CompRehensive Phenotypic Characterization of Patients With Scleroderma-Associated ILD and PH (CRUSADE)

Inclusion Criteria:

• Patients who have scleroderma ILD will be defined as having a total lung capacity of less than 80% predicted and CT evidence of fibrosis. The degree of fibrosis will be scored by a radiologist using the CT comparative scoring method of Wells et al (13).
• Pulmonary Hypertension (PH) as defined as resting mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg with a wedge pressure of ≤ 15 mmHg during right heart catheterization.
• Stable ILD as evident by a stable FEV1 and FVC for 3 months prior to the initiation of the study, and be pulmonary arterial hypertension (PAH)-targeted treatment naïve.

Exclusion Criteria:

• Patients with a left ventricular ejection fraction <50% or clinical, echocardiographic, and/or catheterization data consistent with heart failure with preserved ejection fraction (HFpEF) and/or moderate-severe aortic or mitral valve abnormality
• Patients with severe restrictive lung disease (FVC<40% predicted) and/or obstructive lung disease (FEV1 <55% predicted and FEV1/FVC <70%).
• Patients with radiographic combined pulmonary fibrosis/emphysema (CPFE) will also be excluded if imaging shows predominant emphysema and/or obstruction is moderately severe (FEV1<30%)
• Patients with a history of pulmonary embolism within the last three months or evidence of chronic pulmonary embolism.
• Patients with a known contraindication to right heart catheterization.
• Patients whom have received active or previous pulmonary vasoactive medication within the previous 12 weeks.
• Patients with a contraindication to exercise testing based on American Heart Association/American College of Cardiology (AHA/ACC) guidelines.
• PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg), known pulmonary veno-occlusive disease, and pulmonary capillary hemangiomatosis.
• Persistent pulmonary hypertension of the newborn.
• Pulmonary Hypertension belonging to groups 2 to 5 of the Venice classification.
• Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C.
• Estimated creatinine clearance < 30 mL/min
• Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal.
• Hemoglobin < 75% of the lower limit of the normal range.
• Systolic blood pressure < 100 mmHg.
• Acute or chronic physical impairment (other than dyspnea), limiting the ability to comply with study requirements.
• Pregnant or breast-feeding.
• Known concomitant life-threatening disease with a life expectancy < 12 months.
• Body weight < 40 kg.
• Any condition that prevents compliance with the protocol or adherence to therapy.
• Treatment with endothelin receptor antagonists (ERAs) within 3 months prior to randomization.
• Systemic treatment within 4 week prior to randomization with cyclosporine A or tacrolimus, everolimus, sirolimus (calcineurin or mammalian target of rapamycin (mTOR) inhibitors).
• Treatment with cytochrome P3A (CYP3A) inducers within 4 weeks prior to randomization
• Known hypersensitivity to drugs of the same class as the study drug, or any of their excipients.
• Planned treatment, or treatment, with another investigational drug within 1 month prior to randomization