Fosfomycin Versus Standard of Care in Children With Antibiotic-resistant Urinary Tract Infections

NCT05709028 | Recruiting Phase 3 DMC

• 1 other identifier: FosUTI
• Study Type: interventional
• Target: 300
• Locations: 1 country
• Sites: 5

Brief Summary

Urinary tract infections (UTIs) are among the most common bacterial infections in children. Up to 50% of UTI's are caused by multi-drug resistant ESBL-producing gram negative bacteria that do not respond to treatment with oral penicillin's or cephalosporins. Instead, children often require hospital admission to receive broad-spectrum intravenous antibiotics when they may otherwise be safely managed at home; resulting in prolonged hospital stays and an increased use of health resources. Fosfomycin is a broad-spectrum antibiotic discovered in 1969 that remains susceptible to a large number of organisms due to its low international use. Fosfomycin can be prepared as an oral solution with an orange/tangerine flavour and is currently approved for use in females \>12 years old. Despite extensive evidence of its efficacy in adults and safety in neonates, the use of fosfomycin in children remains limited and fosfomycin is not currently licensed for use in children \<12 years old in Australia. The aim of this clinical trial is to compare the use of oral fosfomycin against standard of care antibiotics for the treatment of antibiotic resistant urinary tract infections in children. The main questions the trial aims to answer are:

1. 1.Is oral fosfomycin non-inferior in efficacy to the current standard of care for the treatment of antibiotic-resistant urinary tract infections in children?
2. 2.Is oral fosfomycin a safe and well-tolerated antibiotic in children?
3. 3.What is the best dosing regimen of oral fosfomycin for the treatment of antibiotic-resistant UTIs in children?

Conditions

Urinary Tract Infections

Outcome Measures

Primary Outcomes (1)

• Treatment failure within 28 days after enrolment between patients treated with standard of care versus oral fosfomycin.

  Treatment failure is defined as: 1. Persistent or recurrent (clinical and microbiologically-confirmed) diagnosis of a UTI between 7 and 28 days after enrolment, with the same uropathogen; or 2. Decision to switch to an alternative antibiotic due to perceived treatment failure; or 3. Isolation of the same pathogenic organism from a new sterile site between 7 and 28 days after enrolment;

  28 days

Secondary Outcomes (5)

• Occurrence of treatment-related adverse events to Day 28

  28 days

• Occurrence of serious adverse events attributable to UTI to Day 28

  28 days

• Evidence of primary treatment failure, defined as: a) Persistent fever (>38.0C) attributable to UTI at 72h after enrolment; and/or b) Failure to return to baseline health at 28 days after enrolment

  28 days

• Evaluation of the cost of hospital resources in the first 28 days of enrolment in children receiving standard of care versus oral fosfomycin; including: a) Cost of prescribed drugs b) Cost of hospital services (inpatient and outpatient)

  28 days

• Assessment of the tolerability of oral antibiotic therapy in children, using a 5-point facial hedonic scale immediately after the first oral dose

  Day 1

Study Arms (2)

Oral fosfomycin

EXPERIMENTAL

* Children who have been diagnosed with an uncomplicated UTI will be administered a single dose of oral fosfomycin trometamol. Then, on Day 2 either; 1. Stop if the child has clinically improved, or 2. Give a second dose of oral fosfomycin trometamol if the child has ongoing fever or clinical symptoms consistent with an uncomplicated UTI, or 3. Give an additional 8 days of oral fosfomycin trometamol with repeat doses every 48 hours (to make up a total 10-day treatment duration) if the child has evidence of a complicated UTI. * Children who have been diagnosed with a complicated UTI will be administered repeat doses of oral fosfomycin trometamol every 48 hours until the child has received a total 10-day course of antibiotics with presumed or proven efficacy against the urinary pathogen.

Drug: Fosfomycin

Standard of Care antibiotics

ACTIVE COMPARATOR

* Children who have been diagnosed with an uncomplicated UTI will be administered a 3-day course of standard of care (SOC) antibiotics with known efficacy against the urinary pathogen. Then, on Day 3 either; 1. Stop of the child has clinically improved, or 2. Give an additional 48 hours of SOC antibiotics if the child has ongoing fever or clinical symptoms consistent with an uncomplicated UTI, or 3. Give an additional 7 days of SOC antibiotics (to make up a total 10-day duration) if the child has evidence of a complicated UTI. * Children who have been diagnosed with a complicated UTI will be administered a total 10-day course of SOC antibiotics with known efficacy against the urinary pathogen.

Drug: Standard of care antibiotics

Interventions

Fosfomycin DRUG

Fosfomycin trometamol is a white crystalline powder which is very soluble in water. The granules are mixed with 90ml of cool water for the constitution to dissolve and will be administered soon after reconstitution. Each 30ml will contain 1g fosfomycin base. * Children ≥ 6 months to \<1 year old will be administered 30ml (=1g fosfomycin base) of dissolved solution and the remainder discarded for each dose. * Children ≥ 1 to 11 years will be administered 60ml (=2g fosfomycin base) of dissolved solution and the remainder discarded for each dose. * Children ≥12 and \<18 years will be administered the entire 90ml solution (= 3g fosfomycin base) for each dose.

Oral fosfomycin

Standard of care antibiotics DRUG

Standard of care antibiotics will be chosen by the treating clinician according to institutional prescribing practices, local antibiograms and medication availability.

Standard of Care antibiotics

Eligibility Criteria

• Age: 6 Months - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Children aged ≥6 months to \<18 years with:
• Symptoms consistent with a clinical diagnosis of a UTI (as per the treating clinician); AND
• Microbiological confirmation: Defined as a urine culture revealing a predominant growth of a bacterial uropathogen \[≥10\^6 CFU/L, or ≥10\^3 CFU/mL\] together with ≥10x10\^6 white blood cells on microscopy; AND
• The bacterial uropathogen is a non-pseudomonal gram-negative organism likely to cause urinary tract infections in children; being one of either: Escherichia coli, Proteus spp., Klebsiella spp., Enterobacter spp., Serratia spp., or Citrobacter spp., AND
• The uropathogen has in vitro evidence of resistance to all oral penicillins and oral first- and second- generation cephalosporins (or is presumed to be resistant based on the pattern of phenotypic testing); AND
• The patient has not yet received \>48 hours of antibiotics with in vitro activity against the urinary pathogen prior to enrolment.

You may not qualify if:

• Evidence of bacteraemia due to the same uropathogen within the same clinical illness; OR
• Evidence of infection at a secondary site (such as meningitis or endocarditis); OR
• Children with features suggestive of sepsis (defined as requiring inotropic support, or \>20ml/kg fluid bolus); OR
• Children who are unable to tolerate or absorb oral antibiotics; OR
• Children with severe renal unsifficiency (creatinine clearance \<10ml/minute/1.73m\^2); OR
• Known allergy to fosfomycin; OR
• A decision by the primary treating physician that enrolment in the trial is not in the child's best interest.

Sponsors & Collaborators

• University of Sydney: lead

Study Sites (5)

Sydney Childrens Hospital

Sydney, New South Wales, 2031, Australia

RECRUITING

The Children's Hospital at Westmead

Sydney, New South Wales, 2145, Australia

NOT YET RECRUITING

Queensland Children's Hospital

Brisbane, Queensland, 4101, Australia

RECRUITING

Royal Childrens Hospital

Melbourne, Victoria, 3052, Australia

RECRUITING

Perth Children's Hospital

Perth, Western Australia, 6000, Australia

RECRUITING

MeSH Terms

Conditions

Urinary Tract Infections

Interventions

Fosfomycin

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

Study Officials

• Phoebe Williams

  University of Sydney

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Michelle L Harrison

CONTACT

0411900359; m.harrison@sydney.edu.au

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Open-label study. Statisticians will be blind to groups when analysing results
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomised controlled trial with an intervention arm and an active control arm (standard-of care)

Study Record Dates

• First Submitted: January 23, 2023
• First Posted: February 1, 2023
• Study Start: August 2, 2023
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): August 1, 2027
• Last Updated: June 6, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

AU (5)