All Times EDT
Keywords: Placebo effect, missing data imputation, weighted test, expectation-maximization (EM) algorithm, power.
To address the issue of a large placebo effect in certain therapeutic areas, rather than the application of the traditional gold standard parallel group placebo-controlled design, different versions of the sequential parallel comparison design have been advocated. In general, the design consists of two consecutive stages and three treatment groups. Stage 1 placebo responders/non-responders are potentially among the pre-specified patient subgroups for formal between-treatment comparisons at the final analysis. In this research, a version of the design is considered for a binary endpoint. To fully utilize all available data, a general weighted combination test is proposed in case placebo has a relatively small effect for some of the study endpoints. The weighted combination of the test based on stage 1 data and the test based on stage 2 data of stage 1 placebo non-responders suggested in the literature uses only a part of the study data and is a special case of this general weighted combination test. A multiple imputation approach is outlined for handling missing not at random data. Simulation is conducted to evaluate the performances of the methods and a data example is employed to illustrate the application of the methods.