Evaluation of Reduced Dwell-Time Bacillus Calmette-Guérin (BCG) Instillation Regimen in High-Risk Non-Muscle Invasive Urothelial Carcinoma

The primary objective of the study is to evaluate the potential clinical impact of a new regimen involving a reduction of **dwell time** during once-weekly BCG instillations for 6 weeks, followed by maintenance therapy for 12 months, in patients with high-risk non-muscle invasive bladder cancer (NMIBC). This evaluation focuses on side effects, adherence to the instillation regimen, and oncological outcomes. The clinical relevance of this objective lies in optimizing treatment protocols to potentially improve patient outcomes and reduce adverse effects associated with BCG therapy.

Secondary objectives include:

• Evaluating the safety of the new regimen to ensure it does not result in inferior treatment outcomes, such as earlier progression and recurrence.
• Assessing whether there is a higher number of completed instillations, which could indicate better patient adherence and treatment efficacy.
• Determining if the treatment is more tolerated with fewer local and systemic side effects, which is crucial for improving patient quality of life and treatment compliance.

The clinical trial involves participants diagnosed with **urothelial cancer**, specifically targeting individuals with non-muscle invasive bladder cancer (NMIBC) for whom Bacillus Calmette-Guérin (BCG) therapy, including maintenance for one year, is planned. The study population includes both male and female subjects, aged 18 years and older, who are capable of understanding the trial protocol and providing informed consent. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants are selected based on their ability to comply with the trial protocol and their histopathological findings, which include Ta high grade without carcinoma in situ (CIS), CIS with or without previous or concomitant Ta tumors, and T1 with or without CIS. The trial population may include vulnerable individuals, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.

The clinical trial is designed to evaluate the impact of a modified regimen involving reduced dwell time during once-weekly **BCG (Bacillus Calmette-Guérin) bacteria** instillations for patients with non-muscle invasive bladder cancer (NMIBC). This study is structured as a randomized, double-blind, controlled trial, with an estimated duration from January 2021 to December 2027. The primary objective is to assess the clinical outcomes, including side effects, adherence to the instillation regimen, and oncological results, over a 12-month maintenance period following an initial 6-week induction phase.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as age above 18, ability to provide informed consent, and specific histopathological findings. The trial includes multiple follow-up visits to monitor the number of instillations completed, side effects, and any necessary adjustments to the treatment regimen. The end-of-study visit will evaluate the primary endpoint, which is the number of participants completing all induction and maintenance instillations. Secondary endpoints include recurrence and progression rates, disease-specific survival, and overall survival over 24 and 60 months.

The expected length of participant involvement is approximately 24 months, with conditions for early termination including significant local or systemic side effects that necessitate cessation of instillations. Participants may also be withdrawn if they are unable to comply with the trial protocol or if they require re-induction therapy due to recurrent or persistent disease. The trial aims to provide valuable insights into the efficacy and safety of the reduced dwell-time regimen in managing NMIBC.

The clinical trial involves the administration of **BCG-medac**, a pharmaceutical product formulated as a powder and solvent for the preparation of a suspension for intravesical use. The active substance in this experimental medication is **BCG (Bacillus Calmette-Guérin) bacteria**, classified under the ATC code L03AX03 as a BCG vaccine. The product is authorized under the marketing authorization number BE236056 and is produced by Medac Gesellschaft für klinische Spezialpräparate mbH (Wedel). The pharmaceutical form is a suspension for injection, specifically designed for intravesical administration. The maximum daily dose is 50 mg/ml, with a total maximum dose of 750 mg/ml over the treatment period. The treatment regimen consists of once-weekly instillations for six weeks, followed by maintenance therapy for 12 months.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the experimental regimen involving the BCG-medac product. The trial aims to assess the clinical impact of a reduced dwell time during BCG instillations, evaluating side effects, adherence to the instillation regimen, and oncological outcomes. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The trial does not include a pediatric formulation, and the product is not classified as an orphan drug.

Efficacy in the clinical trial titled "Nordic Urothelial Cancer Research Group Study on Reduced BCG Dwell-Time in High Risk NMIBC" will be assessed using a combination of primary and secondary endpoints. The primary endpoint focuses on the number of study subjects completing all six induction instillations and subsequent maintenance instillations over a 12-month period. Secondary endpoints include the recurrence rate within 24 months for subjects with an initial complete response, progression rates at 24 and 60 months, disease-specific survival, and overall survival at 24 and 60 months. Additional secondary endpoints involve the total number of BCG instillations per subject, the number of instillations completed with the full dwell time of two hours, and the number of instillations postponed due to side effects. The trial will also monitor the number of subjects where instillations are stopped due to local or systemic side effects and those undergoing re-induction therapy within 24 months due to recurrent or persistent disease.