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

• ClinicalTrials.gov Identifier: NCT04109963
• Recruitment Status: Recruiting
• First Posted: October 1, 2019
• Last Update Posted: October 2, 2019
• Sponsor: University of Calgary
• Collaborators: Canadian Institutes of Health Research (CIHR); Canadian Consortium on Neurodegeneration in Aging
• Information provided by (Responsible Party): University of Calgary

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Vascular Dementia; Cerebral Small Vessel Diseases; Cerebral Small Vessel Ischaemic Disease; Vascular Cognitive Impairment	Device: Remote ischemic conditioning	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Prospective, randomized, parallel arm, open-label, blinded end-point (PROBE) design.
• Masking: Single (Outcomes Assessor)
• Masking Description: Outcomes will be assessed masked to treatment assignment. Participants will be aware of treatment assignment.
• Primary Purpose: Treatment
• Official Title: Trial of Remote Ischemic Pre-Conditioning in Vascular Cognitive Impairment
• Actual Study Start Date: September 26, 2019
• Estimated Primary Completion Date: October 1, 2020
• Estimated Study Completion Date: October 1, 2020

Arms and Interventions

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).

Outcome Measures

Primary Outcome Measures :

1. Adherence [ Time Frame: 30 days ]
   Proportion completing 80% or more sessions.

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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)

Contacts and Locations

Contacts

Contact: Eric E Smith, MD; 1-403-944-1594; eesmith@ucalgary.ca

Contact: Karyn Fischer, RN; 1-403-210-7611; Karyn.Fischer@albertahealthservices.ca

Locations

Canada, Alberta

Foothills Medical Centre; Recruiting

Calgary, Alberta, Canada, T2N 2T9

Contact: Karyn Fischer, MD 403-210-7611 karyn.fischer@albertahealthservices.ca

Contact: Eric E Smith, RN 403-944-1594 eesmith@ucalgary.ca

Sponsors and Collaborators

University of Calgary

Canadian Institutes of Health Research (CIHR)

Canadian Consortium on Neurodegeneration in Aging

Investigators

• Principal Investigator: Eric Smith, MD; University of Calgary

More Information

Study Data/Documents: Individual Participant Data Set 

Identifier: Not yet available
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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: University of Calgary
• ClinicalTrials.gov Identifier: NCT04109963
• Other Study ID Numbers: REB19-0861
• First Posted: October 1, 2019
• Last Update Posted: October 2, 2019
• Last Verified: September 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• 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.
• Access Criteria: Open to the public.
• URL: https://dataverse.scholarsportal.info/dataverse/calgary

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Calgary:

vascular cognitive impairment, cerebral small vessel diseases, remote ischemic conditioning

Additional relevant MeSH terms:

Dementia, Vascular; Cerebral Small Vessel Diseases; Ischemia; Cognitive Dysfunction; Pathologic Processes; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders; Cerebrovascular Disorders; Intracranial Arteriosclerosis; Intracranial Arterial Diseases; Leukoencephalopathies; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases