A Rho-kinase Inhibitor (Fasudil) in the Treatment of Raynaud's Phenomenon
Condition: Raynaud; Scleroderma
MeSH terms: Raynaud Disease; Scleroderma, Systemic; Scleroderma, Diffuse
Study type: Interventional
Phase: Phase 3

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.
    

Intervention name(s): Fasudil
Intervention type(s): Drug
Intervention description(s): 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.
Other intervention name(s): No other name found
Intervention MeSH terms: Fasudil
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: scleroderma; Raynaud's phenomenon; Rho-kinase inhibitor