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

PHASE4RECRUITING

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).

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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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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
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    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

    Study type

    TREATMENT

    phase

    Phase

      PHASE4

    trial

    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
    Image related to Febrile Neutropenia
    • Condition: Febrile Neutropenia

    • DRUG: Piperacillin and Tazobactam for Injection and other drugs

    • Melbourne, Victoria, Australia

    • Sponsor: Murdoch Childrens Research Institute

    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

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    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/ArmIntervention/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.
    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.

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Unfavourable clinical course occurring during the same period of severe neutropeniaIncidence 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 deathDuring the same episode of neutropenia, up to 28 days post-enrolment.

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    Fever recurrenceIncidence of fever recurrence (temperature ≥38 degrees Celsius)Up to 28 days post-enrolment
    Clinical instabilityIncidence 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 cultureIncidence of positive blood cultureUp to 28 days post-enrolment
    28 day all-cause and infection-related mortalityIncidence of all-cause and infection-related mortality, as defined post-mortemUp to 28 days post-enrolment
    Duration of neutropeniaMean days of neutropenia defined as ANC \<500 cells/mm3During the same episode of neutropenia or up to 28 days post-enrolment
    Clinician confidence and acceptabilityMeasured by number of patients for which randomisation is overridden in the Early Stopping arm and the recorded reasonUp to 28 days post-enrolment
    Total antibiotic durationMean number of days antibiotics are administeredUp to 28 days post-enrolment
    Length of hospital stayMean number of days admitted to the study site hospital wardUp to 28 days post-enrolment, or until discharge from hospital (whichever is the later)
    Readmission to hospitalIncidence of unplanned admission to the study site hospitalUp to 28 days post-enrolment
    Development of C. difficile infectionIncidence of C. difficile infection detected in unformed stoolUp to 28 days post-enrolment
    Development of an antibiotic resistant infection or colonisationIncidence 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 confidenceNumber of patients that consent to study as proportion of patients eligibleWithin 48 hours of having informed consent discussion with the study team
    Patient/parent/caregiver acceptabilityNumber of patients for which randomisation is overridden in the Early Stopping arm due to withdrawn consentWithin 48-96 hours post assignment to intervention arm

    Frequently Asked Questions

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    References

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

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