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CACOLAC : Citrulline Administration in the Hospital Patient in Intensive Care for COVID-19 Acute Respiratory Distress Syndrome (CACOLAC)

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ClinicalTrials.gov Identifier: NCT04404426
Recruitment Status : Recruiting
First Posted : May 27, 2020
Last Update Posted : November 6, 2020
Sponsor:
Information provided by (Responsible Party):
Rennes University Hospital

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
ARDS Secondary to COVID-19 Pneumonia Dietary Supplement: L-citrulline Other: Placebo Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
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.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: Double-blind
Primary Purpose: Treatment
Official Title: CACOLAC : Randomized Trial of Citrulline Administration in the Hospital Patient in Intensive Care for COVID-19 Acute Respiratory Distress Syndrome
Actual Study Start Date : November 2, 2020
Estimated Primary Completion Date : September 15, 2021
Estimated Study Completion Date : September 15, 2021


Arm Intervention/treatment
Experimental: L-citrulline
Administration of citrulline enterally for 7 days
Dietary Supplement: L-citrulline
Administration of citrulline enterally for 7 days.

Placebo Comparator: Placebo
Administration of placeboenterally for 7 days
Other: Placebo
Administration of placebo (water) enterally for 7 days




Primary Outcome Measures :
  1. SOFA [ Time Frame: Day 7 ]
    SOFA score for organ failures on D7 or last known SOFA score if the patient has died or been resuscitated


Secondary Outcome Measures :
  1. Number and phenotype of lymphocytes [ Time Frame: Days 1, 3, 7, 10 and 14 ]
    Number and phenotype of lymphocytes on days 1, 3, 7, 10 and 14

  2. HLA-DR [ Time Frame: Days 1, 3, 7, 10 and 14 ]
    Monocytic expression HLA-DR (Flow cytometry) on days 1, 3, 7, 10 and 14

  3. Number of Myeloid-derived suppressor cells [ Time Frame: Days 1, 3, 7, 10 and 14 ]
    Number of Myeloid-derived suppressor cells (Flow cytometry) on days 1, 3, 7, 10 and 14

  4. Plasma cytokines / chemokines [ Time Frame: Days 1, 3, 7, 10 and 14 ]
    Plasma cytokines / chemokines (IL-6, IL-8, IL-10, IL-7, CXCL10, G-CSF, TNF-alpha, IFN-β) at days 1, 3, 7, 10 and 14

  5. Repertoire T [ Time Frame: Days 1, 3, 7, 10 and 14 ]
    Diversity of the repertoire T at days 1, 3, 7, 10 and 14

  6. Lymphocyte T exhaustion [ Time Frame: Days 1, 3, 7, 10 and 14 ]
    T lymphocyte exhaustion: measurement of lymphocyte apoptosis and lymphocyte proliferation on days 1, 3, 7, 10 and 14

  7. Mitochondrial activity [ Time Frame: Days 1, 3, 7, 10 and 14 ]
    Measurement of mitochondrial activity (measurement of the number of mitochondria and their membrane potential, measurement of the expression of Beclin1) on days 1, 3, 7, 10 and 14

  8. Plasma amino acids [ Time Frame: Days 1, 3, 7, 10 and 14 ]
    Plasma amino acids (arginine and its metabolites (ornithine, glutamate, glutamine, citrulline, proline) and tryptophan / kynurenine) on days 1, 3, 7, 10 and 14

  9. SOFA [ Time Frame: Days 3, 7, 10 and 14 ]
    SOFA score of organ failures on days 3, 7, 10 and 14

  10. Duration of hospitalization in intensive care [ Time Frame: Day 28 ]
    Duration of hospitalization in intensive care (days), up to day 28 maximum

  11. Duration of hospital stay in hospital [ Time Frame: Day 28 ]
    Duration of hospital stay in hospital (days), up to day 28 maximum

  12. Duration of mechanical ventilation [ Time Frame: Day 28 ]
    Duration of mechanical ventilation (days), up to day 28 maximum

  13. Mortality in intensive care on day 28 [ Time Frame: Day 28 ]
    Mortality in intensive care on day 28

  14. Hospital mortality on day 28 [ Time Frame: Day 28 ]
    Hospital mortality on day 28

  15. Measurement of the presence of SARS-CoV2 [ Time Frame: Days 1, 3, 7, 10 and 14 ]
    Measurement of the presence of SARS-CoV2 in the tracheal aspiration by PCR on days 1, 3, 7, 10 and 14

  16. Nosocomial infections [ Time Frame: D28 ]
    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

  17. Number of days of exposure to each antibiotic per 1000 days of hospitalization [ Time Frame: Day 28 ]
    Number of days of exposure to each antibiotic per 1000 days of hospitalization (maximum day 28).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age greater than or equal to 18 years;
  • Patients admitted for less than 24 hours in intensive care for ARDS under mechanical ventilation according to the Berlin criteria published in 2012 (JAMA);
  • Origin of ARDS: COVID-19 pneumopathy confirmed by PCR (nasopharyngeal or tracheal sample);
  • Life expectancy> 2 days;
  • Affiliated to a social security scheme;
  • Consent signed by the patient, the relative or the legal representative (except emergency procedure).

Exclusion Criteria:

  • Pregnancy or breastfeeding in progress;
  • State of immunosuppression defined by at least one of these criteria: continuous administration of steroids at any dose for more than a month before hospitalization, steroids in high doses (> 15 mg / kg / day of methylprednisolone or equivalent), radiotherapy or chemotherapy in the previous year, proven humoral or cellular deficiency;
  • Contraindication to enteral nutrition (2016 SRLF recommendations: "Enteral nutrition probably should not be used upstream of a high-flow digestive fistula in the event of intestinal obstruction, small ischemia or digestive hemorrhage active (Strong chord) ").
  • Ongoing immunosuppressive therapy such as chemotherapy, cyclophosphamide, high dose corticosteroid therapy (> 15 mg / kg / day);
  • Participation in intervention research on a drug, or intervention research that may impact the immune system.

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): NCT04404426


Contacts
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Contact: Florian Reizine, MD 02.99.28.42.48 florian.reizine@chu-rennes.fr
Contact: Jean-Marc Tadié, MD 02.99.28.42.48 jeanmarc.tadie@chu-rennes.fr

Locations
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France
Brest University Hospital Not yet recruiting
Brest, Britanny, France, 29000
Contact: Erwan L'Her, MD       erwan.lher@chu-brest.fr   
Principal Investigator: Erwan L'Her, MD         
Rennes University Hospital Recruiting
Rennes, Britanny, France, 35000
Contact: Florian Reizine, MD       florian.reizine@chu-rennes.fr   
Principal Investigator: Florian Reizine, MD         
Saint-Malo Hospital Not yet recruiting
Saint-Malo, Britanny, France, 35400
Contact: Aurélien Frerou, MD       a.frerou@ch-stmalo.fr   
Principal Investigator: Aurélien Frerou, MD         
Vannes Hospital Not yet recruiting
Vannes, Britanny, France, 56000
Contact: Agathe Delbove, MD       agathe.delbove@ch-bretagne-atlantique.fr   
Principal Investigator: Agathe Delbove, MD         
Angers University Hospital Not yet recruiting
Angers, France, 49000
Contact: Pierre Asfar, MD       piasfar@chu-angers.fr   
Principal Investigator: Pierre Asfar, MD         
Sponsors and Collaborators
Rennes University Hospital
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Responsible Party: Rennes University Hospital
ClinicalTrials.gov Identifier: NCT04404426    
Other Study ID Numbers: 35RC20_9815_CACOLAC
CPP 1288 HPS1 ( Other Identifier: CPP Ouest 6 (Brest) )
2020-A01189-30 ( Other Identifier: ID RCB )
First Posted: May 27, 2020    Key Record Dates
Last Update Posted: November 6, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Pneumonia
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Lung Injury