<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03749577</url>
  </required_header>
  <id_info>
    <org_study_id>38RC17.270</org_study_id>
    <nct_id>NCT03749577</nct_id>
  </id_info>
  <brief_title>Nutritional Strategies to Increase Nitric Oxide Signaling in Raynaud's Phenomenon</brief_title>
  <acronym>NivOSe</acronym>
  <official_title>Nutritional Strategies to Increase Nitric Oxide Signaling in Raynaud's Phenomenon</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Grenoble</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University Hospital, Rouen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Grenoble</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators aim at comparing the efficacy of a 2 weeks supplementation by L-citrulline&#xD;
      or beetroot juice to L-citrulline placebo or denitrated beetroot juice respectively on&#xD;
      Raynaud's phenomenon severity. Raynaud's phenomenon severity will be assessed through the&#xD;
      Raynaud Condition Score, daily frequency of attacks or cumulative attack duration (expressed&#xD;
      as min) daily collected by patients in a diary. Each Volunteer will choose his own main&#xD;
      outcome among these 3 criteria.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Raynaud's phenomenon (RP) is a clinical condition that follows an exaggerated&#xD;
      vasoconstriction of extremities in response to a cold or emotional stress. Microvascular&#xD;
      dysfunction and alteration of the endothelial NO-dependent vasodilatation pathway through NO&#xD;
      synthases (NOS) represents one of the main mechanisms.&#xD;
&#xD;
      A pharmacological treatment in RP is proposed to patients when conservative measures are not&#xD;
      efficient enough to control the symptoms: calcium channel blockers remains the first line,&#xD;
      phosphodiesterase type 5 inhibitors as a second line treatment, while intravenous iloprost&#xD;
      remains restricted to patients with digital ischaemia. Vasodilator therapies are commonly&#xD;
      associated with side effects due to the non-specific systemic vasodilation that often result&#xD;
      in permanent discontinuation. Many patients prefer complementary and alternative therapies,&#xD;
      but none has proven its efficacy. Therefore, there is still room for improvement in the&#xD;
      treatment of RP, and research is needed in this area.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">October 1, 2020</start_date>
  <completion_date type="Anticipated">June 30, 2022</completion_date>
  <primary_completion_date type="Anticipated">April 30, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Raynaud Condition Score</measure>
    <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</time_frame>
    <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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Frequency of RP</measure>
    <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)</time_frame>
    <description>number of RP attacks during treatment, as compared to placebo</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in cumulative attack duration</measure>
    <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</time_frame>
    <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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]</measure>
    <time_frame>first winter: week 2, 4, 5, 7, 13, 19; second winter: week 2, 4, 5, 7, 13, 19</time_frame>
    <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.&#xD;
It will be assessed through adverse events collected in the daily dairies cards.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma concentration of L-arginine/ADMA ratio</measure>
    <time_frame>first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7</time_frame>
    <description>It will be quantified and compared under the 4 conditions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma concentration of nitrites</measure>
    <time_frame>first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7</time_frame>
    <description>It will be quantified and compared under the 4 conditions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma concentration of L-arginine</measure>
    <time_frame>first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7</time_frame>
    <description>It will be quantified and compared under the 4 conditions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urinary GMPc</measure>
    <time_frame>first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7</time_frame>
    <description>It will be quantified and compared under the 4 conditions.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Raynaud Phenomenon</condition>
  <arm_group>
    <arm_group_label>L-citrulline</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Six cycles will be conducted over two consecutive winters. One cycle will consist of two 2-week supplementation periods.&#xD;
A 7 days wash-out period will be imposed between treatment periods (placebo and treatment).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Beetroot juice</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Six cycles will be conducted over two consecutive winters. One cycle will consist of two 2-week supplementation periods.&#xD;
A 7 days wash-out period will be imposed between treatment periods (placebo and treatment).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>L-citrulline placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Six cycles will be conducted over two consecutive winters. One cycle will consist of two 2-week supplementation periods.&#xD;
A 7 days wash-out period will be imposed between treatment periods (placebo and treatment).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Denitrated beetroot juice</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Six cycles will be conducted over two consecutive winters. One cycle will consist of two 2-week supplementation periods.&#xD;
A 7 days wash-out period will be imposed between treatment periods (placebo and treatment).</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>L-citrulline</intervention_name>
    <description>L-citrulline 9g per day (capsule, per os) during 14 days;</description>
    <arm_group_label>L-citrulline</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Beetroot juice</intervention_name>
    <description>Concentrated 70 ml beetroot juice bottles containing 6.45 mmol of nitrates</description>
    <arm_group_label>Beetroot juice</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>L-citrulline placebo</intervention_name>
    <description>L-citrulline placebo (maltodextrin) 9g per day (capsule, per os) during 14 days</description>
    <arm_group_label>L-citrulline placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Denitrated beetroot juice</intervention_name>
    <description>Concentrated 70 ml nitrate-depleted beetroot juice</description>
    <arm_group_label>Denitrated beetroot juice</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  BMI &gt; 18&#xD;
&#xD;
          -  Active Raynaud's Phenomenon characterized by a clinical history of Raynaud's&#xD;
&#xD;
               1. Primary RP or secondary to limited (LSSc), limited or diffuse cutaneous&#xD;
                  scleroderma (lcSSc or dcSSc) according to the criteria of Leroy and Medsger.&#xD;
&#xD;
               2. At least 1 RP attacks per week and a specific finger patient picture in RP attack&#xD;
                  (assessed over the 2 weeks preceding inclusion)&#xD;
&#xD;
          -  Stable disease over the previous two months (i.e. recent diagnosis of SSc will be&#xD;
             excluded)&#xD;
&#xD;
          -  Patients insured by a social security scheme or beneficiaries of such a scheme&#xD;
&#xD;
          -  Patients who have dated and signed the informed consent form&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Uncontrolled hypertension, uncontrolled diabetes mellitus, uncontrolled angina&#xD;
&#xD;
          -  Haemodynamic instability&#xD;
&#xD;
          -  Pregnancy (or considering pregnancy in next 4 months) or breast feeding&#xD;
&#xD;
          -  Subject in an exclusion period from another study,&#xD;
&#xD;
          -  Subject under administrative or judicial supervision&#xD;
&#xD;
          -  Subject not able to be contacted in case of emergency&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jean-Luc Cracowski, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Grenoble University Hospital, Clinical Pharmacology Department</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Charles Khouri</last_name>
    <phone>+33 4 76 76 92 60</phone>
    <email>ckhouri@chu-grenoble.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Adeline Paris</last_name>
    <phone>+33 4 76 76 73 83</phone>
    <email>AParis@chu-grenoble.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Grenoble University Hospital</name>
      <address>
        <city>Grenoble</city>
        <zip>38000</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Charles Khouri, PharmD, PhD</last_name>
      <email>ckhouri@chu-grenoble.fr</email>
    </contact>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>July 3, 2018</study_first_submitted>
  <study_first_submitted_qc>November 20, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 21, 2018</study_first_posted>
  <last_update_submitted>May 12, 2021</last_update_submitted>
  <last_update_submitted_qc>May 12, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">May 14, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>l-citrullin</keyword>
  <keyword>beetroot juice</keyword>
  <keyword>Raynaud's phenomenon</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Raynaud Disease</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03749577
org study id: 38RC17.270
nct id: NCT03749577
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: 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
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.
measure: 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)
description: number of RP attacks during treatment, as compared to placebo
measure: 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
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.
measure: 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
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.
measure: Plasma concentration of L-arginine/ADMA ratio
time frame: first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7
description: It will be quantified and compared under the 4 conditions.
measure: Plasma concentration of nitrites
time frame: first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7
description: It will be quantified and compared under the 4 conditions.
measure: Plasma concentration of L-arginine
time frame: first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7
description: It will be quantified and compared under the 4 conditions.
measure: Urinary GMPc
time frame: first winter: week 2, 4, 5, 7; second winter: week 2, 4, 5, 7
description: It will be quantified and compared under the 4 conditions.
arm group label: L-citrulline
arm group type: Experimental
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 group label: Beetroot juice
arm group type: Experimental
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 group label: L-citrulline placebo
arm group type: Placebo Comparator
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 group label: Denitrated beetroot juice
arm group type: Placebo Comparator
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: L-citrulline
description: L-citrulline 9g per day (capsule, per os) during 14 days;
arm group label: L-citrulline
intervention type: Dietary Supplement
intervention name: Beetroot juice
description: Concentrated 70 ml beetroot juice bottles containing 6.45 mmol of nitrates
arm group label: Beetroot juice
intervention type: Dietary Supplement
intervention name: L-citrulline placebo
description: L-citrulline placebo (maltodextrin) 9g per day (capsule, per os) during 14 days
arm group label: L-citrulline placebo
intervention type: Dietary Supplement
intervention name: Denitrated beetroot juice
description: Concentrated 70 ml nitrate-depleted beetroot juice
arm group label: Denitrated beetroot juice
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Jean-Luc Cracowski, MD
role: Principal Investigator
affiliation: Grenoble University Hospital, Clinical Pharmacology Department
last name: Charles Khouri
phone: +33 4 76 76 92 60
email: ckhouri@chu-grenoble.fr
last name: Adeline Paris
phone: +33 4 76 76 73 83
email: AParis@chu-grenoble.fr
facility: 
status: Recruiting
contact: 
country: France
responsible party type: Sponsor
mesh term: Raynaud Disease