A Trial of Fosfomycin vs Ciprofloxacin for Febrile Neutropenia (FOVOCIP)

Fosfomycin Versus Ciprofloxacin for Febrile Neutropenia Prophylaxis in High-risk Haematological Patients (FOVOCIP): a Phase 3, Open-label, Multicentre, Randomised, Non-inferiority Trial.

Prophylaxis with fluoroquinolones in high-risk neutropenic patients is currently under scrutiny due to their toxicity and the potential of selecting multirresistant bacteria. In this setting, the search for an alternative prophylactic drug is a priority. The FOVOCIP study aimed to evaluate the efficacy and safety of fosfomycin compared to ciprofloxacin in this population. This was a multicentre, randomised, phase-3, non-inferiority, open-label trial performed in 11 centres in Spain. Adults diagnosed with acute leukaemia or recipients of a Haematopoietic Stem Cell Transplant were randomised to receive oral fosfomycin or oral ciprofloxacin as prophylaxis. The primary endpoint was rate of febrile neutropenia. Secondary endpoints included safety, including microbiological safety and gut microbiota changes .

1. Subjects must be able to understand the study procedures, comply with them, and provide written informed consent prior to any specific study procedures.

2. Adult subjects ≥ 18 years of age diagnosed with acute leukaemia who are scheduled to receive a first course of intensive chemotherapy.

3. Adult subjects ≥ 18 years of age who are candidates for a first allogeneic haematopoietic stem cell transplant with myeloablative conditioning or adult subjects ≥ 18 years of age who are candidates for a first allogeneic haematopoietic stem cell transplant with reduced-intensity conditioning or an autologous haematopoietic stem cell transplant, provided that at least one of the following risk factors for infection is present:

   1. Functional status (Eastern Cooperative Oncology Group, ECOG) ≥2.
   2. Expected grade 3-4 mucositis.
   3. Age ≥65 years.
   4. Comorbidity index (HCTI) ≥3.
   5. Serum albumin < 35 g/L.
   6. Active or refractory neoplasia at the time of stem cell transplantation.
   7. Total dose of etoposide > 500 mg/m2.
   8. Total dose of cytarabine > 1 g/m2.

4. Functional status (Eastern Cooperative Oncology Group, ECOG) from 0 to 3.

5. Adequate organ function defined as:

   • Liver: bilirubin, alkaline phosphatase or SGOT < 3 times the upper normal limit (unless attributable to tumour activity).
   • Renal: creatinine ≤ 250 μmol/l (2.5 mg/dL) (unless attributable to leukemic infiltration).

6. Life expectancy greater than 3 months.

7. Women of childbearing age must not be pregnant or breastfeeding and must have a negative pregnancy test at the time of screening. Women of childbearing age and men with female partners of childbearing age must commit to using two highly effective forms of contraception and must agree not to become pregnant or father a child while receiving any study therapy and for at least 3 months after completing treatment.

Exclusion criteria

Patients who meet any of the following exclusion criteria will not be eligible for inclusion in this study:

1. Hypersensitivity to fluoroquinolones or fosfomycin.
2. Treatment with broad-spectrum antimicrobial therapy within 4 weeks of the first study treatment.
3. Intensive chemotherapy or previous haematopoietic stem cell transplantation. Treatment with hydroxyurea or corticosteroids used to control white blood cell count is permitted.
4. Fever of infectious origin or documented infection within 4 weeks of the first study treatment.
5. Presence of any serious psychiatric illness or physical condition that, in the opinion of the physicians, contraindicates the patient's inclusion in the clinical trial.