A method for utilizing co-primary efficacy outcome measures to screen regimens for activity in two-stage Phase II clinical trials
A method for utilizing co-primary efficacy outcome measures to screen regimens for activity in two-stage Phase II clinical trials
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DOI：
10.1177/1740774512450101
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发表时间：
2012-08-01
期刊：
影响因子：
2.7
通讯作者：
Yothers, Greg
中科院分区：
文献类型：
--
作者：
Sill, Michael W.;Rubinstein, Larry;Yothers, Greg
背景大多数II期临床试验采用单一的主要终点来确定未来研究的方案。然而，许多疾病以复杂的方式表现出来。例如，偏头痛可引起疼痛、先兆、恐惧症和呕吐。研究人员可能认为，一种药物是有效的，在减少偏头痛和呕吐的严重程度在攻击。尽管如此，他们仍然有兴趣继续开发这种药物，如果它只对其中一种症状有效的话。这样的研究将是一个候选人的临床试验与co-primary endpoints.Purpose目的的文章的目的是提供一种方法，用于设计一个单臂，两阶段的临床试验与二分共同主要终点的疗效，有能力检测活动的任何一个响应措施与高概率时，药物是积极的一个或两个措施，而同时当在两个维度上几乎没有活性时以高概率排斥药物。该设计使早期关闭徒劳的，是灵活的方面达到accounting.Methods的设计提出的背景下，肿瘤临床试验的肿瘤反应和无进展生存期（PFS）的状态后，一定时期。假设两个终点均为二项随机变量分布，根据历史对照确定无意义的成功概率。鉴于权责发生制灵活性的必要性，穷举搜索算法来找到最佳设计似乎不可行，在这个时候。相反，使用特定程序确定实现样本量的临界值。然后，应计窗口被发现达到设计的预期水平的意义，提前终止（PET）的概率，和power.Results的设计说明了一个临床试验，研究贝伐单抗在复发性子宫内膜癌患者。该研究的肿瘤缓解为阴性，但6个月PFS为阳性。该程序进行了比较，修改的程序在literature，表明该方法是competitive.Limitations虽然该程序允许调查人员构建设计与所需的水平的显着性和权力，PET下的零假设是小于为单一的终点study.Conclusions的影响，增加一个额外的终点对样本量往往是最小的，但该研究获得了对治疗反应另一个维度的活性的敏感性。操作特性对于两个端点之间的关联水平是相当稳健的。软件可在线获取。临床试验2012; 9：385--395。http://ctj.sagepub.com
Background Most Phase II clinical trials utilize a single primary end point to determine the promise of a regimen for future study. However, many disorders manifest themselves in complex ways. For example, migraine headaches can cause pain, auras, photophobia, and emesis. Investigators may believe that a drug is effective at reducing migraine pain and the severity of emesis during an attack. Nevertheless, they could still be interested in proceeding with the development of the drug if it is effective against only one of these symptoms. Such a study would be a candidate for a clinical trial with co-primary end points.Purpose The purpose of the article is to provide a method for designing a single arm, two-stage clinical trial with dichotomous co-primary end points of efficacy that has the ability to detect activity on either response measure with high probability when the drug is active on one or both measures, while at the same time rejecting the drug with high probability when there is little activity on both dimensions. The design enables early closure for futility and is flexible with regard to attained accrual.Methods The design is proposed in the context of cancer clinical trials with tumor response and progression-free survival (PFS) status after a certain period. Both end points are assumed to be distributed as binomial random variables, and uninteresting probabilities of success are determined from historical controls. Given the necessity of accrual flexibility, exhaustive searching algorithms to find optimum designs do not seem feasible at this time. Instead, critical values are determined for realized sample sizes using specific procedures. Then accrual windows are found to achieve a design's desired level of significance, probability of early termination (PET), and power.Results The design is illustrated with a clinical trial that examined bevacizumab in patients with recurrent endometrial cancer. This study was negative by tumor response but positive by 6-month PFS. The procedure was compared to modified procedures in the literature, indicating that the method is competitive.Limitations Although the procedure allows investigators to construct designs with desired levels of significance and power, the PET under the null hypothesis is smaller than for single end point studies.Conclusions The impact of adding an additional end point on the sample size is often minimal, but the study gains sensitivity to activity on another dimension of treatment response. The operating characteristics are fairly robust to the level of association between the two end points. Software is available online. Clinical Trials 2012; 9: 385--395. http://ctj.sagepub.com