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

CACOLAC : Randomized Trial of Citrulline Administration in the Hospital Patient in Intensive Care for COVID-19 Acute Respiratory Distress Syndrome

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.

Study Overview

• Status: Completed
• Conditions: ARDS Secondary to COVID-19 Pneumonia
• Intervention / Treatment: Dietary supplement: L-citrulline; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Britanny
    • Rennes, Britanny, France, 35000
      • Rennes University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age greater than or equal to 18 years;
• Patients admitted for less than 48 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SOFA	SOFA score for organ failures on D8 or last known SOFA score if the patient has died or been resuscitated	Day 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number and phenotype of lymphocytes	Number and phenotype of lymphocytes on days 1, 8 and 14	Days 1, 8 and 14
HLA-DR	Monocytic expression HLA-DR (Flow cytometry) on days 1, 8 and 14	Days 1, 8 and 14
Number of Myeloid-derived suppressor cells	Number of Myeloid-derived suppressor cells (Flow cytometry) on days 1, 8 and 14	Days 1, 8 and 14
Plasma cytokines / chemokines	Plasma cytokines / chemokines (IL-6, IL-8, IL-10, IL-7, CXCL10, G-CSF, TNF-alpha, IFN-β) at days 1, 8 and 14	Days 1, 8 and 14
Repertoire T	Diversity of the repertoire T at days 1, 3, 8, 10 and 14	Days 1, 3, 8, 10 and 14
Lymphocyte T exhaustion	T lymphocyte exhaustion: measurement of lymphocyte apoptosis and lymphocyte proliferation on days 1, 8 and 14	Days 1, 8 and 14
Mitochondrial activity	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	Days 1, 8 and 14
Plasma amino acids	Plasma amino acids (arginine and its metabolites (ornithine, glutamate, glutamine, citrulline, proline) and tryptophan / kynurenine) on days 1, 8 and 14	Days 1, 8 and 14
SOFA	SOFA score of organ failures on days 3, 7, 10 and 14	Days 3, 7, 10 and 14
Duration of hospitalization in intensive care	Duration of hospitalization in intensive care (days), up to day 28 maximum	Day 28
Duration of hospital stay in hospital	Duration of hospital stay in hospital (days), up to day 28 maximum	Day 28
Duration of mechanical ventilation	Duration of mechanical ventilation (days), up to day 28 maximum	Day 28
Mortality in intensive care on day 28	Mortality in intensive care on day 28	Day 28
Hospital mortality on day 28	Hospital mortality on day 28	Day 28
Measurement of the presence of SARS-CoV2	Measurement of the presence of SARS-CoV2 in the tracheal aspiration by PCR on days 1, 8 and 14	Days 1, 8 and 14
Nosocomial infections	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	D28
Number of days of exposure to each antibiotic per 1000 days of hospitalization	Number of days of exposure to each antibiotic per 1000 days of hospitalization (maximum day 28).	Day 28

Collaborators and Investigators

• Sponsor: Rennes University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2020
• Primary Completion (Actual): March 25, 2021
• Study Completion (Actual): May 28, 2021

Study Registration Dates

• First Submitted: May 22, 2020
• First Submitted That Met QC Criteria: May 25, 2020
• First Posted (Actual): May 27, 2020

Study Record Updates

• Last Update Posted (Actual): June 2, 2021
• Last Update Submitted That Met QC Criteria: May 28, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; COVID-19; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
• Other Study ID Numbers: 35RC20_9815_CACOLAC; CPP 1288 HPS1 (Other Identifier: CPP Ouest 6 (Brest)); 2020-A01189-30 (Other Identifier: ID RCB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No