## Protocol Section
### Identification Module
**NCT ID:** NCT06426147

**Brief Title:** L-citrulline to Improve Adverse Outcomes in Admitted Children (EChiLiBRiST, Clinical Trial 2, Inpatients)

**Official Title:** A Randomised, Double-blind, Placebo-controlled Trial of L-Citrulline Oral Supplementation to Improve Short and Long-term Outcomes of Admitted Febrile Paediatric Patients With Biomarker-determined High-risk of Adverse Outcomes

#### Organization Study ID Info
**ID:** EChiLiBRiST CT2
#### Organization
**Class:** OTHER
**Full Name:** Barcelona Institute for Global Health
### Status Module
#### Completion Date
**Date:** 2027-04-01

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-23

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-17

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2027-01-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2025-01-01

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-23
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-10
**Study First Submit QC Date:** 2024-05-17
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Barcelona Institute for Global Health

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** 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.

**Detailed Description:** Children admitted to hospital and meeting the study eligibility criteria who are 0-\<60 months of age will be eligible for study inclusion, and for initial biomarker screening using the study-designed rapid triaging PoC test, based on the measurement of sTREM-1. Study participants aged 1m-\<5 years of age with sTREM-1 values classified as moderate (i.e., "yellow") or high-risk (i.e., "red") in the traffic light risk-stratification system will be randomly allocated (1:1) to receive L-Cit intervention or placebo. All study participants will be followed for 6 months, with study visits at the study hospitals or at home or via phone communication after discharge at day 3, day 5, day 7, day 28, and month 6. The study primary outcome will be "adverse disease outcome", defined as a composite of mortality, incident neurological sequelae, major adverse kidney event at discharge, need for organ support, clinical shock, coma, severe respiratory distress or need for readmission within 28 days after recruitment.

### Conditions Module

**Conditions:**

- Infectious Disease

- Infections

- Child, Only

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** QUADRUPLE

**Who Masked:**

- PARTICIPANT

- CARE_PROVIDER

- INVESTIGATOR

- OUTCOMES_ASSESSOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 2200

**Type:** ESTIMATED

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** 1 or 2 sachets every 12 hours (200-300mg/kg/day depending on weight-band) for 28 days

**Intervention Names:**

- Dietary Supplement: L-citrulline

**Label:** L-citrulline

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** 1 or 2 sachets every 12 hours (depending on weight-band) for 28 days

**Intervention Names:**

- Dietary Supplement: Placebo

**Label:** Placebo

**Type:** PLACEBO_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- L-citrulline

**Description:** 1 or 2 sachets every 12 hours (200-300mg/kg/day depending on weight-band) for 28 days

**Name:** L-citrulline

**Type:** DIETARY_SUPPLEMENT

#### Intervention 2

**Arm Group Labels:**

- Placebo

**Description:** 1 or 2 sachets every 12 hours (depending on weight-band) for 28 days

**Name:** Placebo

**Type:** DIETARY_SUPPLEMENT

### Outcomes Module

#### Other Outcomes

**Description:** Concentration of circulating mediators of host immune and endothelial function, inflammation, intestinal barrier function, and neuronal damage at baseline, D3 and D7

**Measure:** Concentration of circulating mediators of host immune and endothelial function, inflammation, intestinal barrier function, and neuronal damage

**Time Frame:** Up to day 7

**Description:** Levels of lactate at baseline and D3

**Measure:** Lactate levels

**Time Frame:** Up to day 3

**Description:** Levels of markers of kidney function (creatinine, urea, saliva urea nitrogen (SUN), uNGAL etc.) at baseline, D3, D7 and at discharge

**Measure:** Levels of markers of kidney function

**Time Frame:** Up to day 7

**Description:** Prognostic performance of PoC-RTT measured sTREM-1 values at baseline among children (0-\<60 months of age) with adverse outcomes up to D28.

**Measure:** PoC-RTT prognostic performance

**Time Frame:** Up to day 28

**Description:** Prognostic performance of a larger panel of prognostic biomarkers (circulating markers of endothelial function, inflammation, intestinal barrier function, and neuronal damage) at baseline.

**Measure:** Prognostic performance of a larger panel of biomarkers

**Time Frame:** At baseline

#### Primary Outcomes

**Description:** 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)

**Measure:** Adverse disease outcome

**Time Frame:** Up to day 28

#### Secondary Outcomes

**Description:** Proportion of participants with mortality between day 0 and day 28 after recruitment and/or up to hospital discharge.

**Measure:** Mortality

**Time Frame:** Up to day 28

**Description:** Proportion of participants with incident neurological sequelae between day 0 and day 28 after recruitment and/or up to hospital discharge.

**Measure:** Incident neurological sequelae

**Time Frame:** Up to day 28

**Description:** 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)

**Measure:** Major adverse kidney event

**Time Frame:** Up to day 28

**Description:** Proportion of participants with need for organ support

**Measure:** Need for organ support

**Time Frame:** Up to day 28

**Description:** Proportion of participants with clinical shock

**Measure:** Clinical shock

**Time Frame:** Up to day 28

**Description:** Proportion of participants with severe respiratory distress

**Measure:** Severe respiratory distress

**Time Frame:** Up to day 28

**Description:** Proportion of participants with coma

**Measure:** Coma

**Time Frame:** Up to day 28

**Description:** Proportion of participants with need for readmission within the first 28 days post-recruitment (after having been discharged)

**Measure:** Need for readmission

**Time Frame:** Up to day 28

**Description:** Median duration of antibiotic treatment up to day 28

**Measure:** Median duration of antibiotic treatment

**Time Frame:** Up to day 28

**Description:** Proportion of participants with oxygen requirement up to D28 and/or up to hospital discharge

**Measure:** Oxygen requirement

**Time Frame:** Up to day 28

**Description:** Proportion of participants with radiological pneumonia among children with RTI up to D28 and/or up to hospital discharge

**Measure:** Radiological pneumonia

**Time Frame:** Up to day 28

**Description:** Proportion of participants with hypoxemia (Sat 02\<90% irrespective of supplementary oxygen in absence of cyanotic heart disease) up to D28 and/or up to hospital discharge

**Measure:** Hypoxemia (Sp02 <90%)

**Time Frame:** Up to day 28

**Description:** Length of hospitalisation up to D28 and/or up to hospital discharge

**Measure:** Lenght of hospitalisation

**Time Frame:** Up to day 28

**Description:** Proportion of participants with mortality up to M6

**Measure:** Mortality

**Time Frame:** Up to month 6

**Description:** Proportion of participants with secondary consultations or hospitalisations up to M6

**Measure:** Secondary consultation or hospitalisations

**Time Frame:** Up to month 6

**Description:** Proportion of participants with serious adverse events up to month 6

**Measure:** Proportion of participants with serious adverse events

**Time Frame:** Up to month 6

**Description:** Proportion of participants with suspected unexpected serious adverse reactions up to M6.

**Measure:** Proportion of participants with suspected unexpected serious adverse reactions

**Time Frame:** Up to month 6

**Description:** Proportion of participants with adverse events up to D30.

**Measure:** Proportion of participants with adverse events

**Time Frame:** Up to day 30

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* 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.
* With an sTREM-1 PoC result classifying their disease as of "moderate-high risk" ("yellow" or "red") upon study recruitment and within D3.
* Residents in the study area or willing to be contacted and traced during the study duration.
* Willing to sign an informed consent document.
* Willing to undergo and adhere to study procedures as explained in the IC document.

Exclusion Criteria:

* 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.
* Patient under NPO or "nothing by mouth" prescription .
* Contraindication for the insertion of a nasogastric tube (NGT) of for the enteral administration of drugs through the NGT in children who cannot tolerate by mouth.
* Critically sick patient whose prognosis is considered by the clinical researcher as fatal outcome in the following hours after screening.
* Any other condition determined by the investigators that makes it unlikely that the participant would complete the follow up until day 28 of study.

**Maximum Age:** 60 Months

**Minimum Age:** 0 Months

**Sex:** ALL

**Standard Ages:**

- CHILD

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** quique.bassat@isglobal.org

**Name:** Quique Bassat, Prof

**Phone:** 93 227 92 12

**Role:** CONTACT

**Contact 2:**

**Email:** barbara.baro@isglobal.org

**Name:** Barbara Baro, PhD

**Phone:** 93 227 92 12

**Role:** CONTACT

#### Overall Officials

**Official 1:**

**Affiliation:** Barcelona Institute for Global Health

**Name:** Quique Bassat, Prof

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**Access Criteria:** On request to any interested professional

**Description:** This clinical trial, as part of the wider EChiLiBRiST project, is committed to EU-funded Horizon 2021 aims to improve and maximize access to and reuse of research data generated by the Project.

Biological samples and data will be shared using material and data transfer agreements with the collaborating institutions.

The full protocol will be available on request to any interested professional and may be published in peer-reviewed journals or deposited in an online repository. A fully de-identified data set of the complete patient-level data will be available for sharing purposes as soon as the the analysis is completed and no later than five years after the publication of the trial.

**Info Types:**

- STUDY_PROTOCOL

- SAP

- ICF

- CSR

**IPD Sharing:** YES

**Time Frame:** A fully de-identified data set of the complete patient-level data will be available for sharing purposes as soon as the data analysis is completed and no later than five years after the publication of the trial.

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000020969

- Term: Disease Attributes

- ID: D000010335

- Term: Pathologic Processes

### Condition Browse Module - Browse Branches

- Abbrev: BC01

- Name: Infections

- Abbrev: All

- Name: All Conditions

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: BC26

- Name: Wounds and Injuries

### Condition Browse Module - Browse Leaves

- ID: M10283

- Name: Infections

- Relevance: HIGH

- As Found: Infectious Disease

- ID: M6368

- Name: Communicable Diseases

- Relevance: HIGH

- As Found: Infectious Disease

- ID: M2454

- Name: Hyperthermia

- Relevance: LOW

- As Found: Unknown

- ID: M8464

- Name: Fever

- Relevance: LOW

- As Found: Unknown

- ID: M22700

- Name: Disease Attributes

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000003141

- Term: Communicable Diseases

- ID: D000007239

- Term: Infections

### Misc Info Module

- Version Holder: 2024-05-31
