Randomized Controlled Trial of Nadofaragene Firadenovec Versus Observation in Intermediate Risk Non-Muscle Invasive Bladder Cancer

The primary objective of this study is to evaluate the **efficacy** of nadofaragene firadenovec administered every three months compared to observation in subjects with intermediate risk non-muscle invasive bladder cancer (IR NMIBC). The clinical relevance of this objective lies in determining the difference in time to recurrence, progression, or death from any cause between the treatment group and the observation group. This is particularly significant for patients who have undergone a transurethral resection of the bladder tumor (TURBT), with or without peri-operative intravesical chemotherapy, within 60 days of randomization. The outcome will be quantified using a hazard ratio, irrespective of treatment discontinuation due to toxicity or lack of tolerability, variations in administered volume, dwell time, or any premature treatment interruptions, as well as the initiation of new anti-cancer therapy prior to recurrence.

Secondary objectives include evaluating the **safety** of nadofaragene firadenovec compared to observation in subjects with IR NMIBC. This assessment is crucial for understanding the risk-benefit profile of the treatment, ensuring that it does not pose undue harm to patients while potentially offering therapeutic benefits.

The clinical trial involves a total of **187 participants** diagnosed with **intermediate risk, non-muscle invasive bladder cancer**. The study population includes both male and female subjects aged **18 years or older**. Participants were selected based on specific criteria, including having undergone a complete transurethral resection of the bladder tumor (TURBT) within 60 days prior to randomization. The trial does not include a vulnerable population. Participants are required to have a life expectancy of more than two years and an Eastern Cooperative Oncology Group (ECOG) status of 2 or less. The trial population is characterized by a general good health status, as evidenced by adequate laboratory values and a normal upper urinary tract. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include the ability to provide written consent and adherence to regional or national COVID-19 management policies. Participants with a history of prostate cancer treated with radiation therapy are eligible if the treatment was completed at least one year prior to randomization and the subject has remained disease-free. Female participants of childbearing potential must have a negative pregnancy test and agree to use effective contraception during the trial and for a specified period after the last dose of the investigational medicinal product.

The clinical trial is designed as a **randomized**, controlled study to evaluate the efficacy of **nadofaragene firadenovec** in subjects with intermediate risk non-muscle invasive bladder cancer (IR NMIBC). The trial will compare the administration of nadofaragene firadenovec every three months against observation in patients who have undergone a transurethral resection of the bladder tumor (TURBT) with or without peri-operative intravesical chemotherapy within 60 days prior to randomization. The primary endpoint is recurrence-free survival, defined as the time from randomization to the first documented recurrence, progression, or death from any cause during the 24-month treatment period.

The trial will commence with a screening visit to confirm eligibility based on inclusion criteria, such as age, laboratory values, and previous treatment history. Participants will be required to provide written consent before any trial-related procedures. Following randomization, study visits will occur every three months to administer the investigational medicinal product (IMP) and monitor patient outcomes. These visits will include assessments of disease progression, adverse events, and compliance with the study protocol. The end-of-study visit will occur at the conclusion of the 24-month treatment period or upon early termination.

Participant involvement is expected to last up to 24 months, with conditions for early termination including treatment discontinuation due to toxicity, lack of tolerability, or initiation of new anti-cancer therapy prior to recurrence. The trial is anticipated to start recruitment in April 2025 and is estimated to conclude by June 2031. The study will adhere to applicable regional or national policies for the management and control of COVID-19, ensuring the safety and well-being of all participants throughout the trial duration.

The clinical trial involves the administration of **nadofaragene firadenovec**, marketed under the name **ADSTILADRIN**, which is an **intravesical suspension**. This experimental medication is designed for **intravesical use** and is administered every three months. The active substance, **nadofaragene firadenovec**, is a replication-deficient recombinant type 5 adenovirus vector. It is not a pediatric formulation and is not classified as an orphan drug. The maximum treatment period for this medication is 24 months. The pharmaceutical form is specifically designed for direct administration into the bladder, ensuring targeted delivery to the site of action.

In this study, the experimental treatment is compared against an observation group, which serves as the non-experimental treatment. Participants in the observation group do not receive any active medication but are monitored for the study's duration to evaluate the efficacy of the experimental treatment. The primary objective is to assess the difference in time to recurrence, progression, or death due to any cause between the two groups. This comparison will be summarized by a hazard ratio, taking into account various factors such as treatment discontinuation due to toxicity or lack of tolerability, administered volume, dwell time, and any prematurely interrupted or terminated treatment during administration. Additionally, the initiation of new anti-cancer therapy prior to recurrence is considered in the analysis.

The efficacy of the investigational medicinal product, **nadofaragene firadenovec**, will be assessed in a phase 3b clinical trial involving subjects with intermediate risk non-muscle invasive bladder cancer (IR NMIBC). The primary endpoint for evaluating efficacy is recurrence-free survival (RFS). This is defined as the time from the date of randomization to the first documented recurrence or progression of the disease, or death from any cause, whichever occurs first during the treatment period of 24 months.

The primary objective of the trial is to compare the efficacy of nadofaragene firadenovec administered every 3 months against observation in subjects who have undergone a transurethral resection of the bladder tumor (TURBT), with or without peri-operative intravesical chemotherapy, within 60 days of randomization. The difference in time to recurrence, progression, or death will be summarized by a hazard ratio. This analysis will be conducted regardless of treatment discontinuation due to toxicity or lack of tolerability, variations in administered volume, dwell time, or any premature interruption or termination of treatment, as well as the initiation of new anti-cancer therapy prior to recurrence.