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

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.

Study Overview

• Status: Recruiting
• Conditions: Raynaud Phenomenon
• Intervention / Treatment: Dietary supplement: L-citrulline; Dietary supplement: Beetroot juice; Dietary supplement: L-citrulline placebo; Dietary supplement: Denitrated beetroot juice

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 Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Charles Khouri; Phone Number: +33 4 76 76 92 60; Email: ckhouri@chu-grenoble.fr
• Study Contact Backup: Name: Adeline Paris; Phone Number: +33 4 76 76 73 83; Email: AParis@chu-grenoble.fr

Study Locations

• France
  • Grenoble, France, 38000
    • Recruiting
    • Grenoble University Hospital
    • Contact: Charles Khouri, PharmD, PhD; Email: ckhouri@chu-grenoble.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Dietary supplement: L-citrulline; L-citrulline 9g per day (capsule, per os) during 14 days;
Experimental: 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).	Dietary supplement: Beetroot juice; Concentrated 70 ml beetroot juice bottles containing 6.45 mmol of nitrates
Placebo Comparator: 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).	Dietary supplement: L-citrulline placebo; L-citrulline placebo (maltodextrin) 9g per day (capsule, per os) during 14 days
Placebo Comparator: 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).	Dietary supplement: Denitrated beetroot juice; Concentrated 70 ml nitrate-depleted beetroot juice

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital, Grenoble
• Collaborators: University Hospital, Rouen
• Investigators: Principal Investigator: Jean-Luc Cracowski, MD, Grenoble University Hospital, Clinical Pharmacology Department

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2020
• Primary Completion (Anticipated): April 30, 2022
• Study Completion (Anticipated): June 30, 2022

Study Registration Dates

• First Submitted: July 3, 2018
• First Submitted That Met QC Criteria: November 20, 2018
• First Posted (Actual): November 21, 2018

Study Record Updates

• Last Update Posted (Actual): May 14, 2021
• Last Update Submitted That Met QC Criteria: May 12, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: beetroot juice; l-citrullin; Raynaud's phenomenon
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Peripheral Vascular Diseases; Raynaud Disease
• Other Study ID Numbers: 38RC17.270

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No