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

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

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.

Study Overview

• Status: Completed
• Conditions: Raynaud's Phenomenon
• Intervention / Treatment: Drug: oral treprostinil; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: oral treprostinil; 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; Change in the Raynaud's Condition Score from baseline (2-week run in), comparing treprostinil treatment phase vs. placebo phase; Other Names: Orenitram; Drug: Placebo; 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; Other Names: Sugar pill
PLACEBO_COMPARATOR: Placebo; Placebo mimics oral treprostinil and will be taken three times a day	Drug: oral treprostinil; Change in the Raynaud's Condition Score from baseline (2-week run in), comparing treprostinil treatment phase vs. placebo phase; Other Names: Orenitram; Drug: Placebo; 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; 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

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: United Therapeutics
• Investigators: Principal Investigator: Aaron Waxman, MD/PhD, Brigham and Womens Hospital; Principal Investigator: Paul Dellaripa, MD, Brigham and Womens Hospital

Publications and helpful links

General Publications

• Ennis H, Hughes M, Anderson ME, Wilkinson J, Herrick AL. Calcium channel blockers for primary Raynaud's phenomenon. Cochrane Database Syst Rev. 2016 Feb 25;2(2):CD002069. doi: 10.1002/14651858.CD002069.pub5.
• Roustit M, Hellmann M, Cracowski C, Blaise S, Cracowski JL. Sildenafil increases digital skin blood flow during all phases of local cooling in primary Raynaud's phenomenon. Clin Pharmacol Ther. 2012 May;91(5):813-9. doi: 10.1038/clpt.2011.302. Epub 2012 Mar 28.
• Vayssairat M. Controlled multicenter double blind trial of an oral analog of prostacyclin in the treatment of primary Raynaud's phenomenon. French Microcirculation Society Multicentre Group for the Study of Vascular Acrosyndromes. J Rheumatol. 1996 Nov;23(11):1917-20.

Study record dates

Study Major Dates

• Study Start: May 1, 2016
• Primary Completion (ACTUAL): December 31, 2021
• Study Completion (ACTUAL): December 31, 2021

Study Registration Dates

• First Submitted: October 8, 2015
• First Submitted That Met QC Criteria: October 20, 2015
• First Posted (ESTIMATE): October 22, 2015

Study Record Updates

• Last Update Posted (ACTUAL): January 10, 2022
• Last Update Submitted That Met QC Criteria: January 5, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Peripheral Vascular Diseases; Raynaud Disease; Antihypertensive Agents; Treprostinil
• Other Study ID Numbers: 2015P001879

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO