Early Neutropenic Fever De-escalation of Antibiotics Study

Phase 3

Not yet recruiting

• Conditions: Antibiotic Stewardship; Hematologic Malignancy; Febrile Neutropenia
• Interventions: Drug: Cessation of antibiotics

• Registration Number: NCT06278896
• Lead Sponsor: Brigham and Women's Hospital

Brief Summary

This is a randomized, open label clinical trial among individuals with hematologic conditions. The trial aims to evaluate the safety and clinical outcomes of de-escalating antibiotic therapy among stable individuals diagnosed with neutropenic fever, in which no bacterial infection has been identified.

Detailed Description

Background:

The Infectious Disease Society of America (IDSA) guidelines for febrile neutropenia conflict with several other international guidelines on duration of antibiotic therapy in patients with febrile neutropenia without a documented infectious source. The IDSA recommends continuing antibiotic therapy until clear signs of marrow recovery, while other guidelines, including the European guidelines, allow for earlier discontinuation if no source of bacterial infection is identified. Benefits of earlier discontinuation of antibiotics include mitigating the risk of induction and amplification of antibiotic resistance, decreased disruption of the microbiome, as well as minimizing potential side effects and complications associated with long-term antibiotic use. To date the only randomized clinical trial in adults evaluating an abridged course of antibiotic therapy in high-risk patients with febrile neutropenia (defined as neutropenia for at least 7 days) was a superiority study that demonstrated fewer days of antibiotic use in the control arm. Safety data were a secondary outcome. Further research is needed to assess the safety and clinical outcomes of targeted antibiotic therapy for patients with febrile neutropenia.

Study Design:

This is a randomized, open label clinical trial among individuals with hematologic conditions. The trial aims to evaluate the safety and clinical outcomes of de-escalating antibiotic therapy among stable individuals diagnosed with neutropenic fever, in which no bacterial infection has been identified.

Treatment Regimen:

Intervention Arm (Arm A): Stop antibiotic therapy after episode of fever if afebrile for 48 hours, no clinically documented source of bacterial infection, and no hemodynamic or respiratory decompensation.

Control Arm (Arm B): Continue antibiotic therapy per IDSA guidelines until count recovery and/or standard of care as deemed by inpatient providers.

Study Participants:

The study population will comprise adults who have hematologic high-risk neutropenia (likely \> 7 days).

Study Timeline

• Study First Submitted: 2024-01-03
• Status Verified: 2024-02
• Study First Submitted QC: 2024-02-23
• Last Update Submitted: 2024-02-23
• Study First Posted: 2024-02-26
• Last Update Posted: 2024-02-26
• Study Start: 2024-03-01
• Primary Completion: 2026-03-01
• Study Completion: 2028-03-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 260

Inclusion Criteria

1. Participant or healthcare proxy with the ability to understand and willingness to sign an informed consent.
2. Adults >18 years old.
3. Likely to have neutropenia > 7 days including such conditions as: acute leukemia; lymphoproliferative disease; multiple myeloma; myelodysplastic syndrome; bone marrow aplasia and autologous or allogeneic hematopoietic stem cell transplantation. Neutropenia defined as absolute neutrophil count <500.
4. Received or planned to receive cytotoxic chemotherapy. No restrictions on prior therapy regarding dose or agent.
5. High-risk neutropenia defined as expected duration of absolute neutrophil count less than 500 cells/µL for seven or more days.
6. Admitted as an inpatient at Mass General Brigham or Dana Farber Cancer Institute (DFCI).
7. Initial fever (defined as a single oral temperature of ≥38.3°C or a temperature of ≥38.0°C sustained over a one-hour period) during hospital admission or as reason for admission.
8. Has been afebrile for 48 hours.

Exclusion Criteria

1. Microbiologically or clinically suspected bacterial infection after index fever.
2. Exposure to treatment antibacterial therapy 72 hours before first fever occurrence other than antibiotics deemed as prophylaxis.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intervention Arm	Cessation of antibiotics	Participants will stop empiric antibiotic therapy after their episode of fever if afebrile for 48 hours, no clinically documented source of bacterial infection, and no hemodynamic or respiratory decompensation.

Primary Outcome Measures

Name	Time	Method
Antibiotic utilization	60 days	To compare the days of antibiotic spectrum coverage (DASC), in each arm between randomization and count recovery.
Mortality, transfer to the ICU, septic shock, culture-confirmed bacteremia	60 days	To compare number of patients with a 60-day composite of mortality, transfer to the ICU, septic shock, culture-confirmed bacteremia in each arm.

Secondary Outcome Measures

Name	Time	Method
Adverse Events	60 days	To compare the rates of grade 3, 4, and 5 adverse events in each arm within 60 days after first neutropenic fever.
Length of stay	60 days	To compare the length of hospital stay in each arm.
Allergic Reactions	60 days	To compare the rates of allergic reactions or side effects attributed to antibiotics that required antibiotic cessation or change within 60 days after first neutropenic fever.
Mortality post F&N	60 days	To compare the rates of mortality within 60 days after first neutropenic fever in each arm.
Bacteremia	60 days	To compare the rates of bacteremia within 60 days after randomization.
Drug resistance	60 days	To compare the rates of acquisition of multidrug resistant gram-negative bacilli (resistant to 3 or more antibiotic classes) and vancomycin resistant enterococci within 60 days after first neutropenic fever in each arm.
Candidiasis	60 days	To compare the rates of candidemia and invasive candidiasis within 60 days after first neutropenic fever in each arm.
Neutropenia	60 days	To compare the rates of neutropenia at antibiotic stop date.
Readmissions	60 days	To compare the rates of non-elective hospital readmission within 60 days in each arm.
Clostridium difficile infection	60 days	To compare the rates of Clostridium difficile infection (CDI) within 60 days after first neutropenic fever infection in each arm.
Fever	60 days	To compare the rates of new fever after index fever in each arm.