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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03749577
Recruitment Status : Not yet recruiting
First Posted : November 21, 2018
Last Update Posted : October 22, 2019
Sponsor:
Collaborator:
University Hospital, Rouen
Information provided by (Responsible Party):
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.

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.

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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

Resource links provided by the National Library of Medicine


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




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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03749577


Contacts
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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
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Principal Investigator: Jean-Luc Cracowski, MD Grenoble University Hospital, Clinical Pharmacology Department
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Responsible Party: University Hospital, Grenoble
ClinicalTrials.gov Identifier: NCT03749577    
Other Study ID Numbers: 38RC17.270
First Posted: November 21, 2018    Key Record Dates
Last Update Posted: October 22, 2019
Last Verified: September 2019

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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:
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Raynaud Disease
Peripheral Vascular Diseases
Vascular Diseases
Cardiovascular Diseases