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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

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

Conditions
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Febrile Neutropenia

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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 ALL or acute lymphoblastic lymphoma patients on a TOT17 protocol or Any disease within 100 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 ≥5 days) 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

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fever recurrence | Incidence of fever recurrence (temperature ≥38 degrees Celsius) | Up to 28 days post-enrolment | 
| 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 | 
| Admission to intensive care unit (ICU) | Incidence of admission to intensive care unit (all cause) | Up to 28 days post-enrolment | 
| New positive blood culture | Incidence of positive blood culture | Up to 28 days post-enrolment | 
| 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 | 
| 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 | 
| 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 | 
| Total antibiotic duration | Mean number of days antibiotics are administered | Up to 28 days post-enrolment | 
| 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) | 
| Readmission to hospital | Incidence of unplanned admission to the study site hospital | Up to 28 days post-enrolment | 
| Development of C. difficile infection | Incidence of C. difficile infection detected in unformed stool | Up to 28 days post-enrolment | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Febrile Neutropenia, Cancer, Haematopoietic Stem Cell Transplantation (HSCT)