Sun_2025_JMIR.Res.Protoc__

BACKGROUND: Cerebral small vessel disease (CSVD) is a leading cause of vascular cognitive impairment, contributing to 36%-67% of vascular dementia cases. Current therapies, primarily cholinesterase inhibitors, offer limited efficacy and significant adverse effects. Traditional Chinese Medicine (TCM), particularly Zishenyizhi pill which is a multi-herb formulation targeting yin deficiency and blood stasis-has shown promise in preliminary studies but lacks robust clinical validation. OBJECTIVE: We designed this study to evaluate the real-world efficacy and safety of Zishenyizhi pill combined with conventional Western therapy for CSVD-related cognitive impairment. METHODS: This multicenter, prospective, non-randomized controlled trial enrolled 246 patients from four institutions in Hunan Province, China. Participants were stratified into two groups: the intervention group received Zishenyizhi pill plus standard Western therapy, while the control group received conventional integrated Chinese-Western therapy. Cognitive outcomes (MoCA, MMSE, VaDAS-cog, TMT-A/B, etc.), TCM syndrome scores, and safety parameters were assessed over 12 weeks. RESULTS: This study was registered in the International Traditional Medicine Clinical Trial Registry (identifier: ITMCTR2025000553) on 20 March 2025. Participant recruitment is scheduled to commence in April 2025, with an anticipated enrollment of 246 participants by December 2026. At present, patient recruitment is underway, and preliminary analysis of medical record data is being conducted. Final data collection is expected to conclude by April 2027, with results projected for publication in Fall 2027. CONCLUSIONS: The anticipated findings suggest that Zishenyizhi pill may improve multiple cognitive domains in patients with cognitive impairment associated with CSVD while demonstrating a favorable safety profile. If validated, Zishenyizhi pill could serve as a safe and effective adjunctive therapy for CSVD-related cognitive dysfunction. CLINICALTRIAL: International Traditional Medicine Clinical Trial Registry, identifier: ITMCTR2025000553. Registered on 20 March 2025.