Inclusion Criteria:

• Male or female subjects must be ≥18 years of age.
• Subjects must have a diagnosis of SSc as defined by the 2013 American College of Rheumatology criteria/EULAR criteria.
• Subjects must have a diagnosis or history of RP, 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 RP attacks, documented in the ePRO diary, occurring over at least 3 separate days of the 5-day eligibility period.
  • Note: A symptomatic Raynaud’s attack for this study is defined as at least 1 color change of the subject’s finger(s) (blue, white, or red) associated with at least 1 symptom (pain, numbness, tingling, and/or discomfort of the finger[s]). The attack is considered over when the color changes back to pre-attack color (normal) and the symptoms return to the subject’s pre-attack level.
• Subjects must complete a minimum of 80% of the daily ePRO diary entry during the baseline period.
• Female subjects of childbearing potential (defined as female subjects who have experienced menarche and who are not permanently sterile or postmenopausal; postmenopausal is defined as 12 consecutive months with no menses without an alternative medical cause) 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; where permitted by local regulations, a legally authorized representative will be allowed to sign the consent form as a proxy for subjects who are unable to physically sign but are able to give a verbal informed consent.

Exclusion Criteria: 

• Female subjects who are pregnant or breastfeeding prior to randomization.
• Subjects with systolic blood pressure 3 × the upper limit of normal at screening.
• Subjects with an estimated glomerular filtration rate 3 × the upper limit of normal at screening.
• Subjects with an alanine aminotransferase and/or aspartate aminotransferase value >3 × the upper limit of normal at screening.
• Subjects who have a DU 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 (e.g., 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, PAH, 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 IP receptor agonists (e.g., 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 IV vasodilators (e.g., calcium channel blockers, PDE5 inhibitors [e.g., sildenafil, tadalafil, or vardenafil], nitrates, and fluoxetine).
• Subjects with any history of acetaminophen intolerability (e.g., 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) of screening.
• Subjects who have participated in ES-201 or ES-301 studies and were randomized and treated with study drug.