Clinical trial NCT02021006: Antibiotic Prophylaxis and Renal Damage In Congenital Abnormalities of the Kidney and Urinary Tract
Official title: Antibiotic Prophylaxis and Renal Damage In Congenital Abnormalities of the Kidney and Urinary Tract
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Vesicoureteral Reflux
Renal Hypodysplasia, Nonsyndromic, 1
Chronic Kidney Disease
Keywords: antibiotic prophylaxis
vesicoureteral reflux
congenital abnormalities of kidney
renal hypodysplasia
chronic kidney disease
Lead sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Sponsor class: OTHER
Collaborators: name: Ministero della Salute, Italy
name: IL Sogno di Stefano
First posted: 2013-12-27
Enrollment: 292
Sex: ALL
Minimum age (years): 1
Maximum age (years): 4
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The exact role of urinary tract infection in the appearance of chronic kidney disease is unclear. Children with congenital malformations of kidney and urinary tract have the higher risk of impairment of renal function. To understand if the use of antibiotic prophylaxis can reduce the risk of urinary tract infection in children with these malformations, this study will randomize children in two groups. Group A will not take antibiotic prophylaxis, Group B will take antibiotic prophylaxis for 2 years. This study will assess if antibiotic prophylaxis reduce the risk of urinary tract infections in these children and if urinary tract infections influence the appearance of renal damage.

Our hypothesis is that prophylaxis reduce the risk of infection in severe vesicoureteral reflux and that urinary tract infections, in morphologically normal kidneys, will not result in chronic renal failure.

Detailed description: Bacterial urinary tract infections (UTI) are common in young children. The presence of fever is considered to be a marker of renal parenchymal involvement. Renal damage during the acute phase of infection may lead to scarring, yet the role that scarring plays in the appearance of chronic kidney failure is unknown. It is also unclear what influence scars have on the natural course of kidney function, especially in children with renal hypodysplasia, with or without vesicoureteral reflux (VUR). Renal hypodysplasia is the most common cause for dialysis and transplantation in the pediatric population.

Patients suffering from recurrent UTIs and VUR have often undergone corrective surgery. For many years, it was also thought necessary to prescribe long-term antibiotic prophylaxis to all children with VUR. These treatment strategies were based on the ideas and opinions of the experts, rather than on hard scientific evidence. As regards the prevention of recurrent UTIs and the subsequent development of renal scarring, a long-term international study on Reflux was not able to demonstrate that surgical correction is more effective than antibiotic prophylaxis. Very little data is available regarding the use of long-term antibiotic prophylaxis in children with high grade reflux with or without renal hypodysplasia.

The use of antibiotics during the first few months of life has been associated with a significant increase in body mass index (BMI). Even though this effect is probably limited, it could have a significant impact on public health given the widespread use of antibiotics and due to the considerable increase in cases of pediatric and adult obesity seen over the last few years.

In spite of the lack of evidence, the use of prophylaxis is largely routine practice in most centres. Therefore, a randomized study is necessary in order to evaluate whether prophylaxis reduces the risk of symptomatic infections and subsequent renal damage.

To assess the role of prophylaxis in patient with high grade vesicoureteral reflux we will perform a multicentre, prospective, randomized, controlled, open-label, study.

Patients enrolled will be randomized in two groups:

Group A: no antibiotic prophylaxis. Group B: antibiotic prophylaxis for 24 months. The choice of which antibiotic to prescribe from the list below is left to the discretion of each investigator, on the basis of local antibiotic resistance patterns.

* nitrofurantoin 1.5-2 mg/kg per day
* amoxicilline/clavulanic acid 15 mg/kg per day (dose expressed in units equivalent to amoxicillin)
* cefixime 2 mg/kg per day
* trimethoprim/sulfamethoxazole 2.5 mg/kg per day (dose expressed in units equivalent to trimethoprim)

The study is comprised of:

* Phase 1: Pre-randomization - screening tests to determine eligibility for the trial.
* Phase 2: Active treatment - this phase follows randomization and foresees 24 months of antibiotic prophylaxis for Group B and clinical surveillance for Group A.
* Phase 3: Follow-up - a further 36 months of clinical, laboratory and instrumental evaluation of renal function and the progression of renal damage for a total follow-up period of 5 years

Eligibility criteria: Inclusion Criteria:

* Age between 1 and 4 months (\> 4 weeks and \<20 weeks of post-natal age)
* Gestational age \> 35 weeks
* Glomerular filtration rate (calculated according to Schwartz) \> 15 ml/min/1.73 m2
* No previous symptomatic UTI
* Imaging Diagnostic work-up completed and presence of grade III to V vesicoureteral reflux
* Informed consent of parents

Exclusion Criteria:

* Age \<1 and \>4 months
* Gestational age \< 35 weeks
* Glomerular filtration rate (calculated according to Schwartz) \< 15 ml/min/1.73 m2 at three months of age
* Patients with neurogenic bladder, myelomeningocele, ureteropelvic junction and/or ureterovesical junction obstruction, or other malformations leading to potential voiding disturbances.
* Presence of urethral valves
* Patients with no or low grade reflux (grade I and II).
* Hypersensitivity to the all the utilized antimicrobial agent
* Children with serious clinical conditions which, according to the investigator, prevent them from being included in the study cohort.
* Use of experimental drugs in the month previous to the beginning of the study
* Children unable to follow the established protocol procedures or whose parents are unable to sign the informed consent.

Primary outcomes:
measure: urinary tract infections rate
timeFrame: during the first 24 months from enrolment
Secondary outcomes:
measure: febrile urinary tract infections
timeFrame: during the first 24 months from enrolment
measure: renal scars
timeFrame: at 2 years and 5 years from enrolment
measure: serum creatinine (renal function)
timeFrame: at the enrolment,1 year, 2 years, 3 years, 4 years, 5 years
measure: hypertension
timeFrame: at 4, 8, 12, 18, 24, 36, 48, 60 months from enrolment
measure: proteinuria
timeFrame: at 4, 8, 12, 18, 24, 36, 48, 60 months from enrolment
measure: body mass index
timeFrame: at 2 and 5 years from enrolment
measure: serum cystatin C (renal function)
timeFrame: at the enrolment,1 year, 2 years, 3 years, 4 years, 5 years
measure: modification in gut microbiota induced by continuous antibiotic exposure during the first months of life
timeFrame: at the enrollment, 4 months, 8 months, 12 months, 2 years, 3 years, 4 years, 5 years
Other outcomes:
Locations:
city: Milan
country: Italy
facility: Pediatric Nephrology Dialysis and Transplant Unit IRCCS Ca'Granda
Study officials:
affiliation: Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan
name: Giovanni Montini, MD
role: STUDY_CHAIR
affiliation: Center for Pediatrics and Adolescent Medicine Division of Pediatric Nephrology, Heidelberg, Germany
name: Franz Schaefer, Professor
role: STUDY_DIRECTOR
affiliation: Center for Pediatrics and Adolescent Medicine Division of Pediatric Nephrology, Heidelberg, Germany
name: Otto Mehls, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Ärztlicher Leiter der Kindernephrologie Klinik und Poliklinik für Kinder- und Jugendmedizin Uniklinik Köln - Köln
name: Lutz T. Weber, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Medical University of Gdansk, Department Paediatric & Adolescent Nephrology & Hypertension - Gdansk - Poland
name: Aleksandra M Zurowska, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Pediatric Nephrology, School of Medicine, Ankara University, Ankara, Turkey
name: Fatos Yalcinkaya, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Paediatric Nephrology Division, Department of Paediatrics, Faculty of Medicine, Baskent University, Ankara, Turkey
name: Esra Baskin, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: UOC Nefrologia, Dialisi e Trapianto, IRCCS Giannina Gaslini, Genova, Italy
name: Enrico Verrina, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan
name: William Morello, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, Gdansk - Poland
name: Piotr Czarniak, MD
role: PRINCIPAL_INVESTIGATOR
References: