Clinical trial NCT06709196: Clinical Trial Testing Whether Targeted Antibiotic Prophylaxis Can Reduce Infections After Cystectomy Compared to Empiric Prophylaxis
Official title: REINFORCE - Reducing Infection-related Readmissions Following Cystectomy. a Multicentre Randomised Clinical Trial Testing Superiority of Individualised Targeted Antibiotic Prophylaxis Over Empiric Prophylaxis At Ureteral Stent Removal to Reduce Infection-related Readmissions Following Cystectomy.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Cystectomy
Bladder Cancer Requiring Cystectomy
Postoperative Infections
Antibiotic Prophylaxis
Ileal Conduit
Keywords: Targeted antimicrobial prophylaxis
Infection-related readmissions
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
First posted: 2024-11-29
Enrollment: 248
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Infection-related readmission rate
timeFrame: 90 days after surgery
Secondary outcomes:
measure: Postoperative complications
timeFrame: 30 and 90 days after surgery
measure: Postoperative readmissions
timeFrame: 30 and 90 days after surgery
measure: Days alive and out of hospital
timeFrame: 30 and 90 days after surgery
measure: Quality of life
timeFrame: 90 days after surgery
measure: Quality of life
timeFrame: 90 days after surgery
measure: Microbiological findings
timeFrame: 90 days after surgery
measure: Antimicrobial treatment
timeFrame: 90 days after surgery
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Department of Urology, Aalborg University Hospital
city: Aarhus
country: Denmark
facility: Department of Urology, Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Department of Urology, Rigshospitalet
city: Herlev
country: Denmark
facility: Department of Urology, Herlev and Gentofte Hospital
city: Odense
country: Denmark
facility: Department of Urology, Odense University Hospital
Study officials:
affiliation: Rigshospitalet, Denmark
name: Andreas Røder, Prof, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: