针对“残留效应”混合效应模型的辨证论治方治疗支气管扩张症的单病例随机对照试验

The"carryover effects"mixed-effects model for syndrome differentiation treatment on bronchiectasis:a series of N-of-1 trials

目的通过一系列单病例随机对照研究,以中药安慰剂为对照,观察辨证论治方治疗支气管扩张症稳定期患者的疗效,采用改进的混合效应模型检测中药的“残留效应”,探索建立一种体现中医药辨证论治特色的单病例随机对照试验方法。方法单中心临床试验,单个病例自身进行多次交叉、随机对照、盲法的研究。试验共3轮,每轮有2个观察期(试验期和对照期),每期各4周。在试验期服用辨证施治的个体化方,对照期服用安慰剂。主要指标是7分制的自我症状评价的李克特量表评分,其他指标是CAT评分、24小时痰量、中医证候评分及安全性指标等。采用配对t检验分析个体数据,针对“残留效应”采用混合效应模型分析群体数据。结果正式入组共21例受试者,15例(75%)受试者完成了3轮次的单病例试验。其中3例在总体症状李克特量表评分上的差异存在统计学意义。在群体水平,针对“残留效应”设计的混合效应模型发现三项指标(总体症状评分,呼吸症状评分与CAT量表评分)的残留效应有统计学意义。剔除“残留效应”后,该模型分析两种方剂对总体症状评分、呼吸系统症状的评分、CAT量表评分和中医证候评分干预效应的差异有统计学意义。单病例试验存在残留效应时,混合效应模型的敏感性高于Meta分析。结论本研究所设计的中药单病例随机对照试验,能体现中医辨证论治特色。改进的混合效应模型能够检测出中药的残留效应,提高了数据统计的敏感性。然而,由于单病例试验的固有性质,本研究方法在个体统计水平上的敏感性偏低,有待更多的病例和病种的研究,以进一步改进。

Objective A series of single-case randomized controlled trials(N-of-1 trials),with placebo Chinese herbs used as a control,were conducted to observe the efficacy of the syndrome differentiation treatment formula in the stable phase of bronchiectasis by using a modified mixed-effects model(MEM)to detect the"carryover effects"of Chinese herbs,and to explore the establishment of an N-of-1 trial method that reflects the characteristics of syndrome differentiation treatment in traditional Chinese medicine(TCM).Methods A single-center clinical trial was conducted in which a single case was studied in a multiple crossover,randomized controlled,and blinded manner.There were three rounds of the trial,each with two observation periods(treatment period and control period)of 4 weeks each.In the treatment period,an individualized formula based on syndrome differentiation was given,and in the control period,a placebo formula was administered.The primary indicator was the patients’self-rated 7-point symptom Likert scale score,and other indicators included chronic obstructive pulmonary disease assessment test(CAT)score,24 h sputum volume,TCM syndrome score,and safety index.Paired t test was used to analyze single case data and MEM designed for"carryover effects"was used to analyze group data.Results A total of 21 subjects were formally enrolled,and 15(75%)completed three rounds of N-of-1 trials.Three of the cases showed statistically significant differences in overall symptom Likert scale score.At the group level,the MEM designed for"carryover effects"found statistically significant residual effects on three indicators(overall symptom score,respiratory symptom score,and CAT score).After excluding the"carryover effects",the model analyzed the statistically significant differences between the intervention effects of the two formulas on the overall symptom score,respiratory symptom score,CAT score and TCM syndrome score.The sensitivity of the MEM was higher than that of the meta-analysis when residual effects existed in the N-of-1 trials.Conclusion The N-of-1 trials of Chinese herbs designed in this study can well demonstrate the characteristics of TCM syndrome differentiation and treatment.The modified MEM can detect the residual effects of TCM and improve the sensitivity of data statistics.However,due to the inherent nature of N-of-1 trials,the sensitivity of this study method at the individual level is low and more cases and diseases need to be studied for further improvement.