436 Background: Intravesical instillation of BCG is an accepted strategy to prevent recurrence of non muscle invasive bladder cancer (NMIBC). However, the optimal number of instillations is unknown. NIMBUS assessed whether a reduced number/standard dose BCG instillations is not inferior to standard number and dose BCG in patients with high-grade (HG) NMIBC. The primary endpoint was time to first recurrence. Methods: The aim was to enroll 824 BCG naïve patients with HG Ta-T1 NMIBC +/- CIS. NIMBUS was an international randomized not blinded trial to establish therapeutic equivalence defined as the lower part of the Confidence Interval (CI) (using one-sided 2.5% level of significance) being higher than a HR (hazard experimental/hazard standard) of 0.75 for recurrence. The treatment arms were: Standard: Induction cycle BCG weekly wks 1-6; maintenance cycles at months 3,6,12 (wks 1,2,3) and Reduced: Induction cycle at wks 1,2,6; maintenance cycles at months 3,6,12 (wks 1,3). Safety was evaluated at yearly intervals by the IDMC and in case inferiority was shown, defined as the upper part of the CI (one-sided 2.5% level) lower than a HR of 0.75, an advice to stop the trial would be given. Results: Available data at July 1, 2019 were analyzed for the IDMC meeting. A total of 345 patients were recruited from Germany (149), the Netherlands (109), France (64), Belgium (22) and Spain (1). Prognostic factors at initial resection were Ta/T1: 46/54%; primary/recurrent disease: 92/8%; single/multiple lesions: 57/43% and concomitant CIS/no CIS: 27/73%. The intention to treat analysis showed a clear difference in time to and number of recurrences between treatment arms: 27% in the reduced arm versus 12% in the standard arm. Known prognostic factors were evenly distributed between arms. Additional safety analyses were performed showing a HR of 0.40 [95% CI: 0.24-0.67]. Conclusions: Safety analysis showed that the reduced frequency schedule of BCG was inferior to the standard frequency schedule for time to first recurrence according to the previously defined stop criterion. Recruitment of patients was stopped immediately. Clinical trial information: NTR4011.
Treatment of EAU intermediate risk category non-muscle invasive bladder carcinoma by standard number and dose of BCG instillations versus reduced number and standard dose of BCG instillations. A subgroup analysis of the ‘NIMBUS’ phase III clinical trial