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

Not Applicable

• Conditions: Raynaud Phenomenon
• Interventions: Dietary Supplement: L-citrulline; Dietary Supplement: L-citrulline placebo; Dietary Supplement: Beetroot juice; Dietary Supplement: Denitrated beetroot juice

• Registration Number: NCT03749577
• Lead Sponsor: University Hospital, Grenoble

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2018-07-03
• Study First Submitted QC: 2018-11-20
• Study First Posted: 2018-11-21
• Study Start: 2020-10-01
• Status Verified: 2021-05
• Last Update Submitted: 2021-05-12
• Last Update Posted: 2021-05-14
• Primary Completion: 2022-04-30
• Study Completion: 2022-06-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• BMI > 18

• Active Raynaud's Phenomenon characterized by a clinical history of Raynaud's

  1. Primary RP or secondary to limited (LSSc), limited or diffuse cutaneous scleroderma (lcSSc or dcSSc) according to the criteria of Leroy and Medsger.
  2. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
L-citrulline	L-citrulline	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).
L-citrulline placebo	L-citrulline placebo	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).
Beetroot juice	Beetroot juice	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).
Denitrated beetroot juice	Denitrated beetroot juice	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).

Primary Outcome Measures

Name	Time	Method
Change in cumulative attack duration	first winter: inclusion visit week 2, week 7, week 13, week 19; second winter: inclusion visit week 2,week 7, week 13, week 19	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.
Frequency of RP	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)	number of RP attacks during treatment, as compared to placebo
Change in Raynaud Condition Score	first winter: inclusion visit week 2, week 7, week 13, week 19; second winter: inclusion visit week 2,week 7, week 13, week 19	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.

Secondary Outcome Measures

Name	Time	Method
Plasma concentration of L-arginine	first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7	It will be quantified and compared under the 4 conditions.
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	first winter: week 2, 4, 5, 7, 13, 19; second winter: week 2, 4, 5, 7, 13, 19	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.
Plasma concentration of L-arginine/ADMA ratio	first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7	It will be quantified and compared under the 4 conditions.
Urinary GMPc	first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7	It will be quantified and compared under the 4 conditions.
Plasma concentration of nitrites	first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7	It will be quantified and compared under the 4 conditions.

Trial Locations

Locations (1)

Grenoble University Hospital; 🇫🇷 Grenoble, France