Remote Preconditioning Over Time To Empower Cerebral Tissue (REM-PROTECT)

Pilot, Randomized, Controlled, Staggered Start, Feasibility Trial of Ischemic Preconditioning, a Promising Novel Treatment for Stroke Prevention

Previous studies in animals and humans has shown that brief periods of reduced blood flow to one organ or tissue in the body can help protect other tissues from subsequent injury caused by reduced blood flow such as a stroke. This phenomenon is known as remote ischemic preconditioning and may help protect brain cells after a stroke. The investigators are studying a specific stroke type called subcortical stroke that is very common and has a high rate of recurrent stroke and cognition problems despite intensive prevention measures.

Study Overview

• Status: Terminated
• Conditions: Ischemic Stroke; Cognitive Decline; Cerebral Small Vessel Disease
• Intervention / Treatment: Device: Ischemic Preconditioning

Detailed Description

In this study, the investigators will enroll 60 patients. All patients will receive best standard medical therapy for 2 years. In addition, the investigators will randomly assign 40 patients to undergo daily active remote ischemic preconditioning for 1 year, and 20 patients to 1 year of standard medical therapy followed by 1 year of daily active remote ischemic preconditioning. Patient structured interviews will be performed to assess if the treatment is well tolerated and easy for stroke patients to use. Magnetic resonance (MR) pictures of the brain will be used to determine if the active treatment stops the progression of brain injury. Cognitive tests and wireless sensor technology measures will used to learn what happens to the patient's brain and body during the active treatment.

After a subject consents to participate in the study, he/she will first participate in a study screening phase to ensure a basic level of tolerability of Remote Ischemic Conditioning (autoRIC™) device. The subject will undergo one full cycle of treatment under observation of the study team, including 4 cycles of alternating 5 minute inflation and 5 minute off periods

If the subject indicates willingness to continue receiving such treatment (screening success), she/she will enter the randomized trial phase, and be randomly allocated to the treatment or control group.

If subject indicates unwillingness to continue receiving such treatment (screening failure), he/she will not advance to the randomized phase of the trial. Screen failure subjects will be followed up with a 3-day post-device screening phone call to ensure safety and obtain information regarding any adverse events.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles UCLA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

I. Clinical

1. Clinical lacunar stroke syndrome within the past 6 months
2. Absence of signs or symptoms of cortical dysfunction
3. No proximal large vessel atherosclerosis, intracranial atherosclerosis or cerebellar stroke.
4. No major cardioembolic source requiring anticoagulation or other specific therapy

II. Imaging

1. Magnetic Resonance Imaging (MRI) presence of a small subcortical ischemic, any 1 or more of:

   1. Diffusion-weighted imaging (DWI) lesion < 2.0cm in size at largest dimension and corresponding to the clinical syndrome.
   2. Well delineated focal hyperintensity <2.0 cm in size at largest dimension (including rostro-caudal extent) on FLAIR or T2 and clearly corresponding to the clinical syndrome. If other focal hyperintensities are present, the case will be discussed with the principal investigator prior to randomization
   3. Multiple (at least 2) hypointense lesions of size 0.3-1.5 cm at largest dimension (including rostro-caudal extent) only in the cerebral hemispheres on FLAIR or T1 in patients whose qualifying event is clinically hemispheric
   4. Well delinated hypointense lesion <1.5 cm in size at the largest dimension (including rostro-caudal extent) on FLAIR or T1 corresponding to the clinical syndrome. MRI must be done at least 1 months after the qualifying stroke
2. Absence of cortical stroke and large (> 1.5cm) subcortical stroke, recent or remote
3. White matter hyperintensity score of 2 (moderate) or 3 (severe) on the European Scale of Age-Related White Matter Change
4. Absence of cerebral amyloid antipathy (CAA) as per Boston Criteria.

Exclusion Criteria:

1. Disabling stroke (Rankin Scale ≥4)
2. Previous intracranial hemorrhage (excluding traumatic) or hemorrhagic stroke
3. Age under 40 years
4. High risk of bleeding (e.g. recurrent GI or GU bleeding, active peptic ulcer disease, etc.)
5. Anticipated requirement for long term use of anticoagulants (e.g. recurrent deep venous thrombosis (DVT)
6. Prior cortical or retinal stroke (diagnosed either clinically or by neuroimaging), or other prior cortical or retinal transient ischemic attack (TIA)
7. Prior ipsilateral carotid endarterectomy
8. Impaired renal function: estimated GFR <40
9. Intolerance or contraindications to aspirin or clopidogrel (including thrombocytopenia, prolonged INR)
10. Mini Mental Status Exam score < 24 (adjusted for age and education)
11. Medical contraindication to MRI
12. Pregnancy or women of child-bearing age who are not following an effective method of contraception
13. Pre-existing neurologic, psychiatric, or advanced systemic disease that would confound the neurological or functional outcome evaluations
14. SBP <90 or > 200
15. Known history of limb vascular disease, limb vascular bypass surgery, or limb deep venous thrombosis
16. Prisoners
17. Homeless individuals
18. Patient unable to give informed consent and no available legally authorized representative to provide informed consent
19. Patient unlikely to be compliant with therapy/ unwilling to return for follow up visits
20. Concurrent participation in another study with investigational drug or device treatment
21. Other likely specific cause of stroke (e.g. dissection, vasculitis, prothrombotic diathesis, drug abuse)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Medical therapy only; Intensive standard medical secondary prevention stroke treatment as per the recommendations of the American Heart Association/American Stroke Association national guidelines.
Active Comparator: Ischemic Preconditioning + Medical; Patients will receive treatment with Cell Aegis remote ischemic preconditioning device once or twice daily for one year. The procedure will consist of up to four 5-minute cycles of bilateral upper extremity ischemia separated by five minutes of reperfusion. Patients will also receive intensive standard medical secondary prevention stroke treatment as per the American Heart Association/American Stroke Association national guidelines.	Device: Ischemic Preconditioning; Patients will undergo ischemic preconditioning once or twice daily for up to four 5-minutes cycles of bilateral upper extremity ischemia separated by 5-minute periods of reperfusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Duration of Adherence to Ischemic Preconditioning Procedure	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Limb Ischemia as Assessed by the Preconditioning Device	12 months
Patient Self-reported Comfort-discomfort on a Scale of 1-5, With Lowest Score = "Very Comfortable" and 5 = "Very Uncomfortable"	12 months

Collaborators and Investigators

• Sponsor: University of California, Los Angeles
• Collaborators: American Heart Association
• Investigators: Principal Investigator: Latisha K Sharma, MD, University of California, Los Angeles

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): March 1, 2020
• Study Completion (Actual): March 1, 2020

Study Registration Dates

• First Submitted: June 17, 2014
• First Submitted That Met QC Criteria: June 18, 2014
• First Posted (Estimate): June 23, 2014

Study Record Updates

• Last Update Posted (Actual): March 10, 2021
• Last Update Submitted That Met QC Criteria: March 9, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: ischemic stroke; cognitive decline; ischemic preconditioning; remote ischemic preconditioning; white matter disease; cerebral small vessel disease; leukoaraiosis; diffusion tensor imaging; white matter hyper intensity score; European scale of age-related white matter change
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Cognition Disorders; Stroke; Ischemic Stroke; Ischemia; Cognitive Dysfunction; Cerebral Small Vessel Diseases
• Other Study ID Numbers: AHA-000-376

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No