中医药临床疗效的体现需要科学的评价方法。既往单指标评价法、综合评价法在应用时存在各种缺陷，病证结合的多主要终点评价为全面客观显示中医药疗效提供可能，而现阶段尚缺乏与之相匹配的分析方法。鉴于此，本课题以适应性设计为研究设计载体，在盲态下评估多主要终点间相关性的基础上，提出“双检验联合（Two-Test Combination, TTC）”建立中医病证多终点指标临床评价方法。该方法解决了传统临床试验设计中多终点间相关性估计不准确的难题，弥补了全局检验法（GST）无法评价单个终点疗效、而检验水准校正法（α-AP）无法评价多终点整体效应的不足。本课题以稳定性心绞痛为疾病模型，以心电图疗效、中医证候积分、生存质量共同作为主要终点，将TTC法评价结果与传统单指标评价结果进行比较，探讨TTC法的可靠性和评价优势。该方法将从试验设计和检验方法两个层面为全方位评价中医药特色治疗优势提供方法学支持。

The development of a scientific evaluation tool is a prerequisite to reflect the effectiveness of Traditional Chinese Medicine (TCM). Previously developed methods, such as single endpoint evaluation and comprehensive evaluation methods, have been reported to have some limitations. Evaluation of multiple primary endpoints which include diseases and symptoms outcomes can reflect the effectiveness of TCM comprehensively and objectively. While, the related evaluation methods are lacking at present. In this study, a novel Two-Test Combination (TTC) approach based on adaptive design was proposed. We used one stage adaptive adjustment strategy to estimate the correlation among multiple primary endpoints in blindness, then introduced alpha-adjustment procedure (α-AP) which accounts for correlated data to calculate the alpha of individual endpoint. The global statistical test (GST) was used to assess the treatment’s global impact. The adaptive design can resolved the inappropriate correlation estimation among multiple endpoints when started randomized controlled trials, and the TTC approach can overcome the shortcomings of GST and α-AP yet maintains their advantages. In this study of compound Danshen dripping pill for stable angina, we measured three outcomes including electrocardiogram effectiveness, score of TCM symptoms, and quality of life as co-primary endpoints. The result of TTC approach was compared with traditional single endpoint evaluation method, in order to test the feasibility of TTC approach. We believe that the introduction of TTC approach will provide methodological aid for the assessment of therapeutic advantage of TCM.

项目背景：中医药临床疗效的体现需要科学的评价方法。既往单指标评价法、综合评价法在应用时存在各种缺陷，病证结合的多主要终点评价为全面客观显示中医药疗效提供可能，而现阶段尚缺乏与之相匹配的分析方法。鉴于此，本课题以适应性设计为研究设计载体，在盲态下评估多主要终点间相关性的基础上，提出“双检验联合（Two-Test Combination, TTC）”建立中医病证多终点指标临床评价方法。研究内容：本课题以复方丹参滴丸和欣康对比治疗稳定性心绞痛的随机对照试验研究为模型，将60例患者随机分为试验组和对照组，每组各30例。以心绞痛疗效、中医证候积分、生存质量三个终点作为主要终点指标。当全部受试者完成试验后，在盲态下采用Spearman秩相关计算多终点间的相关系数。采用检验水准校正法的Bonferroni校正因子法，并结合相关系数，得出单个终点调整后的检验水准，对三个主要终点分别进行组间比较。采用全局检验法的O’Brien非参数法对三个主要终点的试验组间疗效进行整体评价。研究结果：本研究方案已经获得首都医科大学附属北京中医医院伦理委员会的伦理批件，批件号：2016BL-041-01。经过1年的病例收集，已经完成60例患者的入组出组和数据提取，其中欣康组1例患者出现不良事件，其余59例完成随访。多终点间的相关系数为0.205，采用Bonferroni校正因子法计算得出单个终点调整后的检验水准为0.019，结果显示心绞痛疗效、中医证候积分、西雅图心绞痛量表的躯体活动受限程度、心绞痛稳定状态、心绞痛发作情况、疾病认知程度组间相比无差异（P>0.05），治疗满意程度组间相比差异有统计学意义（t=-2.434，P=0.018），欣康组优于复方丹参滴丸组。采用O’Brien非参数法综合三个多主要终点，两组疗效差异无统计学意义（P>0.05）。科学意义：本项目提出在中医药随机对照试验中采用病证结合的多主要终点评价方法，课题采用全局检验法和检验水准校正法两种方法进行评价，对多个主要终点从多个终点整体疗效和单个终点的分别疗效进行评价。并以复方丹参滴丸治疗稳定性心绞痛的临床研究为模型进行验证。出版发表了相关专著及论文。该方法将从试验设计和检验方法两个层面为全方位评价中医药特色治疗优势提供方法学支持。