Intervention: Tadalafil
Trial phase: Phase 4
ATC code: C02KX52 | C02KX54 | G04BE08 | G04CA54 | G04CB51
SMILES: [H][C@]12Cc3c([nH]c4ccccc34)[C@@H](c3ccc4c(c3)OCO4)N1C(=O)CN(C)C2=O
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 24
Group description: This will be a 36-week, single group, open label study assessing the effects of Tadalafil plus Ambrisentan combination therapy in patients with pulmonary arterial hypertension associated with the scleroderma spectrum of disease (PAH-SSD).

tadalafil and ambrisentan upfront combination therapy: tadalafil 20 mg qd and ambrisentan 5 mg qd. 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.
Eligibility criteria:
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 < 70% and a forced expiratory volume in 1 second less than 60% of predicted.

Interstitial lung disease

Based on a combination of pulmonary function tests and chest radiography.
Patients will be excluded if they have a total lung capacity less than 60% of predicted and included if the total lung capacity was ≥ 70%. Patients with a total lung capacity between 60 and 70% of predicted are included if their computed tomography scan demonstrates only minimal interstitial fibrosis
Portal hypertension.
Severe obstructive sleep apnea.
Chronic thromboembolic disease.
Positive antibodies to the human immunodeficiency virus.
History of anorexigen use including fen-phen.
Any other disease known to be associated with pulmonary hypertension.
Subjects with other etiology for pulmonary hypertension besides PAH-SSc.
Subjects with liver function abnormalities (ALT or Aspartate Aminotransferase (AST) > 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.