## Protocol Section
### Identification Module
**NCT ID:** NCT06422338

**Brief Title:** A Rapid Triage Test to Improve Risk-stratification of Febrile Children (EChiLiBRiST, Clinical Trial 1, Outpatients)

**Official Title:** A Multi-country, Two-arm, Open-label, Superiority, Randomised Controlled Trial to Study the Performance of a Rapid Triage Test Compared to Standard of Care (IMCI-based) to Guide Admission/Discharge Decisions During the First Clinical Assessment of Children With Fever

#### Organization Study ID Info
**ID:** EChiLiBRiST CT1
#### Organization
**Class:** OTHER
**Full Name:** Barcelona Institute for Global Health
### Status Module
#### Completion Date
**Date:** 2027-03-01

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-24

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-22

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-12-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-12-01

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-21
**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:** The overall aim of the study is to provide evidence that introducing soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) evaluation at triaging (first clinical assessment), in combination with IMCI-based guidelines (SoC), is a viable strategy to enhance rapid and accurate identification of febrile children at increased risk of life-threatening infections compared to IMCI-based strategies alone (SoC), and to demonstrate whether this results in enhanced decisions of admission/referral vs discharge, and enhanced overall health outcome of children with acute fever in sub-Saharan Africa.

**Detailed Description:** This is a multi-country, open label, two-arm, parallel-group, superiority, individually randomised clinical trial involving 2,606 febrile children per country (two countries, total n=5212). The trial will compare the performance of a point-of-care rapid triage test (POC-RTT) based on sTREM-1 levels (i.e. B-Triage) (in combination with IMCI-based strategies, which are the SoC) to appropriately support admission/referral vs discharge decisions during the first clinical assessment of febrile children aged 2-\<60 months compared to the standard of care based on IMCI guidelines.

Febrile children meeting the study eligibility criteria will be randomly allocated (1:1) to one of the two triaging approaches (arms): 1) IMCI-based standard of care (SoC); or 2) IMCI-enhanced by sTREM-1 levels (SoC + sTREM-1 POC). Blood will be collected from all participants and only those randomised to the intervention arm (arm 2) will have sTREM-1 levels determined at the POC using B-Triage device.

At baseline, all children will undergo two clinical assessments. Primary composite endpoint of "appropriateness of discharge" will be based on the first clinical assessment, which is more representative of real-world clinical practice. However, the ultimate decision on admission/referral vs discharge will be based on the second clinical assessment, which will ensure the safest possible clinical practice in the context of a clinical trial.

1. At baseline, during the first clinical assessment, all participants will be evaluated following the SoC based on IMCI guidelines, which will guide management decisions, including clinical diagnosis and treatment. This IMCI-guideline based evaluation during this first clinical assessment will be conducted by a health worker as per routine clinical practice in the outpatient departments of each study site.

   1. In the participants randomised to the control arm, decision of admission/referral vs discharge home will be informed by IMCI-based evaluation alone (SoC).
   2. In the participants randomised to the intervention arm, decision of admission/referral vs discharge home will be informed by IMCI-based evaluation enhanced by sTREM-1 levels (SoC + sTREM-1 POC). Clinicians will be instructed to admit for further observation any child with sTREM-1 levels equal or superior to 200 pg/mL, as these patients are at moderate or high risk of adverse outcomes and death. On the other hand, children with sTREM-1 levels below 200 pg/mL will be eligible for discharge home at the criteria of the clinician, considering the signs and symptoms found, and based on IMCI guidelines. Hence, should clinicians in charge deem that any of these children still require admission, they will be instructed to continue with the admission regardless of sTREM-1 levels.

   The study intervention will be implemented during the first clinical assessment, and consequently, primary composite endpoint of "appropriateness of discharge" will be based on the decision of admission/referral vs discharge home during this first clinical assessment, which is more representative of routine clinical practice in each study site.
2. All randomised participants will be also evaluated by an independent study physician in a second clinical assessment, for the implementation of a systematised clinical evaluation (IMCI-based) to uncover any danger signs or severity criteria potentially missed or misinterpreted during the first assessment. This second assessment will also include clinical variables of the clinical scores Paediatric Early Warning Score (ED-PEWS), Lactate enhanced-quick Sequential Organ Failure Assessment (LqSOFA) and Logistic Organ Dysfunction Score (LODS), as well as temperature and oxygen saturation measures. Hence, study clinicians during this second clinical assessment might be able to uncover more symptoms and signs that are admission criteria due to the tools available in the context of this clinical trial. Initially discharged patients from both arms showing a danger sign or other severity criteria during this second assessment will be admitted, as well as those from the intervention arm with sTREM-1 high-risk (red light) and moderate-risk (yellow light) levels, in case that the first clinician might not have adhered to the protocol during the first assessment. On the other hand, this second assessment will not overturn the decision of the first clinician if admission has been decided in case of sTREM-1 levels below 200 pg/mL (green light, low-risk).

This second clinical assessment will guide the ultimate decision on admission/referral vs discharge in order to ensure the safest possible clinical practice in the context of a clinical trial.

Moreover, those participants with respiratory symptoms will be eligible for the respiratory tract infection (RTI) sub-study, where digital lung auscultations, a mid-turbinate nasal swab and a saliva sample will be collected.

Throughout the study, all participants will receive treatment as per the routine clinical practice and SoC for each diagnosis at each study site, administered by clinical staff routinely working in the participating facilities.

All participants will have follow-up evaluations by study clinicians on days 3 and 7 post-enrolment, or at any time in-between in case of clinical deterioration according to caregivers' evaluation. All participants will be also followed-up on day 28 for an interview to follow-up on serious adverse events (SAEs), as well as to collect information on secondary consultations and hospitalisation, or death. A follow-up extra visit at day 91 (month 3) can be conducted for an interview to ask for hospitalisation or death.

### Conditions Module

**Conditions:**

- Infectious Disease

- Febrile Illness

- Child, Only

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** OTHER

#### Enrollment Info

**Count:** 5212

**Type:** ESTIMATED

**Phases:**

- NA

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** IMCI-guidelines (standard of care) + Point-Of-Care Rapid Triage Test (POC-RTT) based on sTREM-1 quantification

**Intervention Names:**

- Other: IMCI-enhanced by sTREM-1 levels (SoC + sTREM-1 POC)

**Label:** IMCI-enhanced by sTREM-1 levels (SoC + sTREM-1 POC)

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** IMCI-guidelines (standard of care)

**Label:** IMCI alone

**Type:** NO_INTERVENTION

### Interventions

#### Intervention 1

**Arm Group Labels:**

- IMCI-enhanced by sTREM-1 levels (SoC + sTREM-1 POC)

**Description:** IMCI-guidelines (standard of care) + Point-Of-Care Rapid Triage Test (POC-RTT) based on sTREM-1 quantification

**Name:** IMCI-enhanced by sTREM-1 levels (SoC + sTREM-1 POC)

**Type:** OTHER

### Outcomes Module

#### Other Outcomes

**Description:** Proportion of secondary consultations or admissions on day 91 (month 3) among the two study arms

**Measure:** Secondary consultations or admission

**Time Frame:** Up to day 91

**Description:** Proportion of mortality on day 91 (month 3) among the two study arms.

**Measure:** Mortality

**Time Frame:** Up to day 91

#### Primary Outcomes

**Description:** The primary outcome is the proportion of "appropriateness of discharge" according to the first clinical assessment of febrile children aged 2-\<60 months compared among the 2 study arms.

Inappropriate discharge is defined as a composite of (fulfilling at least one of the following):

1. Presence at baseline of World Health Organization (WHO)-proposed danger signs in discharged children; OR
2. Presence of WHO-proposed danger signs on day 3 post-discharge; OR
3. Requirement for additional visit at the health facility or admission at day 7; OR
4. Death on day 7 post-discharge. The absence of any of these endpoints will be considered an appropriate discharge.

**Measure:** Appropriateness of discharge

**Time Frame:** Up to day 7

#### Secondary Outcomes

**Description:** Proportion of secondary consultations or admissions on day 7 and day 28 among the two study arms.

**Measure:** Secondary consultations or admissions

**Time Frame:** Up to day 28

**Description:** Proportion of mortality on day 7 and day 28 among the two study arms.

**Measure:** Mortality

**Time Frame:** Up to day 28

**Description:** Proportion of referrals of mild infections to higher level facilities at day 7 and day 28 among the two study arms.

**Measure:** Referrals to higher level facilities

**Time Frame:** Up to day 28

**Description:** Proportion of participants diagnosed with severe disease as described in IMCI (i.e. very severe diseases, severe pneumonia, severe dehydration, severe persistent diarrhoea, very severe febrile diseases, severe complicated measles, complicated severe acute malnutrition, mastoiditis, and severe anaemia), at day 3 and day 7 among the two study arms.

**Measure:** Severe disease

**Time Frame:** Up to day 7

**Description:** Median time to symptoms resolution among the two study arms until day 28.

**Measure:** Symptoms duration

**Time Frame:** Up to day 28

**Description:** Median length of hospital stay among the two study arms until day 28

**Measure:** Hospital stay length

**Time Frame:** Up to day 28

**Description:** Proportion of serious adverse events (SAEs) at day 3, day 7, and day 28, among the two study arms.

**Measure:** Serious adverse events

**Time Frame:** Up to day 28

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Age ≥2 months and \<60 months
* Written informed consent from the child's parent or caregiver
* History of fever for ≤7 days OR hypothermia (i.e., axillary temperature \<35.5ºC) OR suspected severe infection (e.g., in children with moderate or severe acute malnutrition).
* Lives within the catchment area of the study facility and must intend to continue to reside there for the duration of the study
* For the RTI sub-study only: presence of respiratory symptoms compatible with RTI.

Exclusion Criteria:

* Weight less than 2.5kg
* Main reason for consultation is an injury, trauma or acute poisoning
* Enrolled in another clinical trial testing a new drug
* Enrolled in a vaccine trial in the last 3 months.
* Any other condition determined by the investigators that makes it unlikely that the participant would complete the study

**Maximum Age:** 60 Months

**Minimum Age:** 2 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 European Union-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

- ID: D000001832

- Term: Body Temperature Changes

- ID: D000018882

- Term: Heat Stress Disorders

- ID: D000014947

- Term: Wounds and Injuries

### 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

- Abbrev: BXM

- Name: Behaviors and Mental Disorders

### 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: HIGH

- As Found: Febrile

- ID: M8464

- Name: Fever

- Relevance: HIGH

- As Found: Febrile

- ID: M22700

- Name: Disease Attributes

- Relevance: LOW

- As Found: Unknown

- ID: M5111

- Name: Body Temperature Changes

- Relevance: LOW

- As Found: Unknown

- ID: M24916

- Name: Stress Disorders, Traumatic

- Relevance: LOW

- As Found: Unknown

- ID: M20924

- Name: Heat Stress Disorders

- Relevance: LOW

- As Found: Unknown

- ID: M17685

- Name: Wounds and Injuries

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000003141

- Term: Communicable Diseases

- ID: D000007239

- Term: Infections

- ID: D000084462

- Term: Hyperthermia

- ID: D000005334

- Term: Fever

### Misc Info Module

- Version Holder: 2024-05-31
