Clinical trial NCT00498615: A Rho-kinase Inhibitor (Fasudil) in the Treatment of Raynaud's Phenomenon
Official title: Efficacy, Tolerability and Biology of a Rho-kinase Inhibitor (Fasudil) in the Treatment of Raynaud's Phenomenon
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Raynaud
Scleroderma
Keywords: scleroderma
Raynaud's phenomenon
Rho-kinase inhibitor
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
First posted: 2007-07-10
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: The Time to Recover 50% of Fall in the Baseline Skin Temperature.
timeFrame: within 60 minutes
measure: Time to Recover to 70% of Fall in the Baseline Skin Temperature After Cold Challenge.
timeFrame: within 60 minutes
Secondary outcomes:
measure: The Blood Flow by Laser Doppler Scans of the Fingers
timeFrame: Blood flow prior to cold challenge 2 hours after taking study drug
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Fredrick M Wigley, M.D.
role: PRINCIPAL_INVESTIGATOR
References: