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

Primary Purpose

Sepsis, Septic Shock

Status
Recruiting
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Experimental treatment L-citrulline (Protéocit®)
Placebo treatment
Sponsored by
Rennes University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sepsis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:

  • 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).

Sites / Locations

  • Rennes University Hospital - Medical ICURecruiting
  • Rennes University Hospital - Surgical ICURecruiting
  • Besançon University HospitalRecruiting
  • Le Mans HospitalRecruiting
  • Tours University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Experimental group

Control group

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

SOFA score
SOFA score for organ failure (5 parameters ranged from 0 to 4 each)

Secondary Outcome Measures

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.
Exposure to each antibiotic
Number of days of exposure to each antibiotic per 1000 days of hospitalization (maximum Day 28)
Mortality in intensive care
Mortality in intensive care
Hospital mortality
Hospital mortality
Number and phenotypes of lymphocytes
Number and phenotypes of lymphocytes on Day 1, Day 3 and Day 7
HLA-DR monocytic expression
HLA-DR monocytic expression (flow cytometry) on Day 1, Day 3 and Day 7
Number of Myeloid-derived suppressor cells
Number of Myeloid-derived suppressor cells (flow cytometry) at on Day 1, Day 3 and Day 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
T repertoire
Diversity of the T repertoire at Day 1, Day 3 and Day 7
T lymphocyte exhaustion
T lymphocyte exhaustion: measurement of lymphocytic apoptosis and lymphocyte proliferation on Day 1, Day 3 and Day 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
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
SOFA score
SOFA score for organ failures on Day 3 and Day 5 (5 parameters ranged from 0 to 4 each)
Duration of hospitalization in intensive care
Duration of hospitalization in intensive care (days), up to Day 28 maximum
Duration of hospitalization at the hospital
Hospital stay at the hospital (days), up to Day 28 maximum
Duration of mechanical ventilation
Duration of mechanical ventilation (days), up to Day 28 maximum.

Full Information

First Posted
August 11, 2020
Last Updated
November 10, 2022
Sponsor
Rennes University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04513288
Brief Title
ICITRU : Randomized Trial of Immunonutrition With L-citrulline in Patients Hospitalized in Intensive Care for Sepsis or Septic Shock
Acronym
ICITRU
Official Title
ICITRU : Randomized Trial of Immunonutrition With L-citrulline in Patients Hospitalized in Intensive Care for Sepsis or Septic Shock
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Recruiting
Study Start Date
May 20, 2022 (Actual)
Primary Completion Date
November 20, 2024 (Anticipated)
Study Completion Date
February 20, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Rennes University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sepsis, Septic Shock

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Prospective, multicenter, placebo-controlled, randomized, double-blind study on two parallel groups.
Masking
Participant
Masking Description
Prospective, multicenter, placebo-controlled, randomized, double-blind study on two parallel groups.
Allocation
Randomized
Enrollment
130 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Experimental group
Arm Type
Experimental
Arm Description
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.
Arm Title
Control group
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Dietary Supplement
Intervention Name(s)
Experimental treatment L-citrulline (Protéocit®)
Intervention Description
Enteral administration of citrulline for 5 days.
Intervention Type
Other
Intervention Name(s)
Placebo treatment
Intervention Description
Enteral administration of iso-nitrogenous placebo for 5 days.
Primary Outcome Measure Information:
Title
SOFA score
Description
SOFA score for organ failure (5 parameters ranged from 0 to 4 each)
Time Frame
Baseline and day 7 or last known SOFA score if the patient died or left intensive care before day 7.
Secondary Outcome Measure Information:
Title
Nosocomial infections
Description
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.
Time Frame
From Inclusion up to Day 28 maximum
Title
Exposure to each antibiotic
Description
Number of days of exposure to each antibiotic per 1000 days of hospitalization (maximum Day 28)
Time Frame
Up to Day 28 maximum
Title
Mortality in intensive care
Description
Mortality in intensive care
Time Frame
Up to Day 28 maximum
Title
Hospital mortality
Description
Hospital mortality
Time Frame
Up to Day 28 maximum
Title
Number and phenotypes of lymphocytes
Description
Number and phenotypes of lymphocytes on Day 1, Day 3 and Day 7
Time Frame
Day 1, 3 and 7
Title
HLA-DR monocytic expression
Description
HLA-DR monocytic expression (flow cytometry) on Day 1, Day 3 and Day 7
Time Frame
Day 1, 3 and 7
Title
Number of Myeloid-derived suppressor cells
Description
Number of Myeloid-derived suppressor cells (flow cytometry) at on Day 1, Day 3 and Day 7
Time Frame
Day 1, 3 and 7
Title
Plasma cytokines / chemokines
Description
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
Time Frame
Day 1, 3 and 7
Title
T repertoire
Description
Diversity of the T repertoire at Day 1, Day 3 and Day 7
Time Frame
Day 1, 3 and 7
Title
T lymphocyte exhaustion
Description
T lymphocyte exhaustion: measurement of lymphocytic apoptosis and lymphocyte proliferation on Day 1, Day 3 and Day 7
Time Frame
Day 1, 3 and 7
Title
Mitochondrial activity
Description
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
Time Frame
Day 1, 3 and 7
Title
Plasma amino acids
Description
Plasma amino acids (arginine and its metabolites (ornithine, glutamate, glutamine, citrulline, proline) and tryptophan / kynurenine) on Day 1, Day 3 and Day 7
Time Frame
Day 1, 3 and 7
Title
SOFA score
Description
SOFA score for organ failures on Day 3 and Day 5 (5 parameters ranged from 0 to 4 each)
Time Frame
Day 3 and Day 5
Title
Duration of hospitalization in intensive care
Description
Duration of hospitalization in intensive care (days), up to Day 28 maximum
Time Frame
Up to Day 28 maximum
Title
Duration of hospitalization at the hospital
Description
Hospital stay at the hospital (days), up to Day 28 maximum
Time Frame
Up to Day 28 maximum
Title
Duration of mechanical ventilation
Description
Duration of mechanical ventilation (days), up to Day 28 maximum.
Time Frame
Up to Day 28 maximum

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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: 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).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mathieu Lesouhaitier, MD
Phone
0033299284321
Email
mathieu.lesouhaitier@chu-rennes.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Jean-Marc Tadié, MD
Phone
0033299284321
Email
jean-marc.tadie@chu-rennes.fr
Facility Information:
Facility Name
Rennes University Hospital - Medical ICU
City
Rennes
State/Province
Bretagne
ZIP/Postal Code
35033
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Benoit Painvin, MD
Email
benoit.painvin@chu-rennes.fr
First Name & Middle Initial & Last Name & Degree
Benoit Painvin, MD
Facility Name
Rennes University Hospital - Surgical ICU
City
Rennes
State/Province
Bretagne
ZIP/Postal Code
35033
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yoann Launey, MD
Email
yoann.launey@chu-rennes.fr
First Name & Middle Initial & Last Name & Degree
Yoann Launey, MD
Facility Name
Besançon University Hospital
City
Besançon
ZIP/Postal Code
25000
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gaël Piton, MD
Email
gpiton@chu-besancon.fr
First Name & Middle Initial & Last Name & Degree
Gaël Piton, MD
Facility Name
Le Mans Hospital
City
Le Mans
ZIP/Postal Code
72037
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christophe Guitton, MD
Email
cguitton@ch-lemans.fr
First Name & Middle Initial & Last Name & Degree
gpiton@chu-besancon.fr Guitton, MD
Facility Name
Tours University Hospital
City
Tours
ZIP/Postal Code
37044
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Charlotte Salmon-Gandonnière, MD
Email
charlotte.salmon@univ-tours.fr
First Name & Middle Initial & Last Name & Degree
Charlotte Salmon, MD

12. IPD Sharing Statement

Plan to Share IPD
Undecided

Learn more about this trial

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

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