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

Scleroderma Clinical Trial

Official title:

Efficacy, Tolerability and Biology of a Rho-kinase Inhibitor (Fasudil) in the Treatment of Raynaud's Phenomenon

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00498615
• Other study ID #: NA_00002801
• Status: Completed
• Phase: Phase 3
• First received: July 6, 2007
• Last updated: November 3, 2014
• Start date: April 2007
• Est. completion date: March 2012

Study information

• Verified date: August 2014
• Source: Johns Hopkins University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: March 2012
• Est. primary completion date: March 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Raynaud
• Raynaud Disease
• Scleroderma
• Scleroderma, Diffuse
• Scleroderma, Systemic

Intervention

Drug:
• Fasudil
Each subject will be randomly assigned to 1 of 6 possible treatment sequences (ABC, ACB, BAC, BCA, CAB, and CBA) in a double-blind manner: A- a single oral dose of 2 placebo tablets; B- a single, oral 40 mg Fasudil dose as one 40 mg tablet and 1 placebo tablet; C- a single oral 80 mg dose as two 40 mg Fasudil tablets. Subjects will be randomized at the screening/baseline visit to a specific treatment sequence based upon a computer generated code on a 1:1:1:1:1:1 ratio for the 6 possible sequences. A single dose consisting of the two tablets will be taken after fasting for 10 hours once during each treatment period. A washout interval of at least 24 hours and no more than 7 days will be maintained between treatment periods. Concomitant medications will not be taken during the study session.

Locations

Country	Name	City	State
United States	Johns Hopkins University	Baltimore	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
Johns Hopkins University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Time to Recover 50% of Fall in the Baseline Skin Temperature.	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.	within 60 minutes	No
Primary	Time to Recover to 70% of Fall in the Baseline Skin Temperature After Cold Challenge.	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.	within 60 minutes	No
Secondary	The Blood Flow by Laser Doppler Scans of the Fingers	The measurement of the blood flow of participants prior to cold challenge 2 hours after receiving study.	Blood flow prior to cold challenge 2 hours after taking study drug	No