NCT04404426: CACOLAC

CACOLAC : Citrulline Administration in the Hospital Patient in Intensive Care for COVID-19 Acute Respiratory Distress Syndrome

Completed NA Last updated 2 June 2021

What this trial tests

NA trial testing L-citrulline in ARDS Secondary to COVID-19 Pneumonia in 33 participants. Completed in 28 May 2021.

Timeline

4 November 2020

Primary endpoint
25 March 2021

28 May 2021

Quick facts

Lead sponsor	Rennes University Hospital
Phase	NA
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	triple
Primary purpose	treatment
Enrollment	33
Start date	4 November 2020
Primary completion	25 March 2021
Estimated completion	28 May 2021
Sites	1 location across France

Drugs / interventions tested

• L-citrulline (Citrulline) — full drug profile →
• Placebo

Conditions studied

• ARDS Secondary to COVID-19 Pneumonia — all drugs for ARDS Secondary to COVID-19 Pneumonia →

Sponsor

Rennes University Hospital

Who can join

18 and older, any sex, with ARDS Secondary to COVID-19 Pneumonia. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets.
   Zhou Y, Liu Y, Gupta S, Paramo MI, et al · · 2023 · cited 160× · PMID 36217030 · DOI 10.1038/s41587-022-01474-0
2. Metabolic Reprogramming in COVID-19.
   Shen T, Wang T. · · 2021 · cited 44× · PMID 34768906 · DOI 10.3390/ijms222111475
3. COVID-19 metabolism: Mechanisms and therapeutic targets.
   Wang T, Cao Y, Zhang H, Wang Z, et al · · 2022 · cited 33× · PMID 35958432 · DOI 10.1002/mco2.157
4. Nitric oxide for the prevention and treatment of viral, bacterial, protozoal and fungal infections.
   Bath PM, Coleman CM, Gordon AL, Lim WS, et al · · 2021 · cited 25× · PMID 35685687 · DOI 10.12688/f1000research.51270.2
5. A Comprehensive Summary of the Knowledge on COVID-19 Treatment.
   Peng Y, Tao H, Satyanarayanan SK, Jin K, et al · · 2021 · cited 18× · PMID 33532135 · DOI 10.14336/ad.2020.1124
6. Outcomes Evaluated in Controlled Clinical Trials on the Management of COVID-19: A Methodological Systematic Review.
   Mathioudakis AG, Fally M, Hashad R, Kouta A, et al · · 2020 · cited 14× · PMID 33333777 · DOI 10.3390/life10120350
7. Role of T Regulatory Cells and Myeloid-Derived Suppressor Cells in COVID-19.
   Alsalman A, Al-Mterin MA, Elkord E. · · 2022 · cited 10× · PMID 35497875 · DOI 10.1155/2022/5545319
8. Post-Acute Sequelae and Mitochondrial Aberration in SARS-CoV-2 Infection.
   Ward C, Schlichtholz B. · · 2024 · cited 4× · PMID 39201736 · DOI 10.3390/ijms25169050