Assess Efficacy of of Oral Treprostinil in Patients With Symptomatic Primary or Secondary Raynaud's Phenomenon

A single center double-blinded, placebo-controlled, crossover study to assess efficacy of
oral treprostinil titrated to a tolerable goal dose of 2.0 mg three times per day (TID) in 20
patients with symptomatic primary or secondary Raynaud's Phenomenon resistant to vasodilatory
therapy. Based on a pre-screening survey of the clinic population we anticipate at least 30
patients per year will be eligible for enrollment. At the clinicians discretion the dose can
be increased as tolerated.

Eligible subjects at the time of signing an informed consent will have a diagnosis of primary
or secondary Raynaud's Phenomenon. Subjects will be recruited from the Raynaud's Clinic,
which is a multidisciplinary clinic held at the Watkins Clinic at the Shapiro Cardiovascular
Center. Subjects will be assessed during a Screening and treatment initiation visit to
determine eligibility for the study.

This study represents the first trial to assess the efficacy of oral treprostinil therapy in
patients with symptomatic primary or secondary Raynaud's phenomenon resistant to vasodilatory
therapy.

Oral treprostinil (UT-15C), a synthetic prostacyclin analog that inhibits platelet
aggregation, induces vasodilation, and suppresses smooth muscle proliferation. In a recent
open label study of escalating doses of oral treprostinil in patients with systemic sclerosis
and digital ischemia, oral treprostinil was effectively absorbed in patients with scleroderma
and was temporally associated with improved cutaneous perfusion and temperature. Thus, oral
treprostinil may provide a new therapeutic option for patients with refractory secondary
Raynaud's Phenomenon.

A recent systematic review demonstrated that oral calcium channel blockers, the most commonly
prescribed drugs for primary RP, are only minimally effective in reducing the frequency of
attacks and severity. Although Sildenafil has been shown to increase digital skin blood flow
during all phases of local cooling in primary RP, its role in primary RP is not yet confirmed
in randomized, controlled trials. To our knowledge, very few studies have assessed the use of
oral prostacyclin therapy for disabling primary RP, although one multicenter, double-blind,
randomized trial of an oral analog of prostacyclin, known as beraprost, reduced the number of
RP attacks but proved no more beneficial than placebo.

Inclusion Criteria:

- Patients aged ≥18-65 years

- Active Raynaud's Phenomenon defined as patients with refractory RP having four or more
RP attacks per week in the 2 weeks before inclusion in the study despite treatment
with vasodilators for at least 3 months

- Patients with primary Raynaud's Phenomenon

- Patients with Raynaud's secondary to connective tissue diseases (including scleroderma
(SSc), limited scleroderma (CREST), mixed connective tissue disease (MCTD), primary
Sjogren's syndrome (SS), systemic lupus erythematosus (SLE), with diagnosis of the
underlying rheumatic disease based on standard criteria

- Patients on stable dose phosphodiesterase inhibitors (sildenafil, tadalafil or
vardenafil), endothelin antagonists, alpha adrenergic antagonists, or calcium channel
blockers defined as 3-months with no change in dose will be allowed to participate

Exclusion Criteria:

- Uncontrolled hypertension, diabetes mellitus, history of orthostatic hypotension,
acute coronary or cerebrovascular event within 3 months, evidence of malignancy,
history of sympathectomy

- Smoking within 3 months or smoking cessation using nicotine products

- Subjects currently taking or other prostacyclins.

- Pregnant or breast feeding or considering pregnancy in next 4 months

- Participation in trial with an investigational drug within 30 days