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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Fredrick M. Wigley, Johns Hopkins University
ClinicalTrials.gov Identifier:
NCT00498615
First received: July 6, 2007
Last updated: November 3, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Raynaud
Scleroderma
Drug: Fasudil
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Efficacy, Tolerability and Biology of a Rho-kinase Inhibitor (Fasudil) in the Treatment of Raynaud's Phenomenon

Resource links provided by NLM:


Further study details as provided by Johns Hopkins University:

Primary Outcome Measures:
  • The Time to Recover 50% of Fall in the Baseline Skin Temperature. [ Time Frame: within 60 minutes ] [ Designated as safety issue: No ]
    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.

  • Time to Recover to 70% of Fall in the Baseline Skin Temperature After Cold Challenge. [ Time Frame: within 60 minutes ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • The Blood Flow by Laser Doppler Scans of the Fingers [ Time Frame: Blood flow prior to cold challenge 2 hours after taking study drug ] [ Designated as safety issue: No ]
    The measurement of the blood flow of participants prior to cold challenge 2 hours after receiving study.


Enrollment: 17
Study Start Date: April 2007
Study Completion Date: March 2012
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
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.
Other Name: No other name found
Experimental: 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.
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.
Other Name: No other name found
Placebo Comparator: placebo
Subject is given a single dose of placebo( blinded to participant and researcher) a cold challenge is given 2 hrs after the dose.
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.
Other Name: No other name found

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

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00498615

Locations
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21224
Sponsors and Collaborators
Johns Hopkins University
Investigators
Principal Investigator: Fredrick M Wigley, M.D. Johns Hopkins University
  More Information

No publications provided

Responsible Party: Fredrick M. Wigley, Professor of Medicine, Johns Hopkins University
ClinicalTrials.gov Identifier: NCT00498615     History of Changes
Other Study ID Numbers: NA_00002801
Study First Received: July 6, 2007
Results First Received: March 25, 2014
Last Updated: November 3, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Johns Hopkins University:
scleroderma
Raynaud's phenomenon
Rho-kinase inhibitor

Additional relevant MeSH terms:
Raynaud Disease
Scleroderma, Diffuse
Scleroderma, Systemic
Cardiovascular Diseases
Connective Tissue Diseases
Peripheral Vascular Diseases
Skin Diseases
Vascular Diseases
Fasudil
Calcium Channel Blockers
Cardiovascular Agents
Enzyme Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors
Therapeutic Uses
Vasodilator Agents

ClinicalTrials.gov processed this record on November 25, 2014