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

NCT07503301 — Not applicable, Enrolling by invitation, 80 participants, Second Affiliated Hospital, Zhejiang University, School of Medicine

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

Registry	NCT07503301, acronym SHIELD
Status	Enrolling by invitation
Phase	Not applicable
Study type	Interventional; randomized, parallel, masking: none, treatment
Enrollment	80 (Estimated)
Sponsor	Second Affiliated Hospital, Zhejiang University, School of Medicine (Other)
Conditions	Stroke, Small Vessel Cerebrovascular Disease
Interventions	Medical-grade ischemic preconditioning training instrument, Standard Treatment (Device, other)
Dates	start 2026-02-01, primary completion 2029-03-01 (estimated), completion 2029-03-01 (estimated), first posted 2026-03-31, last updated 2026-03-31
Locations	1 site in China

-Summary

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.

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+Arms and interventions

Arm	Type	Interventions	Description
Stroke Control Group	Sham comparator	Other: Standard Treatment	standard treatment against stroke
Stroke RIC Group	Experimental	Device: Medical-grade ischemic preconditioning training instrument	standard treatment against stroke + RIC intervention
CSVD Control Group	Sham comparator	Other: Standard Treatment	standard treatment against CSVD
CSVD RIC Group	Experimental	Device: Medical-grade ischemic preconditioning training instrument	standard treatment against CSVD + RIC intervention

Medical-grade ischemic preconditioning training instrument (Device): 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
Standard Treatment (Other): Standard Treatment

+Outcome measures

Primary outcomes

Change in White Matter Hyperintensity (WMH) Volume on Brain MRI [Baseline, Month 3]: 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.
Change in National Institutes of Health Stroke Scale (NIHSS) Score [Baseline, Month 1, Month 3]: 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.
Change in Cognitive Function (MoCA and MMSE Scores) [Baseline, Month 1, Month 3]: 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.

Secondary outcomes

Serum Levels of Inflammatory and Neuroprotective Biomarkers [Baseline, Month 1, Month 3]: 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.
Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) [Throughout the 3-month intervention period]: 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.
Compliance Rate with RIC Intervention [Throughout the 3-month intervention period]: 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).

+Eligibility

Sex: All, ages: 50 Years to 65 Years

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.

+Locations (1)

Facility	City	Country	Status
2ndAffiliated Hospital, School of Medicine, Zhejiang Universit, Hangzhou, Zhejiang 310000	Hangzhou, Zhejiang	China

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