Nutritional Strategies to Increase Nitric Oxide Signaling in Raynaud's Phenomenon

Study Overview
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Brief Summary
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The investigators aim at comparing the efficacy of a 2 weeks supplementation by L-citrulline or beetroot juice to L-citrulline placebo or denitrated beetroot juice respectively on Raynaud's phenomenon severity. Raynaud's phenomenon severity will be assessed through the Raynaud Condition Score, daily frequency of attacks or cumulative attack duration (expressed as min) daily collected by patients in a diary. Each Volunteer will choose his own main outcome among these 3 criteria.

Detailed Description
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Raynaud's phenomenon (RP) is a clinical condition that follows an exaggerated vasoconstriction of extremities in response to a cold or emotional stress. Microvascular dysfunction and alteration of the endothelial NO-dependent vasodilatation pathway through NO synthases (NOS) represents one of the main mechanisms. A pharmacological treatment in RP is proposed to patients when conservative measures are not efficient enough to control the symptoms: calcium channel blockers remains the first line, phosphodiesterase type 5 inhibitors as a second line treatment, while intravenous iloprost remains restricted to patients with digital ischaemia. Vasodilator therapies are commonly associated with side effects due to the non-specific systemic vasodilation that often result in permanent discontinuation. Many patients prefer complementary and alternative therapies, but none has proven its efficacy. Therefore, there is still room for improvement in the treatment of RP, and research is needed in this area.

Official Title
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Nutritional Strategies to Increase Nitric Oxide Signaling in Raynaud's Phenomenon

Conditions
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Raynaud Phenomenon

Intervention / Treatment
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* Dietary Supplement: L-citrulline
* Dietary Supplement: Beetroot juice
* Dietary Supplement: L-citrulline placebo
* Dietary Supplement: Denitrated beetroot juice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI > 18 Active Raynaud's Phenomenon characterized by a clinical history of Raynaud's Primary RP or secondary to limited (LSSc), limited or diffuse cutaneous scleroderma (lcSSc or dcSSc) according to the criteria of Leroy and Medsger. At least 1 RP attacks per week and a specific finger patient picture in RP attack (assessed over the 2 weeks preceding inclusion) Stable disease over the previous two months (i.e. recent diagnosis of SSc will be excluded) Patients insured by a social security scheme or beneficiaries of such a scheme Patients who have dated and signed the informed consent form Exclusion Criteria: Uncontrolled hypertension, uncontrolled diabetes mellitus, uncontrolled angina Haemodynamic instability Pregnancy (or considering pregnancy in next 4 months) or breast feeding Subject in an exclusion period from another study, Subject under administrative or judicial supervision Subject not able to be contacted in case of emergency

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: L-citrulline<br>Six cycles will be conducted over two consecutive winters. One cycle will consist of two 2-week supplementation periods. A 7 days wash-out period will be imposed between treatment periods (placebo and treatment). | Dietary Supplement: L-citrulline<br>* L-citrulline 9g per day (capsule, per os) during 14 days;<br>|
| Experimental: Beetroot juice<br>Six cycles will be conducted over two consecutive winters. One cycle will consist of two 2-week supplementation periods. A 7 days wash-out period will be imposed between treatment periods (placebo and treatment). | Dietary Supplement: Beetroot juice<br>* Concentrated 70 ml beetroot juice bottles containing 6.45 mmol of nitrates<br>|
| Placebo Comparator: L-citrulline placebo<br>Six cycles will be conducted over two consecutive winters. One cycle will consist of two 2-week supplementation periods. A 7 days wash-out period will be imposed between treatment periods (placebo and treatment). | Dietary Supplement: L-citrulline placebo<br>* L-citrulline placebo (maltodextrin) 9g per day (capsule, per os) during 14 days<br>|
| Placebo Comparator: Denitrated beetroot juice<br>Six cycles will be conducted over two consecutive winters. One cycle will consist of two 2-week supplementation periods. A 7 days wash-out period will be imposed between treatment periods (placebo and treatment). | Dietary Supplement: Denitrated beetroot juice<br>* Concentrated 70 ml nitrate-depleted beetroot juice<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Raynaud Condition Score | Change from baseline in the Raynaud's Condition score (RCS). RCS is participant's rating of difficulty considering number of attacks, duration, amount of pain, numbness, or other symptoms caused in the fingers (including painful sores) due to the Raynaud's phenomenon every day and impact of Raynaud's alone on use of hands every day. An 11 point Likert scale is used to rate the difficulty caused by the condition each day with 0 = no difficulty and 10 = extreme difficulty. | first winter: inclusion visit week 2, week 7, week 13, week 19; second winter: inclusion visit week 2,week 7, week 13, week 19 | 
| Frequency of RP | number of RP attacks during treatment, as compared to placebo | 7 days (An attack is defined as an episode of pallor or cyanosis (with or without pain,tingling or numbness). The number of attacks is self-reported every day and averaged over 7-day periods) | 
| Change in cumulative attack duration | Mean duration of Raynaud's attacks for a time period was calculated as sum of recorded durations of attacks in the time period divided by total number of attacks in the time period where duration was recorded. | first winter: inclusion visit week 2, week 7, week 13, week 19; second winter: inclusion visit week 2,week 7, week 13, week 19 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Mean duration of Raynaud's attacks for a time period was calculated as sum of recorded durations of attacks in the time period divided by total number of attacks in the time period where duration was recorded. It will be assessed through adverse events collected in the daily dairies cards. | first winter: week 2, 4, 5, 7, 13, 19; second winter: week 2, 4, 5, 7, 13, 19 | 
| Plasma concentration of L-arginine/ADMA ratio | It will be quantified and compared under the 4 conditions. | first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7 | 
| Plasma concentration of nitrites | It will be quantified and compared under the 4 conditions. | first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7 | 
| Plasma concentration of L-arginine | It will be quantified and compared under the 4 conditions. | first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7 | 
| Urinary GMPc | It will be quantified and compared under the 4 conditions. | first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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l-citrullin, beetroot juice, Raynaud's phenomenon