CompRehensive Phenotypic Characterization of Patients With Scleroderma-Associated ILD and PH
CompRehensive Phenotypic Characterization of Patients With Scleroderma-Associated ILD and PH
Patients with interstitial lung disease (ILD) and scleroderma who develop pulmonary
 hypertension (PH) do not fit well into the current classification system and treatments for
 pulmonary hypertension. This study aims to better understand patients with ILD-PH and
 scleroderma and to determine if treatment with Macitentan is beneficial.
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