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

Sponsor

Murdoch Childrens Research Institute (Other)

Overall Status

Recruiting

CT.gov ID

NCT04948463

Collaborator

(none)

312

Enrollment

Location

Arms

32.5

Anticipated Duration (Months)

9.6

Patients Per Site Per Month

Study Details

Study Description

Brief 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).

Condition or Disease	Intervention/Treatment	Phase
Febrile Neutropenia	Drug: Piperacillin and Tazobactam for Injection Drug: Cefepime Injection Drug: Ceftazidime Injection Drug: Vancomycin Injection Drug: Amikacin Injection Drug: Ciprofloxacin Drug: Piperacillin and Tazobactam for Injection Drug: Cefepime Injection Drug: Ceftazidime Injection Drug: Vancomycin Injection Drug: Amikacin Injection Drug: Ciprofloxacin	Phase 4

Detailed 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

312 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Nov 15, 2021

Anticipated Primary Completion Date :

Jul 1, 2024

Anticipated Study Completion Date :

Aug 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Early Stopping Stopping empiric FN antibiotics after resolution of fever for 48 hours, irrespective of absolute neutrophil count (ANC)	Drug: 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. Drug: Cefepime Injection If non life-threatening hypersensitivity (preferred option) at 50mg/kg (max 2g) 8 hourly, stopping 48 hours post-fever resolution Drug: Ceftazidime Injection If non life-threatening hypersensitivity (second option) at 50mg/kg (max 2g) 8 hourly, stopping 48 hours post-fever resolution Drug: Vancomycin Injection If life-threatening hypersensitivity given with ciprofloxacin at 15mg/kg (max 500mg) 6 hourly, stopping 48 hours post-fever resolution Drug: Amikacin Injection At 18-22.5mg/kg (max 1.5g) daily in combination with other antibiotic/s, stopping 48 hours post-fever resolution Drug: Ciprofloxacin If life-threatening hypersensitivity given with vancomycin at 10 mg/kg (max 400 mg) 12 hourly, stopping 48 hours post-fever resolution
Active Comparator: Standard of care 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	Drug: Piperacillin and Tazobactam for Injection Given if patient has no known allergies, until ANC recovery at 100mg/kg (max 4g) 6 hourly. Drug: Cefepime Injection Given if patient has non life-threatening hypersensitivity (preferred option), until ANC recovery at 50mg/kg (max 2g) 8 hourly. Drug: Ceftazidime Injection If non life-threatening hypersensitivity (second option), given until ANC recovery at 50mg/kg (max 2g) 8 hourly Drug: Vancomycin Injection If life-threatening hypersensitivity given with ciprofloxacin, given until ANC recovery at 15mg/kg (max 500mg) 6 hourly Drug: Amikacin Injection Given until ANC recovery at 18-22.5mg/kg (max 1.5g) daily in combination with other antibiotic/s. Drug: Ciprofloxacin If life-threatening hypersensitivity given with vancomycin, given until ANC recovery at 10 mg/kg (max 400 mg) 12 hourly

Arm

Intervention/Treatment

Experimental: Early Stopping

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

Drug: 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.

Drug: Cefepime Injection

If non life-threatening hypersensitivity (preferred option) at 50mg/kg (max 2g) 8 hourly, stopping 48 hours post-fever resolution

Drug: Ceftazidime Injection

If non life-threatening hypersensitivity (second option) at 50mg/kg (max 2g) 8 hourly, stopping 48 hours post-fever resolution

Drug: Vancomycin Injection

If life-threatening hypersensitivity given with ciprofloxacin at 15mg/kg (max 500mg) 6 hourly, stopping 48 hours post-fever resolution

Drug: Amikacin Injection

At 18-22.5mg/kg (max 1.5g) daily in combination with other antibiotic/s, stopping 48 hours post-fever resolution

Drug: Ciprofloxacin

If life-threatening hypersensitivity given with vancomycin at 10 mg/kg (max 400 mg) 12 hourly, stopping 48 hours post-fever resolution

Active Comparator: Standard of care

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

Drug: Piperacillin and Tazobactam for Injection

Given if patient has no known allergies, until ANC recovery at 100mg/kg (max 4g) 6 hourly.

Drug: Cefepime Injection

Given if patient has non life-threatening hypersensitivity (preferred option), until ANC recovery at 50mg/kg (max 2g) 8 hourly.

Drug: Ceftazidime Injection

If non life-threatening hypersensitivity (second option), given until ANC recovery at 50mg/kg (max 2g) 8 hourly

Drug: Vancomycin Injection

If life-threatening hypersensitivity given with ciprofloxacin, given until ANC recovery at 15mg/kg (max 500mg) 6 hourly

Drug: Amikacin Injection

Given until ANC recovery at 18-22.5mg/kg (max 1.5g) daily in combination with other antibiotic/s.

Drug: Ciprofloxacin

If life-threatening hypersensitivity given with vancomycin, given until ANC recovery at 10 mg/kg (max 400 mg) 12 hourly

Outcome Measures

Primary Outcome Measures

Unfavourable clinical course occurring during the same period of severe neutropenia [During the same episode of neutropenia, up to 28 days post-enrolment.]
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

Secondary Outcome Measures

Fever recurrence [Up to 28 days post-enrolment]
Incidence of fever recurrence (temperature ≥38 degrees Celsius)
Clinical instability [Up to 28 days post-enrolment]
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.
Admission to intensive care unit (ICU) [Up to 28 days post-enrolment]
Incidence of admission to intensive care unit (all cause)
New positive blood culture [Up to 28 days post-enrolment]
Incidence of positive blood culture
28 day all-cause and infection-related mortality [Up to 28 days post-enrolment]
Incidence of all-cause and infection-related mortality, as defined post-mortem
Duration of neutropenia [During the same episode of neutropenia or up to 28 days post-enrolment]
Mean days of neutropenia defined as ANC <500 cells/mm3
Clinician confidence and acceptability [Up to 28 days post-enrolment]
Measured by number of patients for which randomisation is overridden in the Early Stopping arm and the recorded reason
Total antibiotic duration [Up to 28 days post-enrolment]
Mean number of days antibiotics are administered
Length of hospital stay [Up to 28 days post-enrolment, or until discharge from hospital (whichever is the later)]
Mean number of days admitted to the study site hospital ward
Readmission to hospital [Up to 28 days post-enrolment]
Incidence of unplanned admission to the study site hospital
Development of C. difficile infection [Up to 28 days post-enrolment]
Incidence of C. difficile infection detected in unformed stool
Development of an antibiotic resistant infection or colonisation [Up to 28 days post-enrolment]
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)
Patient/parent/caregiver confidence [Within 48 hours of having informed consent discussion with the study team]
Number of patients that consent to study as proportion of patients eligible
Patient/parent/caregiver acceptability [Within 48-96 hours post assignment to intervention arm]
Number of patients for which randomisation is overridden in the Early Stopping arm due to withdrawn consent

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of

Acute myeloid leukemia (AML) or acute lymphoblastic leukaemia (ALL) in dose-intensive phases of induction/re-induction, intensification or consolidation or
Lymphoma in induction or
Any disease within 30 days of allogeneic or autologous HSCT

Neutropenia (<500 cells/mm3)
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)
Commenced on empiric FN antibiotics (any of piperacillin-tazobactam, cefepime, ceftazidime or vancomycin and ciprofloxacin)

Exclusion Criteria:

Prolonged febrile neutropenia (documented daily temperature ≥38.0°C for ≥7 day)
Documented positive blood culture since onset of FN episode and prior to randomisation
Documented other infection (microbiologically or clinically documented) requiring antibiotic treatment since onset of FN episode and prior to randomisation
Admitted to the ICU at the time of randomisation
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)
Within 28 days of last randomisation