A Study On The Evaluation Of The Efficacy Of Core Prescriptions From Treatment Based On Pattern Differentiation Of Insomnia By Famous TCM Practitioners

BackgroundThe treatment based on pattern differentiation,as the most fundamental feature of Traditional Chinese Medicine(TCM)interventions,is in urgent need of appropriate methods for its efficacy evaluation.In the case of insomnia,despite a large amount of clinical experience demonstrating the efficacy of treatment based on pattern differentiation for insomnia with few side effects,the lack of high-quality clinical evidence has prevented it from being adopted and recommended in clinical practice guidelines.This study was supported by the National Natural Science Foundation of China under the key project(No.81230086)"Research on the stepwise progressive evaluation methods for determining the causal relationship between treatment based on syndrome differentiation and its effectiveness" and the project(No.81673964)"Construction of individual knowledge map of Chinese medicine based on multi-scale incomplete data and its treatment(No.81673964)"Construction of individual knowledge map and its treatment pattern based on multi-scale incomplete data".During the pre-study of this project,nine physician-centered cohorts with treatment based on pattern differentiation for insomnia were established for efficacy observation,and the core prescriptions from treatment based on pattern differentiation used by individual physicians and their corresponding effective population characteristics and therapeutic indicators with advantages were obtained through data mining.The efficacy of core prescriptions from treatment based on pattern differentiation based on observational study needs to be confirmed prospectively.ObjectiveTaking insomnia as an example,we evaluated the efficacy and safety of core prescriptions derived from treatment based on pattern differentiation made by famous Traditional Chinese Medicine practitioners based on previous observational studies,and formed a treatment plan for Insomnia Based on clinical evidence in TCM;Combined with the results of the previous studies,a process and a technical approach to the entire system for evaluating the efficacy of treatment based on pattern differentiation were formed.MethodsA multicenter,small-sample,pragmatic randomized controlled trial design was used to study insomnia patients attending outpatient clinics at four research centers(Guang’anmen Hospital of China Academy of Chinese Medical Sciences,the Second Affiliated Hospital of Henan University of Traditional Chinese Medicine,Dongfang Hospital of Beijing University of Traditional Chinese Medicine,and the Hubei Provincial Hospital of Traditional Chinese Medicine)across China.According to the established inclusion and exclusion criteria,patients who met the diagnostic criteria for insomnia in Western medicine and were classified as"phlegm-heat disturbing the mind" in Chinese medicine were included in the study.Using the central randomization method to generate a random sequence and conceal random assignment,subjects were randomly divided into test group A(Qing Phlegm and Ning Shen Formula:Green mica stone,Rhubarb,Huang Lian,Biliary South Star,Zhu Ru,Fu Shen,Hovenia,Atractylodes,Coix Seeds,Dragon’s Tooth),test group B(Xiang Fu Wen Dan Decoction:Vinegar Xiang Fu,Chen Pi,Qing Ban Xia,Chai Hu,Poria,Zhu Ru,Hovenia,Shou Wu Vine),and control group C(Huang Lian Wen Dan Decoction:Huang Lian,Fa Ban Xia,Zhu Ru,tangerine,citrus aurantium,Fu Shen,liquorice,ginger,jujube)3 groups,each with 48 cases,144 cases in total.Subjects received oral Traditional Chinese medicine treatment according to the group,and could be conditionally added or subtracted with evidence.All drugs were prepared as Traditional Chinese medicine compound granules for 4 weeks,and the visit point was set at the 1 st,2nd,3rd and 4th week after treatment.The modified intention-to-treat analysis(mITT)was adopted as the main analysis method,and information of all randomized subjects constituted the full analysis set(FAS)of this study.When examining the study outcomes,data of those with missing baseline of major evaluation indicator,missing treatment information,and no followup records were excluded from the FAS,and the missing values were handled by mean difference complement and last carryover method.The decrease values of Pittsburgh Sleep Quality Index(PSQI)scores before and after treatment were observed in each group of subjects,and the changes in total sleep time(TST),sleep latency(SL),insomnia severity index(ISI),sleep efficiency(SE),and the difference in total clinical efficiency were compared before and after treatment.Patient-reported outcome and physician-reported outcome were measured by 2 versions of the Treatment Effectiveness Assessment Questionnaire,and the subjective effective rate was measured and its outcome was analyzed to evaluate the efficacy of the 2 core prescriptions for individualized treatment based on syndrome differentiation for insomnia by famous Traditional Chinese Medicine practitioners;The adverse events and adverse reactions that occurred in the subjects during the treatment process were observed and their relationship with the intervention was judged,and the incidence of adverse reactions was calculated as an index and basis for safety evaluation.There are 3 study phases in the whole study,and this study is a practical randomized controlled trial,which is one of the 3 phases.The preliminary study consisted of a retrospective study,a prospective cohort study,and a knowledge mapping study.The process of these 3 study phases was combined to compare the results in this study with those of the pre-study.The scientific problems and strategies for solving them are analyzed in each of the three phases of"description-exploration-validation" within this research system.Results1.Recruitment for this study was carried out between May 2019 and December 2020,and a total of 144 patients with insomnia were actually enrolled and randomized in four study centers.Among them,there were cases of subjects losing contact and disengaging from the study during the trial,so the sample data were minimally excluded according to the principle of adjusted intentionality analysis.A total of 133 samples were eventually included in the statistical analysis,with a total of 42 cases in Trial Group A,45 cases in Trial Group B,and 46 cases in Control Group C.The disenrollment rate was 7.64%.The main efficacy index of this study was the decrease value of Pittsburgh Sleep Quality Index(PSQI)scores before and after patients received treatment.After a 4-week treatment with Traditional Chinese medicine discriminative therapy,the decrease value of PSQI was 4.64±3.12 in the group of Qing Phlegm and Ning Shen Formula,4.91±3.52 in the group of Xiang Fu Wen Dan Decoction,and 5.43±3.79 in the control group of Huang Lian Wen Dan Decoction.The efficacy of the control group was the best,and the difference between the groups was not statistically significant(P>0.05).lIn terms of secondary efficacy indexes:the total sleep time per night was prolonged by 1.22±1.07,1.14±1.15,and 1.62±1.54 hours on average in the three groups of insomnia patients after treatment.The number of TST prolongation of less than half an hour was 21.43%,24.44 and 17.39%,respectively,and the total sleep time of 41.30%of patients in the Huang Lian Wen Dan Decoction group was prolonged by more than 2 hours after treatment;the sleep latency time was shortened by 4 43.81 ±46.39,55.44±81.23,and 53.37±59.70 minutes on average in the three groups of patients after treatment;the decrease in I SI scale scores relative to baseline was 6.79±4.71,7.98±4.53,and 7.43 ±5.00 points in the three groups of patients after treatment,respectively.The proportion of patients with moderate to severe insomnia decreased from 59.52%,77.1.1%and 56.52%to 14.38%,13.33%and 8.70%after treatment,respectively;The post-treatment sleep efficiency of patients in the three groups was improved by 15.18%,10.26%,and 14.80%,respectively;the total clinical efficiency of patients in each group after treatment was 73.81%in the group of Qing Phlegm and Ning Shen Formula,73.33%in the group of Xiang Fu Wen Dan Tang,and 76.09%in the group of Huang Lian Wen Bile Tang,with no statistically significant difference between the groups(P>0.05).In terms of patient self-reported outcomes,all patients filled out a treatment effect assessment questionnaire after the end of full treatment,from which it was known that patient satisfaction with the treatment regimen and physicians was high.The subjective efficiency rates above 97%in both the trial and control groups,much higher than the objective outcome assessment of disease efficacy.Among them,about 6-10%of patients chose 5(out of 5)for the entry of "degree of symptom relief after treatment",while the number of those who rated 5 for the entry of "satisfied with the effect of treatment" could reach about 20%;this indicates that patient self-assessment has positive significance for the evaluation of the efficacy of evidencebased treatment.In terms of physician reported outcomes,physicians were also required to complete assessment questionnaires after all treatments had been completed.Physicians combined with the judgment of patients’ clinical symptoms and their performance after receiving treatment,they believe that the idea of syndrome differentiation and treatment used for patients in this study is largely consistent with the tendency of patients to actually develop the disease,and the subjective effectiveness rate of physicians in all three groups was more than 97%.In terms of safety indicators,there were 12 patients in this study that developed adverse reactions,and the average incidence of adverse reactions was 9.02%,and there was no significant difference among the three groups(P>0.05).The adverse effects were alleviated in all patients after timely proper disposal from physicians,and the safety of all these 3 interventions was acceptable.2.The efficacy of the individual famous Traditional Chinese Medicine practitioners’ core prescriptions from treatment based on pattern differentiation in this pragmatic randomized controlled trial(PRCT)was lost compared with the data obtained in the previous cohort study and data mining.The core prescription from treatment based on pattern differentiation of Qing Phlegm and Ning Shen Formula,which was derived from the cohort in Henan and obtained after data mining of 100 prospective observational subjects in the study and corresponding population characteristics,had an overall effective rate of 95.00%in the actual clinical use population obtained based on the cohort study data;however,the overall effective rate in this randomized controlled trial was only 73.81%,which was reduced compared with the cohort study phase.Conclusion1.The study showed that the core prescriptions based on the clinical experience of famous TCM doctors were effective,safe and reliable for patients with insomnia and phlegm-heat disturbance,which could significantly prolong the total sleep time at night,shorten the sleep latency,reduce the severity of insomnia,increase the efficiency of sleep and improve the quality of sleep.The therapeutic effect is comparable to that of classical prescriptions with similar efficacy,and the correspondence with the characteristics of its suitable population is also stronger.2.This study is the third part of the "validation" stage in the construction of the "stepwise progressive method of evaluating the efficacy of evidence-based treatment" system,as an important part of the overall "evidence-treatment-effectiveness" interrelated evidence chain.As an important part of the overall,"evidence-treatment-effect" chain of evidence,it explains the new model of real-world efficacy evaluation.3.It is a feasible research method to compare and confirm the efficacy of the core prescriptions of evidence-based treatment by individual physicians in the real world with traditional classical prescriptions.