Early Neutropenic Fever De-escalation of Antibiotics Study (END)

Early Neutropenic Fever De-escalation (END) of Antibiotics Study

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Febrile Neutropenia; Hematologic Malignancy; Antibiotic Stewardship
• Intervention / Treatment: Drug: Cessation of antibiotics

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 Type: Interventional
• Enrollment (Estimated): 260
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Lindsey R Baden, MD; Phone Number: 617-525-8418; Email: lbaden@bwh.harvard.edu
• Study Contact Backup: Name: Alisse D Hannaford, MD; Phone Number: 617-525-8418; Email: ahannaford@mgh.harvard.edu

Participation Criteria

Eligibility Criteria

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

Description

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 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: Intervention Arm; 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.	Drug: Cessation of antibiotics; 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.; Other Names: Stop antibiotics
No Intervention: Control Arm; Participants will continue antibiotic therapy until count recovery and/or standard of care as deemed by inpatient providers, which is the current guidelines recommended by the IDSA.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality post F&N	To compare the rates of mortality within 60 days after first neutropenic fever in each arm.	60 days
Drug resistance	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.	60 days
Clostridium difficile infection	To compare the rates of Clostridium difficile infection (CDI) within 60 days after first neutropenic fever infection in each arm.	60 days
Candidiasis	To compare the rates of candidemia and invasive candidiasis within 60 days after first neutropenic fever in each arm.	60 days
Adverse Events	To compare the rates of grade 3, 4, and 5 adverse events in each arm within 60 days after first neutropenic fever.	60 days
Allergic Reactions	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.	60 days
Bacteremia	To compare the rates of bacteremia within 60 days after randomization.	60 days
Neutropenia	To compare the rates of neutropenia at antibiotic stop date.	60 days
Length of stay	To compare the length of hospital stay in each arm.	60 days
Readmissions	To compare the rates of non-elective hospital readmission within 60 days in each arm.	60 days
Fever	To compare the rates of new fever after index fever in each arm.	60 days

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Dana-Farber Cancer Institute
• Investigators: Principal Investigator: Lindsey R Baden, MD, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: January 3, 2024
• First Submitted That Met QC Criteria: February 23, 2024
• First Posted (Actual): February 26, 2024

Study Record Updates

• Last Update Posted (Actual): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 23, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Febrile Neutropenia
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Hematologic Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Hematologic Neoplasms; Neutropenia; Febrile Neutropenia; Anti-Infective Agents; Antitubercular Agents; Anti-Bacterial Agents; Antibiotics, Antitubercular
• Other Study ID Numbers: 23-684-END

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