ICITRU : Randomized Trial of Immunonutrition With L-citrulline in Patients Hospitalized in Intensive Care for Sepsis or Septic Shock (ICITRU)

Immunonutrition in intensive care has not yet demonstrated a beneficial effect on organ failure, the acquisition of nosocomial infections, or mortality. It did not correct for acquired immunosuppression in intensive care patients. Despite numerous methodological problems (use of several pharmaconutrients, very heterogeneous set of patients) and the absence of clinical data, deleterious effects have been attributed to immunonutrition in intensive care, in particular in septic patients and patients in intensive care . Arginine (ARG) is a semi-essential amino acid involved in many immunological mechanisms. It is synthesized in sufficient quantity under normal conditions but quickly becomes insufficient under catabolic conditions such as in severe sepsis. Arginine is not only the precursor of nitrogen monoxide (NO) but also an essential substrate for numerous enzymatic reactions which participate in the maintenance of immune homeostasis, in particular T lymphocyte function. Depletion of the cellular medium in arginine will induce an abnormality in the metabolism of immune cells responsible for a dysfunction of these cells (lymphopenia linked to early apoptosis) and thus expose patients to organ failure and nosocomial infections.

It has been found that hypoargininemia in intensive care patients is associated with the persistence of organ dysfunction (SOFA score), the occurrence of nosocomial infections and mortality. Also, it has been demonstrated that in these patients, enteral administration of ARG was not deleterious and increased ornithine synthesis, suggesting a preferential use of ARG via the arginases route, without significant increase in argininaemia or effect on immune functions. L-citrulline (CIT), an endogenous precursor of ARG, constitutes an interesting alternative for increasing the availability of ARG. Sponsor 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. Our hypothesis is therefore that CIT supplementation is more effective than administration of ARG in correcting hypoargininemia, reducing lymphocyte dysfunction, correcting immunosuppression and organ dysfunction in septic patients admitted to intensive care.

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Septic Shock
• Intervention / Treatment: Dietary supplement: Experimental treatment L-citrulline (Protéocit®); Other: Placebo treatment

Detailed Description

Strategy :

Enteral administration of citrulline for 5 days versus iso-nitrogenous placebo. Amino acid assay and immunological parameters (monocytic expression of HLA-DR, MDSCs, cytokines / chemokines, lymphocyte number and phenotype, apoptosis and lymphocyte proliferation and mitochondrial function and T lymphocyte repertoire) will only be carried out on patients included in Rennes (60 patients).

• Study Type: Interventional
• Enrollment (Estimated): 130
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mathieu Lesouhaitier, MD; Phone Number: 0033299284321; Email: mathieu.lesouhaitier@chu-rennes.fr
• Study Contact Backup: Name: Jean-Marc Tadié, MD; Phone Number: 0033299284321; Email: jean-marc.tadie@chu-rennes.fr

Study Locations

• France
  • Besançon, France, 25000
    • Recruiting
    • Besançon University Hospital
    • Contact: Gaël Piton, MD; Email: gpiton@chu-besancon.fr
    • Principal Investigator: Gaël Piton, MD
  • Le Mans, France, 72037
    • Recruiting
    • Le Mans hospital
    • Contact: Christophe Guitton, MD; Email: cguitton@ch-lemans.fr
    • Principal Investigator: gpiton@chu-besancon.fr Guitton, MD
  • Tours, France, 37044
    • Recruiting
    • Tours university Hospital
    • Contact: Charlotte Salmon-Gandonnière, MD; Email: charlotte.salmon@univ-tours.fr
    • Principal Investigator: Charlotte Salmon, MD
  • Bretagne
    • Rennes, Bretagne, France, 35033
      • Recruiting
      • Rennes University Hospital - Medical ICU
      • Contact: Benoit Painvin, MD; Email: benoit.painvin@chu-rennes.fr
      • Principal Investigator: Benoit Painvin, MD
    • Rennes, Bretagne, France, 35033
      • Recruiting
      • Rennes University Hospital - Surgical ICU
      • Contact: Yoann Launey, MD; Email: yoann.launey@chu-rennes.fr
      • Principal Investigator: Yoann Launey, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Septic patients in accordance with the definition of sepsis and septic shock published in 2016 (JAMA) and whose use is recommended by the European Society of Intensive Care Medicine;
• Initial aggression dated less than 4 days before admission to intensive care (selection of "community" patients). The onset of aggression will be defined by the onset of clinical signs of infection;
• Patients hospitalized for less than 48 hours before admission to intensive care (selection of patients without malnutrition and immunosuppression acquired in hospital) *;
• Patients under invasive mechanical ventilation with a foreseeable ventilation duration> 2 days **;
• Exclusive enteral nutrition;
• Affiliation to a social security scheme;
• Consent signed by the patient, relative or legal representative or inclusion under emergency procedure

Non Inclusion Criteria:

• Progressive Sars-CoV2 infection
• Pregnancy in progress;
• Morbid obesity (BMI> 40);
• State of immunosuppression defined by at least one of these criteria: continuous administration of steroids at any dose for more than one month before hospitalization, steroids at high doses (> 0.5 mg / kg / day of methylprednisolone or equivalent), radiotherapy or chemotherapy in the previous year, proven humoral or cellular deficiency;
• Contraindication to enteral nutrition (SRLF 2016 recommendations: "Enteral nutrition should probably not be used upstream of a high flow digestive fistula in cases of intestinal obstruction, ischemia of the small intestine or digestive hemorrhage. active (Strong agreement) ");
• Participation in intervention research on a drug, or intervention research that could impact the immune system

Exclusion Criteria:

- Institution of immunosuppressive therapy such as chemotherapy, cyclophosphamide, high dose corticosteroid therapy (> 0.5 mg / kg / day ; hydrocortisone used in the management of septic shock is not considered an exclusion criterion).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental group; Enteral administration of citrulline for 5 days. L-citrulline (Protéocit®). This commercial form consists only of L-citrulline. Each patient will receive 10 grams per day in 2 doses (1 stick/ 12H = 5 grams / 12H). These sticks contain a powder to be resuspended in 50 mL of water for injection (ppi) for 1 stick. They will be delivered in a 50 mL syringe allowing administration of the product through the nasogastric tube. The solution will be prepared just before administration.	Dietary supplement: Experimental treatment L-citrulline (Protéocit®); Enteral administration of citrulline for 5 days.
Placebo Comparator: Control group; Enteral administration of iso-nitrogenous placebo for 5 days. The placebo used will consist of a mixture of 4 non-essential amino acids. 5 g of L-citrulline provides 1.2 g of nitrogen. For the mixture to be iso-nitrogenous, each of the 4 amino acids will need to provide 0.3 g of nitrogen. The mixture will therefore consist of 21.6% alanine, 32.3% aspartate, 18.2% glycine and 27.9% proline for a total of 8.83 g of amino acids per sachet. 2 administrations (2 sticks) daily for 5 days.	Other: Placebo treatment; Enteral administration of iso-nitrogenous placebo for 5 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SOFA score	SOFA score for organ failure (5 parameters ranged from 0 to 4 each)	Baseline and day 7 or last known SOFA score if the patient died or left intensive care before day 7.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nosocomial infections	Incidence of nosocomial infections during the stay in intensive care (maximum Day 28). The diagnosis of nosocomial infections will be made by following the definitions of nosocomial infections of the CDC (Centers for Disease Control). An independent committee of experts will validate or not the infections.	From Inclusion up to Day 28 maximum
Exposure to each antibiotic	Number of days of exposure to each antibiotic per 1000 days of hospitalization (maximum Day 28)	Up to Day 28 maximum
Mortality in intensive care	Mortality in intensive care	Up to Day 28 maximum
Hospital mortality	Hospital mortality	Up to Day 28 maximum
Number and phenotypes of lymphocytes	Number and phenotypes of lymphocytes on Day 1, Day 3 and Day 7	Day 1, 3 and 7
HLA-DR monocytic expression	HLA-DR monocytic expression (flow cytometry) on Day 1, Day 3 and Day 7	Day 1, 3 and 7
Number of Myeloid-derived suppressor cells	Number of Myeloid-derived suppressor cells (flow cytometry) at on Day 1, Day 3 and Day 7	Day 1, 3 and 7
Plasma cytokines / chemokines	Plasma cytokines / chemokines (IL-6, IL-8, IL-10, IL-7, CXCL10, G-CSF, TNF-alpha, IFN-β) on on Day 1, Day 3 and Day 7	Day 1, 3 and 7
T repertoire	Diversity of the T repertoire at Day 1, Day 3 and Day 7	Day 1, 3 and 7
T lymphocyte exhaustion	T lymphocyte exhaustion: measurement of lymphocytic apoptosis and lymphocyte proliferation on Day 1, Day 3 and Day 7	Day 1, 3 and 7
Mitochondrial activity	Measurement of mitochondrial activity (measurement of the number of mitochondria and their membrane potential, measurement of Beclin1 expression) on Day 1, Day 3 and Day 7	Day 1, 3 and 7
Plasma amino acids	Plasma amino acids (arginine and its metabolites (ornithine, glutamate, glutamine, citrulline, proline) and tryptophan / kynurenine) on Day 1, Day 3 and Day 7	Day 1, 3 and 7
SOFA score	SOFA score for organ failures on Day 3 and Day 5 (5 parameters ranged from 0 to 4 each)	Day 3 and Day 5
Duration of hospitalization in intensive care	Duration of hospitalization in intensive care (days), up to Day 28 maximum	Up to Day 28 maximum
Duration of hospitalization at the hospital	Hospital stay at the hospital (days), up to Day 28 maximum	Up to Day 28 maximum
Duration of mechanical ventilation	Duration of mechanical ventilation (days), up to Day 28 maximum.	Up to Day 28 maximum

Collaborators and Investigators

• Sponsor: Rennes University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2022
• Primary Completion (Estimated): May 20, 2024
• Study Completion (Estimated): June 20, 2024

Study Registration Dates

• First Submitted: August 11, 2020
• First Submitted That Met QC Criteria: August 13, 2020
• First Posted (Actual): August 14, 2020

Study Record Updates

• Last Update Posted (Estimated): November 21, 2023
• Last Update Submitted That Met QC Criteria: November 20, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Shock, Septic; Shock
• Other Study ID Numbers: 35RC19_9778_ICITRU; 2020-A01804-35 (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