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

NCT05254808 | Terminated Phase 3

• 1 other identifier: NL75841.041.20
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 4

Brief 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

Keywords

fosfomycin, nitrofurantoin

Outcome Measures

Primary Outcomes (1)

• Time to recovery

  Duration of absence of cystitis symptoms is defined as 'the number of days with full resolution of relevant cystitis symptoms, in the absence of aggravation to pyelonephritis or urosepsis within the period of 28 days after randomisation'

  28 days

Secondary Outcomes (12)

• Clinical failure

  28 days

• Microbiological failure

  28 days

• Development of pyelonephritis or urosepsis

  28 days

• Relapse

  28 days

• Reinfection

  28 days

Study Arms (3)

Fosfomycin in a single dose of 3000mg on day 1

ACTIVE COMPARATOR

Fosfomycin-trometamol Single dose scheme: 3000mg taken orally once (arm A)

Drug: Fosfomycin

Extended dosing of 3000mg fosfomycin on day 1 and 3

EXPERIMENTAL

Fosfomycin-trometamol Extended dosing scheme: 3000mg taken orally on day 1 and day 3 (arm B)

Drug: Fosfomycin

Nitrofurantoin 100mg bid (slow release) for 5 days

ACTIVE COMPARATOR

Nitrofurantoin 100mg b.i.d. in slow release form (Furabid) taken orally for 5 days (arm C)

Drug: Nitrofurantoin

Interventions

Fosfomycin DRUG

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.

Extended dosing of 3000mg fosfomycin on day 1 and 3; Fosfomycin in a single dose of 3000mg on day 1

Nitrofurantoin DRUG

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.

Also known as: Furabid

Nitrofurantoin 100mg bid (slow release) for 5 days

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult women (\>18 years of age) with a diagnosis of uncomplicated cystitis in primary care

You may not qualify if:

• Presence of signs of tissue invasion according to NHG guideline: fever, malaise, chills, flank or perineal pain, signs of sepsis or delirium
• Pregnancy or nursing
• Diabetes Mellitus
• Immunocompromised state
• Untreated infection with human immunodeficiency virus (hiv)
• Use of high-dose systemic corticosteroids
• Use of other immunosuppressive medication (see table below)
• Presence of an indwelling urinary catheter
• History of abnormalities in urinary tract or kidneys
• Neurogenic bladder dysfunction
• Antibiotic prophylaxis (current or in past 28 days)with nitrofurantoin or fosfomycin or trimethoprim.
• Known GFR \<30mL/min
• Contra-indication for nitrofurantoin or fosfomycin use (e.g. allergic reactions, lung or liver reaction or peripheral neuropathy after previous use in clinical history, acute porphyria, G6PD deficiency)
• Current use of an antibiotic for any reason
• Presence of urine cultures showing resistance for nitrofurantoin or fosfomycin in the last 12 months

Sponsors & Collaborators

• MJM Bonten: lead
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• Saltro: collaborator

Study Sites (4)

Medisch Centrum Heuvelrug

Doorn, Utrecht, 3941 ZE, Netherlands

Location

Huisartsenpraktijk Mariahoek

Utrecht, 3511 GK, Netherlands

Location

Huisartsenpraktijk Binnenstad

Utrecht, 3512 VS, Netherlands

Location

UMC Utrecht

Utrecht, 3584 CX, Netherlands

Location

MeSH Terms

Conditions

Urinary Tract Infections

Interventions

Fosfomycin; Nitrofurantoin

Condition Hierarchy (Ancestors)

Infections; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Nitrofurans; Nitro Compounds; Furans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Marc Bonten, Prof.

  UMC Utrecht

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Coordinating investigator

Model Details: open-label randomized non-inferiority / superiority study

Study Record Dates

• First Submitted: February 14, 2022
• First Posted: February 24, 2022
• Study Start: September 6, 2021
• Primary Completion: February 14, 2022
• Study Completion: February 14, 2022
• Last Updated: March 15, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

NL (4)