Evaluation of Efficacy and Safety of Electromotive Mitomycin C Versus Bacillus Calmette-Guérin in High-Grade Non-Muscle Invasive Bladder Cancer

The primary objective of this multicenter clinical trial is to evaluate the **efficacy** of adjuvant treatment with EMDA-MMC (mitomycin C administered via electric current) compared to the standard BCG (Bacillus Calmette-Guérin) regimen in the adjuvant treatment of high-grade **non-muscle invasive bladder cancer** (NMIBC). This evaluation is clinically relevant as it aims to determine a potentially more effective treatment option for reducing tumor recurrence in patients with high-grade NMIBC, which could lead to improved patient outcomes and reduced disease burden.

Secondary objectives include:

• Assessing the tolerance to adjuvant endovesical chemotherapy with EMDA-MMC compared to the BCG standard in the adjuvant treatment of high-grade NMIBC.
• Evaluating the impact on quality of life of adjuvant endovesical chemotherapy with EMDA-MMC compared to the BCG standard in the adjuvant treatment of high-grade NMIBC.
• Conducting a cost-effectiveness analysis of the routine implementation of the urinary biomarker MCM5 ADXBLADDER® compared to the standard follow-up with urinary cytology and cystoscopy in high-grade NMIBC.

The clinical trial involves participants diagnosed with **non-muscle invasive bladder cancer**. The study population includes both male and female subjects, with an age range of 18 years and older. Participants are required to have a life expectancy of at least 5 years and must be capable of providing informed consent. The trial does not include a vulnerable population. The total number of participants is not specified, as the sponsor has not provided this information. Participants were selected based on specific medical criteria, including having primary non-muscle infiltrating urothelial carcinoma, stages Ta and T1, classified as high grade according to the 2004 WHO guidelines. All participants must have undergone an optically complete transurethral resection (TUR) of the tumor, with additional procedures as indicated by clinical guidelines. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **efficacy** and tolerability of adjuvant treatment with EMDA-MMC compared to standard BCG in patients with high-grade **non-muscle invasive bladder cancer** (NMIBC). This is a multicenter, randomized, double-blind, controlled trial. The trial will also assess the efficacy of the urinary biomarker MCM5 ADXBLADDER in detecting tumor recurrence. The study is expected to run from February 15, 2019, to December 31, 2028, with a maximum treatment period of 12 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, life expectancy, and previous treatment history. Following successful screening, participants will be randomized to receive either EMDA-MMC or BCG, with both groups undergoing six weekly instillations followed by one year of maintenance therapy. Follow-up visits will be scheduled to monitor treatment efficacy and safety, as well as to evaluate the detection rate of tumor recurrence using the MCM5 ADXBLADDER biomarker compared to standard cytology and cystoscopy.

The end-of-study visit will occur at the conclusion of the treatment period or upon early termination. Participants are expected to be involved in the study for up to 12 months, with conditions for early termination including adverse effects, disease progression, or withdrawal of consent. The primary endpoints include disease-free survival and the detection rate of tumor recurrence, while secondary endpoints focus on tumor recurrence rate, progression-free survival, and the impact of treatment on quality of life. The trial aims to provide comprehensive data on the comparative effectiveness of EMDA-MMC and BCG, as well as the utility of the MCM5 ADXBLADDER biomarker in clinical practice.

The clinical trial involves the use of **mitomycin**, a chemotherapeutic agent, as the experimental medication. Mitomycin is administered in the form of a pharmaceutical preparation identified as PHF675. The active substance, mitomycin, is of chemical origin and is also known by the synonym **mitomycin C**. The administration route for mitomycin in this trial is **intravesical use**, which involves direct instillation into the bladder. The dosing regimen consists of an induction phase with six weekly instillations, followed by a maintenance phase lasting one year. The maximum daily dose is 40 mg, with a total maximum dose of 640 mg over the treatment period. The treatment duration is capped at 12 months.

In addition to the experimental treatment, the study includes a comparator treatment using the standard Bacillus Calmette-Guérin (BCG) therapy. BCG is administered similarly, with an induction phase of six weekly instillations and a one-year maintenance phase. This standard-of-care therapy serves as a benchmark to evaluate the efficacy and tolerability of the adjuvant treatment with EMDA-MMC (Electromotive Drug Administration of Mitomycin C) in patients with high-grade non-muscle invasive bladder cancer (NMIBC).

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial also evaluates the efficacy of a urinary biomarker, MCM5 ADXBLADDER, in detecting tumor recurrence, comparing its performance with traditional urinary cytology and cystoscopy methods during the follow-up period for patients treated with either BCG or adjuvant EMDA-MMC.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include **disease-free survival** and the detection rate of tumor recurrence using the MCM5 ADXBLADDER® biomarker, compared to standard cytology. Secondary endpoints encompass the tumor recurrence rate, free survival of tumor progression, rate of tumor progression, and the rate of completion of adjuvant treatment. Additionally, the sensitivity, specificity, negative predictive value (VPN), and positive predictive value (VPP) of the ADXBLADDER® biomarker will be evaluated. The trial will also assess the cost-efficiency of the follow-up model for patients with high-grade non-muscle invasive bladder cancer (NMIBC) treated with adjuvant BCG or EMDA-MMC, the impact of adjuvant treatment on patients' quality of life using the FACT-BL scale, and the occurrence of adverse effects.