Efficacy and Safety of Chinese Herbal Medicine HuoXue LiShui Formula for Chronic Subdural Hematoma (CHARM): Study Protocol for a Multicenter Randomized Controlled Trial

Efficacy and Safety of Chinese Herbal Medicine HuoXue LiShui Formula for Chronic Subdural Hematoma (CHARM): 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 Study protocol Efficacy and Safety of Chinese Herbal Medicine HuoXue LiShui Formula for Chronic Subdural Hematoma (CHARM): Study Protocol for a Multicenter Randomized Controlled Trial Liang Wu, Yanping Tong, Yunfei Li, Dezhu Gao, Wei Wei, Hongbing Zhang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4941851/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Chronic subdural hematoma (CSDH) is one of the most common neurosurgical conditions and occurs mainly in elderly individuals. Surgical evacuation is usually effective for this pathology but commonly carries significant risks, especially in patients with multiple comorbidities. Therefore, interest in nonsurgical treatment with medications such as tranexamic acid, atorvastatin, and dexamethasone is increasing. However, the efficacy of all these medications is still uncertain in patients with CSDH. According to the literature, the operative rate at 24 weeks is 5–33%. In our retrospective study, the Chinese herbal medicine HuoXue LiShui (HXLS) formula significantly reduced the necessity for surgery in patients with CSDH. The results demonstrated that HXLS can achieve low operative rates and good outcomes. Methods/design This is a prospective, multicenter, double-blinded, blinded endpoint, randomized controlled trial designed to include 160 participants 18–90 years of age presenting with CSDH verified via computed tomography or magnetic resonance imaging. The participants will be randomly allocated to receive HXLS granules (treatment group) or placebo (control group) after enrollment two times daily for 8 weeks. The primary endpoint will be the incidence of hematoma progression requiring surgery or recurrence requiring reoperation; the secondary outcomes will include CSDH volume, thickness, neurological outcome, cognitive function, performance in activities of daily living, and quality of life at 24 weeks. Discussion This trial will validate the efficacy and safety of the Chinese herbal medicine HXLS formula in reducing operative rates, improving clinical outcomes in patients with CSDH, and improving nonsurgical management. Trial registration This trial was registered at Clinicaltrials.gov with NCT06427980 on August 17, 2024. ( https://www.clinicaltrials.gov/ct2/show/study/NCT06427980 .) HuoXue LiShui Chronic subdural hematoma Chinese herbal medicine formula Pharmacotherapy Randomized controlled trial Figures Figure 1 Background Chronic subdural hematoma (CSDH) is among the most common neurosurgical conditions, particularly affecting elderly individuals. CSDH consists of persistent blood accumulation between the brain's cortical surface and the dura mater. The incidence of CSDH has increased due to the aging population and the increasing clinical use of anticoagulants and antiplatelet drugs. Annually, the incidence of CSDH in the general population is approximately 1 to 13 per 100,000 individuals [ 1 , 2 ]. Among those aged 80 and older, this incidence significantly increases to 127.1 per 100,000 [ 3 ]. The mortality rate for surgically treated CSDH patients has increased from 11.1–13.5%, and it has increased dramatically to 38.4% among patients aged 90 years or older, regardless of treatment type [ 4 ]. Given the high mortality rate and complicated medical conditions in this age group, effective nonsurgical treatments are highly desirable. Although various studies have proposed nonsurgical options such as steroids, tranexamic acid, and atorvastatin, there are still no clear evidence-based guidelines for their use. Chinese herbal medicine and traditional methods for controlling bleeding, such as improving blood circulation, improving qi, and warming meridians, have been employed for millennia to treat hemorrhagic diseases. These approaches are of particular importance as adjuvant therapies for intracranial hemorrhage [ 5 , 6 ]. However, there is a lack of clinical data on the treatment of CSDH with Chinese herbal medicine. This study aimed to investigate the efficacy of Chinese herbal medicine in treating CSDH. According to the literature, the operative rate for conservative treatment of CSDH within 24 weeks ranges from 5–33% [ 7 – 11 ]. The optimal medication management for CSDH remains uncertain. In our retrospective study [ 12 ], 40 patients with CSDH were treated with Chinese herbal medicine HuoXue LiShui (HXLS) based on traditional Chinese medicine principles. HXLS consists of four traditional Chinese herbs, the composition shown in Table 1 , has the effect of activating blood circulation, breaking blood clots and removing stasis. All patients showed improvement in neurological symptoms and did not require surgery. At three months posttreatment, 85% (34 out of 40) of patients had good outcomes, as indicated by Markwalder grading scale (MGS) scores [ 13 ] of 0–1. These results suggest that the Chinese herbal HXLS formula promotes hematoma absorption, leading to low operative rates and favourable outcomes. To provide evidence-based recommendations for CSDH management, a randomized controlled trial is necessary to validate our findings for HXLS. Table 1 Composition of HuoXue LiShui formula Ingredients Latinname of Medicine Latinname of Origin Family Content Yimucao Leonuri Herba Leonurus japonicus Houtt. Lamiaceae 15g Shuizhi Hirudo Hirudo nipponica Whitman Hirudinidae 1.5g Taoren Persicae Semen Prunus persica (L.) Batsch Rosaceae 6.0g Honghua Carthami Flos Carthamus tinctorius L. Asteraceae 6.0g Chinese Pharmacopoeia Commission. Pharmacopoeia of the People's Republic of China (2020), China Medical Science Press, Beijing, China. Methods Study design The CHARM trial is a prospective, randomized, double-blinded, placebo-controlled, multicenter clinical study designed to compare differences in the incidence of hematoma progression or recurrence requiring operation and the clinical outcome from treatment up to 24 weeks between the HXLS group and the placebo group. In total, 160 patients will be randomly assigned to the HXLS or placebo group at a 1:1 ratio. The Consolidated Standards of Reporting Trials (CONSORT) patient flow diagram is presented in Fig. 1 . Following informed consent and collection of baseline information, treatment will be administered for 24 weeks according to stratified block randomization. Participants in the treatment and control groups will undergo 5 scheduled follow-up visits. Table 2 shows the participant timeline. Table 2 Schedule of enrollment, interventions, and assessments Time point Enrollment Allocation 4th week 8th week 24th week Enrollment Eligibility screen ▲ Informed consent ▲ Randomization ▲ Interventions Formula HuoXue LiShui Placebo Assessments Demographics, medical history ▲ Laboratory data ▲ ▲ ▲ ▲ Neurological examination ▲ ▲ ▲ ▲ Computed tomography ▲ ▲ ▲ ▲ mRS ▲ ▲ ▲ ▲ MGS ▲ ▲ ▲ EQ-5D-5L ▲ ▲ ▲ ▲ Barthel ▲ ▲ ▲ ▲ MoCA ▲ ▲ ▲ ▲ Compliance ▲ ▲ ▲ Durg combination ▲ ▲ ▲ ▲ (S) AEs ▲ ▲ ▲ EQ-5D-5L: EuroQoL 5-Dimension 5-Level questionnaire, MGS: Markwalder Grading Scale, MoCA: Montreal Cognitive Assessment, mRS: Modified Rankin Scale, (S) AE: (severe) adverse event. Study sites and participant recruitment This multicenter study will be conducted from October 2024 to December 2025 at 3 hospitals in China. In the participating centers, all patients diagnosed with CSDH will be tested for eligibility for the CHARM study. After providing informed consent, patients will be randomized to either the treatment or control group. The Beijing Tiantan Hospital, Capital Medical University, as the leader center, facilitates research to guarantee compliance with the protocol, adherence to the International Conference on Harmonization-Good Clinical Practice (ICH-GCP), and data safety. Participants selection Inclusion criteria Age between 18 and 90 years and either gender will be included. Supratentorial, unilateral or bilateral CSDHs will be verified via cranial CT or magnetic resonance imaging (MRI). Primary hematoma or residual hematoma after burr-hole drainage. Stable vital signs and neurological deficits are indicated by a Glassgow Coma Scale (GCS) score ≥ 14 and a modified Rankin scale (mRS) score ≤ 2. No risk of brain herniation or recent immediate need for surgery will be evaluated by 2 attending neurosurgeons. Written informed consent will be obtained from patients or their next of kins according to their cognitive status. Exclusion criteria Unstable vital signs or symptoms of brain herniation, including severe headache, nausea and vomiting, or disturbed consciousness. Progressive or apparent neurological deficit with a GCS score 2. Midline shift > 10 mm on the radiological image. Previous medication treatment for CSDH. Previous intracranial surgery for any other neurological disorder. Structural causes for secondary CSDH, including arachnoid cysts, intracranial tumors, vascular malformations, spontaneous intracranial hypotension, coagulopathy, and conversion from acute subdural hematoma. Known hypersensitivity or allergy to HXLS or to any of the ingredients. Malignant tumors. Life expectancy of 120 U/L). Severe renal impairment (estimated glomerular filtration rate 150 µmol/L). Moderate or severe anemia (hemoglobin ≤ 90 g/L). Severe coagulopathy or a high risk of life-threatening bleeding. Poor medication conditions or the presence of severe comorbidities such that treatment cannot be tolerated or follow-up cannot be completed. Routine oral antithrombotic or antifibrinolytic drugs, steroids, statins, angiotensin-converting enzyme inhibitors, or other traditional Chinese medicines before randomization or are expected to take such medications in the next 24 weeks. Difficulty swallowing oral medication. Pregnancy or lactation. Participating in another study. Criteria for discontinuing or modifying allocated interventions All eligible participants can withdraw their consent at any time and terminate their participation in the study prematurely. During the trial, the following situations should be treated as withdrawals: Participants are unwilling to continue the trial and request to withdraw from the trial. Serious complications, significant physiological changes, serious adverse events (SAE), and other serious events that occur during the trial. Participants who have poor compliance (such as taking drugs in violation of the prescribed dose). Participants who refuse to accept medication or examination and lose of visitors. The allocated interventions cannot be modified during study participation, and crossover to the other study arm is not allowed. Withdrawal from the study and detailed reasons will be recorded if known. Moreover, the principal investigator (PI) is entitled to terminate the study prematurely if patient recruitment remains inadequate or unacceptable risks arise after the Data Safety Monitoring Board (DSMB) assessment. Sample size According to the literature, the operative rate of conservative treatment for CSDH is between 18.7% and 23.5%, so we used an average of 20% for the placebo group. On the basis of our preliminary trial results [ 11 ], HXLS was assumed to reduce the operative rate by 75%, so 5.0% for the treatment group was used. In the setting of α = 0.05 and β = 0.2, the sample size was 73 in each group. Given a 10% dropout rate, 7 more participants will be required in each group. In total, 160 participants will be enrolled. Randomization, blinding and unblinding After written consent is obtained, a computerized random-number list generator will randomly assign eligible participants to a web-based, GCP-compliant electronic data capture (EDC) system. Randomization is performed separately at each center. The randomization of participants will be conducted via the EDC system for data collection in clinical trials. Once a patient has been recruited into the trial, the system will release the randomization code to ensure allocation concealment. The neurosurgeons involved in the CHARM trial will be responsible for recruiting participants who have consented to participate and who meet the established inclusion criteria. The randomization code will be released after the system uploads the signed consent form. An experienced sub-investigator who is not involved in any other aspect of this study will utilize an online EDC system to generate a computerized random-number list, which will subsequently allocate participants to either of the two groups. An extended stratified block algorithm will be employed to create an unpredictable allocation sequence. Clinical investigators cannot influence the process of random assignment. The investigators in charge of the recruitment and follow-up evaluation, participants, outcome assessors, and data analysts will be blinded. An independent pharmacy will hold the unblinding codes. If a severe adverse event is suspected, the investigator will try to contact the PI to discuss options as soon as possible. If unblinding is deemed necessary, the PI will contact the pharmacy, which will reveal the treatment assignment for the individual subject to the local investigator. The local investigator will document and store the unblinding information in the local study file. The date, time and reason for unblinding will be thoroughly recorded. If unblinding occurs, the subject must be discontinued from the study as soon as possible. The subject should be strongly encouraged to perform an end-of-study assessment and remain under medical supervision until the condition becomes stable. Before the outcome assessment begins at every follow-up evaluation, the patients will be reminded not to reveal any information about their group allocation to decrease the risk of unblinding. If the investigator can detect details of group allocation during follow-up, another blinded researcher will evaluate the outcome. Interventions method All eligible patients will be randomized into two groups as follows: HXLS treatment group: HXLS 28.5 g per time, twice daily, for 8 weeks. Control group: placebo 28.5 g per time, twice daily To the greatest extent possible, the appearance, taste, and weight of the placebo will be consistent with those of the oral HXLS granules. With respect to the outer packing, the HXLS and placebo granules will be the same. The HXLS and placebo oral granules will be manufactured by Beijing Tcmages Pharmaceutical Co. Ltd. (Beijing, China) according to the requirements of good manufacturing practices. These materials meet the hygienic requirements of the oral granule product. All test drugs will be collected and counted by designated personnel. Drugs and placebos covering the entire course of treatment for each participant will be packed uniformly and individually. At every visit, participants will receive the drugs scheduled for the next intervention period and the drugs left from the previous period will be returned. Standard care entails meticulously observing new neurological symptoms and comorbidities during the follow-up period in the outpatient clinic. The administration and dosage of concomitant medication for physical conditions will be permitted and recorded in detail. Any queries raised by the participants will be addressed to facilitate the completion of the study. In the event of new neurological symptoms or the gradual progression of hematomas, surgical intervention will be considered, and the administration of the study medication will be discontinued postoperatively. Strategies to improve adherence to interventions Study treatment will occur after enrollment, and follow-up visits will occur at 4, 8, and 24 weeks. At enrollment, participants will receive detailed instructions about Chinese herbal medicine treatment. Moreover, the importance of adherence to the study protocol will be emphasized. Treatment adherence will be monitored during follow-up visits at 4, 8, and 24 weeks by asking whether the participant experienced any side effects or AEs. Study participants can contact one of the researchers with any questions during the study period. The entire study process will be continuously monitored by a blinded local researcher at each center who will perform the follow-up outcome measurements. All study participants will receive standard care and extended follow-up after the study ends. They can claim reimbursement from the study insurance to compensate for trial-associated harm. Relevant concomitant care permitted or prohibited during the trial In addition to the study intervention, patients in both groups will receive treatment in accordance with the established standard of care at the trial center. The use of any intervention or medication that may affect the hematoma is prohibited. Accordingly, in light of the literature, the use of statins, steroids, antifibrinolytics, angiotensin-converting enzyme inhibitors, and other Chinese medicines with components that promote blood circulation is contraindicated. All other medical treatments that are part of routine clinical practice during the course of the study can be administered. Outcome measurements Primary outcome The primary outcome will be the incidence of hematoma progression or recurrence requiring operation for CSDH up to 24 weeks after the start of treatment with the study medication. Surgery will be considered when clinical deterioration occurs, defined as a ≥ 1-point increase in the MGS at any time after the initiation of treatment and/or a midline shift > 5 mm on a follow-up CT scan. Secondary outcome CSDH volume, thickness, and mid-line shift measured via head CT/MRI at baseline and at 4, 8, and 24 weeks; functional outcome by mRS score and MGS grade at baseline and 4, 8, and 24 weeks; quality of life by five-dimensional EuroQol (EQ-5D-5L) at baseline and at 4, 8, and 24 weeks; performance in activities of daily living (Barthel score) at baseline and at 4, 8, and 24 weeks; cognitive function by Montreal Cognitive Assessment (MOCA) score at baseline and at 4, 8, and 24 weeks; number of falling incidents at 24 weeks; mortality at 24 weeks; rate of complications and AEs between groups within 24 weeks. Safety outcome General physical examination (body temperature, heart rate, breathing, and blood pressure), laboratory tests (routine blood tests, liver and kidney function tests), and head computed tomography will be measured at each visit. Quality control The Coordinating Center (CC) will consist of two PIs, two neurosurgeons, two doctors of traditional Chinese medicine, and one methodologist. The CC's role is to train the research members from all study sites regarding every aspect of the study protocol, including recruitment, intervention, and follow-up evaluation, and to coordinate and supervise all standardized data management and quality control. The Trial Steering Committee (TSC) will include three independent neurosurgery experts, one traditional Chinese medicine doctor, and two independent statisticians. It will be responsible for recruiting and progressing the trial, overall supervision, and quality control during the study. It will also ensure standardized training for research members regarding the study protocol. An independent DSMB will consist of two statisticians and two clinical experts. All members will be blinded and independent of the study and investigators. The DSMB will monitor the study data, participant safety, and SAEs throughout the trial and will be responsible for all the statistical analyses. The DSMB will regularly report blinded statistical data to the TSC, and subsequent meetings will be held at the 50% and 100% points of participant inclusion. The IRBs of all the study sites will perform regular inspections of the trial. The inspections will be independent of the investigators and the sponsor. The data management researcher will stay in regular contact with the investigators about trial progress, data consistency, and follow-up visit violations. Although changes or amendments are not expected, any trial deviations from the present protocol will be fully documented via a breach report form. Protocol amendments will be notified to the sponsor within 3 days and then to the relevant parties and centers by sending the updated protocol to the investigators. Any changes must be cleared in written form and signed by all persons in charge, stating the detailed reasons for changes. If necessary, changes must be approved by the IRB and/or individual participants. A copy of the revised protocol will be added to the Investigator Site File. The protocol will be updated on the ClinicalTrials.gov registry website. Data management All collected data will be stored in an online EDC system accessible only to the investigators. A group of blinded research members in charge of the follow-up evaluation will collect primary and secondary outcomes. At the completion of the 24 weeks of follow-up data collection, a data quality audit will be performed. To guarantee confidentiality, all personal information about the participants will be collected and stored in a secure EDC system throughout the duration of the study. All participants will be allocated individual trial identification numbers. Only the lead investigator will have access to all the files corresponding to the participants’ data. After the completion of the study, the results will be made public through publication in a scientific journal, conferences related to neurosurgery, and the clinicaltrials.gov website. The data generated or analysed during this study will be available from the corresponding author upon reasonable request. Statistical analysis Statistical analyses will be performed via a statistical package (SPSS software 25.0). The Kolmogorov‒Smirnov test will be performed to assess the normality of the variables. Data with a normal distribution will be presented as the mean ± standard error of the mean. Variables for skewed distributions will be described as medians and interquartile ranges. Categorical variables are expressed as frequencies with percentages. Comparisons between the groups will be carried out via an independent t test to compare normally distributed data, the Mann‒Whitney U test to compare skewed data, and the χ2 test or Fisher’s exact test to compare categorical data, such as safety analyses with the incidence of AEs. For numerical data collected at different time points throughout the 24 weeks, repeated measures analysis of variance will be performed between the two groups. The significance level will be set at p < 0.05. All researchers will be trained according to the same training protocol. Protocol modifications are not expected. Missing clinical data, if any, will be obtained from the electronic hospital files. Follow-up evaluation at specified time points is mandatory, and missing data are not anticipated. Analyses of all outcomes will be performed according to the intention-to-treat principle, and once enrolled, all participants will be analysed, regardless of the findings. Interim analyses Although there are no anticipated problems that may be detrimental to the participants, serious life-threatening adverse events leading to prolonged hospital stay or death will be reported to the IRB, and our study will be terminated immediately. There will be no interim analyses in this trial. Methods for additional analyses (e.g., subgroup analyses) Prior to statistical analysis, a sub-investigator will review the data record forms to check for legitimacy and identify missing data. Subgroup analysis will be conducted to evaluate patients' outcomes based on their baseline clinical and demographic characteristics, such as sex, age, type of hematoma on CT scan, volume of hematoma, and comorbidities. Safety and ethic HXLS has been used clinically for many years and has good safety in the preliminary study [ 11 ]. To ensure the safety of participants, all participants are given HXLS or placebo treatment in addition to routine therapy and will receive relevant safety checks. Investigators will also take timely symptomatic treatment of AEs in the participants. Any adverse events (AEs) will be recorded, and a thorough assessment of the potential associations between the study interventions and the adverse events will be carried out. A detailed recording of all the AEs during the study will be closely monitored and reported to the ethics committee as soon as possible to facilitate stabilization or termination of the survey if necessary. Serious life-threatening AEs leading to serious complications or death will be reported to the Institutional Review Board (IRB), and the trial will be terminated immediately. Dissemination After the completion of the study, the results will be written as a final trial report through publication in a scientific journal along with international meetings related to neurosurgery and the clinicaltrials.gov website. Discussion The prevalence of CSDH has risen, largely due to the ageing population and the widespread use of anticoagulants and antiplatelet medications. The development and recurrence of CSDH are associated with localized inflammation, the formation of new immature blood vessels, and the breakdown of blood clots [ 14 , 15 ]. Among these, inflammation plays a central role in CSDH progression. Various inflammatory cells and cytokines, both promoting and suppressing inflammation, contribute to this process. Research shows that levels of certain cytokines and chemokines, including interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-α, monocyte chemoattractant protein-1, and eotaxin-3, are significantly higher in CSDH fluid compared to serum [ 14 , 16 – 18 ]. This inflammation weakens the endothelial cell barrier, leading to the development of immature and "leaky" blood vessels, which exacerbate the condition by allowing continuous bleeding [ 19 – 21 ]. Additionally, the presence of high levels of fibrin/fibrinogen degradation products in CSDH fluid indicates excessive clot breakdown, contributing to persistent bleeding. As a result, many drugs targeting different aspects of this cycle are currently under investigation as potential drug treatments for CSDH. Despite several studies [ 13 , 22 – 26 ] to date, the optimal drug therapy for CSDH remains a matter of debate. According to theory of traditional Chinese medicine, the main pathogenesis of CSDH is blood stasis and fluid stagnation. L. Sweet is a common Chinese herbal medicine used for activating blood circulation and inducing diuresis to alleviate edema. Hirudo is used to break blood clots and remove stasis. Tao-Ren and Hong-Hua are classic Chinese herbal medicine pairs that activate blood circulation. These four Chinese herbal medicines are compatible with the HXLS formula [ 12 ], which aims to activate blood circulation and eliminate fluid. Our observational evidence suggests that HXLS may reduce the necessity of surgery with few side effects. Nevertheless, similar to many other Chinese patent medicines, the HXLS formula requires strong clinical evidence regarding its therapeutic effect and safety to support its use. Thus, a randomized controlled trial is needed to evaluate the efficacy and safety of HXLS compared with those of a placebo. In this study, we describe the rationale, design, interventions, and methodological framework of a multicenter, double-blinded, randomized controlled trial to assess whether HXLS can reduce the incidence of hematoma progression or recurrence requiring operation of CSDH as a nonsurgical treatment compared with placebo. Furthermore, we will investigate functional outcomes (mRS and MGS), cognitive function (MoCA), and quality of life (EQ-5D-5L) before and after treatment. Moreover, this study will be conducted in outpatient settings at 3 neurosurgical centers in China, and all patients aged 18–90 years will be included. Effective communication will be strengthened to encourage cooperation and support between neurosurgeons and traditional Chinese medicine physicians throughout the trial. Therefore, the results will be widely applicable. However, there are some limitations to be considered. First, it should be noted that secondary endpoints of mRS, MGS, EQ-5D-5L, Barthel score and MOCA score are subjective. Therefore, participants’ subjective psychological states and living habits might affect our findings. Because these were not primary endpoint, we do not perform further objective assessments. Secondly, we developed a protocol for a multicenter, double-blinded, randomized clinical trial with a long intervention duration of 8 weeks. This is also consistent with the characteristics of traditional Chinese medicine intervention for diseases. However, long-term medication might affect patient compliance. Finally, the study included patients with CSDH, which may not represent all CSDH patients, especially those with CSDH with serious complications. In conclusion, this study aims to determine whether this Chinese herbal medication can reduce the CSDH operative rate and improve clinical outcomes, which may change clinical practice and guideline recommendations. Whether HXLS is suitable for the treatment of all CSDH requires further clinical evaluations in different CSDH populations. Trial status This study is not yet recruiting. Abbreviations HXLS HuoXue LiShui CSDH Chronic Subdural Hematoma CC Coordinating Center CONSORT Consolidated Standards of Reporting Trials MGS Markwalder Grading Scale MoCA Montreal Cognitive Assessment mRS Modified Rankin Scale; PI:Principal Investigator GCS Glassgow Coma Scale CT Computed Tomography SAE Serious Adverse Event AE Adverse Event TSC Trial Steering Committee ICH-GCP International Conference on Harmonization-Good Clinical Practice IRB Institutional Review Board DSMB Data Safety Monitoring Board EDC Electronic Data Capture Declarations Acknowledgements We thank Professor Beibei Xu for providing advisory support for the protocol. Modification of the protocol Although changes or amendments are not to be expected, any trial deviations from the present protocol will be fully documented using a breach report form. Protocol amendments will be notified to the sponsor within 3 days and then to the relevant parties and centers by sending the updated protocol to the investigators. Any changes must be cleared in written form and signed by all persons in charge, stating the detailed reasons for changes. If necessary, changes must be approved by the IRB and/or individual participants. A copy of the revised protocol will be added to the Investigator Site File. The protocol will be updated in the ClinicalTrials.gov registry website. Authors’ contributions WML together with LW created the study design. LW, YPT, DZG, WW, HBZ, YFL, and YPF conceived the study, participated in its design and coordination and helped draft the manuscript. LW, YPT, and YFL drafted the manuscript and calculated the statistics. HBZ and HZ adapted the protocol to Chinese conditions and selected the study sites. All the authors read and approved the final manuscript. Funding This study is funded by the Beijing Traditional Chinese Medicine Technology Development Fund (grant No. BJZYYB-2023-60). The funders had no role in the design, data collection and analysis, interpretation, decision to publish, or preparation of the manuscript. Availability of data and materials After the completion and publication of the CHARM trial, requests for data sharing will be considered by the CHARM Trial Management Group. Ethics approval and consent to participate This study will be performed in accordance with the principles of the Helsinki Declaration and Good Clinical Practice. The CHARM protocol version 3.0, informed consent forms, and all other relevant trial documents have been approved by the ethics committee of Beijing Tiantan Hospital, Capital Medical University (Application Number KY2023-265-03). The study is registered at ClinicalTrials.gov with the number NCT06427980. All participants will be informed about the trial's purpose, risks and potential benefits. If a participant is not mentally competent, a legal representative will also be informed. All sub-centers will obtain written informed consent before the start of baseline measurements and treatment. Consent for publication Not applicable. Competing interests All the authors declare that they have no competing interests. References Yang W, Huang J. Chronic Subdural Hematoma: Epidemiology and Natural History. Neurosurg Clin N Am. 2017;28:205–10. Iorio-Morin C, Touchette C, Lévesque M, Effendi K, Fortin D, Mathieu D. Chronic Subdural Hematoma: Toward a New Management Paradigm for an Increasingly Complex Population. J Neurotrauma. 2018;35:1882–5. Karibe H, Kameyama M, Kawase M, Hirano T, Kawaguchi T, Tominaga T. [Epidemiology of chronic subdural hematomas]. No Shinkei Geka. 2011;39:1149–53. 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Chemokines as markers of local inflammation and angiogenesis in patients with chronic subdural hematoma: a prospective study. Acta Neurochir (Wien). 2012;154:113–20. discussion 120. Frati A, Salvati M, Mainiero F, Ippoliti F, Rocchi G, Raco A, et al. Inflammation markers and risk factors for recurrence in 35 patients with a posttraumatic chronic subdural hematoma: a prospective study. J Neurosurg. 2004;100:24–32. Li T, Wang D, Tian Y, Yu H, Wang Y, Quan W, et al. Effects of atorvastatin on the inflammation regulation and elimination of subdural hematoma in rats. J Neurol Sci. 2014;341:88–96. Wang D, Li T, Wei H, Wang Y, Yang G, Tian Y, et al. Atorvastatin enhances angiogenesis to reduce subdural hematoma in a rat model. J Neurol Sci. 2016;362:91–9. Bounajem MT, Campbell RA, Denorme F, Grandhi R. Paradigms in chronic subdural hematoma pathophysiology: Current treatments and new directions. J Trauma Acute Care Surg. 2021;91:e134–41. Matsumoto H, Matsumoto A, Miyata S, Tomogane Y, Minami H, Masuda A, et al. The Effect of Japanese Herbal Medicines (Kampo) Goreisan and Saireito on the Prevention of Recurrent Chronic Subdural Hematoma: A Prospective Randomized Study. Neurosurgery. 2024;94:80–9. Katayama K, Matsuda N, Kakuta K, Naraoka M, Takemura A, Hasegawa S, et al. The Effect of Goreisan on the Prevention of Chronic Subdural Hematoma Recurrence: Multi-Center Randomized Controlled Study. J Neurotrauma. 2018;35:1537–42. Katsuki M, Kawamura S, Koh A. Japanese herbal Kampo medicine, Keishibukuryogan, for chronic subdural hematoma - Prospective observational study. Surg Neurol Int. 2022;13:307. Kwon S, Jin C, Chung M, Lee J, Cho S-Y, Park S-U, et al. Herbal medicine treatment for patients with chronic subdural hematoma: A systematic review and meta-analysis. Complement Ther Clin Pract. 2021;43:101307. Musmar B, Orscelik A, Salim H, Adeeb N, Spellicy S, Abdelgadir J et al. Efficacy and safety of tranexamic acid in the management of chronic subdural hematoma: a systematic review and meta-analysis. J Neurosurg. 2024;:1–10. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4941851","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":347639546,"identity":"a5758104-93fc-4621-ad8c-126c995927b7","order_by":0,"name":"Liang Wu","email":"","orcid":"","institution":"Beijing Tiantan Hospital, Capital Medical University, Beijing","correspondingAuthor":false,"prefix":"","firstName":"Liang","middleName":"","lastName":"Wu","suffix":""},{"id":347639548,"identity":"b9b13132-5bc7-448b-8729-cba7df9e7d9a","order_by":1,"name":"Yanping Tong","email":"","orcid":"","institution":"Beijing Tiantan Hospital, Capital Medical University, Beijing","correspondingAuthor":false,"prefix":"","firstName":"Yanping","middleName":"","lastName":"Tong","suffix":""},{"id":347639549,"identity":"d5c92d39-0b44-46e8-bbc5-c184f77fd17a","order_by":2,"name":"Yunfei Li","email":"","orcid":"","institution":"Beijing Tiantan Hospital, Capital Medical University, Beijing","correspondingAuthor":false,"prefix":"","firstName":"Yunfei","middleName":"","lastName":"Li","suffix":""},{"id":347639551,"identity":"ec5a6123-f5a3-400e-8023-b736f2fdb544","order_by":3,"name":"Dezhu Gao","email":"","orcid":"","institution":"Beijing Tiantan Hospital, Capital Medical University, Beijing","correspondingAuthor":false,"prefix":"","firstName":"Dezhu","middleName":"","lastName":"Gao","suffix":""},{"id":347639552,"identity":"8e9fac73-c246-4a06-a9dd-7e512a538ccf","order_by":4,"name":"Wei Wei","email":"","orcid":"","institution":"Beijing Tiantan Hospital, Capital Medical University, Beijing","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Wei","suffix":""},{"id":347639553,"identity":"610bbed7-a8f6-4968-a03c-0366152e481f","order_by":5,"name":"Hongbing Zhang","email":"","orcid":"","institution":"Beijing Luhe Hospital Affiliated to Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hongbing","middleName":"","lastName":"Zhang","suffix":""},{"id":347639555,"identity":"2c8774c8-ee8d-4de5-b835-114e07ab6419","order_by":6,"name":"Hui Zhou","email":"","orcid":"","institution":"First People's Hospital of Lianyungang","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Zhou","suffix":""},{"id":347639556,"identity":"62470d9b-e07b-4258-8c25-8f7bc3dfce2d","order_by":7,"name":"Yongping Fan","email":"","orcid":"","institution":"Beijing Tiantan Hospital, Capital Medical University, Beijing","correspondingAuthor":false,"prefix":"","firstName":"Yongping","middleName":"","lastName":"Fan","suffix":""},{"id":347639557,"identity":"2200f6e6-4a6f-4e1a-b577-c0089399a0c1","order_by":8,"name":"Weiming Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYBACPmYQacDAw8DAfADIsIBJMOPUwobQwpYAZEgQoQXB5DEAEsRoYecxk/hQsE3GnH/N1w0/CiQY+NtPp0kwVFgnNrCfPYDdYTxmkjMMbvNYzni77WYP0GESZ3K3STCcSU9s4MlLwKXlNg9Qi8GNs9tu8AC1GEjwbpNgbDuc2CABdip2LX/AWs48u/kHruUfAS0MIC3ne9huI2xpwKeFrfxnD9gWNrPbMgYSPEC/bLZIOJZu3MaTg1ULP//hzQY//ty2Nzh/+NnNN39s5Pjbz2688aHGWraf/QxWLQggAQkeHjAJYrPhVAq37wBBJaNgFIyCUTBCAQDOuFWX4sVboQAAAABJRU5ErkJggg==","orcid":"","institution":"Beijing Tiantan Hospital, Capital Medical University, Beijing","correspondingAuthor":true,"prefix":"","firstName":"Weiming","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2024-08-20 03:56:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4941851/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4941851/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":66747720,"identity":"9c920256-2231-455c-8190-621a5f8547d6","added_by":"auto","created_at":"2024-10-16 06:49:58","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":596135,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the trial design\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4941851/v1/22d48352c901e8e7cf960619.jpg"},{"id":87931570,"identity":"39b1962c-7e9c-41e2-861f-6d754fe8bcaa","added_by":"auto","created_at":"2025-07-30 13:39:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1537903,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4941851/v1/f861c14a-ec25-406f-8181-2f85d9f5cdf3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and Safety of Chinese Herbal Medicine HuoXue LiShui Formula for Chronic Subdural Hematoma (CHARM): Study Protocol for a Multicenter Randomized Controlled Trial","fulltext":[{"header":"Background","content":"\u003cp\u003eChronic subdural hematoma (CSDH) is among the most common neurosurgical conditions, particularly affecting elderly individuals. CSDH consists of persistent blood accumulation between the brain's cortical surface and the dura mater. The incidence of CSDH has increased due to the aging population and the increasing clinical use of anticoagulants and antiplatelet drugs. Annually, the incidence of CSDH in the general population is approximately 1 to 13 per 100,000 individuals [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Among those aged 80 and older, this incidence significantly increases to 127.1 per 100,000 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The mortality rate for surgically treated CSDH patients has increased from 11.1\u0026ndash;13.5%, and it has increased dramatically to 38.4% among patients aged 90 years or older, regardless of treatment type [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Given the high mortality rate and complicated medical conditions in this age group, effective nonsurgical treatments are highly desirable. Although various studies have proposed nonsurgical options such as steroids, tranexamic acid, and atorvastatin, there are still no clear evidence-based guidelines for their use.\u003c/p\u003e \u003cp\u003eChinese herbal medicine and traditional methods for controlling bleeding, such as improving blood circulation, improving qi, and warming meridians, have been employed for millennia to treat hemorrhagic diseases. These approaches are of particular importance as adjuvant therapies for intracranial hemorrhage [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, there is a lack of clinical data on the treatment of CSDH with Chinese herbal medicine. This study aimed to investigate the efficacy of Chinese herbal medicine in treating CSDH.\u003c/p\u003e \u003cp\u003eAccording to the literature, the operative rate for conservative treatment of CSDH within 24 weeks ranges from 5\u0026ndash;33% [\u003cspan additionalcitationids=\"CR8 CR9 CR10\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The optimal medication management for CSDH remains uncertain. In our retrospective study [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], 40 patients with CSDH were treated with Chinese herbal medicine HuoXue LiShui (HXLS) based on traditional Chinese medicine principles. HXLS consists of four traditional Chinese herbs, the composition shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, has the effect of activating blood circulation, breaking blood clots and removing stasis. All patients showed improvement in neurological symptoms and did not require surgery. At three months posttreatment, 85% (34 out of 40) of patients had good outcomes, as indicated by Markwalder grading scale (MGS) scores [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] of 0\u0026ndash;1. These results suggest that the Chinese herbal HXLS formula promotes hematoma absorption, leading to low operative rates and favourable outcomes. To provide evidence-based recommendations for CSDH management, a randomized controlled trial is necessary to validate our findings for HXLS.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComposition of HuoXue LiShui formula\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIngredients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLatinname of Medicine\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLatinname of Origin\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFamily\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eContent\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYimucao\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eLeonuri Herba\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eLeonurus japonicus\u003c/em\u003e Houtt.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eLamiaceae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15g\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShuizhi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eHirudo\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eHirudo nipponica\u003c/em\u003e Whitman\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eHirudinidae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.5g\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTaoren\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePersicae Semen\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ePrunus persica\u003c/em\u003e (L.) Batsch\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eRosaceae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.0g\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHonghua\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eCarthami Flos\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eCarthamus tinctorius\u003c/em\u003e L.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eAsteraceae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.0g\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eChinese Pharmacopoeia Commission. Pharmacopoeia of the People's Republic of China (2020), China Medical Science Press, Beijing, China.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThe CHARM trial is a prospective, randomized, double-blinded, placebo-controlled, multicenter clinical study designed to compare differences in the incidence of hematoma progression or recurrence requiring operation and the clinical outcome from treatment up to 24 weeks between the HXLS group and the placebo group. In total, 160 patients will be randomly assigned to the HXLS or placebo group at a 1:1 ratio. The Consolidated Standards of Reporting Trials (CONSORT) patient flow diagram is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Following informed consent and collection of baseline information, treatment will be administered for 24 weeks according to stratified block randomization. Participants in the treatment and control groups will undergo 5 scheduled follow-up visits. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the participant timeline.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSchedule of enrollment, interventions, and assessments\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime point\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEnrollment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAllocation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4th week\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e8th week\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e24th week\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnrollment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEligibility screen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInformed consent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRandomization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInterventions\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormula HuoXue LiShui\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAssessments\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemographics, medical history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLaboratory data\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeurological examination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComputed tomography\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMGS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEQ-5D-5L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBarthel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMoCA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCompliance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDurg combination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e(S) AEs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e▲\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eEQ-5D-5L: EuroQoL 5-Dimension 5-Level questionnaire, MGS: Markwalder Grading Scale, MoCA: Montreal Cognitive Assessment, mRS: Modified Rankin Scale, (S) AE: (severe) adverse event.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy sites and participant recruitment\u003c/h2\u003e \u003cp\u003eThis multicenter study will be conducted from October 2024 to December 2025 at 3 hospitals in China. In the participating centers, all patients diagnosed with CSDH will be tested for eligibility for the CHARM study. After providing informed consent, patients will be randomized to either the treatment or control group. The Beijing Tiantan Hospital, Capital Medical University, as the leader center, facilitates research to guarantee compliance with the protocol, adherence to the International Conference on Harmonization-Good Clinical Practice (ICH-GCP), and data safety.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eParticipants selection\u003c/h2\u003e \u003cp\u003e \u003cb\u003eInclusion criteria\u003c/b\u003e \u003c/p\u003e \u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eAge between 18 and 90 years and either gender will be included.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eSupratentorial, unilateral or bilateral CSDHs will be verified via cranial CT or magnetic resonance imaging (MRI).\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePrimary hematoma or residual hematoma after burr-hole drainage.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eStable vital signs and neurological deficits are indicated by a Glassgow Coma Scale (GCS) score\u0026thinsp;\u0026ge;\u0026thinsp;14 and a modified Rankin scale (mRS) score\u0026thinsp;\u0026le;\u0026thinsp;2.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eNo risk of brain herniation or recent immediate need for surgery will be evaluated by 2 attending neurosurgeons.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e Written informed consent will be obtained from patients or their next of kins according to their cognitive status.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eExclusion criteria\u003c/b\u003e \u003c/p\u003e \u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eUnstable vital signs or symptoms of brain herniation, including severe headache, nausea and vomiting, or disturbed consciousness.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eProgressive or apparent neurological deficit with a GCS score\u0026thinsp;\u0026lt;\u0026thinsp;14 or mRS score\u0026thinsp;\u0026gt;\u0026thinsp;2.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eMidline shift\u0026thinsp;\u0026gt;\u0026thinsp;10 mm on the radiological image.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePrevious medication treatment for CSDH.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePrevious intracranial surgery for any other neurological disorder.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eStructural causes for secondary CSDH, including arachnoid cysts, intracranial tumors, vascular malformations, spontaneous intracranial hypotension, coagulopathy, and conversion from acute subdural hematoma.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eKnown hypersensitivity or allergy to HXLS or to any of the ingredients.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eMalignant tumors.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eLife expectancy of \u0026lt;\u0026thinsp;1 year.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eAbnormal liver function or liver diseases, including uncontrolled hepatitis (alanine transaminase\u0026thinsp;\u0026gt;\u0026thinsp;120 U/L).\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eSevere renal impairment (estimated glomerular filtration rate\u0026thinsp;\u0026lt;\u0026thinsp;30 ml/min or serum creatinine\u0026thinsp;\u0026gt;\u0026thinsp;150 \u0026micro;mol/L).\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eModerate or severe anemia (hemoglobin\u0026thinsp;\u0026le;\u0026thinsp;90 g/L).\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eSevere coagulopathy or a high risk of life-threatening bleeding.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePoor medication conditions or the presence of severe comorbidities such that treatment cannot be tolerated or follow-up cannot be completed.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eRoutine oral antithrombotic or antifibrinolytic drugs, steroids, statins, angiotensin-converting enzyme inhibitors, or other traditional Chinese medicines before randomization or are expected to take such medications in the next 24 weeks.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003e Difficulty swallowing oral medication.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePregnancy or lactation.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eParticipating in another study.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eCriteria for discontinuing or modifying allocated interventions\u003c/h2\u003e \u003cp\u003eAll eligible participants can withdraw their consent at any time and terminate their participation in the study prematurely. During the trial, the following situations should be treated as withdrawals:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eParticipants are unwilling to continue the trial and request to withdraw from the trial.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSerious complications, significant physiological changes, serious adverse events (SAE), and other serious events that occur during the trial.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eParticipants who have poor compliance (such as taking drugs in violation of the prescribed dose).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eParticipants who refuse to accept medication or examination and lose of visitors.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eThe allocated interventions cannot be modified during study participation, and crossover to the other study arm is not allowed. Withdrawal from the study and detailed reasons will be recorded if known. Moreover, the principal investigator (PI) is entitled to terminate the study prematurely if patient recruitment remains inadequate or unacceptable risks arise after the Data Safety Monitoring Board (DSMB) assessment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003e According to the literature, the operative rate of conservative treatment for CSDH is between 18.7% and 23.5%, so we used an average of 20% for the placebo group. On the basis of our preliminary trial results [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], HXLS was assumed to reduce the operative rate by 75%, so 5.0% for the treatment group was used. In the setting of α\u0026thinsp;=\u0026thinsp;0.05 and β\u0026thinsp;=\u0026thinsp;0.2, the sample size was 73 in each group. Given a 10% dropout rate, 7 more participants will be required in each group. In total, 160 participants will be enrolled.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eRandomization, blinding and unblinding\u003c/h2\u003e \u003cp\u003eAfter written consent is obtained, a computerized random-number list generator will randomly assign eligible participants to a web-based, GCP-compliant electronic data capture (EDC) system. Randomization is performed separately at each center.\u003c/p\u003e \u003cp\u003eThe randomization of participants will be conducted via the EDC system for data collection in clinical trials. Once a patient has been recruited into the trial, the system will release the randomization code to ensure allocation concealment. The neurosurgeons involved in the CHARM trial will be responsible for recruiting participants who have consented to participate and who meet the established inclusion criteria. The randomization code will be released after the system uploads the signed consent form.\u003c/p\u003e \u003cp\u003eAn experienced sub-investigator who is not involved in any other aspect of this study will utilize an online EDC system to generate a computerized random-number list, which will subsequently allocate participants to either of the two groups. An extended stratified block algorithm will be employed to create an unpredictable allocation sequence. Clinical investigators cannot influence the process of random assignment.\u003c/p\u003e \u003cp\u003eThe investigators in charge of the recruitment and follow-up evaluation, participants, outcome assessors, and data analysts will be blinded. An independent pharmacy will hold the unblinding codes. If a severe adverse event is suspected, the investigator will try to contact the PI to discuss options as soon as possible. If unblinding is deemed necessary, the PI will contact the pharmacy, which will reveal the treatment assignment for the individual subject to the local investigator. The local investigator will document and store the unblinding information in the local study file. The date, time and reason for unblinding will be thoroughly recorded.\u003c/p\u003e \u003cp\u003eIf unblinding occurs, the subject must be discontinued from the study as soon as possible. The subject should be strongly encouraged to perform an end-of-study assessment and remain under medical supervision until the condition becomes stable.\u003c/p\u003e \u003cp\u003eBefore the outcome assessment begins at every follow-up evaluation, the patients will be reminded not to reveal any information about their group allocation to decrease the risk of unblinding. If the investigator can detect details of group allocation during follow-up, another blinded researcher will evaluate the outcome.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eInterventions method\u003c/h2\u003e \u003cp\u003eAll eligible patients will be randomized into two groups as follows:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHXLS treatment group: HXLS 28.5 g per time, twice daily, for 8 weeks.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eControl group: placebo 28.5 g per time, twice daily\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eTo the greatest extent possible, the appearance, taste, and weight of the placebo will be consistent with those of the oral HXLS granules. With respect to the outer packing, the HXLS and placebo granules will be the same. The HXLS and placebo oral granules will be manufactured by Beijing Tcmages Pharmaceutical Co. Ltd. (Beijing, China) according to the requirements of good manufacturing practices. These materials meet the hygienic requirements of the oral granule product. All test drugs will be collected and counted by designated personnel. Drugs and placebos covering the entire course of treatment for each participant will be packed uniformly and individually. At every visit, participants will receive the drugs scheduled for the next intervention period and the drugs left from the previous period will be returned.\u003c/p\u003e \u003cp\u003eStandard care entails meticulously observing new neurological symptoms and comorbidities during the follow-up period in the outpatient clinic. The administration and dosage of concomitant medication for physical conditions will be permitted and recorded in detail. Any queries raised by the participants will be addressed to facilitate the completion of the study. In the event of new neurological symptoms or the gradual progression of hematomas, surgical intervention will be considered, and the administration of the study medication will be discontinued postoperatively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStrategies to improve adherence to interventions\u003c/h2\u003e \u003cp\u003eStudy treatment will occur after enrollment, and follow-up visits will occur at 4, 8, and 24 weeks. At enrollment, participants will receive detailed instructions about Chinese herbal medicine treatment. Moreover, the importance of adherence to the study protocol will be emphasized.\u003c/p\u003e \u003cp\u003eTreatment adherence will be monitored during follow-up visits at 4, 8, and 24 weeks by asking whether the participant experienced any side effects or AEs. Study participants can contact one of the researchers with any questions during the study period. The entire study process will be continuously monitored by a blinded local researcher at each center who will perform the follow-up outcome measurements.\u003c/p\u003e \u003cp\u003eAll study participants will receive standard care and extended follow-up after the study ends. They can claim reimbursement from the study insurance to compensate for trial-associated harm.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRelevant concomitant care permitted or prohibited during the trial\u003c/h2\u003e \u003cp\u003eIn addition to the study intervention, patients in both groups will receive treatment in accordance with the established standard of care at the trial center. The use of any intervention or medication that may affect the hematoma is prohibited. Accordingly, in light of the literature, the use of statins, steroids, antifibrinolytics, angiotensin-converting enzyme inhibitors, and other Chinese medicines with components that promote blood circulation is contraindicated. All other medical treatments that are part of routine clinical practice during the course of the study can be administered.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eOutcome measurements\u003c/h2\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003ePrimary outcome\u003c/h2\u003e \u003cp\u003eThe primary outcome will be the incidence of hematoma progression or recurrence requiring operation for CSDH up to 24 weeks after the start of treatment with the study medication. Surgery will be considered when clinical deterioration occurs, defined as a\u0026thinsp;\u0026ge;\u0026thinsp;1-point increase in the MGS at any time after the initiation of treatment and/or a midline shift\u0026thinsp;\u0026gt;\u0026thinsp;5 mm on a follow-up CT scan.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSecondary outcome\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCSDH volume, thickness, and mid-line shift measured via head CT/MRI at baseline and at 4, 8, and 24 weeks;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003efunctional outcome by mRS score and MGS grade at baseline and 4, 8, and 24 weeks;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003equality of life by five-dimensional EuroQol (EQ-5D-5L) at baseline and at 4, 8, and 24 weeks;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eperformance in activities of daily living (Barthel score) at baseline and at 4, 8, and 24 weeks;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ecognitive function by Montreal Cognitive Assessment (MOCA) score at baseline and at 4, 8, and 24 weeks;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003enumber of falling incidents at 24 weeks;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003emortality at 24 weeks;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003erate of complications and AEs between groups within 24 weeks.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eSafety outcome\u003c/h2\u003e \u003cp\u003eGeneral physical examination (body temperature, heart rate, breathing, and blood pressure), laboratory tests (routine blood tests, liver and kidney function tests), and head computed tomography will be measured at each visit.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eQuality control\u003c/h2\u003e \u003cp\u003eThe Coordinating Center (CC) will consist of two PIs, two neurosurgeons, two doctors of traditional Chinese medicine, and one methodologist. The CC's role is to train the research members from all study sites regarding every aspect of the study protocol, including recruitment, intervention, and follow-up evaluation, and to coordinate and supervise all standardized data management and quality control.\u003c/p\u003e \u003cp\u003eThe Trial Steering Committee (TSC) will include three independent neurosurgery experts, one traditional Chinese medicine doctor, and two independent statisticians. It will be responsible for recruiting and progressing the trial, overall supervision, and quality control during the study. It will also ensure standardized training for research members regarding the study protocol.\u003c/p\u003e \u003cp\u003eAn independent DSMB will consist of two statisticians and two clinical experts. All members will be blinded and independent of the study and investigators. The DSMB will monitor the study data, participant safety, and SAEs throughout the trial and will be responsible for all the statistical analyses. The DSMB will regularly report blinded statistical data to the TSC, and subsequent meetings will be held at the 50% and 100% points of participant inclusion.\u003c/p\u003e \u003cp\u003eThe IRBs of all the study sites will perform regular inspections of the trial. The inspections will be independent of the investigators and the sponsor. The data management researcher will stay in regular contact with the investigators about trial progress, data consistency, and follow-up visit violations.\u003c/p\u003e \u003cp\u003eAlthough changes or amendments are not expected, any trial deviations from the present protocol will be fully documented via a breach report form. Protocol amendments will be notified to the sponsor within 3 days and then to the relevant parties and centers by sending the updated protocol to the investigators. Any changes must be cleared in written form and signed by all persons in charge, stating the detailed reasons for changes. If necessary, changes must be approved by the IRB and/or individual participants. A copy of the revised protocol will be added to the Investigator Site File. The protocol will be updated on the ClinicalTrials.gov registry website.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eData management\u003c/h2\u003e \u003cp\u003eAll collected data will be stored in an online EDC system accessible only to the investigators. A group of blinded research members in charge of the follow-up evaluation will collect primary and secondary outcomes. At the completion of the 24 weeks of follow-up data collection, a data quality audit will be performed. To guarantee confidentiality, all personal information about the participants will be collected and stored in a secure EDC system throughout the duration of the study. All participants will be allocated individual trial identification numbers. Only the lead investigator will have access to all the files corresponding to the participants\u0026rsquo; data. After the completion of the study, the results will be made public through publication in a scientific journal, conferences related to neurosurgery, and the clinicaltrials.gov website. The data generated or analysed during this study will be available from the corresponding author upon reasonable request.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses will be performed via a statistical package (SPSS software 25.0). The Kolmogorov‒Smirnov test will be performed to assess the normality of the variables. Data with a normal distribution will be presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard error of the mean. Variables for skewed distributions will be described as medians and interquartile ranges. Categorical variables are expressed as frequencies with percentages.\u003c/p\u003e \u003cp\u003eComparisons between the groups will be carried out via an independent t test to compare normally distributed data, the Mann‒Whitney U test to compare skewed data, and the χ2 test or Fisher\u0026rsquo;s exact test to compare categorical data, such as safety analyses with the incidence of AEs. For numerical data collected at different time points throughout the 24 weeks, repeated measures analysis of variance will be performed between the two groups. The significance level will be set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003cp\u003eAll researchers will be trained according to the same training protocol. Protocol modifications are not expected. Missing clinical data, if any, will be obtained from the electronic hospital files. Follow-up evaluation at specified time points is mandatory, and missing data are not anticipated. Analyses of all outcomes will be performed according to the intention-to-treat principle, and once enrolled, all participants will be analysed, regardless of the findings.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eInterim analyses\u003c/h2\u003e \u003cp\u003eAlthough there are no anticipated problems that may be detrimental to the participants, serious life-threatening adverse events leading to prolonged hospital stay or death will be reported to the IRB, and our study will be terminated immediately. There will be no interim analyses in this trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eMethods for additional analyses (e.g., subgroup analyses)\u003c/h2\u003e \u003cp\u003ePrior to statistical analysis, a sub-investigator will review the data record forms to check for legitimacy and identify missing data. Subgroup analysis will be conducted to evaluate patients' outcomes based on their baseline clinical and demographic characteristics, such as sex, age, type of hematoma on CT scan, volume of hematoma, and comorbidities.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eSafety and ethic\u003c/h2\u003e \u003cp\u003eHXLS has been used clinically for many years and has good safety in the preliminary study [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. To ensure the safety of participants, all participants are given HXLS or placebo treatment in addition to routine therapy and will receive relevant safety checks. Investigators will also take timely symptomatic treatment of AEs in the participants. Any adverse events (AEs) will be recorded, and a thorough assessment of the potential associations between the study interventions and the adverse events will be carried out. A detailed recording of all the AEs during the study will be closely monitored and reported to the ethics committee as soon as possible to facilitate stabilization or termination of the survey if necessary. Serious life-threatening AEs leading to serious complications or death will be reported to the Institutional Review Board (IRB), and the trial will be terminated immediately.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eDissemination\u003c/h2\u003e \u003cp\u003eAfter the completion of the study, the results will be written as a final trial report through publication in a scientific journal along with international meetings related to neurosurgery and the clinicaltrials.gov website.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe prevalence of CSDH has risen, largely due to the ageing population and the widespread use of anticoagulants and antiplatelet medications. The development and recurrence of CSDH are associated with localized inflammation, the formation of new immature blood vessels, and the breakdown of blood clots [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Among these, inflammation plays a central role in CSDH progression. Various inflammatory cells and cytokines, both promoting and suppressing inflammation, contribute to this process. Research shows that levels of certain cytokines and chemokines, including interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-α, monocyte chemoattractant protein-1, and eotaxin-3, are significantly higher in CSDH fluid compared to serum [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This inflammation weakens the endothelial cell barrier, leading to the development of immature and \"leaky\" blood vessels, which exacerbate the condition by allowing continuous bleeding [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Additionally, the presence of high levels of fibrin/fibrinogen degradation products in CSDH fluid indicates excessive clot breakdown, contributing to persistent bleeding. As a result, many drugs targeting different aspects of this cycle are currently under investigation as potential drug treatments for CSDH.\u003c/p\u003e \u003cp\u003eDespite several studies [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR23 CR24 CR25\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] to date, the optimal drug therapy for CSDH remains a matter of debate. According to theory of traditional Chinese medicine, the main pathogenesis of CSDH is blood stasis and fluid stagnation. L. Sweet is a common Chinese herbal medicine used for activating blood circulation and inducing diuresis to alleviate edema. Hirudo is used to break blood clots and remove stasis. Tao-Ren and Hong-Hua are classic Chinese herbal medicine pairs that activate blood circulation. These four Chinese herbal medicines are compatible with the HXLS formula [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], which aims to activate blood circulation and eliminate fluid. Our observational evidence suggests that HXLS may reduce the necessity of surgery with few side effects. Nevertheless, similar to many other Chinese patent medicines, the HXLS formula requires strong clinical evidence regarding its therapeutic effect and safety to support its use. Thus, a randomized controlled trial is needed to evaluate the efficacy and safety of HXLS compared with those of a placebo.\u003c/p\u003e \u003cp\u003eIn this study, we describe the rationale, design, interventions, and methodological framework of a multicenter, double-blinded, randomized controlled trial to assess whether HXLS can reduce the incidence of hematoma progression or recurrence requiring operation of CSDH as a nonsurgical treatment compared with placebo. Furthermore, we will investigate functional outcomes (mRS and MGS), cognitive function (MoCA), and quality of life (EQ-5D-5L) before and after treatment. Moreover, this study will be conducted in outpatient settings at 3 neurosurgical centers in China, and all patients aged 18\u0026ndash;90 years will be included. Effective communication will be strengthened to encourage cooperation and support between neurosurgeons and traditional Chinese medicine physicians throughout the trial. Therefore, the results will be widely applicable.\u003c/p\u003e \u003cp\u003eHowever, there are some limitations to be considered. First, it should be noted that secondary endpoints of mRS, MGS, EQ-5D-5L, Barthel score and MOCA score are subjective. Therefore, participants\u0026rsquo; subjective psychological states and living habits might affect our findings. Because these were not primary endpoint, we do not perform further objective assessments. Secondly, we developed a protocol for a multicenter, double-blinded, randomized clinical trial with a long intervention duration of 8 weeks. This is also consistent with the characteristics of traditional Chinese medicine intervention for diseases. However, long-term medication might affect patient compliance. Finally, the study included patients with CSDH, which may not represent all CSDH patients, especially those with CSDH with serious complications.\u003c/p\u003e \u003cp\u003e In conclusion, this study aims to determine whether this Chinese herbal medication can reduce the CSDH operative rate and improve clinical outcomes, which may change clinical practice and guideline recommendations. Whether HXLS is suitable for the treatment of all CSDH requires further clinical evaluations in different CSDH populations.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section2\"\u003e \u003ch2\u003eTrial status\u003c/h2\u003e \u003cp\u003eThis study is not yet recruiting.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHXLS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHuoXue LiShui\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCSDH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChronic Subdural Hematoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCoordinating Center\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCONSORT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConsolidated Standards of Reporting Trials\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMGS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMarkwalder Grading Scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMoCA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMontreal Cognitive Assessment\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003emRS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eModified Rankin Scale; PI:Principal Investigator\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGCS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGlassgow Coma Scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eComputed Tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSerious Adverse Event\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAdverse Event\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTSC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTrial Steering Committee\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICH-GCP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Conference on Harmonization-Good Clinical Practice\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIRB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInstitutional Review Board\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDSMB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eData Safety Monitoring Board\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEDC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eElectronic Data Capture\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Professor Beibei Xu for providing advisory support for the protocol.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eModification of the protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlthough changes or amendments are not to be expected, any trial deviations from the present protocol will be fully documented using a breach report form. Protocol amendments will be notified to the sponsor within 3 days and then to the relevant parties and centers by sending the updated protocol to the investigators. Any changes must be cleared in written form and signed by all persons in charge, stating the detailed reasons for changes. If necessary, changes must be approved by the IRB and/or individual participants. A copy of the revised protocol will be added to the Investigator Site File. The protocol will be updated in the ClinicalTrials.gov registry website.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWML together with LW created the study design. LW, YPT, DZG, WW, HBZ, YFL, and YPF conceived the study, participated in its design and coordination and helped draft the manuscript. LW, YPT, and YFL drafted the manuscript and calculated the statistics. HBZ and HZ adapted the protocol to Chinese conditions and selected the study sites. All the authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is funded by the Beijing Traditional Chinese Medicine Technology Development Fund (grant No. BJZYYB-2023-60). The funders had no role in the design, data collection and analysis, interpretation, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter the completion and publication of the CHARM trial, requests for data sharing will be considered by the CHARM Trial Management Group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study will be performed in accordance with the principles of the Helsinki Declaration and Good Clinical Practice. The CHARM protocol version 3.0, informed consent forms, and all other relevant trial documents have been approved by the ethics committee of Beijing Tiantan Hospital, Capital Medical University (Application Number KY2023-265-03). The study is registered at ClinicalTrials.gov with the number NCT06427980. All participants will be informed about the trial\u0026apos;s purpose, risks and potential benefits. If a participant is not mentally competent, a legal representative will also be informed. All sub-centers will obtain written informed consent before the start of baseline measurements and treatment.\u0026nbsp;\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\u003eAll the authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYang W, Huang J. Chronic Subdural Hematoma: Epidemiology and Natural History. Neurosurg Clin N Am. 2017;28:205\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIorio-Morin C, Touchette C, L\u0026eacute;vesque M, Effendi K, Fortin D, Mathieu D. Chronic Subdural Hematoma: Toward a New Management Paradigm for an Increasingly Complex Population. J Neurotrauma. 2018;35:1882\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaribe H, Kameyama M, Kawase M, Hirano T, Kawaguchi T, Tominaga T. [Epidemiology of chronic subdural hematomas]. No Shinkei Geka. 2011;39:1149\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKolias AG, Chari A, Santarius T, Hutchinson PJ. Chronic subdural haematoma: modern management and emerging therapies. Nat Rev Neurol. 2014;10:570\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYe Y, Zhu Y-T, Xin X-Y, Zhang J-C, Zhang H-L, Li D. Efficacy of Chinese herbal medicine for tPA thrombolysis in experimental stroke: A systematic review and meta-analysis. Phytomedicine. 2022;100:154072.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZeng L, Tang G, Wang J, Zhong J, Xia Z, Li J, et al. Safety and efficacy of herbal medicine for acute intracerebral hemorrhage (CRRICH): a multicentre randomised controlled trial. BMJ Open. 2019;9:e024932.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrennan PM, Kolias AG, Joannides AJ, Shapey J, Marcus HJ, Gregson BA, et al. The management and outcome for patients with chronic subdural hematoma: a prospective, multicenter, observational cohort study in the United Kingdom. J Neurosurg. 2017;127:732\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSantarius T, Kirkpatrick PJ, Ganesan D, Chia HL, Jalloh I, Smielewski P, et al. Use of drains versus no drains after burr-hole evacuation of chronic subdural haematoma: a randomised controlled trial. Lancet. 2009;374:1067\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMotoie R, Karashima S, Otsuji R, Ren N, Nagaoka S, Maeda K, et al. Recurrence in 787 Patients with Chronic Subdural Hematoma: Retrospective Cohort Investigation of Associated Factors Including Direct Oral Anticoagulant Use. World Neurosurg. 2018;118:e87\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJensen TSR, Andersen-Ranberg N, Poulsen FR, Bergholt B, Hundsholt T, Fugleholm K. The Danish Chronic Subdural Hematoma Study-comparison of hematoma age to the radiological appearance at time of diagnosis. Acta Neurochir (Wien). 2020;162:2007\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRidwan S, Bohrer A-M, Grote A, Simon M. Surgical Treatment of Chronic Subdural Hematoma: Predicting Recurrence and Cure. World Neurosurg. 2019;128:e1010\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTong Y, Liu W, Xu L, Ou Y, Li K, Yang T, et al. Nonsurgical treatment of chronic subdural hematoma with Chinese herbal medicine: A STROBE-compliant retrospective study. Med (Baltim). 2020;99:e21674.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang R, Zhao S, Wang R, Feng H, Zhang J, Li X, et al. Safety and Efficacy of Atorvastatin for Chronic Subdural Hematoma in Chinese Patients: A Randomized ClinicalTrial. JAMA Neurol. 2018;75:1338\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEdlmann E, Giorgi-Coll S, Whitfield PC, Carpenter KLH, Hutchinson PJ. Pathophysiology of chronic subdural haematoma: inflammation, angiogenesis and implications for pharmacotherapy. J Neuroinflammation. 2017;14:108.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeigel R, Schilling L, Krauss JK. The pathophysiology of chronic subdural hematoma revisited: emphasis on aging processes as key factor. Geroscience. 2022;44:1353\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOsuka K, Watanabe Y, Usuda N, Aoyama M, Takeuchi M, Takayasu M. Eotaxin-3 activates the Smad pathway through the transforming growth factor beta 1 in chronic subdural hematoma outer membranes. J Neurotrauma. 2014;31:1451\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStanisic M, Lyngstadaas SP, Pripp AH, Aasen AO, Lindegaard K-F, Ivanovic J, et al. Chemokines as markers of local inflammation and angiogenesis in patients with chronic subdural hematoma: a prospective study. Acta Neurochir (Wien). 2012;154:113\u0026ndash;20. discussion 120.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrati A, Salvati M, Mainiero F, Ippoliti F, Rocchi G, Raco A, et al. Inflammation markers and risk factors for recurrence in 35 patients with a posttraumatic chronic subdural hematoma: a prospective study. J Neurosurg. 2004;100:24\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi T, Wang D, Tian Y, Yu H, Wang Y, Quan W, et al. Effects of atorvastatin on the inflammation regulation and elimination of subdural hematoma in rats. J Neurol Sci. 2014;341:88\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang D, Li T, Wei H, Wang Y, Yang G, Tian Y, et al. Atorvastatin enhances angiogenesis to reduce subdural hematoma in a rat model. J Neurol Sci. 2016;362:91\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBounajem MT, Campbell RA, Denorme F, Grandhi R. Paradigms in chronic subdural hematoma pathophysiology: Current treatments and new directions. J Trauma Acute Care Surg. 2021;91:e134\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsumoto H, Matsumoto A, Miyata S, Tomogane Y, Minami H, Masuda A, et al. The Effect of Japanese Herbal Medicines (Kampo) Goreisan and Saireito on the Prevention of Recurrent Chronic Subdural Hematoma: A Prospective Randomized Study. Neurosurgery. 2024;94:80\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKatayama K, Matsuda N, Kakuta K, Naraoka M, Takemura A, Hasegawa S, et al. The Effect of Goreisan on the Prevention of Chronic Subdural Hematoma Recurrence: Multi-Center Randomized Controlled Study. J Neurotrauma. 2018;35:1537\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKatsuki M, Kawamura S, Koh A. Japanese herbal Kampo medicine, Keishibukuryogan, for chronic subdural hematoma - Prospective observational study. Surg Neurol Int. 2022;13:307.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKwon S, Jin C, Chung M, Lee J, Cho S-Y, Park S-U, et al. Herbal medicine treatment for patients with chronic subdural hematoma: A systematic review and meta-analysis. Complement Ther Clin Pract. 2021;43:101307.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMusmar B, Orscelik A, Salim H, Adeeb N, Spellicy S, Abdelgadir J et al. Efficacy and safety of tranexamic acid in the management of chronic subdural hematoma: a systematic review and meta-analysis. J Neurosurg. 2024;:1\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"HuoXue LiShui, Chronic subdural hematoma, Chinese herbal medicine formula, Pharmacotherapy, Randomized controlled trial","lastPublishedDoi":"10.21203/rs.3.rs-4941851/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4941851/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eChronic subdural hematoma (CSDH) is one of the most common neurosurgical conditions and occurs mainly in elderly individuals. Surgical evacuation is usually effective for this pathology but commonly carries significant risks, especially in patients with multiple comorbidities. Therefore, interest in nonsurgical treatment with medications such as tranexamic acid, atorvastatin, and dexamethasone is increasing. However, the efficacy of all these medications is still uncertain in patients with CSDH. According to the literature, the operative rate at 24 weeks is 5\u0026ndash;33%. In our retrospective study, the Chinese herbal medicine HuoXue LiShui (HXLS) formula significantly reduced the necessity for surgery in patients with CSDH. The results demonstrated that HXLS can achieve low operative rates and good outcomes.\u003c/p\u003e\u003ch2\u003eMethods/design\u003c/h2\u003e \u003cp\u003e This is a prospective, multicenter, double-blinded, blinded endpoint, randomized controlled trial designed to include 160 participants 18\u0026ndash;90 years of age presenting with CSDH verified via computed tomography or magnetic resonance imaging. The participants will be randomly allocated to receive HXLS granules (treatment group) or placebo (control group) after enrollment two times daily for 8 weeks. The primary endpoint will be the incidence of hematoma progression requiring surgery or recurrence requiring reoperation; the secondary outcomes will include CSDH volume, thickness, neurological outcome, cognitive function, performance in activities of daily living, and quality of life at 24 weeks.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThis trial will validate the efficacy and safety of the Chinese herbal medicine HXLS formula in reducing operative rates, improving clinical outcomes in patients with CSDH, and improving nonsurgical management.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eThis trial was registered at Clinicaltrials.gov with NCT06427980 on August 17, 2024. (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.clinicaltrials.gov/ct2/show/study/NCT06427980\u003c/span\u003e\u003cspan address=\"https://www.clinicaltrials.gov/ct2/show/study/NCT06427980\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.)\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of Chinese Herbal Medicine HuoXue LiShui Formula for Chronic Subdural Hematoma (CHARM): Study Protocol for a Multicenter Randomized Controlled Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-16 06:49:52","doi":"10.21203/rs.3.rs-4941851/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1481e5fb-5af1-4438-9704-a0ffde8c6cbd","owner":[],"postedDate":"October 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-30T13:39:16+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-16 06:49:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4941851","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4941851","identity":"rs-4941851","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}