Competing Risks Analysis Methods for Group Sequential and Adaptive Designs

群体序贯设计和自适应设计的竞争风险分析方法

基本信息

  • 批准号:
    9194302
  • 负责人:
  • 金额:
    $ 3.31万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-09-16 至 2017-04-17
  • 项目状态:
    已结题

项目摘要

Project Summary / Abstract Background: Competing risks endpoints are used when patients can fail therapy from several causes. Analyzing these outcomes allows one to assess the direct benefit of treatment on a primary cause of failure in a clinical trial setting. Regression models can be used in clinical trials to adjust for residual imbalances in patient characteristics, improving the power to detect treatment differences. But, more efficient clinical trial designs, such as group sequential trials and adaptive designs, have not been extensively studied with competing risks endpoints, especially when covariate adjustment is used in the analysis. This proposal aims to expand the set of design and analysis options for clinical trials with competing risks outcomes, which is limited. Specific Aims: This study will develop new competing risks methods for clinical trials including 1) a group sequential test for treatment effect based on the Fine-Gray regression model, 2) a group sequential test for treatment effect based on direct binomial regression of cumulative incidence at a fixed time point, and 3) a method permitting use of Gray's test in an adaptive trial that allows modifications based on all interim data. Research Plan and Methods: For each of the tests in specific aims 1 and 2, the goal is deriving the asymptotic distribution of the sequence of test statistics in a group sequential trial. Once this distribution is known, early stopping boundaries of the trial can be chosen to satisfy type I error rate and power requirements. Martingale and empirical process theory will be used to derive these results; the powerful tools provided by this theory are well-suited to time to event data and have been utilized to obtain methods for both fixed sample and group sequential trials. The plan for completing specific aim 3 involves application of the extended Conditional Rejection Principle approach (Irle & Schafer, 2012) to an adaptive trial using Gray's test to analyze a competing risks endpoint. This approach allows use of the full interim data for modifications while maintaining the type I error rate. Showing applicability of this method to Gray's test will involve use of martingale and empirical process theory. Simulation studies will be conducted to verify the asymptotic results and to examine the finite sample properties of the proposed methods. Relevance to the NHLBI's mission: This project aligns with the NHLBI's mission of promoting research and training to promote the prevention and treatment of heart, lung, and blood diseases. The proposed methods will find application in trials where onset of, or death from, a specific type of heart, lung, or blood diseases is the primary interest. The methodology will be illustrated on a clinical trial designed to determine whether a new agent reduces the risk of graft versus host disease after a blood or marrow transplant, where death is treated as a competing risk. This work will provide more efficient and flexible design options for clinical trials like this with competing risks, including an adaptive design with use of full interim information and group sequential testing for a treatment effect that adjusts for covariates.
项目总结/摘要 背景:当患者可能因多种原因导致治疗失败时,使用竞争风险终点。 通过分析这些结果,可以评估治疗失败的主要原因的直接益处, 临床试验环境。回归模型可用于临床试验中,以调整 患者特征,提高检测治疗差异的能力。但是,更有效的临床试验 设计,如组序贯试验和适应性设计,尚未得到广泛研究, 竞争风险终点,尤其是在分析中使用协变量调整时。这项建议旨在 为具有竞争风险结果的临床试验扩展设计和分析选项集,这是有限的。 具体目的:本研究将为临床试验开发新的竞争风险方法,包括1)一组 基于Fine-Gray回归模型的治疗效果序贯检验,2) 基于固定时间点累积发生率的直接二项式回归的治疗效果,和3)a 允许在适应性试验中使用Gray检验的方法,允许根据所有中期数据进行修改。 研究计划和方法:对于具体目标1和2中的每个测试,目标是得出 组序贯试验中检验统计量序列的渐近分布。一旦这个分布 可以选择已知的试验的早期停止边界以满足I型错误率和功率要求。 鞅和经验过程理论将被用来推导这些结果;这提供了强大的工具, 理论非常适合于事件数据的时间,并已被用于获得固定样本和 分组序贯试验。完成具体目标3的计划包括适用扩展的有条件 拒绝原则方法(Irle & Schafer,2012)使用格雷检验分析适应性试验, 竞争风险终点。这种方法允许使用完整的中期数据进行修改, 第一类错误率证明这种方法对格雷检验的适用性将涉及鞅的使用, 经验过程理论将进行模拟研究,以验证渐近结果,并检查 所提出的方法的有限样本性质。与NHLBI使命的相关性:该项目与 NHLBI的使命是促进研究和培训,以促进心脏病的预防和治疗, 肺和血液疾病。所提出的方法将在以下试验中得到应用: 心脏、肺或血液疾病的特定类型是主要兴趣。该方法将在一个 一项临床试验,旨在确定一种新的药物是否能降低移植物抗宿主病的风险, 血液或骨髓移植,其中死亡被视为竞争风险。这项工作将提供更有效的 和灵活的设计选项,为这样的临床试验与竞争的风险,包括适应性设计与使用 完整的中期信息和调整协变量的治疗效果的组序贯检验。

项目成果

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