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

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00498615
• Collaborator: (none)
• Enrollment: 17
• Location: 1
• Arms: 3
• Duration (Months): 59
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Raynaud; Scleroderma	Drug: Fasudil	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy, Tolerability and Biology of a Rho-kinase Inhibitor (Fasudil) in the Treatment of Raynaud's Phenomenon
• Study Start Date: Apr 1, 2007
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
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 Names: 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 Names: 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 Names: No other name found

Outcome Measures

Primary Outcome Measures

1. The Time to Recover 50% of Fall in the Baseline Skin Temperature. [within 60 minutes]

   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.

2. Time to Recover to 70% of Fall in the Baseline Skin Temperature After Cold Challenge. [within 60 minutes]

   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

1. The Blood Flow by Laser Doppler Scans of the Fingers [Blood flow prior to cold challenge 2 hours after taking study drug]

   The measurement of the blood flow of participants prior to cold challenge 2 hours after receiving study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Fredrick M. Wigley, Professor of Medicine, Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT00498615
• Other Study ID Numbers: NA_00002801
• First Posted: Jul 10, 2007
• Last Update Posted: Nov 4, 2014
• Last Verified: Aug 1, 2014

• Keywords provided by Fredrick M. Wigley, Professor of Medicine, Johns Hopkins University: scleroderma; Raynaud's phenomenon; Rho-kinase inhibitor
• Additional relevant MeSH terms: Raynaud Disease; Scleroderma, Systemic; Scleroderma, Diffuse; Fasudil

Study Results

Participant Flow

Arm/Group Title	Sequence 1	Sequence 2	Sequence 3	Sequence 4	Sequence 5	Sequence 6
Arm/Group Description	Subjects received a single dose of Fasudil 80 mg at treatment period 1. At treatment period 2 they will received a single dose of Fasudil 40 mg and at treatment period 3 they received a single dose of placebo. A washout interval of at least 24 hours and no more than 7 days will be maintained between treatment periods.	Subjects received a single dose of Fasudil 40 mg at treatment period 1. At treatment period 2 they will received a single dose of Fasudil 80 mg and at treatment period 3 they received a single dose of placebo. A washout interval of at least 24 hours and no more than 7 days will be maintained between treatment periods	Subjects received a single dose of Fasudil 80 mg at treatment period 1. At treatment period 2 they will received a single dose of placebo and at treatment period 3 they received a single dose of Fasudil 40 mg. A washout interval of at least 24 hours and no more than 7 days will be maintained between treatment periods	Subjects received a single dose of placebo at treatment period 1. At treatment period 2 they will received a single dose of Fasudil 40 mg and at treatment period 3 they received a single dose of Fasudil 80 mg. A washout interval of at least 24 hours and no more than 7 days will be maintained between treatment periods	Subjects received a single dose of Fasudil 40 mg at treatment period 1. At treatment period 2 they will received a single dose of placebo and at treatment period 3 they received a single dose of Fasudil 80 mg. A washout interval of at least 24 hours and no more than 7 days will be maintained between treatment periods	Subjects received a single dose of placebo at treatment period 1. At treatment period 2 they will received a single dose of Fasudil 80 mg and at treatment period 3 they received a single dose of Fasudil 40 mg. A washout interval of at least 24 hours and no more than 7 days will be maintained between treatment periods
Period Title: Fasudil 80mg
STARTED	2	4	3	2	3	3
COMPLETED	2	4	3	2	3	3
NOT COMPLETED	0	0	0	0	0	0
Period Title: Fasudil 80mg
STARTED	2	4	3	2	3	3
COMPLETED	2	4	3	2	3	3
NOT COMPLETED	0	0	0	0	0	0
Period Title: Fasudil 80mg
STARTED	2	4	3	2	3	3
COMPLETED	2	4	3	2	3	3
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	3 Period Crossover Study ( All Participants)
Arm/Group Description	This is a single-center, double-blind, placebo-controlled, randomized, 3-period crossover study of oral fasudil (40 mg or 80 mg) or placebo administered 2 hours before a standardized cold challenge. Men and women between ages 18-80 years with a clinical diagnosis of RP secondary to SSc were eligible for the study.
Overall Participants	17
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	51
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	16 94.1%
>=65 years	1 5.9%
Sex: Female, Male (Count of Participants)
Female	15 88.2%
Male	2 11.8%
Region of Enrollment (participants) [Number]
United States	17 100%

Outcome Measures

1. Primary Outcome

Title	The Time to Recover 50% of Fall in the Baseline Skin Temperature.
Description	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 Frame	within 60 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	40 mg Fasudil	80 mg Fasudil	Placebo
Arm/Group Description	This is a single-center, double-blind, placebo-controlled, randomized, 3-period crossover study of oral fasudil 40 mg administered 2 hours before a standardized cold challenge participant and researchers will not know what is received on the testing day.	participants will receive 80mg of Fasudil at 1 one 3 study periods 2hrs before a cold challenge.	participants will receive placebo at 1 of 3 study periods. participants and researchers will not know which is received.
Measure Participants	17	17	17
Mean (Standard Deviation) [minutes]	7.5 (3.2)	8.2 (3.0)	7.9 (3.1)

2. Secondary Outcome

Title	The Blood Flow by Laser Doppler Scans of the Fingers
Description	The measurement of the blood flow of participants prior to cold challenge 2 hours after receiving study.
Time Frame	Blood flow prior to cold challenge 2 hours after taking study drug

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	80 mg Fasudil	40 mg Fasudil	Placebo
Arm/Group Description	This is a single-center, double-blind, placebo-controlled, randomized, 3-period crossover study of oral fasudil In this arm participants received 80 mg of Fasudil 2 hours before a standardized cold challenge. Men and women between ages 18-80 years with a clinical diagnosis of Raynauds Phenomenon secondary to Scleroderma were eligible for the study.	In this group participants received 40mg of Fasudil 2 hours before cold challenge	In this group participants received placebo 2 hours before cold challenge.
Measure Participants	17	17	17
Mean (Standard Deviation) [perfusion units]	138.3 (55.1)	134.1 (73.4)	122.6 (57.6)

3. Primary Outcome

Title	Time to Recover to 70% of Fall in the Baseline Skin Temperature After Cold Challenge.
Description	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.
Time Frame	within 60 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fasudil 80 mg	40 mg Fasudil	Placebo
Arm/Group Description	Time to recover 70% of baseline skin temperature after cold challenge done 2 hrs after dose. 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 treatments. 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 72 hours and no more than 7 days will be maintained between treatment periods. Concomitant medications will not be taken during the study session.	Time to reach 70% skin temperature after cold challenge done 2 hrs after dosing. 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 treatments. 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 72 hours and no more than 7 days will be maintained between treatment periods. Concomitant medications will not be taken during the study session.	Time to reach 70% of skin temperature after cold challenge done 2 hrs after taking placebo 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 treatments. 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 72 hours and no more than 7 days will be maintained between treatment periods. Concomitant medications will not be taken during the study session.
Measure Participants	17	17	17
Mean (Standard Deviation) [minutes]	17.1 (10.8)	15.0 (9.4)	18.2 (10.7)

Adverse Events

Time Frame	35 days
Arm/Group Title	Placebo		40 mg Fasudil		80mg Fasudil
Arm/Group Description	Placebo was administered 2 hours before a standardized cold challenge.		40 mg Fasudil was administered 2 hours before a standardized cold challenge.		80mg Fasudil was administered 2 hours before a standardized cold challenge.
All Cause Mortality
	Placebo		40 mg Fasudil		80mg Fasudil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		40 mg Fasudil		80mg Fasudil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/17 (0%)		0/17 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		40 mg Fasudil		80mg Fasudil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/17 (0%)		0/17 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.