Stopping Antibiotics After 3 Days for the Treatment of High-risk FEbrile Neutropenia (SAFE)

Stopping Antibiotics After 3 Days for the Treatment of FEbrile Neutropenia in Haematology Patients (SAFE Study): a Randomized Open-label Non-inferiority Trial

The goal of this clinical trial is to compare a short course of antibiotics in patients in whom no bacterial infection is found with the current "golden standard": long-term antibiotic treatment in adult hematology patients who develop neutropenic fever.

The main question it aims to answer is: whether the short-term treatment is equally safe for patients, hence the name 'SAFE study'.

Participants will be randomly assigned (randomized) to one of two treatment options once they develop neutropenic fever: short-term or long-term antibiotic treatment. An additional blood sample, urine sample and stool sample will be collected.

Researchers will compare the short-term and the long-term antibiotic treatment groups to see if the short treatment is equally safe as the long-term treatment group.

Study Overview

• Status: Recruiting
• Conditions: Neutropenia, Febrile
• Intervention / Treatment: Other: Comparison short vs extended EBAT treatment group

• Study Type: Interventional
• Enrollment (Estimated): 410
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Robina Aerts, MD; Phone Number: +32 16 34 48 77; Email: robina.aerts@kuleuven.be
• Study Contact Backup: Name: Johan Maertens, MD, PhD; Phone Number: +32 16 34 66 70; Email: johan.maertens@uzleuven.be

Study Locations

• Belgium
  • Vlaams-Brabant
    • Leuven, Vlaams-Brabant, Belgium, 3000
      • Recruiting
      • University Hospitals Leuven
      • Contact: Yuri Vanbiervliet, MD; Email: yuri.vanbiervliet@uzleuven.be
      • Contact: Robina Aerts, MD; Email: robina.aerts@kuleuven.be

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Voluntary written informed consent of the participant or their legally authorized representative has been obtained prior to any screening procedures;
• Age older than 16 years;

• Intensive therapy is started within three days before randomization for one of the following haematological conditions:

  • Remission induction chemotherapy for newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS); OR
  • Re-induction chemotherapy for relapsed after haematological remission lasting for a minimum duration of 6 months; OR
  • Conditioning regimen to prepare for an allogeneic HCT; OR
  • Conditioning regimen to prepare for an autologous HCT.
• Expected longstanding (≥ 7 days) neutropenia (ANC < 0.5x10^9/L);
• Expected length of hospital stay of at least 10 days.

Exclusion Criteria:

1. Clinically or microbiologically documented infection;
2. Patient already receives broad spectrum antibiotic therapy;
3. Any critical illness for which Intensive Care Unit treatment is required;
4. SOFA score ≥ 11;
5. Longstanding neutropenia (>21 days) prior inclusion;
6. Previous enrolment in this study;
7. Not able to provide written informed consent;
8. Any disorder, which in the Investigator's opinion might jeopardise the participant's safety or compliance with the protocol;
9. Any prior or concomitant treatment(s) that might jeopardise the participant's safety or that would compromise the integrity of the Trial.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Short treatment group; Empirical broad-spectrum antibiotics (EBAT) as per local protocol: Meropenem 3 x 1(/2) g IV; OR; Piperacilline-Tazobactam 4 x 4 g IV; OR; Cefepime 3 x 2 g IV; OR; Ceftazidim 3 x 2 g IV Short treatment group: EBAT will be discontinued: After 3x24 hours;; Irrespective of presence of fever; AND; If no clinical of microbiological infection is documented.	Other: Comparison short vs extended EBAT treatment group; This study compares two management strategies of patients undergoing treatment with chemotherapy or a stem cell transplantation. One strategy is to treat these patients at the time of febrile neutropenia with a fixed 72 hours course of EBAT. The other, more commonly followed strategy is a longer minimum EBAT duration of 5 days as well as other variables like neutrophil recovery and defervescence. In both arms, definitive treatment is given when an infectious cause of the fever is found according to local guidelines (e.g. pneumonia or mucosits with bacteremia).
Active Comparator: Extended treatment group; Empirical broad-spectrum antibiotics (EBAT) as per local protocol: Meropenem 3 x 1(/2) g IV; OR; Piperacilline-Tazobactam 4 x 4 g IV; OR; Cefepime 3 x 2 g IV; OR; Ceftazidim 3 x 2 g IV Extended treatment arm: EBAT will be continued: At least 5x24 hours;; Until afebrile (TMT<38.0°C) for at least 5 consecutive days; OR; Until resolution of neutropenia (ANC >0,5 x109/L); OR; Until they have been treated 10 days, whatever comes first.	Other: Comparison short vs extended EBAT treatment group; This study compares two management strategies of patients undergoing treatment with chemotherapy or a stem cell transplantation. One strategy is to treat these patients at the time of febrile neutropenia with a fixed 72 hours course of EBAT. The other, more commonly followed strategy is a longer minimum EBAT duration of 5 days as well as other variables like neutrophil recovery and defervescence. In both arms, definitive treatment is given when an infectious cause of the fever is found according to local guidelines (e.g. pneumonia or mucosits with bacteremia).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Absence of a serious medical complication (SMC) following 42 days after randomisation. SMC is defined as: Death; and/or ICU admission; and/or Septic shock requiring vasopressive therapy.	42 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Incidence of bacteraemia within 42 days after randomisation	42 days
Clinically documented infections	42 days
Number of documented bacterial infections	42 days
Total days of non-prophylactic antibiotics given to the patient at engraftment	42 days
Total numbers of antibiotic switches before neutrophil recovery	42 days
Incidence of Clostridium difficile infection	42 days
Incidence, severity and duration of diarrhea	42 days
Incidence of candidemia	42 days
Length of hospital stay in the first 42 days after randomization	42 days
Number of patients admitted to the ICU within 42 days after randomisation	42 days
Number of readmissions within 42 days	42 days
Number of patients with a culture (surveillance or diagnostic culture) positive for resistant bacteria: VRE; ESBL; MRSA; and/or CPE	42 days
Duration of hospitalization	42 days
Number of patients in the short treatment arm with ongoing fever at time of EBAT stop	42 days
Incidence of acute GVHD (grade II or higher) in the transplanted study population	42 days

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Collaborators: University Hospital, Ghent; Universitair Ziekenhuis Brussel; University Hospital, Antwerp; AZ Sint-Jan AV; Cliniques universitaires Saint-Luc- Université Catholique de Louvain; Centre Hospitalier Universitaire de Liege
• Investigators: Principal Investigator: Johan Maertens, MD, PhD, Universitaire Ziekenhuizen KU Leuven

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2024
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: June 21, 2023
• First Submitted That Met QC Criteria: June 21, 2023
• First Posted (Actual): July 3, 2023

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Leukemia; Infections; Neutropenia; Stem Cell Transplant Complications
• Additional Relevant MeSH Terms: Wounds and Injuries; Hematologic Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Body Temperature Changes; Heat Stress Disorders; Cytopenia; Neutropenia; Hyperthermia; Fever; Febrile Neutropenia
• Other Study ID Numbers: S66527; 2022-500389-84 (EudraCT Number)

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