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

The investigators aim to use pressure-volume loop derived right ventriculo-vascular coupling,
pulmonary impedance, and invasive cardiopulmonary exercise testing (CPET) to:

1. Comprehensively phenotype patients with scleroderma ILD-PH and pulmonary vascular
exercise limitation (PVL) relative to scleroderma ILD-PH without PVL.

2. Compare the efficacy of chronic Macitentan therapy in improving 1) right ventricular
hemodynamics 2) exercise capacity and 3) symptoms in scleroderma ILD-PH patients with
and without PVL.

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