An Adaptive Phase II Trial Design for Dose Selection and Addition in Microfilarial Infections

Abstract

We propose a frequentist adaptive phase 2 trial design to evaluate the safety and efficacy of three treatment regimens (doses) compared to placebo for four types of helminth (worm) infections. This trial will be carried out in four Subsaharan African countries from spring 2025. Since the safety of the highest dose is not yet established, the study begins with the two lower doses and placebo. Based on safety and early efficacy results from an interim analysis, a decision will be made to either continue with the two lower doses or drop one or both and introduce the highest dose instead. This design borrows information across baskets for safety assessment, while efficacy is assessed separately for each basket. The proposed adaptive design addresses several key challenges: (1) The trial must begin with only the two lower doses because reassuring safety data from these doses is required before escalating to a higher dose. (2) Due to the expected speed of recruitment, adaptation decisions must rely on an earlier, surrogate endpoint. (3) The primary outcome is a count variable that follows a mixture distribution with an atom at 0. To control the familywise error rate in the strong sense when comparing multiple doses to the control in the adaptive design, we extend the partial conditional error approach to accommodate the inclusion of new hypotheses after the interim analysis. In a comprehensive simulation study we evaluate various design options and analysis strategies, assessing the robustness of the design under different design assumptions and parameter values. We identify scenarios where the adaptive design improves the trial's ability to identify an optimal dose. Adaptive dose selection enables resource allocation to the most promising treatment arms, increasing the likelihood of selecting the optimal dose while reducing the required overall sample size and trial duration.