Berry Consultants, College Station, TX, USA.
Clin Trials. 2010 Apr;7(2):121-35. doi: 10.1177/1740774510361541. Epub 2010 Mar 25.
Adaptive dose-ranging trials are more efficient than traditional approaches and may be designed to explicitly address the goals and decisions inherent in learn-phase drug development. We report the design, implementation, and outcome of an innovative Bayesian, response-adaptive, dose-ranging trial of an investigational drug in patients with diabetes, incorporating a dose expansion approach to flexibly address both efficacy and safety.
The design was developed to assess whether one or more doses of an investigational drug demonstrated superior efficacy to an active control while maintaining an acceptable safety profile.
The trial used a two-stage design, in which patients were initially allocated equally to placebo, investigational drug at a low and a medium dose, and an active control. Movement to the second stage was contingent upon evidence of efficacy (measured by change in fasting blood glucose) to add a very low dose of the investigational drug and of safety (measured by weight gain) to add a high dose of the investigational drug. The design incorporated a longitudinal model to maximize use of incomplete data, predictive probabilities to guide the decisions to terminate the trial for futility or move on to Stage 2, and a dose-response model in Stage 2 to borrow information across adjacent doses. Extensive simulations were used to fine tune trial parameters, to define operating characteristics, and to determine the required sample sizes. A data monitoring committee was provided with frequent reports to aid in trial oversight.
In Stage 1, as trial data accrued, the predictive probability that either the low or medium dose of the investigational drug was superior to the active control fell to low values. Stage 1 termination was recommended after 199 subjects were randomized, out of a maximum trial size of 500 subjects, and the final sample size was 218. Thus the trial did not progress to Stage 2.
Because of the relatively narrow dose range to be assessed, and the inability to utilize the highest dose at the beginning of the trial, a fully responsive-adaptive design incorporating dose-response modeling was not considered a viable option. This limited the efficiency gains possible with a full set of adaptive design elements.
The two-stage dose-expansion design functioned as designed, recommending early termination based on a low probability that the tested doses had efficacy greater than the active control.
适应性剂量范围试验比传统方法更有效，并且可以专门针对学习阶段药物开发中固有的目标和决策进行设计。我们报告了一项创新的贝叶斯、基于反应的、探索性药物剂量范围试验的设计、实施和结果，该试验采用了剂量扩展方法，灵活地解决了疗效和安全性问题。
该设计旨在评估一种探索性药物的一个或多个剂量是否比活性对照药物更有效，同时保持可接受的安全性。
该试验采用两阶段设计，患者最初平均分配到安慰剂、低剂量和中剂量的探索性药物以及活性对照药物组。进入第二阶段的条件是有疗效证据（通过空腹血糖变化来衡量），可以增加探索性药物的极低剂量，以及有安全性证据（通过体重增加来衡量），可以增加探索性药物的高剂量。该设计纳入了一个纵向模型，以最大限度地利用不完整的数据，预测概率来指导试验是否因无效而终止或进入第二阶段的决策，并在第二阶段纳入剂量-反应模型，以在相邻剂量之间借用信息。进行了广泛的模拟，以调整试验参数、定义操作特性和确定所需的样本量。数据监测委员会提供了频繁的报告，以协助试验监督。
在第一阶段，随着试验数据的积累，探索性药物的低剂量或中剂量比活性对照药物更有效的预测概率降至低值。在 500 名受试者的最大试验规模中，有 199 名受试者被随机分配后，建议终止第一阶段，最终样本量为 218 名。因此，试验没有进入第二阶段。
由于要评估的剂量范围相对较窄，并且在试验开始时无法使用最高剂量，因此无法考虑采用完全自适应设计并纳入剂量反应建模。这限制了采用全套自适应设计元素可能获得的效率增益。
两阶段剂量扩展设计按预期运行，根据测试剂量比活性对照药物更有效的可能性较低，建议早期终止。
