Intravenous Iloprost in Subjects With Symptomatic Raynaud's Phenomenon Secondary to Systemic Sclerosis (Phase 3)

Inclusion Criteria:

   - Male or female subjects must be greater than or equal to 18 years of age.

   - Subjects must have a diagnosis of Systemic Sclerosis as defined by the 2013 American
   College of Rheumatology criteria/EULAR criteria

   - Subjects must have a diagnosis or history of Raynaud's Phenomenon, self-reported or
   reported by a physician, with at least a 2-phase color change in finger(s) of pallor,
   cyanosis, and/or reactive hyperemia in response to cold exposure or emotion

   - Subjects must have a minimum of 10 symptomatic Raynaud's Phenomenon attacks,
   documented in the electronic patient-reported outcomes (ePRO) diary, occurring over at
   least 3 separate days of the 3- to 5-day eligibility period

   - Subjects must complete a minimum of 80% of the daily ePRO diary entry during the
   baseline period

   - Female subjects of childbearing potential and male subjects must agree to use
   contraception for the duration of the study.

   - Subjects must be willing and able to comply with the study requirements and give
   informed consent for participation in the study

Exclusion Criteria:

   - Female subjects who are pregnant or breastfeeding

   - Subjects with systolic blood pressure <85 mmHg

   - Subjects with an estimated glomerular filtration rate <15 mL/min/1.73 m2

   - Subjects with an alanine aminotransferase and/or aspartate aminotransferase value >3 ×
   the upper limit of normal at screening

   - Subjects who have a digital ulcer infection within 30 days of screening

   - Subjects with a history of cervical or digital sympathectomy, or botulism toxin
   injections in their hands [for RP or digital ulcers] within 90 days of screening.
   Subjects should not have a planned botulism toxin or sympathectomy during their
   participation in the study.

   - Subjects with gangrene or digital amputation within 6 months of screening

   - Subjects with current intractable diarrhea or vomiting

   - Subjects with a risk of clinically significant bleeding events, including those with
   coagulation or platelet disorders at screening

   - Subjects with a history of major trauma or hemorrhage within 30 days of screening.

   - Subjects with clinically significant chronic intermittent bleeding, such as active
   gastric antral vascular ectasia or active peptic ulcer disease, within 60 days of
   screening

   - Subjects who have had any cerebrovascular events (eg, transient ischemic attack or
   stroke) within 6 months of screening

   - Subjects with a history of myocardial infarction or unstable angina within 6 months of
   screening. Subjects should not have a planned coronary procedure during their
   participation in the study

   - Subjects with acute or chronic congestive heart failure (New York Heart Association
   Class III [moderate] or Class IV [severe]) at screening

   - Subjects with a history of more than mild restrictive or congestive cardiomyopathy
   uncontrolled by medication or implanted device

   - Subjects with a history of life-threatening cardiac arrhythmias

   - Subjects with a history of hemodynamically significant aortic or mitral valve disease

   - Subjects with a history of known pulmonary hypertension, pulmonary arterial
   hypertension, or pulmonary veno-occlusive disease

   - Subjects with a history of significant restrictive lung disease, defined as forced
   vital capacity <45% predicted and diffusing capacity of the lungs for carbon monoxide
   <40% predicted (uncorrected for hemoglobin)

   - Subjects with scleroderma renal crisis within 6 months of screening

   - Subjects with a concomitant life-threatening disease with a life expectancy <12 months

   - Subjects who have a clinically significant disorder that, in the opinion of the
   Investigator, could contraindicate the administration of study drug, affect
   compliance, interfere with study evaluations, or confound the interpretation of study
   results

   - Subjects who have taken or are currently taking any parenteral, inhaled, or oral
   prostacyclin or prostacyclin receptor agonists (eg, epoprostenol, treprostinil,
   iloprost, and selexipag) within 8 weeks of screening

   - Subjects who have initiated or had a dose change of any of the following within 2
   weeks of screening: oral, topical, or intravenous (IV) vasodilators (eg, calcium
   channel blockers, phosphodiesterase-5 (PDE5) inhibitors [eg, sildenafil, tadalafil, or
   vardenafil], nitrates, and fluoxetine)

   - Subjects with any history of acetaminophen intolerability (eg, allergic reaction to
   acetaminophen)

   - Subjects with any malignancy that requires treatment during the study period, that has
   required treatment within 1 year of screening (including excision of skin cancer) or
   that is currently not in remission

   - Subjects who have used any investigational medication or device for any indication
   within 30 days or 5 half-lives (whichever is longer)

   - Subjects who have participated in ES-201 or ES-301 studies and were randomized and
   treated with study drug