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Early Versus Late Stopping of Antibiotics in Children With Cancer and High-risk Febrile Neutropenia
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).
Study details:
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.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
Exclusion criteria
Eligibility
Age eligible for study : 0 and older
Healthy volunteers accepted : No
Gender eligible for study: All
Things to know
Study dates
Study start: 2021-11-15
Primary completion: 2026-07-01
Study completion finish: 2026-08-01
Study type
TREATMENT
Phase
PHASE4
Trial ID
NCT04948463
Intervention or treatment
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
Conditions
- • Febrile Neutropenia
Find a site
Closest Location:
Royal Children's Hospital
Research sites nearby
Select from list below to view details:
Royal Children's Hospital
Melbourne, Victoria, Australia
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Participant Group/Arm | Intervention/Treatment |
---|---|
EXPERIMENTAL: Early Stopping
| DRUG: Piperacillin and Tazobactam for Injection
|
ACTIVE_COMPARATOR: Standard of care
| DRUG: Piperacillin and Tazobactam for Injection
|
What is the study measuring?
Primary outcome
Primary Outcome Measure | Primary Outcome Description | Primary Outcome 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
Secondary Outcome Measure | Secondary Outcome Description | Secondary Outcome 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 |
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