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 : Completed
First Posted : May 27, 2020
Last Update Posted : June 2, 2021
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|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||33 participants|
|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)|
|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 4, 2020|
|Actual Primary Completion Date :||March 25, 2021|
|Actual Study Completion Date :||May 28, 2021|
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
Administration of placebo (water) enterally for 7 days
- SOFA [ Time Frame: Day 8 ]SOFA score for organ failures on D8 or last known SOFA score if the patient has died or been resuscitated
- Number and phenotype of lymphocytes [ Time Frame: Days 1, 8 and 14 ]Number and phenotype of lymphocytes on days 1, 8 and 14
- HLA-DR [ Time Frame: Days 1, 8 and 14 ]Monocytic expression HLA-DR (Flow cytometry) on days 1, 8 and 14
- Number of Myeloid-derived suppressor cells [ Time Frame: Days 1, 8 and 14 ]Number of Myeloid-derived suppressor cells (Flow cytometry) on days 1, 8 and 14
- Plasma cytokines / chemokines [ Time Frame: Days 1, 8 and 14 ]Plasma cytokines / chemokines (IL-6, IL-8, IL-10, IL-7, CXCL10, G-CSF, TNF-alpha, IFN-β) at days 1, 8 and 14
- Repertoire T [ Time Frame: Days 1, 3, 8, 10 and 14 ]Diversity of the repertoire T at days 1, 3, 8, 10 and 14
- Lymphocyte T exhaustion [ Time Frame: Days 1, 8 and 14 ]T lymphocyte exhaustion: measurement of lymphocyte apoptosis and lymphocyte proliferation on days 1, 8 and 14
- Mitochondrial activity [ Time Frame: Days 1, 8 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, 8 and 14
- Plasma amino acids [ Time Frame: Days 1, 8 and 14 ]Plasma amino acids (arginine and its metabolites (ornithine, glutamate, glutamine, citrulline, proline) and tryptophan / kynurenine) on days 1, 8 and 14
- SOFA [ Time Frame: Days 3, 7, 10 and 14 ]SOFA score of organ failures on days 3, 7, 10 and 14
- Duration of hospitalization in intensive care [ Time Frame: Day 28 ]Duration of hospitalization in intensive care (days), up to day 28 maximum
- Duration of hospital stay in hospital [ Time Frame: Day 28 ]Duration of hospital stay in hospital (days), up to day 28 maximum
- Duration of mechanical ventilation [ Time Frame: Day 28 ]Duration of mechanical ventilation (days), up to day 28 maximum
- Mortality in intensive care on day 28 [ Time Frame: Day 28 ]Mortality in intensive care on day 28
- Hospital mortality on day 28 [ Time Frame: Day 28 ]Hospital mortality on day 28
- Measurement of the presence of SARS-CoV2 [ Time Frame: Days 1, 8 and 14 ]Measurement of the presence of SARS-CoV2 in the tracheal aspiration by PCR on days 1, 8 and 14
- 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
- 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).
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
|Rennes University Hospital|
|Rennes, Britanny, France, 35000|