Event-Driven Type Design for Clinical Trials With Recurrent Events.

It is common practice in randomized clinical trials with the standard survival outcome to follow patients until a prespecified number of events have been observed, a type of trial known as the event-driven trial. The event-driven design ensures that the target power for a specified Type I error rate is achieved to detect the target hazard ratio, regardless of the specification of other quantities. To understand the treatment effect for chronic conditions, the analysis of recurrent events has gained popularity in randomized controlled trials, particularly large-scale confirmatory trials. In the absence of within-subject correlation among multiple events, a similar event-driven design can be employed for recurrent event outcomes. On the other hand, in the presence of within-subject correlation, one needs to model the correlation among recurrent events in evaluating power and setting the sample size. However, information useful in modeling the within-subject correlation is limited at the design stage. Failing to properly account for correlation may lead to underpowered studies. We propose an event-driven type design for recurrent event outcomes. Our method ensures the target power for the target treatment effect, regardless of the specification of other quantities, by monitoring the robust variance under the marginal rates/means model in a blinded manner. We investigate the operating characteristics of the proposed monitoring procedure in simulation studies. The results of simulation studies showed that the proposed blinded monitoring procedure controlled the power well so that the test possessed the target power and did not lead to serious inflation of the Type I error rate. Furthermore, we illustrate the proposed method using a real clinical trial dataset.