<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/NCT04404426</url>
  </required_header>
  <id_info>
    <org_study_id>35RC20_9815_CACOLAC</org_study_id>
    <secondary_id>CPP 1288 HPS1</secondary_id>
    <secondary_id>2020-A01189-30</secondary_id>
    <nct_id>NCT04404426</nct_id>
  </id_info>
  <brief_title>CACOLAC : Citrulline Administration in the Hospital Patient in Intensive Care for COVID-19 Acute Respiratory Distress Syndrome</brief_title>
  <acronym>CACOLAC</acronym>
  <official_title>CACOLAC : Randomized Trial of Citrulline Administration in the Hospital Patient in Intensive Care for COVID-19 Acute Respiratory Distress Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rennes University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rennes University Hospital</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>
      Respiratory involvement of SARS-CoV2 leads to acute respiratory distress syndrome (ARDS) and&#xD;
      significant immunosuppression (lymphopenia) exposing patients to long ventilation duration&#xD;
      and late mortality linked to the acquisition of nosocomial infections.&#xD;
&#xD;
      Lymphopenia characteristic of severe forms of ARDS secondary to SARS-CoV2 infection may be&#xD;
      linked to expansion of MDSCs and arginine depletion of lymphocytes.&#xD;
&#xD;
      Severe forms of COVID-19 pneumonitis are marked by persistent ARDS with acquisition of&#xD;
      nosocomial infections as well as by prolonged lymphocytic dysfunction associated with the&#xD;
      emergence of MDSC.&#xD;
&#xD;
      It has been found in intensive care patients hypoargininaemia, associated with the&#xD;
      persistence of organ dysfunction (evaluated by the SOFA score), the occurrence of nosocomial&#xD;
      infections and mortality. Also, it has been demonstrated that in these patients, the enteral&#xD;
      administration of ARG was not deleterious and increased the synthesis of ornithine,&#xD;
      suggesting a preferential use of ARG by the arginase route, without significant increase in&#xD;
      argininaemia nor effect on immune functions. L-citrulline (CIT), an endogenous precursor of&#xD;
      ARG, is an interesting alternative to increase the availability of ARG. Recent data&#xD;
      demonstrate that the administration of CIT in intensive care is not deleterious and that it&#xD;
      very significantly reduces mortality in an animal model of sepsis, corrects hypoargininemia,&#xD;
      with convincing data on immunological parameters such as lymphopenia, which is associated&#xD;
      with mortality, organ dysfunction and the occurrence of nosocomial infections. The&#xD;
      availability of ARG directly impacts the mitochondrial metabolism of T lymphocytes and their&#xD;
      function. The hypothesis is therefore that CIT supplementation is more effective than the&#xD;
      administration of ARG to correct hypoargininaemia, decrease lymphocyte dysfunction, correct&#xD;
      immunosuppression and organ dysfunction in septic patients admitted to intensive care.&#xD;
&#xD;
      The main objective is to show that, in patients hospitalized in intensive care for ARDS&#xD;
      secondary to COVID-19 pneumonia, the group of patients receiving L-citrulline for 7 days,&#xD;
      compared to the group receiving placebo, has a score of organ failure decreased on D7&#xD;
      (evaluated by the SOFA score) or by the last known SOFA score if the patient has died or been&#xD;
      resuscitated.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 4, 2020</start_date>
  <completion_date type="Actual">May 28, 2021</completion_date>
  <primary_completion_date type="Actual">March 25, 2021</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>Parallel Assignment</intervention_model>
    <intervention_model_description>Prospective, multicenter, placebo-controlled, randomized, double-blind, two-parallel study, specific enteral administration by citrulline in a subgroup of resuscitation patients admitted for ARDS secondary to COVID-19 pneumonia, at infectious risk nosocomial important because having biological stigmas of immunosuppression on admission and under invasive mechanical ventilation for a prolonged period.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Double-blind</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>SOFA</measure>
    <time_frame>Day 8</time_frame>
    <description>SOFA score for organ failures on D8 or last known SOFA score if the patient has died or been resuscitated</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number and phenotype of lymphocytes</measure>
    <time_frame>Days 1, 8 and 14</time_frame>
    <description>Number and phenotype of lymphocytes on days 1, 8 and 14</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HLA-DR</measure>
    <time_frame>Days 1, 8 and 14</time_frame>
    <description>Monocytic expression HLA-DR (Flow cytometry) on days 1, 8 and 14</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Myeloid-derived suppressor cells</measure>
    <time_frame>Days 1, 8 and 14</time_frame>
    <description>Number of Myeloid-derived suppressor cells (Flow cytometry) on days 1, 8 and 14</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma cytokines / chemokines</measure>
    <time_frame>Days 1, 8 and 14</time_frame>
    <description>Plasma cytokines / chemokines (IL-6, IL-8, IL-10, IL-7, CXCL10, G-CSF, TNF-alpha, IFN-β) at days 1, 8 and 14</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Repertoire T</measure>
    <time_frame>Days 1, 3, 8, 10 and 14</time_frame>
    <description>Diversity of the repertoire T at days 1, 3, 8, 10 and 14</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lymphocyte T exhaustion</measure>
    <time_frame>Days 1, 8 and 14</time_frame>
    <description>T lymphocyte exhaustion: measurement of lymphocyte apoptosis and lymphocyte proliferation on days 1, 8 and 14</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mitochondrial activity</measure>
    <time_frame>Days 1, 8 and 14</time_frame>
    <description>Measurement of mitochondrial activity (measurement of the number of mitochondria and their membrane potential, measurement of the expression of Beclin1) on days 1, 8 and 14</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma amino acids</measure>
    <time_frame>Days 1, 8 and 14</time_frame>
    <description>Plasma amino acids (arginine and its metabolites (ornithine, glutamate, glutamine, citrulline, proline) and tryptophan / kynurenine) on days 1, 8 and 14</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>SOFA</measure>
    <time_frame>Days 3, 7, 10 and 14</time_frame>
    <description>SOFA score of organ failures on days 3, 7, 10 and 14</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of hospitalization in intensive care</measure>
    <time_frame>Day 28</time_frame>
    <description>Duration of hospitalization in intensive care (days), up to day 28 maximum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of hospital stay in hospital</measure>
    <time_frame>Day 28</time_frame>
    <description>Duration of hospital stay in hospital (days), up to day 28 maximum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of mechanical ventilation</measure>
    <time_frame>Day 28</time_frame>
    <description>Duration of mechanical ventilation (days), up to day 28 maximum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality in intensive care on day 28</measure>
    <time_frame>Day 28</time_frame>
    <description>Mortality in intensive care on day 28</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital mortality on day 28</measure>
    <time_frame>Day 28</time_frame>
    <description>Hospital mortality on day 28</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of the presence of SARS-CoV2</measure>
    <time_frame>Days 1, 8 and 14</time_frame>
    <description>Measurement of the presence of SARS-CoV2 in the tracheal aspiration by PCR on days 1, 8 and 14</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Nosocomial infections</measure>
    <time_frame>D28</time_frame>
    <description>Incidence of nosocomial infections during the intensive care unit (maximum D28). The diagnosis of nosocomial infections will be made according to the definitions of nosocomial infections of the CDC. An independent committee of experts will validate or not the infections</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of days of exposure to each antibiotic per 1000 days of hospitalization</measure>
    <time_frame>Day 28</time_frame>
    <description>Number of days of exposure to each antibiotic per 1000 days of hospitalization (maximum day 28).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">33</enrollment>
  <condition>ARDS Secondary to COVID-19 Pneumonia</condition>
  <arm_group>
    <arm_group_label>L-citrulline</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Administration of citrulline enterally for 7 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Administration of placeboenterally for 7 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>L-citrulline</intervention_name>
    <description>Administration of citrulline enterally for 7 days.</description>
    <arm_group_label>L-citrulline</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Administration of placebo (water) enterally for 7 days</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age greater than or equal to 18 years;&#xD;
&#xD;
          -  Patients admitted for less than 48 hours in intensive care for ARDS under mechanical&#xD;
             ventilation according to the Berlin criteria published in 2012 (JAMA);&#xD;
&#xD;
          -  Origin of ARDS: COVID-19 pneumopathy confirmed by PCR (nasopharyngeal or tracheal&#xD;
             sample);&#xD;
&#xD;
          -  Life expectancy&gt; 2 days;&#xD;
&#xD;
          -  Affiliated to a social security scheme;&#xD;
&#xD;
          -  Consent signed by the patient, the relative or the legal representative (except&#xD;
             emergency procedure).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy or breastfeeding in progress;&#xD;
&#xD;
          -  State of immunosuppression defined by at least one of these criteria: continuous&#xD;
             administration of steroids at any dose for more than a month before hospitalization,&#xD;
             steroids in high doses (&gt; 15 mg / kg / day of methylprednisolone or equivalent),&#xD;
             radiotherapy or chemotherapy in the previous year, proven humoral or cellular&#xD;
             deficiency;&#xD;
&#xD;
          -  Contraindication to enteral nutrition (2016 SRLF recommendations: &quot;Enteral nutrition&#xD;
             probably should not be used upstream of a high-flow digestive fistula in the event of&#xD;
             intestinal obstruction, small ischemia or digestive hemorrhage active (Strong chord)&#xD;
             &quot;).&#xD;
&#xD;
          -  Ongoing immunosuppressive therapy such as chemotherapy, cyclophosphamide, high dose&#xD;
             corticosteroid therapy (&gt; 15 mg / kg / day);&#xD;
&#xD;
          -  Participation in intervention research on a drug, or intervention research that may&#xD;
             impact the immune system.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Rennes University Hospital</name>
      <address>
        <city>Rennes</city>
        <state>Britanny</state>
        <zip>35000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>May 22, 2020</study_first_submitted>
  <study_first_submitted_qc>May 25, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 27, 2020</study_first_posted>
  <last_update_submitted>May 28, 2021</last_update_submitted>
  <last_update_submitted_qc>May 28, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 2, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Respiratory Distress Syndrome</mesh_term>
    <mesh_term>Respiratory Distress Syndrome, Newborn</mesh_term>
    <mesh_term>Acute Lung Injury</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT04404426
org study id: 35RC20_9815_CACOLAC
secondary id: CPP 1288 HPS1
secondary id: 2020-A01189-30
nct id: NCT04404426
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Respiratory involvement of SARS-CoV2 leads to acute respiratory distress syndrome (ARDS) and
      significant immunosuppression (lymphopenia) exposing patients to long ventilation duration
      and late mortality linked to the acquisition of nosocomial infections.

      Lymphopenia characteristic of severe forms of ARDS secondary to SARS-CoV2 infection may be
      linked to expansion of MDSCs and arginine depletion of lymphocytes.

      Severe forms of COVID-19 pneumonitis are marked by persistent ARDS with acquisition of
      nosocomial infections as well as by prolonged lymphocytic dysfunction associated with the
      emergence of MDSC.

      It has been found in intensive care patients hypoargininaemia, associated with the
      persistence of organ dysfunction (evaluated by the SOFA score), the occurrence of nosocomial
      infections and mortality. Also, it has been demonstrated that in these patients, the enteral
      administration of ARG was not deleterious and increased the synthesis of ornithine,
      suggesting a preferential use of ARG by the arginase route, without significant increase in
      argininaemia nor effect on immune functions. L-citrulline (CIT), an endogenous precursor of
      ARG, is an interesting alternative to increase the availability of ARG. Recent data
      demonstrate that the administration of CIT in intensive care is not deleterious and that it
      very significantly reduces mortality in an animal model of sepsis, corrects hypoargininemia,
      with convincing data on immunological parameters such as lymphopenia, which is associated
      with mortality, organ dysfunction and the occurrence of nosocomial infections. The
      availability of ARG directly impacts the mitochondrial metabolism of T lymphocytes and their
      function. The hypothesis is therefore that CIT supplementation is more effective than the
      administration of ARG to correct hypoargininaemia, decrease lymphocyte dysfunction, correct
      immunosuppression and organ dysfunction in septic patients admitted to intensive care.

      The main objective is to show that, in patients hospitalized in intensive care for ARDS
      secondary to COVID-19 pneumonia, the group of patients receiving L-citrulline for 7 days,
      compared to the group receiving placebo, has a score of organ failure decreased on D7
      (evaluated by the SOFA score) or by the last known SOFA score if the patient has died or been
      resuscitated.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Prospective, multicenter, placebo-controlled, randomized, double-blind, two-parallel study, specific enteral administration by citrulline in a subgroup of resuscitation patients admitted for ARDS secondary to COVID-19 pneumonia, at infectious risk nosocomial important because having biological stigmas of immunosuppression on admission and under invasive mechanical ventilation for a prolonged period.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: Double-blind
measure: SOFA
time frame: Day 8
description: SOFA score for organ failures on D8 or last known SOFA score if the patient has died or been resuscitated
measure: Number and phenotype of lymphocytes
time frame: Days 1, 8 and 14
description: Number and phenotype of lymphocytes on days 1, 8 and 14
measure: HLA-DR
time frame: Days 1, 8 and 14
description: Monocytic expression HLA-DR (Flow cytometry) on days 1, 8 and 14
measure: Number of Myeloid-derived suppressor cells
time frame: Days 1, 8 and 14
description: Number of Myeloid-derived suppressor cells (Flow cytometry) on days 1, 8 and 14
measure: Plasma cytokines / chemokines
time frame: Days 1, 8 and 14
description: Plasma cytokines / chemokines (IL-6, IL-8, IL-10, IL-7, CXCL10, G-CSF, TNF-alpha, IFN-β) at days 1, 8 and 14
measure: Repertoire T
time frame: Days 1, 3, 8, 10 and 14
description: Diversity of the repertoire T at days 1, 3, 8, 10 and 14
measure: Lymphocyte T exhaustion
time frame: Days 1, 8 and 14
description: T lymphocyte exhaustion: measurement of lymphocyte apoptosis and lymphocyte proliferation on days 1, 8 and 14
measure: Mitochondrial activity
time frame: Days 1, 8 and 14
description: Measurement of mitochondrial activity (measurement of the number of mitochondria and their membrane potential, measurement of the expression of Beclin1) on days 1, 8 and 14
measure: Plasma amino acids
time frame: Days 1, 8 and 14
description: Plasma amino acids (arginine and its metabolites (ornithine, glutamate, glutamine, citrulline, proline) and tryptophan / kynurenine) on days 1, 8 and 14
measure: SOFA
time frame: Days 3, 7, 10 and 14
description: SOFA score of organ failures on days 3, 7, 10 and 14
measure: Duration of hospitalization in intensive care
time frame: Day 28
description: Duration of hospitalization in intensive care (days), up to day 28 maximum
measure: Duration of hospital stay in hospital
time frame: Day 28
description: Duration of hospital stay in hospital (days), up to day 28 maximum
measure: Duration of mechanical ventilation
time frame: Day 28
description: Duration of mechanical ventilation (days), up to day 28 maximum
measure: Mortality in intensive care on day 28
time frame: Day 28
description: Mortality in intensive care on day 28
measure: Hospital mortality on day 28
time frame: Day 28
description: Hospital mortality on day 28
measure: Measurement of the presence of SARS-CoV2
time frame: Days 1, 8 and 14
description: Measurement of the presence of SARS-CoV2 in the tracheal aspiration by PCR on days 1, 8 and 14
measure: Nosocomial infections
time frame: D28
description: Incidence of nosocomial infections during the intensive care unit (maximum D28). The diagnosis of nosocomial infections will be made according to the definitions of nosocomial infections of the CDC. An independent committee of experts will validate or not the infections
measure: Number of days of exposure to each antibiotic per 1000 days of hospitalization
time frame: Day 28
description: Number of days of exposure to each antibiotic per 1000 days of hospitalization (maximum day 28).
arm group label: L-citrulline
arm group type: Experimental
description: Administration of citrulline enterally for 7 days
arm group label: Placebo
arm group type: Placebo Comparator
description: Administration of placeboenterally for 7 days
intervention type: Dietary Supplement
intervention name: L-citrulline
description: Administration of citrulline enterally for 7 days.
arm group label: L-citrulline
intervention type: Other
intervention name: Placebo
description: Administration of placebo (water) enterally for 7 days
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: France
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Respiratory Distress Syndrome
mesh term: Respiratory Distress Syndrome, Newborn
mesh term: Acute Lung Injury
sharing ipd: Undecided