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

NCT ID: NCT00498615

Last Updated: 2014-11-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 17 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-04-30
• Study Completion Date: 2012-03-31

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.

Conditions

Raynaud; Scleroderma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Fasudil 80 mg

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.

Group Type: EXPERIMENTAL

Fasudil

Intervention Type: DRUG

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.

40 mg 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.

Group Type: EXPERIMENTAL

Fasudil

Intervention Type: DRUG

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.

placebo

Subject is given a single dose of placebo( blinded to participant and researcher) a cold challenge is given 2 hrs after the dose.

Group Type: PLACEBO_COMPARATOR

Fasudil

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

No other name found

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Johns Hopkins University

OTHER

Sponsor Role: lead

Responsible Party

Fredrick M. Wigley

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Fredrick M Wigley, M.D.

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Locations

Johns Hopkins University

Baltimore, Maryland, United States

Countries

United States

Other Identifiers

NA_00002801

Identifier Type: -

Identifier Source: org_study_id