Early Versus Late Stopping of Antibiotics in Children With Cancer and High-risk Febrile Neutropenia

Febrile Neutropenia Clinical Trial

— ELSA-FN  

Official title:

Early Versus Late Stopping of Antibiotics in Children With Cancer and High-risk Febrile Neutropenia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04948463
• Other study ID #: 74690
• Status: Recruiting
• Phase: Phase 4
• Start date: November 15, 2021
• Est. completion date: August 2026

Study information

• Verified date: March 2024
• Source: Murdoch Childrens Research Institute
• Contact: Alannah Rudkin
• Phone: 03 8341 6200
• Email: alannah.rudkin[@]mcri.edu.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomised controlled trial will determine the non-inferiority of stopping empiric antibiotics prior to absolute neutrophil count (ANC) recovery (Early Stopping) versus stopping antibiotics upon ANC recovery (Standard of Care/ Late Stopping) , in children with cancer and high-risk febrile neutropenia (FN).

Description:

Febrile neutropenia (FN) is a common complication of childhood cancer treatment and a leading cause of hospital admission and antibiotic exposure. Management typically involves broad-spectrum antibiotics until resolution of fever and absolute neutrophil count (ANC) recovery >500 cells/mm3. However, despite the frequency with which FN occurs, evidence to guide duration of antibiotics is limited to observational studies and small randomised controlled trials.Current international clinical guidelines provide conflicting recommendations on when to cease empiric antibiotics for FN. Early cessation of antibiotics in FN may translate to reduced antibiotic exposure and limit potential harms including drug side-effects, antimicrobial resistance, Clostridioides difficile infection and microbiome disruption. This randomised controlled trial will use a composite endpoint of fever recurrence, physiological instability, new bacteremia, intensive care admission and death to determine the non-inferiority of stopping antibiotics prior to ANC recovery compared with standard of care (SOC), in children with cancer and high-risk FN. Adopting a health informatics approach, patient identification, consent, randomisation and reporting of outcomes will be embedded within the electronic medical record (EMR). Children with high-risk FN who have been afebrile and clinically stable for at least 48 hours will be randomised to cease antibiotics or continue SOC. Data on primary outcomes, antibiotic duration, length of stay, C. difficile infection and antimicrobial resistance will be automatically collected by the EMR. This is the first study of its kind in children with high-risk FN and adopts a novel embedded trial design. Results will inform optimal antibiotic duration in FN, potentially reducing unnecessary antibiotic exposure.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 312
• Est. completion date: August 2026
• Est. primary completion date: July 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

Inclusion Criteria:

1. Diagnosis of

• Acute myeloid leukemia (AML) or acute lymphoblastic leukaemia (ALL) in dose-intensive phases of induction/re-induction, intensification or consolidation or
• ALL or acute lymphoblastic lymphoma patients on a TOT17 protocol or
• Any disease within 100 days of allogeneic or autologous HSCT

2. Neutropenia (<500 cells/mm3)

3. Afebrile (temperature <38.0°C) period for at least 48 hours and no more than 96 hours after at least one temperature measured by axillary or tympanic thermometer (=38.0°C)

4. Commenced on empiric FN antibiotics (any of piperacillin-tazobactam, cefepime, ceftazidime or vancomycin and ciprofloxacin)

Exclusion Criteria:

1. Prolonged febrile neutropenia (documented daily temperature =38.0°C for =5 days)

2. Documented positive blood culture since onset of FN episode and prior to randomisation

3. Documented other infection (microbiologically or clinically documented) requiring antibiotic treatment since onset of FN episode and prior to randomisation

4. Admitted to the ICU at the time of randomisation

5. Clinical instability (One or more conscious state, respiratory rate, blood pressure, heart rate or oxygen saturations in MET criteria OR two or more respiratory rate, blood pressure, heart rate or oxygen saturations simultaneously (+/- 4 hrs) in the clinical review criteria in 48 hours prior to randomisation)

6. Within 28 days of last randomisation

Related Conditions & MeSH terms

• Febrile Neutropenia
• Fever
• Hyperthermia
• Neutropenia

Intervention

Drug:
• Piperacillin and Tazobactam for Injection
Given if patient has no known allergies, until ANC recovery at 100mg/kg (max 4g) 6 hourly.
• Cefepime Injection
Given if patient has non life-threatening hypersensitivity (preferred option), until ANC recovery at 50mg/kg (max 2g) 8 hourly.
• Ceftazidime Injection
If non life-threatening hypersensitivity (second option), given until ANC recovery at 50mg/kg (max 2g) 8 hourly
• Vancomycin Injection
If life-threatening hypersensitivity given with ciprofloxacin, given until ANC recovery at 15mg/kg (max 500mg) 6 hourly
• Amikacin Injection
Given until ANC recovery at 18-22.5mg/kg (max 1.5g) daily in combination with other antibiotic/s.
• Ciprofloxacin
If life-threatening hypersensitivity given with vancomycin, given until ANC recovery at 10 mg/kg (max 400 mg) 12 hourly
• Piperacillin and Tazobactam for Injection
Given if patient has no known allergies at 100mg/kg (max 4g) 6 hourly, stopping 48 hours post-fever resolution.
• Cefepime Injection
If non life-threatening hypersensitivity (preferred option) at 50mg/kg (max 2g) 8 hourly, stopping 48 hours post-fever resolution
• Ceftazidime Injection
If non life-threatening hypersensitivity (second option) at 50mg/kg (max 2g) 8 hourly, stopping 48 hours post-fever resolution
• Vancomycin Injection
If life-threatening hypersensitivity given with ciprofloxacin at 15mg/kg (max 500mg) 6 hourly, stopping 48 hours post-fever resolution
• Amikacin Injection
At 18-22.5mg/kg (max 1.5g) daily in combination with other antibiotic/s, stopping 48 hours post-fever resolution
• Ciprofloxacin
If life-threatening hypersensitivity given with vancomycin at 10 mg/kg (max 400 mg) 12 hourly, stopping 48 hours post-fever resolution

Locations

Country	Name	City	State
Australia	Royal Children's Hospital	Melbourne	Victoria

Sponsors (1)

Lead Sponsor	Collaborator
Murdoch Childrens Research Institute

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Unfavourable clinical course occurring during the same period of severe neutropenia	Incidence of unfavourable clinical course, defined as any of the following: recurrence of fever, clinical instability (see below definition), admission to the intensive care unit, new positive blood culture collected after randomisation, or death	During the same episode of neutropenia, up to 28 days post-enrolment.
Secondary	Fever recurrence	Incidence of fever recurrence (temperature =38 degrees Celsius)	Up to 28 days post-enrolment
Secondary	Clinical instability	Incidence of clinical instability defined as; one or more vital signs (conscious state, respiratory rate, blood pressure, heart rate, oxygen saturation) meeting mandatory emergency (MET) call criteria OR two or more vital signs simultaneously (within 4 hours of each other) meeting clinical review criteria.	Up to 28 days post-enrolment
Secondary	Admission to intensive care unit (ICU)	Incidence of admission to intensive care unit (all cause)	Up to 28 days post-enrolment
Secondary	New positive blood culture	Incidence of positive blood culture	Up to 28 days post-enrolment
Secondary	28 day all-cause and infection-related mortality	Incidence of all-cause and infection-related mortality, as defined post-mortem	Up to 28 days post-enrolment
Secondary	Duration of neutropenia	Mean days of neutropenia defined as ANC <500 cells/mm3	During the same episode of neutropenia or up to 28 days post-enrolment
Secondary	Clinician confidence and acceptability	Measured by number of patients for which randomisation is overridden in the Early Stopping arm and the recorded reason	Up to 28 days post-enrolment
Secondary	Total antibiotic duration	Mean number of days antibiotics are administered	Up to 28 days post-enrolment
Secondary	Length of hospital stay	Mean number of days admitted to the study site hospital ward	Up to 28 days post-enrolment, or until discharge from hospital (whichever is the later)
Secondary	Readmission to hospital	Incidence of unplanned admission to the study site hospital	Up to 28 days post-enrolment
Secondary	Development of C. difficile infection	Incidence of C. difficile infection detected in unformed stool	Up to 28 days post-enrolment
Secondary	Development of an antibiotic resistant infection or colonisation	Incidence of antibiotic resistant infection or colonisation including Methicillin-resistant Staphylococcus aureus (MRSA), extended spectrum beta-lactamases (ESBL)-producing enterobacterales, carbapenem-resistant enterobacteriaceae (CRE), Vancomycin-resistant Enterococcus (VRE)	Up to 28 days post-enrolment
Secondary	Patient/parent/caregiver confidence	Number of patients that consent to study as proportion of patients eligible	Within 48 hours of having informed consent discussion with the study team
Secondary	Patient/parent/caregiver acceptability	Number of patients for which randomisation is overridden in the Early Stopping arm due to withdrawn consent	Within 48-96 hours post assignment to intervention arm