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 < 14 or mRS 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 < 1 year.
Abnormal liver function or liver diseases, including uncontrolled hepatitis (alanine transaminase > 120 U/L).
Severe renal impairment (estimated glomerular filtration rate < 30 ml/min or serum creatinine > 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:
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Participants are unwilling to continue the trial and request to withdraw from the trial.
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Serious complications, significant physiological changes, serious adverse events (SAE), and other serious events that occur during the trial.
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Participants who have poor compliance (such as taking drugs in violation of the prescribed dose).
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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:
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HXLS treatment group: HXLS 28.5 g per time, twice daily, for 8 weeks.
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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
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CSDH volume, thickness, and mid-line shift measured via head CT/MRI at baseline and at 4, 8, and 24 weeks;
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functional outcome by mRS score and MGS grade at baseline and 4, 8, and 24 weeks;
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quality of life by five-dimensional EuroQol (EQ-5D-5L) at baseline and at 4, 8, and 24 weeks;
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performance in activities of daily living (Barthel score) at baseline and at 4, 8, and 24 weeks;
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cognitive function by Montreal Cognitive Assessment (MOCA) score at baseline and at 4, 8, and 24 weeks;
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number of falling incidents at 24 weeks;
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mortality at 24 weeks;
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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.