Evaluation of Progression-Free Survival in High-Risk Non-Muscle Invasive Bladder Cancer Treated with Mycobacterium bovis Bacillus Calmette-Guérin, Strain Moreau RJ

The primary objective of this study is the **assessment of progression-free survival** in patients diagnosed with high-risk non-muscle invasive bladder cancer (NMIBC) treated with adjuvant IMUNO BCG Moreau RJ. This objective is clinically relevant as progression-free survival is a critical endpoint in evaluating the efficacy of treatments for NMIBC, providing insights into the potential of IMUNO BCG Moreau RJ to delay or prevent disease progression.

Secondary objectives include:

• Evaluation of disease progression rates at 12 and 24 months, which helps in understanding the long-term efficacy of the treatment.
• Assessment of disease-free survival, offering additional data on the treatment's ability to maintain remission.
• Quality of life assessment, which is crucial for evaluating the impact of treatment on patients' overall well-being.
• Assessment of adverse reactions, providing important safety data.
• Evaluation of the rate of drop-out due to toxicity, which informs on the treatment's tolerability.
• Assessment of the immune response, which may elucidate the mechanism of action of the treatment.

The clinical trial involves participants diagnosed with **high-risk non-muscle invasive bladder cancer**. The study population includes both male and female subjects, aged between 18 and 85 years. Participants are required to have a **urothelial tumor** and a high-risk non-muscle invasive bladder tumor, defined as Ta-T1 and GIIb or GIII, either diagnosed de novo or relapsed, with or without associated in situ carcinoma, or isolated carcinoma in situ without a visible tumor. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants must have a risk of recurrence or progression greater than or equal to 7 points, according to CUETO tables. The selection process required the signature of informed consent before any study-related activities, including necessary evaluations for selection. No specific lifestyle considerations such as diet or physical activity are mentioned for this trial.

The clinical trial is designed to evaluate the **progression-free survival** in patients diagnosed with **high-risk non-muscle invasive bladder cancer** treated with the adjuvant IMUNO BCG Moreau RJ. This is a phase IV, open-label, multicenter trial. The study employs a randomized, controlled design to ensure the reliability of the results. The trial is expected to last until August 2025, with recruitment having commenced in May 2019. Participants will be involved in the study for a maximum treatment period of 54 weeks, with the primary endpoint being the rate of progression at 24 months post the last transurethral resection.

Study visits are structured to include an initial screening visit, where eligibility is confirmed based on criteria such as age between 18 and 85 years, diagnosis of a high-risk non-muscle invasive bladder tumor, and a risk of recurrence or progression of at least 7 points according to CUETO tables. Following the screening, participants will undergo regular follow-up visits to monitor disease progression, adverse reactions, and quality of life, using validated questionnaires like the Functional Assessment of Cancer Therapy-Bladder Cancer (FACT-BL) v. 4. The end-of-study visit will assess the final outcomes, including disease-free survival and any adverse reactions experienced during the trial.

Participants may be withdrawn from the study early if they experience severe adverse reactions that make continuation impossible, or if they choose to withdraw consent. The trial will also evaluate secondary endpoints such as the progression rate at 12 months, immunological response through cytokine analysis in urine, and the dropout rate due to toxicity. The investigational product, IMUNO BCG Moreau RJ, is administered intravesically as a **powder for solution for instillation**, with a maximum daily dose of 80 mg. The trial aims to provide comprehensive data on the efficacy and safety of this treatment in the specified patient population.

The clinical trial involves the use of **IMUNO BCG Moreau RJ**, a **biological** product of **biotechnological origin**. The active substance in this experimental medication is **Mycobacterium bovis Bacillus Calmette-Guérin**, strain Moreau Rio de Janeiro, live. This product is formulated as a **powder for solution for instillation** and is intended for **intravesical use**. The maximum daily dose is 80 mg, with a total maximum dose of 80 mg over a treatment period of up to 54 weeks. The product is classified under the ATC code L03AX, which pertains to other cytokines and immunomodulators. The administration schedule and participant compliance will be monitored throughout the trial to ensure adherence to the dosing regimen.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of the experimental medication, IMUNO BCG Moreau RJ, to assess its efficacy in the treatment of high-risk non-muscle invasive bladder cancer. The trial aims to evaluate progression-free survival in patients diagnosed with high-risk non-muscle infiltrating bladder tumors (NMIBT) treated with this adjuvant therapy. Compliance with the treatment protocol will be closely monitored to ensure the integrity of the trial results.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the rate of progression at 24 months following the last transurethral resection (LTRU). This progression rate is defined as the proportion of patients who experience tumor progression within a 24-month follow-up period, as classified by the TNM classification system approved by the International Union Against Cancer in its 8th edition of 2017.

Secondary endpoints include the progression rate at 12 months, disease-free survival, quality of life, adverse reactions, dropout rate due to toxicity, and immunological response. The progression rate at 12 months will measure the proportion of patients whose tumors have progressed within a 12-month follow-up period. Disease-free survival will be assessed from the date of the first instillation to recurrence or end of follow-up, using the TNM classification. Quality of life will be evaluated using the Functional Assessment of Cancer Therapy-Bladder Cancer (FACT-BL) v. 4 questionnaire, which is published, validated, and adapted to Spanish. Adverse reactions will be described using the MedDRA dictionary, detailing the number, frequency, and severity of adverse events. The dropout rate due to toxicity will be determined by evaluating study withdrawals due to side effects. Immunological response will be analyzed by measuring cytokines in urine prior to instillation at induction visits 1, 2, 5, and 6.