Trial of Remote Ischemic Pre-conditioning in Vascular Cognitive Impairment

Study Overview
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Brief Summary
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Cerebral small vessel disease is a common cause of cognitive impairment. Remote ischemic pre-conditioning (RIC) is a technique to induce brief periods of limb ischemia-reperfusion that is hypothesized to increase tolerance of the brain to hypoperfusion and increase cerebral blood flow. Patients with cognitive impairment, preserved basic activities of daily living, and brain computed tomography (CT) or magnetic resonance imaging (MRI) evidence of confluent white matter hyperintensities or multiple brain infarcts will be randomized to either RIC performed once a day on one arm, or twice per day on one arm, for 30 days, to test tolerability and effects on MRI markers of blood flow.

Detailed Description
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Cerebral small vessel disease (cSVD) accounts for 20-25% of all strokes and is the most common cause of vascular cognitive impairment (VCI) as well as a major contributor to mixed dementia, potentially interacting with Alzheimer's disease. Remote ischemic pre-conditioning (RIC) is a technique to induce brief periods of limb ischemia-reperfusion that is hypothesized to increase tolerance of the brain to hypoperfusion. This is a prospective, open-label randomized controlled clinical trial with blinded endpoint assessment (PROBE). Participants that complete a 14-day run-in period will be randomized to 30 days of either: a) RIC performed once per day on one arm, or b) RIC performed twice per day on one arm. Each RIC session will consist of 4 cycles of unilateral upper arm ischemia for 5 minutes followed by reperfusion for another 5 minutes, administered by modified blood pressure monitor (under an Investigational Trail Authorization from Health Canada). The primary outcome is tolerability, defined as the proportion in each trial arm that complete 80% or more of the assigned RIC sessions. Secondary outcomes will include pain scores, cognition, and MRI markers of cerebral blood flow and white matter integrity.

Official Title
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Trial of Remote Ischemic Pre-Conditioning in Vascular Cognitive Impairment

Conditions
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Vascular Dementia, Cerebral Small Vessel Diseases, Cerebral Small Vessel Ischaemic Disease, Vascular Cognitive Impairment

Intervention / Treatment
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* Device: Remote ischemic conditioning


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Evidence of cerebral small vessel disease on CT or MRI, defined as either beginning confluent white matter hypodensities/hyperintensities (ARWMC scale) or two or more supratentorial infarcts Montreal Cognitive Assessment <25 Concern on the part of the patient, caregiver, or clinician that there has been a decline from previous level of cognitive functioning Independent with basic activities of daily living (response (a) to questions 2, 4, 5, 6, 7, 8, 9, and 14 on the Bristol Activities of Daily Living scale). Exclusion Criteria: Cortical infarcts larger than 10 mm axial diameter Neuroimaging evidence of mass lesion, intracerebral hemorrhage, vascular malformation, or evidence of non-vascular disease such as hydrocephalus. Residence in long-term care facility. Other significant neurological or psychiatric disease (e.g. multiple sclerosis). Does not have a study partner who can provide corroborative information. English or French is not sufficiently proficient for clinical assessment and neuropsychological testing Montreal Cognitive Assessment score <13 Unable to undergo MRI due to medical contraindications or inability to tolerate the procedure. Co-morbid medical illness that in the judgment of the study investigator makes it unlikely that the participant will be able to complete three months of study follow-up. On therapeutic anticoagulation with doses used for treatment of deep venous thrombosis, pulmonary embolism, or for stroke prevention in atrial fibrillation. Significant bleeding diathesis. Any symptomatic or previously known arm soft-tissue disease, vascular injury, or peripheral vascular disease Hypertension with systolic blood pressure >=180 mmHg despite medical treatment at the time of enrolment. Planned revascularization (any angioplasty or vascular surgery) within the next 3 months. Planned surgical procedure within the next 3 months. Currently receiving an investigational drug or device by other studies Blood pressure cuff cannot be sized properly (arm circumference is <23 cm or >42 cm)

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomized, parallel arm, open-label, blinded end-point (PROBE) design.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: RIC once per day<br>RIC performed once a day on one arm. Each RIC session will consist of 4 cycles of unilateral or simultaneous bilateral upper arm ischemia for 5 minutes followed by reperfusion for another 5 minutes. The procedure will be performed by using an electric auto-control device with cuffs that inflate to a pressure of 200 mmHg during the ischemic period. | Device: Remote ischemic conditioning<br>* Remote ischemic conditioning therapy to the upper arm will be delivered by an automated device (RIC VCI) manufactured by Seagull Aps (Denmark).<br>|
| Active Comparator: RIC twice per day<br>RIC performed twice a day on one arm, approximately 12 hours apart. Each RIC session will consist of 4 cycles of unilateral or simultaneous bilateral upper arm ischemia for 5 minutes followed by reperfusion for another 5 minutes. The procedure will be performed by using an electric auto-control device with cuffs that inflate to a pressure of 200 mmHg during the ischemic period. | Device: Remote ischemic conditioning<br>* Remote ischemic conditioning therapy to the upper arm will be delivered by an automated device (RIC VCI) manufactured by Seagull Aps (Denmark).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adherence | Proportion completing 80% or more sessions. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Discontinuation | Cessation of device use | 30 days | 
| Randomization | Proportion completing the run-in period and proceeding to randomization | 14 days | 
| Physical examination | Proportion with signs of arm soft tissue or neurovascular injury | 30 days | 
| Arm deep venous thrombosis | Arm deep venous thrombosis | 30 days | 
| Pain | Mean peak and end-cycle pain levels reported using the Numeric Rating Scale for pain (based on subjective report, ranging from 0 [no pain] to 10 [worst possible pain]). | 30 days | 
| MRI cerebral blood flow | Change in cerebral blood flow measured by arterial spin label MRI | 30 days and 90 days | 
| MRI white matter hyperintensity volume | Change in white matter hyperintensity volume on FLAIR | 30 days and 90 days | 
| MRI diffusion tensor imaging | Change in MRI peak skeletonized mean diffusivity | 30 days and 90 days | 
| Global cognition | Change in Montreal Cognitive Assessment | 30 days and 90 days | 
| Neuropsychological tests | Change in Trail-Making A and B | 30 days and 90 days | 
| Neuropsychiatric symptoms | Change in Mild Behavioural Impairment Checklist | 30 days and 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vascular cognitive impairment, cerebral small vessel diseases, remote ischemic conditioning