A two-way enriched clinical trial design: combining advantages of placebo lead-in and randomized withdrawal

A new clinical trial design, designated the two-way enriched design (TED), is introduced, which augments the standard randomized placebo-controlled trial with second-stage enrichment designs in placebo non-responders and drug responders. The trial is run in two stages. In the first stage, patients are randomized between drug and placebo. In the second stage, placebo non-responders are re-randomized between drug and placebo and drug responders are re-randomized between drug and placebo. All first-stage data, and second-stage data from first-stage placebo non-responders and first-stage drug responders, are utilized in the efficacy analysis. The authors developed one, two and three degrees of freedom score tests for treatment effect in the TED and give formulae for asymptotic power and for sample size computations. The authors compute the optimal allocation ratio between drug and placebo in the first stage for the TED and compare the operating characteristics of the design to the standard parallel clinical trial, placebo lead-in and randomized withdrawal designs. Two motivating examples from different disease areas are presented to illustrate the possible design considerations.