Efficacy and safety of Nafamostat Mesilate for sepsis (EASNMS) : study protocol for a multicenter randomized controlled trial

Efficacy and safety of Nafamostat Mesilate for sepsis (EASNMS) : study protocol for a multicenter 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 Research Article Efficacy and safety of Nafamostat Mesilate for sepsis (EASNMS) : study protocol for a multicenter randomized controlled trial Hongyu Yang, Jianshuang Feng, Yuteng Ma, Xiaochun Ma, Xu Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6629099/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Jul, 2025 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background Sepsis is the leading cause of death in critically ill patients, with an in-hospital mortality rate of approximately 25–40%. Coagulation activation serves as an initial factor to the progression of sepsis into multiple organ dysfunction syndrome (MODS). Therefore, anticoagulant therapy may be beneficial. Both basic experiments and clinical studies have evaluated the protective effect of Nafamostat Mesilate (NM) in sepsis. However, there is still a lack of randomized controlled trials (RCTs) to further confirm the therapeutic effect and safety of NM in sepsis patients. Methods This multicenter, double-blind, RCT was designed to recruit 778 subjects who met Sepsis 3.0 criteria. Participants will be randomly assigned (1:1) to receive either intravenous administration of NM or glucose along with standard treatment. The primary outcome is the all-cause mortality rate in the intensive care unit (ICU), and the secondary outcomes include the improvement in SOFA scores, changes in Japanese Association for Acute Medicine (JAAM)/International Society on Thrombosis and Hemostasis (ISTH) scores, 28-day all-cause mortality rate, and the incidence of adverse events. The allocation will remain concealed from investigators, participants, and statisticians to maintain blinding. Discussion The EASNMS trial aims to assess the efficacy and safety of NM for treating sepsis across various regions in China. As an additional treatment option, NM may potentially enhance the prognosis of sepsis patients. Trial registration ClinicalTrials.gov NCT06078839. Registered on September 20, 2023 Sepsis Nafamostat Mesilate coagulation activation Figures Figure 1 Introduction Sepsis is a fatal condition characterized by a maladaptive host response to infection, resulting in the impairment of organ function. 1 .Sepsis not only incurs substantial healthcare costs, but also is a leading cause of death in critically ill patients, with approximately 25% to 40% of patients dying during hospitalization 2-4 . Sepsis is a clinical syndrome resulting from the interaction between coagulation, inflammation, immunity and other systems. In sepsis, pathogens invade the body and induce the production of proinflammatory cytokines, which further damage endothelial cells and promote coagulation activation. Coagulation activation occurs in most sepsis patients, including activation of the coagulation system, damage of endothelial cells, inhibition of fibrinolytic system, and even onset of disseminated intravascular coagulation (DIC) 5 6 .Patients with sepsis-associated coagulation activation can experience widespread microvascular thrombosis, potentially leading to multiple organ dysfunction 7 . A recent observational study conducted in Japan found that among 1,895 sepsis patients treated in intensive care unit (ICU), 29% were diagnosed with sepsis-induced coagulopathy (SIC) 8 . Studies have confirmed that sepsis patients with coagulopathy have a substantially higher incidence of multiple organ failure and a higher mortality rate 9 10 . Therefore, coagulation activation is an initial factor for sepsis to develop into multiple organ dysfunction syndrome (MODS), and anticoagulant therapy is necessary. Nafamostat mesylate (NM) is classified as a serine protease inhibitor and possesses a molecular weight of 539.58 g/mol. The pharmacological effects of NM include: (1) anticoagulant activity, achieved by inhibiting the activity of thrombin, factors VIIa, Xa, and XIIa 11 . (2) potent and broad-spectrum protease inhibitory activity, which inhibits free trypsin. Trypsin bound to α2-macroglobulin and phospholipase A2 12 . (3) antiplatelet activity, which inhibits platelet aggregation and promotes the disaggregation of aggregated platelets 13 . NM is rapidly metabolized in the body, with a half-life of 5 to 8 minutes, which is significantly shorter than that of heparin 14 15 . NM is eliminated approximately 80% by the liver and 20% by the blood 16 . About 90% of the blood clearance of NM is mediated by red blood cells, which reduces the likelihood of bleeding and makes it safer for clinical use 17 . Previous studies have reported the role of NM in patients with acute pancreatitis and DIC, both of which involve coagulation activation in the pathophysiological mechanisms 18-20 . To the best of our knowledge, the effectiveness and safety of intravenous NM. for the treatment of sepsis patients have not been reported to date. Therefore, we aim to conduct a prospective, multicenter, blinded, randomized controlled trial(RCT) in China to evaluate the therapeutic effects and safety of NM on sepsis patients in the ICU. Methods and trial design Study design The EASNMS study is a multicenter, randomized, double-blind, placebo-controlled trial. The EASNMS study protocol has been approved by the Research and Ethics Committee of the First Affiliated Hospital of China Medical University ([2023] No. 453, Shenyang, China). Participants will be allocated to either the NM group or the control group in a 1:1 ratio through random assignment. The control group will be administered a solution of 5% glucose exclusively, whereas the NM group will receive a continuous intravenous infusion of NM, initiated within 6 hours of enrollment and maintained for a duration of 7 days. Throughout the study, researchers, participants, and statisticians will remain blinded. The study protocol is summarized in the flowchart (Figure 1). The study protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines 21 Study participants Currently, participants are being recruited from all ICUs from 32 hospitals in China. These ICUs are part of university hospitals located in 15 provinces in the Southwest, Northwest, Northeast and East China regions, integrating clinical practice, research, and teaching (Supplementary Figure 1 for participating hospitals). Patients who fulfill the inclusion criteria, do not meet the exclusion criteria, and provide their informed consent will be incorporated into the study. The consent form addresses the procedures related to the collection and utilization of participants' data and biological samples. Enrollment should be completed within 6 hours of the patient's ICU admission. The recruitment duration is from October 2023 to October 2025. Inclusion criteria Patients are eligible for the trial if they meet the criteria for Sepsis 3.0 (The Third International Consensus Definition for Sepsis and Septic Shock) 1 . Exclusion criteria Patients will be excluded if they fulfill any of the exclusion criteria: 1. Age ＜ 18 years old. 2. Pregnant and lactating women. 3. Patients with a history of high sensitivity to NM (e.g., those who have experienced significant bleeding complications after previous use of NM). 4. Patients at high risk of bleeding or with bleeding: - Patients with acute trauma or active bleeding (e.g., multiple rib fractures, significant injuries to the lung, liver, kidney, spleen, retroperitoneal bleeding, pelvic fractures, etc.) - History of severe brain injury, intracranial surgery, stroke, cerebral aneurysm, or arteriovenous malformation within 1 month before enrollment - Patients with congenital bleeding disorders such as hemophilia - Patients with underlying fulminant hepatitis, decompensated cirrhosis, or other severe liver diseases 5. Patients who have received the following medications: - Heparin and heparin analogs (including low molecular weight heparin, danaparoid, etc.) within the last 12 hours before enrollment - Warfarin within the last 7 days before enrollment with an INR above normal range - Thrombolytic therapy within 3 days before enrollment - Platelet inhibitors (such as aspirin, clopidogrel, prasugrel, ticagrelor, etc.) within 7 days before enrollment - Currently using other novel anticoagulants (factor Xa inhibitors, such as rivaroxaban, apixaban, and edoxaban, as well as direct thrombin inhibitors including dabigatran) 6. Expected stay in ICU ≤ 24 hours. 7. Cardiopulmonary resuscitation performed within seven days prior to enrollment. 8. Involvement in additional clinical trials within the 30 days prior to enrollment. 9. Due to irreversible disease states, such as advanced malignant tumors or the terminal stages of other illnesses. Risks, adverse events, and informed consent The protocol aims to ensure the safety of participants. On one hand, for patients with critical illnesses, the dosage of NM is moderate. We calculate the dosage of NM based on the weight of each subject, administering a continuous intravenous infusion of 2 mg/kg/24 h. On the other hand, patients with higher potential risks are excluded according to the exclusion criteria. It is essential to emphasize that adverse events (AEs) and serious adverse events (SAEs) will be systematically documented and monitored throughout the 28-day study period, starting from the point of enrollment, in accordance with the protocols established by the National Medical Products Administration of the People's Republic of China. Researchers will assess the relationship between the events and the intervention, and report AEs and SAEs to the central ethics committee as well as the Data Safety Monitoring Committee. Recruitment Researchers provide potential participants with comprehensive information about the trial, including theobjectives, expected duration and benefits, participants' rights, potential risks, and alternative treatment options. All individuals involved in the trial must be capable of understanding the information presented; if a participant is unable to comprehend it, a legally designated representative will make decisions on his/her behalf. Participants are required to voluntarily sign an informed consent form and retain the right to withdraw from the study at any time without facing negative consequences. If there are any significant information updates or changes during the study, we will promptly notify the participants and regain their consent. These practices adhere to the principles outlined in the Helsinki Declaration and the International Council for Harmonisation Good Clinical Practice (ICH GCP). Randomization and allocation concealment Randomization for this study is implemented through a centralized interactive web response system. A total of 32 ICUs are involved, each represented by a corresponding investigator. Each eligible participant who meets the inclusion criteria and signs the informed consent form will be entered into the website and randomized using software-generated random numbers. Independent drug administrators receive grouping information based on these random numbers and then allocate the study drugs to nurses for management. Interventions NM treatment group: administered at a dose of 2.0 mg/kg/day, dissolved in 5% glucose solution, and prepared to a total volume of 50 ml (maximum concentration of 10 mg/ml) in a 50 ml syringe. The NM ampules (50 mg) were manufactured by Jiangsu Durui Pharmaceutical Co, Ltd. Placebo group: only 50 ml of 5% glucose is added to a 50 ml syringe. Dosage and administration: Continuous intravenous infusion administered over a duration of seven days. A new preparation of the medication is made every 24 hours, with any remaining solution discarded. Participants in both cohorts will be provided with standard medical care by their attending physician in accordance with the International Guidelines for Management of Sepsis and Septic Shock 1 . The use of Xuebijing, ulinastatin, or other traditional Chinese medicines containing safflower, salvia, leech, notoginseng, ligusticum chuanxiong, and similar ingredients is prohibited during the study. Blinding The independent drug administrator at each center, typically a clinical research nurse, will be tasked with the preparation of either the placebo or NM. Both groups will use 50 ml transparent syringes to ensure identical appearance. The administration procedures are the same and will be carried out by the nurse in charge of each patient's treatment. When available participants are enrolled, the independent drug administrator will receive group information based on a random number. Upon determining the allocation, the drug administrator, who possesses exclusive access to the sequence ID and its associated medication, will direct the research assistant to attach labels bearing the ID to the respective syringes containing either NM or glucose. The participants, along with all members of the research and healthcare team, as well as the outcome assessors, will remain unaware of the allocation of the study drug. Data analysis will be conducted by researchers who are unaware of the patients' group assignments. Criteria for exiting or suspending the trial 1. In accordance with Good Clinical Practice (GCP) and International Council for Harmonisation (ICH) guidelines, all participants retain the right to withdraw from the clinical trial at any point throughout the duration of the study. 2. Severe deviation or violation of the protocol that affects the drug's endpoint indicators or safety 3. If spontaneous life-threatening bleeding symptoms occur during the trial, including intracranial hemorrhage and massive gastrointestinal bleeding (such as hematemesis or melena), as well as severe airway bleeding, the trial should be immediately discontinued. If only mild bleeding symptoms occur, such as minor gastrointestinal bleeding (only coffee-ground vomitus), slight nasal mucosal bleeding, gum bleeding, airway bleeding, skin mucosal and puncture site oozing, large bruises, or skin purpura, the researcher should judge whether it is inappropriate for the subject to continue the trial 4. If the clinical condition requires the use of anticoagulant or antiplatelet drugs as judged by the researcher Outcomes The primary outcome is all-cause mortality in ICU. The secondary outcomes encompass the following factors: 1. the improvement in SOFA scores; 2.changes in DIC score [Japanese Association for Acute Medicine (JAAM)/International Society on Thrombosis and Hemostasis (ISTH)score); 3. 28-day all-cause mortality; 4. incidence of AEs. Table 1 presents the daily bleeding monitoring sheet. Plans to promote participant retention and complete follow‑up Patient participation is required solely during their ICU stay. Data will be collected at enrollment and continue for a 28-day follow-up period, with specific time points detailed in Table 2. The research timeline encompasses the screening period (Day 0, prior to enrollment), the intervention phase (Days 1–7), ICU discharge, and the subsequent 28-day follow-up period. Outcomes will be assessed at the time of discharge and 28 days after enrollment through the hospital's electronic information system or via a telephone follow-up approach, in which patients or their family members will be contacted. If participants discontinue or deviate from the intervention protocols, efforts will be made to ensure they complete the study follow-up 22 . Sample size calculation Based on literature results 23 24 , the estimated ICU mortality rate is 30% for the experimental group and 40% for the control group, with a superiority margin of 0 (control group - experimental group). With a one-sided alpha of 0.025 and a beta of 0.2, and assuming an equal sample size ratio of 1 (experimental group: control group), the calculated sample size is 354 cases for the experimental group and 354 cases for the control group, a total of 708 cases. Considering a 10% dropout rate, a total sample size of 778 cases is required. Data collection and management -Baseline characteristics -Vital signs, blood lactate levels, infection parameters, coagulation parameters, JAAM score, ISTH score, APACHE-II score, SOFA score, use of antibiotics and vasopressors, fluid resuscitation (24-hour fluid balance and types), use of blood products, and CRRT application including anticoagulation strategy. - Outcomes including ICU survival status, 28-day survival status, hospital survival status. - ICU length of stay. - Time of ICU discharge (within 28 days of enrollment). - Duration of mechanical ventilation. - Duration of vasopressor use. - Complications, including spontaneous bleeding (intracranial hemorrhage, gastrointestinal bleeding, epistaxis, gum bleeding, airway bleeding, skin and mucous membrane bleeding, puncture site bleeding, large ecchymoses, skin purpura, etc.), allergic reactions, and other AEs. The researchers will collect the required data from the medical records of patients who meet the inclusion criteria and record it on paper case report forms (CRFs). Data collection will be conducted by clinical researchers under the supervision of the principal investigator, who will be responsible for the accuracy, completeness, and timeliness of the reported data. All data should be recorded clearly to ensure accurate interpretation and maintain traceability. Remote data entry will be performed after training the data entry personnel. A manual comparison between the CRFs and the database will be conducted to ensure consistency between the data in the database and the results recorded in the case report forms. All participating centers received qualification from the National Medical Products Administration. Data analysis The analysis of data will be performed in accordance with the intention-to-treat (ITT) principle. Continuous variables will be reported as mean ± standard deviation (SD) or median with interquartile range (IQR [range]). The ICU mortality rates for both cohorts will be computed and analyzed by chi-square test, and the risk difference (control group - experimental group) computed alongside its 95% confidence interval (CI) using the Clopper-Pearson method. If the lower bound of the 95% confidence interval for the risk difference exceeds zero, the experimental group will be deemed superior to the control group. Quantitative data will be analyzed by t-tests or Wilcoxon rank-sum tests for comparisons between groups, whereas ordinal data will be evaluated using rank-sum tests. Categorical data will be analyzed using chi-square tests or Fisher's exact test. All statistical analyses will be conducted utilizing SPSS 26.0, and a two-sided P -value less than 0.05 are considered statistically significant. Missing values will be handled using multiple imputation methods. Patient and public involvement The trial will not involve patients or the general public. The findings will be shared at conferences or published in a journal. The authors of any publication will include the researchers and collaborators who participated in the trial. Data safety monitoring committee The DSMC is composed of experts with extensive clinical research experience and a background in ethical review, including clinicians, statisticians, ethicists, legal advisors, and patient representatives. Its primary responsibilities encompass the regular monitoring of data safety, assessment of AEs, evaluation of research progress, ensuring compliance with ethical standards, and maintaining consistent reporting and communication. The DSMC meets quarterly and on an AD hoc basis in case of emergency. The data review process includes data collection, cleaning, review, and AE reporting. To ensure data security, we use Advanced Encryption Standard (AES), strict access controls, regular data backup and privacy protection measures. In addition, DSMC is responsible for training and education, conducts regular risk assessments and develops response measures. Through the effective operation of DSMC, we are able to ensure the safety and integrity of research data, protect patient rights. Trial sponsor The First Affiliated Hospital of China Medical University, situated at No. 155, Nanjing North Street, Shenyang, China, with a postal code of 110001, is the sponsor of the trial. The sponsor was not involved in key aspects such as the design of the study, the collection, management and analysis of data, interpretation of results, report writing, or decisions related to the submission and publication of the final report. This practice ensures the independence and objectivity of the research and avoids potential conflicts of interest, thereby enhancing the credibility and transparency of the findings. By delegating these core tasks to independent research teams, the scientific and impartial nature of the research is further enhanced. Discussion This trial is a multicenter, randomized, double-blind, placebo-controlled trial. The conclusion of this trial will offer insights into the effectiveness and safety of intravenous NM in sepsis patients. Sepsis patients are prone to developing coagulation system disorders, which can progress to SIC. Studies have confirmed that sepsis patients with coagulation dysfunction are significantly more prone to developing MODS and have a higher mortality rate 9 . Brittney Williams et al. analyzed the intricate pathophysiology of SIC, with a particular emphasis on the contribution of procoagulant innate immune signaling to the activation of hemostatic processes. This includes tissue factor production, thrombin generation, endothelial dysfunction, and compromised antithrombotic functions 25 . In 2019, the International Society on Thrombosis and Haemostasis recommended initiating anticoagulant therapy for patients meeting the diagnostic criteria for SIC 26 . Previous studies have demonstrated that NM reduced the pathological damage of pancreatitis in animal models 27-29 . These studies provide a solid experimental basis for the application of NM in acute pancreatitis. In recent years, systematic reviews and meta-analyses on the effective prevention of pancreatitis (PEP) after endoscopic retrograde cholangiopancreatography (ERCP) have further validated the practical application value of NM in the treatment of pancreatitis 30 31 . NM, as a synthetic protease inhibitor, has also been studied for the treatment of DIC 32-34 . At present, NM is mostly used in critically ill patients who are treated by continuous renal replacement therapy (CRRT) with high risk of bleeding. To date, only one study involving the use of NM in sepsis patients has been published by Kamijo et al. Kamijo et al. conducted a nationwide registry study to evaluate the impact of NM on survival outcomes in sepsis patients receiving blood purification treatment in Japanese ICUs. The results indicated that the use of NM significantly reduced both in-hospital mortality and ICU mortality. This clinical study provides strong evidence for the practical application of NM in the treatment of sepsis 35 . Although this study included sepsis patients, NM is still used as an anticoagulant for CRRT, not intravenous treatment. Additionally, this study was retrospective and did not adopt Sepsis 3.0 criteria. Therefore, the role of NM in the treatment of sepsis patients still requires to be validated by prospective studies.In addition to evidence from clinical studies, there are animal models to explore the mechanism of action of NM in sepsis. NM can reduce intestinal permeability, thereby lowering the risk of bacterial translocation 36 . NM can also reduce fibrinolytic injury by inhibiting the increase of plasminogen activator inhibitor-1 (PAI-1) in plasma, although there is no significant improvement in clinical parameters 37 . The above researches provide a theoretical basis for the application of NM in the management of sepsis. Most clinical studies on NM are based on retrospective analyses. Despite various proposed strategies, there are significant gaps in the research field, including: (1) a lack of large-scale, multicenter clinical trials to validate the efficacy of NM across different populations and stages of sepsis; (2) insufficient understanding of the overall mechanism of action of NM in the treatment of sepsis; (3) limited studies on the combined use of NM with other therapeutic approaches; (4) inadequate research on the long-term effects and safety of NM. Therefore, more comprehensive clinical evidence is needed to assess the safety and efficacy of NM in sepsis patients. Trial status The trial opened to recruitment on 01 October 2023. The current protocol version is 2.0 (dated April 2024). Recruitment is expected to be completed by 01 October 2025. Abbreviations MODS Multiple organ dysfunction syndrome NM Nafamostat Mesilate RCTs Randomized controlled trials ICU Intensive care unit JAAM Japanese Association for Acute Medicine ISTH International Society on Thrombosis and Hemostasis DIC disseminated intravascular coagulation SIC sepsis-induced coagulopathy Declarations Acknowledgements Not applicable Authors’ contributions XL served as the chief investigator, leading the conceptualization of the study and overseeing the development of the research protocol. XM, XL, and HY contributed to the study design and protocol refinement. YM and JF provided expertise in trial methodology. HY and JF were responsible for participant recruitment. All authors critically reviewed and approved the final manuscript. Funding This trial was supported by the National Key R&D Program of China (No. 2022YFC2304605). Availability of data and materials Trial data will remain confidential and accessible only to the research team. Anonymized datasets may be shared in publications as per the study's publication policy. External requests for data access will require approval from the ethics committee. Ethics approval and consent to participate This study protocol has been approved by the Research and Ethics Committee of the First Affiliated Hospital of China Medical University ([2023] No. 453, Shenyang, China). The findings of this study will be shared in peer-reviewed journals and will be presented at conferences. Consent for publication Not applicable. Competing interests The principal investigators of this trial declare no competing financial or non-financial interests relevant to the conduct or outcomes of this study. Author details 1 Department of Critical Care Medicine, the First Affiliated Hospital of China Medical University, North Nanjing Street 155, Shenyang 110001, Liaoning Province, PR China 2 Department of Gastrointestinal Surgery, the First Affiliated Hospital of China Medical University, North Nanjing Street 155, Shenyang 110001, Liaoning Province, PR China References Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315(8):801-10. doi: 10.1001/jama.2016.0287 [published Online First: 2016/02/24] Fleischmann-Struzek C, Mellhammar L, Rose N, et al. Incidence and mortality of hospital- and ICU-treated sepsis: results from an updated and expanded systematic review and meta-analysis. Intensive Care Med 2020;46(8):1552-62. doi: 10.1007/s00134-020-06151-x [published Online First: 2020/06/24] Rhee C, Dantes R, Epstein L, et al. 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Pharmacological studies of FUT-175, nafamstat mesilate. II. Effects on experimental acute pancreatitis. Folia Pharmacologica Japonica 1984;84(4):373-84. doi: 10.1254/fpj.84.373 Park J-S, Jeong S, Kim JM, Lee DH. Preventative Effect of Nafamostat Mesilate Infusion into the Main Pancreatic Duct on Post-ERCP Pancreatitis in a Porcine Model: Initial Pilot Study. Journal of Investigative Surgery 2019;33(4):325-31. doi: 10.1080/08941939.2018.1511015 Narumi K, Okada T, Lin Y, Kikuchi S. Efficacy of nafamostat mesylate in the prevention of pancreatitis after endoscopic retrograde cholangiopancreatography: a systematic review and meta-analysis of randomized controlled trials. Sci Rep 2023;13(1):23012. doi: 10.1038/s41598-023-50181-6 [published Online First: 20231227] Horvath IL, Kleiner D, Nagy R, et al. Nafamostat Reduces the Incidence of post-ERCP Pancreatitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Clin Pharmacol Ther 2024;115(2):206-12. doi: 10.1002/cpt.3118 [published Online First: 20231229] Yonekura S, Umeda Y, Ogawa Y, et al. Effects of intermittent nafamostat mesylate in divided doses in patients with disseminated intravascular coagulation occurring with hematopoietic malignancies. Current Therapeutic Research 1996;57(3):203-14. doi: 10.1016/s0011-393x(96)80126-3 Tanaka S, Ohmine T. A case of abdominal aortic aneurysm presenting as symptomatic disseminated intravascular coagulation treated with endovascular aneurysm repair and postoperative administration of Nafamostat mesylate. Surgical Case Reports 2024;10(1) doi: 10.1186/s40792-024-01926-6 Minakata D, Fujiwara SI, Ikeda T, et al. Comparison of gabexate mesilate and nafamostat mesilate for disseminated intravascular coagulation associated with hematological malignancies. Int J Hematol 2019;109(2):141-46. doi: 10.1007/s12185-018-02567-w [published Online First: 20181208] Kamijo H, Mochizuki K, Nakamura Y, et al. Nafamostat Mesylate Improved Survival Outcomes of Sepsis Patients Who Underwent Blood Purification: A Nationwide Registry Study in Japan. J Clin Med 2020;9(8) doi: 10.3390/jcm9082629 [published Online First: 2020/08/23] Plaeke P, De Man J, Hens S, et al. Sa1172 - Effects of the Non-Selective Protease Inhibitor Nafamostat Mesylate on Intestinal Permeability and Bacterial Translocation in a Murine Model of Sepsis. Gastroenterology 2018;154(6):S-267-S-68. doi: 10.1016/s0016-5085(18)31253-8 Hryszko T, Inaba K, Ihara H, et al. Nafamostat attenuated the impairment of fibrinolysis in animal sepsis model by suppressing the increase of plasminogen activator inhibitor type 1. J Trauma 2006;60(4):859-64. doi: 10.1097/01.ta.0000215566.74588.27 [published Online First: 2006/04/14] Tables Table 1 Daily bleeding monitor sheet Classification Manifestation Intervention Major bleeding - Intracranial bleeding - Gastrointestinal hemorrhage (haematemesis, tarry stool) - Severe airway bleeding - Other fatal bleeding Stop infusionof study drugsand recordedin the CRF Minor bleeding -Mild gum bleeding - Mild epistaxis - Airway mucosa bleeding - Puncture site bleeding - Bruise or skin purpura -Minor hemorrhage of digestive tract Attending physicians monitorand make a decision CRF, case report form Table 2 Study period Time point Enrollment Intervention Follow-up Follow-up D0 D1 D2 D3 D5 D7 Discharge of ICU D28 Enrollment Informed consent × Inclusion/exclusion × Randomization × Intervention NM × × × × × 5% glucose × × × × × Assessment Demographic data × Primary disease × Base condition × Blood routine × × × × × × × Serum chemistry examinations a × × × × × × × Coagulation function b × × × × × × × Inflammation parameters (PCT, CRP) × × × × × × × Blood gas × × × × × × × SOFA score × × × × × × × APACHE II score × × × × × × × ISTH score × × × × × × × JAAM score × × × × × × × Mechanical ventilation × × × × × × × × CRRT × × × × × × × × Duration in ICU × Outcome × × AEs/SAEs × × × × × × × ICU, intensive care unit; SOFA, sequential organ failure assessment; APACHE II, acute physiology and chronic health evaluation II; ISTH, International Society on Thrombosis and Hemostasis; JAAM, Japanese Association for Acute Medicine; CRRT, continuous renal replacement therapy; AEs, adverse events; SAE, severe adverse events a Serum chemistry includes ALT, AST, TBIL, ALB, Pre-ALB, Scr, BUN, BNP, and cytokines b Coagulation parameters include PT, INR, APTT, Fibrinogen, D-D, FDP, and AT-III Supplementary Files CONSORT2010Checklist.doc SPIRIT2013Checklist.doc SupplementaryFigure1.docx Cite Share Download PDF Status: Published Journal Publication published 29 Jul, 2025 Read the published version in Trials → Version 1 posted Reviewers agreed at journal 26 Jun, 2025 Reviewers invited by journal 26 Jun, 2025 Editor assigned by journal 19 Jun, 2025 First submitted to journal 18 Jun, 2025 Editorial decision: Minor revision 15 Jun, 2025 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. 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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-6629099","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":476856286,"identity":"3246eb7b-b8e9-4c84-8804-40e9c8f55c42","order_by":0,"name":"Hongyu Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvElEQVRIiWNgGAWjYBADOQZmUrUYk64lsYFopQY3cswkfrbZpW84znuA4U0Zgzy/2AHCWiR725JzNxzmS2Ccc47BcObsBCJs4TnDnDuzmceAmbeNIcHgNhFaJP+cqU+XJEmLNE/F4QR+ZmK1SJ55VmwtU3HcsJ+ZL+HgnHMShP3Cdzx54803BtXybPxnDz54U2Yjzy9NQIvCAQ4DKJOH4QAPmwR+5SAg38D+AK6FgYeNsI5RMApGwSgYeQAAupE9Cd2W6bwAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0007-1545-0791","institution":"The First Affiliated Hospital of China Medical University","correspondingAuthor":true,"prefix":"","firstName":"Hongyu","middleName":"","lastName":"Yang","suffix":""},{"id":476856287,"identity":"d1a08c4b-423e-4372-8076-877058384db9","order_by":1,"name":"Jianshuang Feng","email":"","orcid":"","institution":"China Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jianshuang","middleName":"","lastName":"Feng","suffix":""},{"id":476856288,"identity":"33210a77-e8fc-498a-b0b1-db1a407c197f","order_by":2,"name":"Yuteng Ma","email":"","orcid":"","institution":"China Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuteng","middleName":"","lastName":"Ma","suffix":""},{"id":476856289,"identity":"d110a587-0904-45d5-89ad-1c938c4a096b","order_by":3,"name":"Xiaochun Ma","email":"","orcid":"","institution":"China Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaochun","middleName":"","lastName":"Ma","suffix":""},{"id":476856290,"identity":"6c22c525-4863-4ef1-9e96-741d6661d677","order_by":4,"name":"Xu Li","email":"","orcid":"","institution":"China Medical University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xu","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2025-05-09 13:24:48","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6629099/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6629099/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-025-08979-4","type":"published","date":"2025-07-29T16:13:19+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85747855,"identity":"0d07006e-77f2-4ea4-95d5-f9bc1dbc59a5","added_by":"auto","created_at":"2025-07-01 09:39:16","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":91996,"visible":true,"origin":"","legend":"\u003cp\u003eThe flowchart of the EASNMS study. ICU, intensive care unit; SOFA, sequential organ failure assessment; DIC, disseminated intravascular coagulation; iv, intravenous; JAAM, Japanese Association for Acute Medicine; ISTH, International Society on Thrombosis and Haemostasis.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6629099/v1/72c644e228e8b301bf60ad43.jpg"},{"id":88268331,"identity":"be3d18d0-268f-475e-bcbf-0842cae721ef","added_by":"auto","created_at":"2025-08-04 16:51:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":740907,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6629099/v1/128170c5-485a-439c-b01d-ed29082b390a.pdf"},{"id":85748599,"identity":"8b79db63-225d-4505-8443-1b06d4375bab","added_by":"auto","created_at":"2025-07-01 09:47:15","extension":"doc","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":226816,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORT2010Checklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-6629099/v1/39c041da56df893aca830f6c.doc"},{"id":85747837,"identity":"7e25e7c5-e55c-4e4c-8fe1-5ba64f8f2160","added_by":"auto","created_at":"2025-07-01 09:39:15","extension":"doc","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":129024,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRIT2013Checklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-6629099/v1/b9bebc0b4c3777d88ec83f66.doc"},{"id":85747839,"identity":"f8c00981-99d0-460f-8c2c-c545418b3798","added_by":"auto","created_at":"2025-07-01 09:39:15","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":14309,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6629099/v1/c366e0082594585d8a120d90.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eEfficacy and safety of Nafamostat Mesilate for sepsis (EASNMS) : study protocol for a multicenter randomized controlled trial\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSepsis is a fatal condition characterized by a maladaptive host response to infection, resulting in the impairment of organ function. \u003csup\u003e1\u003c/sup\u003e.Sepsis not only incurs substantial healthcare costs, but also is a leading cause of death in critically ill patients, with approximately 25% to 40% of patients dying during hospitalization\u003csup\u003e2-4\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSepsis is a clinical syndrome resulting from the interaction between coagulation, inflammation, immunity and other systems. In sepsis, pathogens invade the body and induce the production of proinflammatory cytokines, which further damage endothelial cells and promote coagulation activation. Coagulation activation occurs in most sepsis patients, including activation of the coagulation system, damage of endothelial cells, inhibition of fibrinolytic system, and even onset of disseminated intravascular coagulation (DIC)\u003csup\u003e5 6\u003c/sup\u003e.Patients with sepsis-associated coagulation activation can experience widespread microvascular thrombosis, potentially leading to multiple organ dysfunction\u003csup\u003e7\u003c/sup\u003e. A recent observational study conducted in Japan found that among 1,895 sepsis patients treated in intensive care unit (ICU), 29% were diagnosed with sepsis-induced coagulopathy (SIC)\u003csup\u003e8\u003c/sup\u003e.\u0026nbsp;Studies have confirmed that sepsis patients with coagulopathy have a substantially higher incidence of multiple organ failure and a higher mortality rate\u003csup\u003e9 10\u003c/sup\u003e. Therefore, coagulation activation is an initial factor for sepsis to develop into multiple organ dysfunction syndrome (MODS), and anticoagulant therapy is necessary.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNafamostat mesylate (NM) is classified as a serine protease inhibitor and possesses a molecular weight of 539.58 g/mol. The pharmacological effects of NM include: (1) anticoagulant activity, achieved by inhibiting the activity of thrombin, factors VIIa, Xa, and XIIa\u003csup\u003e11\u003c/sup\u003e.\u0026nbsp;(2) potent and broad-spectrum protease inhibitory activity, which inhibits free trypsin. Trypsin bound to α2-macroglobulin and phospholipase A2\u003csup\u003e12\u003c/sup\u003e. (3) antiplatelet activity, which inhibits platelet aggregation and promotes the disaggregation of aggregated platelets\u003csup\u003e13\u003c/sup\u003e. NM is rapidly metabolized in the body, with a half-life of 5 to 8 minutes,\u0026nbsp;which is significantly shorter than that of heparin\u003csup\u003e14 15\u003c/sup\u003e. NM is eliminated approximately 80% by the liver and 20% by the blood\u003csup\u003e16\u003c/sup\u003e.\u0026nbsp;About 90% of the blood clearance of NM is mediated by red blood cells, which reduces the likelihood of bleeding and makes it safer for clinical use\u003csup\u003e17\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePrevious studies have reported the role of NM in patients with acute pancreatitis and DIC, both of which involve coagulation activation in the pathophysiological mechanisms\u003csup\u003e18-20\u003c/sup\u003e\u003cstrong\u003e.\u003c/strong\u003e To the best of our knowledge, the effectiveness and safety of intravenous NM. for the treatment of sepsis patients have not been reported to date. Therefore, we aim to conduct a prospective, multicenter, blinded, randomized controlled trial(RCT) in China to evaluate the therapeutic effects and safety of NM on sepsis patients in the ICU.\u003c/p\u003e"},{"header":"Methods and trial design","content":"\u003cp\u003eStudy design\u003c/p\u003e\n\u003cp\u003eThe EASNMS study is a multicenter, randomized, double-blind, placebo-controlled trial. The EASNMS study protocol has been approved by the Research and Ethics Committee of the First Affiliated Hospital of China Medical University ([2023] No. 453, Shenyang, China). Participants will be allocated to either the NM group or the control group in a 1:1 ratio through random assignment. The control group will be administered a solution of 5% glucose exclusively, whereas the NM group will receive a continuous intravenous infusion of NM, initiated within 6 hours of enrollment and maintained for a duration of 7 days. Throughout the study, researchers, participants, and statisticians will remain blinded. The study protocol is summarized in the flowchart (Figure 1). The study protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines\u003csup\u003e21\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eStudy participants\u003c/p\u003e\n\u003cp\u003eCurrently, participants are being recruited from all ICUs from 32 hospitals in China. These ICUs are part of university hospitals located in 15 provinces in the Southwest, Northwest, Northeast and East China regions, integrating clinical practice, research, and teaching (Supplementary Figure 1 for participating hospitals). Patients who fulfill the inclusion criteria, do not meet the exclusion criteria,\u0026nbsp;and provide their informed consent will be incorporated into the study. The consent form addresses the procedures related to the collection and utilization of participants\u0026apos; data and biological samples. Enrollment should be completed within 6 hours of the patient\u0026apos;s ICU admission. The recruitment duration is from October 2023 to October 2025.\u003c/p\u003e\n\u003cp\u003eInclusion criteria\u003c/p\u003e\n\u003cp\u003ePatients are eligible for the trial if they meet the criteria for Sepsis 3.0 (The Third International Consensus Definition for Sepsis and Septic Shock)\u003csup\u003e1\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExclusion criteria\u003c/p\u003e\n\u003cp\u003ePatients will be excluded if they fulfill any of the exclusion criteria:\u003c/p\u003e\n\u003cp\u003e1. Age\u0026nbsp;＜\u0026nbsp;18 years old.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp;Pregnant and lactating women.\u003c/p\u003e\n\u003cp\u003e3. Patients with a history of high sensitivity to NM (e.g., those who have experienced significant bleeding complications after previous use of NM).\u003c/p\u003e\n\u003cp\u003e4. Patients at high risk of bleeding or with bleeding:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;- Patients with acute trauma or active bleeding (e.g., multiple rib fractures, significant injuries to the lung, liver, kidney, spleen, retroperitoneal bleeding, pelvic fractures, etc.)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;- History of severe brain injury, intracranial surgery, stroke, cerebral aneurysm, or arteriovenous malformation within 1 month before enrollment\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;- Patients with congenital bleeding disorders such as hemophilia\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;- Patients with underlying fulminant hepatitis, decompensated cirrhosis, or other severe liver diseases\u003c/p\u003e\n\u003cp\u003e5. Patients who have received the following medications:\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;- Heparin and heparin analogs (including low molecular weight heparin, danaparoid, etc.) within the last 12 hours before enrollment\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;- Warfarin within the last 7 days before enrollment with an INR above normal range\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;- Thrombolytic therapy within 3 days before enrollment\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;- Platelet inhibitors (such as aspirin, clopidogrel, prasugrel, ticagrelor, etc.) within 7 days before enrollment\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;- Currently using other novel anticoagulants (factor Xa inhibitors, such as rivaroxaban, apixaban, and edoxaban, as well as direct thrombin inhibitors including dabigatran)\u003c/p\u003e\n\u003cp\u003e6. Expected stay in ICU \u0026le; 24 hours.\u003c/p\u003e\n\u003cp\u003e7. Cardiopulmonary resuscitation performed within seven days prior to enrollment.\u003c/p\u003e\n\u003cp\u003e8. Involvement in additional clinical trials within the 30 days prior to enrollment.\u003c/p\u003e\n\u003cp\u003e9. Due to irreversible disease states, such as advanced malignant tumors or the terminal stages of other illnesses.\u003c/p\u003e\n\u003cp\u003eRisks, adverse events, and informed consent\u003c/p\u003e\n\u003cp\u003eThe protocol aims to ensure the safety of participants. On one hand, for patients with critical illnesses, the dosage of NM is moderate. We calculate the dosage of NM based on the weight of each subject, administering a continuous intravenous infusion of 2 mg/kg/24 h. On the other hand, patients with higher potential risks are excluded according to the exclusion criteria. \u0026nbsp;It is essential to emphasize that adverse events (AEs) and serious adverse events (SAEs) will be systematically documented and monitored throughout the 28-day study period, starting from the point of enrollment, in accordance with the protocols established by the National Medical Products Administration of the People\u0026apos;s Republic of China. Researchers will assess the relationship between the events and the intervention, and report AEs and SAEs to the central ethics committee as well as the Data Safety Monitoring Committee.\u003c/p\u003e\n\u003cp\u003eRecruitment\u003c/p\u003e\n\u003cp\u003eResearchers provide potential participants with comprehensive information about the trial, including theobjectives, expected duration and benefits, participants\u0026apos; rights, potential risks, and alternative treatment options. All individuals involved in the trial must be capable of understanding the information presented; if a participant is unable to comprehend it, a legally designated representative will make decisions on his/her behalf. Participants are required to voluntarily sign an informed consent form and retain the right to withdraw from the study at any time without facing negative consequences. If there are any significant information updates or changes during the study, we will promptly notify the participants and regain their consent. These practices adhere to the principles outlined in the Helsinki Declaration and the International Council for Harmonisation Good Clinical Practice (ICH GCP).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRandomization and allocation concealment\u003c/p\u003e\n\u003cp\u003eRandomization for this study is implemented through a centralized interactive web response system. A total of 32 ICUs are involved, each represented by a corresponding investigator. Each eligible participant who meets the inclusion criteria and signs the informed consent form will be entered into the website and randomized using software-generated random numbers. Independent drug administrators receive grouping information based on these random numbers and then allocate the study drugs to nurses for management.\u003c/p\u003e\n\u003cp\u003eInterventions\u003c/p\u003e\n\u003cp\u003eNM treatment group: administered at a dose of 2.0 mg/kg/day, dissolved in 5% glucose solution, and prepared to a total volume of 50 ml (maximum concentration of 10 mg/ml) in a 50 ml syringe. The NM ampules (50 mg) were manufactured by Jiangsu Durui Pharmaceutical Co, Ltd.\u003c/p\u003e\n\u003cp\u003ePlacebo group: only 50 ml of 5% glucose is added to a 50 ml syringe.\u003c/p\u003e\n\u003cp\u003eDosage and administration: Continuous intravenous infusion administered over a duration of seven days. A new preparation of the medication is made every 24 hours, with any remaining solution discarded. Participants in both cohorts will be provided with standard medical care by their attending physician in accordance with the International Guidelines for Management of Sepsis and Septic Shock \u003csup\u003e1\u003c/sup\u003e. The use of Xuebijing, ulinastatin, or other traditional Chinese medicines containing safflower, salvia, leech, notoginseng, ligusticum chuanxiong, and similar ingredients is prohibited during the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBlinding\u003c/p\u003e\n\u003cp\u003eThe independent drug administrator at each center, typically a clinical research nurse, will be tasked with the preparation of either the placebo or NM. Both groups will use 50 ml transparent syringes to ensure identical appearance. The administration procedures are the same and will be carried out by the nurse in charge of each patient\u0026apos;s treatment. When available participants are enrolled, the independent drug administrator will receive group information based on a random number. Upon determining the allocation, the drug administrator, who possesses exclusive access to the sequence ID and its associated medication, will direct the research assistant to attach labels bearing the ID to the respective syringes containing either NM or glucose. The participants, along with all members of the research and healthcare team, as well as the outcome assessors, will remain unaware of the allocation of the study drug. Data analysis will be conducted by researchers who are unaware of the patients\u0026apos; group assignments.\u003c/p\u003e\n\u003cp\u003eCriteria for exiting or suspending the trial\u003c/p\u003e\n\u003cp\u003e1. In accordance with Good Clinical Practice (GCP) and International Council for Harmonisation (ICH) guidelines, all participants retain the right to withdraw from the clinical trial at any point throughout the duration of the study.\u003c/p\u003e\n\u003cp\u003e2. Severe deviation or violation of the protocol that affects the drug\u0026apos;s endpoint indicators or safety\u003c/p\u003e\n\u003cp\u003e3. If spontaneous life-threatening bleeding symptoms occur during the trial, including intracranial hemorrhage and massive gastrointestinal bleeding (such as hematemesis or melena), as well as severe airway bleeding, the trial should be immediately discontinued. If only mild bleeding symptoms occur, such as minor gastrointestinal bleeding (only coffee-ground vomitus), slight nasal mucosal bleeding, gum bleeding, airway bleeding, skin mucosal and puncture site oozing, large bruises, or skin purpura, the researcher should judge whether it is inappropriate for the subject to continue the trial\u003c/p\u003e\n\u003cp\u003e4. If the clinical condition requires the use of anticoagulant or antiplatelet drugs as judged by the researcher\u003c/p\u003e\n\u003cp\u003eOutcomes\u003c/p\u003e\n\u003cp\u003eThe primary outcome is all-cause mortality in ICU. The secondary outcomes encompass the following factors:\u0026nbsp;1. the improvement in SOFA scores; 2.changes in DIC score [Japanese Association for Acute Medicine (JAAM)/International Society on Thrombosis and Hemostasis (ISTH)score); 3. 28-day all-cause mortality; 4. incidence of AEs.\u0026nbsp;Table 1 presents the daily bleeding monitoring sheet.\u003c/p\u003e\n\u003cp\u003ePlans to promote participant retention and complete follow‑up\u003c/p\u003e\n\u003cp\u003ePatient participation is required solely during their ICU stay. Data will be collected at enrollment and continue for a 28-day follow-up period, with specific time points detailed in Table 2. The research timeline encompasses the screening period (Day 0, prior to enrollment), the intervention phase (Days 1\u0026ndash;7), ICU discharge, and the subsequent 28-day follow-up period. Outcomes will be assessed at the time of discharge and 28 days after enrollment through the hospital\u0026apos;s electronic information system or via a telephone follow-up approach, in which patients or their family members will be contacted. If participants discontinue or deviate from the intervention protocols, efforts will be made to ensure they complete the study follow-up\u003csup\u003e22\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eSample size calculation\u003c/p\u003e\n\u003cp\u003eBased on literature results\u003csup\u003e23 24\u003c/sup\u003e, the estimated ICU mortality rate is 30% for the experimental group and 40% for the control group, with a superiority margin of 0 (control group - experimental group). With a one-sided alpha of 0.025 and a beta of 0.2, and assuming an equal sample size ratio of 1 (experimental group: control group), the calculated sample size is 354 cases for the experimental group and 354 cases for the control group, a total of 708 cases. Considering a 10% dropout rate, a total sample size of 778 cases is required.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData collection and management\u003c/p\u003e\n\u003cp\u003e-Baseline characteristics\u003c/p\u003e\n\u003cp\u003e-Vital signs, blood lactate levels, infection parameters, coagulation parameters, JAAM score, ISTH score, APACHE-II score, SOFA score, use of antibiotics and vasopressors, fluid resuscitation (24-hour fluid balance and types), use of blood products, and CRRT application including anticoagulation strategy.\u003c/p\u003e\n\u003cp\u003e- Outcomes including ICU survival status, 28-day survival status, hospital survival status.\u003c/p\u003e\n\u003cp\u003e- ICU length of stay.\u003c/p\u003e\n\u003cp\u003e- Time of ICU discharge (within 28 days of enrollment).\u003c/p\u003e\n\u003cp\u003e- Duration of mechanical ventilation.\u003c/p\u003e\n\u003cp\u003e- Duration of vasopressor use.\u003c/p\u003e\n\u003cp\u003e- Complications, including spontaneous bleeding (intracranial hemorrhage, gastrointestinal bleeding, epistaxis, gum bleeding, airway bleeding, skin and mucous membrane bleeding, puncture site bleeding, large ecchymoses, skin purpura, etc.), allergic reactions, and other AEs.\u003c/p\u003e\n\u003cp\u003eThe researchers will collect the required data from the medical records of patients who meet the inclusion criteria and record it on paper case report forms (CRFs). Data collection will be conducted by clinical researchers under the supervision of the principal investigator, who will be responsible for the accuracy, completeness, and timeliness of the reported data. All data should be recorded clearly to ensure accurate interpretation and maintain traceability. Remote data entry will be performed after training the data entry personnel. A manual comparison between the CRFs and the database will be conducted to ensure consistency between the data in the database and the results recorded in the case report forms.\u0026nbsp;All participating centers received qualification from the National Medical Products Administration.\u003c/p\u003e\n\u003cp\u003eData analysis\u003c/p\u003e\n\u003cp\u003eThe analysis of data will be performed in accordance with the intention-to-treat (ITT) principle. Continuous variables will be reported as mean \u0026plusmn; standard deviation (SD) or median with interquartile range (IQR [range]). The ICU mortality rates for both cohorts will be computed and analyzed by chi-square test, and the risk difference (control group - experimental group) computed alongside its 95% confidence interval (CI) using the Clopper-Pearson method. If the lower bound of the 95% confidence interval for the risk difference exceeds zero, the experimental group will be deemed superior to the control group. Quantitative data will be analyzed by t-tests or Wilcoxon rank-sum tests for comparisons between groups, whereas ordinal data will be evaluated using rank-sum tests. Categorical data will be analyzed using chi-square tests or Fisher\u0026apos;s exact test. All statistical analyses will be conducted utilizing SPSS 26.0, and a two-sided \u003cem\u003eP\u003c/em\u003e-value less than 0.05 are considered statistically significant. Missing values will be handled using multiple imputation methods.\u003c/p\u003e\n\u003cp\u003ePatient and public involvement\u003c/p\u003e\n\u003cp\u003eThe trial will not involve patients or the general public. The findings will be shared at conferences or published in a journal. The authors of any publication will include the researchers and collaborators who participated in the trial.\u003c/p\u003e\n\u003cp\u003eData safety monitoring committee\u003c/p\u003e\n\u003cp\u003eThe DSMC is composed of experts with extensive clinical research experience and a background in ethical review, including clinicians, statisticians, ethicists, legal advisors, and patient representatives. Its primary responsibilities encompass the regular monitoring of data safety, assessment of AEs, evaluation of research progress, ensuring compliance with ethical standards, and maintaining consistent reporting and communication. The DSMC meets quarterly and on an AD hoc basis in case of emergency. The data review process includes data collection, cleaning, review, and AE reporting. To ensure data security, we use Advanced Encryption Standard (AES), strict access controls, regular data backup and privacy protection measures. In addition, DSMC is responsible for training and education, conducts regular risk assessments and develops response measures. Through the effective operation of DSMC, we are able to ensure the safety and integrity of research data, protect patient rights.\u003c/p\u003e\n\u003cp\u003eTrial sponsor\u003c/p\u003e\n\u003cp\u003eThe First Affiliated Hospital of China Medical University, situated at No. 155, Nanjing North Street, Shenyang, China, with a postal code of 110001, is the sponsor of the trial. The sponsor was not involved in key aspects such as the design of the study, the collection, management and analysis of data, interpretation of results, report writing, or decisions related to the submission and publication of the final report. This practice ensures the independence and objectivity of the research and avoids potential conflicts of interest, thereby enhancing the credibility and transparency of the findings. By delegating these core tasks to independent research teams, the scientific and impartial nature of the research is further enhanced.\u003c/p\u003e"},{"header":"Discussion ","content":"\u003cp\u003eThis trial is a multicenter, randomized, double-blind, placebo-controlled trial. The conclusion of this trial will offer insights into the effectiveness and safety of intravenous NM in sepsis patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSepsis patients are prone to developing coagulation system disorders, which can progress to SIC. Studies have confirmed that sepsis patients with coagulation dysfunction are significantly more prone to developing MODS and have a higher mortality rate\u003csup\u003e9\u003c/sup\u003e. Brittney Williams et al. analyzed the intricate pathophysiology of SIC, with a particular emphasis on the contribution of procoagulant innate immune signaling to the activation of hemostatic processes. This includes tissue factor production, thrombin generation, endothelial dysfunction, and compromised antithrombotic functions\u003csup\u003e25\u003c/sup\u003e. In 2019, the International Society on Thrombosis and Haemostasis recommended initiating anticoagulant therapy for patients meeting the diagnostic criteria for SIC\u003csup\u003e26\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003ePrevious studies have demonstrated that NM reduced the pathological damage of pancreatitis in animal models\u003csup\u003e27-29\u003c/sup\u003e. These studies provide a solid experimental basis for the application of NM in acute pancreatitis. In recent years, systematic reviews and meta-analyses on the effective prevention of pancreatitis (PEP) after endoscopic retrograde cholangiopancreatography (ERCP) have further validated the practical application value of NM in the treatment of pancreatitis\u003csup\u003e30 31\u003c/sup\u003e. NM, as a synthetic protease inhibitor, has also been studied for the treatment of DIC\u0026nbsp;\u003csup\u003e32-34\u003c/sup\u003e. At present, NM is mostly used in critically ill patients who are \u0026nbsp;treated by continuous renal replacement therapy (CRRT) with high risk of bleeding. To date, only one study involving the use of NM in sepsis patients has been published by Kamijo et al. Kamijo et al. conducted a nationwide registry study to evaluate the impact of NM on survival outcomes in sepsis patients receiving blood purification treatment in Japanese ICUs. The results indicated that the use of NM significantly reduced both in-hospital mortality and ICU mortality. This clinical study provides strong evidence for the practical application of NM in the treatment of sepsis\u003csup\u003e35\u003c/sup\u003e. Although this study included sepsis patients, NM is still used as an anticoagulant for CRRT, not intravenous treatment. Additionally, this study was retrospective and did not adopt Sepsis 3.0 criteria. Therefore, the role of NM in the treatment of sepsis patients still requires to be validated by prospective studies.In addition to evidence from clinical studies, there are animal models to explore the mechanism of action of NM in sepsis.\u0026nbsp;NM can reduce intestinal permeability, thereby lowering the risk of bacterial translocation\u003csup\u003e36\u003c/sup\u003e. NM can also reduce fibrinolytic injury by inhibiting the increase of plasminogen activator inhibitor-1 (PAI-1) in plasma, although there is no significant improvement in clinical parameters\u003csup\u003e37\u003c/sup\u003e. The above researches provide a theoretical basis for the application of NM in the management of sepsis.\u003c/p\u003e\n\u003cp\u003eMost clinical studies on NM are based on retrospective analyses. Despite various proposed strategies, there are significant gaps in the research field, including: (1) a lack of large-scale, multicenter clinical trials to validate the efficacy of NM across different populations and stages of sepsis; (2) insufficient understanding of the overall mechanism of action of NM in the treatment of sepsis; (3) limited studies on the combined use of NM with other therapeutic approaches; (4) inadequate research on the long-term effects and safety of NM. Therefore, more comprehensive clinical evidence is needed to assess the safety and efficacy of NM in sepsis patients.\u003c/p\u003e\u003cp\u003eTrial status\u003c/p\u003e\n\u003cp\u003eThe trial opened to recruitment on 01 October 2023. The current protocol version is 2.0 (dated April 2024). Recruitment is expected to be completed by 01 October 2025.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eMODS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Multiple organ dysfunction syndrome\u003c/p\u003e\n\u003cp\u003eNM \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Nafamostat Mesilate\u003c/p\u003e\n\u003cp\u003eRCTs \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Randomized controlled trials\u003c/p\u003e\n\u003cp\u003eICU \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Intensive care unit\u003c/p\u003e\n\u003cp\u003eJAAM\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Japanese Association for Acute Medicine\u003c/p\u003e\n\u003cp\u003eISTH \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; International Society on Thrombosis and Hemostasis\u003c/p\u003e\n\u003cp\u003eDIC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;disseminated intravascular coagulation\u003c/p\u003e\n\u003cp\u003eSIC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; sepsis-induced coagulopathy\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXL served as the chief investigator, leading the conceptualization of the study and overseeing the development of the research protocol. XM, XL, and HY contributed to the study design and protocol refinement. YM and JF provided expertise in trial methodology. HY and JF were responsible for participant recruitment. All authors critically reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis trial was supported by the National Key R\u0026amp;D Program of China (No. 2022YFC2304605).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTrial data will remain confidential and accessible only to the research team. Anonymized datasets may be shared in publications as per the study\u0026apos;s publication policy. External requests for data access will require approval from the ethics committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study protocol has been approved by the Research and Ethics Committee of the First Affiliated Hospital of China Medical University ([2023] No. 453, Shenyang, China).\u0026nbsp;The findings of this study will be shared in peer-reviewed journals and will be presented at conferences.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe principal investigators of this trial declare no competing financial or non-financial interests relevant to the conduct or outcomes of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003e Department of Critical Care Medicine, the First Affiliated Hospital of China Medical University, North Nanjing Street 155, Shenyang 110001, Liaoning Province, PR China\u003c/p\u003e\n\u003cp\u003e2 Department of Gastrointestinal Surgery, the First Affiliated Hospital of China Medical University, North Nanjing Street 155, Shenyang 110001, Liaoning Province, PR China\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSinger M, Deutschman CS, Seymour CW, et al. 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Nafamostat Reduces the Incidence of post-ERCP Pancreatitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. \u003cem\u003eClin Pharmacol Ther\u003c/em\u003e 2024;115(2):206-12. doi: 10.1002/cpt.3118 [published Online First: 20231229]\u003c/li\u003e\n\u003cli\u003eYonekura S, Umeda Y, Ogawa Y, et al. Effects of intermittent nafamostat mesylate in divided doses in patients with disseminated intravascular coagulation occurring with hematopoietic malignancies. \u003cem\u003eCurrent Therapeutic Research\u003c/em\u003e 1996;57(3):203-14. doi: 10.1016/s0011-393x(96)80126-3\u003c/li\u003e\n\u003cli\u003eTanaka S, Ohmine T. A case of abdominal aortic aneurysm presenting as symptomatic disseminated intravascular coagulation treated with endovascular aneurysm repair and postoperative administration of Nafamostat mesylate. \u003cem\u003eSurgical Case Reports\u003c/em\u003e 2024;10(1) doi: 10.1186/s40792-024-01926-6\u003c/li\u003e\n\u003cli\u003eMinakata D, Fujiwara SI, Ikeda T, et al. Comparison of gabexate mesilate and nafamostat mesilate for disseminated intravascular coagulation associated with hematological malignancies. \u003cem\u003eInt J Hematol\u003c/em\u003e 2019;109(2):141-46. doi: 10.1007/s12185-018-02567-w [published Online First: 20181208]\u003c/li\u003e\n\u003cli\u003eKamijo H, Mochizuki K, Nakamura Y, et al. Nafamostat Mesylate Improved Survival Outcomes of Sepsis Patients Who Underwent Blood Purification: A Nationwide Registry Study in Japan. \u003cem\u003eJ Clin Med\u003c/em\u003e 2020;9(8) doi: 10.3390/jcm9082629 [published Online First: 2020/08/23]\u003c/li\u003e\n\u003cli\u003ePlaeke P, De Man J, Hens S, et al. Sa1172 - Effects of the Non-Selective Protease Inhibitor Nafamostat Mesylate on Intestinal Permeability and Bacterial Translocation in a Murine Model of Sepsis. \u003cem\u003eGastroenterology\u003c/em\u003e 2018;154(6):S-267-S-68. doi: 10.1016/s0016-5085(18)31253-8\u003c/li\u003e\n\u003cli\u003eHryszko T, Inaba K, Ihara H, et al. Nafamostat attenuated the impairment of fibrinolysis in animal sepsis model by suppressing the increase of plasminogen activator inhibitor type 1. \u003cem\u003eJ Trauma\u003c/em\u003e 2006;60(4):859-64. doi: 10.1097/01.ta.0000215566.74588.27 [published Online First: 2006/04/14]\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 Daily bleeding monitor sheet\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eClassification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eManifestation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eMajor bleeding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e- Intracranial bleeding\u003c/p\u003e\n \u003cp\u003e- Gastrointestinal hemorrhage\u003c/p\u003e\n \u003cp\u003e(haematemesis, tarry stool)\u003c/p\u003e\n \u003cp\u003e- Severe airway bleeding\u003c/p\u003e\n \u003cp\u003e- Other fatal bleeding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eStop infusionof study drugsand recordedin the CRF\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eMinor bleeding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003e-Mild gum bleeding\u003c/p\u003e\n \u003cp\u003e- Mild epistaxis\u003c/p\u003e\n \u003cp\u003e- Airway mucosa bleeding\u003c/p\u003e\n \u003cp\u003e- Puncture site bleeding\u003c/p\u003e\n \u003cp\u003e- Bruise or skin purpura\u003c/p\u003e\n \u003cp\u003e-Minor hemorrhage of digestive tract\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eAttending physicians monitorand make a decision\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCRF, case report form\u003c/p\u003e\n\u003cp\u003eTable 2 Study period\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime point\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEnrollment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFollow-up\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFollow-up\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eD0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eD1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eD2\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eD3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eD5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eD7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDischarge of ICU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eD28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEnrollment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eInformed consent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eInclusion/exclusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRandomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5% glucose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAssessment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDemographic data\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePrimary disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBase condition\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBlood routine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSerum chemistry examinations\u003csup\u003e\u0026nbsp;a\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCoagulation function\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eInflammation parameters (PCT, CRP)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBlood gas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSOFA score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAPACHE II score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eISTH score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eJAAM score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMechanical ventilation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCRRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDuration in ICU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAEs/SAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026times;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eICU, intensive care unit; SOFA, sequential organ failure assessment; APACHE II, acute physiology and chronic health evaluation II; ISTH, International Society on Thrombosis and Hemostasis; JAAM, Japanese Association for Acute Medicine; CRRT, continuous renal replacement therapy; AEs, adverse events; SAE, severe adverse events\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003eSerum chemistry includes ALT, AST, TBIL, ALB, Pre-ALB, Scr, BUN, BNP, and cytokines\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Coagulation parameters include PT, INR, APTT, Fibrinogen, D-D, FDP, and AT-III\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Sepsis, Nafamostat Mesilate, coagulation activation","lastPublishedDoi":"10.21203/rs.3.rs-6629099/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6629099/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSepsis is the leading cause of death in critically ill patients, with an in-hospital mortality rate of approximately 25\u0026ndash;40%. Coagulation activation serves as an initial factor to the progression of sepsis into multiple organ dysfunction syndrome (MODS). Therefore, anticoagulant therapy may be beneficial. Both basic experiments and clinical studies have evaluated the protective effect of Nafamostat Mesilate (NM) in sepsis. However, there is still a lack of randomized controlled trials (RCTs) to further confirm the therapeutic effect and safety of NM in sepsis patients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis multicenter, double-blind, RCT was designed to recruit 778 subjects who met Sepsis 3.0 criteria. Participants will be randomly assigned (1:1) to receive either intravenous administration of NM or glucose along with standard treatment. The primary outcome is the all-cause mortality rate in the intensive care unit (ICU), and the secondary outcomes include the improvement in SOFA scores, changes in Japanese Association for Acute Medicine (JAAM)/International Society on Thrombosis and Hemostasis (ISTH) scores, 28-day all-cause mortality rate, and the incidence of adverse events. The allocation will remain concealed from investigators, participants, and statisticians to maintain blinding.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThe EASNMS trial aims to assess the efficacy and safety of NM for treating sepsis across various regions in China. As an additional treatment option, NM may potentially enhance the prognosis of sepsis patients.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eClinicalTrials.gov NCT06078839. Registered on September 20, 2023\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of Nafamostat Mesilate for sepsis (EASNMS) : study protocol for a multicenter randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-01 09:39:02","doi":"10.21203/rs.3.rs-6629099/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-06-26T12:05:32+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-26T12:05:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-19T11:36:19+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-06-19T03:14:07+00:00","index":"","fulltext":""},{"type":"decision","content":"Minor revision","date":"2025-06-16T03:35:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f02cfeff-1cd0-45ce-9e40-8ad9e90ef7ec","owner":[],"postedDate":"July 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-04T16:42:59+00:00","versionOfRecord":{"articleIdentity":"rs-6629099","link":"https://doi.org/10.1186/s13063-025-08979-4","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2025-07-29 16:13:19","publishedOnDateReadable":"July 29th, 2025"},"versionCreatedAt":"2025-07-01 09:39:02","video":"","vorDoi":"10.1186/s13063-025-08979-4","vorDoiUrl":"https://doi.org/10.1186/s13063-025-08979-4","workflowStages":[]},"version":"v1","identity":"rs-6629099","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6629099","identity":"rs-6629099","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}