Macitentan for the Treatment of Digital Ulcers in Systemic Sclerosis Patients

Recurrent digital ulcers (DU) are a manifestation of vascular disease in patients with
systemic sclerosis (SSc), are an important source of morbidity and lead to impaired function
in these patients. In this study, we are investigating whether treatment with the endothelin
receptor antagonist, macitentan, decreases the development of new digital ulcers in patients
with SSc. Macitentan is a highly potent, tissue-targeting dual endothelin receptor
antagonist. Through complete blockade of endothelin action, macitentan is expected to
protect tissue from the damaging effect of elevated endothelin. This therapy is not approved
for the treatment of systemic sclerosis, but the use of an ERA is an attractive approach in
combating the structural vascular damage observed in SSc leading to complications such as
DUs.

Inclusion Criteria :

- Patients ≥ 18 years of age

- Women of childbearing potential must use two reliable methods of contraception

- Diagnosis of SSc according to the classification criteria of the American College of
Rheumatology (ACR)

- At least one visible, active ischemic digital ulcers(DU) at baseline

- History of at least one additional recent active ischemic DU

Exclusion Criteria :

- DUs due to condition other than SSc

- Symptomatic PAH

- BMI < 18 kg/m2

- AST and/or ALT > 1.5 x ULN

- Hemoglobin < 75% of the lower limit of the normal range

- Systolic blood pressure < 95 mmHg or diastolic blood pressure < 50 mmHg

- Severe malabsorption; any severe organ failure (e.g., lung, kidney), or any
life-threatening condition.

- Females who are pregnant or breastfeeding or plan to do so during the course of this
study.

- Substance or alcohol abuse or dependence, or tobacco use at any level.

- Treatment with PDE5 inhibitors.

- Patients on statins, who have received treatment for less than 3 months prior to
Screening or whose treatment has not been stable during this period.

- Patients on vasodilators, who have received treatment for less than 2 weeks prior to
Screening or whose treatment has not been stable during this period.

- Treatment with prostanoids within 3 months.

- Treatment with disease modifying agents if present for less than 3 months prior to
Screening or whose treatment has not been stable for at least 1 month prior to
Screening.

- Treatment with oral corticosteroids (> 10 mg/day of prednisone or equivalent).

- Treatment with ERAs within 3 months.

- Systemic antibiotics to treat infected DU(s) within 4 weeks.