Efficacy of DaXianXiong decoction in preventing the progression of severity of acute pancreatitis: Study protocol for a randomized controlled trial

Efficacy of DaXianXiong decoction in preventing the progression of severity of acute pancreatitis: Study protocol for a randomized controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Efficacy of DaXianXiong decoction in preventing the progression of severity of acute pancreatitis: Study protocol for a randomized controlled trial Dongsheng Ren, Judan Tan, Yun Lu, Zhenchun Luo, Yuling Zhou, Qinghai Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4443242/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 I ntroduction: Developing countries are facing an increase in the incidence of acute pancreatitis (AP) — characterized by rapid onset, fast progression, high rate of severity, and high mortality. Progression of AP into severe acute pancreatitis (SAP) results in a series of complications such as organ dysfunction, local abscesses, pseudocysts, and necrosis. As no effective intervention measure has yet been developed, supportive therapy remains the major approach for the early treatment of AP. DaXianXiong decoction is a widely used TCM formulation; however, limited research is conducted on its clinical efficacy. Here, we propose a standardized clinical trial to evaluate the effectiveness and safety of DaXianXiong decoction in preventing the progression of AP to SAP. M ethods and analysis: This study is a randomized, double-blind, placebo-controlled, single-center clinical trial. Sixty eligible patients will be randomly allocated in a 1:1 ratio to the intervention group and the control group. Both groups will receive standard Western medical treatment for pancreatitis. However, the intervention group will additionally receive DaXianXiong decoction, while the control group will receive a placebo similar to the decoction. The primary outcomes will include incidence of SAP, modified CTSI score, APACHE II score, Modified Marshall score, and levels of the inflammation factor. The secondary outcomes will include the effect of the gastrointestinal dysfunction treatment. Evaluations will be conducted at baseline, 24 h after intervention, and days 3, 7, and 28 after intervention in both groups. D iscussion: This trial will help us assess the effectiveness and safety of DaXianXiong decoction in patients with AP. E thics and dissemination: Ethical approval was obtained from the Ethics Committee of the First Affiliated Hospital of Chongqing Traditional Chinese Medicine University (Ethical Review Number:2023-ky-51). The results of this study will be published in a peer-reviewed journal. The study sponsor does not have any role in study-related activities or in the final publication of the study. T rial Registration: This trial is registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/).Registration number: ChiCTR2300076885, Date: 2020-10-23, version 1.1. acute pancreatitis DaXianXiong decoction traditional Chinese medicine protocol severe acute pancreatitis Figures Figure 1 Figure 2 1 Introduction Acute pancreatitis (AP) is a prevalent exocrine inflammatory disorder of the pancreas. It is characterized by severe abdominal pain and multi-organ dysfunction, which can lead to pancreatic necrosis and persistent organ failure. The worldwide incidence of AP is typically 30–40 cases per 100,000 population, with more than 2000 fatalities per year [1] . It is the third most frequent principal diagnosis related to gastrointestinal and pancreatic conditions among hospital admissions in the United States [2] and the fourth most common in China [3] . Treatment for AP accounts for a significant proportion of healthcare utilization and expenditure [4] . Severe acute pancreatitis (SAP) is the most life-threatening form of AP. The Revised Atlanta Classification of Severity of AP defines SAP as the persistent organ failure for ≥48 h [5] . SAP is considered the advanced stage of AP and is characterized by severe clinical manifestations and complications. Approximately 20% of patients diagnosed with AP eventually develop SAP [6] . Although significant advancements have been made in the treatment of SAP, the mortality rate is still quite high (20–40%) [1, 7, 8] . During AP, the premature activation of trypsin within the pancreatic acinar cells triggers pancreatic autodigestion, resulting in a localized inflammatory response. This inflammatory process releases both pro- and anti-inflammatory cytokines as well as other inflammatory mediators, which attract neutrophils, monocytes, and lymphocytes that infiltrate the pancreas [9] . As a result, the local inflammatory response amplifies and disseminates through the systemic circulation, resulting in a systemic inflammatory response [10] . Systemic inflammation initially manifests as the systemic inflammatory response syndrome (SIRS). Patients with persistent SIRS are at an increased risk of developing systemic organ dysfunction, which may progress to organ failure [7, 11] . Therefore, the success or failure of the early treatment for AP determines whether complications such as secondary infections, local abscesses, cysts, and necrosis develop in the later stages of the disease. Currently, apart from supportive care such as maintaining an adequate circulatory volume, offering oxygen supplementation, utilizing mechanical ventilation (when necessary), and close monitoring for respiratory/cardiovascular/renal insufficiency, the crucial intensive care for the early treatment for SAP is typically conducted through two main methods. Adequate fluid resuscitation is the first treatment to be considered and applied. Although it is the primary treatment for shock in SAP, it can also cause interstitial edema. This injury can trigger acute respiratory distress syndrome and abdominal compartment syndrome, leading to the development of multiple organ dysfunction syndrome (MODS) [12] . At present, there is no consensus on the type, rate, dosage, and endpoint of fluid resuscitation. More research is required to further improve the fluid therapy strategies in each phase of the treatment for SAP, including resuscitation, optimization, stabilization, and evacuation [13] . The second method involves the use of strategies for accelerating the recovery of gastrointestinal functions in AP. These strategies include fasting with nasogastric drainage to eliminate gastric secretions and using anticholinergic agents or H2-blocking agents and somatostatin to inhibit pancreatic secretion. Apart from actively maintaining the hemodynamic stability, ensuring effective blood perfusion, and reducing the workload on the pancreas, there are currently no other effective interventions that directly act on the gastrointestinal tract for promoting the recovery of gastrointestinal motility. In addition, early enteral nutrition therapy is not widely practiced in SAP because it may lead to complications such as nausea, vomiting, and ileus [14] . Most clinical institutions in China still rely primarily on fasting and gastrointestinal decompression to manage AP in its early stages. During the early stages of the AP, interventions to block the inflammatory storm, restore gastrointestinal motility, complement the deficiencies of conventional Western medicine treatment, slow down its progression to SAP so as to improve the prognosis, and reduce mortality are crucial. However, very few reports are available on the interventions for SAP. Chinese herbal medicines (CHMs) are rich in bioactive compounds and are widely employed in clinical practice worldwide [15] . A large number of CHMs, including Chinese pleiotropic natural products and formulas, with significant effects on AP have been identified. These CHMs target various proteins or biological networks involved in the pathogenesis of AP [16-18] . In addition, CHMs have a broader approach, as they target multiple pathways and networks involved in the disease process [19] . Therefore, they are more promising therapeutic agents than Western medicine, which typically have single specific targets. DaXianXiong decoction, originally documented in the classical Chinese medical book “ Shang Han Lun ” ( Treatise on Febrile Diseases ), is a notable herbal formula traditionally used for clearing internal heat in the gastrointestinal tract. This decoction consists of Da Huan g [Rhei Radix et Rhizoma], Mang Xiao [Natrii Sulfas], and Gan Sui [Kansui Radix] . It is being used in China for more than three decades as a traditional treatment for AP. Traditional beliefs regarding the management of acute pancreatitis advocated for "bowel rest" to prevent further irritation of the inflamed pancreas. However, contemporary evidence supports the contrary approach, emphasizing the benefits of early feeding. The SEPEN guidelines recommend that enteral nutrition (EN) should be initiated early, within 24-72 hours after admission for patients with acute pancreatitis, to prevent intolerance to oral feeding [20] . This approach is feasible, safe, tolerable, and has significant clinical benefits in terms of mortality, organ failure, and infectious complications for both time-points compared with delayed EN [21-23] . Similarly, the AGA guidelines also recommend early (within 24 hours) initiation of enteral feeding rather than keeping patients nil per os [24] . In China, the "Chinese Guidelines for the Diagnosis and Treatment of Acute Pancreatitis 2021" emphasize the early initiation of enteral nutrition therapy (within 24 hours) as safe and effective, which can reduce complications and mortality rates. All of this evidence makes it possible to consider the early administration of traditional Chinese medicine formulations to patients with acute pancreatitis. However, the clinical efficacy of DaXianXiong decoction in preventing the progression to SAP is still unclear because of the lack of high-quality randomized controlled trials. The primary objective of this study is to evaluate the therapeutic efficacy of traditional Chinese medicine (TCM) in the treatment of AP to establish an evidence-based framework for developing a standardized diagnostic and treatment approach. Specifically, this study aims to: (1) determine the efficacy of DaXianXiong decoction in preventing the progression of AP to SAP; (2) elucidate the effects of DaXianXiong decoction in reducing the levels of inflammation factors of AP; (3) clarify the efficacy of the decoction in improving the clinical symptoms of gastrointestinal dysfunction and improve enteral nutrition; and (4) investigate the efficacy and safety of the decoction by identifying related complications. 2 Methods/design 2.1 Trial design This is a single-center, randomized, double-blind, placebo-controlled study. It adheres to the guidelines mentioned in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement (Supplementary Material S1). During the trial, all eligible participants will be randomly assigned to either the intervention group or the placebo group. Both groups will receive the standard treatment for AP. A detailed workflow depicting the study process is presented in Figure 1. The trial is supported by the Chongqing Special Incentive Program for Scientific Research Institutions Program (No. jxyn2021215). The study sponsor does not have any role in study-related activities or in the final publication of the study. 2.2Study population Patients will be enrolled from the intensive care unit in Chongqing Traditional Chinese Medicine Hospital, a grade III level A hospital in China. 2.3 Recruitment of participants The study group will be recruiting the participants and handle their allocation into their respective groups. Eligible patients who are willing to participate in the trial will be provided with an informed consent form with details of the study objectives, procedures, and potential risks (Supplementary Material S2). Patient privacy will be strictly maintained. Physical documents related to the study will be secured in a locked office. 2.4 Patient and public involvement Our research will not include any design, implementation, and reporting from patients or public. 2.5 Inclusion criteria We will select patients based on the following inclusion criteria: Presence of AP as confirmed using the revised Atlanta classification (Table 1). 18–75 years of age. Time of illness onset should be under 24 h. Table 1. Diagnostic criteria for acute pancreatitis Fulfill two of the three criteria mentioned below 1 Upper abdominal pain 2 Serum amylase or lipase (or both) >3 times the upper limit of normal values 3 Typical findings on imaging: contrast-enhanced CT (CECT) or MRI or abdominal ultrasound 2.6 Exclusion criteria We will use the following exclusion criteria: 1. Patients with severe diseases affecting vital organs, such as liver dysfunction, heart failure, and malignant tumors, will be excluded. 2. Patients participating in another study within 3 months to enrollment will be excluded. 3. Those with known allergy to any of the prescribed medicine will be excluded. 4. Pregnant or lactating women will also be excluded. 2.7 Withdrawal cases Participants can withdraw from the study at any point without any repercussions. If a participant discontinues the interventional method or decides to participate in another study, they will no longer be included in the present study. However, even when a participant withdraws from the study, the data collected up to that point will be retained and included in the analysis, unless specifically requested otherwise. The withdrawal and non-compliance of participants will also be documented. Incomplete data will be addressed based on the withdrawal rate. If the rate is <5–10%, we will perform data cleaning. If the withdrawal rate exceeds 10%, the missing data will be managed through imputation, intention-to-treat analysis, and sensitivity analysis. 2.8 Management of dropout cases All subjects who provide informed consent and meet the eligibility criteria for enrollment in this randomized controlled trial (RCT), irrespective of the timing or reasons for their withdrawal later, will be categorized as dropouts if they are lost to follow-up. However, patients who discontinued the treatment regimen because of complete symptom remission will not be considered dropouts. The investigators will comprehensively document the reasons for each dropout in the case report form (CRF). Real-world circumstances, including adverse events (AEs), will be accounted for during the statistical analysis. In addition, we will carefully record and preserve the data about all enrolled patients who will receive the assigned investigational medications, regardless of their withdrawal status, for observation purposes and use them as both a data archive and for intention-to-treat analysis. 2.9 Criteria for termination of the experiment The experiment will be terminated under the following three situations: (1) The subjects encountered drug-related serious AEs. (2) The subjects exhibited non-compliance with the protocol regarding the administration of the investigational drug. (3) The investigators determine that further continuation of the trial might pose potential harm to the subjects. 2.10 Interventions All participants will be provided with detailed information about the study. Once informed consent is obtained and baseline assessments are completed, eligible participants will be randomly allocated to the intervention or placebo group. Throughout the study, the participants will be prohibited from using any other TCM formulation. Both groups will receive standard treatments. In addition to the standard treatment, the intervention group will receive DaXianXiong decoction (Figure 2). The constituent botanical drugs of the DaXianXiong decoction are listed in Table 2. The DaXianXiong decoction includes three herbs, namely, Rhei Radix et Rhizoma (Shengdahuang) 30 g, Natrii Sulfas (Mangxiao) 30 g, and Kansui Radix (Gansui) 3 g. The dosage of each herb was determined based on the guidelines outlined in The Chinese Pharmacopoeia (Ch. P), 2020 edition [25] . Table 2 Components of DaXianXiong Decoction Drug name Part this formula use Location of manufacture Dose (g) Usage Medicine form, dosage, frequency Registration status (Y/N) Quality control report (Y/N) Storage condition Da Huan g [Rhei Radix et Rhizoma] Roots Sichuan Neautus Co., Ltd., Sichuan, China 7.5 Nasal feeding or oral administration Powder, dissolved in 50 mL of warm water, every 6 h, lasts 48 h Y Y Powder: stored in the pharmacy department; 18–20 °C and 45–75% humidity Decoction: kept in the ward; 26–28°C and 50–60% humidity Mang Xia o [Natrii Sulfas] Mineral Sichuan Neautus Co., Ltd., Sichuan, China 7.5 Nasal feeding or oral administration Powder, dissolved in 50 mL of warm water, every 6 h, lasts 48 h Y Y Powder: stored in the pharmacy department; 18–20 °C and 45–75% humidity Decoction: kept in the ward; 26–28 °C and 50–60% humidity Gan Sui [Kansui Radix] Roots Sichuan Neautus Co., Ltd., Sichuan, China 0.5 Nasal feeding or oral administration Powder, dissolved in 50 mL of warm water, every 6 h, lasts 48 h Y Y Powder: stored in the pharmacy department; 18–20 °C and 45–75% humidity Decoction: kept in the ward; 26–28°C and 50–60% humidity The Department of Pharmacy of the CQTCM Hospital will perform the following processing steps on the DaXianXiong decoction: water extraction, separation, concentration, drying, and granulation. Each sachet will contain 10.5 g of powdered decoction. The production and processing procedures will be conducted as per the guidelines specified in the Ch. P of The Chinese Pharmacopoeia . The powder will be processed and filled in standardized clean production workshops. The treatment method will involve nasal feeding or oral administration of the DaXianXiong decoction four times a day, once every 6 h, and dissolved in 50 mL of warm boiled water. The course of the treatment will be 48 h. We will design placebos similar to the intervention drugs in terms of the shape, color, smell, and solubility, so that participants have a similar sensory experience. Placebos have no efficacy or side effects. They will also be produced by the Department of Pharmacy of the CQTCM Hospital. In the event of a serious AE or allergic reaction caused by the research medication, the principal investigator will open the emergency envelope and discontinue the trial for that participant. Details of the event and unblinding will be recorded in the CRF, and the patient will receive appropriate treatment. The relevant departments and ethics committees will be promptly notified within 24 h. 2.11 Randomization Randomization will be conducted by an independent statistician using SPSS Statistics 26.0 software. Using a predetermined random number table, 60 participants will be randomly assigned to either the intervention or placebo group. A random distribution table will be created in triplicate to ensure accuracy and reliability of our random scheme, and its copies will be provided to the project leader, pharmacist and statistician for reference and implementation. 2.12 Blinding This study will be conducted as a double-blind trial to ensure that both participants and researchers remain unaware of group assignments. Each participant will be provided with a package containing medication numbers and labels. Random numbers will be securely sealed in double opaque envelopes and managed by a specialist (ZCL). Each participant will be provided with their designated emergency letter, which will be carefully kept in a secure storage until the study is completed. 2.13 Outcome measures The outcome measures will be determined at various time points throughout the study, including baseline (T0), 24 h after the final treatment (T1, endpoint 1), 3 days after the final treatment (T2, endpoint 2), 7 days after the final treatment (T3, endpoint 3), and 28 days after the final treatment (T4, final endpoint). The data collection and assessment schedule are listed in Table 3. 2.14 Primary outcomes 2.14.1 Occurrence of SAP 1) SAP Incidence: It will be determined using the following formula: SAP incidence = number of cases of SAP patients/number of cases of total patients100%. 2) Modified computed tomography severity index (CTSI): According to the analysis of the area under the curve, the modified CTSI demonstrates the highest accuracy in predicting SAP. It is a simpler and more accurate scoring tool, showing a stronger statistical correlation with factors such as length of hospital stay, development of infection, organ failure, and mortality [26, 27] . It will be determined using the following formula: CTSI = (original scorecurrent score)/original score100%. 3) APACHE II score: The APACHE II (Acute Physiology and Chronic Health Evaluation II) scoring system has a high sensitivity and exhibits a negative predictive value in predicting pancreatic necrosis and organ failure. This makes it an ideal prognostic tool for assessing the severity of AP and in guiding clinical decision-making, particularly in resource-limited developing countries [28] . It is determined using the following formula: APACHE II = (original scorecurrent score)/original score100%. 4) Modified Marshall score: Organ failure plays a significant role in the severity of AP. The Revised Atlanta classification recommends the use of the Modified Marshall scoring system as the primary tool for assessing organ failure. The Modified Marshall scoring system encompasses scoring systems for respiratory, cardiovascular, and renal systems to evaluate organ dysfunction in AP [9] . 2.14.2 Levels of inflammation factor The level of an inflammation factor is a surrogate marker for important clinical endpoint variables in AP. Multiple studies have shown that C-reactive protein (CRP) is a good surrogate marker for SAP [29, 30] . Additionally, interleukin-6 (IL-6) is superior in predicting SAP compared to other commonly used markers such as erythrocyte sedimentation rate (ESR). The level of an inflammation factor can be determined using the following formula: [31] inflammation factor = (original figurecurrent figure)/original figure100% We will also employ IL-1, IL-4, IL-8, and IL-10 to investigate the potential targets of the DaXianXiong decoction. In pancreatitis, cytokines such as TNFα secreted by acinar cells and DAMPs play a major role in activating immune cells such as neutrophils and macrophages. This process leads to increased pancreatic damage, systemic inflammation, and the development of SAP [12, 32] . 2.15 Secondary outcomes 2.15.1 Gastrointestinal dysfunction treatment effect A comprehensive assessment of the gastrointestinal function is essential for the early detection of SAP. This assessment involves evaluating symptoms such as abdominal pain, distention, hematemesis, hematochezia, number of independent defecations, and digestive function. Signs such as tenderness, rebound tenderness, muscle tension, and the number of bowel sounds are also considered. Additionally, scores such as the gastrointestinal function score used in MODS diagnostic criteria can provide a standardized measurement of the gastrointestinal function. 2.15.2 Curative effects Given the constraints of ethics and experimental techniques, certain indicators are valuable for assessing the improvements and prognosis of AP patients. These include the time to bowel sound recovery, time to first defecation, and the gastrointestinal function score. These measures provide predictive information regarding the gastrointestinal function and can be useful in evaluating the prognosis of AP patients. We will also record hospitalization costs and duration. 2.16 Safety outcomes The safety outcomes of the investigational medication were assessed at T0, T1, T2, T3, and T4 by considering the following: 1) Measurement of vital signs: Heart rate, blood pressure, temperature, and respiration. 2) Laboratory tests: Blood routine, stool routine, and urine routine. 3) Liver function tests: Alanine aminotransferase, aspartate aminotransferase, and bilirubin. 4) Renal function tests: Urea nitrogen and creatinine. 5) Electrocardiogram. 2.17 Adverse events All AEs will be carefully documented, including the start and end dates, severity, relationship to the study drug, and participant’s continued involvement in the study. Any serious AE will be promptly reported to the Research Ethics Committee within 24 h. If an AE occurred, the patient will be advised to discontinue the use of the decoction, and the researchers will evaluate whether it is related to the formulation. Emergency safety measures will be implemented, if necessary, to ensure the well-being of participants. Persistence of AEs will be monitored until their resolution. Please note that AEs are not the complications clearly related to AP, such as acute respiratory distress syndrome, abdominal compartment syndrome, and acute kidney injury. 2.18 Sample size where μ 1 and μ 2 are the means of the intervention and placebo groups, respectively, and σ is the standard deviation. The study aims to maintain the type I error probability ( α ) to <5% and the type II error probability ( β ) to <10%, with the α at 0.05 and the β at 0.1. To determine the sample size, we referred to literature reports in Chinese [33] on the use of DaXianXiong decoction for the treatment of AP. We used the time blood amylase took to return to the normal levels to determine the clinical efficacy of the decoction. We fixed the total sample size for the study at 60. We allocated 30 participants to the intervention group and the remaining 30 to the placebo group. 2.19 Data and sample collection To minimize selection bias, three study members will receive comprehensive training on the criteria and methods used for case collection. Detailed records of participant medication will be collected, and any interfering or contaminating factors will be excluded from the statistical analysis. Participants will be provided with a consent form with a clear outline of the use of their data, allowing them to choose whether to continue participating or withdraw from the trial. Biological specimens collected for storage will be handled according to ethical guidelines and they will be destroyed after their intended use. 2.20 Data management and monitoring An independent Data and Safety Monitoring Board will be established to monitor the conduct and safety of the study. Two of our research team members will be responsible for updating our clinical trial-related information into the Chinese Clinical Trial Register (ChiCTR) website and for making sure that no data are missed. However, if this becomes inevitable, we will use various processing methods to handle the issue. We will also perform a sensitivity analysis of the test results simultaneously. 2.21 Adherence to study interventions Throughout the study, participants will be given clear oral and written instructions to ensure proper adherence to the intervention. We will closely monitor their progress and provide personalized guidance when necessary. Any unused medication will be collected, documented, and returned as part of the study protocol. 2.22 Data analysis Data analyses will be performed using SPSS 24.0 software. Continuous variables with a normal distribution will be analyzed using Student’s t -test, while non-normally distributed variables will be analyzed using the Wilcoxon rank-sum test. Categorical variables will be analyzed using Pearson’s χ 2 test. Continuous variables will be presented as mean ± standard deviation, while categorical variables will be presented as percentages. Values with P -value ≤ 0.05 will be considered statistically significant, and all tests will be two-sided. 2.23 Frequency and plans for auditing trial conduct The trial conduct will be audited at specified frequencies by an independent team that does not include the investigators and sponsor. The details of the auditing frequency and plans are provided in Table 2. 3 Discussion For early prevention of the progression of AP to SAP, both timely diagnosis and timely treatment are crucial because of the severe clinical manifestations of SAP and its high mortality rates [34] . TCM has been recognized as an effective alternate medical practice that can promote and maintain the health of individuals, particularly in Asia [35, 36] . If successful, the proposed clinical study, which is the first randomized, double-blind, placebo-controlled, mono-center trial to evaluate the efficacy and safety of the DaXianXiong decoction in preventing the progression of AP to SAP, can pave the way for a larger multicenter trial to further investigate the efficiency and cost-effectiveness of the TCM treatment in a larger population. 3.1 Trial status The recruitment for the trial commenced in December 2023 and we expect it to conclude by December 2024. 3.2 Modification of the protocol Any modifications to the program will require the consent of both the project leader and the supervisor. After obtaining approval from the ethics committee, the sponsor and all members of the research team will be notified of the changes. 3.3 Data availability statement The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. 3.4 Limitations Indeed, the study has limitations because of the small sample size. Additionally, the mechanism path of the DaXianXiong decoction remains unclear and requires further investigation. However, these limitations provide further opportunities for expanding the findings and gaining a deeper understanding of the treatment. Declarations Author contributions D. Ren and J. Tan served as the primary investigator for this study, contributing to its conceptualization, design and drafting of the manuscript. Y. Zhou and Z.Luo was involved in the conception and critical revision for the significant intellectual content. D. 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Clin Nutr, 2020, 39(3): 612-631.https://doi.org/10.1016/j.clnu.2020.01.004 Qi D, Yu B, Huang J, et al. Meta-Analysis of Early Enteral Nutrition Provided Within 24 Hours of Admission on Clinical Outcomes in Acute Pancreatitis [J]. JPEN J Parenter Enteral Nutr, 2018, 42(7): 1139-1147.https://doi.org/10.1002/jpen.1139 Li X, Ma F, Jia K. Early enteral nutrition within 24 hours or between 24 and 72 hours for acute pancreatitis: evidence based on 12 RCTs [J]. Med Sci Monit, 2014, 20: 2327-2335.https://doi.org/10.12659/msm.892770 Bakker O J, van Brunschot S, Farre A, et al. Timing of enteral nutrition in acute pancreatitis: meta-analysis of individuals using a single-arm of randomised trials [J]. Pancreatology, 2014, 14(5): 340-346.https://doi.org/10.1016/j.pan.2014.07.008 Crockett S D, Wani S, Gardner T B, et al. American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis [J]. Gastroenterology, 2018, 154(4): 1096-1101.https://doi.org/10.1053/j.gastro.2018.01.032 Xu X, Xu H, Shang Y, et al. Development of the general chapters of the Chinese Pharmacopoeia 2020 edition: A review [J]. J Pharm Anal, 2021, 11(4): 398-404.https://doi.org/10.1016/j.jpha.2021.05.001 Mahmoudi S, Martin S, Koch V, et al. Value of Dual-Energy CT Perfusion Analysis in Patients with Acute Pancreatitis: Correlation and Discriminative Diagnostic Accuracy with Varying Disease Severity [J]. Diagnostics (Basel), 2022, 12(11).https://doi.org/10.3390/diagnostics12112601 Mortele K J, Wiesner W, Intriere L, et al. A modified CT severity index for evaluating acute pancreatitis: improved correlation with patient outcome [J]. AJR Am J Roentgenol, 2004, 183(5): 1261-1265.https://doi.org/10.2214/ajr.183.5.1831261 Harshit Kumar A, Singh Griwan M. A comparison of APACHE II, BISAP, Ranson's score and modified CTSI in predicting the severity of acute pancreatitis based on the 2012 revised Atlanta Classification [J]. Gastroenterol Rep (Oxf), 2018, 6(2): 127-131.https://doi.org/10.1093/gastro/gox029 Rau B, Steinbach G, Baumgart K, et al. Serum amyloid A versus C-reactive protein in acute pancreatitis: clinical value of an alternative acute-phase reactant [J]. Crit Care Med, 2000, 28(3): 736-742.https://doi.org/10.1097/00003246-200003000-00022 Mäkelä J T, Eila H, Kiviniemi H, et al. Computed tomography severity index and C-reactive protein values predicting mortality in emergency and intensive care units for patients with severe acute pancreatitis [J]. Am J Surg, 2007, 194(1): 30-34.https://doi.org/10.1016/j.amjsurg.2006.08.089 van den Berg F F, de Bruijn A C, van Santvoort H C, et al. Early laboratory biomarkers for severity in acute pancreatitis; A systematic review and meta-analysis [J]. Pancreatology, 2020, 20(7): 1302-1311.https://doi.org/10.1016/j.pan.2020.09.007 Sendler M, Weiss F U, Golchert J, et al. Cathepsin B-Mediated Activation of Trypsinogen in Endocytosing Macrophages Increases Severity of Pancreatitis in Mice [J]. Gastroenterology, 2018, 154(3): 704-718.e710.https://doi.org/10.1053/j.gastro.2017.10.018 SHIPING H R X Q SClinical Effect of Daxianxiong Decoction Retention Enema Ultrasonic Evaluation on Acute Pancreatitis[J].Journal of Emergency in Traditional Chinese Medicine,2015: 710-712 Froghi F, Soggiu F, Ricciardi F, et al. Ward-based Goal-Directed Fluid Therapy (GDFT) in Acute Pancreatitis (GAP) trial: study protocol for a feasibility randomised controlled trial [J]. BMJ Open, 2019, 9(10): e028783.https://doi.org/10.1136/bmjopen-2018-028783 Hao P, Jiang F, Cheng J, et al. Traditional Chinese Medicine for Cardiovascular Disease: Evidence and Potential Mechanisms [J]. J Am Coll Cardiol, 2017, 69(24): 2952-2966.https://doi.org/10.1016/j.jacc.2017.04.041 Dai Y J, Wan S Y, Gong S S, et al. Recent advances of traditional Chinese medicine on the prevention and treatment of COVID-19 [J]. Chin J Nat Med, 2020, 18(12): 881-889.https://doi.org/10.1016/s1875-5364(20)60031-0 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4443242","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":310048114,"identity":"3ca565dd-a581-4eaf-875a-7a900afff2e2","order_by":0,"name":"Dongsheng Ren","email":"","orcid":"","institution":"Chongqing Traditional Chinese Medicine Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dongsheng","middleName":"","lastName":"Ren","suffix":""},{"id":310048115,"identity":"92780d4d-82d3-42c1-a7a2-e98de1be676c","order_by":1,"name":"Judan Tan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuElEQVRIiWNgGAWjYBACPiA+IPHDhoeBHcjiIUYLGwMD4wHLnjQeBmYStDAfqGA7zECCFokcgwM3eM7L8DczH5N4w2Anp9tAUEtawsEZFrd5JA6zpUnOYUg2NjtAUEvygcMSPLd5DJh5zKR5GA4kbiOsJbHh8B+2cyRpST5wQILtAClaeJ4lHJDsSQb5JdlyjgERfuFnzzH+IPHDzp6/vfngjTcVdnIEtaABA9KUj4JRMApGwSjAAQD60jbxj0oWcgAAAABJRU5ErkJggg==","orcid":"","institution":"Chongqing Traditional Chinese Medicine Hospital","correspondingAuthor":true,"prefix":"","firstName":"Judan","middleName":"","lastName":"Tan","suffix":""},{"id":310048116,"identity":"ab9aa45f-b1de-4e44-a867-4b0eddaf6029","order_by":2,"name":"Yun Lu","email":"","orcid":"","institution":"Hospital of Chengdu University of TCM","correspondingAuthor":false,"prefix":"","firstName":"Yun","middleName":"","lastName":"Lu","suffix":""},{"id":310048117,"identity":"dbc92ef6-9ad8-4f9a-872d-56d8d3afe862","order_by":3,"name":"Zhenchun Luo","email":"","orcid":"","institution":"Chongqing Traditional Chinese Medicine Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhenchun","middleName":"","lastName":"Luo","suffix":""},{"id":310048118,"identity":"cf79fbcb-d2b2-407a-94af-02e0803782f6","order_by":4,"name":"Yuling Zhou","email":"","orcid":"","institution":"Chongqing Traditional Chinese Medicine Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuling","middleName":"","lastName":"Zhou","suffix":""},{"id":310048119,"identity":"23d34b19-f9f1-40e5-8978-f23dd983265c","order_by":5,"name":"Qinghai Liu","email":"","orcid":"","institution":"Chongqing Traditional Chinese Medicine Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qinghai","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2024-05-19 06:53:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4443242/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4443242/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57953299,"identity":"d0277ce5-32a1-494d-9a4a-9193c93d4968","added_by":"auto","created_at":"2024-06-07 23:01:38","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":201242,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eWorkflow\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"figure1workflow.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4443242/v1/19c504e0697b62c5b8d4ec9d.jpg"},{"id":57953300,"identity":"d3cb7b93-1129-46a4-8052-084fc7686387","added_by":"auto","created_at":"2024-06-07 23:01:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":392434,"visible":true,"origin":"","legend":"\u003cp\u003eDaXianXiong decoction\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4443242/v1/5d76be69e6bd0945d0461125.png"},{"id":64934013,"identity":"fdb2a773-5844-4b50-a137-24cb78928562","added_by":"auto","created_at":"2024-09-20 14:24:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":957440,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4443242/v1/69b06bea-d91a-413e-8c46-645ef8502859.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy of DaXianXiong decoction in preventing the progression of severity of acute pancreatitis: Study protocol for a randomized controlled trial","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eAcute pancreatitis (AP) is a prevalent exocrine inflammatory disorder of the pancreas. It is characterized by severe abdominal pain and multi-organ dysfunction, which can lead to pancreatic necrosis and persistent organ failure. The worldwide incidence of AP is typically 30\u0026ndash;40 cases per 100,000 population, with more than 2000 fatalities per year\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e[1]\u003c/sup\u003e. It is the third most frequent principal diagnosis related to gastrointestinal and pancreatic conditions among hospital admissions in the United States\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e[2]\u003c/sup\u003e and the fourth most common in China\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e[3]\u003c/sup\u003e. Treatment for AP accounts for a significant proportion of healthcare utilization and expenditure\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e[4]\u003c/sup\u003e. Severe acute pancreatitis (SAP) is the most life-threatening form of AP. The Revised Atlanta Classification of Severity of AP defines SAP as the persistent organ failure for \u0026ge;48 h\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e[5]\u003c/sup\u003e. SAP is considered the advanced stage of AP and is characterized by severe clinical manifestations and complications. Approximately 20% of patients diagnosed with AP eventually develop SAP \u003csup\u003e[6]\u003c/sup\u003e. Although significant advancements have been made in the treatment of SAP, the mortality rate is still quite high (20\u0026ndash;40%) \u003csup\u003e[1, 7, 8]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eDuring AP, the premature activation of trypsin within the pancreatic acinar cells triggers pancreatic autodigestion, resulting in a localized inflammatory response. This inflammatory process releases both pro- and anti-inflammatory cytokines as well as other inflammatory mediators, which attract neutrophils, monocytes, and lymphocytes that infiltrate the pancreas\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e[9]\u003c/sup\u003e. As a result, the local inflammatory response amplifies and disseminates through the systemic circulation, resulting in a systemic inflammatory response \u003csup\u003e[10]\u003c/sup\u003e. Systemic inflammation initially manifests as the systemic inflammatory response syndrome (SIRS). Patients with persistent SIRS are at an increased risk of developing systemic organ dysfunction, which may progress to organ failure\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e[7, 11]\u003c/sup\u003e. Therefore, the success or failure of the early treatment for AP determines whether complications such as secondary infections, local abscesses, cysts, and necrosis develop in the later stages of the disease.\u003c/p\u003e\n\u003cp\u003eCurrently, apart from supportive care such as maintaining an adequate circulatory volume, offering oxygen supplementation, utilizing mechanical ventilation (when necessary), and close monitoring for respiratory/cardiovascular/renal insufficiency, the crucial intensive care for the early treatment for SAP is typically conducted through two main methods. Adequate fluid resuscitation is the first treatment to be considered and applied. Although it is the primary treatment for shock in SAP, it can also cause interstitial edema. This injury can trigger acute respiratory distress syndrome and abdominal compartment syndrome, leading to the development of multiple organ dysfunction syndrome (MODS) \u003csup\u003e[12]\u003c/sup\u003e. At present, there is no consensus on the type, rate, dosage, and endpoint of fluid resuscitation. More research is required to further improve the fluid therapy strategies in each phase of the treatment for SAP, including resuscitation, optimization, stabilization, and evacuation \u003csup\u003e[13]\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe second method involves the use of strategies for accelerating the recovery of gastrointestinal functions in AP. These strategies include fasting with nasogastric drainage to eliminate gastric secretions and using anticholinergic agents or H2-blocking agents and somatostatin to inhibit pancreatic secretion. Apart from actively maintaining the hemodynamic stability, ensuring effective blood perfusion, and reducing the workload on the pancreas, there are currently no other effective interventions that directly act on the gastrointestinal tract for promoting the recovery of gastrointestinal motility. In addition, early enteral nutrition therapy is not widely practiced in SAP because it may lead to complications such as nausea, vomiting, and ileus\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003csup\u003e[14]\u003c/sup\u003e. Most clinical institutions in China still rely primarily on fasting and gastrointestinal decompression to manage AP in its early stages.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDuring the early stages of the AP, interventions to block the inflammatory storm, restore gastrointestinal motility, complement the deficiencies of conventional Western medicine treatment, slow down its progression to SAP so as to improve the prognosis, and reduce mortality are crucial. However, very few reports are available on the interventions for SAP. Chinese herbal medicines (CHMs) are rich in bioactive compounds and are widely employed in clinical practice worldwide \u003csup\u003e[15]\u003c/sup\u003e. A large number of CHMs, including Chinese pleiotropic natural products and formulas, with significant effects on AP have been identified. These CHMs target various proteins or biological networks involved in the pathogenesis of AP \u003csup\u003e[16-18]\u003c/sup\u003e. In addition, CHMs have a broader approach, as they target multiple pathways and networks involved in the disease process \u003csup\u003e[19]\u003c/sup\u003e. Therefore, they are more promising therapeutic agents than Western medicine, which typically have single specific targets.\u003c/p\u003e\n\u003cp\u003eDaXianXiong decoction, originally documented in the classical Chinese medical book \u0026ldquo;\u003cem\u003eShang Han Lun\u003c/em\u003e\u0026rdquo; (\u003cem\u003eTreatise on Febrile Diseases\u003c/em\u003e), is a notable herbal formula traditionally used for clearing internal heat in the gastrointestinal tract. This decoction consists of Da Huan\u003cem\u003eg [Rhei Radix et Rhizoma],\u003c/em\u003e Mang Xiao\u003cem\u003e\u0026nbsp;[Natrii Sulfas],\u003c/em\u003e and Gan Sui\u003cem\u003e\u0026nbsp;[Kansui Radix]\u003c/em\u003e. It is being used in China for more than three decades as a traditional treatment for AP. Traditional beliefs regarding the management of acute pancreatitis advocated for \u0026quot;bowel rest\u0026quot; to prevent further irritation of the inflamed pancreas. However, contemporary evidence supports the contrary approach, emphasizing the benefits of early feeding. The SEPEN guidelines recommend that enteral nutrition (EN) should be initiated early, within 24-72 hours after admission for patients with acute pancreatitis, to prevent intolerance to oral feeding\u003csup\u003e[20]\u003c/sup\u003e. This approach is feasible, safe, tolerable, and has significant clinical benefits in terms of mortality, organ failure, and infectious complications for both time-points compared with delayed EN\u003csup\u003e[21-23]\u003c/sup\u003e. Similarly, the AGA guidelines also recommend early (within 24 hours) initiation of enteral feeding rather than keeping patients nil per os\u003csup\u003e[24]\u003c/sup\u003e. In China, the \u0026quot;Chinese Guidelines for the Diagnosis and Treatment of Acute Pancreatitis 2021\u0026quot; emphasize the early initiation of enteral nutrition therapy (within 24 hours) as safe and effective, which can reduce complications and mortality rates. All of this evidence makes it possible to consider the early administration of traditional Chinese medicine formulations to patients with acute pancreatitis. However, the clinical efficacy of DaXianXiong decoction in preventing the progression to SAP is still unclear because of the lack of high-quality randomized controlled trials.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe primary objective of this study is to evaluate the therapeutic efficacy of traditional Chinese medicine (TCM) in the treatment of AP to establish an evidence-based framework for developing a standardized diagnostic and treatment approach. Specifically, this study aims to: (1) determine the efficacy of DaXianXiong decoction in preventing the progression of AP to SAP; (2) elucidate the effects of DaXianXiong decoction in reducing the levels of inflammation factors of AP; (3) clarify the efficacy of the decoction in improving the clinical symptoms of gastrointestinal dysfunction and improve enteral nutrition; and (4) investigate the efficacy and safety of the decoction by identifying related complications.\u0026nbsp;\u003c/p\u003e"},{"header":"2 Methods/design","content":"\u003cp\u003e2.1 Trial design\u003c/p\u003e\n\u003cp\u003eThis is a single-center, randomized, double-blind, placebo-controlled study. It adheres to the guidelines mentioned in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement (Supplementary Material S1).\u003c/p\u003e\n\u003cp\u003eDuring the trial, all eligible participants will be randomly assigned to either the intervention group or the placebo group. Both groups will receive the standard treatment for AP. A detailed workflow depicting the study process is presented in Figure 1. The trial is supported by the Chongqing Special Incentive Program for Scientific Research Institutions Program (No. jxyn2021215). The study sponsor does not have any role in study-related activities or in the final publication of the study.\u003c/p\u003e\n\u003cp\u003e2.2Study population\u003c/p\u003e\n\u003cp\u003ePatients will be enrolled from the intensive care unit in Chongqing Traditional Chinese Medicine Hospital, a grade III level A hospital in China.\u003c/p\u003e\n\u003cp\u003e2.3 Recruitment of participants\u003c/p\u003e\n\u003cp\u003eThe study group will be recruiting the participants and handle their allocation into their respective groups. Eligible patients who are willing to participate in the trial will be provided with an informed consent form with details of the study objectives, procedures, and potential risks (Supplementary Material S2). Patient privacy will be strictly maintained. Physical documents related to the study will be secured in a locked office.\u003c/p\u003e\n\u003cp\u003e2.4 Patient and public involvement\u003c/p\u003e\n\u003cp\u003eOur research will not include any design, implementation, and reporting from patients or public.\u003c/p\u003e\n\u003cp\u003e2.5 Inclusion criteria\u003c/p\u003e\n\u003cp\u003eWe will select patients based on the following inclusion criteria:\u003c/p\u003e\n\u003col class=\"decimal_type\"\u003e\n \u003cli\u003ePresence of AP as confirmed using the revised Atlanta classification (Table 1).\u003c/li\u003e\n \u003cli\u003e18\u0026ndash;75 years of age.\u003c/li\u003e\n \u003cli\u003eTime of illness onset should be under 24 h.\u003c/li\u003e\n\u003c/ol\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"680\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eTable 1. Diagnostic criteria for acute pancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eFulfill two of the three criteria mentioned below\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.370044052863436%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"91.62995594713657%\" valign=\"top\"\u003e\n \u003cp\u003eUpper abdominal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.370044052863436%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"91.62995594713657%\" valign=\"top\"\u003e\n \u003cp\u003eSerum amylase or lipase (or both) \u0026gt;3 times the upper limit of normal values\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.370044052863436%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"91.62995594713657%\" valign=\"top\"\u003e\n \u003cp\u003eTypical findings on imaging: contrast-enhanced CT (CECT) or MRI or abdominal ultrasound\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e2.6 Exclusion criteria\u003c/p\u003e\n\u003cp\u003eWe will use the following exclusion criteria:\u003c/p\u003e\n\u003cp\u003e1. Patients with severe diseases affecting vital organs, such as liver dysfunction, heart failure, and malignant tumors, will be excluded.\u003c/p\u003e\n\u003cp\u003e2. Patients participating in another study within 3 months to enrollment will be excluded.\u003c/p\u003e\n\u003cp\u003e3. Those with known allergy to any of the prescribed medicine will be excluded.\u003c/p\u003e\n\u003cp\u003e4. Pregnant or lactating women will also be excluded.\u003c/p\u003e\n\u003cp\u003e2.7 Withdrawal cases\u003c/p\u003e\n\u003cp\u003eParticipants can withdraw from the study at any point without any repercussions. If a participant discontinues the interventional method or decides to participate in another study, they will no longer be included in the present study. However, even when a participant withdraws from the study, the data collected up to that point will be retained and included in the analysis, unless specifically requested otherwise. The withdrawal and non-compliance of participants will also be documented. Incomplete data will be addressed based on the withdrawal rate. If the rate is \u0026lt;5\u0026ndash;10%, we will perform data cleaning. If the withdrawal rate exceeds 10%, the missing data will be managed through imputation, intention-to-treat analysis, and sensitivity analysis.\u003c/p\u003e\n\u003cp\u003e2.8 Management of dropout cases\u003c/p\u003e\n\u003cp\u003eAll subjects who provide informed consent and meet the eligibility criteria for enrollment in this randomized controlled trial (RCT), irrespective of the timing or reasons for their withdrawal later, will be categorized as dropouts if they are lost to follow-up. However, patients who discontinued the treatment regimen because of complete symptom remission will not be considered dropouts. The investigators will comprehensively document the reasons for each dropout in the case report form (CRF). Real-world circumstances, including adverse events (AEs), will be accounted for during the statistical analysis. In addition, we will carefully record and preserve the data about all enrolled patients who will receive the assigned investigational medications, regardless of their withdrawal status, for observation purposes and use them as both a data archive and for intention-to-treat analysis.\u003c/p\u003e\n\u003cp\u003e2.9 Criteria for termination of the experiment\u003c/p\u003e\n\u003cp\u003eThe experiment will be terminated under the following three situations:\u003c/p\u003e\n\u003cp\u003e(1) The subjects encountered drug-related serious AEs.\u003c/p\u003e\n\u003cp\u003e(2) The subjects exhibited non-compliance with the protocol regarding the administration of the investigational drug.\u003c/p\u003e\n\u003cp\u003e(3) The investigators determine that further continuation of the trial might pose potential harm to the subjects.\u003c/p\u003e\n\u003cp\u003e2.10 Interventions\u003c/p\u003e\n\u003cp\u003eAll participants will be provided with detailed information about the study. Once informed consent is obtained and baseline assessments are completed, eligible participants will be randomly allocated to the intervention or placebo group. Throughout the study, the participants will be prohibited from using any other TCM formulation. Both groups will receive standard treatments. In addition to the standard treatment, the intervention group will receive DaXianXiong decoction (Figure 2). The constituent botanical drugs of the DaXianXiong decoction are listed in Table 2. The DaXianXiong decoction includes three herbs, namely, \u003cem\u003eRhei Radix et Rhizoma\u003c/em\u003e(Shengdahuang) 30 g, \u003cem\u003eNatrii Sulfas\u003c/em\u003e(Mangxiao) 30 g, and \u003cem\u003eKansui Radix\u003c/em\u003e(Gansui) 3 g. The dosage of each herb was determined based on the guidelines outlined in \u003cem\u003eThe Chinese Pharmacopoeia\u003c/em\u003e (Ch. P), 2020 edition \u003csup\u003e[25]\u003c/sup\u003e.\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"751\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"9\" valign=\"top\"\u003e\n \u003cp\u003eTable 2 Components of DaXianXiong Decoction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.788282290279627%\" valign=\"top\"\u003e\n \u003cp\u003eDrug name\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.589880159786951%\" valign=\"top\"\u003e\n \u003cp\u003ePart this formula use\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.584553928095872%\" valign=\"top\"\u003e\n \u003cp\u003eLocation of manufacture\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.057256990679095%\" valign=\"top\"\u003e\n \u003cp\u003eDose (g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.117177097203728%\" valign=\"top\"\u003e\n \u003cp\u003eUsage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.712383488681757%\" valign=\"top\"\u003e\n \u003cp\u003eMedicine form, dosage, frequency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.51664447403462%\" valign=\"top\"\u003e\n \u003cp\u003eRegistration status (Y/N)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.649800266311585%\" valign=\"top\"\u003e\n \u003cp\u003eQuality control report (Y/N)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.984021304926765%\" valign=\"top\"\u003e\n \u003cp\u003eStorage condition\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.788282290279627%\" valign=\"top\"\u003e\n \u003cp\u003eDa Huan\u003cem\u003eg [Rhei Radix et Rhizoma]\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.589880159786951%\" valign=\"top\"\u003e\n \u003cp\u003eRoots\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.584553928095872%\" valign=\"top\"\u003e\n \u003cp\u003eSichuan Neautus Co., Ltd., Sichuan, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.057256990679095%\" valign=\"top\"\u003e\n \u003cp\u003e7.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.117177097203728%\" valign=\"top\"\u003e\n \u003cp\u003eNasal feeding or oral administration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.712383488681757%\" valign=\"top\"\u003e\n \u003cp\u003ePowder, dissolved in 50 mL of warm water, every 6 h, lasts 48 h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.51664447403462%\" valign=\"top\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.649800266311585%\" valign=\"top\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.984021304926765%\" valign=\"top\"\u003e\n \u003cp\u003ePowder: stored in the pharmacy department; 18\u0026ndash;20 \u0026deg;C and 45\u0026ndash;75% humidity\u003c/p\u003e\n \u003cp\u003eDecoction: kept in the ward; 26\u0026ndash;28\u0026deg;C and 50\u0026ndash;60% humidity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.788282290279627%\" valign=\"top\"\u003e\n \u003cp\u003eMang Xia\u003cem\u003eo [Natrii Sulfas]\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.589880159786951%\" valign=\"top\"\u003e\n \u003cp\u003eMineral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.584553928095872%\" valign=\"top\"\u003e\n \u003cp\u003eSichuan Neautus Co., Ltd., Sichuan, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.057256990679095%\" valign=\"top\"\u003e\n \u003cp\u003e7.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.117177097203728%\" valign=\"top\"\u003e\n \u003cp\u003eNasal feeding or oral administration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.712383488681757%\" valign=\"top\"\u003e\n \u003cp\u003ePowder, dissolved in 50 mL of warm water, every 6 h, lasts 48 h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.51664447403462%\" valign=\"top\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.649800266311585%\" valign=\"top\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.984021304926765%\" valign=\"top\"\u003e\n \u003cp\u003ePowder: stored in the pharmacy department; 18\u0026ndash;20 \u0026deg;C and 45\u0026ndash;75% humidity\u003c/p\u003e\n \u003cp\u003eDecoction: kept in the ward; 26\u0026ndash;28 \u0026deg;C and 50\u0026ndash;60% humidity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"8.788282290279627%\" valign=\"top\"\u003e\n \u003cp\u003eGan Sui\u003cem\u003e[Kansui Radix]\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.589880159786951%\" valign=\"top\"\u003e\n \u003cp\u003eRoots\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.584553928095872%\" valign=\"top\"\u003e\n \u003cp\u003eSichuan Neautus Co., Ltd., Sichuan, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.057256990679095%\" valign=\"top\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.117177097203728%\" valign=\"top\"\u003e\n \u003cp\u003eNasal feeding or oral administration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.712383488681757%\" valign=\"top\"\u003e\n \u003cp\u003ePowder, dissolved in 50 mL of warm water, every 6 h, lasts 48 h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.51664447403462%\" valign=\"top\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.649800266311585%\" valign=\"top\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.984021304926765%\" valign=\"top\"\u003e\n \u003cp\u003ePowder: stored in the pharmacy department; 18\u0026ndash;20 \u0026deg;C and 45\u0026ndash;75% humidity\u003c/p\u003e\n \u003cp\u003eDecoction: kept in the ward; 26\u0026ndash;28\u0026deg;C and 50\u0026ndash;60% humidity\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eThe Department of Pharmacy of the CQTCM Hospital will perform the following processing steps on the DaXianXiong decoction: water extraction, separation, concentration, drying, and granulation. Each sachet will contain 10.5 g of powdered decoction. The production and processing procedures will be conducted as per the guidelines specified in the Ch. P of \u003cem\u003eThe Chinese Pharmacopoeia\u003c/em\u003e. The powder will be processed and filled in standardized clean production workshops. The treatment method will involve nasal feeding or oral administration of the DaXianXiong decoction four times a day, once every 6 h, and dissolved in 50 mL of warm boiled water. The course of the treatment will be 48 h.\u003c/p\u003e\n\u003cp\u003eWe will design placebos similar to the intervention drugs in terms of the shape, color, smell, and solubility, so that participants have a similar sensory experience. Placebos have no efficacy or side effects. They will also be produced by the Department of Pharmacy of the CQTCM Hospital.\u003c/p\u003e\n\u003cp\u003eIn the event of a serious AE or allergic reaction caused by the research medication, the principal investigator will open the emergency envelope and discontinue the trial for that participant. Details of the event and unblinding will be recorded in the CRF, and the patient will receive appropriate treatment. The relevant departments and ethics committees will be promptly notified within 24 h.\u003c/p\u003e\n\u003cp\u003e2.11 Randomization\u003c/p\u003e\n\u003cp\u003eRandomization will be conducted by an independent statistician using SPSS Statistics 26.0 software. Using a predetermined random number table, 60 participants will be randomly assigned to either the intervention or placebo group. A random distribution table will be created in triplicate to ensure accuracy and reliability of our random scheme, and its copies will be provided to the project leader, pharmacist and statistician for reference and implementation.\u003c/p\u003e\n\u003cp\u003e2.12 Blinding\u003c/p\u003e\n\u003cp\u003eThis study will be conducted as a double-blind trial to ensure that both participants and researchers remain unaware of group assignments. Each participant will be provided with a package containing medication numbers and labels. Random numbers will be securely sealed in double opaque envelopes and managed by a specialist (ZCL). Each participant will be provided with their designated emergency letter, which will be carefully kept in a secure storage until the study is completed.\u003c/p\u003e\n\u003cp\u003e2.13 Outcome measures\u003c/p\u003e\n\u003cp\u003eThe outcome measures will be determined at various time points throughout the study, including baseline (T0), 24 h after the final treatment (T1, endpoint 1), 3 days after the final treatment (T2, endpoint 2), 7 days after the final treatment (T3, endpoint 3), and 28 days after the final treatment (T4, final endpoint). The data collection and assessment schedule are listed in Table 3.\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\" width=\"1039\" height=\"831\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e2.14 Primary outcomes\u003c/p\u003e\n\u003cp\u003e2.14.1 Occurrence of SAP\u003c/p\u003e\n\u003cp\u003e1) SAP Incidence: It will be determined using the following formula:\u003c/p\u003e\n\u003cp\u003eSAP incidence = number of cases of SAP patients/number of cases of total patients100%.\u003c/p\u003e\n\u003cp\u003e2) Modified computed tomography severity index (CTSI): According to the analysis of the area under the curve, the modified CTSI demonstrates the highest accuracy in predicting SAP. It is a simpler and more accurate scoring tool, showing a stronger statistical correlation with factors such as length of hospital stay, development of infection, organ failure, and mortality\u003csup\u003e[26, 27]\u003c/sup\u003e. It will be determined using the following formula:\u003c/p\u003e\n\u003cp\u003eCTSI = (original scorecurrent score)/original score100%.\u003c/p\u003e\n\u003cp\u003e3) APACHE II score: The APACHE II (Acute Physiology and Chronic Health Evaluation II) scoring system has a high sensitivity and exhibits a negative predictive value in predicting pancreatic necrosis and organ failure. This makes it an ideal prognostic tool for assessing the severity of AP and in guiding clinical decision-making, particularly in resource-limited developing countries\u003csup\u003e[28]\u003c/sup\u003e. It is determined using the following formula:\u003c/p\u003e\n\u003cp\u003eAPACHE II = (original scorecurrent score)/original score100%.\u003c/p\u003e\n\u003cp\u003e4) Modified Marshall score: Organ failure plays a significant role in the severity of AP. The Revised Atlanta classification recommends the use of the Modified Marshall scoring system as the primary tool for assessing organ failure. The Modified Marshall scoring system encompasses scoring systems for respiratory, cardiovascular, and renal systems to evaluate organ dysfunction in AP\u003csup\u003e[9]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e2.14.2 Levels of inflammation factor\u003c/p\u003e\n\u003cp\u003eThe level of an inflammation factor is a surrogate marker for important clinical endpoint variables in AP. Multiple studies have shown that C-reactive protein (CRP) is a good surrogate marker for SAP\u003csup\u003e[29, 30]\u003c/sup\u003e. Additionally, interleukin-6 (IL-6) is superior in predicting SAP compared to other commonly used markers such as erythrocyte sedimentation rate (ESR). The level of an inflammation factor can be determined using the following formula:\u003csup\u003e[31]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003einflammation factor = (original figurecurrent figure)/original figure100%\u003c/p\u003e\n\u003cp\u003eWe will also employ IL-1, IL-4, IL-8, and IL-10 to investigate the potential targets of the DaXianXiong decoction. In pancreatitis, cytokines such as TNF\u0026alpha; secreted by acinar cells and DAMPs play a major role in activating immune cells such as neutrophils and macrophages. This process leads to increased pancreatic damage, systemic inflammation, and the development of SAP\u003csup\u003e[12, 32]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e2.15 Secondary outcomes\u003c/p\u003e\n\u003cp\u003e2.15.1 Gastrointestinal dysfunction treatment effect\u003c/p\u003e\n\u003cp\u003eA comprehensive assessment of the gastrointestinal function is essential for the early detection of SAP. This assessment involves evaluating symptoms such as abdominal pain, distention, hematemesis, hematochezia, number of independent defecations, and digestive function. Signs such as tenderness, rebound tenderness, muscle tension, and the number of bowel sounds are also considered. Additionally, scores such as the gastrointestinal function score used in MODS diagnostic criteria can provide a standardized measurement of the gastrointestinal function.\u003c/p\u003e\n\u003cp\u003e2.15.2 Curative effects\u003c/p\u003e\n\u003cp\u003eGiven the constraints of ethics and experimental techniques, certain indicators are valuable for assessing the improvements and prognosis of AP patients. These include the time to bowel sound recovery, time to first defecation, and the gastrointestinal function score. These measures provide predictive information regarding the gastrointestinal function and can be useful in evaluating the prognosis of AP patients. We will also record hospitalization costs and duration.\u003c/p\u003e\n\u003cp\u003e2.16 Safety outcomes\u003c/p\u003e\n\u003cp\u003eThe safety outcomes of the investigational medication were assessed at T0, T1, T2, T3, and T4 by considering the following:\u003c/p\u003e\n\u003cp\u003e1) Measurement of vital signs: Heart rate, blood pressure, temperature, and respiration.\u003c/p\u003e\n\u003cp\u003e2) Laboratory tests: Blood routine, stool routine, and urine routine.\u003c/p\u003e\n\u003cp\u003e3) Liver function tests: Alanine aminotransferase, aspartate aminotransferase, and bilirubin.\u003c/p\u003e\n\u003cp\u003e4) Renal function tests: Urea nitrogen and creatinine.\u003c/p\u003e\n\u003cp\u003e5) Electrocardiogram.\u003c/p\u003e\n\u003cp\u003e2.17 Adverse events\u003c/p\u003e\n\u003cp\u003eAll AEs will be carefully documented, including the start and end dates, severity, relationship to the study drug, and participant\u0026rsquo;s continued involvement in the study. Any serious AE will be promptly reported to the Research Ethics Committee within 24 h. If an AE occurred, the patient will be advised to discontinue the use of the decoction, and the researchers will evaluate whether it is related to the formulation. Emergency safety measures will be implemented, if necessary, to ensure the well-being of participants. Persistence of AEs will be monitored until their resolution. Please note that AEs are not the complications clearly related to AP, such as acute respiratory distress syndrome, abdominal compartment syndrome, and acute kidney injury.\u003c/p\u003e\n\u003cp\u003e2.18 Sample size\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\" width=\"827\" height=\"151\"\u003e\u003c/p\u003e\n\u003cp\u003ewhere \u003cem\u003e\u0026mu;\u003c/em\u003e\u003csub\u003e1\u003c/sub\u003e and \u003cem\u003e\u0026mu;\u003csub\u003e2\u003c/sub\u003e\u003c/em\u003e are the means of the intervention and placebo groups, respectively, and \u003cem\u003e\u0026sigma;\u003c/em\u003e is the standard deviation. The study aims to maintain the type I error probability (\u003cem\u003e\u0026alpha;\u003c/em\u003e) to \u0026lt;5% and the type II error probability (\u003cem\u003e\u0026beta;\u003c/em\u003e) to \u0026lt;10%, with the \u003cem\u003e\u0026alpha;\u003c/em\u003e at 0.05 and the \u003cem\u003e\u0026beta;\u003c/em\u003e at 0.1. To determine the sample size, we referred to literature reports in Chinese \u003csup\u003e[33]\u003c/sup\u003e on the use of DaXianXiong decoction for the treatment of AP. We used the time blood amylase took to return to the normal levels to determine the clinical efficacy of the decoction. We fixed the total sample size for the study at 60. We allocated 30 participants to the intervention group and the remaining 30 to the placebo group.\u003c/p\u003e\n\u003cp\u003e2.19 Data and sample collection\u003c/p\u003e\n\u003cp\u003eTo minimize selection bias, three study members will receive comprehensive training on the criteria and methods used for case collection. Detailed records of participant medication will be collected, and any interfering or contaminating factors will be excluded from the statistical analysis.\u003c/p\u003e\n\u003cp\u003eParticipants will be provided with a consent form with a clear outline of the use of their data, allowing them to choose whether to continue participating or withdraw from the trial. Biological specimens collected for storage will be handled according to ethical guidelines and they will be destroyed after their intended use.\u003c/p\u003e\n\u003cp\u003e2.20 Data management and monitoring\u003c/p\u003e\n\u003cp\u003eAn independent Data and Safety Monitoring Board will be established to monitor the conduct and safety of the study. Two of our research team members will be responsible for updating our clinical trial-related information into the Chinese Clinical Trial Register (ChiCTR) website and for making sure that no data are missed. However, if this becomes inevitable, we will use various processing methods to handle the issue. We will also perform a sensitivity analysis of the test results simultaneously.\u003c/p\u003e\n\u003cp\u003e2.21 Adherence to study interventions\u003c/p\u003e\n\u003cp\u003eThroughout the study, participants will be given clear oral and written instructions to ensure proper adherence to the intervention. We will closely monitor their progress and provide personalized guidance when necessary. Any unused medication will be collected, documented, and returned as part of the study protocol.\u003c/p\u003e\n\u003cp\u003e2.22 Data analysis\u003c/p\u003e\n\u003cp\u003eData analyses will be performed using SPSS 24.0 software. Continuous variables with a normal distribution will be analyzed using Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test, while non-normally distributed variables will be analyzed using the Wilcoxon rank-sum test. Categorical variables will be analyzed using Pearson\u0026rsquo;s \u003cem\u003e\u0026chi;\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e test. Continuous variables will be presented as mean \u0026plusmn; standard deviation, while categorical variables will be presented as percentages. Values with \u003cem\u003eP\u003c/em\u003e-value \u0026le; 0.05 will be considered statistically significant, and all tests will be two-sided.\u003c/p\u003e\n\u003cp\u003e2.23 Frequency and plans for auditing trial conduct\u003c/p\u003e\n\u003cp\u003eThe trial conduct will be audited at specified frequencies by an independent team that does not include the investigators and sponsor. The details of the auditing frequency and plans are provided in Table 2.\u003c/p\u003e"},{"header":"3 Discussion ","content":"\u003cp\u003eFor early prevention of the progression of AP to SAP, both timely diagnosis and timely treatment are crucial because of the severe clinical manifestations of SAP and its high mortality rates \u003csup\u003e[34]\u003c/sup\u003e. TCM has been recognized as an effective alternate medical practice that can promote and maintain the health of individuals, particularly in Asia \u003csup\u003e[35, 36]\u003c/sup\u003e. If successful, the proposed clinical study, which is the first randomized, double-blind, placebo-controlled, mono-center trial to evaluate the efficacy and safety of the DaXianXiong decoction in preventing the progression of AP to SAP, can pave the way for a larger multicenter trial to further investigate the efficiency and cost-effectiveness of the TCM treatment in a larger population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.1 Trial status\u003c/p\u003e\n\u003cp\u003eThe recruitment for the trial commenced in December 2023 and we expect it to conclude by December 2024.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.2 Modification of the protocol\u003c/p\u003e\n\u003cp\u003eAny modifications to the program will require the consent of both the project leader and the supervisor. After obtaining approval from the ethics committee, the sponsor and all members of the research team will be notified of the changes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.3 Data availability statement\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.4 Limitations\u003c/p\u003e\n\u003cp\u003eIndeed, the study has limitations because of the small sample size. Additionally, the mechanism path of the DaXianXiong decoction remains unclear and requires further investigation. However, these limitations provide further opportunities for expanding the findings and gaining a deeper understanding of the treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eD. Ren and J. Tan served as the primary investigator for this study, contributing to its conceptualization, design and drafting of the manuscript. Y. Zhou and Z.Luo was involved in the conception and critical revision for the significant intellectual content. D. Ren and Q.Liu contributed to the study\u0026apos;s design and provided statistical guidance. J. Tan,Y. Zhou and Y. L was involved in the conception and design. All authors revised the protocol for intellectual content and approved the final manuscript. All adhere to trial authorship guidelines.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol involving human participants was reviewed and approved by the Chongqing Traditional Chinese Medicine hospital on 6 September 2022 (Ethical Review Number: 2023-KY-52).\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePetrov M S, Yadav D. Global epidemiology and holistic prevention of pancreatitis [J]. Nat Rev Gastroenterol Hepatol, 2019, 16(3): 175-184.https://doi.org/10.1038/s41575-018-0087-5\u003c/li\u003e\n\u003cli\u003ePeery A F, Crockett S D, Murphy C C, et al. Burden and Cost of Gastrointestinal, Liver, and Pancreatic Diseases in the United States: Update 2021 [J]. 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American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis [J]. Gastroenterology, 2018, 154(4): 1096-1101.https://doi.org/10.1053/j.gastro.2018.01.032\u003c/li\u003e\n\u003cli\u003eXu X, Xu H, Shang Y, et al. Development of the general chapters of the Chinese Pharmacopoeia 2020 edition: A review [J]. J Pharm Anal, 2021, 11(4): 398-404.https://doi.org/10.1016/j.jpha.2021.05.001\u003c/li\u003e\n\u003cli\u003eMahmoudi S, Martin S, Koch V, et al. Value of Dual-Energy CT Perfusion Analysis in Patients with Acute Pancreatitis: Correlation and Discriminative Diagnostic Accuracy with Varying Disease Severity [J]. Diagnostics (Basel), 2022, 12(11).https://doi.org/10.3390/diagnostics12112601\u003c/li\u003e\n\u003cli\u003eMortele K J, Wiesner W, Intriere L, et al. A modified CT severity index for evaluating acute pancreatitis: improved correlation with patient outcome [J]. 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Chin J Nat Med, 2020, 18(12): 881-889.https://doi.org/10.1016/s1875-5364(20)60031-0\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"acute pancreatitis, DaXianXiong decoction, traditional Chinese medicine, protocol, severe acute pancreatitis","lastPublishedDoi":"10.21203/rs.3.rs-4443242/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4443242/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eI\u003c/strong\u003entroduction: Developing countries are facing an increase in the incidence of acute pancreatitis (AP) — characterized by rapid onset, fast progression, high rate of severity, and high mortality. Progression of AP into severe acute pancreatitis (SAP) results in a series of complications such as organ dysfunction, local abscesses, pseudocysts, and necrosis. As no effective intervention measure has yet been developed, supportive therapy remains the major approach for the early treatment of AP. DaXianXiong decoction is a widely used TCM formulation; however, limited research is conducted on its clinical efficacy. Here, we propose a standardized clinical trial to evaluate the effectiveness and safety of DaXianXiong decoction in preventing the progression of AP to SAP.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eM\u003c/strong\u003eethods and analysis: This study is a randomized, double-blind, placebo-controlled, single-center clinical trial. Sixty eligible patients will be randomly allocated in a 1:1 ratio to the intervention group and the control group. Both groups will receive standard Western medical treatment for pancreatitis. However, the intervention group will additionally receive DaXianXiong decoction, while the control group will receive a placebo similar to the decoction. The primary outcomes will include incidence of SAP, modified CTSI score, APACHE II score, Modified Marshall score, and levels of the inflammation factor. The secondary outcomes will include the effect of the gastrointestinal dysfunction treatment. Evaluations will be conducted at baseline, 24 h after intervention, and days 3, 7, and 28 after intervention in both groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD\u003c/strong\u003eiscussion: This trial will help us assess the effectiveness and safety of DaXianXiong decoction in patients with AP.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eE\u003c/strong\u003ethics and dissemination: Ethical approval was obtained from the Ethics Committee of the First Affiliated Hospital of Chongqing Traditional Chinese Medicine University (Ethical Review Number:2023-ky-51). The results of this study will be published in a peer-reviewed journal. The study sponsor does not have any role in study-related activities or in the final publication of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eT\u003c/strong\u003erial Registration: This trial is registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/).Registration number: ChiCTR2300076885, Date: 2020-10-23, version 1.1.\u003c/p\u003e","manuscriptTitle":"Efficacy of DaXianXiong decoction in preventing the progression of severity of acute pancreatitis: Study protocol for a randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-07 23:01:33","doi":"10.21203/rs.3.rs-4443242/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":"0fc5b663-e2d2-4939-8d51-1657507694e2","owner":[],"postedDate":"June 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-24T00:38:16+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-07 23:01:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4443242","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4443242","identity":"rs-4443242","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}