A Multicenter Randomized Trial Comparing Fosfomycin Calcium and Ciprofloxacin Hydrochloride for Febrile Neutropenia in Acute Leukemia Patients

The primary objective of this multicenter randomized trial is to demonstrate the **non-inferiority** in efficacy of oral **fosfomycin** versus oral **ciprofloxacin** in preventing febrile neutropenia in patients with acute leukemia treated with intensive chemotherapy and/or recipients of hematopoietic stem cell transplantation. This is clinically relevant as febrile neutropenia is a significant complication in these patients, leading to increased morbidity and potential treatment delays.

Secondary objectives include:

• Evaluating febrile neutropenia of infectious etiology.
• Comparing overall survival from baseline to resolution of neutropenia in both treatment arms.
• Assessing the safety and tolerability of both prophylactic strategies.
• Performing surveillance cultures to determine the rate of Gram-negative multiresistant colonization (GNMRB), analyzing the time course of colonization, and identifying clinical factors associated with the clearance or persistence of GNMRB bacteria in the gut of previously colonized patients.
• Evaluating the utility of a metagenomic approach in the identification of underdetected colonization, as compared to traditional surveillance cultures.
• Analyzing changes in the fecal microbiome of patients from initiation of chemotherapy to resolution of neutropenia and comparing these changes between both treatment arms.

The clinical trial involves **adult subjects** aged 18 years and older, both male and female, diagnosed with acute leukemia. Participants are either receiving their first course of chemotherapy or are candidates for a first hematopoietic stem cell transplantation. The study population is characterized by an expected **neutropenia** lasting at least seven days, with additional risk factors for infection such as grade 3-4 mucositis, age 65 years or older, or a comorbidity index of 3 or higher. Participants must have a performance status of 0 to 3 on the Eastern Cooperative Oncology Group (ECOG) scale and adequate organ function. Women of childbearing potential must not be pregnant or breastfeeding and must use effective contraception. The trial does not include a vulnerable population. The sponsor has not provided information on the total number of participants.

The clinical trial is designed to evaluate the **non-inferiority** of oral **fosfomycin** compared to oral **ciprofloxacin** in preventing febrile neutropenia in patients with acute leukemia undergoing intensive chemotherapy or hematopoietic stem cell transplantation. This is a multicenter, randomized, double-blind, controlled trial. The trial is categorized as a low-intervention Phase III study, with an estimated duration from March 14, 2022, to May 14, 2025. Participants will be randomly assigned to receive either fosfomycin or ciprofloxacin, both administered orally, with a maximum daily dose of 1500 g for fosfomycin and 1000 g for ciprofloxacin, over a treatment period of up to two weeks.

The study involves several key visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis, expected duration of neutropenia, and organ function. Participants must provide written informed consent and meet specific inclusion criteria, including being adults aged 18 or older with a diagnosis of acute leukemia or candidates for a first stem cell transplant. The screening visit will also include a pregnancy test for women of childbearing age. Follow-up visits will be scheduled to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. The primary endpoint is the occurrence of febrile neutropenia requiring antibacterial treatment, with secondary endpoints including the absolute neutrophil count and overall survival. The end-of-study visit will occur when the participant achieves an absolute neutrophil count greater than 0.5x10^9/L, or if more than 60 days have elapsed since the onset of neutropenia, or on the first day of the next chemotherapy cycle, whichever is earlier.

Participant involvement is expected to last until the end-of-study visit, with conditions for early termination including failure to achieve the required neutrophil count within the specified timeframe or the occurrence of significant adverse events. The trial aims to ensure minimal additional risk or burden to participants compared to standard clinical practice, adhering to the guidelines for low-intervention clinical trials.

The clinical trial involves the administration of **fosfomycin calcium** as the experimental medication. Fosfomycin calcium is provided in an oral pharmaceutical form, identified by the code PHF00170MIG. The maximum daily dose for fosfomycin calcium is 1500 grams, with a total maximum dose of 1500 grams over the treatment period. The administration route is oral, and the treatment duration is limited to a maximum of 2 days. Fosfomycin calcium is classified under the ATC code J01XX01, indicating its use as an antibiotic. The chemical origin of the active substance is confirmed, and it is not formulated for pediatric use.

The comparator treatment in this trial is **ciprofloxacin hydrochloride** and **ciprofloxacin**, which are also administered orally. The pharmaceutical form for ciprofloxacin is designated as PHF00134MIG. The maximum daily dose for ciprofloxacin is 1000 grams, with a total maximum dose of 1000 grams over the treatment period. Similar to fosfomycin, the administration route is oral, and the treatment duration is capped at 2 days. Ciprofloxacin is classified under the ATC code J01MA02, also indicating its role as an antibiotic. The active substances are of chemical origin, and the formulation is not intended for pediatric use.

Both treatments are administered orally, and the trial aims to demonstrate the non-inferiority of fosfomycin compared to ciprofloxacin in preventing febrile neutropenia in patients with acute leukemia undergoing intensive chemotherapy or hematopoietic stem cell transplantation. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed treatment regimen.

The efficacy of the clinical trial comparing oral **fosfomycin** and oral **ciprofloxacin** for the prevention of febrile neutropenia in patients with acute leukemia will be assessed using specific primary endpoints. These endpoints include the occurrence of febrile neutropenia requiring antibacterial treatment, achieving an Absolute Neutrophil Count (ANC) greater than 0.5x10⁹/L, and the time to reach this ANC level. If a subject fails to achieve more than 0.5x10⁹/L neutrophils, the study will conclude when more than 60 days have elapsed since the onset of neutropenia or on the first day of the next chemotherapy cycle, whichever occurs earlier. Additionally, mortality will be considered as a primary endpoint.