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

Primary Purpose

Raynaud Phenomenon

Status
Unknown status
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
L-citrulline
Beetroot juice
L-citrulline placebo
Denitrated beetroot juice
Sponsored by
University Hospital, Grenoble
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Raynaud Phenomenon focused on measuring l-citrullin, beetroot juice, Raynaud's phenomenon

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Grenoble University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Placebo Comparator

Placebo Comparator

Arm Label

L-citrulline

Beetroot juice

L-citrulline placebo

Denitrated beetroot juice

Arm Description

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).

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).

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).

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).

Outcomes

Primary Outcome Measures

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.
Frequency of RP
number of RP attacks during treatment, as compared to placebo
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.

Secondary Outcome Measures

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.
Plasma concentration of L-arginine/ADMA ratio
It will be quantified and compared under the 4 conditions.
Plasma concentration of nitrites
It will be quantified and compared under the 4 conditions.
Plasma concentration of L-arginine
It will be quantified and compared under the 4 conditions.
Urinary GMPc
It will be quantified and compared under the 4 conditions.

Full Information

First Posted
July 3, 2018
Last Updated
May 12, 2021
Sponsor
University Hospital, Grenoble
Collaborators
University Hospital, Rouen
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1. Study Identification

Unique Protocol Identification Number
NCT03749577
Brief Title
Nutritional Strategies to Increase Nitric Oxide Signaling in Raynaud's Phenomenon
Acronym
NivOSe
Official Title
Nutritional Strategies to Increase Nitric Oxide Signaling in Raynaud's Phenomenon
Study Type
Interventional

2. Study Status

Record Verification Date
May 2021
Overall Recruitment Status
Unknown status
Study Start Date
October 1, 2020 (Actual)
Primary Completion Date
April 30, 2022 (Anticipated)
Study Completion Date
June 30, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Grenoble
Collaborators
University Hospital, Rouen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Raynaud Phenomenon
Keywords
l-citrullin, beetroot juice, Raynaud's phenomenon

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
L-citrulline
Arm Type
Experimental
Arm Description
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).
Arm Title
Beetroot juice
Arm Type
Experimental
Arm Description
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).
Arm Title
L-citrulline placebo
Arm Type
Placebo Comparator
Arm Description
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).
Arm Title
Denitrated beetroot juice
Arm Type
Placebo Comparator
Arm Description
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).
Intervention Type
Dietary Supplement
Intervention Name(s)
L-citrulline
Intervention Description
L-citrulline 9g per day (capsule, per os) during 14 days;
Intervention Type
Dietary Supplement
Intervention Name(s)
Beetroot juice
Intervention Description
Concentrated 70 ml beetroot juice bottles containing 6.45 mmol of nitrates
Intervention Type
Dietary Supplement
Intervention Name(s)
L-citrulline placebo
Intervention Description
L-citrulline placebo (maltodextrin) 9g per day (capsule, per os) during 14 days
Intervention Type
Dietary Supplement
Intervention Name(s)
Denitrated beetroot juice
Intervention Description
Concentrated 70 ml nitrate-depleted beetroot juice
Primary Outcome Measure Information:
Title
Change in Raynaud Condition Score
Description
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.
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
Title
Frequency of RP
Description
number of RP attacks during treatment, as compared to placebo
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)
Title
Change in cumulative attack duration
Description
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.
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
Secondary Outcome Measure Information:
Title
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Description
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.
Time Frame
first winter: week 2, 4, 5, 7, 13, 19; second winter: week 2, 4, 5, 7, 13, 19
Title
Plasma concentration of L-arginine/ADMA ratio
Description
It will be quantified and compared under the 4 conditions.
Time Frame
first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7
Title
Plasma concentration of nitrites
Description
It will be quantified and compared under the 4 conditions.
Time Frame
first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7
Title
Plasma concentration of L-arginine
Description
It will be quantified and compared under the 4 conditions.
Time Frame
first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7
Title
Urinary GMPc
Description
It will be quantified and compared under the 4 conditions.
Time Frame
first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Charles Khouri
Phone
+33 4 76 76 92 60
Email
ckhouri@chu-grenoble.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Adeline Paris
Phone
+33 4 76 76 73 83
Email
AParis@chu-grenoble.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jean-Luc Cracowski, MD
Organizational Affiliation
Grenoble University Hospital, Clinical Pharmacology Department
Official's Role
Principal Investigator
Facility Information:
Facility Name
Grenoble University Hospital
City
Grenoble
ZIP/Postal Code
38000
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Charles Khouri, PharmD, PhD
Email
ckhouri@chu-grenoble.fr

12. IPD Sharing Statement

Learn more about this trial

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

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