Theoretically, calculating the sample size required for achieving the desired power is straightforward with true coefficient of variance (CV) estimates and true test/reference geometric mean ratios (GMRs) of selected parameters. However, true variance estimates are often not known and are, instead, based on published literature or pilot trials. An open-label, two-stage, adaptive, sequential two-period crossover study was used to determine relative bioavailability of a single 100 mg dose of diazoxide manufactured at two different international sites. This design was utilized due to the lack of intra-subject variance estimation data for diazoxide pharmacokinetic parameters. Second-stage sample size was estimated using intra-participant variance from the first stage. Thirty-six healthy adults (age, 18–55 years) were randomized (1:1) to receive a single dose of test/reference product, a single dose of diazoxide (100 mg capsule), under fasting conditions with crossover after 14 days. GMRs (90% confidence interval [CI]) of area under curve from time zero to infinity (AUC0-inf) and maximum plasma concentrations (Cmax) of test versus reference product were 1.06 (1.03–1.10) and 1.17 (1.14–1.20), respectively. Bioequivalence was declared at stage 1 because 90% CIs were between 0.80 and 1.25; stage 2 was not initiated since the estimated power was >99% for both AUC0-inf and Cmax. Results of this study demonstrate efficient use of an adaptive, two-stage sequential design to assess bioequivalence. Similar study design may be effectively used in other bioequivalence studies wherein CV and GMRs of relevant parameters are unknown and sample size estimation is difficult.

中文翻译：

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在禁食条件下在健康参与者中在两个不同的国际地点生产的二氮嗪的相对生物利用度：开放标签，两阶段，自适应，连续两期交叉研究

从理论上讲，通过选择参数的真实方差系数（CV）估计值和真实测试/参考几何平均比率（GMR），可以轻松计算出实现所需功效所需的样本大小。但是，真正的方差估计通常是未知的，而是基于已公开的文献或试验性试验。使用开放标签，两阶段，自适应，连续两周期交叉研究来确定在两个不同的国际站点生产的单剂量100 mg二氮嗪的相对生物利用度。由于缺乏用于二氮嗪药代动力学参数的受试者内部方差估计数据，因此采用了该设计。使用第一阶段的参与者内部差异估算第二阶段的样本量。36名健康成年人（年龄18-55岁）被随机分配（1：1）在禁食条件下接受单剂量的测试/参考产品，单剂量的二氮嗪（100毫克胶囊），并在14天后交叉使用。从零开始到无穷大时曲线下面积的GMR（90％置信区间[CI]）与参考产品的测试血浆最大浓度（Cmax）分别为1.06（1.03-1.10）和1.17（1.14-1.20） ， 分别。在第一阶段宣布具有生物等效性，因为90％的置信区间在0.80至1.25之间；阶段2未启动，因为AUC0-inf和Cmax的估计功率均大于99％。这项研究的结果表明有效利用自适应的两阶段顺序设计来评估生物等效性。类似的研究设计可以有效地用于其他生物等效性研究，在这些研究中，相关参数的CV和GMR未知，样本大小估计困难。