Febrile Neutropenia
Conditions
Keywords
Febrile Neutropenia, Cancer, Haematopoietic Stem Cell Transplantation (HSCT)
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).
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.
Interventions
DRUGPiperacillin and Tazobactam for Injection
Given if patient has no known allergies, until ANC recovery at 100mg/kg (max 4g) 6 hourly.
Given if patient has non life-threatening hypersensitivity (preferred option), until ANC recovery at 50mg/kg (max 2g) 8 hourly.
If non life-threatening hypersensitivity (second option), given until ANC recovery at 50mg/kg (max 2g) 8 hourly
If life-threatening hypersensitivity given with ciprofloxacin, given until ANC recovery at 15mg/kg (max 500mg) 6 hourly
Given until ANC recovery at 18-22.5mg/kg (max 1.5g) daily in combination with other antibiotic/s.
DRUGCiprofloxacin
If life-threatening hypersensitivity given with vancomycin, given until ANC recovery at 10 mg/kg (max 400 mg) 12 hourly
Sponsors
Murdoch Childrens Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
Australia
Contacts
PRINCIPAL_INVESTIGATORGabrielle Haeusler
Murdoch Childrens Research Institute
Outcome results
None listed