Trial of Remote Ischemic Pre-conditioning in Vascular Cognitive Impairment (TRIC-VCI)

Trial of Remote Ischemic Pre-Conditioning in Vascular Cognitive Impairment

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.

Study Overview

• Status: Recruiting
• Conditions: Cerebral Small Vessel Diseases; Vascular Dementia; Vascular Cognitive Impairment; Cerebral Small Vessel Ischaemic Disease
• Intervention / Treatment: Device: Remote ischemic conditioning

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.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Eric E Smith, MD; Phone Number: 1-403-944-1594; Email: eesmith@ucalgary.ca
• Study Contact Backup: Name: Karyn Fischer, RN; Phone Number: 1-403-210-7611; Email: Karyn.Fischer@albertahealthservices.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Recruiting
      • Foothills Medical Centre
      • Contact: Karyn Fischer, MD; Phone Number: 403-210-7611; Email: karyn.fischer@albertahealthservices.ca
      • Contact: Eric E Smith, RN; Phone Number: 403-944-1594; Email: eesmith@ucalgary.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: RIC once per day; 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; Remote ischemic conditioning therapy to the upper arm will be delivered by an automated device (RIC VCI) manufactured by Seagull Aps (Denmark).
Active Comparator: RIC twice per day; 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; Remote ischemic conditioning therapy to the upper arm will be delivered by an automated device (RIC VCI) manufactured by Seagull Aps (Denmark).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Calgary
• Collaborators: Canadian Institutes of Health Research (CIHR); Canadian Consortium on Neurodegeneration in Aging
• Investigators: Principal Investigator: Eric Smith, MD, University of Calgary

Publications and helpful links

General Publications

• Ganesh A, Barber P, Black SE, Corbett D, Field TS, Frayne R, Hachinski V, Ismail Z, Mai LM, McCreary CR, Sahlas D, Sharma M, Swartz RH, Smith EE. Trial of remote ischaemic preconditioning in vascular cognitive impairment (TRIC-VCI): protocol. BMJ Open. 2020 Oct 14;10(10):e040466. doi: 10.1136/bmjopen-2020-040466.

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2019
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): March 1, 2023

Study Registration Dates

• First Submitted: September 27, 2019
• First Submitted That Met QC Criteria: September 27, 2019
• First Posted (Actual): October 1, 2019

Study Record Updates

• Last Update Posted (Actual): June 9, 2022
• Last Update Submitted That Met QC Criteria: June 7, 2022
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: vascular cognitive impairment, cerebral small vessel diseases, remote ischemic conditioning
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Neurocognitive Disorders; Dementia; Cognition Disorders; Intracranial Arterial Diseases; Intracranial Arteriosclerosis; Leukoencephalopathies; Ischemia; Cognitive Dysfunction; Dementia, Vascular; Cerebral Small Vessel Diseases
• Other Study ID Numbers: REB19-0861

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The completely de-identified study dataset will be posted to the University of Calgary section of the PRISM dataverse at the time of publication of the main study results in a peer-reviewed journal.
• IPD Sharing Time Frame: The study dataset will be made publicly available at the time of publication of the main study results in a peer-reviewed journal.
• IPD Sharing Access Criteria: Open to the public.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: Not yet available
   Information comments: The dataset with individual de-identified participant data will be hosted on the University of Calgary PRISM dataverse once the main results results are published. The identifier will be assigned when the dataset is uploaded.

Drug and device information, study documents

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