Evaluation of Preoperative Electromotive Mitomycin-C Administration in Non-Muscle Invasive Bladder Carcinoma: A Randomized Controlled Trial

The primary objective of this study is to determine the impact of **electromotive drug administration (EMDA)** with **mitomycin C (MMC)** before transurethral resection (TUR) in patients with primary and recurrent low-grade non-muscle invasive bladder tumors. The study aims to evaluate the recurrence rate, defined as the appearance of a new non-muscle invasive bladder tumor with a staging T grade equal to or lower than the baseline tumor, and/or progression, defined as the appearance of a new bladder tumor with a staging T grade higher than the baseline tumor. Additionally, the study will assess the time to the first event in patients with non-muscle invasive bladder cancer (NMIBC) who receive MMC+EMDA before TUR compared to passive diffusion MMC instillation after TUR. This is clinically relevant as it may provide insights into optimizing treatment strategies for NMIBC, potentially improving patient outcomes by reducing recurrence and progression rates.

Secondary objectives include:

• Analyzing the progression rate and the time to progression in patients with EMDA before TUR compared to passive diffusion MMC instillation after TUR.
• Evaluating the tolerance of preoperative MMC+EMDA treatment.
• Quantifying the percentage of patients in each group who complete the treatment, defined as the administration of preoperative EMDA+MMC or postoperative passive diffusion MMC.
• Evaluating the impact of inflammatory markers, specifically the neutrophil/lymphocyte ratio and platelet/lymphocyte ratio, on the risk of recurrence and progression of non-muscle invasive urothelial carcinoma.

The clinical trial involves participants diagnosed with **non-muscle invasive bladder tumors**, specifically targeting individuals with primary and recurrent low-grade tumors. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants are required to have a general health status that includes preserved renal function and normal liver function, as indicated by specific laboratory values. The trial does not include a vulnerable population. The selection of participants is based on the presence of suspected urothelial cell carcinoma Ta or T1, as determined by cystoscopy and/or ultrasound, and includes those with primary papillary tumors or recurrent low-grade single or multiple tumors. The sponsor has not provided the total number of participants involved in the study. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. Key inclusion criteria emphasize the necessity for documented and signed authorization to participate in the clinical trial.

The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the impact of preoperative administration of **mitomycin** via electromotive drug administration (EMDA) in patients with non-muscle invasive bladder tumors. The trial aims to assess the recurrence-free survival and progression-free survival in patients receiving mitomycin with EMDA before transurethral resection (TUR) compared to those receiving passive diffusion mitomycin instillation after TUR. The study is categorized as a Phase IV trial, indicating it is a post-marketing study to gather additional information on the drug's effect in a larger population.

The trial is expected to last approximately five years, with an estimated recruitment start date of April 24, 2023, and an estimated end date of April 24, 2028. Participants will be involved in the study for a maximum treatment period of one day, with the primary endpoint being the time to first event, defined as the appearance of a new non-muscle invasive bladder tumor or progression to a higher staging T grade.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as suspected urothelial cell carcinoma Ta or T1, primary papillary tumor, and preserved renal and liver function. Follow-up visits will be scheduled to monitor the recurrence and progression of the disease, as well as to assess any adverse effects and therapeutic completion rates. The end-of-study visit will conclude the participant's involvement, evaluating the overall impact of the treatment on recurrence-free and progression-free survival.

Participants may be terminated early from the study if they experience significant adverse effects, fail to comply with study procedures, or withdraw consent. The trial will ensure that all participants provide documented and signed authorization to participate, adhering to ethical standards and regulatory requirements.

The clinical trial involves the use of **Mitomycin**, an experimental medication, administered to evaluate its impact on patients with non-muscle invasive bladder cancer. **Mitomycin** is provided in the form of a **solution for injection/infusion**. The active substance, **Mitomycin**, is of chemical origin. The medication is administered via **intravesical use**, which involves delivering the drug directly into the bladder. The maximum daily dose is 40 mg, with a total dose not exceeding 40 mg over the treatment period. The treatment is designed to be administered over a maximum period of one day. The study aims to assess the efficacy of electromotive drug administration (EMDA) of **Mitomycin** before transurethral resection (TUR) compared to passive diffusion instillation after TUR.

In addition to the experimental treatment, the study may involve the use of standard-of-care therapies as non-experimental treatments. These may include chemotherapy regimens that are typically employed in the management of non-muscle invasive bladder cancer. The trial does not utilize a placebo or comparator treatment, focusing instead on the direct comparison of EMDA and passive diffusion methods of **Mitomycin** administration. Participant compliance with the dosing schedule will be monitored to ensure adherence to the treatment protocol. The study is structured to provide insights into the recurrence and progression rates of bladder tumors following the administration of **Mitomycin** using the specified methods.

Efficacy in this clinical trial will be assessed by evaluating the impact of electromotive drug administration (EMDA) with **mitomycin C** (MMC) on patients with non-muscle invasive bladder cancer. The primary endpoints for efficacy evaluation include recurrence-free survival and progression-free survival. These endpoints will measure the time until the appearance of a new non-muscle invasive bladder tumor with staging T grade equal to or lower than the baseline tumor for recurrence, and the appearance of a new bladder tumor with staging T grade higher than the baseline tumor for progression.

Secondary endpoints will include the total cases of adverse effects by group, therapeutic completion rate by group, and the impact of recurrence-free survival and progression-free survival depending on inflammatory response parameters. The trial will compare the efficacy of MMC administered via EMDA before transurethral resection (TUR) against passive diffusion MMC instillation after TUR. The schedule for measuring these parameters will be aligned with the trial's timeline, which is estimated to conclude by April 2028. The trial will utilize validated scales and laboratory tests to ensure accurate and reliable data collection and analysis.