Traditional Chinese Patent Medicine Qizhijiangtang Capsule for Non- Proliferative Diabetic Retinopathy: Study Protocol for a Randomized Controlled Trial

Traditional Chinese Patent Medicine Qizhijiangtang Capsule for Non- Proliferative Diabetic Retinopathy: Study Protocol for a Randomized Controlled Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Traditional Chinese Patent Medicine Qizhijiangtang Capsule for Non- Proliferative Diabetic Retinopathy: Study Protocol for a Randomized Controlled Trial Bing Pang, He Guo, Yue-ying Zhang, Shuo Feng, Hua-jie Hu, Ye Sun, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2428596/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Diabetic retinopathy remains a leading cause of vision loss globally. Here, we investigated the efficacy and safety of Qizhijiangtang capsule (QZJC), a kind of traditional Chinese patent medicine, for patients with NPDR. Methods: This study is a multi-center, randomized, controlled clinical trial. A total of 100 participants will be randomly assigned in a 1:1 ratio to QZJC group or QZJC placebo group. The treatment duration lasts 24 weeks. The primary outcome is the changes in the degree of retinal microaneurysm lesions assessed by fundus photography and fundus fluorescence angiography before and after treatment. The secondary outcomes include the changes in corrected visual acuity, blood glucose, glycosylated hemoglobin, urinary microalbumin excretion rate, the improvement of TCM syndromes and TCM symptoms. Discussion: We postulate that NPDR patients will benefit from QZJC. If successful, this work will provide preliminary evidence that QZJC could delay the progress of DR. Trial registration: Chinese Clinical Trial Registry no. ChiCTR1900023506. The protocol has registered at http://www.chictr.org.cn/showprojen.aspx?proj=39622. Registered 31 May 2019. Template (preprint statement) : This manuscript has been preprinted [https://doi.org/10.21203/rs.3.rs-596869/v1]. Traditional Chinese patent medicine Qizhijiangtang Capsule Non-proliferative diabetic retinopathy Randomized controlled trial Protocol Figures Figure 1 Figure 2 Background Diabetic retinopathy (DR) is the most frequently occurring complication of diabetes mellitus (DM). The quantity of people suffered with DR has been estimated to increase from 463 million in 2019 to 700 million by 2045[ 1 ]. It has been reported that DR is a primary cause of preventable blindness in labor age population globally. During the stage of proliferative diabetic retinopathy (PDR), the patients may experience severe vision impairment, which is irreversible and dramatically affects the life quality of diabetic patients. Therefore, early prevention and treatment of DR is essential. Current therapies for DR mainly aimed at PDR or diabetic macular edema, drugs intervention for early stage are still limited. Traditional Chinese herbal medicine may provide an alternative and complementary therapy for targeting the early and potentially reversible retinal damage [ 2 ]. Qizhijiangtang capsule (QZJC), a kind of traditional Chinese patent medicine, which has been approved in China. QZJC consists of Astragalus mongholicus Bunge, Rehmannia glutinosa (Gaertn.) DC., Polygonatum cyrtonema Huaand, and Terminalia chebula Retz. QZJC has been proven to regulate glucolipid metabolism, improve the insulin resistance, inhibit the glomerulosclerosis and renal interstitial fibrosis, et al [ 3 – 4 ]. However, its effect on DR is still unclear. We will carry out a clinical trial to investigate the efficacy and safety of QZJC targeting NPDR. Methods Ethics and permissions The protocol has been approved by the Medical Ethics Committee of Guang’anmen Hospital of the China Academy of Chinese Medical Sciences (No.2019-008-KY). The protocol has registered at http://www.chictr.org.cn/showprojen.aspx?proj=39622. Trial registration number: ChiCTR1900023506. Setting and participants Six hospitals in China agree to participate in this study, including Guang’ anmen Hospital of China Academy of Chinese Medical Sciences, Beijing Shijitan Hospital, Capital Medical University, Beijing Changping District Hospital of Chinese Medicine, Beijing Shunyi District Hospital of Chinese Medicine, Beijing Miyun District Hospital of Chinese Medicine, and Beijing Pinggu District Hospital of Chinese Medicine. All the participants will be provided with general information of the study and the possible risks and benefits, and the informed consent will be obtained from all participants prior to entry into the trial ( Figure 1 ). Eligibility Criteria Diagnostic criteria Diagnostic criteria for type 2 diabetes (T2DM) are based on the guideline for the prevention and control of T2DM in China (2017 Edition) [5], which is defined as: (1) In patients with classic diabetic symptoms of hyperglycemia, a random plasma glucose ≥ 11.1 mmol/L; or (2) Fasting plasma glucose ≥ 7.0 mmol/L; or (3) Two-hour plasma glucose ≥ 11.1 mmol/L after an oral glucose tolerance test. Diagnostic criteria for DR are based on Proposed International Clinical Diabetic Retinopathy and Diabetic Macular Edema Disease Severity Scales by American Academy of Ophthalmology. Diagnosis and classification of type 2 diabetic retinopathy is defined as: (1) Mild NPDR: microaneurysm only; (2)Moderate NPDR: More than just microaneurysms but less than severe NPDR; (3)Severe NPDR: Any of the following: more than 20 intraretinal hemorrhages in each of 4 quadrants; definite venous beading in 2+ quadrants; Prominent intraretinal microvascular abnormalities in 1+ quadrant; And no signs of proliferative retinopathy; (4) Proliferative DR: One or more of the following: neovascularization, vitreous/preretinal hemorrhage [6]. TCM syndrome differentiation Diagnosis of deficiency of dual qi and yin combined with blood stasis syndrome are based on Traditional Chinese medicine Clinical Pathway of Xiaoke disease [7]. Inclusion criteria 1. Participants should be between 30 and 70 years old; 2. Participants should meet the diagnostic criteria for T2DM. 3. Participants should meet the diagnostic criteria for DR and the stage of NPDR. 4. Participants should meet the diagnostic criteria of deficiency of dual qi and yin combined with blood stasis syndrome. 5. Participants should sign informed consent forms. 6. Anti-hyperglycemic drugs have been used steadily in the past three months and can be expected to remain unchanged throughout the study. Exclusion criteria 1.Participants experience postoperative retinal photocoagulation, suitable photocoagulation therapy, or suffer with the stage of PDR (IV, V, VI stage), type 1 diabetic retinopathy, other ocular complications, such as glaucoma, severe cataracts, retinal detachment, and retinopathy not related to DM, etc. 2. Participants with s serious complications of heart, brain and kidney or with other serious primary diseases. 3. Participants with recurrent hypoglycemia, diabetic ketoacidosis and severe infection within recent months. 4. Participants with impaired liver and kidney function. 5. Pregnant, pregnant or lactating women, or those with a history of drug allergy. 6. Alcohol abuse and/or psychoactive substances, drug abusers and addicts. Randomization, concealment and blind A specific randomization sequence will be generated by an independent clinical research organization (CRO) from the Institute of Basic Research in Clinical Medicine of the China Academy of Chinese Medical Sciences. Eligible participants will be randomized to the intervention group or the control group at a 1:1 ratio. The researchers will sequentially enroll patients based on randomization code. To ensure concealment, the block sizes will not be disclosed and not be available to both participants and researchers until the trial is end. In the event of a medical emergency, the participant’s randomization code and treatment allocation can be identified. Both participants, investigators and the statistician will be blinded. In addition, QZJC and QZJC placebo will be manufactured as granules with the same color and smell, the appearance of them are identical. After production, study drugs will be packaged and transferred to numbered package in accordance with the randomization sequence. Interventions A total of 100 participants will be recruited and randomly assigned to either the intervention or the control group. All the participants will be treated with conventional treatment, including a healthy low-fat diet, moderate physical activity, anti-hyperglycemic, lipid-lowering and anti-hypertensive drugs, to ensure access to steady levels of body weight, blood glucose, blood lipids and blood pressure. On the basis, the intervention group used 2.5g QZJC three times per day, while the control group used 2.5g QZJC placebo three times per day, both of them are recommended to be taken after meals with boiled warm water. The treatment duration will be 24 weeks, and we will follow up for another 2 years. Outcomes Primary outcome The primary outcome of the study is the changes in the degree of retinal microaneurysm lesions assessed by fundus photography and fundus fluorescence angiography before and after treatment. This will be determined according to the following scale: none, mild non-proliferative phase, moderate non-proliferative phase, severe non-proliferative phase, and proliferative phase, which are divided into aggravated, stable, and improved conditions. The aggravated condition is defined as retinal microaneurysm lesions with a degree of severity > grade 1 after treatment. The stable condition was defined as a degree of retinal microaneurysm lesions before and after treatment that is unchanged, while the improved condition is defined as a degree off retinal microaneurysm lesions that is reduced by >1 grade after treatment. Secondary outcomes Secondary outcomes are listed as the corrected visual acuity, fasting blood glucose, 2-hour postprandial blood glucose, glycosylated hemoglobin, urinary microalbumin excretion rate, the improvement of TCM syndromes and TCM symptoms from baseline to 24 weeks. Safety assessment and adverse events monitoring. Safety assessment outcomes are listed as vital signs, routine blood test, routine urine test and routine stool test, electrocardiogram, liver function, renal function will be performed at every 12 weeks from baseline. Adverse events (AEs) will be documented at every visit, including the occurrence time, severity, duration, solution and transfer. AEs will be divided into three levels: mild, moderate and severe, and the causality between TCPMs for trials and AEs will be judged. In case of any AEs, such as subjective discomfort of the patient and abnormal laboratory test, it will be taken measures immediately to protect the safety of the participants. Any serious AEs during the test must be reported to the Ethics Committee of the unit immediately, and notify the telephone number and contact person of the units listed in the CRF form. The “Severe Adverse Event (SAE)” form must be filled in. All AEs will be recorded, monitored, and treated until resolved. Study Procedure The study will include a 2-week washout period, a 24-week treatment period and a 2-year follow-up period. Subjects who are diagnosed with NPDR will be given a 2-week lifestyle intervention at run-in period, all of them will provide written informed consent prior to participation. After the intervention period begin, participant visits will conduct every 4 weeks. All data will be documented on the CRFs ( Figure 2 ). Sample size calculation According to data from preliminary trial [8], the rate of retinal microvascular disease was reduced by 2.9% in the placebo group, and we predicted that the rate of retinal microvascular disease would be reduced by 6.5% in the TCPM group. The standard deviation was set as 2.17. The superiority margin was assumed to increase 1.4 percentage on the basis of placebo. The ratio of the two groups was set as 1:1. The significance level is targeted at 0.025 for one-sided test. The power achieved to detect a difference is set as 0.9. Sample size will be calculated the independent proportions power analysis using PASS 11.0 software, approximately 45 participants in each group will be needed. The sample size used in our study was increased by an additional 10% in case of lost of follow-up. Hence, the final sample size is estimated to be 50 in each group. Data collection and management The researchers will record original data into the case report form (CRF), the supervisor will check whether the trial is launched consistent with the protocol, and the data in the CRFs is identical with the original data, errors and inconsistencies will be timely corrected. Before data entry, the data administrators will check the CRFs again to ensure the accuracy of the data, the data administrator will also record the coding process in the coding book. Duplicate entry is adopted for inputting the data. If problems are found in the input process, they will be registered and reported in time, so as to deal with the problems quickly. The data administrator will write the computer programs and input data. After entering the data, the CRFs need to be filed and saved. The researchers will keep the clinical trial data until 5 years after the end of the clinical trial. Statistical analysis Analysis subjects Three analysis sets will be used in this trial, including full analysis set (FAS), per protocol set (PPS) and safety set (SS). FAS includes all randomized subjects and drop-out subjects who have been treated at least once and excluded for reasonable reasons. For the subjects who failed to observe the efficacy, the principle of the last observation carried forward (LOCF) will be applied to handle with the missing outcome data. PPS is a set of compliance protocol, including that the participants have good compliance of using 80-120% quantity of the study drugs; the baseline characteristics are not missing, and the data of the primary outcome can be obtained; and it does not run counter to the protocol. SS is a set that received at least one-time treatment and has data recorded with safety assessment. Statistical method Statistical analysis will be completed by the third-party statisticians using SAS 9.3 software. Continuous data will be expressed as the mean, median, standard deviation, minimum value, and maximum value, while categorical data will be expressed as the number of cases and percentages. To compare baseline characteristics between the two groups, independent t tests will be used to analyze continuous data, and chi-squared test or Fisher exact test will be used for categorical data. With regard to outcome analysis, the classified variables will be performed using the chi-squared test or Fisher exact test, and continuous variables will be performed using t test for normally distributed data and Wilcoxon rank sum test for non-normal distribution data. Moreover, repeated measures analysis of variance (ANOVA) will be applied to determine to further investigate the effects of treatment and time course. A two-tailed test will be applied, and P < 0.05 will be considered to indicate a statistical significance. Discussion In the UPLC-QE-Orbitrap-MS analysis, a total of 52 compounds were identified in QZJC capsules, many of the compounds have been proved by modern pharmacological studies to have the effect of improving related symptoms of DM and its complications, reflecting the characteristics of synergistic action of multiple components in QZJC[ 9 ]. In the previous experiments, QZJC has been demonstrated that ameliorated retinal vascular permeability and inhibited retinal neovascularization via up-regulating prostacyclin2 (PGI2) and down-regulating VEGF and von willebrand factor (vWF); it also attenuated inflammation via promotion of nitric oxide (NO) and superoxide dismutase (SOD) expression [ 10 ]. Currently, we therefore design a randomized and controlled multicenter clinical trial to assess the efficacy and safety of QZJC. We hypothesize that QZJC could have a potential retinal protective effect on NPDR patients. If successful, the findings of this trial may provide an alternative treatment for NPDR patients. It may also provide scientific evidence for delaying the progress of DR. This trial also has some limitations. Firstly, as the test instruments of each research center are different, the error of test results is inevitable. Secondly, there might be several individual differences in the subjects, possibly leading to different efficacy of the drug. The improvements need to be seen in the future. Dissemination plans The results will be disseminated through peer-reviewed journal articles and presented abstracts and posters at scientific conferences in the field of diabetes and TCM, as well as the general public through internet and newspaper. Declarations Acknowledgements Not applicable. Authors' contribution Pang B drafted the trial protocol. Ni Q provided critical advice and comments on the protocol. Guo H, Zhang YY, Hu HJ, Sun Y, Cao AM, Lu CQ, and Zhang WH referred and recruited the patients. Feng S is responsible for statistical analysis. All of the authors participated in the design and development of the trial protocol. All authors read and approved the final manuscript. Funding This study is supported by grants from Capital Health Research and Development of Special Fund (2016-1-4151); National Natural Science Foundation of China (82104832); Special program for excellent scientific personnel training of Chinese Academy of traditional Chinese Medicine (ZZ13-YQ-032); Institutional Research Foundation of Guang' anmen Hospital, China Academy of Chinese Medical Science (59957). Availability of data and material Once the main findings of the project have been published, the trial steering committee will review all requests for data before access is granted. If appropriate, we will make the anonymized data and associated documentation available to users under a data-sharing agreement. The full protocol is available at http://www.chictr.org.cn/edit.aspx?pid=39622&htm=4. Ethics approval and consent to participate The protocol has been approved by the Medical Ethics Committee of Guang’anmen Hospital of the China Academy of Chinese Medical Sciences (No.2019-008-KY). The trial registration number is as follows: Chinese Clinical Trial Registry no. ChiCTR1900023506, and any important changes in the protocol will be reflected there. The study will implement in accordance with the items of the Declaration of Helsinki. The trial will perform based on the Standard Protocol Items: Recommendations for Intervention Trials (SPIRIT) guidelines. All participants will provide voluntary written informed consent form (ICF) after a full discussion about the potential benefits and risks before the study, and ICFs will be signed by participants prior to entry into the trial. Consent for publication All authors gave consent for the publication of the manuscript. Competing interests The authors declare no conflict of interest. References International Diabetes Federation. IDF Diabetes Atlas. 8th. Brussels, Belgium: International Diabetes Federation; 2017. Pang B, Li QW, Qin YL,et al. Traditional Chinese medicine for diabetic retinopathy. Medicine 2020;99(7): e19102. Zhang XT, Chen Y, Yu CJ, et al. Effect of Qizhi Jiangtang capsule on insulin resistance in diabetic rats and its mechanism. Jilin Da Xue Xue Bao (Yi Xue Ban) 2014;40(4):805-811. Wu S, Guo ZA, Yu CJ, et al. Effects of Qizhi Jiangtang capsule on BMP-7 and TGF-β1/Smads signaling pathway of kidney in diabetic nephropathy rats. Zhongguo Zhong Xi Yi Jie He Shen Bing Za Zhi 2014;15(4):297-301. Chinese Diabetes Society. Guidelines for the prevention and control of type 2 diabetes in China (2017 Edition). Zhongguo Shi Yong Nei Ke Za Zhi 2018;38(4):292-338. Wilkinson CP, Ferris FL 3rd, Klein RE, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 2003; 110(9):1677-82. Department of Medical Administration of National Administration of Traditional Chinese Medicine. Traditional Chinese medicine of clinical pathway of 95 kinds of disease in 22 specialized subjects (bound volume). National Administration of Traditional Chinese Medicine Press . 2010:145-166. Lian FM, Wu L, Tian JX, et al. The effectiveness and safety of a danshen-containing Chinese herbal medicine for diabetic retinopathy: a randomized, double-blind, placebo-controlled multicenter clinical trial. J Ethnopharmacol 2015;164:71-7. Shi JC, Zhang SR, Chai Z, et al. Analysis of chemical constituents in Qizhi Jiangtang capsules based on UPLC-QE-Orbitrap-MS analysis. Zhongguo Shiyan Fangji Xue Za Zhi .2020;1-14. Zhang C. The effect and mechanism of Qizhi Jiangtang capsule protect the retina of type 2 diabetic rats. Jilin University, 2015(Dissertation). Additional Declarations No competing interests reported. Supplementary Files SPIRIT920.doc Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2428596","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":164250879,"identity":"16c9fae0-57bc-41d5-91e0-5848e90e5449","order_by":0,"name":"Bing Pang","email":"","orcid":"","institution":"Guang’ anmen Hospital of China Academy of Chinese Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Bing","middleName":"","lastName":"Pang","suffix":""},{"id":164250881,"identity":"060aa312-bb46-4419-8296-f1aaf23931cc","order_by":1,"name":"He Guo","email":"","orcid":"","institution":"Guang’ anmen Hospital of China Academy of Chinese Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"He","middleName":"","lastName":"Guo","suffix":""},{"id":164250884,"identity":"94b7677c-3d04-48d8-be26-ccd066ccc814","order_by":2,"name":"Yue-ying Zhang","email":"","orcid":"","institution":"Guang’ anmen Hospital of China Academy of Chinese Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Yue-ying","middleName":"","lastName":"Zhang","suffix":""},{"id":164250885,"identity":"337a2355-a07d-4d3b-8aee-329d3b25a0cc","order_by":3,"name":"Shuo Feng","email":"","orcid":"","institution":"China Academy of Chinese Medical Sciences Guang’ amen Hospital Southern District","correspondingAuthor":false,"prefix":"","firstName":"Shuo","middleName":"","lastName":"Feng","suffix":""},{"id":164250886,"identity":"2e06ac0d-1240-44bb-a0c8-a717ffd02392","order_by":4,"name":"Hua-jie Hu","email":"","orcid":"","institution":"Beijing Shunyi District Hospital of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hua-jie","middleName":"","lastName":"Hu","suffix":""},{"id":164250888,"identity":"a79c5c92-9e76-4557-912a-05163c320850","order_by":5,"name":"Ye Sun","email":"","orcid":"","institution":"Beijing Pinggu District Hospital of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ye","middleName":"","lastName":"Sun","suffix":""},{"id":164250891,"identity":"de3a9933-2248-4e1c-8785-9039d915263f","order_by":6,"name":"Ai-mei Cao","email":"","orcid":"","institution":"Beijing Changping District Hospital of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ai-mei","middleName":"","lastName":"Cao","suffix":""},{"id":164250894,"identity":"19226a45-4b07-4125-bab1-ef7b0abbcd5b","order_by":7,"name":"Chun-qian Lu","email":"","orcid":"","institution":"Beijing Miyun District Hospital of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chun-qian","middleName":"","lastName":"Lu","suffix":""},{"id":164250896,"identity":"112495af-8601-4e9b-b6ca-54517827fcda","order_by":8,"name":"Wei-hua Zhang","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Wei-hua","middleName":"","lastName":"Zhang","suffix":""},{"id":164250897,"identity":"38c408d5-f687-4761-8f15-582fb1f2f4bb","order_by":9,"name":"Qing Ni","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxUlEQVRIiWNgGAWjYDACZgaGAwwMNnL87I2NDz+QoCXNWLLncLOxBAl2HUo0uJHeJsBDjFpzduaNhwt+HUgwuPmwjUGCwU5Ot4GAFstmtoLDM/vu5EneTmx7UMCQbGx2gIAWg8M8Bod5e54V891ObDeQYDiQuI1ILYcTG24ebJPgIVoLz4/DiRNuMBKtBegX3gZQICcCA9mAGL+cP7z5M88fUFQef/jwQ4WdHEEtIF0MjG0INlEAqOwPcSpHwSgYBaNghAIAbS9JNEOrqBIAAAAASUVORK5CYII=","orcid":"","institution":"Guang’ anmen Hospital of China Academy of Chinese Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Qing","middleName":"","lastName":"Ni","suffix":""}],"badges":[],"createdAt":"2022-12-30 12:59:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2428596/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2428596/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":31169930,"identity":"c7dca8c3-e087-4663-84f1-313cf8f0bd8f","added_by":"auto","created_at":"2023-01-05 15:48:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":57815,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of enrollment, intervention and assessments\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-2428596/v1/8c738e5228cda46122aa0255.png"},{"id":31169931,"identity":"0425f1c6-7da3-4e4b-8a03-2d39c91e7865","added_by":"auto","created_at":"2023-01-05 15:48:45","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":101859,"visible":true,"origin":"","legend":"\u003cp\u003eSchedule of enrolment, interventions, and assessments\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-2428596/v1/700c2b762fb3f0824be17acd.png"},{"id":32089688,"identity":"7c653fa7-6ba7-45eb-9134-1a5a81901d2c","added_by":"auto","created_at":"2023-01-26 17:29:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":405207,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2428596/v1/e3e7d1ab-b3f6-4d22-ac8d-41dcad92c9f0.pdf"},{"id":31169929,"identity":"44853983-c318-4b88-b2de-94ac88fe6023","added_by":"auto","created_at":"2023-01-05 15:48:44","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":124416,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRIT920.doc","url":"https://assets-eu.researchsquare.com/files/rs-2428596/v1/b9d34384bafcf19e32daf965.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Traditional Chinese Patent Medicine Qizhijiangtang Capsule for Non- Proliferative Diabetic Retinopathy: Study Protocol for a Randomized Controlled Trial","fulltext":[{"header":"Background","content":"\u003cp\u003eDiabetic retinopathy (DR) is the most frequently occurring complication of diabetes mellitus (DM). The quantity of people suffered with DR has been estimated to increase from 463\u0026nbsp;million in 2019 to 700\u0026nbsp;million by 2045[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It has been reported that DR is a primary cause of preventable blindness in labor age population globally. During the stage of proliferative diabetic retinopathy (PDR), the patients may experience severe vision impairment, which is irreversible and dramatically affects the life quality of diabetic patients. Therefore, early prevention and treatment of DR is essential. Current therapies for DR mainly aimed at PDR or diabetic macular edema, drugs intervention for early stage are still limited. Traditional Chinese herbal medicine may provide an alternative and complementary therapy for targeting the early and potentially reversible retinal damage [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Qizhijiangtang capsule (QZJC), a kind of traditional Chinese patent medicine, which has been approved in China. QZJC consists of Astragalus mongholicus Bunge, Rehmannia glutinosa (Gaertn.) DC., Polygonatum cyrtonema Huaand, and Terminalia chebula Retz. QZJC has been proven to regulate glucolipid metabolism, improve the insulin resistance, inhibit the glomerulosclerosis and renal interstitial fibrosis, \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, its effect on DR is still unclear. We will carry out a clinical trial to investigate the efficacy and safety of QZJC targeting NPDR.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eEthics and permissions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe protocol has been approved by the Medical Ethics Committee of Guang\u0026rsquo;anmen Hospital of the China Academy of Chinese Medical Sciences (No.2019-008-KY). The protocol has registered at http://www.chictr.org.cn/showprojen.aspx?proj=39622. Trial registration number:\u0026nbsp;ChiCTR1900023506.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSetting and participants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSix hospitals in China agree to participate in this study, including\u0026nbsp;Guang\u0026rsquo; anmen Hospital of China Academy of Chinese Medical Sciences, Beijing Shijitan Hospital, Capital Medical University, Beijing Changping District Hospital of Chinese Medicine, Beijing Shunyi District Hospital of Chinese Medicine, Beijing Miyun District Hospital of Chinese Medicine, and Beijing Pinggu District Hospital of Chinese Medicine. All the participants will be provided with general information of the study\u0026nbsp;and the possible risks and benefits, and the informed consent will be obtained from all participants prior to entry into the trial\u0026nbsp;(\u003cstrong\u003eFigure 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDiagnostic criteria\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eDiagnostic criteria for type 2 diabetes (T2DM) are based on\u0026nbsp;the guideline for the prevention and control of T2DM in China (2017 Edition)\u0026nbsp;[5], which\u0026nbsp;is defined as: (1) In patients with classic diabetic symptoms of hyperglycemia, a random plasma glucose \u0026ge; 11.1 mmol/L; or (2) Fasting plasma glucose \u0026ge; 7.0 mmol/L; or (3) Two-hour plasma glucose \u0026ge; 11.1 mmol/L after an oral glucose tolerance test.\u003c/p\u003e\n\u003cp\u003eDiagnostic criteria for DR are based on Proposed International Clinical Diabetic Retinopathy and Diabetic Macular Edema Disease Severity Scales by\u0026nbsp;American Academy of Ophthalmology.\u0026nbsp;Diagnosis and classification of type 2 diabetic retinopathy is defined as: (1) Mild NPDR: microaneurysm only; (2)Moderate NPDR: More than just microaneurysms but less than severe NPDR; (3)Severe NPDR: Any of the following: more than 20 intraretinal hemorrhages in each of 4 quadrants; definite venous beading in 2+ quadrants; Prominent intraretinal microvascular abnormalities in 1+ quadrant; And no signs of proliferative retinopathy; (4) Proliferative DR: One or more of the following: neovascularization, vitreous/preretinal hemorrhage [6]. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTCM syndrome differentiation\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eDiagnosis of deficiency of dual qi and yin combined with blood stasis syndrome are based on Traditional Chinese medicine Clinical Pathway of \u003cem\u003eXiaoke\u0026nbsp;\u003c/em\u003edisease [7].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInclusion criteria\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e1. Participants should be between 30 and 70 years old;\u003c/p\u003e\n\u003cp\u003e2. Participants should meet the diagnostic criteria for T2DM.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. Participants should meet the diagnostic criteria for DR and the stage of NPDR.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4. Participants should meet the diagnostic criteria of deficiency of dual qi and yin combined with blood stasis syndrome.\u003c/p\u003e\n\u003cp\u003e5. Participants should sign informed consent forms.\u003c/p\u003e\n\u003cp\u003e6. Anti-hyperglycemic drugs have been used steadily in the past three months and can be expected to remain unchanged throughout the study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eExclusion criteria\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e1.Participants experience postoperative retinal photocoagulation, suitable photocoagulation therapy,\u0026nbsp;or suffer with the stage of PDR (IV, V, VI stage), type 1 diabetic retinopathy, other ocular complications, such as glaucoma, severe cataracts, retinal detachment, and retinopathy not related to DM, etc.\u003c/p\u003e\n\u003cp\u003e2. Participants\u0026nbsp;with s serious complications of heart, brain and kidney or with other serious primary diseases.\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp;Participants\u0026nbsp;with recurrent hypoglycemia, diabetic ketoacidosis and severe infection within recent months.\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp;Participants\u0026nbsp;with impaired liver and kidney function.\u003c/p\u003e\n\u003cp\u003e5. Pregnant, pregnant or lactating women, or those with a history of drug allergy.\u003c/p\u003e\n\u003cp\u003e6. Alcohol abuse and/or psychoactive substances, drug abusers and addicts.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomization, concealment and blind\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA specific randomization sequence will be generated by an independent clinical research organization (CRO) from the Institute of Basic Research in Clinical Medicine of the China Academy of Chinese Medical Sciences. Eligible participants will be randomized to the intervention group or the control group at a 1:1 ratio. The researchers will sequentially enroll patients based on randomization code. To ensure concealment, the block sizes will not be disclosed and not be available to both participants and researchers until the trial is end. In the event of a medical emergency, the participant\u0026rsquo;s randomization code and treatment allocation can be identified. Both participants, investigators and the statistician will be blinded. In addition,\u0026nbsp;QZJC and QZJC placebo will be manufactured as granules with the same color and smell, the appearance of them are identical.\u0026nbsp;After production, study drugs will be packaged and transferred to numbered package in accordance with the randomization sequence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 100 participants will be recruited and\u0026nbsp;randomly assigned to either the intervention or the control group. All the participants will be treated with conventional treatment, including\u0026nbsp;a healthy low-fat diet, moderate physical activity,\u0026nbsp;anti-hyperglycemic, lipid-lowering and anti-hypertensive drugs, to ensure access\u0026nbsp;to steady levels of body weight, blood glucose, blood lipids and blood\u0026nbsp;pressure. On the basis,\u0026nbsp;the intervention group used\u0026nbsp;2.5g QZJC three times per day, while the control group used\u0026nbsp;2.5g QZJC placebo three times per day, both of them are recommended to be taken after meals with boiled warm water.\u0026nbsp;The treatment duration will be 24 weeks, and we will follow up for another 2 years.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePrimary outcome\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome of the study is the changes in the degree of retinal microaneurysm lesions assessed by fundus photography and fundus fluorescence angiography before and after treatment. This will be determined according to the following scale: none, mild non-proliferative phase, moderate non-proliferative phase, severe non-proliferative phase, and proliferative phase, which are divided into aggravated, stable, and improved conditions. The aggravated condition is defined as retinal microaneurysm lesions with a degree of severity \u0026gt; grade 1 after treatment. The stable condition was defined as a degree of retinal microaneurysm lesions before and after treatment that is unchanged, while the improved condition is defined as a degree off retinal microaneurysm lesions that is reduced by \u0026gt;1 grade after treatment.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSecondary outcomes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSecondary outcomes are listed as the corrected visual acuity, fasting blood glucose, 2-hour postprandial blood glucose, glycosylated hemoglobin, urinary microalbumin excretion rate, the improvement of TCM syndromes and TCM symptoms from baseline to 24 weeks.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSafety assessment and adverse events monitoring.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eSafety assessment outcomes are listed as vital signs, routine blood test, routine urine test and routine stool test, electrocardiogram, liver function, renal function will be performed at every 12 weeks from baseline. Adverse events (AEs) will be documented at every visit, including the occurrence time, severity, duration, solution and transfer. AEs will be divided into three levels: mild, moderate and severe, and the causality between TCPMs for trials and AEs will be judged.\u0026nbsp;In case of any AEs, such as subjective discomfort of the patient and abnormal laboratory test, it will be taken measures immediately to protect the safety of the participants. Any serious AEs during the test must be reported to the Ethics Committee of the unit immediately, and notify the telephone number and contact person of the units listed in the CRF form. The \u0026ldquo;Severe Adverse Event (SAE)\u0026rdquo; form must be filled in. All AEs will be recorded, monitored, and treated until resolved.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Procedure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study will include a 2-week washout period, a 24-week\u0026nbsp;treatment\u0026nbsp;period and a 2-year follow-up period.\u0026nbsp;Subjects who are diagnosed with NPDR will be given a 2-week lifestyle intervention at run-in\u0026nbsp;period,\u0026nbsp;all of them will provide written informed consent prior to participation.\u0026nbsp;After the intervention period begin, participant visits will conduct every 4 weeks. All data will be documented on the CRFs (\u003cstrong\u003eFigure 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size calculation\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to data from preliminary trial [8], the rate of retinal microvascular disease was reduced by 2.9% in the placebo group, and we predicted that the rate of retinal microvascular disease would be reduced by 6.5% in the TCPM group. The standard deviation was set as 2.17. The superiority margin was assumed to increase 1.4 percentage on the basis of placebo. The ratio of the two groups was set as 1:1. The significance level is targeted at 0.025 for one-sided test. The power achieved to detect a difference is set as 0.9. Sample size will be calculated the independent proportions power analysis using PASS 11.0 software, approximately 45 participants in each group will be needed. The sample size used in our study was increased by an additional 10% in case of lost of follow-up. Hence, the final sample size is estimated to be 50 in each group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe researchers will record original data into the case report form (CRF), the supervisor will check whether the trial is launched consistent with the protocol, and the data in the CRFs is identical with the original data, errors and inconsistencies will be timely corrected. Before data entry, the data administrators will check the CRFs again to ensure the accuracy of the data, the data administrator will also record the coding process in the coding book. Duplicate entry is adopted for inputting the data. If problems are found in the input process, they will be registered and reported in time, so as to deal with the problems quickly. The data administrator will write the computer programs and input data. After entering the data, the CRFs need to be filed and saved. The researchers will keep the clinical trial data until 5 years after the end of the clinical trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalysis subjects\u003c/p\u003e\n\u003cp\u003eThree analysis sets will be used in this trial, including full analysis set (FAS), per protocol set (PPS) and\u0026nbsp;safety set (SS).\u0026nbsp;FAS includes all randomized subjects and drop-out subjects who have been treated at least once and excluded for reasonable reasons. For the subjects who failed to observe the efficacy, the principle of the last observation carried forward (LOCF) will be applied to handle with the missing outcome data. PPS is a set of compliance protocol, including that the participants\u0026nbsp;have good compliance of using 80-120% quantity of the study drugs;\u0026nbsp;the baseline characteristics are not missing, and\u0026nbsp;the data of the primary outcome\u0026nbsp;can be obtained; and\u0026nbsp;it does not run counter to the protocol.\u0026nbsp;SS is a set that received at least one-time treatment and has data recorded with safety assessment.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical method\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis will be completed by the third-party statisticians using SAS 9.3 software. Continuous data will be expressed as the mean, median, standard deviation, minimum value, and maximum value, while categorical data will be expressed as the number of cases and percentages. To compare baseline characteristics between the two groups, independent t tests will be used to analyze continuous data, and chi-squared test or Fisher exact test will be used for categorical data. With regard to outcome analysis, the classified variables will be performed using the chi-squared test or Fisher exact test, and continuous variables will be performed using t test for normally distributed data and\u0026nbsp;Wilcoxon rank\u0026nbsp;sum test for non-normal distribution data. Moreover, repeated measures analysis of variance (ANOVA) will be applied to determine to further investigate the effects of treatment and time course.\u0026nbsp;A two-tailed test will be applied, and\u0026nbsp;\u003cem\u003eP \u0026lt; 0.05\u003c/em\u003e will be considered to indicate a statistical significance.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the UPLC-QE-Orbitrap-MS analysis, a total of 52 compounds were identified in QZJC capsules, many of the compounds have been proved by modern pharmacological studies to have the effect of improving related symptoms of DM and its complications, reflecting the characteristics of synergistic action of multiple components in QZJC[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In the previous experiments, QZJC has been demonstrated that ameliorated retinal vascular permeability and inhibited retinal neovascularization via up-regulating prostacyclin2 (PGI2) and down-regulating VEGF and von willebrand factor (vWF); it also attenuated inflammation via promotion of nitric oxide (NO) and superoxide dismutase (SOD) expression [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Currently, we therefore design a randomized and controlled multicenter clinical trial to assess the efficacy and safety of QZJC. We hypothesize that QZJC could have a potential retinal protective effect on NPDR patients. If successful, the findings of this trial may provide an alternative treatment for NPDR patients. It may also provide scientific evidence for delaying the progress of DR. This trial also has some limitations. Firstly, as the test instruments of each research center are different, the error of test results is inevitable. Secondly, there might be several individual differences in the subjects, possibly leading to different efficacy of the drug. The improvements need to be seen in the future.\u003c/p\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eDissemination plans\u003c/h2\u003e \u003cp\u003eThe results will be disseminated through peer-reviewed journal articles and presented abstracts and posters at scientific conferences in the field of diabetes and TCM, as well as the general public through internet and newspaper.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePang B drafted the trial protocol. Ni Q provided critical advice and comments on the protocol.\u0026nbsp;Guo H, Zhang YY,\u0026nbsp;Hu HJ, Sun Y, Cao AM, Lu CQ, and Zhang WH referred and recruited the patients. Feng S is responsible for\u0026nbsp;statistical analysis.\u0026nbsp;All of the authors participated in the design and development of the trial protocol. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is supported by grants from Capital Health Research and Development of Special Fund (2016-1-4151); National Natural Science Foundation of China (82104832); Special program for excellent scientific personnel training of Chinese Academy of traditional Chinese Medicine (ZZ13-YQ-032); Institutional Research Foundation of Guang\u0026apos; anmen Hospital, China Academy of Chinese Medical Science (59957).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOnce the main findings of the project have been published, the trial steering committee will review all requests for data before access is granted. If appropriate, we will make the anonymized data and associated documentation available to users under a data-sharing agreement.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe full protocol is available at http://www.chictr.org.cn/edit.aspx?pid=39622\u0026amp;htm=4.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe protocol has been approved by the Medical Ethics Committee of Guang\u0026rsquo;anmen Hospital of the China Academy of Chinese Medical Sciences (No.2019-008-KY). The trial registration number is as follows: Chinese Clinical Trial Registry no. ChiCTR1900023506, and any important changes in the protocol will be reflected there. The study will implement in accordance with the items of the Declaration of Helsinki. The trial will perform based on the Standard Protocol Items: Recommendations for Intervention Trials (SPIRIT) guidelines. All participants will provide voluntary written informed consent form (ICF) after a full discussion about the potential benefits and risks before the study, and ICFs will be signed by participants prior to entry into the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors gave consent for the publication of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eInternational Diabetes Federation. IDF Diabetes Atlas. 8th. Brussels, Belgium: International Diabetes Federation; 2017. \u003c/li\u003e\n\u003cli\u003ePang B, Li QW, Qin YL,et al. Traditional Chinese medicine for diabetic retinopathy. \u003cem\u003eMedicine\u003c/em\u003e 2020;99(7): e19102.\u003c/li\u003e\n\u003cli\u003eZhang XT, Chen Y, Yu CJ, et al. Effect of Qizhi Jiangtang capsule on insulin resistance in diabetic rats and its mechanism. \u003cem\u003eJilin Da Xue Xue Bao (Yi Xue Ban) \u003c/em\u003e2014;40(4):805-811.\u003c/li\u003e\n\u003cli\u003eWu S, Guo ZA, Yu CJ, et al. Effects of Qizhi Jiangtang capsule on BMP-7 and TGF-\u0026beta;1/Smads signaling pathway of kidney in diabetic nephropathy rats. \u003cem\u003eZhongguo Zhong Xi Yi Jie He Shen Bing Za Zhi \u003c/em\u003e2014;15(4):297-301.\u003c/li\u003e\n\u003cli\u003eChinese Diabetes Society. Guidelines for the prevention and control of type 2 diabetes in China (2017 Edition). \u003cem\u003eZhongguo Shi Yong Nei Ke Za Zhi\u003c/em\u003e 2018;38(4):292-338.\u003c/li\u003e\n\u003cli\u003eWilkinson CP, Ferris FL 3rd, Klein RE, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. \u003cem\u003eOphthalmology\u003c/em\u003e 2003; 110(9):1677-82.\u003c/li\u003e\n\u003cli\u003eDepartment of Medical Administration of National Administration of Traditional Chinese Medicine. Traditional Chinese medicine of clinical pathway of 95 kinds of disease in 22 specialized subjects (bound volume). \u003cem\u003eNational Administration of Traditional Chinese Medicine Press\u003c/em\u003e. 2010:145-166.\u003c/li\u003e\n\u003cli\u003eLian FM, Wu L, Tian JX, et al. The effectiveness and safety of a danshen-containing Chinese herbal medicine for diabetic retinopathy: a randomized, double-blind, placebo-controlled multicenter clinical trial. \u003cem\u003eJ Ethnopharmacol\u003c/em\u003e 2015;164:71-7.\u003c/li\u003e\n\u003cli\u003eShi JC, Zhang SR, Chai Z, et al. Analysis of chemical constituents in Qizhi Jiangtang capsules based on UPLC-QE-Orbitrap-MS analysis. \u003cem\u003eZhongguo Shiyan Fangji Xue Za Zhi\u003c/em\u003e.2020;1-14.\u003c/li\u003e\n\u003cli\u003eZhang C. The effect and mechanism of Qizhi Jiangtang capsule protect the retina of type 2 diabetic rats. Jilin University, 2015(Dissertation).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Traditional Chinese patent medicine, Qizhijiangtang Capsule, Non-proliferative diabetic retinopathy, Randomized controlled trial, Protocol","lastPublishedDoi":"10.21203/rs.3.rs-2428596/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2428596/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eDiabetic retinopathy remains a leading cause of vision loss globally. Here, we investigated the efficacy and safety of Qizhijiangtang capsule (QZJC), a kind of traditional Chinese patent medicine, for patients with NPDR.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This study is a multi-center, randomized, controlled clinical trial. A total of 100 participants will be randomly assigned in a 1:1 ratio to QZJC group or QZJC placebo group. The treatment duration lasts 24 weeks. The primary outcome is the changes in the degree of retinal microaneurysm lesions assessed by fundus photography and fundus fluorescence angiography before and after treatment. The secondary outcomes include the changes in corrected visual acuity, blood glucose, glycosylated hemoglobin, urinary microalbumin excretion rate, the improvement of TCM syndromes and TCM symptoms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion: \u003c/strong\u003eWe postulate that NPDR patients will benefit from QZJC. If successful, this work will provide preliminary evidence that QZJC could delay the progress of DR.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c/strong\u003e Chinese Clinical Trial Registry no. ChiCTR1900023506. The protocol has registered at http://www.chictr.org.cn/showprojen.aspx?proj=39622. Registered 31 May 2019.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTemplate (preprint statement)\u003c/strong\u003e: This manuscript has been preprinted [https://doi.org/10.21203/rs.3.rs-596869/v1].\u003c/p\u003e","manuscriptTitle":"Traditional Chinese Patent Medicine Qizhijiangtang Capsule for Non- Proliferative Diabetic Retinopathy: Study Protocol for a Randomized Controlled Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-01-05 15:48:40","doi":"10.21203/rs.3.rs-2428596/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ba49ee74-bfd6-4d6d-9622-f1defcb85bdd","owner":[],"postedDate":"January 5th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-01-26T17:29:17+00:00","versionOfRecord":[],"versionCreatedAt":"2023-01-05 15:48:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2428596","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2428596","identity":"rs-2428596","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}