FOsfomycin Randomised controlled trial for E.coli Complicated urinary tract infections as Alternative Stepdown Treatment |
|- candidate number||27210|
|- NTR Number||NTR6449|
|- ISRCTN||ISRCTN no longer applicable|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||15-mei-2017|
|- Secondary IDs|| NL60186.041.17|
|- Public Title||FOsfomycin Randomised controlled trial for E.coli Complicated urinary tract infections as Alternative Stepdown Treatment |
|- Scientific Title||FOsfomycin Randomised controlled trial for E.coli Complicated urinary tract infections as Alternative Stepdown Treatment |
|- hypothesis||Oral fosfomycin-trometamol is non-inferior to oral ciprofloxacin with regard to clinical cure rate in the step-down treatment of E.coli AF-UTI in women.|
|- Healt Condition(s) or Problem(s) studied||Urinary tract infections, Antibiotics|
|- Inclusion criteria||Hospitalised |
Competent women (≥18 years), able to give informed consent
AF-UTI as presumptive diagnosis and primary reason for hospitalisation*
Adequate intravenous antibiotic therapy for ≥48 - ≤120 hours**
Candidate for safe iv to oral switch as judged by the attending physician
Urine (≥104 CFU/ml) OR blood culture: Escherichia coli , ciprofloxacin S AND fosfomycin S***
* Acute Febrile Urinary Tract Infections (AF-UTI) are UTI with at least one of the forthcoming systemic symptoms: fever or low temperature (≥38.0 C ͦ or <36 C ͦ), rigors, delirium or hemodynamic instability as a result of sepsis requiring intravenous fluids AND at least one of the following local symptoms: lower abdominal pain, low back pain, flank pain or costo-vertebral angle pain or tenderness on physical examination, any of the following symptoms of UTI (dysuria, urinary urgency, urinary frequency, suprapubic/pelvic discomfort, macroscopic hematuria, new urinary incontinence or worsening of pre-existing incontinence). The local study investigator determines the presumptive diagnosis as the primary reason for hospitalisation with consultation of the attending physician.
**Amoxicillin+/-clavulanic acid / 2nd or 3rd cephalosporin/ aminoglycoside/ carbapenem/ fluoroquinolones/ trimethoprim-sulfamethoxazole OR a combination AND in vitro susceptibility of the causative E.coli to at least one of the used agents
*** If a participating microbiological laboratory only processes urine cultures ≥ 105 CFU/ml, only these will be included
|- Exclusion criteria||Pregnant or nursing women
Glomerular filtration rate < 30 ml/min/1,73 m3 or renal replacement therapy
Concomitant systemic antibacterial treatment for another reason than AF-UTI including concomitant prophylactic antibacterial therapy #
Ascertained or presumptive hypersensitivity to the active compounds and/or any excipient of the products or to any quinole
Participation to any trial with an investigational product involved in the 30 days before the screening visit
Every other laboratory result, clinical condition, disease or treatment that, in investigator’s opinion, make the subject non suitable for the study
Specific comorbidity or diagnosis##
Contraindications/interactions for any of the active compounds or medication ###
Patients with inadequate understanding of the study risks or its requirements or unwilling to plan a follow-up visit
# If prophylactic antibiotic therapy for UTI could not be paused during study therapy, the patient should be excluded Except for continuation of prophylactic antibacterial therapy
## Renal transplant patients, polycystic kidney disease, neutropenia (<500 /μl), paraplegia, long-term indwelling catheters (placed ≥24 hours before admission), urostomy, ileal loops, double-J catheter, nephrostomy catheter, suprapubic catheter, suspicion/presence of renal abscess, suspicion of septic metastatic foci/endocarditis
### Concurrent use of Tizanidin, Clozapin or Theophyllin. If pausing or conversion of this medicine disadvantages the participant, she will be excluded. Patients with a history of tendon disease/disorder related to quinolone treatment. Patients with known risk factors for prolongation of the QT interval. Glucose-6-phosphate dehydrogenase deficiency
|- mec approval received||yes|
|- multicenter trial||yes|
|- Type||2 or more arms, randomized|
|- planned startdate ||1-sep-2017|
|- planned closingdate||1-sep-2019|
|- Target number of participants||240|
|- Interventions||Treatment in the study arm consists of oral fosfomycin 3000mg every 24 hours.
Treatment in the standard of care arm consist of oral ciprofloxacin 500mg twice daily.
Both study and control arms will receive a placebo in order to maintain masking.
|- Primary outcome||The primary endpoint is the cumulative incidence of survival and clinical cure (resolution of symptoms) 6-10 days post-treatment|
|- Secondary outcome||The secondary endpoints of the study include: |
1. The cumulative incidence of microbiological cure 6-10 days post-treatment
2. The cumulative incidence of survival AND clinical cure (resolution of symptoms) AND microbiological cure 6-10 days post-treatment
3. The cumulative incidence of acquired fosfomycin resistance, ciprofloxacin resistance or ESBL-producing bacteria in urine culture 6-10 days post-treatment
4. The cumulative incidence of survival and clinical cure (resolution of symptoms) 30-35 days post-treatment
5. The cumulative incidence of mortality for any reason or related to UTI or study medicines within 30-35 days post-treatment
6. The cumulative incidence of ICU admissions for any reason or related to UTI or study medicines within 30-35 days post-treatment
7. The cumulative incidence of readmissions for any reason or related to UTI or study medicines within 30-35 days post-treatment
8. The cumulative incidence of relapses within 30-35 days post-treatment
9. The cumulative incidence of reinfections within 30-35 days post-treatment
10.The cumulative incidence of additional antibiotic use for UTI within 30-35 days post-treatment
11. The cumulative incidence of early discontinuation of study medicines because of adverse events OR because of loss of complaints
12. Total days of hospitalisation and Intensive Care Unit stay within 30-35 days post-treatment
13. The cumulative incidence of absenteeism within 30-35 days post-treatment
14. The cumulative incidence of study protocol related and unrelated adverse events, within 30-35 days post-treatment
15. Patient characteristics associated with the primary or secondary outcomes in both study arms (Charlson comorbidity index, Diabetes Mellitus y/n, indwelling catheter y/n, age ≥ 65 years, treatment restrictions at admission y/n, treatment restrictions at randomisation y/n, renal stones y/n)
16. Disease related characteristics associated with the primary or secondary outcomes in both study arms (systemic symptoms, ICU admission before iv-oral switch, local symptoms, bacteraemia y/n, time being afebrile before iv-oral switch, CRP, kreatinin, WBC at admission)
17. Treatment related characteristics associated with the primary or secondary outcomes in both study arms (duration of oral treatment, compliance, duration, name and dose empirical intravenous antibiotic treatment)
|- Timepoints||The primary endpoint is on 6-10 days post-end of treatment.
The secondary endpoints are on 6-10 days post-end of treatment or 30-35 days post-end of treatment.
|- Trial web site||Available via: http://portal.juliuscentrum.nl/research/nl-nl/cohortsandprojects.aspx|
|- CONTACT FOR PUBLIC QUERIES||M.D. T. ten Doesschate|
|- CONTACT for SCIENTIFIC QUERIES||M.D.
|- Sponsor/Initiator ||University Medical Center Utrecht (UMCU)|
(Source(s) of Monetary or Material Support)
|University Medical Center, Utrecht, Prof. M.J.M. Bonten|
|- Brief summary||Rationale: Difficulties arise in the treatment of complicated Urinary Tract Infections (cUTI) among which Acute Febrile-Urinary Tract Infection (AF-UTI) due to rising resistance of Enterobacteriaceae to the orally available antibiotics ciprofloxacin, trimethoprim-sulfamethoxazole and amoxicillin+clavulanic acid. Instead of an early intravenous-oral (iv-oral) switch patients may require full antibiotic courses intravenously. Fosfomycin possesses a high bactericidal activity to Escherichia coli with low resistance rates. Fosfomycin-trometamol 3000mg (FT), dosed every 24 hours, reaches sufficient antibiotic concentrations in urine and bladder wall, has good tolerability and is considered safe. Therefore, FT is a potential alternative antibiotic option for the stepdown treatment of AF-UTI.
Objective: To determine the non-inferiority of fosfomycin-trometamol in comparison to the standard of care ciprofloxacin in the stepdown treatment of AF-UTI with regard to clinical cure and survival
Study design: Randomised, double-blind, double-dummy, non-inferior, investigator initiated multicenter trial |
Study population: Consenting female patients (≥18 years), on appropriate intravenous therapy for E.coli AF-UTI and fulfilling the criteria for an iv-to-oral switch.
Intervention: After an empirical intravenous antibiotic treatment an iv-oral switch is made to either oral fosfomycin 3000mg, every 24 hours, or oral ciprofloxacin 500mg every 12 hours for a total antibiotic duration of 10 days. Patients will receive an indistinguishable placebo for either fosfomycin or ciprofloxacin.
Main study parameters/endpoints: The primary endpoint is the cumulative incidence of survival and clinical cure (resolution of symptoms) 6-10 days post-treatment. Secondary endpoints are microbiological cure 6-10 days post-treatment, the cumulative incidence of early study discontinuation, the cumulative incidence of clinical cure, the cumulative incidence of mortality, ICU admittances, relapses, reinfections, readmissions, additional antibiotic treatment for Urinary Tract Infections (UTI), adverse events, the total days of hospitalisation and days of absenteeism within 30-35 days post-treatment.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The burden for participants is considered low; participants do not require a longer duration of antibiotic treatment, or a prolonged duration of hospital stay. There are hardly no extra investigations nor extra hospital visits. To conserve the double-blind study design, all patients will receive a placebo. This study is considered to be of low-risk; the pathogen causing AF-UTI has documented susceptibility to both ciprofloxacin and fosfomycin; patients are not acutely ill at the moment of randomisation as they are candidates for an iv-oral switch; both ciprofloxacin and fosfomycin have good safety profiles. Furthermore, fosfomycin-trometamol has been used extensively as a single-dose oral therapy; previous studies have demonstrated a pharmacokinetic profile suitable for treating cUTI with a high bio-availability, reaching sufficient levels in urine and bladder walll. Clinical cure for cUTI with oral fosfomycin-trometamol has been described in observational studies. Overall the future benefit of this trial, obtaining a new stepdown antibiotic option for cUTI caused by resistent Enterobactericaeae, outweighs the involved risks.
|- Main changes (audit trail)||25-aug-2017: IK:|
Withdrawal of Zambon The Netherlands BV as fund
|- RECORD||15-mei-2017 - 5-okt-2017|
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