1 Introduction
Acute ischemic stroke (AIS) carries a significant risk of early recurrence, with approximately 6.5% of patients experiencing a subsequent stroke within 3 months.
[1] This risk is substantially elevated in high-risk subgroups, particularly those with an Essen stroke risk score (ESRS) ≥ 3,
[2] approximately 7.9%, underscoring the need for more effective secondary prevention strategies in this vulnerable population.
[3] The pathogenesis of AIS involves multiple interrelated mechanisms—including excitotoxicity, oxidative and nitrosative stress, apoptosis, and sustained inflammation—which collectively contribute to brain injury and increase susceptibility to recurrent events.
[4–
7] Targeting these pathways through neuroprotective interventions represents a promising therapeutic direction.
Traditional Chinese medicine (TCM), with its long history and holistic approach, has been increasingly recognized as a valuable complementary option in stroke management.
[8–
10] Accumulating preclinical and clinical observations suggest that certain TCM formulations possess anti-inflammatory, antioxidant, and neuroregulatory properties, which may address multifactorial injury processes not fully covered by conventional antithrombotic therapy alone.
[11–
13] Among these, the Naoshuantong capsule (NC)—a compound preparation derived from five herbal components (Pu Huang, Chi Shao, Yu Jin, Tian Ma, and Lou Lu, for details, see Supplemental Digital of Appendix 1–Appendix 4,
https://links.lww.com/CARES/A6)—has shown particular promise. Experimental studies indicate that NC exerts multitarget neuroprotective effects, such as reducing infarct volume, improving neurological function, suppressing apoptosis, modulating inflammatory responses, attenuating excitotoxicity, and enhancing cerebral hemodynamics and metabolism.
[14–
16]Despite these encouraging preclinical findings and positive signals from preliminary clinical trials observed for the efficacy of NC in treating ischemic stroke (IS), robust evidence from large-scale, rigorously designed studies remains scarce.
[17–
19] Currently, there is a lack of high-quality clinical data demonstrating the superior efficacy of NC specifically in high-risk AIS patients, who continue to face substantial residual recurrence risk under standard secondary prevention.
Therefore, the efficacy and safety of NC in high-recurrence-risk patients with acute IS (RESPACE), a well-design clinical trial, will be conducted to evaluate the efficacy and safety of NC in the treatment of patients with IS who are at a high risk of recurrence, which will provide a solid evidence base for its integration into routine care for high-risk AIS patients.
2 Methods
2.1 Study design
The RESPACE trial is a multicenter, randomized, double-blind, parallel, placebo-controlled study, which will enroll patients from emergency departments and neurology wards that receive patients with AIS in China. The study will be conducted in nearly 100 centers in China, and a total of 3150 participants will be recruited and allocated randomly to either the NC treatment group or the control group. Participating centers will be selected based on predefined criteria, including hospital level, stroke unit capabilities, annual stroke volume, qualified personnel, and infrastructure, and will compete for enrollment (see Supplemental Digital of Appendix 5,
https://links.lww.com/CARES/A6, for detailed criteria). Both groups will undergo a treatment period of 90 days. Participants will be followed up at 30, 60, 90, and 180 days after randomization (D30, D60, D90, and D180, respectively) to collect efficacy and safety outcomes in person. Participants will be assessed with a relevant scale or laboratory biochemical examination on the scheduled day for each treatment and the follow-up period. The trial is designed according to the principles of the Declaration of Helsinki.
2.2 Ethics
Ethical approval was granted by the research ethics committee of The First Affiliated Hospital of Henan University of Chinese Medicine (approval number: 2023HL-098-02; September 8, 2023), Zhengzhou, China and registered in public clinical trial database, and was approved by the local institutional review boards of all participating sites. Any severe adverse events (AEs) will be reported to the committees immediately, and any revisions to the study design can only be made with the permission of the committees. This study was initiated in September 2023.
2.3 Participant recruitment
We will recruit patients with AIS who are of ages 18 to 80 years, with ESRS ≥ 3 and National Institute of Health Stroke Scale (NIHSS) score ≤ 15, have at least 2 elements of the Diagnostic Scale for Syndrome Elements of IS,
[20,
21] and can be treated within 72 h of symptom onset. All patients or their legally authorized representatives will provide written informed consent before any study-specific procedure. Table 1 lists the summary of inclusion and exclusion criteria.
2.4 Diagnostic criteria for symptom pattern in TCM practice
The Ischemic Stroke TCM Syndrome Factor Diagnostic Scale (ISTSFDS) can help to classify and diagnose the TCM symptom patterns objectively with the application of syndrome factors. Six syndrome factors are considered, encompassing internal wind, internal fire, phlegm dampness, blood stasis, Qi-deficiency, and Yin-deficiency. For the diagnosis of each syndrome element to be established, a score of 10 or more is required. Patients who will participate in the study must meet the diagnostic criteria for 3 or more of the following syndrome elements: internal wind, internal fire, phlegm-damp, and blood stasis.
2.5 Randomization, allocation, and blinding
Patients will be randomly assigned to the NC group and control group in a 1:1 ratio using block randomization. A randomization allocation sequence will be assigned to each group based on a computer-generated random number table created by an independent statistician using SAS version 9.4 software. All patients will be centrally randomized to the study using an interactive web response system, which links a sequential patient randomization number to the treatment codes. This trial is double-blind; the patient and all those involved in the clinical outcomes and the assessment of outcomes will be blinded to the treatment group. The two forms of drugs are visually identical and cannot be distinguished in appearance, taste, or packaging.
Emergency unblinding will be permitted only when knowledge of the assigned intervention is essential for the clinical management of an AE. In such cases, the site principal investigator must be immediately notified for approval, followed by prompt notification to the monitor and sponsor. All telephone communications are recorded by the Contract Research Organization (CRO). Following any unblinding event, the investigator must document the date, time, and reason in writing and discontinue the investigational product.
2.6 Treatment
Eligible patients will be randomly assigned to either the experimental group or the control group. The treatment assignments are presented in Figure 1. Participants in the experimental group will receive NC, 3 capsules (0.4 g each), 3 times daily for 90 days. The control group will receive an NC placebo, 3 capsules (0.4 g each), 3 times daily for 90 days. All patients will receive a standard treatment, which is referred to in the current guidelines (Chinese Society of Neurology and Chinese Stroke Society, 2018 for the acute treatment phase, and Chinese Guidelines for the Secondary Prevention of Ischemic Stroke and Transient Ischemic Attack 2022 for the secondary prevention),
[22,
23] which will be predefined and uniformly implemented across all participating centers (see Supplemental Digital content Appendix 6,
https://links.lww.com/CARES/A6 for details).
2.7 Follow-up procedures
Face-to-face follow-up will be conducted at days 30 ± 3, 60 ± 3, and 90 ± 7 after randomization. And telephone or face-to-face long-term follow-up will also be conducted at day 180 ± 14. The contents of each visit are listed in Table 2. Standardized case report forms are used for data collection, and data are then entered by separate data entry personnel via the Electronic Data Capture system.
2.8 Efficacy outcomes
The primary outcome is any stroke (ischemic or hemorrhagic) within 90 days after symptom onset. The secondary outcomes include IS within 90 days, vascular events (IS/hemorrhagic stroke/myocardial infarction/vascular death) within 90 days, the proportion of patients with the mRS score ≤ 1 on day 90, and EuroQol 5-dimension 5-level (EQ-5D-5L) scale scores change from baseline to day 90 after symptom onset. The definitions of outcomes are listed in Table 3.
2.9 Safety outcomes
The primary safety outcome is severe AEs during the treatment period. Other safety outcomes include any AE, all-cause mortality, any bleeding (severe or moderate bleeding and intracerebral hemorrhage), severe or moderate bleeding as defined by the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) criteria, and hepatorenal dysfunction during the treatment period.
2.10 Exploratory outcomes
To assess the long-term efficacy of NC, the exploratory outcomes include ISTSFDS change from baseline to day 90 after symptom onset, vascular events within 180 days, the proportion of patients with mRS ≤ 1 on day 180, and EQ-5D-5L scale scores change from baseline to day 180 after symptom onset.
2.11 Data Safety and Monitoring Board (DSMB)
The clinical endpoint events and safety endpoints will be reviewed by an independent clinical event committee blinded to treatment assignment. The Data Safety and Monitoring Board (DSMB) is mandated to convene in accordance with the protocol, overseeing the trial's progress and safety, and to submit regular reports to the committee. Following each session, the DSMB will furnish the Steering Committee with written recommendations. The DSMB holds the responsibility to suggest the premature termination of the study in the event of any unforeseen safety concerns.
2.12 Sample size calculation
According to Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients With Acute Nondisabling Cerebrovascular Events Ⅱ (CHANCE-2), we assume an 8.0% stroke event rate within 90 days for the control group among AIS patients with ESRS scores of 3 or higher.
[3] It is expected that the use of NC will reduce the risk of stroke recurrence by 37.5% compared with the control group, resulting in a 90-day stroke recurrence rate of 5.0%. With a test level of 0.05 (2-sided test), a power of 0.9, and a dropout rate of 10%, the trial will require a total of 3150 subjects, with 1575 in each group.
2.13 Statistical analysis
An intention-to-treat analysis will be performed for statistical analysis. For baseline characteristics, continuous variables will be provided as the mean ± standard deviation or median with interquartile range and compared using a t test or a Wilcoxon sum of rank test. Categorical variables will be provided as frequency with percentage and will be compared using either the χ2 test or the Fisher exact test.
Participants will be censored at their last follow-up assessment when experiencing a clinical event, at the end of the study, or at the time of withdrawal from the study. Statistically, the cumulative risk of stroke will be reported as a Kaplan–Meier estimate during the 90-day follow-up. Cox proportional hazards methods will be used for hazard ratio calculation with 95% confidence interval, with trial centers set as a random effect. The treatment effect will be assessed by the log-rank test. Detailed analysis plans will be given in the statistical analysis plan before the database is locked and the blind is broken. All statistical analyses will be performed using the SAS statistical software, version 9.4 (SAS Institute Inc). A P < 0.05 in two tails is considered statistically significant.
3 Discussion
Patients at high risk of stroke recurrence often present with a more complex clinical profile compared with those at lower risk. Notably, comorbidities such as hypertension and diabetes mellitus—frequently observed in this population—have been associated with reduced responsiveness to antiplatelet therapy.
[24] Given the elevated recurrence risk in these patients, the development and optimization of effective combination strategies for secondary prevention remain a critical priority in the management of AIS.
[25]NC, a compound preparation derived from five herbal components including Pu Huang, Chi Shao, Yu Jin, Tian Ma, and Lou Lu, exerts significant neuroprotective effects in IS through a multicomponent, multitarget synergistic mechanism, primarily centered on the suppression of neuroinflammation.
[14–
16] The integration of its bioactive compounds—such as paeoniflorin, apigenin, and gastrodin—targets key inflammatory pathways in activated microglia, the primary immune cells in the brain.
[26] Paeoniflorin downregulates proinflammatory cytokines, curbing microglial proliferation and neuroinflammatory responses. Apigenin operates via dual pathways, inhibiting inducible nitric oxide synthase and cyclooxygenase-2 to reduce nitric oxide and prostaglandin E2 (PGE2) production, while simultaneously suppressing p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation, thereby attenuating microglial overactivation.
[27] Gastrodin further modulates the phosphatidylinositol 3-kinase/protein kinase (PI3K/AKT) signaling pathway, leading to decreased expression of critical inflammatory mediators like tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β).
[28] This coordinated suppression of the inflammatory cascade by NC's components plays a pivotal role in reversing vascular endothelial cell injury, preserving blood–brain barrier integrity, and protecting cerebral parenchyma. Beyond its core anti-inflammatory action, preclinical evidence highlights NC's multitargeted neuroprotective profile, which encompasses mitigating cerebral infarction, ameliorating neurological deficits, inhibiting neuronal apoptosis, reducing excitatory amino acid toxicity, and improving cerebral hemodynamics and metabolism.
[15] Collectively, these synergistic mechanisms position NC as a comprehensive therapeutic strategy for IS, addressing the complex pathophysiology of the condition through a holistic pharmacological approach.
Several prior studies have explored the efficacy and safety of NC in patients with AIS. For example, a meta-analysis of 13 randomized controlled trials (RCTs) involving 1360 IS patients demonstrated that NC was significantly associated with improved overall response rates, enhanced neurological function, elevated blood adiponectin levels, reduced neurological deficits, and decreased atherosclerotic plaque area.
[17] Another meta-analysis encompassing 27 RCTs with 3319 patients indicated that NC could improve neurological function across different phases of IS, reduce the risk of cerebrovascular disease recurrence, and enhance quality of life during the acute period, suggesting a potential role for NC in the secondary prevention of IS.
[18] Nevertheless, the methodological limitations and notable heterogeneity among the included trials in these meta-analyses underscore the need for further validation of NC's true therapeutic value through well-designed, standardized RCTs.
To our knowledge, the RESPACE trial represents the first and largest randomized controlled double-blind trial in TCM research targeting secondary stroke prevention among patients with high risk of recurrence. While the 90-day treatment duration and 180-day follow-up period were pragmatically designed due to time constraints, this landmark study innovatively investigated the potential therapeutic effects of NC in reducing vascular events.
4 Conclusion
In summary, the RESPACE trial will provide high-quality evidence of NC for the secondary prevention of IS among high-recurrence-risk patients with AIS within 72 h.
© The Author(s) 2026. Published by Wolters Kluwer Health, Inc. on behalf of Higher Education Press.
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