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.

Condition	Intervention	Phase
Urinary Tract Infections	Drug: antibiotic to reduce the recurrence of infection	Phase IV

Further Study Details: 

Primary Outcomes: 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: 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.
Expected Total Enrollment:  660

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 pielonephritic 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.

Ages Eligible for Study:  2 Months   -   6 Years,  Genders Eligible for Study:  Both

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

Italy
      Pediatric Unit, Ospedale di Mestre, Mestre Venezia,  Italy
      Pediatric Unit, Ospedale di Verona, Verona,  Italy
      Pediatric Department, Ospedale Maggiore, Bologna,  Italy
      Pediatric Unit, Ospedale di Belluno, Belluno,  Italy
      - Pediatric Department, Ospedale di Bolzano, Bolzano,  Italy
      Pediatric Unit, Ospedale di Cuneo, Cuneo,  Italy
      Nephrology, Dialysis and transplant Unit Pediatric Depatment,, Padova,  35128,  Italy
      Pediatric Unit, Ospedale di Ravenna, Ravenna,  Italy
Italy, Bologna
      Pediatric Unit, Ospedale di Bentivoglio, Bentivoglio,  Bologna,  Italy
Italy, Padova
      Pediatric Unit, Ospedale di Este - Monselice, Monselice,  Padova,  Italy
      Pediatric Unit, Ospedale di Piove di Sacco e Chioggia, Piove di Sacco,  Padova,  Italy
Italy, Treviso
      Pediatric Unit, Ospedale di Castelfranco, Castelfranco Veneto,  Treviso,  Italy
      Pediatric Unit, Ospedale di Motta di Livenza, Motta di Livenza Oderzo,  Treviso,  Italy
Italy, Venezia
      Pediatric Unit, Ospedale di Dolo, Dolo,  Venezia,  Italy
Italy, Verona
      Pediatric Unit, Ospedale di Soave, Soave,  Verona,  Italy
Italy, Vicenza
      Pediatric Unit, Ospedale di Schio/Thiene, Thiene,  Vicenza,  Italy

Study chairs or principal investigators

Graziella Zacchello, Professor,  Study Chair,  Departement of Pediatrics, University of Padova   
Antonella Toffolo, Dr,  Principal Investigator,  Pediatric Unit Ospedale di Oderzo (TV) Italy   
Alessandro Calderan, Dr,  Principal Investigator,  Unaffiliated   
Giovanni Montini, Dr,  Principal Investigator,  Nephrology, Dialysis and Transplant Unit, Pediatric Departement, Azienda Ospedaliera-Università, Padova   

Study ID Numbers:  IRIS 2
Last Updated:  September 9, 2005
Record first received:  September 7, 2005
ClinicalTrials.gov Identifier:  NCT00156546
Health Authority: Italy: National Monitoring Centre for Clinical Trials - Ministry of Health
ClinicalTrials.gov processed this record on 2005-09-13