Clinical trial NCT04948463: Early Versus Late Stopping of Antibiotics in Children With Cancer and High-risk Febrile Neutropenia
Official title: Early Versus Late Stopping of Antibiotics in Children With Cancer and High-risk Febrile Neutropenia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Febrile Neutropenia
Keywords: Febrile Neutropenia
Cancer
Haematopoietic Stem Cell Transplantation (HSCT)
Lead sponsor: Murdoch Childrens Research Institute
Sponsor class: OTHER
First posted: 2021-07-02
Enrollment: 312
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Unfavourable clinical course occurring during the same period of severe neutropenia
timeFrame: During the same episode of neutropenia, up to 28 days post-enrolment.
Secondary outcomes:
measure: Fever recurrence
timeFrame: Up to 28 days post-enrolment
measure: Clinical instability
timeFrame: Up to 28 days post-enrolment
measure: Admission to intensive care unit (ICU)
timeFrame: Up to 28 days post-enrolment
measure: New positive blood culture
timeFrame: Up to 28 days post-enrolment
measure: 28 day all-cause and infection-related mortality
timeFrame: Up to 28 days post-enrolment
measure: Duration of neutropenia
timeFrame: During the same episode of neutropenia or up to 28 days post-enrolment
measure: Clinician confidence and acceptability
timeFrame: Up to 28 days post-enrolment
measure: Total antibiotic duration
timeFrame: Up to 28 days post-enrolment
measure: Length of hospital stay
timeFrame: Up to 28 days post-enrolment, or until discharge from hospital (whichever is the later)
measure: Readmission to hospital
timeFrame: Up to 28 days post-enrolment
measure: Development of C. difficile infection
timeFrame: Up to 28 days post-enrolment
measure: Development of an antibiotic resistant infection or colonisation
timeFrame: Up to 28 days post-enrolment
measure: Patient/parent/caregiver confidence
timeFrame: Within 48 hours of having informed consent discussion with the study team
measure: Patient/parent/caregiver acceptability
timeFrame: Within 48-96 hours post assignment to intervention arm
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: Royal Children's Hospital
state: Victoria
Study officials:
affiliation: Murdoch Childrens Research Institute
name: Gabrielle Haeusler
role: PRINCIPAL_INVESTIGATOR
References: