Two-stage adaptive enrichment design for testing an active factor

ABSTRACT

We propose an adaptive enrichment approach to test an active factor, which is a factor whose effect is non-zero in at least one subpopulation. We implement a two-stage play-the-winner design where all subjects in the second stage are enrolled from the subpopulation that has the highest observed effect in the first stage. We recommend a weighted Fisher’s combination of the most powerful test for each stage, respectively: the first stage Hotelling’s test and the second stage noncentral chi-square test. The test is further extended to cover binary outcomes and time-to-event outcomes.

KEYWORDS:

• Active factor
• gene-treatment interaction
• adaptive enrichment trial
• fisher’s combination

Additional information

Funding

Drs. Ding and Wu were supported by an NIH/NIA grant [P30AG028740], which funded an exploratory study on adaptive multi-factor multi-stage clinical trial methods to accelerate efforts in identifying efficacious and effective interventions for preventing decline in physical function, loss of mobility and progression to disability among older adults. Drs. Dean and Wu were also supported by an NIH/NIAID grant (R01AI139761) to develop innovative study designs and analysis methods.