Total events of composite endpoint as primary endpoint in cardiovascular outcome trials

Music City Center 

In cardiovascular outcome trials (CVOT), multiple types of events, including recurrent cardiovascular events and fatal events, are often of interest. The time to first event is usually chosen as the primary endpoint. To reflect the total burden of disease, some CVOTs may consider total number of composite events as the primary endpoint instead of time to first event. However, use of total events as the primary endpoint may complicate the study design particularly when fatal events are included.
This project conducted simulation studies to explore how different design parameters (e.g., overdispersion and fatal events proportion) impact adaptive design strategy when the total number of events (recurrent and fatal events) is the primary endpoint. The patient-level number of events within a certain period was generated by a Poisson-Gamma mixture framework. A joint-frailty setting for event rates was used to incorporate the correlation between recurrent and fatal events. As a result, more information is included in planned interim data in higher overdispersion scenarios. To account for the true information fraction used at interim, a boundary adjustment at final analysis is proposed.

CVOT

Recurrent Events

Adaptive Design



Overdispersion 

Biopharmaceutical Section