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

Study Overview
=================
Brief Summary
-----------------
This study represents the first trial to assess the efficacy of oral treprostinil therapy in patients with symptomatic primary or secondary Raynaud's Phenomenon (RP) resistant to vasodilatory therapy. The study will be randomized 1:1 UT-15C to placebo. The design is a crossover study and all subjects will be randomized to receive oral treprostinil sustained release tablets or matching placebo for 12 weeks and then crossover for 12 weeks. All subjects will be exposed for 12 weeks of treatment with oral UT-15C during the study.

Detailed Description
-----------------
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.

Official Title
-----------------
A Double-blinded, Placebo-controlled, Crossover Study to Assess Efficacy of Oral Treprostinil Titrated to Highest Tolerable Dose in 20 Patients With Symptomatic Primary or Secondary Raynaud's Phenomenon Resistant to Vasodilatory Therapy

Conditions
-----------------
Raynaud's Phenomenon

Intervention / Treatment
-----------------
* Drug: oral treprostinil
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: oral treprostinil<br>Dosing of oral treprostinil will be initiated at 0.125 mg three times daily. Dose escalations of oral treprostinil can occur every 72 hours (three consecutive doses) in 0.125 mg increments. Subjects will be titrated as tolerated to a goal dose of 2mg TID over a 6-week period. | Drug: oral treprostinil<br>* Change in the Raynaud's Condition Score from baseline (2-week run in), comparing treprostinil treatment phase vs. placebo phase<br>* Other names: Orenitram;Drug: Placebo<br>* Placebo is a sugar pill manufactured to resemble UT-15C. Change in the Raynaud's Condition Score from baseline (2-week run in), comparing treprostinil treatment phase vs. placebo phase<br>* Other names: Sugar pill;|
| Placebo Comparator: Placebo<br>Placebo mimics oral treprostinil and will be taken three times a day | Drug: oral treprostinil<br>* Change in the Raynaud's Condition Score from baseline (2-week run in), comparing treprostinil treatment phase vs. placebo phase<br>* Other names: Orenitram;Drug: Placebo<br>* Placebo is a sugar pill manufactured to resemble UT-15C. Change in the Raynaud's Condition Score from baseline (2-week run in), comparing treprostinil treatment phase vs. placebo phase<br>* Other names: Sugar pill;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Raynaud's Condition Score | Change in the Raynaud's Condition Score from baseline (2-week run in), comparing treprostinil treatment phase vs. placebo phase | from baseline (2-week run in) to 6 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in number of Raynaud's Phenomenon attacks | Change in the number of Raynaud's Phenomenon attacks per week during the sixth week of treatment phase compared to the number of Raynaud's Phenomenon attacks per week at baseline. | from baseline (2-week run in) to 6 weeks of treatment | 
| Change in duration of Raynaud's Phenomenon attacks | Change in the total duration of Raynaud's Phenomenon attacks per week during the sixth week of treatment compared to the total duration of Raynaud's Phenomenon attacks per week at baseline. | from baseline (2-week run in) to 6 weeks of treatment | 
| Reduction of ulcer burden among secondary Raynaud's Phenomenon patients | Decrease ulcer burden in secondary Raynaud's Phenomenon patients by reducing the time to heal active ulcers and/or reducing the number of new ulcers. | from baseline (2-week run in) to 6 weeks of treatment |