An adaptive, phase II, dose-finding clinical trial design to evaluate L-carnitine in the treatment of septic shock based on efficacy and predictive probability of subsequent phase III success.
An adaptive, phase II, dose-finding clinical trial design to evaluate L-carnitine in the treatment of septic shock based on efficacy and predictive probability of subsequent phase III success.
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DOI：
10.1097/ccm.0b013e318287f850
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发表时间：
2013-07
影响因子：
8.8
通讯作者：
Jones AE
中科院分区：
文献类型：
--
作者：
Lewis RJ;Viele K;Broglio K;Berry SM;Jones AE
败血症是美国第十大死因。尽管进行了广泛的研究，但脓毒症的死亡率在过去几十年中并未显着改善。我们描述了一种创新的 II 期临床试验设计，用于评估添加左旋肉碱治疗血管加压药依赖性感染性休克。该设计融合了多种提高效率的功能，包括正常动态线性剂量反应模型、自适应随机化，以及根据未来使用 28 天死亡率结果的 III 期试验成功的概率，提前停止无效或成功。将在急诊科和 ICU 进行的试验的试验设计和计算机模拟。建议研究静脉注射左旋肉碱。拟议的试验使用早期终点，即序贯器官衰竭评估评分的 48 小时变化，来推动适应性随机化和剂量选择。我们使用现有数据对序贯器官衰竭评估变化与 28 天死亡率之间的预期关系进行建模，从而使用蒙特卡罗模拟确定试验的操作特征。由此产生的试验有效地确定了左旋肉碱的最佳剂量，并为是否继续开发进入 III 期提供了明确的指导。
Sepsis is the tenth leading cause of death in the United States. Despite extensive research, mortality rates for sepsis have not substantially improved in the last several decades. We describe an innovative phase II clinical trial design for evaluating the addition of l-carnitine to the treatment of vasopressor-dependent septic shock. The design incorporates a variety of features to increase efficiency, including a normal dynamic linear dose–response model, adaptive randomization, and early stopping for futility or success based on the probability that a future phase III trial using a 28-day mortality outcome would be successful. Trial design and computer simulation of a trial to be conducted in the emergency department and ICU. Proposed to study intravenous l-carnitine. The proposed trial uses an early endpoint, the 48-hour change in Sequential Organ Failure Assessment score, to drive adaptive randomization and dose selection. We use existing data to model the expected relationship between the Sequential Organ Failure Assessment change and the 28-day mortality to determine the trial's operating characteristics using Monte Carlo simulation. The resulting trial efficiently identifies the best dose of l-carnitine and provides clear guidance regarding whether to continue development into phase III.