SepsisICITRUNCT04513288
ICITRU : Randomized Trial of Immunonutrition With L-citrulline in Patients Hospitalized in Intensive Care for Sepsis or Septic Shock
A study testing Experimental treatment L-citrulline (Protéocit®) in people with Sepsis and Septic Shock, run by Rennes University Hospital at 5 sites in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sepsis, Septic Shock
- What is being tested?
- Experimental treatment L-citrulline (Protéocit®)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 130 participants
- Where
- 5 sitesFrance
- Study dates
- 20 May 2022to 20 Nov 2026
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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;
Show all 14Show fewer
- 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
Who cannot join
- 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).
Trial locations and contacts
5 sites in 1 country. Contact the study team or a site near you to ask about taking part.
5 sites in 1 country
France5 sites, 4 recruiting
- Recruiting
Besançon University Hospital
Besançon, 25000
Gaël Piton, MD, gpiton@chu-besancon.fr
Gaël Piton, MD
- Recruiting
Le Mans Hospital
Le Mans, 72037
Christophe Guitton, MD, cguitton@ch-lemans.fr
gpiton@chu-besancon.fr Guitton, MD
- Recruiting
Rennes University Hospital - Medical ICU
Rennes, Brittany Region, 35033
Benoit Painvin, MD, benoit.painvin@chu-rennes.fr
Benoit Painvin, MD
- Terminated
Rennes University Hospital - Surgical ICU
Rennes, Brittany Region, 35033
- Recruiting
Tours University Hospital
Tours, 37044
Charlotte Salmon-Gandonnière, MD, charlotte.salmon@univ-tours.fr
Charlotte Salmon, MD
About this study
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.
Read the 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).
- Conditions
- Sepsis, Septic Shock
- Being tested
- Experimental treatment L-citrulline (Protéocit®), Placebo treatment
- Medical subject headings
- Sepsis, Shock, Septic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Experimental treatment L-citrulline (Protéocit®)Dietary supplement
Enteral administration of citrulline for 5 days.
Placebo treatmentOther
Enteral administration of iso-nitrogenous placebo for 5 days.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Other: Placebo treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
SOFA score
SOFA score for organ failure (5 parameters ranged from 0 to 4 each)
Measured: 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
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.
Measured: 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)
Measured: Up to Day 28 maximum
Mortality in intensive care
Mortality in intensive care
Measured: Up to Day 28 maximum
Hospital mortality
Hospital mortality
Measured: Up to Day 28 maximum
Number and phenotypes of lymphocytes
Number and phenotypes of lymphocytes on Day 1, Day 3 and Day 7
Measured: Day 1, 3 and 7
HLA-DR monocytic expression
HLA-DR monocytic expression (flow cytometry) on Day 1, Day 3 and Day 7
Measured: 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
Measured: 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
Measured: Day 1, 3 and 7
T repertoire
Diversity of the T repertoire at Day 1, Day 3 and Day 7
Measured: 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
Measured: 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
Measured: 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
Measured: 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)
Measured: Day 3 and Day 5
Duration of hospitalization in intensive care
Duration of hospitalization in intensive care (days), up to Day 28 maximum
Measured: Up to Day 28 maximum
Duration of hospitalization at the hospital
Hospital stay at the hospital (days), up to Day 28 maximum
Measured: Up to Day 28 maximum
Duration of mechanical ventilation
Duration of mechanical ventilation (days), up to Day 28 maximum.
Measured: Up to Day 28 maximum
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Aug 2020
- Study start20 May 2022
- Primary completion20 Nov 2026 (estimated)
- Study completion20 Nov 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for SepsisStudies of the same condition, open and under way.
- More trials run by Rennes University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Prospective, multicenter, placebo-controlled, randomized, double-blind study on two parallel groups.
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 130 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Rennes University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04513288
- Sponsor's protocol ID
- 35RC19_9778_ICITRU
- Other IDs
- 2020-A01804-35
- Acronym
- ICITRU
- Status last verified
- Oct 2024
- First submitted
- 11 Aug 2020
- Last updated
- 8 Oct 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 8 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- ICITRU : Randomized Trial of Immunonutrition With L-citrulline in Patients Hospitalized in Intensive Care for Sepsis or Septic Shock
- ClinicalTrials.gov ID
- NCT04513288
- Acronym / sponsor ID
- ICITRU / 35RC19_9778_ICITRU
- Conditions
- Sepsis, Septic Shock
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 130 participants (estimated)
- Lead sponsor
- Rennes University HospitalUniversity, hospital or other
- Study start
- 20 May 2022 (actual)
- Primary completion
- 20 Nov 2026 (estimated)
- Study completion
- 20 Nov 2026 (estimated)
- First posted
- 14 Aug 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
- Model description
- Prospective, multicenter, placebo-controlled, randomized, double-blind study on two parallel groups.
| Arm | Type | Receives |
|---|---|---|
| Experimental group | Experimental | Dietary Supplement: Experimental treatment L-citrulline (Protéocit®)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. |
| Control group | Placebo comparator | Other: Placebo treatmentEnteral 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- 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;
Key exclusion criteria (1 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Experimental treatment L-citrulline (Protéocit®)Enteral administration of citrulline for 5 days. | Dietary supplement | Experimental group |
| Placebo treatmentEnteral administration of iso-nitrogenous placebo for 5 days. | Other | Control group |
Primary outcome
SOFA score
Time frame: Baseline and day 7 or last known SOFA score if the patient died or left intensive care before day 7.
SOFA score for organ failure (5 parameters ranged from 0 to 4 each)
16 secondary outcomes
Nosocomial infections
Time frame: From Inclusion up to Day 28 maximum
Exposure to each antibiotic
Time frame: Up to Day 28 maximum
Mortality in intensive care
Time frame: Up to Day 28 maximum
Hospital mortality
Time frame: Up to Day 28 maximum
Number and phenotypes of lymphocytes
Time frame: Day 1, 3 and 7
HLA-DR monocytic expression
Time frame: Day 1, 3 and 7
Number of Myeloid-derived suppressor cells
Time frame: Day 1, 3 and 7
Plasma cytokines / chemokines
Time frame: Day 1, 3 and 7
T repertoire
Time frame: Day 1, 3 and 7
T lymphocyte exhaustion
Time frame: Day 1, 3 and 7
Mitochondrial activity
Time frame: Day 1, 3 and 7
Plasma amino acids
Time frame: Day 1, 3 and 7
SOFA score
Time frame: Day 3 and Day 5
Duration of hospitalization in intensive care
Time frame: Up to Day 28 maximum
Duration of hospitalization at the hospital
Time frame: Up to Day 28 maximum
Duration of mechanical ventilation
Time frame: Up to Day 28 maximum
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Oct 2024.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Experimental treatment L-citrulline (Protéocit®) in people with Sepsis and Septic Shock, run by Rennes University Hospital at 5 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 8 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Mathieu Lesouhaitier, MD (0033299284321, mathieu.lesouhaitier@chu-rennes.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
SOFA score (time frame: Baseline and day 7 or last known SOFA score if the patient died or left intensive care before day 7.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Oct 2024.