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

NCT ID: NCT02021006

Last Updated: 2023-09-28

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE3
• Total Enrollment: 292 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-31
• Study Completion Date: 2025-01-31

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

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

ANTIBIOTIC PROPHYLAXIS

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)

Group Type: ACTIVE_COMPARATOR

nitrofurantoin

Intervention Type: DRUG

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)

Amoxicillin-Potassium Clavulanate Combination

Intervention Type: DRUG

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)

Trimethoprim/sulfamethoxazole

Intervention Type: DRUG

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)

Cefixime

Intervention Type: DRUG

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)

NO PROPHYLAXIS

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

Group Type: EXPERIMENTAL

No prophylaxis

Intervention Type: OTHER

children will be followed, but no antibiotic prophylaxis will be administered

Interventions

nitrofurantoin

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

No prophylaxis

children will be followed, but no antibiotic prophylaxis will be administered

Intervention Type: OTHER

Amoxicillin-Potassium Clavulanate Combination

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

Trimethoprim/sulfamethoxazole

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

Cefixime

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

Other Intervention Names

Furadantin; amoxicilline/clavulanic acid, augmentin, clavulin; bactrim; cefixoral

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.

• Minimum Eligible Age: 1 Month
• Maximum Eligible Age: 4 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ministero della Salute, Italy

OTHER

Sponsor Role: collaborator

IL Sogno di Stefano

OTHER

Sponsor Role: collaborator

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

OTHER

Sponsor Role: lead

Responsible Party

Giovanni Montini

Prof.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Giovanni Montini, MD

Role: STUDY_CHAIR

Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan

Franz Schaefer, Professor

Role: STUDY_DIRECTOR

Center for Pediatrics and Adolescent Medicine Division of Pediatric Nephrology, Heidelberg, Germany

Otto Mehls, Professor

Role: PRINCIPAL_INVESTIGATOR

Center for Pediatrics and Adolescent Medicine Division of Pediatric Nephrology, Heidelberg, Germany

Lutz T. Weber, Professor

Role: PRINCIPAL_INVESTIGATOR

Ärztlicher Leiter der Kindernephrologie Klinik und Poliklinik für Kinder- und Jugendmedizin Uniklinik Köln - Köln

Aleksandra M Zurowska, Professor

Role: PRINCIPAL_INVESTIGATOR

Medical University of Gdansk, Department Paediatric & Adolescent Nephrology & Hypertension - Gdansk - Poland

Fatos Yalcinkaya, Professor

Role: PRINCIPAL_INVESTIGATOR

Department of Pediatric Nephrology, School of Medicine, Ankara University, Ankara, Turkey

Esra Baskin, Professor

Role: PRINCIPAL_INVESTIGATOR

Paediatric Nephrology Division, Department of Paediatrics, Faculty of Medicine, Baskent University, Ankara, Turkey

Enrico Verrina, MD

Role: PRINCIPAL_INVESTIGATOR

UOC Nefrologia, Dialisi e Trapianto, IRCCS Giannina Gaslini, Genova, Italy

William Morello, MD

Role: PRINCIPAL_INVESTIGATOR

Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan

Piotr Czarniak, MD

Role: PRINCIPAL_INVESTIGATOR

Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, Gdansk - Poland

Locations

Pediatric Nephrology Dialysis and Transplant Unit IRCCS Ca'Granda

Milan, , Italy

Countries

Italy

References

Morello W, Baskin E, Jankauskiene A, Yalcinkaya F, Zurowska A, Puccio G, Serafinelli J, La Manna A, Krzemien G, Pennesi M, La Scola C, Becherucci F, Brugnara M, Yuksel S, Mekahli D, Chimenz R, De Palma D, Zucchetta P, Vajauskas D, Drozdz D, Szczepanska M, Caliskan S, Lombet J, Minoli DG, Guarino S, Gulleroglu K, Ruzgiene D, Szmigielska A, Barbi E, Ozcakar ZB, Kranz A, Pasini A, Materassi M, De Rechter S, Ariceta G, Weber LT, Marzuillo P, Alberici I, Taranta-Janusz K, Caldas Afonso A, Tkaczyk M, Catala M, Cabrera Sevilla JE, Mehls O, Schaefer F, Montini G; PREDICT Study Group. Antibiotic Prophylaxis in Infants with Grade III, IV, or V Vesicoureteral Reflux. N Engl J Med. 2023 Sep 14;389(11):987-997. doi: 10.1056/NEJMoa2300161. Epub 2023 Sep 12.

Reference Type: DERIVED

PMID: 37702442 (View on PubMed)

Other Identifiers

PREDICT trial

Identifier Type: -

Identifier Source: org_study_id