EXtended Use of FOsfomycin for the Treatment of CYstitis in Primary Care

Summary

Cystitis is the most frequent reason for women to visit their general practitioner. More than 600.000 women suffer from urinary tract infections in The Netherlands each year. Currently, the 1st choice treatment for uncomplicated cystitis is nitrofurantoin (NIT) for 5 days. The second choice is 3 gram fosfomycin-trometamol (FT) in a single dose. FT is increasingly prescribed because it has few side-effects and it has a patient-friendly dosing scheme. Previous research did not show significant difference in efficacy between fosfomycin and nitrofurantoin, but a clinical trial from 2018 claims a single dose of FT might be inferior to 5 days of nitrofurantoin. Pharmacodynamic and pharmacokinetic research suggests that a single dose of FT may be insufficient to cure cystitis. Overall, it remains unknown whether a single gift of FT is as efficacious as 5 days of nitrofurantoin for uncomplicated cystitis with regard to clinical cure and if an additional gift of FT would overcome this. A clinical trial is therefore warranted.

Objective: To investigate the comparative effectiveness and side-effects of 5 days of nitrofurantoin, single dose FT, and extended use of FT in uncomplicated cystitis in primary care.

Study design: An open-label randomized non-inferiority / superiority study with 3 arms.

Study population: 777 non-pregnant women with symptoms of uncomplicated cystitis, with 259 subjects in each study arm.

Intervention: (A) FT in a single dose of 3000mg on day 1; (B) extended dosing of 3000mg FT on day 1 and 3 (C) nitrofurantoin 100mg bid (slow release) for 5 days.

Main study parameters/endpoints: primary: days of absence of cystitis symptoms within 28 days. Secondary: clinical failure on day 28, microbiological failure on day 28, incidence of side-effects, cost-effectiveness Burden and risks associated with participation, benefit and group relatedness: A potential risk of participation is that the treatment arm to which the patient is allocated is either less efficacious, has more adverse events or higher recurrence rate than the other treatment arms. However, NIT and FT are both frequently used for urinary tract infections and considered safe and effective compounds for uncomplicated cystitis. According to previous studies, a second dose of FT is well tolerated. The potential risks of participation on severe adverse events is expected to be negligible as the risk of severe clinical failure after cystitis treatment is only 1% according to previous studies and differences between NIT and FT have not been observed previously. A potential benefit of participating to this study is that a more patient friendly treatment scheme is equally effective. For future patients the guidelines could be improved and become more patient-friendly. The burden of participation is considered low. Study participants need to complete a short daily questionnaire on a mobile application up to 28 days.

Conditions

• Urinary Tract Infections

Interventions

DRUG

Fosfomycin

Fosfomycin is a phosphoenolpyruvate (PEP) analogue that is produced by Streptomyces spp. It has a bactericidal action, primarily by inhibiting bacterial cell wall (peptidoglycan) synthesis. In the Netherlands, Fosfomycin is orally available as fosfomycin-trometamol (Monuril). Fosfomycin-trometamol is identical to fosfomycin-tromethamine. Fosfomycin-trometamol is a phosphoric acid derivative of fosfomycin, available in a single dose sachet containing white granules. One sachet contains 5.63 g of fosfomycin-trometamol, corresponding with 3000mg fosfomycin.

DRUG

Nitrofurantoin

Nitrofurantoin belongs to the group of nitrofuranes. Both nitrofurantoin and its metabolites have antibacterial activity, which is enhanced under acidic conditions. Nitrofurantoin is reduced to (active) metabolites by bacterial enzymes. These metabolites inhibit bacterial enzymes that are essential for energy metabolism and inhibit bacterial protein synthesis by binding to ribosomes. Active therapeutic concentrations are only reached in urine and not in other tissues. Several manufacturers produce generic nitrofurantoin in the solid oral form. Three different formulations exist: a macrocrystalized form, nitrofurantoin monohydrate (microcrystals) and a mixture of macrocrystals (75%) and monohydrate 25%) contained in a delayed-release gel matrix (Furabid®) In this trail only Furabid® will be used. Macrocrystals are slower dissolved and absorbed in comparison to the monohydrate.

Sponsors & Collaborators

• ZonMw: The Netherlands Organisation for Health Research and Development

  collaborator OTHER

• Saltro

  collaborator UNKNOWN

• MJM Bonten

  lead OTHER

Principal Investigators

• Marc Bonten, Prof. · UMC Utrecht

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

FEMALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2021-09-06

Primary Completion

2022-02-14

Completion

2022-02-14

Countries

• Netherlands

Study Locations