Speaker
Description
We propose a frequentist, adaptive trial design to investigate the safety and efficacy of three dose levels compared to placebo for the treatment of worm infections. As the safety of the highest dose is not yet established, the study starts with the two lower doses and the control arm. Based on safety and efficacy endpoints observed in an interim analysis, it is decided to either continue with the two lower doses or to drop one or both of these doses and to start an arm with the highest dose instead.
The proposed adaptive design addresses several challenges: First, the adaptation must rely on an early surrogate endpoint, as the primary endpoint is assessed 12 months after recruitment and is therefore unavailable at the interim analysis. Second, the primary outcome variable follows a mixture distribution with a lognormal component and a point mass at zero. To control the familywise error rate in the adaptive design, we extend the partial conditional error approach to accommodate the addition of new hypotheses after the interim analysis.
In a comprehensive simulation study a range of design options and analysis strategies are compared and the robustness of the design with respect to design assumptions and parameter values is investigated. The relative effect and confidence intervals across both stages for each dose are estimated using the inverse normal method. The simulation results demonstrate under which conditions the adaptive design enhances the trial's efficiency to identify the optimal dose. Adaptive dose selection allows for resource allocation to promising treatment arms and thereby can increase the chance to select the optimal dose while reducing the required overall sample size and trial duration.
96432313587