Study On Core Outcome Set For Premature Ovarian Insufficiency Treated With Traditional Chinese Medicine

Background:Premature ovarian insufficiency(POI)is refractory and irreversible,with a low pregnancy rate and a strong need for fertility in most patients.Traditional Chinese Medicine(TCM)with POI has unique advantages and low side effects.Previous literature studies have shown that the methodological quality of clinical trials is low,and there is still a lack of high quality evidence-based medicine.One of the important influencing factors affecting the quality of clinical trial studies is the non-standardized,inconsistent and selective reporting of efficacy evaluation indicators.In this study,we systematically summarized the clinical studies related evaluation outcomes of TCM in the treatment of POI through a comprehensive literature search,and found that there were indeed problems such as irregular evaluation outcomes,excessive selection of outcomes,unclear definition of outcomes,diverse and inconsistent measurement tools and measurement time points.Based on the background above,this study with the support of the Fourteenth Key Project of the Chinese Academy of Traditional Chinese Medicine on "Health Technology Assessment of the Effect of Chinese Medicine on Pregnancy Outcome of Early Ovarian Insufficiency Based on Real World Data"(Z0733),we improved the quality of clinical studies for evidence synthesis by developing a core outcome set for clinical studies of TCM in the treatment of POI,and provided reference for subsequent researchers to conduct the selection of clinical efficacy evaluation outcomes for TCM.Objective:To address the current problems of excessive and inconsistent selection of clinical efficacy evaluation outcomes of TCM in the treatment of POI,non-standardized definitions,and diverse measurement tools and measurement time points,to develop a core outcome set for clinical studies of TCM in the treatment of POI,to clarify outcome definitions,and to recommend measurement tools and measurement time points,to provide reference for the development of core outcome sets for similar TCM clinical studies in the future,as well as to provide reference for subsequent investigators to conduct TCM clinical studies for POI provide outcome selection.Method:Referring to the international Core outcome measures in effectiveness trials(COMET)Handbook,relevant normative guidelines and the traditional Chinese medicine core outcome set development group standards,this study carried out the development of the item pool of outcome indicators and the consensus study of the core outcome set for clinical studies of TCM in the treatment of POI.Pre-establishment of a working group for core outcome set development and program registration.In the first step,to analyze the current situation of the outcome indicators of clinical research literature of TCM in the treatment of POI was conducted by computer search of Chinese and English databases,English databases including PubMed,EMbase,The Cochrane Library and Web of Science,Chinese databases including China national knowledge infrastructure(CNKI),Wanfang Data Knowledge Service Platform(Wanfang),VIP China Science and Technology Journal Database(VIP)and China Biomedical Literature Database(SinoMed),with the theme of Premature ovarian insufficiency and the intervention of TCM,and the search time limit was from January 2017 to December 2021,to conduct a descriptive analysis of the outcome indicators included in clinical trial studies of TCM in the treatment of POI;in the second step,the analysis of outcome indicators of clinical trial registration protocols of TCM in the treatment of POI was performed by searching the Chinese Clinical Trials Registry(ChiCTR)and the American Clinical Trials Registry(clinical trials.gov)databases.With the theme of Premature ovarian insufficiency,the intervention was TCM,and the search time was not limited,and the outcome indicators not mentioned in the published clinical studies were extracted and supplemented;in the third step,the indicators based on patient questionnaires were collected and analyzed,and the outcome indicators valued by the patients were obtained through semi-structured interviews with the patients.Meanwhile,the clinical efficacy evaluation indicators obtained from published clinical research literature,clinical research registration protocols and patient semi-structured interviews were de-duplicated and integrated,normalized and discussed by the expert steering committee to form a pool of clinical efficacy evaluation indicators for TCM in the treatment of POI;in the fourth step,soliciting experts’ opinions through the Delphi survey method,experts rate the importance of the indicators in the indicator pool,and initially screen out the indicators that experts agree are important.In the fifth step,the core outcome set of Premature ovarian insufficiency in TCM clinical research was finally formed through a consensus meeting,while the existing core outcome measurement tools and measurement time points were obtained through literature search and related book review,and reliable measurement tools were recommended for the study after their quality was assessed by using the Guideline for selecting outcome measurement instruments for outcomes included in a Core Outcome Set(COS-SOMIN)inventory assessment tool,the measurement time point was determined by expert discussion.Results:1.Outcome Pool Construction:The literature was initially searched for 46,914 documents,and after screening by weighting and reading the full text,554 clinical studies were finally included,including 549 in Chinese and 5 in English,with a total of 3,245 indicators reported,and a total of 98 outcome indicators were found to be involved after merging the indicators of the same name.A total of 46 clinical registries were obtained,and 14 clinical registries were included after screening,with a total of 101 indicators reported,and a total of 50 outcome indicators were found to be involved after combining the indicators of the same name.Semi-structured interviews were conducted with a total of 20 patients,15 with fertility needs and 5 without fertility needs,and a total of 51 indicators were reported,involving 20 outcome indicators.Finally,3397 efficacy evaluation indicators were obtained cumulatively,and 113 outcome indicators were found to be involved after combining indicators of the same name,and the minimum number of individual clinical study outcome indicators was 1 and the maximum number was up to 18.The top 10 outcome indicators in terms of frequency were:follicle stimulating hormone(FSH),estradiol(E2),total effective rate,luteinizing hormone(LH),adverse effects,anti-mullerian hormone(AMH),Antral follicle count(AFC),TCM evidence score,perimenopausal symptoms,and endometrial thickness.After de-duplication,collation and merging and normalization,as well as discussion by the expert steering committee to screen out indicators that were not strongly associated with clinical study objectives and disease,the final pool of indicators contained 77 outcome indicators.2.Delphi Survey:In the first round of expert Delphi survey,71 experts participated in the scoring,30 indicators were≥75%of experts considered them important,and experts added 13 additional indicators they considered important;in the second round of expert Delphi survey,65 experts participated in the scoring,23 indicators were≥75%of experts considered them important,and experts added 8 additional indicators they considered important.Before the consensus meeting,after the expert steering committee discussion,there were 20 outcome indicators that finally entered the consensus meeting.3.Consensus Meeting:Through the consensus meeting expert voting and discussion,the finalized core indicator set included 3 outcome domains and 8 core outcome indicators,the 3 outcome domains were ovarian reserve functions menstruation-related indicators and fertility outcome,and the 8 core outcome indicators were follicle stimulating hormone(FSH),Chinese medicine evidence/symptoms.The 8 core outcomes were follicle stimulating hormone(FSH),estradiol(E2),anti-mullerian hormone(AMH),sinus follicle count(AFC),menstrual symptoms,pregnancy rate,live birth rate,and the numbers of retrieved oocytes.Different outcomes are recommended according to different patient needs,with ovarian reserve function and menstruation-related indicators as general indicators,fertility outcome-related indicators as specific indicators for evaluating patients with fertility needs.4.Measurement Tools:Determine the measurement methods and tools for the above outcomes through expert discussions,Follicle-stimulating hormone(FSH),estradiol(E2),and anti-mullerian hormone(AMH)are recommended for immunoassay;ultrasound is recommended for Antral follicle count(AFC)and the numbers of retrieved oocytes;Pregnancy rates are recommended for serum Human Chorionic Gonadotropin(HCG)and ultrasound.Live birth rates were assessed by clinician observation.For the menstrual symptom,the measurement tool Menstrual Symptom Questionnaire(MDQ)was queried and its quality was assessed by using the COS-SOMIN inventory assessment tool.It was found that the reliability and structural validity of the scale were high,but the content validity,cross-cultural validity and calibration validity of the scale were not sufficiently studied,so further exploration is needed to select a measurement tool with high acceptance and stable performance.The measurement time points were discussed and determined to be before treatment,3 months,6 months,1 year and 2 years of follow-up after treatment.Conclusion:This study formed a core outcome set for clinical trial studies of TCM in the treatment of POI,practiced the method of developing core outcome set,and explored the key points of developing core outcome set with TCM characteristics,analyzed the problems in developing,and studied the connotation and extension of core outcome and its embodiment with TCM characteristics.A core outcome set of POI has been developed that meets the requirements of international standards and also takes into account the characteristics of Chinese medicine,which is favorable to improve the consistency of outcome reporting of similar POI of TCM clinical studies,solve the problem of inconsistent selection of outcomes,conducive to generating high-quality evidence through systematic review,providing favorable support for TCM efficacy and enhancing the value of TCM clinical studies.