临床疗效导向的中医药RCT设计与实践

【作者】 陈莹；

【导师】 商洪才； 常静玲；

【作者基本信息】 北京中医药大学 ， 中医内科学（专业学位）， 2022， 博士

【摘要】 背景:随机对照试验是公认的临床疗效评价“金标准”,被广泛应用于中医药领域,并产生出一批高质量的临床研究证据发表于国际期刊。但仍存在一部分随机对照试验方案设计不严谨、研究目的不明确、对照组设置不合理、结局指标选择不恰当等问题,影响研究结论的可靠性,难以体现中医药的真实疗效。研究者如何充分、合理地应用已有的临床资源进行随机对照试验设计以提供更多高质量证据,是一个重点问题。本研究提出以临床疗效为导向、以PICO模型为框架的中医药随机对照试验设计方法,以期为中医药随机对照试验设计提供借鉴和参考。随机对照试验的目的是为临床实践提供循证医学证据,而在临床实践中,临床疗效具有重要地位,在对患者进行诊疗时,根据疗效反馈来调整诊疗方案,最终达到治疗疾病的目的。以临床疗效为导向设计随机对照试验,使试验设计要素来源于临床疗效,而试验结果又将回归临床,指导临床实践,并在临床实践中发现新问题,构成周而复始的循环过程,实现临床实践效果持续性优化。临床疗效导向的中医药随机对照试验设计方法的实施需要依托于研究模型,通过提供规范化和结构化的程序形成研究框架。PICO是国际上通用的构建临床研究问题的模型,包括研究对象(participants)、干预措施(interventions)、对照措施(comparisons)和结局指标(outcomes),通过一致的、系统的方法将研究问题结构化,指导研究设计,提高方法学质量。目的:1 提出并构建以临床疗效为导向、以PICO模型为框架的中医药随机对照试验设计方法。2以蚓激酶治疗急性脑梗死为例,阐述此方法的设计原理,为此方法的实践提供依据。3根据此方法的设计原理进行实践,以蚓激酶治疗急性脑梗死为例,设计临床疗效导向的随机对照试验。方法:1梳理中医药随机对照试验的现状及存在的问题,针对问题提出临床疗效导向的中医药随机对照试验设计方法。从研究问题的结构化构建角度,利用PICO模型作为此方法的设计框架,探讨此方法的实施步骤。2以蚓激酶治疗急性脑梗死为例,阐述此方法的设计原理。从系统评价和meta分析、横断面研究、回顾性队列研究中获取PICO模型,并从临床疗效角度对其进行优化,得到随机对照试验的设计要素。3根据临床疗效导向的PICO模型,结合临床实际情况,以蚓激酶治疗急性脑梗死为例设计随机对照试验,对此方法进行实践示范。结果:1在中医药随机对照试验设计中,存在研究目的不明确、对照组设置不合理、结局指标选择不恰当等问题。针对这些问题,本研究提出以临床疗效为导向的中医药随机对照试验设计方法。此方法提取PICO模型作为设计要素,形成了系统评价和meta分析、真实世界横断面研究、真实世界回顾性队列研究三个实施步骤。2以蚓激酶治疗急性脑梗死为例,阐述此方法的设计原理:(1)在系统评价和meta分析中,从既往随机对照试验的文献中获取研究对象的基本特征包括年龄、性别、发病时间、诊断标准、纳入标准8条、排除标准14条(P),获取干预措施常用的4种规格、7种剂量、2种服用频率、8种合并用药及疗程(I),获取3种常用的对照措施(C),通过meta分析得到1 1个对干预措施敏感的结局指标(O),达到了利用文献从临床疗效角度对PICO模型进行提取并优化的目的。(2)在横断面研究中,从真实世界急性脑梗死患者的数据中获取研究对象的基本特征包括年龄、性别、发病时间、既往史、家族史、烟酒史、NIHSS评分、mRS评分、ADL评分、中风分型、中医证候要素分布等(P),以纤维蛋白原是否升高为暴露因素(I),通过Logistic回归筛选出9个可能与急性脑梗死患者纤维蛋白原变化有关的特异性结局指标(O),获取了针对研究人群发病特点的PICO模型。(3)在回顾性队列研究中,从两组基线数据中获取研究对象的基本特征包括年龄、性别、发病时间、既往史、烟酒史、NIHSS评分、mRS评分、ADL评分、中风分型、中医证候要素分布等(P),获取干预措施常用的4种剂量、3种服用频率及疗程(I),对照措施为空白对照(C),通过回顾性队列研究得到1个特异性结局指标(O),达到了利用真实世界数据从临床疗效角度对PICO模型进行提取并优化的目的。3根据设计原理对此方法进行实践,以蚓激酶治疗急性脑梗死为例,设计临床疗效导向的随机对照试验。将前文中提取的临床疗效导向的PICO模型进行整合,并结合临床实际情况,设计研究对象、干预措施、对照措施、结局指标如下。研究对象为220例急性脑梗死患者,随机分为试验组(蚓激酶+阿司匹林)和对照组(蚓激酶安慰剂+阿司匹林),诊断标准为《中国各类主要脑血管病诊断要点2019》中制定的“脑梗死诊断标准”。纳入标准为:(1)确诊的首发急性脑梗死;(2)急性脑梗死症状出现时间在72小时之内;(3)脑梗死症状发生前mRS评分≤2分;(4)未进行静脉或动脉溶栓治疗,及血管内介入治疗;(5)5分<NIHSS评分<15分;(6)35周岁≤年龄≤85周岁;(7)受试者同意参加试验并签署知情同意书。排除标准为:(1)出血性脑血管疾病;(2)短暂性脑缺血发作及无症状脑梗死;(3)心源性栓塞等共18条排除标准。试验组给予蚓激酶肠溶胶囊(60万单位tid)+阿司匹林肠溶片(100mgqd),对照组给予蚓激酶肠溶胶囊安慰剂(1粒tid)+阿司匹林肠溶片(10Omg qd),用药疗程90天,随访至180天。主要结局指标为mRS量表,次要结局指标为NIHSS评分、ADL评分、纤维蛋白原、血小板聚集率、凝血酶原时间、活化部分凝血活酶时间、超敏C反应蛋白。对试验进行安全性评价、依从性评价,并收集缺血性中风证候要素诊断量表。结论:本研究针对中医药随机对照试验设计存在的问题,提出并构建了以临床疗效为导向、以PICO模型为框架的中医药随机对照试验设计方法,具有系统性和科学性;以蚓激酶治疗急性脑梗死为例,具体阐述该研究方法的设计原理及实践过程,以期为中医药随机对照试验设计提供借鉴和参考,促进相关临床研究质量的提升。更多还原

【Abstract】 Background:The gold standard for assessing clinical efficacy is the randomized controlled trial.In Traditional Chinese Medicine(TCM),it is frequently employed.Numerous credible clinical research evidence of TCM has been published in international publications.However,uncertain research objectives,unrealistic control group settings,and the improper use of outcomes are some of the issues that still exist in randomized controlled trial.These issues make it difficult to portray the genuine efficacy of TCM and compromise the reliability of the research results.A crucial concern is how investigators may properly and logically use the clinical resources offered for randomized controlled trial design to produce more high-quality evidence.This study suggests a way for designing randomized controlled trial in TCM using clinical efficacy as the orientation and the PICO model as the framework.This design method will serve as a guide for designing randomized controlled trial in TCM.Randomized controlled trial is designed to provide evidence-based medical evidence for clinical practice.Clinical efficacy also plays a significant role in clinical practice.When treating patients,we modify the plan of treatment in response to the efficacy of treatment,ultimately achieving the goal of treating the disease.Designing randomized controlled trial with clinical efficacy as the orientation will allow trial design components to be developed from clinical efficacy and trial findings to be sent back to the clinic to direct clinical practice and discover fresh questions in clinical practice.This entails a cyclic procedure to accomplish ongoing clinical practice effects optimization.A study model is required for the execution of a clinical efficacy-oriented randomized controlled trial design strategy for TCM since it provides a consistent and organized procedure for the investigation.PICO,which stands for participants,interventions,comparisons,and outcomes,is an internationally recognized approach for creating clinical research questions.It establishes clear,structured research questions that direct research design and boost methodological quality.Objectives:1 To put out and build a design method,which use clinical efficacy as the orientation and the PICO model as the framework for randomized controlled trial in TCM.2 To clarify the design rationale and offer a foundation for its use,with the example of lumbrokinase for acute ischemic stroke.3 To create a clinical efficacy-oriented randomized controlled trial using the design rationale in actual practice,with the the example of lumbrokinase for acute ischemic stroke.Methods:1 Analyze the current state and issues of TCM randomized controlled trial,and provide a solution of clinical efficacy-oriented design method in TCM randomized controlled trial.From the standpoint of the organized development of the research question,the PICO model is employed as the design framework for this method,and the implementation processes of this method are addressed.2 The design rationale of this method is illustrated by using lumbrokinase for acute ischemic stroke as an example.Systematic evaluation and meta-analysis,cross-sectional study,and retrospective cohort study are used to create the PICO model,which is optimized by clinical efficacy to produce design components for randomized controlled trial.3 A randomized controlled trial protocol based on the clinical efficacy as the orientation and PICO model as the framework is created to show this design method in action,using the lumbrokinase for acute ischemic stroke as an example.Results:1 There were issues with the randomized controlled trial design in TCM,including uncertain research objectives,unrealistic control group settings,and the improper use of outcomes.This study suggested a clinical efficacy-oriented randomized controlled trial design method for TCM to overcome these issues.The three implementation steps of this method were systematic evaluation and meta-analysis,real-world cross-sectional study,and real-world retrospective cohort study.Then extracted the PICO model from the three implementation steps as design components.2 The use of lumbrokinase for acute ischemic stroke served as an example of the rationale for the design of this method.(1)In systematic evaluation and meta-analysis,age,sex,time of onset,diagnostic criteria,8 inclusion criteria,and 14 exclusion criteria for participants were taken from the literature of prior randomized controlled trials.There were 4 sizes,7 doses,2 dosing frequencies,8 combinations,and regularly course of treatment for interventions.There were 3 commonly used comparisons.Through meta-analysis,11 intervention-sensitive outcomes were found.The goal of utilizing the literature to optimize the PICO model from the standpoint of clinical efficacy was accomplished.(2)In cross-sectional study,basic study subject characteristics like age,sex,time of onset,history of prior illness,family history of illness,history of smoking and drinking,NIHSS score,mRS score,ADL score,staging of acute ischemic stroke,and TCM syndrome elements were gathered from data of actual acute ischemic stroke patients.Used elevated fibrinogen as an intervention.By using logistic regression,9 distinct outcomes that might be linked to fibrinogen alterations in acute ischemic stroke were identified.PICO models of the patients’ onset characteristics were obtained.(3)In retrospective cohort study,basic study subject characteristics like age,sex,time of onset,history of prior illness,history of smoking and drinking,NIHSS score,mRS score,ADL score,stroke type in TCM,and TCM syndrome elements were gathered from the baseline data of both groups.Obtained common regimens for the interventions,including 3 dosing frequencies and 4 doses.The comparison was blank control.The retrospective cohort study produced one specific outcome.The goal of utilizing the real-world data to optimize the PICO model from the standpoint of clinical efficacy was accomplished.3 As an example,this design method was used to create a clinical efficacy-oriented randomized controlled trial of lumbrokinase for acute ischemic stroke.220 patients with acute ischemic stroke would be included in the study.They would be randomized into two groups:the intervention group(lumbrokinase plus aspirin)and the control group(lumbrokinase placebo plus aspirin).The diagnostic standard used was the Diagnostic criteria of cerebrovascular diseases in China(version 2019).The inclusion criteria were:(1)Participant was diagnosed with acute ischemic stroke for the first time.(2)Symptoms of acute ischemic stroke appeared within 72 hours.(3)Before the onset of symptoms of acute ischemic stroke,the mRS score of the participant was less than or equal to 2.(4)Participant hadn’t received intravenous thrombolysis,arterial thrombolysis or intravascular intervention.(5)The participant’s NIHSS score was greater than 5 and less than 15.(6)The age of the participant was between 35 and 85 years old.(7)Agreed to participate in the trial and signed informed consent form.The exclusion criteria were:(1)The participant had a hemorrhagic cerebrovascular disease.(2)Transient ischemic attack or silent ischemic stroke.(3)Known or suspicion for cardiogenic embolism.There were 15 other exclusion criteria.Lumbrokinase enteric capsules(600,000 units tid)and aspirin enteric tablets(100mg qd)were given to the intervention group.Lumbrokinase placebo enteric capsules(1 capsule tid)and aspirin enteric tablets(100mg qd)were given to the control group.All medications were taken for 90 days,with a 180-day follow-up.The mRS scale was the primary outcome.NIHSS score,ADL score,fibrinogen,platelet aggregation rate,prothrombin time,activated partial thromboplastin time,and hypersensitive C-reactive protein were secondary outcomes.The trial was also assessed for safety,compliance,and collected of Diagnostic Scale for TCM Syndromes of Acute Ischemic Stroke.Conclusions:In order to solve the issues with TCM’s randomized controlled trial design in a methodical and scientific way,the study developed and created a design method using clinical efficacy as the orientation and the PICO model as the framework.In order to provide guidance for the design of a TCM randomized controlled trial and to improve the quality of relevant clinical researches,the design rationale and practice procedure of this design method were outlined using lumbrokinase for acute ischemic stroke as an example.更多还原