A Trial of Ischemic Preconditioning in Raynaud's Phenomenon (RP)

Study Overview
=================
Brief Summary
-----------------
This trial will test the efficacy of brief periods of controlled limb ischemia (remote ischemic preconditioning, RIPC) as an effective treatment of patients with Raynaud's Phenomenon (RP).The hypothesis of this trial is that due to its vasoprotective effects, RIPC would be more effective than placebo in the treatment of both primary and secondary RP, as defined by decreased frequency, duration, and severity of attacks. This trial was also designed to monitor the tolerance of RIPC in a rheumatologic population. Patients will not be required to stop any current treatment for RP.

Detailed Description
-----------------
Raynaud's phenomenon (RP) is defined as vasospasms of arteries causing pallor and at least one other color change upon reperfusion such as cyanosis or redness. The current treatments for RP (channel blockers, PDE5 inhibitors, etc.) have only modest efficacy and are associated with many side-effects including headaches, flushing, hypotension and fluid retention that require stopping the medication. Thus, identification of an innovative treatment is an important therapeutic goal in RP patients. Ischemic preconditioning is a simple non-invasive procedure which consists of 4 consecutive episodes of brief ischemia caused by placing a pneumatic cuff at the level of the brachial artery and inflating it to 200 mm Hg for 2.5 minutes, followed by 2.5 minutes of reperfusion. Over 20 years IPC has generated tremendous scientific interest being described as the most powerful available form of in vivo protection against ischemic injury. This clinical trial will measure the efficiency of RIPC in decreasing the frequency, duration and severity of RP attacks. 24 patients will be recruited from the Rheumatology clinic of St. Joseph's Health Care in London, Ontario. As they enter the trial, subjects will be assigned to a treatment or a placebo group according to a pre-set randomization schedule. The trial will be single-blinded (patient). The primary outcome measures (frequency, duration and severity) will be assessed by the patient on a daily basis using a journal provided by the investigator. Secondary outcome measures will include functions questionnaires (Raynaud's Condition Score, s-HAQ-DI, DASH) and biological markers of endothelial damage (P-selectin, I-CAM, VEGF), will be conducted every two weeks: at baseline, post-placebo, post-washout, and post-treatment phases. Patients participation will span 8 weeks. The first two weeks are a baseline measurement for the status of RP using the journals, questionnaires, and serum tests. The treatment period will last 6 weeks in which the subject will be completing the arm of the IPC regimen to which he/she has been assigned. Other results which may arise from the trial are: The tolerance of RIPC in rheumatology patients, by monitoring side-effects. The attitude of rheumatology patients in using non-pharmacological treatments, by a questionnaire. Elucidating parts of the RP mechanism, by measuring bio-markers Differences between primary and secondary RP, by stratified randomization The results will be analyzed for all three primary outcome measures as a difference of between baseline and treatment. These differences will be compared between treatment and placebo and each will be stratified for primary vs. secondary and possibly other demographic data. This trial, if positive, will offer another treatment to RP patients. This option will possibly have fewer side-effects and be better accepted because it is a common and safe non-pharmacological intervention.

Official Title
-----------------
A Randomized, Single-blinded Placebo-controlled Trial of Ischemic Preconditioning in Raynaud's Phenomenon (RP)

Conditions
-----------------
Raynaud Disease, Raynaud's Phenomenon

Intervention / Treatment
-----------------
* Device: Manual blood pressure cuff inflation over brachial artery


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Primary or secondary RP, as diagnosed by a rheumatologist Clinical need for treatment for RP At least 7 RP attacks per week Systolic blood pressure above 80mmHg Willing to provide informed consent Exclusion Criteria: New or changed dose of drugs used for RP treatment in the last 2 weeks: calcium channel blockers, alpha1-adrenergic blockers, angiotensin II receptor antagonists, nitroglycerin, prostaglandins, pentoxifylline, endothelin antagonists and/or phosphodiesterase type 5 inhibitors. Non-compliance with past therapies

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Arm - 200 mmHg<br>Patients who start in the active arm of the study will receive ischemic preconditioning (IPC) treatment consisting of applying the blood pressure cuff to a pressure of 200 mmHg for 2 minutes and thirty seconds with a resting period of two minutes and thirty seconds between treatments. This procedure is performed four times, for a total of twenty minutes per treatment. This treatment will be done three times a week. Patients may choose to treat at home with a portable manual blood pressure machine or may be treated in clinic by research staff. Patients will receive treatment for two weeks followed by a wash-out period (no treatment) of two weeks. Patients will then receive the placebo treatment. This completes their participation in the study. | Device: Manual blood pressure cuff inflation over brachial artery<br>* A manual blood pressure cuff (sphygmomanometer) is used in the study as a tourniquet in order to perform a controlled, consistent level of ischemia (200mmHg/active arm or 60 mmHg/placebo arm).<br>|
| Placebo Comparator: Placebo Arm - 60 mmHg<br>Patients who start in the placebo arm will receive placebo treatment, consisting of applying the blood pressure cuff to a pressure of 60 mmHg for 2 minutes and thirty seconds with a resting period of two minutes and thirty seconds between treatments. This procedure is performed four times, for a total of twenty minutes per treatment. This treatment will be done three times a week for two weeks followed by a two week wash-out and then two weeks in the active treatment phase, thus completing their participation in the study. | Device: Manual blood pressure cuff inflation over brachial artery<br>* A manual blood pressure cuff (sphygmomanometer) is used in the study as a tourniquet in order to perform a controlled, consistent level of ischemia (200mmHg/active arm or 60 mmHg/placebo arm).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in frequency of RP attacks | The subject will self-assess the number of RP attacks daily in their RP diary. | Entire study duration (8 weeks including pretreatment and washout period) | 
| Changes in severity of RP attacks | Severity will be evaluated on a scale of 1 to 10. The subject will self-assess the severity in their RP diary. (0 = no difficulty with RP condition, 10 = extreme difficulty with RP condition). | Entire study duration (8 weeks including pretreatment and washout period) | 
| Changes in duration of RP attacks | The subject will self-assess the duration (in minutes) of RP attacks daily in their RP diary. | Entire study duration (8 weeks including pretreatment and washout period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functions questionnaires (Raynaud's Condition Score) |  | Every 2 weeks at clinic visits (baseline, after intervention, after washout, and after placebo) for a total of 6 weeks | 
| Biological marker of endothelial damage (P-selectin) |  | Every 2 weeks at clinic visits (baseline, after intervention, after washout, and after placebo) for a total of 6 weeks | 
| Biological marker of endothelial damage (I-CAM) |  | Every 2 weeks at clinic visits (baseline, after intervention, after washout, and after placebo) for a total of 6 weeks | 
| Biological marker of endothelial damage (VEGF) |  | Every 2 weeks at clinic visits (baseline, after intervention, after washout, and after placebo) for a total of 6 weeks | 
| Functions questionnaires (HAQ-DI) | Health Assessment Questionnaire - Disability Index | Every 2 weeks at clinic visits (baseline, after intervention, after washout, and after placebo) for a total of 6 weeks | 
| Functions questionnaires (DASH) | Disabilities of the Arm, Shoulder, and Hand | Every 2 weeks at clinic visits (baseline, after intervention, after washout, and after placebo) for a total of 6 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ischemic preconditioning, Raynaud's Phenomenon, (RP)