Efficacy and Safety of Circumcision Alone on Risk of Febrile Urinary Tract Infections in Boys With Posterior Urethral Valves: a Prospective Randomized Open-label Multicentric Trial Enriched With Historic Controls. (CIRCUP 2)

Boys with posterior urethral valves (PUV) are at increased risk of developing febrile urinary tract infections (fUTIs). As shown in the CIRCUP trial, circumcision plus antibiotic prophylaxis reduces the risk of FUTIs compared with antibiotic prophylaxis alone. This multicenter randomised controlled trial prospectively compares circumcision alone with circumcision plus antibiotic prophylaxis for the prevention of fUTIs in boys with PUV, enriched with external historical data from the CIRCUP trial)

Study Overview

• Status: Not yet recruiting
• Conditions: Posterior Urethral Valves
• Intervention / Treatment: Procedure: Circumcision; Drug: Antibiotics strategy

Detailed Description

Posterior urethral valves (PUV) are the most common cause of Lower Urinary Tract Obstruction (LUTO) in boys. They affect around 1:5000 births, causing increased intravesical pressure during fetal kidney development. They are associated with congenital renal dysplasia, abnormal bladder function and represent the most common obstructive cause of End-Stage Renal Failure in childhood. Postnatal primary valve ablation is the treatment of choice.

Despite optimal postnatal management, these patients present an increased risk of febrile urinary tract infection (fUTI). Febrile urinary tract infections in infants cause morbidity, require intravenous treatment and if they recur, can contribute to renal damage. Long-term prophylactic antibiotic treatment was therefore, until recently, the standard of care.

At the same time, circumcision was also supposed to decrease the rate of fUTI. This is why we conducted, between 2012 and 2017, the CIRCUP randomized controlled trial (PHRC-I) to determine whether circumcision in addition to antibiotic prophylaxis further decreased the risk of fUTI in boys with PUV, within the first two years of life.

We chose boys with PUV as they were undergoing surgery for their valve resection in any case, and the circumcision did not require an additional anaesthesia.

The results of the CIRCUP study were clear. The risk of fUTI was 3% in the Circumcision and antibiotic prophylaxis group vs 20% in the antibiotic prophylaxis alone group (RR: 10.3 (95% CI: 1.3 - 82.5)) (Circumcision and risk of febrile urinary tract infection in boys with posterior urethral valves. Harper L et al. 2022. Eur Urol (5), Annex 1).

The results from this study brought us, as well as several other teams (who either contacted us directly or as comments to our published study) to question the utility of antibiotic prophylaxis in circumcised boys with PUV (antibiotic prophylaxis has potential deleterious effects, both individually, and in terms of public health perspective). Circumcision alone could be a legitimate prophylactic strategy, in terms of balance between efficacy and risk of promoting antibiotic resistance.

We therefore aim to conduct a new clinical trial in boys with PUV to assess the effects of circumcision alone (without antibiotic prophylaxis) on the risk of fUTI using an efficient randomized trial design in this pediatric rare disease setting by incorporating data from the previous CIRCUP trial. This would allow us the identify risk of presenting a febrile UTI in circumcised boys with PUV and no antibiotic prophylaxis. This would help us determine the optimal strategy for UTI prevention in this population and discuss options with the parents.

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Aurore Capelli, PhD; Phone Number: +33557820877; Email: aurore.capelli@chu-bordeaux.fr
• Study Contact Backup: Name: Luke HARPER, MD; Phone Number: 05 56 79 56 17; Email: luke.harper@chu-bordeaux.fr

Study Locations

• France
  • Besançon, France
    • CHU de Besançon
    • Contact: Yann Chaussy, MD; Phone Number: 03 81 81 93 33; Email: ychaussy@chu-besancon.fr
  • Bordeaux, France
    • CHU de Bordeaux
    • Contact: Luke HARPER, MD; Phone Number: 05 56 79 98 11; Email: luke.harper@chu-bordeaux.fr
  • Limoges, France
    • CHU de Limoges
    • Contact: Quentin BALLOUHEY, MD; Phone Number: 06 32 85 96 60; Email: quentin.ballouhey@chu-limoges.fr
  • Marseille, France
    • APHM
    • Contact: Alice Faure, MD; Phone Number: 04 91 38 66 82; Email: alice.faure@ap-hm.fr
  • Montpellier, France
    • CHU de Montpellier
    • Contact: Nicolas Kalfa, MD; Phone Number: 04 67 33 87 84; Email: nicolaskalfa@gmail.com
  • Nantes, France
    • CHU de Nantes
    • Contact: Thomas Loubersac, MD; Phone Number: 02 40 08 33 33; Email: thomas.loubersac@chu-nantes.fr
  • Paris, France, 75019
    • APHP Hopital Robert Debré
    • Contact: Matthieu Peycelon, MD; Phone Number: 01 40 03 36 82; Email: matthieu.peycelon@aphp.fr
  • Paris, France, 75012
    • APHP Hôpital Armand Trousseau
    • Contact: Pauline Clermidi, MD; Phone Number: 01 71 73 80 05; Email: pauline.clermidi@aphp.fr
  • Paris, France, 75015
    • APHP Hôpital Necker
    • Contact: Thomas Blanc, MD; Phone Number: 01 44 49 41 86; Email: thomas.blanc@aphp.fr
  • Reims, France
    • CHU de Reims
    • Contact: Nadia Boudaoud, MD; Phone Number: 03 26 78 36 15; Email: nboudaoud@chu-reims.fr
  • Rennes, France
    • CHU de Rennes
    • Contact: Alexis Arnaud, MD; Phone Number: 02 99 28 43 21; Email: alexis.arnaud@chu-rennes.fr
  • Saint-Denis, France, 97400
    • CHU de la réunion
    • Contact: Etienne SUPLY, MD; Phone Number: 02 62 90 50 50; Email: etienne.suply@chu-reunion.fr
  • Toulouse, France
    • CHU de Toulouse
    • Contact: Olivier Abbo, MD; Phone Number: 05 34 55 85 99; Email: abbo.o@chu-toulouse.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

- Inclusion Criteria:

For prospective groups:

Male child aged 1 to 31 days Posterior urethral valves diagnosed by cystography within the first 28 days of life Valve resection and circumcision performed before 1 month of life. Adult guardians (>18 years) Parental guardians affiliated with a social security system Parental guardians who have signed an informed consent allowing their child to participate in the study Parental guardians giving consent must be able to understand the trial in its entirety

For retrospective groups from CIRCUP : Parental guardians who are not opposed to their child's participation in the trial

- Exclusion Criteria: Mental state rendering the person giving consent incapable of understanding the trial Parents being a relative of the investigator or a relative of someone from the team directly involved in the trial, including assistant doctors, pharmacists, nurses, and trial coordinators Known contra-indication to all antibiotics used in the study (alfatil, Bactrim, augmentin) Long-term antibiotics use indicated for other reasons than PUV

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Research strategy; Prospective strategy administered to participants of CIRCUP 2: Antibiotics-sparing strategy: Circumcision alone, performed at the time of valve resection	Procedure: Circumcision; Circumcision performed at the time of valve resection
Active Comparator: Reference strategy 1; Circumcision, performed at the time of valve resection, plus daily antibiotic prophylaxis up to two years Prospective strategy administered to participants of CIRCUP 2 + Use of data from historical controls from CIRCUP	Procedure: Circumcision; Circumcision performed at the time of valve resection; Drug: Antibiotics strategy; daily antibiotic prophylaxis up to two years
Active Comparator: Reference strategy 2; Daily antibiotic prophylaxis up to two years Use of data from historical controls from CIRCUP	Drug: Antibiotics strategy; daily antibiotic prophylaxis up to two years

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first febrile urinary tract infections (fUTI) between baseline and 2 years	The diagnosis of fUTI is defined as fever (>38.5° Celsius) with evidence of pyuria and culture-proven infection on urinalysis, obtained by urethral catheterization or suprapubic aspiration, as well as biological signs of inflammation.	between baseline and 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median number of fUTIs	Median number of fUTIs at 2 years in children with at least 1 fUTI during follow-up	at 2 years
The proportion of children with worsening renal scans (defined as an increase in heterogeneity and number of cortical defects)	The proportion of children with worsening renal scans (defined as an increase in heterogeneity and number of cortical defects) between baseline and 2-years	between baseline and 2-years
Absolute risk difference of first fUTI with circumcision alone versus circumcision and antibiotic prophylaxis	Absolute risk difference of first fUTI with circumcision alone versus circumcision and antibiotic prophylaxis	at 2 years
Absolute risk difference of first fUTI with circumcision alone versus antibiotic prophylaxis alone	Absolute risk difference of first fUTI with circumcision alone versus antibiotic prophylaxis alone	at 2 years
Absolute risk difference of first fUTI with circumcision and antibiotic prophylaxis versus antibiotic prophylaxis alone	Absolute risk difference of first fUTI with circumcision and antibiotic prophylaxis versus antibiotic prophylaxis alone	at 2 years

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Investigators: Principal Investigator: Luke HARPER, MD, University Hospital, Bordeaux

Publications and helpful links

General Publications

• Harper L, Blanc T, Peycelon M, Michel JL, Leclair MD, Garnier S, Flaum V, Arnaud AP, Merrot T, Dobremez E, Faure A, Fourcade L, Poli-Merol ML, Chaussy Y, Dunand O, Collin F, Huiart L, Ferdynus C, Sauvat F. Circumcision and Risk of Febrile Urinary Tract Infection in Boys with Posterior Urethral Valves: Result of the CIRCUP Randomized Trial. Eur Urol. 2022 Jan;81(1):64-72. doi: 10.1016/j.eururo.2021.08.024. Epub 2021 Sep 22.

Study record dates

Study Major Dates

• Study Start (Estimated): April 13, 2026
• Primary Completion (Estimated): April 13, 2032
• Study Completion (Estimated): April 13, 2032

Study Registration Dates

• First Submitted: April 7, 2026
• First Submitted That Met QC Criteria: April 7, 2026
• First Posted (Actual): April 14, 2026

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Antibiotic prophylaxis; Circumcision; Posterior urethral valves; Febrile Urinary Infection
• Additional Relevant MeSH Terms: Therapeutics; Surgical Procedures, Operative; Urologic Surgical Procedures; Urogenital Surgical Procedures; Body Modification, Non-Therapeutic; Cosmetic Techniques; Urologic Surgical Procedures, Male; Circumcision, Male
• Other Study ID Numbers: CHUBX 2023/52; 2024-519166-48-01 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No