An interventional study of Early Discontinuation of Antibiotics and Standard of Care in Febrile Neutropenia, sponsored by University Health Network, Toronto. Recruiting at 4 sites in Canada. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-07-17.
Sponsored by University Health Network, Toronto · Not applicable, Interventional, and Treatment
Infections are a common complication in patients with cancer. They are a significant cause of complications and death in this population. Patients with cancer and low neutrophil counts due to chemotherapy or disease often have a fever and receive antibiotic treatment. The optimal duration of this treatment is largely unknown. Late, there have been some data suggesting the safety of early discontinuation of antibiotics, though most centers still give more prolonged antibiotic therapies in this situation. The unnecessary prolonged antibiotic use may increase infections with multi-drug-resistant bacteria, which carry a high death rate. Also, an increase in infections caused by Clostridioides difficile and an increase in fungal infections can happen. However, some are concerned that stopping antibiotics while the neutrophil count is still low will result in life-threatening infections. Our study aims to test whether shorter antibiotic treatment in these situations is as safe as more prolonged treatment, resulting in better antibiotic prescription practices in this population.
Background Febrile neutropenia is a common complication of chemotherapy-induced neutropenia and neutropenia related to the disease. It occurs in 80% of patients with hematological malignancies with a significant impact on morbidity and mortality. The issue of antibiotic treatment duration in febrile neutropenia is unresolved. The rationale for continuing antibiotics until neutrophil recovery is based on the concern that neutropenic patients may have an ongoing risk of life-threatening infection, and neutropenia may conceal classical manifestations of infection. On the other hand, prolonged broad-spectrum antibiotic treatment has been associated with the emergence of antibiotic resistance, Clostridioides difficile infection and invasive fungal infections, as well as adverse effects and allergic reactions. The evidence suggesting the beneficial effects of prolonged antibiotic treatment is derived from 2 small randomized controlled trials (RCTs) from the 1970s, which showed an increase in infections and mortality with early stoppage of antibiotics. Two recently done RCTs, the HOW LONG and the SHORT studies, suggested that early discontinuation of antibiotics is feasible and is not associated with adverse outcomes. However, the first was not powered for safety outcomes and the second included a lower-risk population and a de-escalation strategy. Despite these reassuring studies, most centres still utilize the resolution of neutropenia as one of the criteria for stopping antibiotics in patients with febrile neutropenia.
Objective This pilot RCT will assess the feasibility of conducting a full future RCT. In the full trial, the investigators will compare early antibiotic discontinuation to the continuation of antibiotics until the resolution of neutropenia in high-risk febrile neutropenic patients, aiming to prove non-inferiority.
Methods The investigators will conduct a pilot open-label, multicentre RCT involving centres in Canada and Israel. The investigators will include adult patients with acute leukemia or patients undergoing allogeneic hematopoietic stem-cell transplantation diagnosed with febrile neutropenia of unknown source. Patients who have received antibiotics for at least 72 hours and are still neutropenic will be recruited if afebrile for at least 24 hours. Patients will be randomized to either early discontinuation or prolonged treatment in a 1:1 ratio using stratified, permuted block randomization. Patients randomized to the intervention arm will have antibiotics stopped at randomization, whereas those in the control group will receive antibiotics until resolution of neutropenia. The outcomes for this pilot study will be to assess the recruitment rate and understand the barriers to obtaining physician and patient consent; assess adherence to the allocated intervention and understand the reasons for crossovers; and measure primary outcome data for sample size re-estimation. This trial will serve as an internal pilot and the outcome data generated will contribute to the full trial. The primary outcome of the full trial will be a composite of all-cause mortality, transfer to intensive care units, or any clinically or microbiologically documented infection.
396 studies on the registry are indexed under Neutropenia; 57 are open to participants now.
This study's planned enrollment of 80 is below the median of 93 across 276 interventional studies indexed under Neutropenia.
Browse Neutropenia studies →University Health Network, Toronto is the lead sponsor of 1,411 studies on the registry; 292 are open to participants now.
Of its 17 completed or terminated interventional studies of FDA-regulated products, 3 (18%) have results posted.
Counted across the registry records on this site, refreshed daily.
Documented febrile neutropenia as defined by the IDSA guidelines [1]:
Patient without a clinically or microbiologically documented infection (CDI/MDI).
We will require the following criteria to rule out infection:
The subject will comply with the following criteria:
Exclusion Criteria:
Antibiotic treatment will be stopped at the time of allocation to the intervention group
Other: Early Discontinuation of Antibiotics
Antibiotic treatment will be continued until the resolution of neutropenia (ANC \> 0.5x109/L)
Other: Standard of Care
Antibacterial treatment (i.e piperacillin/tazobactam, ceftazidime, cefepime, meropenem, vancomycin, amikacin, tobramycin, ciprofloxacin) will be stopped after 72 hours of treatment and defervescence for 24 hours, irrespective of neutrophil count
Antibacterial treatment (i.e piperacillin/tazobactam, ceftazidime, cefepime, meropenem, vancomycin, amikacin, tobramycin, ciprofloxacin) will be continued until resolution of neutropenia
Recruitment
number of patients enroled per site per month
Time frame: through study completion, approximately 2 years
Adherence
percentage of participants that adhered to the allocated intervention (meaning they stopped antibiotics within 2 days of the intervention they were randomized to)
Time frame: 30 days from randomization
Complete outcome data
percentage of participants that were lost to follow up
Time frame: 30 days from randomization
Rate of all-cause mortality
All-cause mortality
Time frame: 30 days from randomization
Rate of transfer to the ICU
transfer to the intensive care unit will be derived from the participant's electronic health record
Time frame: 30 days from randomization
Rate of any clinically or microbiologically documented infection
any clinically diagnosed infection (i.e pneumonia, intra-abdominal infection, skin-soft tissue infection when no bacteria was isolated) or any microbiologically documented infection (isolation of a bacteria/fungi from a sterile site with the exception of blood contaminants in a single blood culture or isolation of bacteria/fungi from a non-sterile site accompanied by a clinical syndrome). This will not include viral infections.
Time frame: 30 days from randomization
Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR) analysis
DOOR for our study will be (ordinal outcome scale): 1. The participant survived until day 30 without CDI, MDI or being transferred to ICU. 2. The participant had a CDI or MDI but was not transferred to ICU, and they survived. 3. The participant was transferred to ICU but survived. 4. Death.
Time frame: 30 days from randomization
total febrile days
total febrile days
Time frame: 30 days from randomization
total antibiotic free days
total antibiotic free days
Time frame: 30 days from randomization
recurrent fever resulting in restarting antibiotics
recurrent fever resulting in restarting antibiotics
Time frame: 30 days from randomization
Rate of Clostridioides difficile associated diarrhea
loose stool (based on Bristol chart) and positive test for C. difficile in stool
Time frame: 30 days from randomization
total in-hospital days
total in-hospital days
Time frame: 30 days from randomization
readmission
readmission rates for any reason other than planned chemotherapy
Time frame: 30 days from randomization
mold-active antifungal treatment
days of therapy with voriconazole, posaconazole, isavuconazole, echinocandins, amphotericin
Time frame: 30 days from randomization
Development of an antibiotic resistant infection or colonization
defined as clinical isolates resistant to antibiotics previously used in the febrile episode or isolation of any of the bacteria below: extended-spectrum β-lactamase (ESBL) producing Enterobacterales, carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant Pseudomonas, carbapenem-resistant Acinetobacter baumannii, Stenotrophomonas maltophilia, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) in both clinical and surveillance sampling
Time frame: 30 days from randomization
Rate of adverse events
adverse events
Time frame: 30 days from randomization
diversity of gut microbiome
diversity of gut microbiome will be measured using the Shannon index
Time frame: 30 days from randomization
cost-effectiveness analysis
will acquire patient-level in-hospital costs from the finance departments of the participating hospitals
Time frame: 30 days from randomization
Plan to share: Yes — The study protocol and statistical analysis plan will be shared directly after publication. Individual participant data that underlie the results reported in the article will be made available, after deidentification (text, tables, figures, and appendices), for other scientific research approved by an ethical board from 6 months until 24 months after article publication. The data will only be shared to achieve the aims of the approved proposal. Proposals should be directed to the Steering Committee of the clinical trial. Data requestors need to sign a data access agreement to gain access. After 24 months, the data will be available at the UHN without investigator support besides deposited metadata.
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