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

• ClinicalTrials.gov Identifier: NCT03749577
• Recruitment Status: Not yet recruiting
• First Posted: November 21, 2018
• Last Update Posted: October 22, 2019
• Sponsor: University Hospital, Grenoble
• Collaborator: University Hospital, Rouen
• Information provided by (Responsible Party): University Hospital, Grenoble

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Raynaud Phenomenon	Dietary Supplement: L-citrulline; Dietary Supplement: Beetroot juice; Dietary Supplement: L-citrulline placebo; Dietary Supplement: Denitrated beetroot juice	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Nutritional Strategies to Increase Nitric Oxide Signaling in Raynaud's Phenomenon
• Estimated Study Start Date: November 1, 2019
• Estimated Primary Completion Date: April 30, 2021
• Estimated Study Completion Date: June 30, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Change in Raynaud Condition Score [ Time Frame: 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.
2. Frequency of RP [ Time Frame: 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
3. Change in cumulative attack duration [ Time Frame: 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.

Secondary Outcome Measures :

1. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 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.

2. Plasma concentration of L-arginine/ADMA ratio [ Time Frame: first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7 ]
   It will be quantified and compared under the 4 conditions.
3. Plasma concentration of nitrites [ Time Frame: first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7 ]
   It will be quantified and compared under the 4 conditions.
4. Plasma concentration of L-arginine [ Time Frame: first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7 ]
   It will be quantified and compared under the 4 conditions.
5. Urinary GMPc [ Time Frame: first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7 ]
   It will be quantified and compared under the 4 conditions.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Charles Khouri; +33 4 76 76 92 60; ckhouri@chu-grenoble.fr

Contact: Adeline Paris; +33 4 76 76 73 83; AParis@chu-grenoble.fr

Sponsors and Collaborators

University Hospital, Grenoble

University Hospital, Rouen

Investigators

• Principal Investigator: Jean-Luc Cracowski, MD; Grenoble University Hospital, Clinical Pharmacology Department

More Information

• Responsible Party: University Hospital, Grenoble
• ClinicalTrials.gov Identifier: NCT03749577
• Other Study ID Numbers: 38RC17.270
• First Posted: November 21, 2018
• Last Update Posted: October 22, 2019
• Last Verified: September 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital, Grenoble:

l-citrullin; beetroot juice; Raynaud's phenomenon

Additional relevant MeSH terms:

Raynaud Disease; Peripheral Vascular Diseases; Vascular Diseases; Cardiovascular Diseases