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

A Multicenter Randomized Trial of Fosfomycin vs Ciprofloxacin for Febrile Neutropenia in Hematological Patients: Efficacy and Microbiological Safety

Randomized phase 3 trial to compare efficacy and safety of oral fosfomycin versus ciprofloxacin to prevent febrile neutropenia in patients with acute leukemia or recipients of hematopoietic stem cell transplant.

Study Overview

• Status: Recruiting
• Conditions: Febrile Neutropenia
• Intervention / Treatment: Drug: Fosfomycin Calcium

Detailed Description

Multicenter, prospective, randomized, open label phase III trial to assess the efficacy and safety of oral fosfomycin vs. oral ciprofloxacin in the prevention of febrile neutropenia in patients with acute leukemia who are treated with intensive chemotherapy and/or are recipients of a hematopoietic stem cell transplant.

Non-inferiority design.

156 patients will be recruited: 78 in each arm

• Study Type: Interventional
• Enrollment (Estimated): 156
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Teresa Bernal, MD PHD; Phone Number: 37613 +34 985108000; Email: bernalmaria@uniovi.es
• Study Contact Backup: Name: Javier Fernandez Dominguez, BD; Phone Number: +34985108000; Email: javifdom@gmail.com

Study Locations

• Spain
  • Asturias
    • Oviedo, Asturias, Spain, 33011
      • Recruiting
      • Instituto de Investigación Sanitaria del Principado de Asturias
      • Contact: Teresa Bernal del Castillo, MD PHD; Phone Number: 37613 +34 985108000; Email: bernalmaria@uniovi.es
      • Contact: Javier Fernandez Domínguez, PHD; Email: javifdom@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subjects who are able to understand study procedures, comply with them, and provide written informed consent before any study-specific procedure.
2. Adult subjects ≥ 18 years of age with acute leukemia diagnosis who are going to receive their first intensive chemotherapy cycle or adult subjects ≥ 18 years of age who are candidates to receive a first stem cell transplant.

3. Expected neutropenia 100x109/L lasting at least seven days. In case of expected neutropenia range 100-500x109/L lasting seven days or more, at least one of the following risk factors for infection must be present:

   1. Performance status (Eastern Cooperative Oncology Group, ECOG) ≥2.
   2. Expected mucositis grade 3-4.
   3. Age ≥65 years.
   4. Comorbidity Index (HCTI) ≥3.
   5. Serum albumin< 35 g/L.
   6. Total dose of etoposide > 500 mg/m2
   7. Total dose of cytarabine > 1 g/m2
   8. Active or refractory neoplasia at the moment of stem cell transplant.
4. Performance status (Eastern Cooperative Oncology Group, ECOG) of 0 to 3.

5. Adequate organ function defined as:

   Liver: bilirubin, alkaline phosphatase, or SGOT < 3 times the upper normal limit (unless it is attributable to tumor activity).

   Renal : creatinine ≤ 250 μmol/l (2.5 mg/dL) (unless it is attributable to AML activity).

6. Life expectancy higher than 3 months.
7. Women of child-bearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of child-bearing potential and men with female partners of child-bearing potential must agree to practice 2 highly effective contraceptive measures of birth control 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:

1. Hypersensitivity to fluoroquinolones or fosfomycin.
2. Treatment with broad spectrum antimicrobial therapy within 4 weeks of first study treatment.
3. Prior Intensive chemotherapy or stem cell transplant. Treatment with hydroxyurea or corticosteroids used to control white blood cell counts are permitted.
4. Fever of infectious origin or documented infection within 4 weeks of first study treatment.
5. Presence of any severe psychiatric disease or physical condition that, according to the physicians criteria, contraindicates the inclusion of the patient into the clinical trial.
6. Subjects that have participated previously in this study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fosfomycin; Drug: Fosfomycin: oral capsules containing 700 mg of calcium fosfomycin, equivalent to 500 mg of active drug.	Drug: Fosfomycin Calcium; Oral fosfomycin, three times daily, starting from the first day of induction chemotherapy or conditioning until absolute neutrophil count >0,5x109/L.
Active Comparator: Ciprofloxacin; Oral ciprofloxacin, tablets containing 500 mg of active drug.	Drug: Fosfomycin Calcium; Oral fosfomycin, three times daily, starting from the first day of induction chemotherapy or conditioning until absolute neutrophil count >0,5x109/L.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Febrile neutropenia of infectious origin	Febrile neutropenia that requires antibacterial treatment.	Immediately after the intervention until febrile neutropenia develops, neutrophil count >0,5x109/L up to 60 days maximum

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Documented infections	Rate and type of documented infections	Immediately after the intervention until febrile neutropenia develops, neutrophil count >0,5x109/L up to 60 days maximum
Use of broad spectrum antibiotics	Index of days of antibiotics per hospitalization days. Antibiotics will be classified according the Watch/Reserve classification	Immediately after the intervention until febrile neutropenia develops, neutrophil count >0,5x109/L up to 60 days maximum
Overall survival		Time from the day of randomization to the date of death, whatever the cause of death, up to 12 weeks.
Drug related adverse events	Incidence of Adverse Events (AE), severity and type of AEs.	Immediately after the intervention until febrile neutropenia develops, neutrophil count >0,5x109/L up to 60 days maximum
Evolution of resistome	Rate of patients colonized by multidrug resistant bacteria as determined by metagenomic sequencing	Immediately after the intervention until febrile neutropenia develops, neutrophil count >0,5x109/L up to 60 days maximum
Microbiome evolution	Changes in the gut microbiome produced under both prophylactic strategies during the study period.	Immediately after the intervention until febrile neutropenia develops, neutrophil count >0,5x109/L up to 60 days maximum
Microbiological safety	Rate of patients colonized by multidrug resistant bacteria as determined by surveillance cultures	Immediately after the intervention until febrile neutropenia develops, neutrophil count >0,5x109/L up to 60 days maximum

Collaborators and Investigators

• Sponsor: Fundación para la Investigación Biosanitaria del Principado de Asturias
• Collaborators: Instituto de Salud Carlos III; Instituto de Investigación Marqués de Valdecilla
• Investigators: Principal Investigator: Teresa Bernal, MD PHD, Hospital Universitario Central Asturias

Study record dates

Study Major Dates

• Study Start (Actual): March 14, 2022
• Primary Completion (Estimated): March 14, 2024
• Study Completion (Estimated): March 14, 2024

Study Registration Dates

• First Submitted: March 9, 2022
• First Submitted That Met QC Criteria: April 4, 2022
• First Posted (Actual): April 5, 2022

Study Record Updates

• Last Update Posted (Actual): September 14, 2023
• Last Update Submitted That Met QC Criteria: September 12, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Wounds and Injuries; Hematologic Diseases; Agranulocytosis; Leukopenia; Leukocyte Disorders; Body Temperature Changes; Heat Stress Disorders; Neutropenia; Hyperthermia; Fever; Febrile Neutropenia; Physiological Effects of Drugs; Anti-Infective Agents; Anti-Bacterial Agents; Calcium-Regulating Hormones and Agents; Calcium; Fosfomycin
• Other Study ID Numbers: FOVOCIP; 2021-000354-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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