ARDS Secondary to COVID-19 PneumoniaCACOLACNCT04404426
CACOLAC : Citrulline Administration in the Hospital Patient in Intensive Care for COVID-19 Acute Respiratory Distress Syndrome
A study testing L-citrulline in people with ARDS Secondary to COVID-19 Pneumonia, run by Rennes University Hospital at 1 site in France.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- ARDS Secondary to COVID-19 Pneumonia
- What is being tested?
- L-citrulline
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 33 participants
- Where
- 1 siteFrance
- Study dates
- 4 Nov 2020to 28 May 2021
- Phase
- Interventional
- Are there results?
- None posted in the registry
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
- 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).
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read more
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.
- Conditions
- ARDS Secondary to COVID-19 Pneumonia
- Being tested
- L-citrulline, Placebo
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-citrullineDietary supplement
Administration of citrulline enterally for 7 days.
PlaceboOther
Administration of placebo (water) enterally for 7 days
| Study group | Role | What they receive |
|---|---|---|
| L-citrulline | Experimental | Administration of citrulline enterally for 7 days Receives: Dietary Supplement: L-citrulline |
| Placebo | Placebo comparator | Administration of placeboenterally for 7 days Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
SOFA
SOFA score for organ failures on D8 or last known SOFA score if the patient has died or been resuscitated
Measured: Day 8
Secondary outcomes (17)
Number and phenotype of lymphocytes
Number and phenotype of lymphocytes on days 1, 8 and 14
Measured: Days 1, 8 and 14
HLA-DR
Monocytic expression HLA-DR (Flow cytometry) on days 1, 8 and 14
Measured: 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
Measured: 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
Measured: Days 1, 8 and 14
Repertoire T
Diversity of the repertoire T at days 1, 3, 8, 10 and 14
Measured: 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
Measured: 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
Measured: 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
Measured: Days 1, 8 and 14
SOFA
SOFA score of organ failures on days 3, 7, 10 and 14
Measured: Days 3, 7, 10 and 14
Duration of hospitalization in intensive care
Duration of hospitalization in intensive care (days), up to day 28 maximum
Measured: Day 28
Duration of hospital stay in hospital
Duration of hospital stay in hospital (days), up to day 28 maximum
Measured: Day 28
Duration of mechanical ventilation
Duration of mechanical ventilation (days), up to day 28 maximum
Measured: Day 28
Mortality in intensive care on day 28
Mortality in intensive care on day 28
Measured: Day 28
Hospital mortality on day 28
Hospital mortality on day 28
Measured: 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
Measured: 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
Measured: 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).
Measured: Day 28
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 May 2020
- Study start4 Nov 2020
- Primary completion25 Mar 2021
- Study completion28 May 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for ARDS Secondary to COVID-19 PneumoniaStudies 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, two-parallel study, specific enteral administration by citrulline in a subgroup of resuscitation patients admitted for ARDS secondary to COVID-19 pneumonia, at infectious risk nosocomial important because having biological stigmas of immunosuppression on admission and under invasive mechanical ventilation for a prolonged period.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 33 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rennes University Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04404426
- Sponsor's protocol ID
- 35RC20_9815_CACOLAC
- Other IDs
- CPP 1288 HPS1, 2020-A01189-30
- Acronym
- CACOLAC
- Status last verified
- May 2021
- First submitted
- 22 May 2020
- Last updated
- 2 Jun 2021
- Results posted
- No
- Data monitoring committee
- No
- 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 2 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- CACOLAC : Randomized Trial of Citrulline Administration in the Hospital Patient in Intensive Care for COVID-19 Acute Respiratory Distress Syndrome
- ClinicalTrials.gov ID
- NCT04404426
- Acronym / sponsor ID
- CACOLAC / 35RC20_9815_CACOLAC
- Conditions
- ARDS Secondary to COVID-19 Pneumonia
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 33 participants (actual)
- Lead sponsor
- Rennes University HospitalUniversity, hospital or other
- Study start
- 4 Nov 2020 (actual)
- Primary completion
- 25 Mar 2021 (actual)
- Study completion
- 28 May 2021 (actual)
- First posted
- 27 May 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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
- Model description
- Prospective, multicenter, placebo-controlled, randomized, double-blind, two-parallel study, specific enteral administration by citrulline in a subgroup of resuscitation patients admitted for ARDS secondary to COVID-19 pneumonia, at infectious risk nosocomial important because having biological stigmas of immunosuppression on admission and under invasive mechanical ventilation for a prolonged period.
| Arm | Type | Receives |
|---|---|---|
| L-citrulline | Experimental | Dietary Supplement: L-citrullineAdministration of citrulline enterally for 7 days |
| Placebo | Placebo comparator | Other: PlaceboAdministration of placeboenterally for 7 days |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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;
Key exclusion criteria (5 listed)
- 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.
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 |
|---|---|---|
| L-citrullineAdministration of citrulline enterally for 7 days. | Dietary supplement | L-citrulline |
| PlaceboAdministration of placebo (water) enterally for 7 days | Other | Placebo |
Primary outcome
SOFA
Time frame: Day 8
SOFA score for organ failures on D8 or last known SOFA score if the patient has died or been resuscitated
17 secondary outcomes
Number and phenotype of lymphocytes
Time frame: Days 1, 8 and 14
HLA-DR
Time frame: Days 1, 8 and 14
Number of Myeloid-derived suppressor cells
Time frame: Days 1, 8 and 14
Plasma cytokines / chemokines
Time frame: Days 1, 8 and 14
Repertoire T
Time frame: Days 1, 3, 8, 10 and 14
Lymphocyte T exhaustion
Time frame: Days 1, 8 and 14
Mitochondrial activity
Time frame: Days 1, 8 and 14
Plasma amino acids
Time frame: Days 1, 8 and 14
SOFA
Time frame: Days 3, 7, 10 and 14
Duration of hospitalization in intensive care
Time frame: Day 28
Duration of hospital stay in hospital
Time frame: Day 28
Duration of mechanical ventilation
Time frame: Day 28
Mortality in intensive care on day 28
Time frame: Day 28
Hospital mortality on day 28
Time frame: Day 28
Measurement of the presence of SARS-CoV2
Time frame: Days 1, 8 and 14
Nosocomial infections
Time frame: D28
Number of days of exposure to each antibiotic per 1000 days of hospitalization
Time frame: Day 28
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jun 2021.
- Individual participant dataSharing planned: Undecided
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. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing L-citrulline in people with ARDS Secondary to COVID-19 Pneumonia, run by Rennes University Hospital at 1 site 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 6 inclusion and 5 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: finished, as of the sponsor's last update on 2 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
SOFA (time frame: Day 8). 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 2 Jun 2021.