A Rho-kinase Inhibitor (Fasudil) in the Treatment of Raynaud's Phenomenon

Phase 3

Completed

Conditions: Raynaud
Scleroderma

Interventions: Drug: Fasudil

Registration Number: NCT00498615

Lead Sponsor: Johns Hopkins University

Brief Summary: Raynaud's phenomenon is thought to occur when, in response to cold or emotional stress, there is closure of the digital arteries and cutaneous arterioles leading to the clinical finding of sharp demarcated digital pallor and cyanosis of the distal skin of the fingers and/or toes. Patients often continue to experience problems despite current available treatment. The investigators' study will investigate the use of a new vasodilator called Fasudil, a Rho-kinase inhibitor. The investigators' hypothesis is that Fasudil will prevent vasoconstriction of digital and cutaneous arteries during a standard laboratory based cold exposure and will therefore improve digital blood flow and skin temperature recovery time following cold challenge. These data will provide the rationale for a more elaborate clinical trials in real life situations.

Detailed Description: Raynaud's phenomenon (RP) is a reversible vasospastic disorder of digital arteries and cutaneous arterioles characterized by typical skin color changes and tissue ischemia (1). Avoidance of common triggers such as cold temperatures and emotional stress often leads to improvement of symptoms. When such a strategy yields inadequate benefits, pharmacologic therapy is needed.

Cutaneous vasoconstriction occurs through a general sympathetic adrenergic response and through local mechanisms in response to cold. While under normal conditions, the vasomotor tone is regulated mainly by a.2A- adrenoreceptors (a.2A-AR) expressed on vascular smooth muscle cells (VSMC) (2); during cold exposure the normally "silent" a.2C-AR relocate from the Golgi complex to the cell surface, driving the cold-induced vasoconstrictive response (3). Interestingly, the reactivity to a.2-AR stimulation is highly increased in cutaneous arteries of patients with systemic sclerosis (SSc; scleroderma) (4), and block- age of a.2C-AR has shown to shorten the time to recover digital skin temperature after a cold challenge in patients with Raynaud's Phenomenon secondary to Scleroderma (5).

The RhoA/Rho kinase pathway is activated by cooling and mediates vasoconstriction of cutaneous arteries by inducing a.2C-AR relocation to the cell surface and by increasing calcium-dependent Vascular Smooth Muscle Cells (VSMC )contractility (6). Rho kinase inhibition has been shown to effectively reduce

a.2-AR-mediated response during cold exposure and to prevent cold-induced vasoconstriction in human skin (6) Therefore, RhoA/Rho kinase inhibition may provide a highly selective intervention directed toward the mechanisms underlying thermosensitive vasomotor responses in the skin of Raynaud's Phenomenon patients.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 17

Inclusion Criteria

diagnosis of scleroderma
definite Raynaud's

Exclusion Criteria

symptomatic orthostatic hypotension
evidence of current malignancy
active ischemic digital ulcer and/or tissue gangrene
history of sympathectomy at any time
upper extremity deep vein thrombosis or lymphedema within 3 months of the study
recent surgical procedure requiring general anesthesia
current alcohol or illicit drug use
use of any investigational drug within 30 days of the study sessions
pregnancy or current breast feeding
subjects felt by the investigators to active disease that would affect their ability to safely participate in the study.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Fasudil 80 mg	Fasudil	Subject is given a single dose of 80 mg of Fasudil ( blinded to participant and researcher) a cold challenge is given 2 hrs after the dose.
40 mg Fasudil	Fasudil	Subject is given a single dose of 40 mg of Fasudil ( blinded to participant and researcher) a cold challenge is given 2 hrs after the dose.
placebo	Fasudil	Subject is given a single dose of placebo( blinded to participant and researcher) a cold challenge is given 2 hrs after the dose.

Primary Outcome Measures

Name	Time	Method
Time to Recover to 70% of Fall in the Baseline Skin Temperature After Cold Challenge.	within 60 minutes	The time to recover 70% of the drop from baseline (prechallenge) skin temperature was derived for each subject for each cold challenge. After each of 3 study interventions received by each participant. Each participant received Fasudil 4o mg, 80 mg and placebo in a randomized sequence blinded to the participant and researchers.
The Time to Recover 50% of Fall in the Baseline Skin Temperature.	within 60 minutes	The time to recover 50% of the drop from baseline (prechallenge) skin temperature was derived for each subject for each cold challenge. After each of 3 study interventions received by each participant. Each participant received Fasudil 4o mg, 80 mg and placebo in a randomized sequence blinded to the participant and researchers.

Secondary Outcome Measures

Name	Time	Method
The Blood Flow by Laser Doppler Scans of the Fingers	Blood flow prior to cold challenge 2 hours after taking study drug	The measurement of the blood flow of participants prior to cold challenge 2 hours after receiving study.