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Antibiotic Prophylaxis and Renal Damage In Congenital Abnormalities of the Kidney and Urinary Tract (PREDICT)

Primary Purpose

Vesicoureteral Reflux, Renal Hypodysplasia, Nonsyndromic, 1, Chronic Kidney Disease

Status
Active
Phase
Phase 3
Locations
Italy
Study Type
Interventional
Intervention
nitrofurantoin
No prophylaxis
Amoxicillin-Potassium Clavulanate Combination
Trimethoprim/sulfamethoxazole
Cefixime
Sponsored by
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Vesicoureteral Reflux focused on measuring antibiotic prophylaxis, vesicoureteral reflux, congenital abnormalities of kidney, renal hypodysplasia, chronic kidney disease

Eligibility Criteria

1 Month - 4 Months (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Pediatric Nephrology Dialysis and Transplant Unit IRCCS Ca'Granda

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

ANTIBIOTIC PROPHYLAXIS

NO PROPHYLAXIS

Arm Description

Children in this arm will take antibiotic prophylaxis for 2 years. Patients in this arm will do clinical/instrumental follow-up for 5 years. The antibiotic for prophylaxis will be chosen by Physicians according to the local resistance spectrum of bacteria responsible of UTIs Physicians can chose one the following schedules: nitrofurantoin 1.5-2 mg/kg per day Amoxicillin-Potassium Clavulanate Combination 15 mg/kg per day (dose expressed in units equivalent to amoxicilline) cefixime 2 mg/kg per day trimethoprim/sulfamethoxazole 2.5 mg/kg per day (dose expressed in units equivalent to trimethoprim)

Children in this arm will not take antibiotic prophylaxis. Patients in this arm will do clinical/instrumental follow-up for 5 years

Outcomes

Primary Outcome Measures

urinary tract infections rate
Urinary tract infections will be strictly monitored in all enrolled patients (both group A and group B). The rate of urinary tract infections in the first 24 months from the enrolment will be compared between 2 groups

Secondary Outcome Measures

febrile urinary tract infections
Febrile urinary tract infections will be strictly monitored in all enrolled patients (both group A and group B). The rate of febrile urinary tract infections in the first 24 months from the enrolment will be compared between 2 groups
renal scars
the appearance of renal scars in a dimercaptosuccinic acid (DMSA) scan will be detected at 2 and 5 years from enrolment and compared between the 2 groups.
serum creatinine (renal function)
The renal function (serum creatinine) will be monitored for all enrolled patients to explore the appearance and progression of renal damage
hypertension
the appearance of hypertension will be monitored at every visit in all enrolled children
proteinuria
the appearance of proteinuria will be monitored at every visit in all enrolled children
body mass index
body mass index will be evaluated at 2 and 5 years of follow-up and it will be correlated to the use of antibiotic prophylaxis
serum cystatin C (renal function)
The renal function (serum cystatin-C) will be monitored for all enrolled patients to explore the appearance and progression of renal damage
modification in gut microbiota induced by continuous antibiotic exposure during the first months of life
A stool sample will be collected, frozen and stored for gut microbiota and resistome profile analysis

Full Information

First Posted
December 1, 2013
Last Updated
September 26, 2023
Sponsor
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Collaborators
Ministero della Salute, Italy, IL Sogno di Stefano
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1. Study Identification

Unique Protocol Identification Number
NCT02021006
Brief Title
Antibiotic Prophylaxis and Renal Damage In Congenital Abnormalities of the Kidney and Urinary Tract
Acronym
PREDICT
Official Title
Antibiotic Prophylaxis and Renal Damage In Congenital Abnormalities of the Kidney and Urinary Tract
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 2013 (undefined)
Primary Completion Date
January 2020 (Actual)
Study Completion Date
January 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Collaborators
Ministero della Salute, Italy, IL Sogno di Stefano

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Vesicoureteral Reflux, Renal Hypodysplasia, Nonsyndromic, 1, Chronic Kidney Disease
Keywords
antibiotic prophylaxis, vesicoureteral reflux, congenital abnormalities of kidney, renal hypodysplasia, chronic kidney disease

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
292 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ANTIBIOTIC PROPHYLAXIS
Arm Type
Active Comparator
Arm Description
Children in this arm will take antibiotic prophylaxis for 2 years. Patients in this arm will do clinical/instrumental follow-up for 5 years. The antibiotic for prophylaxis will be chosen by Physicians according to the local resistance spectrum of bacteria responsible of UTIs Physicians can chose one the following schedules: nitrofurantoin 1.5-2 mg/kg per day Amoxicillin-Potassium Clavulanate Combination 15 mg/kg per day (dose expressed in units equivalent to amoxicilline) cefixime 2 mg/kg per day trimethoprim/sulfamethoxazole 2.5 mg/kg per day (dose expressed in units equivalent to trimethoprim)
Arm Title
NO PROPHYLAXIS
Arm Type
Experimental
Arm Description
Children in this arm will not take antibiotic prophylaxis. Patients in this arm will do clinical/instrumental follow-up for 5 years
Intervention Type
Drug
Intervention Name(s)
nitrofurantoin
Other Intervention Name(s)
Furadantin
Intervention Description
antibiotic prophylaxis of urinary tract infections The antibiotic for prophylaxis will be chosen by Physicians according to the local resistance spectrum of bacteria responsible of UTIs Physicians can chose one the following schedules: nitrofurantoin 1.5-2 mg/kg per day amoxicilline/clavulanic acid 15 mg/kg per day (dose expressed in units equivalent to amoxicilline) cefixime 2 mg/kg per day trimethoprim/sulfamethoxazole 2.5 mg/kg per day (dose expressed in units equivalent to trimethoprim)
Intervention Type
Other
Intervention Name(s)
No prophylaxis
Intervention Description
children will be followed, but no antibiotic prophylaxis will be administered
Intervention Type
Drug
Intervention Name(s)
Amoxicillin-Potassium Clavulanate Combination
Other Intervention Name(s)
amoxicilline/clavulanic acid, augmentin, clavulin
Intervention Description
antibiotic prophylaxis of urinary tract infections The antibiotic for prophylaxis will be chosen by Physicians according to the local resistance spectrum of bacteria responsible of UTIs Physicians can chose one the following schedules: nitrofurantoin 1.5-2 mg/kg per day amoxicilline/clavulanic acid 15 mg/kg per day (dose expressed in units equivalent to amoxicilline) cefixime 2 mg/kg per day trimethoprim/sulfamethoxazole 2.5 mg/kg per day (dose expressed in units equivalent to trimethoprim)
Intervention Type
Drug
Intervention Name(s)
Trimethoprim/sulfamethoxazole
Other Intervention Name(s)
bactrim
Intervention Description
antibiotic prophylaxis of urinary tract infections The antibiotic for prophylaxis will be chosen by Physicians according to the local resistance spectrum of bacteria responsible of UTIs Physicians can chose one the following schedules: nitrofurantoin 1.5-2 mg/kg per day amoxicilline/clavulanic acid 15 mg/kg per day (dose expressed in units equivalent to amoxicilline) cefixime 2 mg/kg per day trimethoprim/sulfamethoxazole 2.5 mg/kg per day (dose expressed in units equivalent to trimethoprim)
Intervention Type
Drug
Intervention Name(s)
Cefixime
Other Intervention Name(s)
cefixoral
Intervention Description
antibiotic prophylaxis of urinary tract infections The antibiotic for prophylaxis will be chosen by Physicians according to the local resistance spectrum of bacteria responsible of UTIs Physicians can chose one the following schedules: nitrofurantoin 1.5-2 mg/kg per day amoxicilline/clavulanic acid 15 mg/kg per day (dose expressed in units equivalent to amoxicilline) cefixime 2 mg/kg per day trimethoprim/sulfamethoxazole 2.5 mg/kg per day (dose expressed in units equivalent to trimethoprim)
Primary Outcome Measure Information:
Title
urinary tract infections rate
Description
Urinary tract infections will be strictly monitored in all enrolled patients (both group A and group B). The rate of urinary tract infections in the first 24 months from the enrolment will be compared between 2 groups
Time Frame
during the first 24 months from enrolment
Secondary Outcome Measure Information:
Title
febrile urinary tract infections
Description
Febrile urinary tract infections will be strictly monitored in all enrolled patients (both group A and group B). The rate of febrile urinary tract infections in the first 24 months from the enrolment will be compared between 2 groups
Time Frame
during the first 24 months from enrolment
Title
renal scars
Description
the appearance of renal scars in a dimercaptosuccinic acid (DMSA) scan will be detected at 2 and 5 years from enrolment and compared between the 2 groups.
Time Frame
at 2 years and 5 years from enrolment
Title
serum creatinine (renal function)
Description
The renal function (serum creatinine) will be monitored for all enrolled patients to explore the appearance and progression of renal damage
Time Frame
at the enrolment,1 year, 2 years, 3 years, 4 years, 5 years
Title
hypertension
Description
the appearance of hypertension will be monitored at every visit in all enrolled children
Time Frame
at 4, 8, 12, 18, 24, 36, 48, 60 months from enrolment
Title
proteinuria
Description
the appearance of proteinuria will be monitored at every visit in all enrolled children
Time Frame
at 4, 8, 12, 18, 24, 36, 48, 60 months from enrolment
Title
body mass index
Description
body mass index will be evaluated at 2 and 5 years of follow-up and it will be correlated to the use of antibiotic prophylaxis
Time Frame
at 2 and 5 years from enrolment
Title
serum cystatin C (renal function)
Description
The renal function (serum cystatin-C) will be monitored for all enrolled patients to explore the appearance and progression of renal damage
Time Frame
at the enrolment,1 year, 2 years, 3 years, 4 years, 5 years
Title
modification in gut microbiota induced by continuous antibiotic exposure during the first months of life
Description
A stool sample will be collected, frozen and stored for gut microbiota and resistome profile analysis
Time Frame
at the enrollment, 4 months, 8 months, 12 months, 2 years, 3 years, 4 years, 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Month
Maximum Age & Unit of Time
4 Months
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Giovanni Montini, MD
Organizational Affiliation
Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Franz Schaefer, Professor
Organizational Affiliation
Center for Pediatrics and Adolescent Medicine Division of Pediatric Nephrology, Heidelberg, Germany
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Otto Mehls, Professor
Organizational Affiliation
Center for Pediatrics and Adolescent Medicine Division of Pediatric Nephrology, Heidelberg, Germany
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Lutz T. Weber, Professor
Organizational Affiliation
Ärztlicher Leiter der Kindernephrologie Klinik und Poliklinik für Kinder- und Jugendmedizin Uniklinik Köln - Köln
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Aleksandra M Zurowska, Professor
Organizational Affiliation
Medical University of Gdansk, Department Paediatric & Adolescent Nephrology & Hypertension - Gdansk - Poland
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Fatos Yalcinkaya, Professor
Organizational Affiliation
Department of Pediatric Nephrology, School of Medicine, Ankara University, Ankara, Turkey
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Esra Baskin, Professor
Organizational Affiliation
Paediatric Nephrology Division, Department of Paediatrics, Faculty of Medicine, Baskent University, Ankara, Turkey
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Enrico Verrina, MD
Organizational Affiliation
UOC Nefrologia, Dialisi e Trapianto, IRCCS Giannina Gaslini, Genova, Italy
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
William Morello, MD
Organizational Affiliation
Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Piotr Czarniak, MD
Organizational Affiliation
Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, Gdansk - Poland
Official's Role
Principal Investigator
Facility Information:
Facility Name
Pediatric Nephrology Dialysis and Transplant Unit IRCCS Ca'Granda
City
Milan
ZIP/Postal Code
20122
Country
Italy

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Antibiotic Prophylaxis and Renal Damage In Congenital Abnormalities of the Kidney and Urinary Tract

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