Information growth for sequential monitoring of clinical trials with a stepped wedge cluster randomized design and unknown intracluster correlation.

BACKGROUND/AIMS: In a stepped wedge study design, study clusters usually start with the baseline treatment and then cross over to the intervention at randomly determined times. Such designs are useful when the intervention must be delivered at the cluster level and are becoming increasingly common in practice. In these trials, if the outcome is death or serious morbidity, one may have an ethical imperative to monitor the trial and stop before maximum enrollment if the new therapy is proven to be beneficial. In addition, because formal monitoring allows for the stoppage of trials when a significant benefit for new therapy has been ruled out, their use can make a research program more efficient. However, use of the stepped wedge cluster randomized study design complicates the implementation of standard group sequential monitoring methods. Both the correlation of observations introduced by the clustered randomization and the timing of crossover from one treatment to the other impact the rate of information growth, an important component of an interim analysis.

METHODS

We simulated cross-sectional stepped wedge study data in order to evaluate the impact of sequential monitoring on the Type I error and power when the true intracluster correlation is unknown. We studied the impact of varying intracluster correlations, treatment effects, methods of estimating the information growth, and boundary shapes.

RESULTS

While misspecified information growth can impact both the Type I error and power of a study in some settings, we observed little inflation of the Type I error and only moderate reductions in power across a range of misspecified information growth patterns in our simulations.

CONCLUSION

Taking the study design into account and using either an estimate of the intracluster correlation from the ongoing study or other data in the same clusters should allow for easy implementation of group sequential methods in future stepped wedge designs.