Small Vessel Disease and Cerebral Infarct Healing InErvation Via Limb Distant Adaptation (SHIELD)

the Role and Mechanism of Distant Ischemic Adaptation in Improving Cognitive Impairment in Cerebral Infarction and Cerebral Small Vessel Disease

Cerebral infarction (ischemic stroke) and cerebral small vessel disease (CSVD) represent major global causes of disability, cognitive decline, and mortality. Despite advances in reperfusion therapies, many patients experience residual neurological deficits and remain at high risk for recurrent stroke and vascular dementia. Effective adjunctive treatments that are safe, accessible, and capable of improving long-term outcomes are urgently needed.

Distant ischemic adaptation (also known as remote ischemic conditioning, RIC) is a non-invasive, safe, and cost-effective intervention that induces endogenous protection against ischemic injury by applying brief, intermittent ischemia to a remote limb. While several large-scale clinical trials (e.g., RICAMIS, RECAST) have demonstrated promising neuroprotective effects of RIC in acute ischemic stroke, results remain inconsistent across studies, particularly in patients with CSVD. Key challenges include the lack of standardized RIC protocols and the absence of specific biomarkers to predict treatment response and elucidate underlying mechanisms.

To address these gaps, this study aims to identify potential effector proteins and specific biomarkers that mediate the therapeutic effects of RIC in patients with cerebral infarction and CSVD. By collecting and analyzing serum samples from RIC-treated patients and controls, we seek to uncover molecular mechanisms underlying RIC-induced neuroprotection and cognitive preservation. The findings may establish a theoretical foundation for optimizing RIC therapy, provide novel drug targets, and ultimately improve clinical outcomes for patients suffering from ischemic stroke and small vessel disease.

Study Overview

• Status: Enrolling by invitation
• Conditions: Stroke; Small Vessel Cerebrovascular Disease
• Intervention / Treatment: Other: Standard Treatment; Device: Medical-grade ischemic preconditioning training instrument

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310000
      • 2ndAffiliated Hospital, School of Medicine, Zhejiang Universit, Hangzhou, Zhejiang 310000

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged between 50 and 65 years.
• Definite diagnosis of cerebral infarction or cerebral small vessel disease-related cerebral infarction confirmed by brain MRI or other imaging examinations.
• Ability to complete the 3-month follow-up and RIC intervention (for the experimental group).
• Few underlying comorbidities, limited to hypertension and hyperlipidemia; clear consciousness with the ability to provide informed consent.
• Modified Rankin Scale (mRS) score < 2, with no severe cognitive impairment as assessed by the Montreal Cognitive Assessment (MoCA).
• Enrolled within 48 hours after the onset of stroke symptoms (i.e., from the time the patient was last known to be well, during the acute phase).

Exclusion Criteria:

• Complicated with diabetes mellitus, smoking history, or other metabolic disorders.
• Complicated with other types of stroke (e.g., cardioembolic stroke, large artery atherosclerotic stroke, etc.).
• Presence of severe cognitive impairment, depression, or other psychiatric or neurological disorders.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Stroke Control Group; standard treatment against stroke	Other: Standard Treatment; Standard Treatment
Experimental: Stroke RIC Group; standard treatment against stroke + RIC intervention	Device: Medical-grade ischemic preconditioning training instrument; The remote ischemic conditioning (RIC) intervention consists of two sessions per day, with 5 cycles per session (each cycle comprising 5 minutes of inflation followed by 5 minutes of deflation), performed alternately on both upper arms. The inflation pressure is set at baseline systolic blood pressure + 20 mmHg, gradually increased up to a maximum of 200 mmHg. If the patient experiences discomfort, the pressure may be appropriately reduced to allow adaptation, then gradually increased again. At least 3 complete cycles must be completed per session, and an overall compliance rate of ≥80% is considered as achieving the target. Concurrently, patients will receive standard medical treatment (antihypertensive therapy, lipid-lowering therapy, and single antiplatelet therapy). The total intervention duration is 3 months. For enrolled patients with cerebral infarction, management will be conducted by the neurosurgery department. During hospitalization, the RIC procedure will be administered an
Sham Comparator: CSVD Control Group; standard treatment against CSVD	Other: Standard Treatment; Standard Treatment
Experimental: CSVD RIC Group; standard treatment against CSVD + RIC intervention	Device: Medical-grade ischemic preconditioning training instrument; The remote ischemic conditioning (RIC) intervention consists of two sessions per day, with 5 cycles per session (each cycle comprising 5 minutes of inflation followed by 5 minutes of deflation), performed alternately on both upper arms. The inflation pressure is set at baseline systolic blood pressure + 20 mmHg, gradually increased up to a maximum of 200 mmHg. If the patient experiences discomfort, the pressure may be appropriately reduced to allow adaptation, then gradually increased again. At least 3 complete cycles must be completed per session, and an overall compliance rate of ≥80% is considered as achieving the target. Concurrently, patients will receive standard medical treatment (antihypertensive therapy, lipid-lowering therapy, and single antiplatelet therapy). The total intervention duration is 3 months. For enrolled patients with cerebral infarction, management will be conducted by the neurosurgery department. During hospitalization, the RIC procedure will be administered an

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in White Matter Hyperintensity (WMH) Volume on Brain MRI	Brain MRI will be performed to assess changes in white matter hyperintensity volume, including lesion extent and DWI signal characteristics. The primary outcome is the change in WMH volume from baseline to 3 months.	Baseline, Month 3
Change in National Institutes of Health Stroke Scale (NIHSS) Score	The NIHSS is a 15-item neurological examination scale used to assess stroke severity. Scores range from 0 to 42, with higher scores indicating more severe neurological deficits. The primary outcome is the change in NIHSS score from baseline to 3 months.	Baseline, Month 1, Month 3
Change in Cognitive Function (MoCA and MMSE Scores)	Cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). The MoCA scores range from 0 to 30, with higher scores indicating better cognitive function. The MMSE scores range from 0 to 30, with higher scores indicating better cognitive status. The primary outcome is the change in both scores from baseline to 3 months.	Baseline, Month 1, Month 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Levels of Inflammatory and Neuroprotective Biomarkers	Serum samples will be collected to assess dynamic changes in inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6) and neuroprotective factors. Changes in biomarker levels will be compared between baseline and follow-up time points.	Baseline, Month 1, Month 3
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)	Safety will be assessed by monitoring the frequency, severity, and relatedness of adverse events and serious adverse events, including allergic reactions, changes in liver and renal function, and coagulation parameters.	Throughout the 3-month intervention period
Compliance Rate with RIC Intervention	Adherence to the RIC intervention will be evaluated. Compliance is defined as completing ≥80% of the prescribed RIC sessions (two sessions per day, 5 cycles per session, over 3 months).	Throughout the 3-month intervention period

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2026
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): March 1, 2029

Study Registration Dates

• First Submitted: March 25, 2026
• First Submitted That Met QC Criteria: March 25, 2026
• First Posted (Actual): March 31, 2026

Study Record Updates

• Last Update Posted (Actual): March 31, 2026
• Last Update Submitted That Met QC Criteria: March 25, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: stroke
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Stroke; Cerebral Small Vessel Diseases
• Other Study ID Numbers: 2026-0150

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No