An open-label clinical trial of ambrisentan and tadalafil combination therapy in pulmonary arterial hypertension associated with the scleroderma spectrum of disease (ATPAHSS-O)
This will be a 36-week study comparing the effects of tadalafil and ambrisentan combination therapy in patients with pulmonary arterial hypertension associated with systemic sclerosis (PAH-SSc).
Subjects not previously treated with an endothelin-receptor antagonist, PDE V inhibitor, or prostacyclin-derivative will be enrolled. They will be ?18 years old, with mean PA pressure ? 25 mm Hg and PVR ?3 Woods units by right heart catheterization. They will have a diagnosis of PAH-SSc without associated interstitial lung disease.
Subjects who fulfill inclusion/exclusion criteria will receive tadalafil and ambrisentan. Conventional PAH care with diuretics, oxygen and digitalis will be provided as needed. Investigators, data analysts and subjects will be masked to the treatment assignment. Before receiving study drug subjects will undergo baseline clinical assessment, including NYHA classification, and complete SF-36, and MLHF questionnaires, 6MWD with Borg dyspnea grade, hemodynamic measurements with pressure/flow determinations, echocardiography and cardiac MRI examinations. Baseline blood testing including B-type natriuretic peptide will be obtained. Clinical assessment (history and physical exam, laboratory testing, NYHA classification and SF-36 and MLHF questionnaires) and 6MWT with Borg Dyspnea Score will be repeated at 4, 16, 24, and 36. Right heart catheterization will be performed at weeks 0 and 36. Echocardiography for TAPSE measurement will be performed at weeks 0, 16 and 36. Cardiac MRI will be performed at weeks 0, and 36.
Once entered every participant will be followed until the completion of the study protocol. To reach therapeutic goals, the study medications will be up titrated at week 4. Study participants will begin with tadalafil 20 mg once daily (qd) and ambrisentan 5 mgs daily. Up-titration of study medications will occur at week 4 (ambrisentan 10 mgs daily and tadalafil 40 mg qd). If a subject experiences an intolerable adverse event as a result of an uptitration in the study drug dose, the dose of study drug maybe down titrated to 20 mg of tadalafil and/or 5mg of ambrisentan. If the subject is still experiencing an intolerable adverse event, then the investigator will withdraw the subject from the study.
I. 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.
II. 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.
III. Subjects will be older than 18 years of age with a diagnosis of PAH-SSc.
IV. Subjects will be NYHA functional class II or III.
V. Negative urine pregnancy test for women of childbearing age at screening and baseline visits.
VI. Ability and willingness to provide written informed consent