Explorating The Clinical Suitability Characteristics Of Qizhitongluo Capsule On Patient Of Post-stroke Based On Adaptive Enrichment Design

BackgroundThe "combination of disease and syndrome" model of Western medicine and TCM syndrome differentiation is one of the commonly used clinical research models of Chinese medicine and a hot spot in clinical research of Chinese medicine.It not only emphasizes the diagnosis of diseases,but also the judgment of TCM syndromes.The gold standard of the research model is a Randomized Controlled clinical trial.In recent years,the challenge of the clinical research model of disease and syndrome has gradually emerged:the same syndrome contains many symptoms,and each individual or(and)each Chinese medicine compound focuses on these many symptoms in the same syndrome.Namely,due to the heterogeneity of the patient population,although the same disease with the same syndrome,,the symptoms shown will also be differently.At present,the combination of diseases and syndromes in clinical studies of traditional Chinese medicine compound prescriptions has problems such as fuzzy,immobilization,and insensitivity,which have brought great challenges to the "precise clinical positioning of traditional Chinese medicine compound prescriptions" and affected the precise curative effect of traditional Chinese medicine.In addition,traditional randomized controlled trials called the "gold standard" also face many challenges:①Sample size is large,research cycle is long,and a lot of resources are required;②lacking flexibility and variability research plan;screening patients by Inclusion criteria and exclusion criteria,resulting in the scope is limited,and extrapolation is poor.These challenges force researchers to continuously seek new methods that can solve the heterogeneity of patients,help the Chinese medicine compound to clarify the clinical positioning,and solve the confusion caused by Traditional Randomized Controlled Trials.Adaptive enrichment design makes modification prospectively to the the one or more aspects of the experimental design(such as sample size adjustment or inclusion and exclusion)based on the cumulative data of the previous trial subjects on the basis of ensuring the integrity and effectiveness of the trial.The purpose is to detect and correct timely the unreasonable assumptions and test related parameters(such as sample size adjustment and type I error control,etc.).At the beginning of the trial design,in order to screen the best suitable patient population characteristics of the target drug through this method to ensure the tested patients obtain the best curative effect,avoid invalid exposure of the patients in the trial,and realize the individualized treatment.ObjectiveAdaptive enrichment subgroup analysis method was used to explore and screen the appropriate patient population characteristics(including the baseline characteristics of patients and the syndromes and syndromes of Qi-Xu-Xue-Yu Zheng)of Qizhitongluo Capsules in the treatment of ischemic stroke(Qi-Xu-Xue-Yu Zheng)in the recovery period.Providing certain methodological thinking and support for the clinical precision medication of traditional Chinese medicine compound prescriptions.MethodThis study is based on the data obtained from the previously completed clinical trial "Qizhitongluo Capsule treat post-stroke(Qi-Xu-Xue-Yu Zheng)in recovery period multicenter randomized double-blind controlled clinical trial(Clinical Trials gov.ID:NCT01762163)",which carry out adaptive enrichment design.The data source consists of data from the Qizhitongluo capsule group and the placebo group(the number of cases in the two groups respectively is 308 and 154,a total of 462 cases),divided by the "interim analysis" node set in the original study.The data source is divided into two stages,namely:the first stage,the data of 231 patients included before the interim analysis(152 cases in the Qizhi Tongluo capsule group;79 cases in the placebo group)were analyzed by exploratory subgroup analysis method,screening suitable patient population characteristics of QizhiTongluo capsules in the treatment of post-stroke in recovery period(Qi-Xu-Xue-Yu Zheng),including baseline characteristics and syndrome element characteristics;the second stage is the verification stage,the variables selected in the previous stage are verified in the latter stage 156 cases in Qizhitongluo capsule group;75 cases in placebo group,231 cases in total)and in the entire study(308 cases in Qizhitongluo capsule group,154 cases in placebo group,a total of 462 cases)to further determine whether the variables of Qizhitongluo Capsules selected in the first stage are suitable for the patient group in another part of the patient group or even the whole group.The statistical analysis uses IBM SPSS Statistics 22 software.The patient’s baseline information analysis uses t-test,exact probability,chi-square test,and the value of a is 0.05;exploratory subgroup analysis is based on the patient’s baseline characteristics(gender,age,BMI index,with or without basis treatment,etc.And the symptoms of(Qi-Xu-Xue-Yu Zheng))were grouped to gain the mean,difference and corresponding standard deviation by t-test,and the value of a was 0.025.Result(1)Baseline analysis results:Using t-test,chi-square test,and precise probability method to determine age,gender,ethnicity,height,weight,BMI,body temperature,breathing,resting heart rate,pulse,SBP,DBP course,no aura or discomfort,recovery period,anterior circulatory disorder,Qi-Xu-Xue-Yu Zheng,acupuncture treatment,rehabilitation treatment,history of drug allergy,history of alcohol or drug dependence,other treatment drugs,past medical history and treatment history;for skin,eyes,ear,nose,throat,neck,heart,lung,abdomen,genitourinary system,Limbs,nervous system,lymph nodes,back,others,blood stasis total score,tongue quality,headache,limbs,complexion,additional scores were compared between the two groups.The results showed that there was no statistically significant difference in all indicators between the two groups(P=0,170-1.000),the difference in pulse condition between groups was statistically significant(P=0.010).(2)Results of subgroup analysis:Based on the data obtained from the "Randomized Double-blind Controlled Clinical Trial of Qizhitongluo Capsule in the treatment of post-Stroke in recovery stage(Qi-Xu-Xue-Yu Zheng)",the data of 231 patients before the interim analysis(152 cases in the Qizhi Tongluo Capsule Group;79 cases in the placebo group).Exploratory subgroup analysis was conducted to explore and screen suitable patient population characteristics variables of Qizhitongluo Capsules for the treatment of post-stroke in recovery period(Qi-Xu-Xue-Yu Zheng)by t test,α was 0.025.The subgroup analysis of the above variables shows that:①Compare the difference in lower limb motor function scores of the two groups after 12 weeks,P=0.001<0.05,the difference is 2.35,it can be concluded that the Qizhitongluo capsule group and the placebo group have a difference in the lower limb motor score difference.Statistical significance means that the efficacy of Qizhitongluo capsule group is better than that of placebo group.②In the basic treatment analysis,the subgroup without acupuncture treatment P=0.003<0.025,the difference is 2.21.That is,the Qizhitongluo capsule group and the placebo group have statistical significance in the comparison of lower limb motor scores,and in patients without acupuncture treatment,Qizhitongluo Capsule group is better than placebo group;③In the BMI>24 group,the lower limb motor function scores of the Qizhitongluo capsule group and the placebo group were compared(P=0.009),the difference was 2.94.That is,the lower limb function motor scores of the Qizhitongluo capsule group and the placebo group are statistically significant.Among the subgroups with BMI>24,the Qizhitongluo capsule group has better efficacy than the placebo group.④In the subgroup analysis of Qi deficiency syndrome,the lower limb motor function scores of Qizhitongluo capsule group and placebo group were compared in the symptoms of "loose stools or first hard and late loose stools"(P=0.013),the difference was 2.38;namely,the lower limb function motor scores of the Qizhitongluo capsule group and the placebo group are statistically significant.In the group of patients with Qi Xu Zheng-loose stools or first hard and late loose stools,the Qizhi Tongluo Capsule group had better efficacy than the placebo group.⑤Subgroup analysis was performed on age,gender,course of disease,basic treatment-rehabilitation treatment,basic diseases(hypertension,hyperlipidemia,diabetes,hyperviscosity),blood stasis syndrome elements,etc.All P>0.025 That is,the comparison of the lower limb function motor scores between the Qizhitongluo capsule group and the placebo group was not statistically significant.(3)Result verification:The three variables obtained above were verified in the patients included after the interim analysis(156 cases in the Qizhi Tongluo capsule group;75 cases in the placebo group,231 cases in total),the results are as follows:in the non-acupuncture treatment group,the Qizhitongluo capsule group was compared with the placebo group,P=0.001,the difference was 3.18;The comparison between the two groups in the loose stools or first-hard post-liquid group was P=0.013,the difference was 2.92;the comparison between the two groups in the BMI>24 group was P=0.001,the difference was 3.00.The verification results in the entire test population are as follows:in the non-acupuncture treatment group,comparing the Qizhitongluo capsule group and the placebo group,P=0.000,with a difference of 2.61;the comparison of the two groups in the loose stools or first-hard loose stools group was P=0.001,the difference was 2.10;comparison of the two groups in the BMI>24 group,P=0.003,the difference is 2.42.That is,in any of the above patient groups with "BMI>24","loose stools or first hard and late loose stools in Qi-Xu Zheng",and "no acupuncture treatment",Qizhitongluo Capsule is more effective in the treatment of post-stroke in the recovery period(Qi-Xu-Xue-Yu Zheng)than those of the placebo groupConclusion(1)Adopting adaptive enrichment methods and conducting exploratory subgroup analysis can enrich the characteristics of suitable patient groups for Qizhitongluo Capsules in the recovery period of post-stroke(Qi-Xu-Xue-Yu Zheng),including the absence of acupuncture treatment,BMI>24,and loose stools or first hard and late loose stools with Qi-Xu Zheng;(2)The application of adaptive enrichment design provides methodological support for screening the clinically suitable characteristic variables of traditional Chinese medicine compound prescriptions,and provides evidence for patient inclusion,optimal allocation of treatment and reduction of invalid exposure of patients in later clinical studies,in order to realize traditional Chinese medicine compound prescriptions Precise clinical positioning.