Fosfomycin versus ciprofloxacin for febrile neutropenia prophylaxis in high-risk haematological patients (FOVOCIP): a phase 3, open-label, multicentre, randomised, non-inferiority trial.

Background: Prophylaxis with fluoroquinolones in high-risk neutropenic patients is currently under scrutiny. The FOVOCIP study aimed to evaluate the efficacy and safety of fosfomycin compared to ciprofloxacin in this population. Methods: 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. Intention-To-Treat (ITT) and Per-Protocol (PP) analyses were done for the primary endpoint, with a non-inferiority margin of -5%. Findings: A total of 174 patients were screened and 166 randomized (83 per arm, 50% female). In the ITT population, febrile neutropenia occurred in 74.7% (62 of 83 patients) and 73.49% (61 of 83 patients) in the fosfomycin and ciprofloxacin group, respectively. The corresponding success rates (patients without febrile neutropenia) were 25.3% in the fosfomycin group and 26.51% int the ciprofloxacin group, risk difference -1.2%, (95% confidence interval [CI]: -14.5 to 12.12, lower boundary of the 90% CI -12.3). In the PP population, febrile neutropenia occurred in 82.19% (60 of 73 patients) and 76.25% (61 of 80 patients) in the fosfomycin and ciprofloxacin group respectively. The corresponding success rates were 17.81% in the fosfomycin group and 23.75% in the ciprofloxacin group, risk difference -5.94%, (95% CI: -18.75 to 6.86, lower boundary of the 90% CI -16.7). Gram negative bacteria were responsible for 90% and 10% of the bacteraemias in the fosfomycin and ciprofloxacin group, respectively. Two patients (3%) in the experimental group became colonized by multidrug resistant Gram-negative bacteria, compared with nine patients (11%) in the control group (P = 0.04). There were no differences in other safety endpoints. Interpretation: Fosfomycin did not demonstrate non-inferiority to ciprofloxacin in the prevention of febrile neutropenia in high-risk haematological patients. The higher incidence of Gram-negative bacteraemia also discourages its use. This trial is registered with ClinicalTrials.gov (NCT05311254) and EUDRACT (2021-000354-25) and is complete. Funding: Instituto de Salud Carlos III (PI21/1590 AES 2021, co-funded by European Union), Agencia SEKUENS (IDE/2024/000797), Instituto de Investigación del Principado de Asturias (ITM25-INT).