Early Versus Late Stopping of Antibiotics in Adults With High-risk Hematological Malignancies/Receiving Cellular Therapies and Fever
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 details:
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.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
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.
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)
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- NA
Study ID
NCT07051525
Intervention or treatment
DRUG: Early antibiotic cessation alert
Conditions
- Leukemia
- CART Therapy
- Transplantation, Stem Cell
- Infections, Bacterial
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Research sites nearby
Closest Location:
Peter MacCallum Cancer Centre
Select from list below to view details:
Peter MacCallum Cancer Centre
Melbourne, Victoria, Australia
Royal Melbourne Hospital
Melbourne, Victoria, Australia
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Who is running the clinical trial?
Peter MacCallum Cancer Centre, 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: STOP - early discontinuation of empiric antibiotic therapy
| Drug: Early antibiotic cessation alert |
NO_INTERVENTION: SOC - standard of care continuation of empiric antibiotic therapy
|
What is the study measuring?
Primary Outcome
| 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
| 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 |
References
Clinical Trials Gov: Early Versus Late Stopping of Antibiotics in Adults With High-risk Hematological Malignancies/Receiving Cellular Therapies and FeverOther trials to consider
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