Efficacy and safety of Huatan Qushi Huoxue Fang granules on obese non-alcoholic fatty liver disease: study protocol for a multicenter, randomized, double-blind, placebo-controlled trial

Efficacy and safety of Huatan Qushi Huoxue Fang granules on obese non-alcoholic fatty liver disease: study protocol for a multicenter, randomized, double-blind, placebo-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 Efficacy and safety of Huatan Qushi Huoxue Fang granules on obese non-alcoholic fatty liver disease: study protocol for a multicenter, randomized, double-blind, placebo-controlled trial Lihui Zhang, Sutong Liu, Qing Zhao, Xiaoyan Liu, Xuehua Sun, Tao Wang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4814797/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 The global burden of non-alcoholic fatty liver disease (NAFLD) is parallel to the increasing obesity rates around the world. Phlegm stasis syndrome is a common traditional Chinese medicine syndrome type of obese NAFLD, which is often treated by resolving phlegm, dispelling dampness, and promoting blood circulation. This study mainly explores the clinical efficacy and safety of Huatan Qushi Huoxue Fang (HTQSHXF) granules in the treatment of obese NAFLD. Methods This is a multicenter, randomized, double-blind, placebo-controlled clinical trial that will recruit 248 obese NAFLD patients from three hospitals in China. Randomly allocate patients to either the HTQSHXF group or the placebo group in a 1:1 ratio. The intervention phase lasts for 12 weeks. The primary outcome will be the change in relative liver fat content from baseline to week 12 measured by Magnetic resonance proton density fat fraction (MRI-PDFF). The secondary outcomes will be Body fat percentage (BFR), Waist to hip ratio (WHR), Body Mass Index (BMI), Controlled attenuation parameter (CAP), Liver tiffness value (LSM), serum liver function, blood lipids, blood glucose, Free fatty acids (FFA), Cytokeratin 18-M30 (CK18-M30), and Cytokeratin 18-M65 (CK18-M65). The results will be monitored at baseline and 12 weeks of intervention. Adverse events that occur in this study will be promptly managed and recorded. Discussion This study will use more recognized quantitative methods to explore the efficacy and safety of HTQSHXF granules in treating obese NAFLD, providing clinical evidence for its translational application. Trial registration http://www.chictr.org.cn . Trial number: ChiCTR2200060901. Registered on 14 Jun 2022. Huatan Qushi Huoxue Fang Randomized controlled trial Non-alcoholic fatty liver disease Obese Traditional Chinese medicine Figures Figure 1 Background Non alcoholic fatty liver disease (NAFLD) is a chronic progressive liver disease caused by overnutrition and insulin resistance in genetically susceptible individuals [ 1 ]. Its disease spectrum includes non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH), and related fibrosis and cirrhosis [ 2 ]. With the prevalence of obesity and type 2 diabetes, the global prevalence and incidence rate of NAFLD are increasing[ 3 ]. Moreover, NAFLD and metabolic syndrome are mutually causal, jointly promoting liver decompensation and the development of malignant tumors such as hepatocellular carcinoma [ 4 ]. Therefore, NAFLD has become an increasingly serious global public health issue [ 5 ]. Obesity is an independent risk factor for NAFLD. Obese and overweight patients have a three fold increased risk of developing NAFLD compared to non obese or lean individuals [ 6 ]. The prevalence of NAFLD among overweight and obese populations worldwide is 70.0% and 75.3%, respectively [ 7 ]. Long term excessive consumption of highly greasy or sweet refined foods or foods with strong flavors can lead to impaired spleen function. Water and grains cannot be effectively converted into essence, qi, blood, and body fluids, leading to the formation of grease and fat [ 8 ]. They stop in the fascia cavity with the flow of qi and blood, resulting in obesity [ 9 ]. When grease and fat accumulate in the liver, it can cause stagnation of liver qi, preventing liver from effectively performing its functions of dredging and regulating [ 10 ]. This leads to the production of pathological products such as phlegm, dampness, and blood stasis. Phlegm, dampness, and blood stasis intertwine in the liver, further damaging its function [ 11 ]. Therefore, phlegm, dampness, and blood stasis are the main pathological factors of NAFLD. This study recruited obese NAFLD patients with phlegm stasis syndrome, with the diagnostic criteria for this syndrome based on the expert consensus on the Chinese medical diagnosis and treatment of nonalcoholic fatty liver disease (2017) formulated by the Gastroenterology Branch of the China Association of Chinese Medicine [ 12 ]. Traditional Chinese Medicine has certain advantages in the treatment of NAFLD. Previous multi-center clinical studies have shown that a comprehensive Traditional Chinese Medicine (TCM) treatment plan based on the use of HTQSHXF granules can significantly improve clinical symptoms such as abdominal distension, discomfort in the right hypochondrium, and fatigue in patients with NASH [ 13 ]. It also increases the liver/spleen CT ratio, reduces Body Mass Index (BMI), and decreases serum Alanine aminotransferase (ALT) and Triglyceride (TG) levels [ 13 ]. Experimental studies have shown that HTQSHXF granules can improve hepatic steatosis and inflammatory injury in rat models of NASH, reduce serum levels of ALT, Aspartate aminotransferase (AST), Total cholesterol (TC), TG, and Fasting blood glucose (FBG), and lower Free fatty acids (FFA) levels in liver homogenates. The therapeutic mechanism may be related to the activation of the ADPN/AMPK/ACC and ADPN/AKT/NF-κB signaling pathways [ 14 , 15 ]. The herbal drugs of HTQSHXF granules is shown in Table 1 . However, we have not yet used a double-blind design to observe the effects of HTQSHXF granules on Magnetic resonance proton density fat fraction (MRI-PDFF), Controlled attenuation parameter (CAP), and other indicators in NAFLD patients across multiple medical institutions. This study aims to explore the clinical efficacy and safety of HTQSHXF granules in obese NAFLD patients using a multi-center, randomized, double-blind design. Table 1 Standard formulation of HTQSHXF granules Pinyin name Latin scientific name Amount (%) TCMH action Zexie Alismatis Rhizoma 24.78 promoting diuresis and eliminating dampness, as well as regulating qi flow and dissipating blood stasis Danshen Salvia miltiorrhiza Bunge 12.40 invigorating blood circulation to remove blood stasis, cooling the blood, and calming the spirit Yujin Radix Curcumae Aromaticae 12.40 invigorating blood flow to alleviate pain, regulating qi flow, and relieving depression Haizao Sargassum 12.40 resolving phlegm, eliminating dampness, softening hard masses, and eliminating phlegm Juemingzi Catsia tora Linn 8.26 clears the liver and improves vision Shanzha Crataegus pinnatifida 12.40 eliminates food stagnation and dissipates blood stasis Shuifeiji Silybum marianum 12.40 clears heat and detoxifies Chaihu Radix Bupleuri 4.96 soothing the liver and regulating qi, acts as the guiding herb to introduce the prescription into the liver meridian TCMH traditional Chinese medicine herb Methods Study design This is a multicenter, randomized, double-blind, placebo-controlled parallel clinical trial study, aiming to recruit 248 obese NAFLD patients with phlegm-dampness and blood stasis. 88 cases were allocated to the First Affiliated Hospital of Henan University of TCM, 80 cases to Hepatology Department of Shuguang Hospital, Shanghai University of TCM, and 80 cases to the Hepatology Department of Shaanxi Provincial Hospital of CM. Cases in each center were allocated in a 1:1 ratio between the HTQSHXF group and placebo group. Under the condition of dietary and exercise management, the HTQSHXF group will take oral HTQSHXF granules, while the placebo group will take oral placebo. The treatment duration is 12 weeks. The schedule details are listed in Table 2 . This protocol was approved by the Medical Ethics Committee of The First Affiliated Hospital of Henan University of TCM (approval number: 2022HL-038-01). The trial protocol (version 1.0, Jun 14, 2022) and was registered in the Chinese Clinical Trial Registry (ChiCTR2200060901). The flowchart of the trial is shown in Fig. 1 . We present the following article in accordance with the SPIRIT 2013 reporting checklist [ 16 ]. For more details about the checklist, please see Additional file 1. Table 2 , Study procedure table. Study Period Visit 1 Visit 2 -7 to 0 days 12 weeks (± 3 days) Data collection at baseline Informed consent form × Demographic information × Life history × previous history × medical history × Inclusion and exclusion criteria × Efficacy evaluation MRI-PDFF × × ALT × × AST × × ALP × × GGT × × TG × × TC × × HDL-C × × LDL-C × × CAP × × LSM × × FFA × × FINS × × FBG × × HOMA-IR × × CK18-M30 × × CK18-M65 × × BFR × × WHR × × BMI × × Safety evaluation Vital signs × Blood routine × × Renal function × × Electrocardiogram × × Other work Record adverse events × × Evaluation of subject behavior intervention compliance × Recovery and record of study drug × MRI-PDFF Magnetic resonance proton density fat fraction, ALT Alanine aminotransferase, AST Aspartate aminotransferase, ALP Alkaline phosphatase, GGT Gamma glutamyl transferase, TG Triglyceride, TC Total cholesterol, HDL-C High-density lipoprotein cholesterol, LDL-C Low-density lipoprotein cholesterol, CAP Controlled attenuation parameter, LSM liver tiffness value, FFA Free fatty acids, FINS Fasting insulin FBG Fasting blood glucose, HOMA-IR Homeostasis model assessment of insulin resistance, CK18-M30 Cytokeratin 18-M30, CK18-M65 Cytokeratin 18-M65, BFR Body fat percentage, WHR Waist to hip ratio, BMI Body mass index. Eligibility criteria Diagnostic criteria Diagnostic criteria for obese NAFLD patients 1.Diagnostic criteria for NAFLD: Formulated in accordance with the Guidelines for Prevention and Treatment of Non-alcoholic Fatty Liver Disease (2018 Update) established by the Fatty Liver and Alcoholic Liver Disease Group of the Chinese Society of Hepatology [ 17 ]. (1) The patient had no history of excessive drinking (the weekly consumption of ethanol (alcohol) in the past 12 months was less than 210g for males and less than 140g for females) and had no other specific causes of fatty liver. (2) Imaging manifestations: B-ultrasound, CAP, Computed Tomography (CT), or MRI-PDFF suggest that the patient has hepatic steatosis. 2. Diagnostic criteria for Obesity: Refer to the " Guideline for primary care of obesity:practice version (2019) " [ 18 ] : BMI ≥ 28kg/m 2 , or waist circumference ≥ 85cm for men and ≥ 80cm for women. The diagnosis of obese NAFLD patients must meet both the first and second criteria mentioned above. Diagnostic criteria for phlegm stasis syndrome Based on the syndrome differentiation standards formulated by the Chinese Society of Traditional Chinese Medicine's Gastroenterology Branch in the "Expert Consensus on the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Chinese Medicine" (2017), the following is proposed according to the clinical manifestations of NAFLD patients. Main symptoms: pain or discomfort in the right flank area. Secondary symptoms: Obesity, generalized heaviness and lethargy, chest and abdominal fullness, loose or unformed stool, dullness tongue with possible ecchymosis or petechiae, white and greasy tongue coating, taut and slippery or deep and sluggish pulse. Patients need to have the main symptoms and any two of the secondary symptoms to diagnose the phlegm stasis syndrome. Inclusion criteria Age: 18–65 years old, no gender limit. Simultaneously meeting the diagnostic criteria for obese NAFLD patients and the diagnostic criteria for traditional Chinese medicine phlegm stasis syndrome type. 1×ULN < serum ALT ≤ 3×ULN. Fasting blood glucose ≤ 7.0 mmol/L. Sign an informed consent form. Have not taken any other drugs for treating NAFLD or obesity, or have discontinued these drugs before 4 weeks of observation. Exclusion criteria Any one of the following should be excluded. Viral hepatitis, drug-induced liver disease, total parenteral nutrition, hepatolenticular degeneration, autoimmune liver disease, etc. Patients with severe heart, brain, kidney, hematopoietic system diseases, as well as emotional disorders such as anxiety and depression, and mental illness. Fatty liver caused by long-term use of glucocorticoids, chlorpromazine, insulin, etc. Type I diabetes patients. Patients with various types of malignant tumors. Pregnant and lactating women. Subjects participating in other clinical trials. Withdrawal criteria and termination criteria 1. If the following situations occur, the researcher will decide whether the patient should withdraw from the study. (1) Appearing allergic reactions or serious adverse events. (2) During the experiment, the patient developed other diseases that affected the efficacy and safety assessment. (3) Cases that have to be unblinded during the study due to various reasons. (4) After randomization, serious violations of inclusion or exclusion criteria were found. 2. The situation which the patient decides to withdraw on their own (1) Regardless of the reason, if the patient is unwilling or unable to continue the clinical trial and requests to withdraw from the trial to the supervising physician, the trial will be terminated. (2) Although the patient did not explicitly request to withdraw from the trial, they will no longer accept medication and monitoring. Randomization and blinding The randomization plan for this study was entrusted to Henan Provincial Evidence Based Medicine Research Center for Traditional Chinese Medicine. The block length is 8 and the number of blocks is 31. Adopting a double-blind experimental design. A two-level randomized medication number is generated by Henan Provincial Evidence Based Medicine Research Center of TCM using statistical software packages. The first level is the group corresponding to each case number (Group A, Group B), and the second level is the treatment corresponding to two groups (HTQSHXF group and placebo group). The two-level blind bottoms are separately sealed and stored by Henan Province Evidence Based Medicine Research Center for TCM. Distribute and package drugs according to random grouping codes. Each coded trial drug has a corresponding emergency letter, which contains a note indicating that the coded drug belongs to the category of phlegm resolving, dampness dispelling, and blood activating granules or placebo, In order to unblind in case of emergency. The envelope is made of thick, opaque kraft paper, and the number of emergency letters should be the same as the number of participants. The envelope should indicate clinical study number. The envelope is sent to the research unit along with the packaged drugs. After the study was completed, the data was locked after blind verification was conducted without any errors. The staff of Evidence Based Medicine Research Center conducted the first unblinding, informing statistical experts of the groups corresponding to each case number with codes A and B, in order to conduct statistical analysis of all data. After the statistical analysis is completed, write a summary report and conduct a second unblinding at the clinical summary meeting to announce the exact groups of Group A and Group B. Interventions Both the HTQSHXF group and the placebo group were treated with a diet and exercise regimen as the basic treatment. Dietary plan Developed in accordance with the Expert Consensus on Fasting Therapy in Traditional Chinese Medicine (2019 Edition) [ 19 ]. The dietary principles are formulated based on the Chinese Dietary Guidelines for Residents (2016). Implement a dietary plan of light fasting for 2 days per week and a 5-day conditioning period. Provide dietary prescriptions based on the patient's height, weight, and dietary habits, and implement dietary management. Implement overall calorie control in daily diet. Daily total calorie limit: Men should be below 25kcal/kg, and women should be below 20kcal/kg. The dietary structure is mainly low fat, protein rich, and fiber rich. Patients must record their diet every day, check in before meals, and upload it to the WeChat group to provide dietary guidance at any time. Exercise plan According to specific situation of the patient, exercise prescriptions should be issued, and the guiding principles are as follows. During the light fasting period, patients engage in light physical activities, mainly walking, which can be combined with traditional Chinese medicine techniques such as Tai Chi, Eight Section Brocade, and Five Animal Play. It is recommended to do about 120 minutes of brisk walking or jogging every day, which can be divided into 3–4 sessions, with each session lasting about 30 minutes. The conditioning period is mainly characterized by long-term, regular, moderate to low intensity, and aerobic exercise. The types of sports include brisk walking, jogging, cycling, swimming, aerobics, rope skipping, etc. Exercise for 30 to 60 minutes each time. Persist at least once a day. At least 5 times a week. Suggest implementing the exercise in the afternoon or evening. Drug intervention HTQSHXF group: HTQSHXF granules (12 g/bag). 2 bag each time, dissolve the particles in 100ml hot water and drink twice a day. Take it 1 hour after breakfast and dinner every day. Take the medication 6 days a week and stop taking it for 1 day. The treatment will last for 12 weeks. Placebo group: placebo (HTQSHXF mimetic agent, 12 g/bag. Raw materials are maltodextrin, lemon yellow pigment, sunset yellow pigment, caramel pigment, lactose, and bittering agent). The administration method is completely consistent with the HTQSHXF group. Drug preparation: HTQSHXF granules and corresponding mimetics were prepared by Jiangsu Jiangyin Tianjiang Pharmaceutical Co., Ltd. batch number: 2205302. Drug combination: If there is any concomitant medication during the patient's participation in the study, researchers should record it in detail in the CRF form. It is allowed to undergo necessary treatment under the guidance of clinical doctors for other diseases or symptoms, but the use of drugs with hepatoprotective, anti-inflammatory, and lipid-lowering effects should be prohibited before the termination of the trial. Outcomes Primary Outcome MRI-PDFF. Secondary outcomes ALT, AST, Alkaline phosphatase (ALP), Gamma glutamyl transferase (GGT), TG, TC, High-density lipoprotein cholesterol (HDL-C), Low-density lipoprotein cholesterol (LDL-C), CAP, Liver tiffness value (LSM), FFA, Fasting insulin (FINS), FBG, Homeostasis model assessment of insulin resistance (HOMA-IR), Cytokeratin 18-M30 (CK18-M30), Cytokeratin 18-M65 (CK18-M65), Body fat percentage (BFR), Waist to hip ratio (WHR) and BMI. Safety outcomes Vital signs, blood routine, renal function, electrocardiogram. Observation time Researchers will conduct visits, observations, and records in the 0th and 12 weeks of the study. Adverse events Adverse events refer to any symptoms, syndromes, or diseases that occur during the observation period of clinical research and can affect the patient's health, as well as clinically relevant situations discovered in the laboratory or other diagnostic processes. The term "adverse event" does not imply a causal relationship with the investigational drug. Any adverse reactions that occur during the study period will be recorded in the "Adverse Event Form" and tracked for investigation. The handling process and results will be recorded in detail until the laboratory test returns to normal and symptoms and signs disappear. When adverse reactions are detected, researchers determine the diagnosis and treatment measures based on the condition, and decide whether to discontinue observation or break the blindness. Efficacy data that were available prior to blinding could be counted in the efficacy analysis. Otherwise, the case will be considered as a terminated case and will not be included in the efficacy analysis. Data collection and registration All clinical doctors and researchers are required to undergo training and assessment before conducting this clinical trial. Only after passing the assessment can they participate in this study. The subjects need to undergo two visits, namely the 0th and 3rd months. The informed consent of the subjects and information from two visits will be recorded in a paper Case Report Form (CRF) form. The CRF form is the source file for clinical trial subjects, and researchers in each center should truthfully fill it out and properly store it according to regulations. After the study is completed, it will be uniformly saved and managed by the main center. The completed CRF form will be reviewed by the clinical monitor and handed over to the data administrator. The data management personnel use the online EDC data program ( http://edc.hnzhy.com/portal/ ) of Henan Province Evidence Based Medicine Research Center for data entry and management. Data of the subjects will be anonymous, and all collected data will be kept confidential. Sample size In this study, the sample size was estimated based on the level of MRI-PDFF, which serves as the primary efficacy indicator. The calculation formula is as follows: n E =n C = \(\:{\frac{\left[{Z}_{\frac{\alpha\:}{2}}\sqrt{2\stackrel{-}{P}\left(1-\stackrel{-}{P}\right)}+{Z}_{\beta\:}\sqrt{{P}_{E}\left(1-{P}_{E}\right)+{P}_{C}\left(1-{P}_{C}\right)}\right]}{{\left({P}_{E}-{P}_{C}\right)}^{2}}}^{2}\) According to the literature, after 12 weeks of treatment, 25.9% of patients in the control group (placebo intervention) had a reduction of more than 30% in MRI-PDFF levels, while 53.3% of patients in the treatment group (Chinese traditional treatment) experienced a similar reduction [ 20 ]. Therefore, it is anticipated that following 12 weeks of dietary and exercise intervention, 35% of patients will have a reduction of more than 30% in MRI-PDFF levels. Furthermore, when combined with the treatment of HTQSHXF granules for 12 weeks, the proportion of patients with a reduction of MRI-PDFF levels exceeding 30% is expected to reach 57.4%. Assuming α = 0.05, β = 0.10, Z α/2 =1.96, Z β =1.645, P E =0.574, P C =0.35, n E : n C =1:1, \(\:\stackrel{-}{P}\) =( P E + P C )/2. The calculated sample size required for each group is 99 cases. Considering a 20% dropout rate, the final estimated sample size is 248 cases, with 124 cases in each group. Statistical analysis Entrust a third party to conduct data management and blind review, and be responsible for developing statistical analysis plans and writing statistical analysis reports. The data statistical analysis was completed using SPSS 22.0 statistical software. Qualitative data is expressed in terms of rate and composition ratio. If the quantitative data follows a normal distribution, it should be expressed as mean ± standard deviation; otherwise, the median should be used. When comparing the primary outcome MRI-PDFF with all secondary outcomes between two groups: If the data conforms to a normal distribution, t-test will be used (significance level of 0.05 will be used for inter group homogeneity of variance test, and t 'test will be used if the variances are not equal); If the data does not follow a normal distribution, Wilcoxon rank sum test will be used. P < 0.05 is considered statistically significant. All baseline variables will undergo descriptive analysis. Quality control To prevent potential bias in the study, the following measures are taken for quality control: A multicenter, randomized, double-blind design was adopted to address the bias in the selection of subjects by researchers. In response to the bias in efficacy evaluation, a third-party evaluation is adopted under the premise of unified evaluation standards, and evaluating physician will conduct the research under blinded conditions throughout. To address the bias in multicenter study, targeted training for researchers will be provided, and researcher statements will be signed to strengthen guidance for researchers during the study process. Designate a fixed researcher to undertake the recording of study medical records and the work of logging in and filling out electronic CRF. To address the bias generated by the subjects, we aim to improve their compliance in the following aspects: 1) Effective communication: Researchers should conscientiously implement informed consent to ensure that subjects fully understand the study requirements and cooperate with the study. 2) Regular education: The researcher designates a dedicated person to conduct regular WeChat or phone follow-up before important event milestones. 3) Strengthen the diet and exercise management of subjects: Establish a dedicated WeChat group, where nutritionists develop a diet and exercise plan, and supervise subjects to clock in, adjust their diet, exercise regularly, undergo regular follow-up visits, and take medication regularly. 4) The distribution of drugs is managed and recorded by a fixed researcher. Discussion There are a total of 18 chemical active ingredients in the HTQSHXF granules, which are quercetin, chlorogenic acid, silymarin, rutin, ferulic acid, hesperidin, salvianolic acid B, naringenin, kaempferol, danshensu sodium, hyperoside, quercetin, apigenin, hesperetin, 23-acetyl zeaxanthin C, saikosaponin b2, saikosaponin b1, and tanshinone IIA [ 21 ]. Our previous study has shown that quercetin may improve the degree of hepatic steatosis and alleviate liver inflammation in NASH rats by regulating the PI3K/AKT/NF-κB signaling pathway [ 22 ]. Existing studies have shown that naringin can improve lipid status and severity of liver steatosis in obese NAFLD patients [ 23 ][ 24 ]. Hesperidin can improve liver steatosis, liver enzymes, metabolism, and inflammatory parameters in NAFLD patients. Rutin may improve diabetes NAFLD by activating Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK) pathway [ 25 ]. In addition, chlorogenic acid [ 26 ], silymarin [ 27 ], ferulic acid [ 28 ], salvianolic acid B [ 29 ], kaempferol [ 30 ], hyperoside [ 31 ] apigenin [ 32 ], and tanshinone IIA [ 33 ] also have certain therapeutic effects on NAFLD. Liver tissue pathological biopsy remains the gold standard for diagnosing NAFLD [ 34 ]. However, the invasive nature of liver biopsy and the risk of complications such as bleeding limit its clinical application [ 35 ]. Moreover, the liver tissue samples obtained from liver biopsy can only represent 1/50000 of the liver volume[ 36 ]. MRI-PDFF is an objective non-invasive quantitative imaging method for evaluating the overall liver fat content. MRI-PDFF ≥ 5% can confirm the diagnosis of fatty liver, while MRI-PDFF ≥ 10% may indicate moderate to severe fatty liver [ 37 ]. A systematic review and meta-analysis involving a total of 636 suspected NAFLD patients who underwent liver biopsy and MRI-PDFF simultaneously found that MRI-PDFF diagnosed fatty liver (S0 vs. S1-3), moderate to severe fatty liver (S0-1 vs. S2-3), and severe fatty liver (S0-2 vs. S3) patients with liver biopsy confirmed AUROC (0.98, 0.91, and 0.90, respectively), sensitivity (0.93, 0.74, 0.74), specificity (0.94, 0.90, 0.87), as well as positive predictive values (16.21, 7.19, 5.89) and negative predictive values (0.08, 0.20, and 0.29). 9, 0.29) are all very high [ 38 ]. This suggests that MRI-PDFF has excellent diagnostic value for liver fat quantification in NAFLD patients, and has high sensitivity and specificity in distinguishing different degrees of liver fat degeneration. It can be used as a reference standard for non-invasive quantification of liver fat content and has been recommended for evaluating changes in liver fat content in clinical trials of new drugs [ 39 ][ 40 ]. Therefore, this study used non-invasive MRI-PDFF as the main therapeutic indicator to quantitatively evaluate liver fat fraction. A multicenter study has been conducted in the past to treat NASH patients with a combination of diet and exercise based on the formula of HTQSHXF granules. This study included a total of 202 NASH patients. 101 NASH patients in the treatment group and 101 in the control group received medication treatment on the basis of health education, diet and exercise. The TCM granules taken by the treatment group are based on HTQSHXF granules, and are added according to the patient's symptoms based on syndrome differentiation: patients with spleen deficiency and dampness excess symptoms are added with Codonopsis pilosula, stir fried Atractylodes macrocephala, and raw Coix seed; patients with liver and gallbladder dampness and heat symptoms are added with Tianjihuang, Yinchen, and lotus leaves; patients with liver and kidney yin deficiency symptoms are added with goji berries, Polygonum multiflorum, and Huai Niugeng. The control group received polyene phosphatidylcholine capsules. The results showed that on the 90th and 180th day of treatment, the treatment group was superior to the control group in reducing serum ALT and TG, lowering BMI, and improving liver/spleen CT values in NASH patients. And it is significantly better than the control group in improving clinical symptoms such as epigastric distension, liver discomfort, and fatigue. The above study adopted a multi-center, randomized, controlled, and superiority design. Despite being a multi-center study, the complexity of administering medication to the treatment group made it impossible to implement a double-blind design. This failure to control for external variables such as subjective biases from researchers and participants led to various unknown factors influencing the experimental results, reducing their reliability and validity. Drawing from the lessons of previous studies with less rigorous designs, this study ensures that the treatment group only takes HTQSHXF granules without any additional medications. The control group received the corresponding placebo. This study design adopts a multi-center, randomized, double-blind approach to enable a more scientific evaluation of the efficacy and safety of the HTQSHXF granules based on the research results. Despite this, there are still certain limitations in the study design. For example, the number of research centers is relatively small, with only three units participating. The treatment duration of 3 months is relatively short. Additionally, the primary efficacy indicator does not include liver histopathological biopsy. We hope to conduct higher-quality multi-center, randomized, double-blind clinical studies in the future to provide stronger evidence-based medical support and guidelines for the treatment of obese NAFLD. Trial status This is an ongoing clinical trial. The recruitment time for the first subject was March 17, 2023. We plan to complete the recruitment of all subjects by September 2025, and all data will be locked in by December 2025. Abbreviations NAFLD non-alcoholic fatty liver disease NASH non-alcoholic steatohepatitis HTQSHXF Huatan Qushi Huoxue Fang TCM Traditional Chinese Medicine SPIRIT Standard Protocol Items: Recommendations for Interventional Trials MRI-PDFF Magnetic resonance proton density fat fraction BFR Body fat percentage WHR Waist to hip ratio BMI Body Mass Index CAP Controlled attenuation parameter LSM Liver tiffness value FFA Free fatty acids CK18-M30 Cytokeratin 18-M30 CK18-M65 Cytokeratin 18-M65 ALT Alanine aminotransferase AST Aspartate aminotransferase ALP Alkaline phosphatase GGT Gamma glutamyl transferase TG Triglyceride TC Total cholesterol HDL-C High-density lipoprotein cholesterol LDL-C Low-density lipoprotein cholesterol FBG Fasting blood glucose FINS Fasting insulin HOMA-IR Homeostasis model assessment of insulin resistance CRF Case Report Form AMPK Adenosine 5‘-monophosphate (AMP)-activated protein kinase Declarations Acknowledgements The authors thanks Henan Provincial Evidence Based Medicine Research Center for Traditional Chinese Medicine for designing the blinding and random allocation scheme; The authors also thanks the researchers from the other two centers for their contributions. Finally, the authors would like to thank all participants for their cooperation. Author contributions WZ and ML designed this study. LZ and SL drafted the manuscript and made equal contributions to the study. QZ, XL, XS, TW, FL, MY participated in the study plan. WZ modified and edited the manuscript. All authors have read and approved the final version of the manuscript. Funding This work was sponsored by Henan Province's "double first-class" creation of scientific research in traditional Chinese medicine (No. STG-ZYX02-202117, No. HSRP-DFCTCM-2023-7-23), National Traditional Chinese Medicine Clinical Research Base Scientific Research Special Project (No.2022JDZX098, 2022JDZX114), National Natural Science Foundation of China (No.82205086), Science and Technology Key Project of Henan Province (No. 232102310438), and The 9th China Association for Science and Technology Young Talent Support Project (No. 2023QNRC001). The funder had no role in the design, implementation, analysis, data interpretation, or decision process of submitting the results of this study. Availability of data and materials Not applicable. Ethics approval and consent to participate This study will follow the Helsinki Declaration and Good Clinical Practice guidelines, and will require informed consent from the subjects. This protocol has been reviewed and approved by the Medical Ethics Committee of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine (Approval Number: 2022HL-038-01). The study results will be published in the form of a paper. Consent for publication Not applicable. Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References Bugianesi E, Petta S. NAFLD/NASH. J Hepatol. 2022;77(2):549–50. Powell EE, Wong VW, Rinella M. 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Quek J, Chan KE, Wong ZY, Tan C, Tan B, Lim WH, Tan DJH, Tang ASP, Tay P, Xiao J, Yong JN, Zeng RW, Chew NWS, Nah B, Kulkarni A, Siddiqui MS, Dan YY, Wong VW, Sanyal AJ, Noureddin M, Muthiah M, Ng CH. Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2023;8(1):20–30. Xu L, Zhao W, Wang D, Ma X. Chinese Medicine in the Battle Against Obesity and Metabolic Diseases. Front Physiol. 2018;9:850. Li C, Zhang H, Li X. The Mechanism of Traditional Chinese Medicine for the Treatment of Obesity. Diabetes Metab Syndr Obes. 2020;13:3371–81. Fan Q, Xu F, Liang B, Zou X. The Anti-Obesity Effect of Traditional Chinese Medicine on Lipid Metabolism. Front Pharmacol. 2021;12:696603. Shang Z, Gao Y, Xue Y, Zhang C, Qiu J, Qian Y, Fang M, Zhang X, Sun X, Kong X, Gao Y. Shenge Formula attenuates high-fat diet-induced obesity and fatty liver via inhibiting ACOX1. Phytomedicine. 2024;123:155183. Zhang SS, Li JX. Consensus Opinion of Traditional Chinese Medicine Diagnosis and Treatment Experts on Non alcoholic Fatty Liver Disease. J Tradit Chin Med. 2017;58(19):1706–10. in Chinese. Zhao WX, Liu QZ, Liu JY, Ji AY, Ma SP. Clinical Observation of Huatan Lishi Houxue Fang for 96 Patients with Non-Alcoholic Steatohepatitis. J Tradit Chin Med. 2012;53(12):1025–7. in Chinese. Zhao WX, Yan L, Shao MY, Zhang LH. Effect of Huatan Qushi Huoxue prescription on the ADPN/AMPK/ACC signaling pathway in rats with nonalcoholic steatohepatitis. J Clin Hepatol. 2017;33(5):932–6. in Chinese. Zhao WX, Zhang LH, Cui JJ, Yang XQ, Zhang QF, Xu SC. Huatan Qushi Huoxue Recipe Intervened Nonalcoholic Steatohepatitis Rats by ADPN/AKT /NF-κB Signal Pathway. Chin J Integr Med. 2017;37(8):961–7. in Chinese. Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ (Clinical Res ed). 2013;346:e7586. National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, Chinese Medical Association. Guidelines of prevention and treatment for nonalcoholic fatty liver diseases: A 2018 update. Chin J Hepatol. 2018;26(03):195–203. in Chinese. Chinese Medical Association, Journal of Chinese Medical Association, Chinese Society of General Practice. Guideline for primary care of obesity:practice version. (2019). Chin J Gen Pract. (2019);19(2):102–107. in Chinese. Li H, Xiao MZ, Li HF, Ke B, Xi RX. Expert Consensus on Traditional Chinese Medicine Fasting Therapy (Draft for Comments). Chin J Integr Trad W Med L Des. 2019;29(6):577–80. in Chinese. Zhao J, Wang Q, Zhao X, Wu L, Li J, Zhang W, Xu S, Han C, Du Y, Tong X, Duan W, Cao D, Ren H, Zhao X, Ou X, Jia J, You H. Electro-acupuncture reduced steatosis on MRI-PDFF in patients with non-alcoholic steatohepatitis: a randomized controlled pilot clinical trial. Chin Med. 2023;18(1):19. Liu MH, Huang YS, Zhang ZL, Zhang LH, Liu ST, Zhao WX. The Effect of Processing and Decoction Methods on the Content of 18 Components in Huatan Qushi Huoxue Fang. Guid J Tradit Chin Med Pharm. 2023;29(10):36–42. in Chinese. Liu MH, Zhang LH, Ma QL, Zhao WX. Effect of the quercetin on the non-alcoholic steatohepatitis in rats and its mechanism. Chin J Clin Pharmacol. 2019;35(20):2597–601. in Chinese. Namkhah Z, Naeini F, Mahdi Rezayat S, Mehdi Yaseri, Mansouri S, Javad Hosseinzadeh-Attar M. Does naringenin supplementation improve lipid profile, severity of hepatic steatosis and probability of liver fibrosis in overweight/obese patients with NAFLD? A randomised, double-blind, placebo-controlled, clinical trial. Int J Clin Pract. 2021;75(11):e14852. Cheraghpour M, Imani H, Ommi S, Alavian SM, Karimi-Shahrbabak E, Hedayati M, Yari Z, Hekmatdoost A. Hesperidin improves hepatic steatosis, hepatic enzymes, and metabolic and inflammatory parameters in patients with nonalcoholic fatty liver disease: A randomized, placebo-controlled, double-blind clinical trial. Phytother Res. 2019;33(8):2118–25. Liu Y, Sun Z, Dong R, Liu P, Zhang X, Li Y, Lai X, Cheong HF, Wu Y, Wang Y, Zhou H, Gui D, Xu Y. Rutin ameliorated lipid metabolism dysfunction of diabetic NAFLD via AMPK/SREBP1 pathway. Phytomedicine. 2024;126:155437. Shi A, Li T, Zheng Y, Song Y, Wang H, Wang N, Dong L, Shi H. Chlorogenic Acid Improves NAFLD by Regulating gut Microbiota and GLP-1. Front Pharmacol. 2021;12:693048. Published 2021 Jun 30. Wu J, Lou YG, Yang XL, Wang R, Zhang R, Aa JY, Wang GJ, Xie Y. Silybin regulates P450s activity by attenuating endoplasmic reticulum stress in mouse nonalcoholic fatty liver disease. Acta Pharmacol Sin. 2023;44(1):133–44. Luo Z, Li M, Yang Q, Zhang Y, Liu F, Gong L, Han L, Wang M. Ferulic Acid Prevents Nonalcoholic Fatty Liver Disease by Promoting Fatty Acid Oxidation and Energy Expenditure in C57BL/6 Mice Fed a High-Fat Diet. Nutrients. 2022;14(12):2530. Meng LC, Zheng JY, Qiu YH, Zheng L, Zheng JY, Liu YQ, Miao XL, Lu XY. Salvianolic acid B ameliorates non-alcoholic fatty liver disease by inhibiting hepatic lipid accumulation and NLRP3 inflammasome in ob/ob mice. Int Immunopharmacol. 2022;111:109099. Lu Y, Shao M, Zhang C, Xiang H, Wang J, Wu T, Ji G. Kaempferol attenuates nonalcoholic steatohepatitis by regulating serum and liver bile acid metabolism. Front Pharmacol. 2022;13:946360. Published 2022 Sep 29. Wang L, Zhi Y, Ye Y, Zhang M, Ma X, Tie H, Ma X, Zheng N, Xia W, Song Y. Identify Molecular Mechanisms of Jiangzhi Decoction on Nonalcoholic Fatty Liver Disease by Network Pharmacology Analysis and Experimental Validation. Biomed Res Int. 2020;2020:8829346. Lu Z, Liu L, Zhao S, Zhao J, Li S, Li M. Apigenin attenuates atherosclerosis and non-alcoholic fatty liver disease through inhibition of NLRP3 inflammasome in mice. Sci Rep. 2023;13(1):7996. Xu L, Zhang Y, Ji N, Du Y, Jia T, Wei S, Wang W, Zhang S, Chen W. Tanshinone IIA regulates the TGF-β1/Smad signaling pathway to ameliorate non-alcoholic steatohepatitis-related fibrosis. Exp Ther Med. 2022;24(1):486. Cataldo I, Sarcognato S, Sacchi D, Cacciatore M, Baciorri F, Mangia A, Cazzagon N, Guido M. Pathology of non-alcoholic fatty liver disease. Pathologica. 2021;113(3):194–202. Brunt EM. Nonalcoholic Fatty Liver Disease: Pros and Cons of Histologic Systems of Evaluation. Int J Mol Sci. 2016;17(1):97. Giashuddin S, Alawad M. Histopathological Diagnosis of Nonalcoholic Steatohepatitis (NASH). Methods Mol Biol. 2022;2455:1–18. Caussy C, Reeder SB, Sirlin CB, Loomba R, Noninvasive. Quantitative Assessment of Liver Fat by MRI-PDFF as an Endpoint in NASH Trials. Hepatology. 2018;68(2):763–72. Gu J, Liu S, Du S, Zhang Q, Xiao J, Dong Q, Xin Y. Diagnostic value of MRI-PDFF for hepatic steatosis in patients with non-alcoholic fatty liver disease: a meta-analysis. Eur Radiol. 2019;29(7):3564–73. Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, Alkhouri N, Bansal MB, Baum S, Neuschwander-Tetri BA, Taub R, Moussa SE. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019;394(10213):2012–24. Flint A, Andersen G, Hockings P, Johansson L, Morsing A, Sundby Palle M, Vogl T, Loomba R, Plum-Mörschel L. Randomised clinical trial: semaglutide versus placebo reduced liver steatosis but not liver stiffness in subjects with non-alcoholic fatty liver disease assessed by magnetic resonance imaging. Aliment Pharmacol Ther. 2021;54(9):1150–61. Additional Declarations No competing interests reported. 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of Henan University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Sutong","middleName":"","lastName":"Liu","suffix":""},{"id":338049910,"identity":"3d06f9c5-c021-4205-b77e-05956a0e79bb","order_by":2,"name":"Qing Zhao","email":"","orcid":"","institution":"The First Affiliated Hospital of Henan University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Qing","middleName":"","lastName":"Zhao","suffix":""},{"id":338049911,"identity":"752af655-f136-4cc5-8d3a-ce58e4fab2ed","order_by":3,"name":"Xiaoyan Liu","email":"","orcid":"","institution":"The First Affiliated Hospital of Henan University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xiaoyan","middleName":"","lastName":"Liu","suffix":""},{"id":338049913,"identity":"67b8c18c-2e23-4a4f-b0ec-1411698c2fca","order_by":4,"name":"Xuehua Sun","email":"","orcid":"","institution":"Shuguang 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02:10:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4814797/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4814797/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":64005672,"identity":"7a81b805-0a06-44a6-9f35-6440aeb7fcc2","added_by":"auto","created_at":"2024-09-04 21:39:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":60040,"visible":true,"origin":"","legend":"\u003cp\u003eThe flowchat of the trial\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4814797/v1/368b382b31bf1465c7251c66.png"},{"id":64378112,"identity":"2008fc9f-9856-453d-9be0-8cc452736841","added_by":"auto","created_at":"2024-09-12 10:52:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":805672,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4814797/v1/41869c0a-5b5a-4147-b061-41cf74dbad77.pdf"},{"id":64005673,"identity":"1af5c34c-8611-4524-93ec-c71a05eda897","added_by":"auto","created_at":"2024-09-04 21:39:26","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":38920,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITitem.docx","url":"https://assets-eu.researchsquare.com/files/rs-4814797/v1/45303c81d086a96bc9122ff7.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and safety of Huatan Qushi Huoxue Fang granules on obese non-alcoholic fatty liver disease: study protocol for a multicenter, randomized, double-blind, placebo-controlled trial","fulltext":[{"header":"Background","content":"\u003cp\u003eNon alcoholic fatty liver disease (NAFLD) is a chronic progressive liver disease caused by overnutrition and insulin resistance in genetically susceptible individuals [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Its disease spectrum includes non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH), and related fibrosis and cirrhosis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. With the prevalence of obesity and type 2 diabetes, the global prevalence and incidence rate of NAFLD are increasing[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Moreover, NAFLD and metabolic syndrome are mutually causal, jointly promoting liver decompensation and the development of malignant tumors such as hepatocellular carcinoma [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Therefore, NAFLD has become an increasingly serious global public health issue [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Obesity is an independent risk factor for NAFLD. Obese and overweight patients have a three fold increased risk of developing NAFLD compared to non obese or lean individuals [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The prevalence of NAFLD among overweight and obese populations worldwide is 70.0% and 75.3%, respectively [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLong term excessive consumption of highly greasy or sweet refined foods or foods with strong flavors can lead to impaired spleen function. Water and grains cannot be effectively converted into essence, qi, blood, and body fluids, leading to the formation of grease and fat [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. They stop in the fascia cavity with the flow of qi and blood, resulting in obesity [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. When grease and fat accumulate in the liver, it can cause stagnation of liver qi, preventing liver from effectively performing its functions of dredging and regulating [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This leads to the production of pathological products such as phlegm, dampness, and blood stasis. Phlegm, dampness, and blood stasis intertwine in the liver, further damaging its function [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Therefore, phlegm, dampness, and blood stasis are the main pathological factors of NAFLD. This study recruited obese NAFLD patients with phlegm stasis syndrome, with the diagnostic criteria for this syndrome based on the expert consensus on the Chinese medical diagnosis and treatment of nonalcoholic fatty liver disease (2017) formulated by the Gastroenterology Branch of the China Association of Chinese Medicine [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTraditional Chinese Medicine has certain advantages in the treatment of NAFLD. Previous multi-center clinical studies have shown that a comprehensive Traditional Chinese Medicine (TCM) treatment plan based on the use of HTQSHXF granules can significantly improve clinical symptoms such as abdominal distension, discomfort in the right hypochondrium, and fatigue in patients with NASH [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. It also increases the liver/spleen CT ratio, reduces Body Mass Index (BMI), and decreases serum Alanine aminotransferase (ALT) and Triglyceride (TG) levels [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Experimental studies have shown that HTQSHXF granules can improve hepatic steatosis and inflammatory injury in rat models of NASH, reduce serum levels of ALT, Aspartate aminotransferase (AST), Total cholesterol (TC), TG, and Fasting blood glucose (FBG), and lower Free fatty acids (FFA) levels in liver homogenates. The therapeutic mechanism may be related to the activation of the ADPN/AMPK/ACC and ADPN/AKT/NF-κB signaling pathways [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The herbal drugs of HTQSHXF granules is shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. However, we have not yet used a double-blind design to observe the effects of HTQSHXF granules on Magnetic resonance proton density fat fraction (MRI-PDFF), Controlled attenuation parameter (CAP), and other indicators in NAFLD patients across multiple medical institutions. This study aims to explore the clinical efficacy and safety of HTQSHXF granules in obese NAFLD patients using a multi-center, randomized, double-blind design.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStandard formulation of HTQSHXF granules\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePinyin name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLatin scientific name\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAmount (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTCMH action\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZexie\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eAlismatis Rhizoma\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epromoting diuresis and eliminating dampness, as well as regulating qi flow and dissipating blood stasis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDanshen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eSalvia miltiorrhiza Bunge\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003einvigorating blood circulation to remove blood stasis, cooling the blood, and calming the spirit\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYujin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eRadix Curcumae Aromaticae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003einvigorating blood flow to alleviate pain, regulating qi flow, and relieving depression\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaizao\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eSargassum\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eresolving phlegm, eliminating dampness, softening hard masses, and eliminating phlegm\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJuemingzi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eCatsia tora Linn\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eclears the liver and improves vision\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShanzha\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eCrataegus pinnatifida\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eeliminates food stagnation and dissipates blood stasis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShuifeiji\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eSilybum marianum\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eclears heat and detoxifies\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChaihu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eRadix Bupleuri\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003esoothing the liver and regulating qi, acts as the guiding herb to introduce the prescription into the liver meridian\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cb\u003eTCMH\u003c/b\u003e traditional Chinese medicine herb\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis is a multicenter, randomized, double-blind, placebo-controlled parallel clinical trial study, aiming to recruit 248 obese NAFLD patients with phlegm-dampness and blood stasis. 88 cases were allocated to the First Affiliated Hospital of Henan University of TCM, 80 cases to Hepatology Department of Shuguang Hospital, Shanghai University of TCM, and 80 cases to the Hepatology Department of Shaanxi Provincial Hospital of CM. Cases in each center were allocated in a 1:1 ratio between the HTQSHXF group and placebo group. Under the condition of dietary and exercise management, the HTQSHXF group will take oral HTQSHXF granules, while the placebo group will take oral placebo. The treatment duration is 12 weeks. The schedule details are listed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. This protocol was approved by the Medical Ethics Committee of The First Affiliated Hospital of Henan University of TCM (approval number: 2022HL-038-01). The trial protocol (version 1.0, Jun 14, 2022) and was registered in the Chinese Clinical Trial Registry (ChiCTR2200060901). The flowchart of the trial is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. We present the following article in accordance with the SPIRIT 2013 reporting checklist [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. For more details about the checklist, please see Additional file 1.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e, Study procedure table.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy Period\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVisit 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVisit 2\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-7 to 0 days\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 weeks (\u0026plusmn;\u0026thinsp;3 days)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eData collection at baseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInformed consent form\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemographic information\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLife history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eprevious history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emedical history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInclusion and exclusion\u003c/p\u003e \u003cp\u003ecriteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEfficacy evaluation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMRI-PDFF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGGT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDL-C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDL-C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLSM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFFA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFINS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFBG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHOMA-IR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCK18-M30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCK18-M65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBFR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWHR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSafety evaluation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVital signs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood routine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal function\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElectrocardiogram\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOther work\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecord adverse events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEvaluation of subject behavior intervention compliance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecovery and record of study drug\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026times;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eMRI-PDFF Magnetic resonance proton density fat fraction, ALT Alanine aminotransferase, AST Aspartate aminotransferase, ALP Alkaline phosphatase, GGT Gamma glutamyl transferase, TG Triglyceride, TC Total cholesterol, HDL-C High-density lipoprotein cholesterol, LDL-C Low-density lipoprotein cholesterol, CAP Controlled attenuation parameter, LSM liver tiffness value, FFA Free fatty acids, FINS Fasting insulin FBG Fasting blood glucose, HOMA-IR Homeostasis model assessment of insulin resistance, CK18-M30 Cytokeratin 18-M30, CK18-M65 Cytokeratin 18-M65, BFR Body fat percentage, WHR Waist to hip ratio, BMI Body mass index.\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEligibility criteria\u003c/h2\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003eDiagnostic criteria\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section4\"\u003e \u003ch2\u003eDiagnostic criteria for obese NAFLD patients\u003c/h2\u003e \u003cp\u003e1.Diagnostic criteria for NAFLD: Formulated in accordance with the Guidelines for Prevention and Treatment of Non-alcoholic Fatty Liver Disease (2018 Update) established by the Fatty Liver and Alcoholic Liver Disease Group of the Chinese Society of Hepatology [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e(1) The patient had no history of excessive drinking (the weekly consumption of ethanol (alcohol) in the past 12 months was less than 210g for males and less than 140g for females) and had no other specific causes of fatty liver.\u003c/p\u003e \u003cp\u003e(2) Imaging manifestations: B-ultrasound, CAP, Computed Tomography (CT), or MRI-PDFF suggest that the patient has hepatic steatosis.\u003c/p\u003e \u003cp\u003e2. Diagnostic criteria for Obesity: Refer to the \" Guideline for primary care of obesity:practice version (2019) \" [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] : BMI\u0026thinsp;\u0026ge;\u0026thinsp;28kg/m\u003csup\u003e2\u003c/sup\u003e, or waist circumference\u0026thinsp;\u0026ge;\u0026thinsp;85cm for men and \u0026ge;\u0026thinsp;80cm for women.\u003c/p\u003e \u003cp\u003eThe diagnosis of obese NAFLD patients must meet both the first and second criteria mentioned above.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eDiagnostic criteria for phlegm stasis syndrome\u003c/h2\u003e \u003cp\u003eBased on the syndrome differentiation standards formulated by the Chinese Society of Traditional Chinese Medicine's Gastroenterology Branch in the \"Expert Consensus on the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Chinese Medicine\" (2017), the following is proposed according to the clinical manifestations of NAFLD patients.\u003c/p\u003e \u003cp\u003eMain symptoms: pain or discomfort in the right flank area.\u003c/p\u003e \u003cp\u003eSecondary symptoms: Obesity, generalized heaviness and lethargy, chest and abdominal fullness, loose or unformed stool, dullness tongue with possible ecchymosis or petechiae, white and greasy tongue coating, taut and slippery or deep and sluggish pulse.\u003c/p\u003e \u003cp\u003ePatients need to have the main symptoms and any two of the secondary symptoms to diagnose the phlegm stasis syndrome.\u003c/p\u003e \u003cp\u003e \u003cb\u003eInclusion criteria\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAge: 18\u0026ndash;65 years old, no gender limit.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSimultaneously meeting the diagnostic criteria for obese NAFLD patients and the diagnostic criteria for traditional Chinese medicine phlegm stasis syndrome type.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e1\u0026times;ULN\u0026thinsp;\u0026lt;\u0026thinsp;serum ALT\u0026thinsp;\u0026le;\u0026thinsp;3\u0026times;ULN.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eFasting blood glucose\u0026thinsp;\u0026le;\u0026thinsp;7.0 mmol/L.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSign an informed consent form.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e Have not taken any other drugs for treating NAFLD or obesity, or have discontinued these drugs before 4 weeks of observation.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eExclusion criteria\u003c/h2\u003e \u003cp\u003eAny one of the following should be excluded.\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eViral hepatitis, drug-induced liver disease, total parenteral nutrition, hepatolenticular degeneration, autoimmune liver disease, etc.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatients with severe heart, brain, kidney, hematopoietic system diseases, as well as emotional disorders such as anxiety and depression, and mental illness.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eFatty liver caused by long-term use of glucocorticoids, chlorpromazine, insulin, etc.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eType I diabetes patients.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePatients with various types of malignant tumors.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePregnant and lactating women.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSubjects participating in other clinical trials.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eWithdrawal criteria and termination criteria\u003c/b\u003e \u003c/p\u003e \u003cp\u003e1. If the following situations occur, the researcher will decide whether the patient should withdraw from the study.\u003c/p\u003e \u003cp\u003e(1) Appearing allergic reactions or serious adverse events.\u003c/p\u003e \u003cp\u003e(2) During the experiment, the patient developed other diseases that affected the efficacy and safety assessment.\u003c/p\u003e \u003cp\u003e(3) Cases that have to be unblinded during the study due to various reasons.\u003c/p\u003e \u003cp\u003e(4) After randomization, serious violations of inclusion or exclusion criteria were found.\u003c/p\u003e \u003cp\u003e2. The situation which the patient decides to withdraw on their own\u003c/p\u003e \u003cp\u003e(1) Regardless of the reason, if the patient is unwilling or unable to continue the clinical trial and requests to withdraw from the trial to the supervising physician, the trial will be terminated.\u003c/p\u003e \u003cp\u003e(2) Although the patient did not explicitly request to withdraw from the trial, they will no longer accept medication and monitoring.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eRandomization and blinding\u003c/h2\u003e \u003cp\u003eThe randomization plan for this study was entrusted to Henan Provincial Evidence Based Medicine Research Center for Traditional Chinese Medicine. The block length is 8 and the number of blocks is 31. Adopting a double-blind experimental design. A two-level randomized medication number is generated by Henan Provincial Evidence Based Medicine Research Center of TCM using statistical software packages. The first level is the group corresponding to each case number (Group A, Group B), and the second level is the treatment corresponding to two groups (HTQSHXF group and placebo group). The two-level blind bottoms are separately sealed and stored by Henan Province Evidence Based Medicine Research Center for TCM. Distribute and package drugs according to random grouping codes. Each coded trial drug has a corresponding emergency letter, which contains a note indicating that the coded drug belongs to the category of phlegm resolving, dampness dispelling, and blood activating granules or placebo, In order to unblind in case of emergency. The envelope is made of thick, opaque kraft paper, and the number of emergency letters should be the same as the number of participants. The envelope should indicate clinical study number. The envelope is sent to the research unit along with the packaged drugs. After the study was completed, the data was locked after blind verification was conducted without any errors. The staff of Evidence Based Medicine Research Center conducted the first unblinding, informing statistical experts of the groups corresponding to each case number with codes A and B, in order to conduct statistical analysis of all data. After the statistical analysis is completed, write a summary report and conduct a second unblinding at the clinical summary meeting to announce the exact groups of Group A and Group B.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eInterventions\u003c/h2\u003e \u003cp\u003eBoth the HTQSHXF group and the placebo group were treated with a diet and exercise regimen as the basic treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eDietary plan\u003c/h2\u003e \u003cp\u003eDeveloped in accordance with the Expert Consensus on Fasting Therapy in Traditional Chinese Medicine (2019 Edition) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e The dietary principles are formulated based on the Chinese Dietary Guidelines for Residents (2016). Implement a dietary plan of light fasting for 2 days per week and a 5-day conditioning period. Provide dietary prescriptions based on the patient's height, weight, and dietary habits, and implement dietary management. Implement overall calorie control in daily diet. Daily total calorie limit: Men should be below 25kcal/kg, and women should be below 20kcal/kg. The dietary structure is mainly low fat, protein rich, and fiber rich. Patients must record their diet every day, check in before meals, and upload it to the WeChat group to provide dietary guidance at any time.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eExercise plan\u003c/h2\u003e \u003cp\u003eAccording to specific situation of the patient, exercise prescriptions should be issued, and the guiding principles are as follows.\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDuring the light fasting period, patients engage in light physical activities, mainly walking, which can be combined with traditional Chinese medicine techniques such as Tai Chi, Eight Section Brocade, and Five Animal Play. It is recommended to do about 120 minutes of brisk walking or jogging every day, which can be divided into 3\u0026ndash;4 sessions, with each session lasting about 30 minutes.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eThe conditioning period is mainly characterized by long-term, regular, moderate to low intensity, and aerobic exercise. The types of sports include brisk walking, jogging, cycling, swimming, aerobics, rope skipping, etc. Exercise for 30 to 60 minutes each time. Persist at least once a day. At least 5 times a week. Suggest implementing the exercise in the afternoon or evening.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eDrug intervention\u003c/h2\u003e \u003cp\u003eHTQSHXF group: HTQSHXF granules (12 g/bag). 2 bag each time, dissolve the particles in 100ml hot water and drink twice a day. Take it 1 hour after breakfast and dinner every day. Take the medication 6 days a week and stop taking it for 1 day. The treatment will last for 12 weeks.\u003c/p\u003e \u003cp\u003ePlacebo group: placebo (HTQSHXF mimetic agent, 12 g/bag. Raw materials are maltodextrin, lemon yellow pigment, sunset yellow pigment, caramel pigment, lactose, and bittering agent). The administration method is completely consistent with the HTQSHXF group.\u003c/p\u003e \u003cp\u003eDrug preparation: HTQSHXF granules and corresponding mimetics were prepared by Jiangsu Jiangyin Tianjiang Pharmaceutical Co., Ltd. batch number: 2205302.\u003c/p\u003e \u003cp\u003eDrug combination: If there is any concomitant medication during the patient's participation in the study, researchers should record it in detail in the CRF form. It is allowed to undergo necessary treatment under the guidance of clinical doctors for other diseases or symptoms, but the use of drugs with hepatoprotective, anti-inflammatory, and lipid-lowering effects should be prohibited before the termination of the trial.\u003c/p\u003e \u003c/div\u003e "},{"header":"Outcomes","content":"\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003ePrimary Outcome\u003c/h2\u003e \u003cp\u003eMRI-PDFF.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eSecondary outcomes\u003c/h2\u003e \u003cp\u003eALT, AST, Alkaline phosphatase (ALP), Gamma glutamyl transferase (GGT), TG, TC, High-density lipoprotein cholesterol (HDL-C), Low-density lipoprotein cholesterol (LDL-C), CAP, Liver tiffness value (LSM), FFA, Fasting insulin (FINS), FBG, Homeostasis model assessment of insulin resistance (HOMA-IR), Cytokeratin 18-M30 (CK18-M30), Cytokeratin 18-M65 (CK18-M65), Body fat percentage (BFR), Waist to hip ratio (WHR) and BMI.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eSafety outcomes\u003c/h2\u003e \u003cp\u003eVital signs, blood routine, renal function, electrocardiogram.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eObservation time\u003c/h2\u003e \u003cp\u003eResearchers will conduct visits, observations, and records in the 0th and 12 weeks of the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eAdverse events\u003c/h2\u003e \u003cp\u003eAdverse events refer to any symptoms, syndromes, or diseases that occur during the observation period of clinical research and can affect the patient's health, as well as clinically relevant situations discovered in the laboratory or other diagnostic processes. The term \"adverse event\" does not imply a causal relationship with the investigational drug. Any adverse reactions that occur during the study period will be recorded in the \"Adverse Event Form\" and tracked for investigation. The handling process and results will be recorded in detail until the laboratory test returns to normal and symptoms and signs disappear. When adverse reactions are detected, researchers determine the diagnosis and treatment measures based on the condition, and decide whether to discontinue observation or break the blindness. Efficacy data that were available prior to blinding could be counted in the efficacy analysis. Otherwise, the case will be considered as a terminated case and will not be included in the efficacy analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eData collection and registration\u003c/h2\u003e \u003cp\u003eAll clinical doctors and researchers are required to undergo training and assessment before conducting this clinical trial. Only after passing the assessment can they participate in this study. The subjects need to undergo two visits, namely the 0th and 3rd months. The informed consent of the subjects and information from two visits will be recorded in a paper Case Report Form (CRF) form. The CRF form is the source file for clinical trial subjects, and researchers in each center should truthfully fill it out and properly store it according to regulations. After the study is completed, it will be uniformly saved and managed by the main center. The completed CRF form will be reviewed by the clinical monitor and handed over to the data administrator. The data management personnel use the online EDC data program (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://edc.hnzhy.com/portal/\u003c/span\u003e\u003cspan address=\"http://edc.hnzhy.com/portal/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) of Henan Province Evidence Based Medicine Research Center for data entry and management. Data of the subjects will be anonymous, and all collected data will be kept confidential.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eIn this study, the sample size was estimated based on the level of MRI-PDFF, which serves as the primary efficacy indicator. The calculation formula is as follows:\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003en\u003csub\u003eE\u003c/sub\u003e=n\u003csub\u003eC\u003c/sub\u003e=\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\frac{\\left[{Z}_{\\frac{\\alpha\\:}{2}}\\sqrt{2\\stackrel{-}{P}\\left(1-\\stackrel{-}{P}\\right)}+{Z}_{\\beta\\:}\\sqrt{{P}_{E}\\left(1-{P}_{E}\\right)+{P}_{C}\\left(1-{P}_{C}\\right)}\\right]}{{\\left({P}_{E}-{P}_{C}\\right)}^{2}}}^{2}\\)\u003c/span\u003e\u003c/span\u003e\u003c/h2\u003e \u003cp\u003eAccording to the literature, after 12 weeks of treatment, 25.9% of patients in the control group (placebo intervention) had a reduction of more than 30% in MRI-PDFF levels, while 53.3% of patients in the treatment group (Chinese traditional treatment) experienced a similar reduction [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Therefore, it is anticipated that following 12 weeks of dietary and exercise intervention, 35% of patients will have a reduction of more than 30% in MRI-PDFF levels. Furthermore, when combined with the treatment of HTQSHXF granules for 12 weeks, the proportion of patients with a reduction of MRI-PDFF levels exceeding 30% is expected to reach 57.4%. Assuming α\u0026thinsp;=\u0026thinsp;0.05, β\u0026thinsp;=\u0026thinsp;0.10, Z\u003csub\u003eα/2\u003c/sub\u003e=1.96, Z\u003csub\u003eβ\u003c/sub\u003e=1.645, \u003cem\u003eP\u003c/em\u003e\u003csub\u003eE\u003c/sub\u003e=0.574, \u003cem\u003eP\u003c/em\u003e\u003csub\u003eC\u003c/sub\u003e=0.35, \u003cem\u003en\u003c/em\u003e\u003csub\u003e\u003cem\u003eE\u003c/em\u003e\u003c/sub\u003e:\u003cem\u003en\u003c/em\u003e\u003csub\u003e\u003cem\u003eC\u003c/em\u003e\u003c/sub\u003e=1:1, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\stackrel{-}{P}\\)\u003c/span\u003e\u003c/span\u003e=(\u003cem\u003eP\u003c/em\u003e\u003csub\u003eE\u003c/sub\u003e+\u003cem\u003eP\u003c/em\u003e\u003csub\u003eC\u003c/sub\u003e)/2. The calculated sample size required for each group is 99 cases. Considering a 20% dropout rate, the final estimated sample size is 248 cases, with 124 cases in each group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec23\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eEntrust a third party to conduct data management and blind review, and be responsible for developing statistical analysis plans and writing statistical analysis reports. The data statistical analysis was completed using SPSS 22.0 statistical software. Qualitative data is expressed in terms of rate and composition ratio. If the quantitative data follows a normal distribution, it should be expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation; otherwise, the median should be used. When comparing the primary outcome MRI-PDFF with all secondary outcomes between two groups: If the data conforms to a normal distribution, t-test will be used (significance level of 0.05 will be used for inter group homogeneity of variance test, and t 'test will be used if the variances are not equal); If the data does not follow a normal distribution, Wilcoxon rank sum test will be used. \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 is considered statistically significant. All baseline variables will undergo descriptive analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eQuality control\u003c/h2\u003e \u003cp\u003eTo prevent potential bias in the study, the following measures are taken for quality control:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eA multicenter, randomized, double-blind design was adopted to address the bias in the selection of subjects by researchers.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eIn response to the bias in efficacy evaluation, a third-party evaluation is adopted under the premise of unified evaluation standards, and evaluating physician will conduct the research under blinded conditions throughout.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo address the bias in multicenter study, targeted training for researchers will be provided, and researcher statements will be signed to strengthen guidance for researchers during the study process. Designate a fixed researcher to undertake the recording of study medical records and the work of logging in and filling out electronic CRF.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo address the bias generated by the subjects, we aim to improve their compliance in the following aspects: 1) Effective communication: Researchers should conscientiously implement informed consent to ensure that subjects fully understand the study requirements and cooperate with the study. 2) Regular education: The researcher designates a dedicated person to conduct regular WeChat or phone follow-up before important event milestones. 3) Strengthen the diet and exercise management of subjects: Establish a dedicated WeChat group, where nutritionists develop a diet and exercise plan, and supervise subjects to clock in, adjust their diet, exercise regularly, undergo regular follow-up visits, and take medication regularly. 4) The distribution of drugs is managed and recorded by a fixed researcher.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThere are a total of 18 chemical active ingredients in the HTQSHXF granules, which are quercetin, chlorogenic acid, silymarin, rutin, ferulic acid, hesperidin, salvianolic acid B, naringenin, kaempferol, danshensu sodium, hyperoside, quercetin, apigenin, hesperetin, 23-acetyl zeaxanthin C, saikosaponin b2, saikosaponin b1, and tanshinone IIA [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Our previous study has shown that quercetin may improve the degree of hepatic steatosis and alleviate liver inflammation in NASH rats by regulating the PI3K/AKT/NF-κB signaling pathway [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Existing studies have shown that naringin can improve lipid status and severity of liver steatosis in obese NAFLD patients [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e][\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Hesperidin can improve liver steatosis, liver enzymes, metabolism, and inflammatory parameters in NAFLD patients. Rutin may improve diabetes NAFLD by activating Adenosine 5\u0026lsquo;-monophosphate (AMP)-activated protein kinase (AMPK) pathway [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In addition, chlorogenic acid [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], silymarin [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], ferulic acid [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], salvianolic acid B [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], kaempferol [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], hyperoside [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] apigenin [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], and tanshinone IIA [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] also have certain therapeutic effects on NAFLD.\u003c/p\u003e \u003cp\u003eLiver tissue pathological biopsy remains the gold standard for diagnosing NAFLD [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. However, the invasive nature of liver biopsy and the risk of complications such as bleeding limit its clinical application [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Moreover, the liver tissue samples obtained from liver biopsy can only represent 1/50000 of the liver volume[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. MRI-PDFF is an objective non-invasive quantitative imaging method for evaluating the overall liver fat content. MRI-PDFF\u0026thinsp;\u0026ge;\u0026thinsp;5% can confirm the diagnosis of fatty liver, while MRI-PDFF\u0026thinsp;\u0026ge;\u0026thinsp;10% may indicate moderate to severe fatty liver [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. A systematic review and meta-analysis involving a total of 636 suspected NAFLD patients who underwent liver biopsy and MRI-PDFF simultaneously found that MRI-PDFF diagnosed fatty liver (S0 vs. S1-3), moderate to severe fatty liver (S0-1 vs. S2-3), and severe fatty liver (S0-2 vs. S3) patients with liver biopsy confirmed AUROC (0.98, 0.91, and 0.90, respectively), sensitivity (0.93, 0.74, 0.74), specificity (0.94, 0.90, 0.87), as well as positive predictive values (16.21, 7.19, 5.89) and negative predictive values (0.08, 0.20, and 0.29). 9, 0.29) are all very high [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. This suggests that MRI-PDFF has excellent diagnostic value for liver fat quantification in NAFLD patients, and has high sensitivity and specificity in distinguishing different degrees of liver fat degeneration. It can be used as a reference standard for non-invasive quantification of liver fat content and has been recommended for evaluating changes in liver fat content in clinical trials of new drugs [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e][\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Therefore, this study used non-invasive MRI-PDFF as the main therapeutic indicator to quantitatively evaluate liver fat fraction.\u003c/p\u003e \u003cp\u003eA multicenter study has been conducted in the past to treat NASH patients with a combination of diet and exercise based on the formula of HTQSHXF granules. This study included a total of 202 NASH patients. 101 NASH patients in the treatment group and 101 in the control group received medication treatment on the basis of health education, diet and exercise. The TCM granules taken by the treatment group are based on HTQSHXF granules, and are added according to the patient's symptoms based on syndrome differentiation: patients with spleen deficiency and dampness excess symptoms are added with Codonopsis pilosula, stir fried Atractylodes macrocephala, and raw Coix seed; patients with liver and gallbladder dampness and heat symptoms are added with Tianjihuang, Yinchen, and lotus leaves; patients with liver and kidney yin deficiency symptoms are added with goji berries, Polygonum multiflorum, and Huai Niugeng. The control group received polyene phosphatidylcholine capsules. The results showed that on the 90th and 180th day of treatment, the treatment group was superior to the control group in reducing serum ALT and TG, lowering BMI, and improving liver/spleen CT values in NASH patients. And it is significantly better than the control group in improving clinical symptoms such as epigastric distension, liver discomfort, and fatigue. The above study adopted a multi-center, randomized, controlled, and superiority design. Despite being a multi-center study, the complexity of administering medication to the treatment group made it impossible to implement a double-blind design. This failure to control for external variables such as subjective biases from researchers and participants led to various unknown factors influencing the experimental results, reducing their reliability and validity.\u003c/p\u003e \u003cp\u003eDrawing from the lessons of previous studies with less rigorous designs, this study ensures that the treatment group only takes HTQSHXF granules without any additional medications. The control group received the corresponding placebo. This study design adopts a multi-center, randomized, double-blind approach to enable a more scientific evaluation of the efficacy and safety of the HTQSHXF granules based on the research results. Despite this, there are still certain limitations in the study design. For example, the number of research centers is relatively small, with only three units participating. The treatment duration of 3 months is relatively short. Additionally, the primary efficacy indicator does not include liver histopathological biopsy. We hope to conduct higher-quality multi-center, randomized, double-blind clinical studies in the future to provide stronger evidence-based medical support and guidelines for the treatment of obese NAFLD.\u003c/p\u003e \u003cdiv id=\"Sec26\" class=\"Section2\"\u003e \u003ch2\u003eTrial status\u003c/h2\u003e \u003cp\u003eThis is an ongoing clinical trial. The recruitment time for the first subject was March 17, 2023. We plan to complete the recruitment of all subjects by September 2025, and all data will be locked in by December 2025.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eNAFLD \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003enon-alcoholic fatty liver disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eNASH \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003enon-alcoholic steatohepatitis \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eHTQSHXF \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eHuatan Qushi Huoxue Fang\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eTCM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eTraditional Chinese Medicine\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eSPIRIT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eStandard Protocol Items: Recommendations for Interventional Trials\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eMRI-PDFF\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eMagnetic resonance proton density fat fraction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eBFR \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eBody fat percentage\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eWHR \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eWaist to hip ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eBMI \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eBody Mass Index\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eCAP \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eControlled attenuation parameter\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eLSM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eLiver tiffness value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eFFA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eFree fatty acids\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eCK18-M30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eCytokeratin 18-M30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eCK18-M65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eCytokeratin 18-M65\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eALT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eAlanine aminotransferase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eAST \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eAspartate aminotransferase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eALP \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eAlkaline phosphatase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eGGT\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eGamma glutamyl transferase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eTG \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eTriglyceride\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eTC \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eTotal cholesterol\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eHDL-C\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eHigh-density lipoprotein cholesterol\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eLDL-C\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eLow-density lipoprotein cholesterol\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eFBG \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eFasting blood glucose\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eFINS \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eFasting insulin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eHOMA-IR\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eHomeostasis model assessment of insulin resistance\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eCRF \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eCase Report Form\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.758483033932137%\" valign=\"top\"\u003e\n \u003cp\u003eAMPK \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"79.24151696606786%\" valign=\"top\"\u003e\n \u003cp\u003eAdenosine 5\u0026lsquo;-monophosphate (AMP)-activated protein kinase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thanks Henan Provincial Evidence Based Medicine Research Center for Traditional Chinese Medicine for designing the blinding and random allocation scheme; The authors also thanks the researchers from the other two centers for their contributions. Finally, the authors would like to thank all participants for their cooperation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWZ and ML designed this study. LZ and SL drafted the manuscript and made equal contributions to the study. QZ, XL, XS, TW, FL, MY participated in the study plan. WZ modified and edited the manuscript. All authors have read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was sponsored by Henan Province\u0026apos;s \u0026quot;double first-class\u0026quot; creation of scientific research in traditional Chinese medicine (No. STG-ZYX02-202117, No. HSRP-DFCTCM-2023-7-23), National Traditional Chinese Medicine Clinical Research Base Scientific Research Special Project (No.2022JDZX098, 2022JDZX114), National Natural Science Foundation of China (No.82205086), Science and Technology Key Project of Henan Province (No. 232102310438), and The 9th China Association for Science and Technology Young Talent Support Project (No. 2023QNRC001).\u0026nbsp;The funder had no role in the design, implementation, analysis, data interpretation, or decision process of submitting the results of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study will follow the Helsinki Declaration and Good Clinical Practice guidelines, and will require informed consent from the subjects.\u0026nbsp;This protocol has been reviewed and approved by the Medical Ethics Committee of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine (Approval Number: 2022HL-038-01).\u0026nbsp;The study results will be published in the form of a paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBugianesi E, Petta S. 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Kaempferol attenuates nonalcoholic steatohepatitis by regulating serum and liver bile acid metabolism. Front Pharmacol. 2022;13:946360. Published 2022 Sep 29.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang L, Zhi Y, Ye Y, Zhang M, Ma X, Tie H, Ma X, Zheng N, Xia W, Song Y. Identify Molecular Mechanisms of Jiangzhi Decoction on Nonalcoholic Fatty Liver Disease by Network Pharmacology Analysis and Experimental Validation. Biomed Res Int. 2020;2020:8829346.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLu Z, Liu L, Zhao S, Zhao J, Li S, Li M. Apigenin attenuates atherosclerosis and non-alcoholic fatty liver disease through inhibition of NLRP3 inflammasome in mice. Sci Rep. 2023;13(1):7996.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu L, Zhang Y, Ji N, Du Y, Jia T, Wei S, Wang W, Zhang S, Chen W. Tanshinone IIA regulates the TGF-β1/Smad signaling pathway to ameliorate non-alcoholic steatohepatitis-related fibrosis. Exp Ther Med. 2022;24(1):486.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCataldo I, Sarcognato S, Sacchi D, Cacciatore M, Baciorri F, Mangia A, Cazzagon N, Guido M. Pathology of non-alcoholic fatty liver disease. Pathologica. 2021;113(3):194\u0026ndash;202.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrunt EM. Nonalcoholic Fatty Liver Disease: Pros and Cons of Histologic Systems of Evaluation. Int J Mol Sci. 2016;17(1):97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiashuddin S, Alawad M. Histopathological Diagnosis of Nonalcoholic Steatohepatitis (NASH). Methods Mol Biol. 2022;2455:1\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCaussy C, Reeder SB, Sirlin CB, Loomba R, Noninvasive. Quantitative Assessment of Liver Fat by MRI-PDFF as an Endpoint in NASH Trials. Hepatology. 2018;68(2):763\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGu J, Liu S, Du S, Zhang Q, Xiao J, Dong Q, Xin Y. Diagnostic value of MRI-PDFF for hepatic steatosis in patients with non-alcoholic fatty liver disease: a meta-analysis. Eur Radiol. 2019;29(7):3564\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, Alkhouri N, Bansal MB, Baum S, Neuschwander-Tetri BA, Taub R, Moussa SE. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019;394(10213):2012\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFlint A, Andersen G, Hockings P, Johansson L, Morsing A, Sundby Palle M, Vogl T, Loomba R, Plum-M\u0026ouml;rschel L. Randomised clinical trial: semaglutide versus placebo reduced liver steatosis but not liver stiffness in subjects with non-alcoholic fatty liver disease assessed by magnetic resonance imaging. Aliment Pharmacol Ther. 2021;54(9):1150\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e\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":"Huatan Qushi Huoxue Fang, Randomized controlled trial, Non-alcoholic fatty liver disease, Obese, Traditional Chinese medicine","lastPublishedDoi":"10.21203/rs.3.rs-4814797/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4814797/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe global burden of non-alcoholic fatty liver disease (NAFLD) is parallel to the increasing obesity rates around the world. Phlegm stasis syndrome is a common traditional Chinese medicine syndrome type of obese NAFLD, which is often treated by resolving phlegm, dispelling dampness, and promoting blood circulation. This study mainly explores the clinical efficacy and safety of Huatan Qushi Huoxue Fang (HTQSHXF) granules in the treatment of obese NAFLD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis is a multicenter, randomized, double-blind, placebo-controlled clinical trial that will recruit 248 obese NAFLD patients from three hospitals in China. Randomly allocate patients to either the HTQSHXF group or the placebo group in a 1:1 ratio. The intervention phase lasts for 12 weeks. The primary outcome will be the change in relative liver fat content from baseline to week 12 measured by Magnetic resonance proton density fat fraction (MRI-PDFF). The secondary outcomes will be Body fat percentage (BFR), Waist to hip ratio (WHR), Body Mass Index (BMI), Controlled attenuation parameter (CAP), Liver tiffness value (LSM), serum liver function, blood lipids, blood glucose, Free fatty acids (FFA), Cytokeratin 18-M30 (CK18-M30), and Cytokeratin 18-M65 (CK18-M65). The results will be monitored at baseline and 12 weeks of intervention. Adverse events that occur in this study will be promptly managed and recorded.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThis study will use more recognized quantitative methods to explore the efficacy and safety of HTQSHXF granules in treating obese NAFLD, providing clinical evidence for its translational application.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003e \u003cspan class=\"ExternalRef\"\u003e \u003cspan class=\"RefSource\"\u003ehttp://www.chictr.org.cn\u003c/span\u003e \u003cspan address=\"http://www.chictr.org.cn\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e \u003c/span\u003e. Trial number: ChiCTR2200060901. Registered on 14 Jun 2022.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of Huatan Qushi Huoxue Fang granules on obese non-alcoholic fatty liver disease: study protocol for a multicenter, randomized, double-blind, placebo-controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-04 21:39:22","doi":"10.21203/rs.3.rs-4814797/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":"fd38091d-41e9-42ac-ace1-6b782d2f2f97","owner":[],"postedDate":"September 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-12T10:44:25+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-04 21:39:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4814797","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4814797","identity":"rs-4814797","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}