In low and middle-income countries, children admitted to hospital are not similarly ill, and do not all have a comparable prognosis. In fact, understanding at first encounter their risk of developing adverse outcomes (including mortality) could allow a more focused management and the tailoring of specific interventions to decrease in hospital mortality, and post discharge adverse longer-term outcomes. This clinical trial, part of the EChiLiBRiST larger project ("Development and validation of a quantitative point-of-care test for the measurement of severity biomarkers to improve risk stratification of fever syndromes and enhance child survival") has the two-fold objective of:
1. Assessing whether a POINT-OF-CARE rapid triaging test (PoC RTT) based on the quantitative measurement at the bedside of the "prognostic" biomarker sTREM-1 (soluble-triggering receptor expressed on myeloid cells 1) can reliably identify those admitted children with a higher risk of adverse outcomes; and 2. Assessing whether the therapeutic intervention (the L-arginine precursor, L-Citrulline, key in the nitric oxide biosynthesis), administered orally for 28 days to those children aged 1-\<60 months identified as "moderate-to-high risk" by the prognostic biomarker can improve outcomes as compared to those receiving an indistinguishable placebo.
This second objective will be assessed in a prospective multi-country, multi-site, individually randomised, two-arm, placebo-controlled, double blind clinical trial involving \~888 children 1-\<60m of age admitted to hospital and determined to be at high risk of adverse outcomes by their baseline sTREM-1 levels. The trial will compare the efficacy of a twice-daily dose of L-citrulline syrup vs placebo (200-300mg/kg/day depending on weight-band; for 28 days) in reducing adverse outcomes in children with severe disease. The trial will be running independently but in parallel in two high-mortality settings in Mozambique and in Ethiopia.
Enrolled in the initial prognostic screening component.
Sick children with fever (axillary temperature>37.5ºC) or a history of fever (within the preceding 72h) or with suspected severe disease.
1m-<60 months of age.
With an indication for admission, or having already been admitted to hospital due to their illness.
Admission to hospital for social reasons (and not on account of their disease).
Children for which informed consent document has not been signed.
Known allergy or contraindication to any of the study supplements including lactose intolerance or observing a lactose-free diet.
Concurrent participation in any other clinical trial.
Parallel
L-citrulline
Dietary supplement1 or 2 sachets every 12 hours (200-300mg/kg/day depending on weight-band) for 28 days
Placebo
Dietary supplement1 or 2 sachets every 12 hours (depending on weight-band) for 28 days
Adverse disease outcome
Proportion of participants with "adverse disease outcome" defined as a composite of (i.e., the occurrence between D0 and D28 after recruitment of at least one -or more- of the following adverse outcomes): * Mortality * Incident neurological sequelae * Major adverse kidney event at discharge (MAKE-DC, defined as a severe AKI event between 2-7 days or a discharge eGFR\<60mL/min per 1.73m2) * Need for organ support * Clinical shock * Coma * Severe respiratory distress * Need for readmission within the first 28 days post-recruitment (after having been discharged)
Mortality
Proportion of participants with mortality between day 0 and day 28 after recruitment and/or up to hospital discharge.
Incident neurological sequelae
Proportion of participants with incident neurological sequelae between day 0 and day 28 after recruitment and/or up to hospital discharge.
Major adverse kidney event
Proportion of participants with major adverse kidney event at discharge (MAKE-DC, defined as a severe AKI event between 2-7 days or a discharge eGFR\<60mL/min per 1.73m2)
Need for organ support
Proportion of participants with need for organ support
Concentration of circulating mediators of host immune and endothelial function, inflammation, intestinal barrier function, and neuronal damage
Concentration of circulating mediators of host immune and endothelial function, inflammation, intestinal barrier function, and neuronal damage at baseline, D3 and D7
Lactate levels
Levels of lactate at baseline and D3
Levels of markers of kidney function
Levels of markers of kidney function (creatinine, urea, saliva urea nitrogen (SUN), uNGAL etc.) at baseline, D3, D7 and at discharge
PoC-RTT prognostic performance
Prognostic performance of PoC-RTT measured sTREM-1 values at baseline among children (0-\<60 months of age) with adverse outcomes up to D28.
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