specified in the package inserts for Tadalafil (Adcirca) and Ambrisentan (Letairis) not listed above.