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

Murdoch Childrens Research Institute

Status and phase: Enrolling; Phase 4

Conditions: Febrile Neutropenia

Treatments: Drug: Ceftazidime Injection; Drug: Piperacillin and Tazobactam for Injection; Drug: Cefepime Injection; Drug: Vancomycin Injection; Drug: Ciprofloxacin; Drug: Amikacin Injection

Study type: Interventional

Funder types: Other

Identifiers

NCT04948463

74690

Details and patient eligibility

About

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).

Full 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.

Enrollment: 312 estimated patients

Sex: All

Ages: Under 18 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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312 participants in 2 patient groups

Early Stopping

Experimental group

Description:

Stopping empiric FN antibiotics after resolution of fever for 48 hours, irrespective of absolute neutrophil count (ANC)

Treatment:

Drug: Amikacin Injection

Drug: Amikacin Injection

Drug: Cefepime Injection

Drug: Ciprofloxacin

Drug: Vancomycin Injection

Drug: Ceftazidime Injection

Drug: Vancomycin Injection

Drug: Cefepime Injection

Drug: Ciprofloxacin

Drug: Piperacillin and Tazobactam for Injection

Drug: Piperacillin and Tazobactam for Injection

Drug: Ceftazidime Injection

Standard of care

Active Comparator group

Description:

Continuing empiric FN antibiotics until resolution of fever for 48 hours and recovery of ANC as defined by the treating clinician but usually to ≥200-500/mm3

Treatment:

Drug: Amikacin Injection

Drug: Amikacin Injection

Drug: Cefepime Injection

Drug: Ciprofloxacin

Drug: Vancomycin Injection

Drug: Ceftazidime Injection

Drug: Vancomycin Injection

Drug: Cefepime Injection

Drug: Ciprofloxacin

Drug: Piperacillin and Tazobactam for Injection

Drug: Piperacillin and Tazobactam for Injection

Drug: Ceftazidime Injection