SAFE study: Stopping Antibiotics after 3 days for the treatment of FEbrile Neutropenia in Haematology patients, a randomized open-label non-inferiority trial

The primary objective of the SAFE study is to evaluate whether a short course of antibiotic treatment, specifically 72 hours with a **broad-spectrum antibiotic**, is as safe as an extended treatment regimen for patients with high-risk **febrile neutropenia** in hematology. This is clinically relevant as it may reduce antibiotic exposure, potentially minimizing side effects and resistance, while maintaining patient safety.

The clinical trial involves participants diagnosed with **febrile neutropenia**, focusing on hematology patients undergoing intensive therapy. The study population includes both male and female subjects aged 16 years and older. Participants are expected to have a longstanding neutropenia with an absolute neutrophil count of less than 0.5x10^9/L and an anticipated hospital stay of at least 10 days. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include individuals who have commenced intensive therapy within three days prior to randomization for specific hematological conditions, such as remission induction chemotherapy for newly diagnosed acute myeloid leukemia or myelodysplastic syndrome, re-induction chemotherapy for relapsed hematological remission, or conditioning regimens for hematopoietic cell transplantation. Participants must provide voluntary written informed consent or have consent provided by a legally authorized representative. Lifestyle factors such as diet and physical activity are not specified in the trial data.

The clinical trial is designed to evaluate the safety of a short antibiotic treatment strategy for **febrile neutropenia** in hematology patients. This study is a randomized, open-label, non-inferiority trial comparing a 72-hour course of broad-spectrum antibiotics to an extended treatment regimen. The trial aims to determine if the shorter treatment duration is as effective as the longer one in preventing serious medical complications. The trial is expected to run from July 2023 to July 2027, with participant involvement lasting up to 42 days post-randomization.

Participants will be randomly assigned to either the short or extended treatment group. The study involves several key visits: an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor health status and treatment efficacy. The end-of-study visit will assess the primary endpoint, which is the absence of serious medical complications within 42 days after randomization. Secondary endpoints include the incidence of bacteraemia, documented infections, and other health outcomes within the same period.

Inclusion criteria require participants to be over 16 years old, with expected neutropenia lasting at least seven days and a hospital stay of at least ten days. Participants must have started intensive therapy for specific hematological conditions within three days before randomization. The trial will exclude individuals who do not meet these criteria. Participants may be withdrawn from the study if they experience adverse events or if they withdraw consent.

The trial will utilize known antibiotics such as **ceftazidime**, **meropenem**, **piperacillin**, **cefepime**, and **imipenem**, administered intravenously. The maximum treatment period for each antibiotic is 42 days, with specific daily and total dose limits. The study is categorized as low-intervention, focusing on treatment duration rather than the investigational medicinal products themselves.

The clinical trial involves the administration of several **antibiotics** to evaluate their efficacy in treating febrile neutropenia in hematology patients. The first experimental medication is **Ceftazidime**, which is provided as a solution for injection. The maximum daily dose is 9 grams, administered intravenously. The treatment period can extend up to 42 days, depending on the patient's response and clinical judgment. Ceftazidime is a known antibiotic with a chemical origin, and its administration is monitored to ensure compliance with the dosing schedule.

**Meropenem** is another experimental medication used in this trial. It is supplied as a powder for solution for injection or infusion. The maximum daily dose is 6 grams, administered intravenously. The treatment duration is also up to 42 days. Meropenem is a chemically derived antibiotic, and its administration is carefully monitored to ensure adherence to the prescribed dosing regimen.

**Piperacillin** is included in the study as a powder for solution for injection or infusion. The maximum daily dose is 16 grams, administered intravenously. The treatment period is up to 42 days. Piperacillin, a known antibiotic of chemical origin, requires strict monitoring to ensure participant compliance with the dosing schedule.

**Cefepime** is administered as an infusion with a maximum daily dose of 6 grams, delivered intravenously. The treatment can last up to 42 days. Cefepime is a chemically synthesized antibiotic, and its administration is monitored to ensure adherence to the dosing protocol.

Lastly, **Imipenem** is provided as a solution for infusion with a maximum daily dose of 4 grams, administered intravenously. The treatment duration is up to 42 days. Imipenem is a known antibiotic of chemical origin, and participant compliance with the dosing schedule is closely monitored throughout the trial.

All medications are administered intravenously, and the trial does not include any non-experimental treatments such as placebo or comparator treatments. The study focuses on the safety and efficacy of short-term antibiotic treatment in high-risk febrile neutropenia patients, with compliance monitoring being a critical component of the trial protocol.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the **absence of a serious medical complication (SMC)** within 42 days following randomization. SMC is defined as death, ICU admission, or septic shock requiring vasopressive therapy. Secondary endpoints include the incidence of bacteraemia, clinically documented infections, and the number of documented bacterial infections within 42 days after randomization. Additional secondary endpoints involve the total days of non-prophylactic antibiotics administered at engraftment, the total number of antibiotic switches before neutrophil recovery, and the incidence of **Clostridium difficile** infection. Other parameters include the incidence, severity, and duration of diarrhea, incidence of candidemia, length of hospital stay, number of ICU admissions, and readmissions within 42 days. The study will also monitor the number of patients with cultures positive for resistant bacteria such as VRE, ESBL, MRSA, and CPE, as well as the duration of hospitalization and the incidence of acute GVHD (grade II or higher) in the transplanted study population.