Cross-validated risk scores adaptive enrichment (CADEN) design

We propose a Cross-validated ADaptive ENrichment design (CADEN) in which a trial population is enriched with a subpopulation of patients who are predicted to benefit from the treatment more than an average patient (the sensitive group). This subpopulation is found using a risk score constructed from the baseline (potentially high-dimensional) information about patients. The design incorporates an early stopping rule for futility. Simulation studies are used to assess the properties of CADEN against the original (non-enrichment) cross-validated risk scores (CVRS) design that constructs a risk score at the end of the trial. We show that when there exists a sensitive group of patients, CADEN achieves a higher power and a reduction in the expected sample size, in comparison to the CVRS design. We illustrate the application of the design in a real clinical trial. We conclude that the new design offers improved statistical efficiency in comparison to the existing non-enrichment method, as well as increased benefit to patients. The method has been implemented in an R package caden.