Trial of Remote Ischemic Pre-conditioning in Vascular Cognitive Impairment

Phase 2

• Conditions: Cerebral Small Vessel Ischaemic Disease; Vascular Cognitive Impairment; Vascular Dementia; Cerebral Small Vessel Diseases
• Interventions: Device: Remote ischemic conditioning

• Registration Number: NCT04109963
• Lead Sponsor: University of Calgary

Brief Summary

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

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2019-09-26
• Study First Submitted: 2019-09-27
• Study First Submitted QC: 2019-09-27
• Study First Posted: 2019-10-01
• Status Verified: 2021-08
• Last Update Submitted: 2022-06-07
• Last Update Posted: 2022-06-09
• Primary Completion: 2022-12-31
• Study Completion: 2023-03-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 24

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).

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
RIC twice per day	Remote ischemic conditioning	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.
RIC once per day	Remote ischemic conditioning	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.

Primary Outcome Measures

Name	Time	Method
Adherence	30 days	Proportion completing 80% or more sessions.

Secondary Outcome Measures

Name	Time	Method
Neuropsychiatric symptoms	30 days and 90 days	Change in Mild Behavioural Impairment Checklist
Arm deep venous thrombosis	30 days	Arm deep venous thrombosis
Randomization	14 days	Proportion completing the run-in period and proceeding to randomization
MRI white matter hyperintensity volume	30 days and 90 days	Change in white matter hyperintensity volume on FLAIR
MRI cerebral blood flow	30 days and 90 days	Change in cerebral blood flow measured by arterial spin label MRI
MRI diffusion tensor imaging	30 days and 90 days	Change in MRI peak skeletonized mean diffusivity
Global cognition	30 days and 90 days	Change in Montreal Cognitive Assessment
Discontinuation	30 days	Cessation of device use
Physical examination	30 days	Proportion with signs of arm soft tissue or neurovascular injury
Pain	30 days	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 \[worst possible pain\]).
Neuropsychological tests	30 days and 90 days	Change in Trail-Making A and B

Trial Locations

Locations (1)

Foothills Medical Centre; 🇨🇦 Calgary, Alberta, Canada