Evaluation of Antibiotic Prophylaxis with Fosfomycin Calcium, Bromhexine Hydrochloride, Sulfamethoxazole, and Trimethoprim in Pre-Surgical Benign Prostate Hyperplasia

The primary objective of this study is to demonstrate that not treating a patient with a polymicrobial **urine bacterial culture** (UBC) performed before benign prostate hyperplasia (BPH) surgery is not inferior to treating with antibiotics in terms of urinary tract infection incidence over a one-month post-surgery period. This is clinically relevant as it may influence the decision-making process regarding the necessity of antibiotic treatment prior to endoscopic surgery for BPH, potentially reducing unnecessary antibiotic use and its associated risks.

Secondary objectives include: - Comparing the rate of procedure cancellations in each group. - Comparing infection characteristics between the groups. - Describing the economic impact of not treating with antibiotics a polymicrobial UBC before endoscopic treatments of BPH. - Evaluating, through joint analysis, that not treating a patient with a polymicrobial UBC before BPH surgery is both clinically not inferior in terms of urinary tract infection incidence and not more expensive over a 1-month post-surgery period than treating. - Producing a budget impact analysis of a change in prescribing practices for polymicrobial UBC before endoscopic surgery of BPH from the French Health Insurance perspective over a 5-year period. - Comparing the baseline urine microbiota of men who developed a post-operative infectious complication to those who did not.

The clinical trial focuses on **Benign Prostate Hyperplasia** and involves a study population consisting exclusively of adult men aged 18 years and older. The participants are required to be affiliated with a French social security system or its equivalent and must provide written informed consent. The trial does not include female subjects or vulnerable populations. Participants are scheduled for surgery to address lower urinary tract symptoms due to benign prostate hyperplasia, with procedures such as Urolift, Rezum, Aquabeam, monopolar or bipolar transurethral resection of the prostate, enucleation of the prostate (Holep, Greenlep, Bipolep), or simple prostatectomy. A key characteristic of the study population is the presence of a polymicrobial pre-operative urine culture, identifying three or more pathogens. The trial population was selected based on their ability to comply with study requirements and understand the clinical research. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the **non-inferiority** of not administering antibiotics to patients with polymicrobial urinary bacterial culture (UBC) before undergoing surgery for lower urinary tract symptoms (LUTS) due to **Benign Prostate Hyperplasia** (BPH). This study is a randomized, controlled, double-blind trial, ensuring that neither the participants nor the investigators are aware of the treatment allocations, thus minimizing bias. The trial is expected to commence on November 15, 2024, and conclude by December 15, 2027, with a total duration of approximately three years.

Participants will be adult men aged 18 years or older, scheduled for endoscopic surgery for BPH, and must have a polymicrobial pre-operative urine culture. The trial will include an initial screening visit to confirm eligibility based on the inclusion criteria, such as age, social security affiliation, and informed consent. Following randomization, participants will be assigned to either the treatment group receiving antibiotics or the control group without antibiotics. The primary endpoint is the incidence of symptomatic urinary tract infections within one month post-surgery, assessed by a blinded independent adjudication committee.

Study visits will be structured as follows: an inclusion visit for screening and baseline assessments, followed by regular follow-up visits to monitor for any signs of urinary infection and to collect data on secondary endpoints, such as infection characteristics and economic impact. The end-of-study visit will occur one month post-surgery to evaluate the primary and secondary outcomes. Participant involvement is expected to last for the duration of the trial, with the possibility of early termination if the participant withdraws consent, experiences adverse effects, or fails to comply with study requirements.

The trial will utilize **fosfomycin calcium** and a combination of **bromhexine hydrochloride, sulfamethoxazole, and trimethoprim** as the investigational products, administered orally. The maximum treatment period for these antibiotics is one day, with a maximum daily dose of 6 grams for fosfomycin calcium. The study aims to provide insights into the clinical and economic implications of antibiotic use in this context, potentially influencing future prescribing practices for polymicrobial UBC before BPH surgery.

The clinical trial involves the administration of **Fosfomycin Calcium** as an experimental medication. Fosfomycin Calcium is a chemical compound classified under the ATC code J01XX01. It is administered in an oral pharmaceutical form, designated as PHF00170MIG. The maximum daily dose is 6 grams, with a total maximum dose of 6 grams over a treatment period of one day. The medication is not a pediatric formulation and is used in the trial as a test product. Participant compliance with the dosing schedule is monitored to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, the study includes a comparator treatment consisting of a combination of **Bromhexine Hydrochloride**, **Sulfamethoxazole**, and **Trimethoprim**. This combination is also administered orally in the same pharmaceutical form, PHF00170MIG. The substances are chemically derived and classified under the ATC code J01EE01. Although the maximum daily and total dose amounts are recorded as 0 milligrams, the treatment period is set for one day. This combination serves as a comparator in the trial to evaluate its efficacy against the experimental treatment. Compliance with the administration schedule is similarly monitored to ensure accurate data collection.

Efficacy in this clinical trial will be assessed primarily through the incidence of symptomatic urinary infections over a one-month post-operative period. This is defined by the presence of symptoms such as urine burning, fever, and urgencies, in conjunction with significant **bacteriuria**. These symptoms will be validated by a blinded independent adjudication committee to ensure objectivity and accuracy in the assessment.

Secondary endpoints include several parameters: the number of patients whose procedures are cancelled in each group, the characteristics of infections (including type of bacteria and clinical data), and the cost of antibiotics used for treating a polymicrobial urine bacterial culture (UBC) before and after endoscopic treatments of benign prostatic hyperplasia (BPH). Additionally, the trial will evaluate the probability that the experimental strategy is clinically and economically non-inferior to the control strategy, considering different values of economic non-inferiority margins and a constant clinical non-inferiority margin of 10%. The economic impact of changes in prescribing practices for polymicrobial UBC before endoscopic surgery of BPH will also be assessed from the perspective of the French Health Insurance over a five-year period. Furthermore, a description of baseline urine microbiota in both groups (patients who developed an infection and those who did not) will be provided.