Early Versus Late Stopping of Antibiotics in Adults With High-risk Hematological Malignancies/Receiving Cellular Therapies and Fever (ELSA-Adult)

Early Versus Late Stopping of Antibiotics in Adults With High Risk Haematological Malignancies/Receiving Cellular Therapies and Fever (ELSA- Adult)

Pre-neutropenic fever (PNF) (fever following chemotherapy but before developing low white cells) and neutropenic fever (NF) (fever in the setting of low white cells) are very common after chemotherapy for acute leukemia, bone marrow transplantation or Chimeric Antigen Receptor T-cell (CAR T) therapy. Often, there is no bacterial cause for fever found, and in the setting of a well patient with resolved fever, some studies have shown it to be safe to cease antibiotic therapy which was commenced at the onset of fever. This reduces the overall exposure to antibiotics, which can be beneficial to the patient (reduced risk of resistant bugs emerging, reduced serious side effects). However, some subgroups of high-risk patients have been underrepresented in these studies (in particular, those who have received a bone marrow transplant from a donor, those with longer duration of low white cells) and none have been performed in Australia, hence applying this data to our setting and patient groups is indirect and further data are needed. This study plans to recruit participants who have received chemotherapy for acute leukemia or a stem cell transplant (either their own cells or a donor's cells) or CAR T-cell therapy and perform a trial to compare early stopping of antibiotics (STOP arm) to the standard of care, which traditionally involves continuing antibiotics until the white cell count reaches above a specific threshold. The primary study outcome is duration of days free of antibiotics within 28 days of study allocation. The investigators will also observe for important clinical outcomes including rates of fever recurrence, bloodstream and other infections, intensive care admission and mortality. Patients will stay in hospital during this period, even in the setting of stopping antibiotics, and these antibiotics can be recommenced urgently according to the sepsis protocol if there is concern for infection.

Study Overview

• Status: Recruiting
• Conditions: Leukemia; CART Therapy; Infections, Bacterial; Transplantation, Stem Cell
• Intervention / Treatment: Drug: Early antibiotic cessation alert

Detailed Description

This study is designed to assess the safety, benefits and impacts of early cessation of empiric antibiotics in all fever (both pre-neutropenic (PNF) and neutropenic (NF)) that develops post conditioning or chemotherapy until count recovery in high-risk hematology patients who meet clear inclusion criteria. This is in recognition of the fact that both PNF and NF are often not infective in nature, and that cessation is likely an important and safe approach in both scenarios. Secondly, the patient's pre-neutropenic and neutropenic status is highly fluid and can rapidly change from one to the other (within a day), making strict definitions of neutropenia arbitrary and not particularly useful for implementation in the clinical setting. Furthermore, as a programmatic-type intervention that is embedded in clinical workflow, approaching high-risk patients with fever in a standardized way would enable consistency and inform clear and concise management protocols. Stratification will allow for assessment of each patient sub-group to provide more granular data.

As an Australian first, this study will exploit the full potential of electronic medical record (EMR) systems, embedding all key aspects of the trial including screening, randomization and data collection into standard clinical and EMR workflows. This highly novel and innovative clinical trial methodology has the potential to improve trial efficiency, data quality and transferability between healthcare centers and will systematically evaluate the barriers and enablers of embedded trials (ELSA-EMR).

The study hypothesizes that early cessation of antibiotics in adult patients with high risk fever is safe, acceptable, cost-effective and will minimize an unnecessarily prolonged health care intervention

• Study Type: Interventional
• Enrollment (Estimated): 214
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Principal Investigator; Phone Number: +61448503643; Email: infectiousdiseases.clinicaltrials@petermac.org

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Recruiting
      • Peter Maccallum Cancer Centre
      • Contact: Infectious Diseases Clinical Trials team; Phone Number: +61448503643; Email: infectiousdiseases.clinicaltrials@petermac.org
      • Principal Investigator: Abby Douglas, MBBS PhD FRACP
    • Melbourne, Victoria, Australia, 3050
      • Recruiting
      • Royal Melbourne Hospital
      • Contact: Infectious Diseases Clinical Trials team; Phone Number: +61448503643; Email: infectiousdiseases.clinicaltrials@petermac.org
      • Principal Investigator: Monica A Slavin, MD MBBS PhD FRACP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Adult patients ( ≥18 years) who are receiving either:

• Conditioning chemotherapy for an autologous or allogeneic haematopoietic cell transplant or CAR T cell therapy, OR
• Induction remission chemotherapy for acute leukaemia,

AND develop fever ( ≥38degC) between time of initiation of chemotherapy/conditioning administration and ANC recovery to ≥500 cells/mm3 post the ANC nadir,

AND fever subsequently has settled (<38degC) for ≥48 and <96h hours.

[participants will be stratified into pre-neutropenic (ANC ≥500 cells/mm3) and neutropenic (ANC<500 cells/mm3) strata based on ANC level at 48 hours post fever onset, as per international consensus definition of neutropenic fever]

Exclusion Criteria:

• - Prolonged fever prior to defervescence (documented daily temperature ≥38.0°C for ≥ 5 days)
• Documented positive blood culture for bacteria since onset of fever episode and prior to randomisation
• Documented other infection (clinically or microbiologically defined) requiring antibacterial treatment
• Grade 2 or higher mucositis (WHO) or neutropenic enterocolitis
• Clinically unstable and/or admission to ICU at time of potential randomization
• Within 28 days of last randomization
• Prior randomization during current chemotherapy/conditioning cycle
• Pregnant or breastfeeding
• Currently being treated for CRS Grade 3 or 4, and/or ICANS Grade 3 or 4 (defined as per ASTCT Consensus Guidelines, Lee et al)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: STOP - early discontinuation of empiric antibiotic therapy; Short course antibiotics (STOP): Antibiotics will be commenced at onset of fever and stopped once afebrile for 48-96 hours and clinically stable.	Drug: Early antibiotic cessation alert; For all patients, antibiotics will be commenced at onset of fever. For those in the intervention arm an alert will fire in the electronic medical record once a patient is afebrile for 48-96 hours and clinically stable.
No Intervention: SOC - standard of care continuation of empiric antibiotic therapy; Standard of care (SOC): Antibiotics will be commenced at onset of fever and continued for a duration as per clinician's discretion, typically until resolution of fever, clinical recovery and ANC ≥200- 500 cells/mm3.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days free of antibiotic therapy in 28 days post randomization (termed empiric antibiotic free days (EAFDs))	The primary study outcome is duration of days free of antibiotics within 28 days of study allocation. Measured as antibiotic free days in last 28 days post fever onset	28 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days alive and free of antibiotic therapy in 28 days post randomization	Days alive and free of antibiotic therapy in 28 days post randomization	28 days after randomization
Recurrence of fever (>38deg Celsius) beyond randomization	Recurrence of fever (>38deg Celsius, confirmed on second reading within 1 hour) post randomization during the same episode of neutropenia, not associated with blood product transfusion; In CAR T treated patients, grade of cytokine release syndrome (CRS), immune-cell associated neurotoxicity (ICANS) at time of fever and any recurrent fever.	same episode of neutropenia - until ANC>500 cells/mm3
Number of occasions antibiotic therapy is recommenced with treatment intent	Number of events antibiotic therapy is recommenced with treatment intent (excluding prophylaxis)	Within 28 days after randomization
Days of antibiotic therapy during neutropenic period	Days of antibiotic therapy during neutropenic period until ANC>500 cells/mm3	Neutropenic period - until ANC>500 cells/mm3
Number of intensive care unit (ICU) admissions	Admission to intensive care for organ support during the same pre-neutropenic and neutropenic period post randomization	pre-neutropenic and neutropenic period post randomization (until ANC>500 cells/mm3)
Number of events of clinical instability	Number of events of clinical instability (defined by blood pressure, oxygen saturations, respiratory rate and heart rate meeting at least 1 Medical Emergency Team (MET) call criteria or 2 clinical review criteria)	28 days after randomization
Number of events of new positive blood culture	Number of events of new positive blood culture post randomization (defined by CDC criteria)	28 days after randomization
28 day all-cause mortality and infection-related mortality	28 day all-cause mortality and infection-related mortality (as assessed by an independent data safety monitoring board)	28 days after randomization
Measure number of patient days of total hospital admission	Duration of in-hospital length of stay calculated from randomization date and time to discharge from hospital ward or Hospital-In-The-Home (HITH)	Measure number of days of total hospital length of stay during enrolment (admission until discharge from hospital inpatient and HITH)
Total number of days of in-hospital length of stay	Duration of in-hospital length of stay calculated from randomization date and time to discharge/transfer from in- hospital ward	Total number of days of in-hospital length of stay
Total hospital length of stay post randomisation	Duration of in-hospital length of stay calculated from randomization date and time to discharge from hospital ward or HITH	Total hospital length of stay post randomization to discharge (from ward or HITH)
Number of unplanned hospital readmissions	Unplanned readmission to hospital within 60 days of randomization, defined as any admission that is not due to planned chemotherapy, conditioning or routine neutropenic monitoring as per standard protocols.	within 60 days of randomization
Number of positive C.difficile infections	Number of development of C.difficile infection (defined by diarrhea, positive toxin polymerase chain reaction (PCR) and lack of other cause) within 6 months of randomization	within 6 months of randomization
Number of antibiotic resistant infection or colonizations	New antibiotic resistant (Methicillin-resistant Staphylococcus aureus (MRSA), Extended-Spectrum Beta-Lactamases (ESBL) producing Enterobacterales, Carbapenem-resistant Enterobacterales (CRE), Vancomycin-resistant Enterococcus (VRE) infection or colonization detected within 180 days post randomization	within 180 days post randomization
Number of Clinically defined infections during pre-neutropenic and neutropenic period	Number of Clinically defined infections during pre-neutropenic and neutropenic period	pre-neutropenic and neutropenic period until ANC>500 cells/mm3
Number of clinically defined infections post randomization	Number of clinically defined infections post randomization	post randomization until 28days
Number of microbiologically defined infections during pre-neutropenic and neutropenic period	Number of microbiologically defined infections during pre-neutropenic and neutropenic period	during pre-neutropenic and neutropenic period until ANC>500 cells/mm3
Number of microbiologically defined infections post randomization	Number of microbiologically defined infections post randomisation	post randomization until 28days

Collaborators and Investigators

• Sponsor: Peter MacCallum Cancer Centre, Australia
• Collaborators: Melbourne Health
• Investigators: Principal Investigator: Abby P Douglas, MBBS PhD FRACP, Peter MacCallum Cancer Centre; National Centre for Infections in Cancer

Study record dates

Study Major Dates

• Study Start (Actual): December 3, 2025
• Primary Completion (Estimated): December 5, 2027
• Study Completion (Estimated): February 5, 2028

Study Registration Dates

• First Submitted: April 21, 2025
• First Submitted That Met QC Criteria: June 25, 2025
• First Posted (Actual): July 4, 2025

Study Record Updates

• Last Update Posted (Actual): December 15, 2025
• Last Update Submitted That Met QC Criteria: December 7, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Febrile neutropenia; EPIC; ELSA; Febrile neutropaenia; antibitoics
• Additional Relevant MeSH Terms: Cytopenia; Neoplasms; Infections; Neoplasms by Histologic Type; Leukocyte Disorders; Hematologic Diseases; Bacterial Infections and Mycoses; Leukopenia; Agranulocytosis; Neutropenia; Hemic and Lymphatic Diseases; Leukemia; Febrile Neutropenia; Bacterial Infections; Anti-Infective Agents; Anti-Bacterial Agents
• Other Study ID Numbers: 24/236; 2024.406 (Other Identifier: Royal Melbourne Hospital Research Office); ERM113654 (Other Identifier: Peter MacCallum Cancer Centre)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No