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

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.

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.

Study Overview

• Status: Recruiting
• Conditions: Postoperative Infections; Antibiotic Prophylaxis; Cystectomy; Ileal Conduit; Bladder Cancer Requiring Cystectomy
• Intervention / Treatment: Drug: Pivmecillinam; Drug: Pivmecillinam; Drug: Amoxicillin clavulanic acid; Drug: Amoxicillin; Drug: Cefuroxime; Drug: Ciprofloxacin; Drug: Linezolid; Drug: Nitrofurantoin; Drug: Trimethoprim; Drug: Sulfamethoxazole trimethoprim; Drug: Fluconazole

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.

• Study Type: Interventional
• Enrollment (Estimated): 248
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Maja Vejlgaard; Phone Number: +4535456152; Email: maja.vejlgaard.02@regionh.dk

Study Locations

• Denmark
  • Aalborg, Denmark, 9100
    • Not yet recruiting
    • Department of Urology, Aalborg University Hospital
    • Contact: Knud Fabrin, MD
  • Aarhus, Denmark, 8200
    • Not yet recruiting
    • Department of Urology, Aarhus University Hospital
    • Contact: Jørgen Bjerggaard Jensen, Prof, MD, PhD
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Department of Urology, Rigshospitalet
    • Contact: Andreas Røder, Prof, MD, PhD
  • Herlev, Denmark, 2730
    • Not yet recruiting
    • Department of Urology, Herlev and Gentofte Hospital
    • Contact: Gitte Lam, MD
  • Odense, Denmark, 5000
    • Not yet recruiting
    • Department of Urology, Odense University Hospital
    • Contact: Lars Lund, Prof, MD, DMSci

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Pivmecillinam; Orally administered pivmecillinam 400mg; Drug: Pivmecillinam; Orally administered targeted antimicrobial prophylaxis based on a urine culture.; Drug: Amoxicillin clavulanic acid; Orally administered targeted antimicrobial prophylaxis based on a urine culture.; Drug: Amoxicillin; Orally administered targeted antimicrobial prophylaxis based on a urine culture.; Drug: Cefuroxime; Orally administered targeted antimicrobial prophylaxis based on a urine culture.; Drug: Ciprofloxacin; Orally administered targeted antimicrobial prophylaxis based on a urine culture.; Drug: Linezolid; Orally administered targeted antimicrobial prophylaxis based on a urine culture.; Drug: Nitrofurantoin; Orally administered targeted antimicrobial prophylaxis based on a urine culture.; Drug: Trimethoprim; Orally administered targeted antimicrobial prophylaxis based on a urine culture.; Drug: Sulfamethoxazole trimethoprim; Orally administered targeted antimicrobial prophylaxis based on a urine culture.; Drug: Fluconazole; Orally administered targeted antimicrobial prophylaxis based on a urine culture.
Active Comparator: 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.	Drug: Pivmecillinam; Orally administered pivmecillinam 400mg; Drug: Pivmecillinam; Orally administered targeted antimicrobial prophylaxis based on a urine culture.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infection-related readmission rate	The rate of readmissions where the main cause of readmission is symptoms of infection.	90 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative complications	Postoperative complications using the validated Clavien-Dindo classification score, ranging from 1-5 where 1-2 are minor complications and 3-5 are major complications.	30 and 90 days after surgery
Postoperative readmissions	All-cause postoperative readmissions, including the the main cause, timing, and duration.	30 and 90 days after surgery
Days alive and out of hospital	The number of days that the participants are alive and not admitted to the hospital.	30 and 90 days after surgery
Quality of life	Quality-of-life using the validated European Organisation of Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30). Results will be presented as scores ranging from 0-100 where high scores in the global health status and functional scales represent a better quality of life and high scores in the symptom scales represent a high level of symptomatology.	90 days after surgery
Quality of life	Quality-of-life using the validated European Organisation of Research and Treatment of Cancer (EORTC) Quality of Life Muscle-invasive Bladder Cancer Questionnaire (QLQ-BLM30). Results will be presented as scores ranging from 0-100 where high scores in the global health status and functional scales represent a better quality of life and high scores in the symptom scales represent a high level of symptomatology.	90 days after surgery
Microbiological findings	Microbiological findings and antimicrobial susceptibility analyses in pre- and postoperative microbiological samples.	90 days after surgery
Antimicrobial treatment	All antimicrobial treatment registered in the Electronic Medical Records.	90 days after surgery

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Investigators: Principal Investigator: Andreas Røder, Prof, MD, PhD, Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2025
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: November 25, 2024
• First Submitted That Met QC Criteria: November 27, 2024
• First Posted (Actual): November 29, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 8, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Targeted antimicrobial prophylaxis; Infection-related readmissions
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases; Anti-Bacterial Agents; Anti-Infective Agents; Antineoplastic Agents; Antifungal Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Enzyme Inhibitors; Folic Acid Antagonists; Steroid Synthesis Inhibitors; Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Topoisomerase Inhibitors; Topoisomerase II Inhibitors; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anti-Dyskinesia Agents; Protein Synthesis Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Anti-Infective Agents, Urinary; Cytochrome P-450 CYP2C8 Inhibitors; beta-Lactamase Inhibitors; Linezolid; Amoxicillin; Fluconazole; Trimethoprim; Sulfamethoxazole; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination; Trimethoprim, Sulfamethoxazole Drug Combination; Ciprofloxacin; Nitrofurantoin; Cefuroxime; Amdinocillin Pivoxil
• Other Study ID Numbers: 2024-514312-27-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No