中药临床试验重复测量设计与分析方法的探讨
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摘要
研究背景
中药防治疾病基于中医学“整体观念”和“恒动观念”等辩证观点和认识,中药临床试验中对其临床疗效的评价应体现中医学理论特点。中药临床试验研究与化学药物临床研究相比,具有不同的特点——治疗理念不同且更需要对主观评测指标和客观评测指标的动态观测和评价。在中药临床疗效评价中应用重复测量设计与分析方法可以更为合理和客观地评价中药干预措施对疾病临床结局的时间上的总体效应。
目的
探讨重复测量设计与分析方法在中药临床试验的临床疗效评价中的应用以及存在问题和解决办法,以客观、全面地评价中药临床疗效的时间变化趋势以及可能影响因素。
方法
本研究以此生脉胶囊治疗慢性心力衰竭临床试验为载体,探索在中药临床试验中采用重复测量设计与分析方法的适用条件和存在问题。生脉胶囊治疗慢性心力衰竭临床试验采用具有一个重复测量因素的双盲随机安慰剂对照试验设计。该试验为平行对照,试验组142例受试者接受生脉胶囊治疗,对照组139例接受安慰剂治疗,两组同时给予包括利尿剂、扩血管剂、洋地黄类、β-受体阻滞剂和ACE抑制剂等标准治疗。所有受试者心功能分级在Ⅱ～Ⅳ、射血分数小于45%。本研究分析的效应指标包括左室设想分数(EF)、中医症状总分、生存质量和NYHA心功能评级。该试验进行了临床疗效分析、安全性评价和重复测量分析。临床疗效分析分析采用依从方案受试者分析(PPS)和意图治疗分析(ITT)。重复测量分析中采用了单变量、多变量多元方差分析、线性混合模型拟合、多水平模型拟合和GEE算法等对不同类型重复测量数据进行分析。通过该试验的一般临床疗效分析与各种重复测量分析方法的分析结果对比,就重复测量设计与分析方法做出评价。同时,比较多种重复测量分析方法在临床疗效评价中的差别,采用敏感性分析的方法,对比、评价各种方法的适应性。
结果
生脉胶囊治疗慢性心力衰竭临床试验临床疗效分析的PPS和ITT分析结果显示,试验组和对照组的病死率、非致死性重要临床事件发生率以及EF、中医症状总分、生存质量和NYHA心功能评级的比较均无显著性差异。该试验安全性评
BackgroundThe preventions and treatments of diseases with Traditional Chinese Medicine (TCM) are based on the concepts of wholism and dynamics, which regards the various parts of the human body as an organic whole, and emphasizes the body being in a continuous dynamic status both in physiologically and pathologically. Therefore, the evaluations for clinical effectiveness in Clinical trials for TCM should be an embodiment of the concepts. The clinical trials of TCM were difference from the clinical research of artificial drugs, because it is on two distinct therapeutic theories. The clinical research of TCM will pay more attention to dynamical trends of clinical outcome. It should be more rational and objective that the repeated measures designs and analysis is used to assess the temporal effects on clinical outcome of treatments of diseases in the clinical trials of TCM.ObjectivesThe main interest of this study is methodological: to explore the advantages gained and problems encountered while applying repeated measures designs and analysis for the clinical trials of TCM, and in order to evaluate more roundly the dynamical trends and affecting factors of clinical effectiveness of TCM.
MethodsThis study was performed its methodological practise with the example of clinical trial for chronic heart failure (CHF) to treatment with Shengmai Capsule. The clinical trial for CHF with Shengmai Capsule was designed as a double-blind randomized placebo-controlled trial with one factor of repeated measures. In the trial, we assigned 142 patients with chronic heart failure to treatment with Shengmai Capsule and 139 to placebo. Patients were required to have chronic heart failure (NYHA II-IV), previous admission for an ejection fraction of less than 45%, and to have been treated optimally with diuretics, vasodilator, digitalis, beta- blockers and angiotensin-converting enzyme inhibitors unless not tolerated. The four response variables selected for the study were measurements of left ventricular ejection fraction (EF), total scores of symptoms of TCM, quality of life (QOL) and NYHA (New York Heart Association) functional classification. Per-protocol subjects' analysis (PPS) and intention-to-treat analysis(ITT) for clinical effectiveness, safety evaluation and repeated measures analysis were performed in the trial. In data analysis for this trial, univariate analysis, multivariate analysis of variance (MANOVA), linear mixed effects model, multilevel model and generalized estimating equations (GEE) method were selected to employ. The results of PPS and ITT were compared with that of repeated measures analysis. Meanwhile, a sensitivity analysis for different repeated measures analysis and replacing missing values was dealt to, appraise applicability of these methods.ResultsThe results from PPS and ITT analysis for this trial showed that there were no statistical significant differences between Shengmai group and placebo group in all-cause mortality, incidence rate of important clinical events, measurements of EF, total scores of symptoms, QOL and NYHA functional classification. The safety evaluation in the trial also indicated that there were no significant increase at risk of adverse reactions in Shengmai group. The results of repeated measures analysis showed that time effects of EF, QOL, total scores of symptoms and changes of NYHA functional classification were high significant, but grouped effect was no significant. The results
revealed that there were obvious tendency in each group, which the several outcome variables were changed along with period points. There were differences among the tendencies of several variables. The temporal tendencies of EF and QOL were an approximative linearity, but the total scores of symptoms and the changes of NYHA functional classification were displayed non-linear tendencies. The results also showed that the tendencies of several variables were affected by some covariates. The result of MANOVA of repeated measures for EF, total scores of symptoms and QOL showed that age and centers were the significant covariates. The findings indicated age and centers affected the tendencies of outcome variables. Hereinto, the affecting of age factor was mostly on EF and QOL, but that of the centers factor focused on EF and total scores of symptoms. The findings from linear mixed effects modelling and multilevel modelling methods revealed that a desirable trend in temporal effect, however, there was no significant difference in the trend between two groups. The temporal tendency of EF was affected by using of digitalis and centers, that of total scores of symptoms was affected by course of CHF, and that of QOL was affected by the interaction of time point by centers. The findings from GEE method indicated that there was a clear tendency in the changes of NYHA functional classification, which was affected by baseline of functional classification. It is suitable for replacing missing values with the means in the same group through the sensitivity analysis. An affect on the results of MANOVA of repeated measures was appeared with or without replacing missing values, but the modeling methods got less impact without replacing missing values. The test power of both univariate ANOVA and MANOVA of repeated measures was higher than that of PPS and ITT analysis. Comparing between several methods of repeated measures analysis, the results from linear mixed modelling and multilevel modelling were no distinguishable change. This indicated that the results from modelling methods were reliable.ConclusionsIn summary, the power of ANOVA and MANOVA of repeated measures were higher. The repeated measures design and analysis can roundly describe and evaluate the changes over time, and analyze the tendency of changes of outcome variables and its affecting factors. Therefore, the repeated measures
design and analysis can entirely and dynamically evaluate the repeated measures data in clinical trials. Applying the repeated measures design and analysis to clinical effectiveness in clinical trials for TCM, it was in accord with the conception of wholism and dynamics in the therapeutical effects in TCM theories. It is important in practicality to applying the repeated measures design and analysis reasonably.
中药防治疾病基于中医学“整体观念”和“恒动观念”等辩证观点和认识,中药临床试验中对其临床疗效的评价应体现中医学理论特点。中药临床试验研究与化学药物临床研究相比,具有不同的特点——治疗理念不同且更需要对主观评测指标和客观评测指标的动态观测和评价。在中药临床疗效评价中应用重复测量设计与分析方法可以更为合理和客观地评价中药干预措施对疾病临床结局的时间上的总体效应。
目的
探讨重复测量设计与分析方法在中药临床试验的临床疗效评价中的应用以及存在问题和解决办法,以客观、全面地评价中药临床疗效的时间变化趋势以及可能影响因素。
方法
本研究以此生脉胶囊治疗慢性心力衰竭临床试验为载体,探索在中药临床试验中采用重复测量设计与分析方法的适用条件和存在问题。生脉胶囊治疗慢性心力衰竭临床试验采用具有一个重复测量因素的双盲随机安慰剂对照试验设计。该试验为平行对照,试验组142例受试者接受生脉胶囊治疗,对照组139例接受安慰剂治疗,两组同时给予包括利尿剂、扩血管剂、洋地黄类、β-受体阻滞剂和ACE抑制剂等标准治疗。所有受试者心功能分级在Ⅱ～Ⅳ、射血分数小于45%。本研究分析的效应指标包括左室设想分数(EF)、中医症状总分、生存质量和NYHA心功能评级。该试验进行了临床疗效分析、安全性评价和重复测量分析。临床疗效分析分析采用依从方案受试者分析(PPS)和意图治疗分析(ITT)。重复测量分析中采用了单变量、多变量多元方差分析、线性混合模型拟合、多水平模型拟合和GEE算法等对不同类型重复测量数据进行分析。通过该试验的一般临床疗效分析与各种重复测量分析方法的分析结果对比,就重复测量设计与分析方法做出评价。同时,比较多种重复测量分析方法在临床疗效评价中的差别,采用敏感性分析的方法,对比、评价各种方法的适应性。
结果
生脉胶囊治疗慢性心力衰竭临床试验临床疗效分析的PPS和ITT分析结果显示,试验组和对照组的病死率、非致死性重要临床事件发生率以及EF、中医症状总分、生存质量和NYHA心功能评级的比较均无显著性差异。该试验安全性评
BackgroundThe preventions and treatments of diseases with Traditional Chinese Medicine (TCM) are based on the concepts of wholism and dynamics, which regards the various parts of the human body as an organic whole, and emphasizes the body being in a continuous dynamic status both in physiologically and pathologically. Therefore, the evaluations for clinical effectiveness in Clinical trials for TCM should be an embodiment of the concepts. The clinical trials of TCM were difference from the clinical research of artificial drugs, because it is on two distinct therapeutic theories. The clinical research of TCM will pay more attention to dynamical trends of clinical outcome. It should be more rational and objective that the repeated measures designs and analysis is used to assess the temporal effects on clinical outcome of treatments of diseases in the clinical trials of TCM.ObjectivesThe main interest of this study is methodological: to explore the advantages gained and problems encountered while applying repeated measures designs and analysis for the clinical trials of TCM, and in order to evaluate more roundly the dynamical trends and affecting factors of clinical effectiveness of TCM.
MethodsThis study was performed its methodological practise with the example of clinical trial for chronic heart failure (CHF) to treatment with Shengmai Capsule. The clinical trial for CHF with Shengmai Capsule was designed as a double-blind randomized placebo-controlled trial with one factor of repeated measures. In the trial, we assigned 142 patients with chronic heart failure to treatment with Shengmai Capsule and 139 to placebo. Patients were required to have chronic heart failure (NYHA II-IV), previous admission for an ejection fraction of less than 45%, and to have been treated optimally with diuretics, vasodilator, digitalis, beta- blockers and angiotensin-converting enzyme inhibitors unless not tolerated. The four response variables selected for the study were measurements of left ventricular ejection fraction (EF), total scores of symptoms of TCM, quality of life (QOL) and NYHA (New York Heart Association) functional classification. Per-protocol subjects' analysis (PPS) and intention-to-treat analysis(ITT) for clinical effectiveness, safety evaluation and repeated measures analysis were performed in the trial. In data analysis for this trial, univariate analysis, multivariate analysis of variance (MANOVA), linear mixed effects model, multilevel model and generalized estimating equations (GEE) method were selected to employ. The results of PPS and ITT were compared with that of repeated measures analysis. Meanwhile, a sensitivity analysis for different repeated measures analysis and replacing missing values was dealt to, appraise applicability of these methods.ResultsThe results from PPS and ITT analysis for this trial showed that there were no statistical significant differences between Shengmai group and placebo group in all-cause mortality, incidence rate of important clinical events, measurements of EF, total scores of symptoms, QOL and NYHA functional classification. The safety evaluation in the trial also indicated that there were no significant increase at risk of adverse reactions in Shengmai group. The results of repeated measures analysis showed that time effects of EF, QOL, total scores of symptoms and changes of NYHA functional classification were high significant, but grouped effect was no significant. The results
revealed that there were obvious tendency in each group, which the several outcome variables were changed along with period points. There were differences among the tendencies of several variables. The temporal tendencies of EF and QOL were an approximative linearity, but the total scores of symptoms and the changes of NYHA functional classification were displayed non-linear tendencies. The results also showed that the tendencies of several variables were affected by some covariates. The result of MANOVA of repeated measures for EF, total scores of symptoms and QOL showed that age and centers were the significant covariates. The findings indicated age and centers affected the tendencies of outcome variables. Hereinto, the affecting of age factor was mostly on EF and QOL, but that of the centers factor focused on EF and total scores of symptoms. The findings from linear mixed effects modelling and multilevel modelling methods revealed that a desirable trend in temporal effect, however, there was no significant difference in the trend between two groups. The temporal tendency of EF was affected by using of digitalis and centers, that of total scores of symptoms was affected by course of CHF, and that of QOL was affected by the interaction of time point by centers. The findings from GEE method indicated that there was a clear tendency in the changes of NYHA functional classification, which was affected by baseline of functional classification. It is suitable for replacing missing values with the means in the same group through the sensitivity analysis. An affect on the results of MANOVA of repeated measures was appeared with or without replacing missing values, but the modeling methods got less impact without replacing missing values. The test power of both univariate ANOVA and MANOVA of repeated measures was higher than that of PPS and ITT analysis. Comparing between several methods of repeated measures analysis, the results from linear mixed modelling and multilevel modelling were no distinguishable change. This indicated that the results from modelling methods were reliable.ConclusionsIn summary, the power of ANOVA and MANOVA of repeated measures were higher. The repeated measures design and analysis can roundly describe and evaluate the changes over time, and analyze the tendency of changes of outcome variables and its affecting factors. Therefore, the repeated measures
design and analysis can entirely and dynamically evaluate the repeated measures data in clinical trials. Applying the repeated measures design and analysis to clinical effectiveness in clinical trials for TCM, it was in accord with the conception of wholism and dynamics in the therapeutical effects in TCM theories. It is important in practicality to applying the repeated measures design and analysis reasonably.
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