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

NCT04513288 | Recruiting DMC

• 2 other identifiers: 35RC19_9778_ICITRU2020-A01804-35
• Study Type: interventional
• Target: 130
• Locations: 1 country
• Sites: 5

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.

Conditions

Sepsis; Septic Shock

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (16)

• Nosocomial infections

  From Inclusion up to Day 28 maximum

• Exposure to each antibiotic

  Up to Day 28 maximum

• Mortality in intensive care

  Up to Day 28 maximum

• Hospital mortality

  Up to Day 28 maximum

• Number and phenotypes of lymphocytes

  Day 1, 3 and 7

Study Arms (2)

Experimental group

EXPERIMENTAL

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®)

Control group

PLACEBO COMPARATOR

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

Interventions

Experimental treatment L-citrulline (Protéocit®) DIETARY_SUPPLEMENT

Enteral administration of citrulline for 5 days.

Experimental group

Placebo treatment OTHER

Enteral administration of iso-nitrogenous placebo for 5 days.

Control group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;
• 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

Sponsors & Collaborators

• Rennes University Hospital: lead

Study Sites (5)

Rennes University Hospital - Medical ICU

Rennes, Brittany Region, 35033, France

RECRUITING

Rennes University Hospital - Surgical ICU

Rennes, Brittany Region, 35033, France

TERMINATED

Besançon University Hospital

Besançon, 25000, France

RECRUITING

Le Mans Hospital

Le Mans, 72037, France

RECRUITING

Tours University Hospital

Tours, 37044, France

RECRUITING

MeSH Terms

Conditions

Sepsis; Shock, Septic

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Central Study Contacts

Mathieu Lesouhaitier, MD

CONTACT

0033299284321; mathieu.lesouhaitier@chu-rennes.fr

Jean-Marc Tadié, MD

CONTACT

0033299284321; jean-marc.tadie@chu-rennes.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Prospective, multicenter, placebo-controlled, randomized, double-blind study on two parallel groups.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Prospective, multicenter, placebo-controlled, randomized, double-blind study on two parallel groups.

Study Record Dates

• First Submitted: August 11, 2020
• First Posted: August 14, 2020
• Study Start: May 20, 2022
• Primary Completion (Estimated): November 20, 2026
• Study Completion (Estimated): November 20, 2026
• Last Updated: October 8, 2024

Record last verified: 2024-10

Locations

FR (5)