Clinical Trial Testing Whether Targeted Antibiotic Prophylaxis Can Reduce Infections After Cystectomy Compared to Empiric Prophylaxis

NCT ID: NCT06709196

Last Updated: 2025-01-09

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 248 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-01-07
• Study Completion Date: 2027-01-31

Brief Summary

The aim of this trial is to test whether postoperative antibiotics targeted towards bacteria in the urine can reduce the risk of infection after surgical removal of the bladder (cystectomy) compared to a standardised antibiotic prophylaxis.

Participants undergoing cystectomy will be randomly assigned to postoperatively receive (A) a standardised orally administered antibiotic prophylaxis currently given at Rigshospitalet, Copenhagen or (B) a conventional orally administered antibiotic prophylaxis targeting bacteria found in the urine postoperatively.

The investigators' hypothesis is that the targeted prophylactic antibiotic strategy will reduce the number of infection-related readmissions within 90 days of surgery compared to the standardised prophylaxis.

Detailed Description

Surgical removal of the urinary bladder (cystectomy) remains one of the most complex abdominal surgeries. The procedure carries a high risk of infectious complications, and nearly one in three patients are readmitted with infection within 90 days of surgery. Due to lack of high-evidence research on prophylactic antibiotic strategies after cystectomy, the timing, duration, and type of prophylaxis varies considerably across surgical centres and nearly always encompasses a one-size-fits-all approach with an empiric antibiotic. With antibiotic stewardship gaining ground, both patients and the community at large may benefit from a more individualised targeted approach.

The investigators aim to reduce infectious complications in the postoperative course of cystectomy by conducting an investigator-initiated randomised clinical trial testing superiority of targeted antibiotic prophylaxis after cystectomy against the current standard-of-care empiric prophylaxis.

The REINFORCE trial is a multicentre, open-label, randomised, superiority trial. Cystectomy patients will be randomly assigned with a 1:1 allocation to receive one of the following orally administered antibiotic treatments on the day of ureteral stent removal: (A) Standard-of-care arm: Three doses of pivmecillinam 400mg or (B) Intervention arm: Single-day treatment of an antibiotic susceptible to the bacteria detected in a postoperative urine sample collected during index hospitalisation. If no bacteria are detected the participant will not receive antibiotics.

Patients scheduled for cystectomy will be screened for inclusion in the urological outpatient clinic at their allocated hospital. Patients who meet the inclusion and exclusion criteria will be informed of the trial and invited to participate. After informed consent, a preoperative urine culture will be collected and analysed for microbials, and two validated EORTC quality of life questionnaires will be filled out electronically.

After cystectomy during index hospitalisation, participants will deliver a postoperative urine sample, which will be analysed for bacteria and antibiotic susceptibility, and participants will be randomised into one of the two arms.

Apart from the intervention, all participants will follow the standard-of-care pre-, peri-, and postoperative treatment as per hospital guidelines. Participants will be followed for 90 days postoperatively, where complication rates and readmission rates will be collected from the Electronic Medical Records, and participants will be asked to fill out the quality of life questionnaires again.

The primary outcome is infection-related hospital readmissions within 90 days of cystectomy. We aim for an absolute risk reduction in the infection-related readmission rate of 15% (from 29% to 14%), corresponding to a number needed to treat of six patients to reduce one infection-related readmission. With a 1:1 allocation, changing block size, power of 80%, one-sided test, significance level of 0.024 accounting for alpha spending of two sequential analyses using the O'Brien-Fleming boundaries, and an anticipated dropout rate of 5%, a total of 248 participants (124 per arm) needs to be randomised.

All randomised participants will follow an intention-to-treat analysis, regardless of adherence to protocol. If some participants do not receive the allocated treatment, a per-protocol sub-analysis will be performed. The trial utilises a group sequential design to allow for the possibility of early stopping for efficacy, futility, or safety at interim analysis, which will be performed after 50% of participants have been followed for 90 postoperative days.

International guidelines are currently unable to make evidence-based recommendations on how to avoid infections after cystectomy and current antibiotic prophylactic strategies vary greatly across centres. By performing a large multicentre randomised trial to test targeted antibiotic prophylaxis, the investigators aim to improve recovery for patients who have undergone cystectomy by reducing the risk of infections in the months after surgery.

Conditions

Cystectomy; Bladder Cancer Requiring Cystectomy; Postoperative Infections; Antibiotic Prophylaxis; Ileal Conduit

Study Design

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

Study Groups

Targeted antimicrobial prophylaxis

The participants in this arm will receive a single-day orally administered targeted antimicrobial prophylaxis on the day of ureteral stent removal based on the microbiological analysis of a postoperative urine culture.

Group Type: EXPERIMENTAL

Pivmecillinam

Intervention Type: DRUG

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Amoxicillin clavulanic acid

Intervention Type: DRUG

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Amoxicillin

Intervention Type: DRUG

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Cefuroxime

Intervention Type: DRUG

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Ciprofloxacin

Intervention Type: DRUG

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Linezolid

Intervention Type: DRUG

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Nitrofurantoin

Intervention Type: DRUG

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Trimethoprim

Intervention Type: DRUG

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Sulfamethoxazole trimethoprim

Intervention Type: DRUG

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Fluconazole

Intervention Type: DRUG

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Empiric antimicrobial prophylaxis

The participants in this arm will receive three doses of orally administered pivmecillinam 400mg morning, noon, and evening on the day of ureteral stent removal.

Group Type: ACTIVE_COMPARATOR

Pivmecillinam

Intervention Type: DRUG

Orally administered pivmecillinam 400mg

Interventions

Pivmecillinam

Orally administered pivmecillinam 400mg

Intervention Type: DRUG

Pivmecillinam

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Intervention Type: DRUG

Amoxicillin clavulanic acid

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Intervention Type: DRUG

Amoxicillin

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Intervention Type: DRUG

Cefuroxime

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Intervention Type: DRUG

Ciprofloxacin

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Intervention Type: DRUG

Linezolid

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Intervention Type: DRUG

Nitrofurantoin

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Intervention Type: DRUG

Trimethoprim

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Intervention Type: DRUG

Sulfamethoxazole trimethoprim

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Intervention Type: DRUG

Fluconazole

Orally administered targeted antimicrobial prophylaxis based on a urine culture.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Age at surgery ≥ 18 years
• Ability to understand and sign an informed consent
• Malignant or benign indication for undergoing cystectomy
• Planned ileal conduit as urinary diversion

Exclusion Criteria

• Previous severe allergic reaction to antimicrobial treatment
• Long-term prophylactic antibiotic treatment which is expected to be continued after the cystectomy

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Rigshospitalet, Denmark

OTHER

Sponsor Role: lead

Responsible Party

Maja Vejlgaard

Coordinating investigator, MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Andreas Røder, Prof, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Rigshospitalet, Denmark

Locations

Department of Urology, Aalborg University Hospital

Aalborg, , Denmark

Site Status: NOT_YET_RECRUITING

Department of Urology, Aarhus University Hospital

Aarhus, , Denmark

Site Status: NOT_YET_RECRUITING

Department of Urology, Rigshospitalet

Copenhagen, , Denmark

Site Status: RECRUITING

Department of Urology, Herlev and Gentofte Hospital

Herlev, , Denmark

Site Status: NOT_YET_RECRUITING

Department of Urology, Odense University Hospital

Odense, , Denmark

Site Status: NOT_YET_RECRUITING

Countries

Denmark

Central Contacts

Maja Vejlgaard

Role: CONTACT

maja.vejlgaard.02@regionh.dk

+4535456152

Facility Contacts

Knud Fabrin, MD

Role: primary

Jørgen Bjerggaard Jensen, Prof, MD, PhD

Role: primary

Andreas Røder, Prof, MD, PhD

Role: primary

Gitte Lam, MD

Role: primary

Lars Lund, Prof, MD, DMSci

Role: primary

References

Vejlgaard M, Stroomberg HV, Ynddal MS, Moser C, Joensen UN, Roder A. Multicentre, open-label, phase IV, randomised trial testing superiority of individualised targeted antibiotic prophylaxis over empiric prophylaxis at ureteral stent removal following cystectomy: study protocol for the REINFORCE trial. Trials. 2025 Jul 28;26(1):258. doi: 10.1186/s13063-025-08981-w.

Reference Type: DERIVED

PMID: 40722189 (View on PubMed)

Other Identifiers

2024-514312-27-00

Identifier Type: CTIS

Identifier Source: secondary_id

2024-514312-27-00

Identifier Type: -

Identifier Source: org_study_id