Clinical trial NCT00156546: Evaluation of the Effectiveness of Antibiotic Prophylaxis in Children With a Previous Urinary Tract Infection
Official title: Evaluation of the Effectiveness of Antibiotic Prophylaxis in Children With a History of Upper Urinary Tract Infections:a Multicentre Randomised Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Urinary Tract Infections
Keywords: Urinary tract infections
Children
Antibiotic prophylaxis
Renal scintigraphy
Vesico ureteral reflux
Lead sponsor: University of Padova
Sponsor class: OTHER
Collaborators: name: Regione Veneto
name: IL Sogno di Stefano
First posted: 2005-09-12
Enrollment: 660
Sex: ALL
Minimum age (years): 2
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Our hypothesis is that long-term antimicrobial prophylaxis does not reduce the recurrence of infection and the risk of appearance of kidney scars in children with a documented previous upper UTI.

Detailed description: Background

Upper urinary tract infections (UTI) are common in children, especially when functional and anatomical abnormalities of the urinary tract co-exist, such as vesico-ureteral reflux (VUR), urinary tract obstruction uropathy and bladder dysfunction. They are associated with the risk of long-term complications, including permanent renal damage (renal scarring), which occurs in 15% of cases. The objective of the diagnosis and medical treatment of UTI in children is the prevention of such complications. Medical treatment includes long-term antimicrobial prophylaxis to be continued for periods ranging from 6 months to 2 years. Recent studies have revealed the emergence of therapy-induced resistance. A review of the literature has highlighted the lack of properly designed, large clinical trials, demonstrating the efficacy of long-term low-dose antimicrobial prophylaxis in terms of reduction in UTI recurrence.

Methods and design

The study is a controlled, randomised, open-label, 3-armed, parallel-group clinical trial comparing no prophylaxis (group 1) with prophylaxis with co-trimoxazole 15 mg/kg daily (group 2) and with amoxicillin + clavulanic acid 15 mg/kg daily (group 3) for 12 months.

Assuming that the incidence of recurrences is 20%, defining efficacy as an incidence of 10% per group and setting  error = 0.05 and power = 90%, 220 patients per group (i.e. a total of 660 patients) are required The study population will consist of children aged between 2 months and 6 years, with normal renal function (creatinine clearance  70 ml/min/1.73m2) and a first episode of documented UTI, who presents at least one of the following: an acute pyelonephritic lesion at the DMSA scan and/or a VUR at the baseline micturating cystography.

Patients will be followed-up for 12 months. Urinalysis and urine cultures will be performed every month and clinical examinations after 6 and 12 months; both will be performed whenever UTI is suspected. Sonography, Doppler sonography (optional) and DMSA scintigraphy will be performed at baseline and at the end of the study.

Eligibility criteria: Inclusion Criteria:

* Age between 2 months and 6 years
* Creatinine clearance (calculated according to Schwartz)  70 ml/min/1.73 m2 (for children in their first year of life, serum creatinine levels within normal range for age and sex)
* First documented upper UTI (diagnostic criteria in Table 1)
* Imaging Diagnostic work-up completed (Table 2) with at least the presence of an acute lesion at the DMSA scan and or a primary non severe reflux ( 1st or 3rd degree)
* Informed consent of parents

Exclusion Criteria:

* Patients with chronic renal insufficiency or  30% relative function of one kidney at DMSA scan
* Patients with urinary tract disorders, such as vesico-ureteral reflux due to complex malformations of the urinary tract, obstruction of the posterior urethra, ureterocele or single kidney, neurogenic bladder
* Patients with reflux  4th degree
* Patients with pyelonephritis that developed during prophylaxis instituted because of prenatal diagnosis of urinary tract dilatation  Hypersensitivity to one of the two selected antimicrobial agents

Primary outcomes:
measure: The primary end-point is UTI Recurrence Rate during the 12-month observation period and the Development of renal damage (parenchymal scar) after 12 months.
Secondary outcomes:
measure: The secondary objectives are the comparison, in terms of efficacy and effectiveness, between two antimicrobial agents that are currently approved for prophylactic use: co-trimoxazole 15 mg/kg daily versus amoxicillin + clavulanic acid 15 mg/kg daily.
Other outcomes:
Locations:
city: Bentivoglio
country: Italy
facility: Pediatric Unit, Ospedale di Bentivoglio
state: Bologna
city: Monselice
country: Italy
facility: Pediatric Unit, Ospedale di Este - Monselice
state: Padova
city: Piove di Sacco
country: Italy
facility: Pediatric Unit, Ospedale di Piove di Sacco e Chioggia
state: Padova
city: Castelfranco Veneto
country: Italy
facility: Pediatric Unit, Ospedale di Castelfranco
state: Treviso
city: Motta di Livenza Oderzo
country: Italy
facility: Pediatric Unit, Ospedale di Motta di Livenza
state: Treviso
city: Dolo
country: Italy
facility: Pediatric Unit, Ospedale di Dolo
state: Venezia
city: Soave
country: Italy
facility: Pediatric Unit, Ospedale di Soave
state: Verona
city: Thiene
country: Italy
facility: Pediatric Unit, Ospedale di Schio/Thiene
state: Vicenza
city: Belluno
country: Italy
facility: Pediatric Unit, Ospedale di Belluno
city: Bologna
country: Italy
facility: Pediatric Department, Ospedale Maggiore
city: Bolzano
country: Italy
facility: - Pediatric Department, Ospedale di Bolzano
city: Cuneo
country: Italy
facility: Pediatric Unit, Ospedale di Cuneo
city: Mestre Venezia
country: Italy
facility: Pediatric Unit, Ospedale di Mestre
city: Padova
country: Italy
facility: Nephrology, Dialysis and transplant Unit Pediatric Depatment,
city: Ravenna
country: Italy
facility: Pediatric Unit, Ospedale di Ravenna
city: Verona
country: Italy
facility: Pediatric Unit, Ospedale di Verona
Study officials:
affiliation: Departement of Pediatrics, University of Padova
name: Graziella Zacchello, Professor
role: STUDY_CHAIR
affiliation: Pediatric Unit Ospedale di Oderzo (TV) Italy
name: Antonella Toffolo, Dr
role: PRINCIPAL_INVESTIGATOR
name: Alessandro Calderan, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Nephrology, Dialysis and Transplant Unit, Pediatric Departement, Azienda Ospedaliera-Università, Padova
name: Giovanni Montini, Dr
role: PRINCIPAL_INVESTIGATOR
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citation: Ghiro L, Cracco AT, Sartor M, Comacchio S, Zacchello G, Dall'Amico R; Veneto Urinary Tract Infection Study Group. Retrospective study of children with acute pyelonephritis. Evaluation of bacterial etiology, antimicrobial susceptibility, drug management and imaging studies. Nephron. 2002 Jan;90(1):8-15. doi: 10.1159/000046308.
citation: Montini G, Rigon L, Zucchetta P, Fregonese F, Toffolo A, Gobber D, Cecchin D, Pavanello L, Molinari PP, Maschio F, Zanchetta S, Cassar W, Casadio L, Crivellaro C, Fortunati P, Corsini A, Calderan A, Comacchio S, Tommasi L, Hewitt IK, Da Dalt L, Zacchello G, Dall'Amico R; IRIS Group. Prophylaxis after first febrile urinary tract infection in children? A multicenter, randomized, controlled, noninferiority trial. Pediatrics. 2008 Nov;122(5):1064-71. doi: 10.1542/peds.2007-3770.
citation: Hewitt IK, Zucchetta P, Rigon L, Maschio F, Molinari PP, Tomasi L, Toffolo A, Pavanello L, Crivellaro C, Bellato S, Montini G. Early treatment of acute pyelonephritis in children fails to reduce renal scarring: data from the Italian Renal Infection Study Trials. Pediatrics. 2008 Sep;122(3):486-90. doi: 10.1542/peds.2007-2894.