Raynaud, Scleroderma
Conditions
Keywords
scleroderma, Raynaud's phenomenon, Rho-kinase inhibitor
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.
Interventions
DRUGFasudil
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.
Sponsors
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 3 Period Crossover Study ( All Participants) 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. | 17 |
| Total | 17 |
Baseline characteristics
| Characteristic | 3 Period Crossover Study ( All Participants) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Age, Continuous | 51 years |
| Region of Enrollment United States | 17 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 17 | 0 / 17 | 0 / 17 |
| serious Total, serious adverse events | 0 / 17 | 0 / 17 | 0 / 17 |
Outcome results
Primary
The Time to Recover 50% of Fall in the Baseline Skin Temperature.
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 40 mg Fasudil | The Time to Recover 50% of Fall in the Baseline Skin Temperature. | 7.5 minutes | Standard Deviation 3.2 |
| 80 mg Fasudil | The Time to Recover 50% of Fall in the Baseline Skin Temperature. | 8.2 minutes | Standard Deviation 3 |
| Placebo | The Time to Recover 50% of Fall in the Baseline Skin Temperature. | 7.9 minutes | Standard Deviation 3.1 |
Primary
Time to Recover to 70% of Fall in the Baseline Skin Temperature After Cold Challenge.
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 40 mg Fasudil | Time to Recover to 70% of Fall in the Baseline Skin Temperature After Cold Challenge. | 17.1 minutes | Standard Deviation 10.8 |
| 80 mg Fasudil | Time to Recover to 70% of Fall in the Baseline Skin Temperature After Cold Challenge. | 15.0 minutes | Standard Deviation 9.4 |
| Placebo | Time to Recover to 70% of Fall in the Baseline Skin Temperature After Cold Challenge. | 18.2 minutes | Standard Deviation 10.7 |
Secondary
The Blood Flow by Laser Doppler Scans of the Fingers
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 40 mg Fasudil | The Blood Flow by Laser Doppler Scans of the Fingers | 138.3 perfusion units | Standard Deviation 55.1 |
| 80 mg Fasudil | The Blood Flow by Laser Doppler Scans of the Fingers | 134.1 perfusion units | Standard Deviation 73.4 |
| Placebo | The Blood Flow by Laser Doppler Scans of the Fingers | 122.6 perfusion units | Standard Deviation 57.6 |