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.

翻译：我们提出了一种频率学派的适应性II期临床试验设计，用于评估三种治疗方案（剂量）相较于安慰剂对四种蠕虫感染的安全性与疗效。该试验将于2025年春季起在四个撒哈拉以南非洲国家开展。由于最高剂量的安全性尚未确定，研究将从两个较低剂量及安慰剂开始。基于中期分析的安全性与早期疗效结果，将决定是继续使用两个较低剂量，或是剔除一个或两个低剂量并引入最高剂量。该设计在安全性评估中借鉴了跨篮信息，而疗效则针对每个篮单独评估。所提出的适应性设计解决了若干关键挑战：（1）试验必须仅从两个较低剂量开始，因为在升级至更高剂量前需要这些剂量的安全性数据提供保障。（2）由于预期招募速度较快，适应性决策必须依赖一个更早的替代终点。（3）主要结局是一个计数变量，其服从在0点处存在原子点的混合分布。为了在适应性设计中比较多个剂量与对照时以强意义控制族错误率，我们扩展了部分条件错误方法，以容纳中期分析后新假设的纳入。在一项全面的模拟研究中，我们评估了多种设计方案与分析策略，考察了设计在不同设计假设与参数值下的稳健性。我们识别出适应性设计能够提升试验识别最优剂量能力的若干场景。适应性剂量选择使得资源能够分配到最有希望的治疗组，在减少所需总样本量与试验时长的同时，提高了选择最优剂量的可能性。