Clinical trial NCT04266639: Rheo-Erythrocrine Dysfunction as a Biomarker for RIC Treatment in Acute Ischemic Stroke
Official title: Rheo-Erythrocrine Dysfunction as a Biomarker for RIC Treatment in Acute Ischemic Stroke - Pilot, Single-center, Randomized, Patient-assessor Blinded, Sham-controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Stroke, Acute
Ischemic Stroke
Cerebrovascular Disorders
Central Nervous System Diseases
Keywords: Remote Ischemic Conditioning
Neuroprotection
Lead sponsor: Aarhus University Hospital
Sponsor class: OTHER
First posted: 2020-02-12
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Pilot, Single-center, Randomized, Patient-assessor blinded, Sham-controlled Trial
Primary purpose: TREATMENT

Brief summary: This study aims to investigate whether Remote Ischemic Conditioning (RIC) improves rheo-erythrocrine dysfunction in acute ischemic stroke

Detailed description: Stroke is a leading cause of death and disability worldwide. Of all strokes, 85% are ischemic strokes caused by a thrombus or an embolus. The additional 15% are caused by hemorrhage. Currently the only approved treatments for ischemic strokes are thrombolysis given within 4.5 hours and thrombectomy performed within 6 hours of symptom onset - in some cases up to 24 hours. The majority of stroke patients are not however eligible for acute reperfusion therapy, mainly due to time constrains and late presentation. Novel neuroprotective strategies available for all stroke patients are thus urgently needed.

Remote Ischemic Conditioning (RIC) is a simple intervention in which transient ischemia is induced in an extremity by repetitive inflation-deflation of a blood pressure cuff. It remains uncertain exactly how the protective effect of RIC is transmitted and communicated between the extremity and the brain. Both humoral, immunological and neuronal pathways seem to be involved. Treatment with RIC and has proven to be a safe, feasible and low-cost treatment in clinical settings.

Biomarkers of the RIC treatment is a new area of stroke research and are important to establish in order to assess and predict responders of the conditioning treatment. Rheo-erythrocrine dysfunction of the Red Blood Cell (RBC) is a novel biomarker in both ischemic strokes in general and on the effect of RIC. Red Blood Cells with a diameter of 6-8 μm must be highly deformable in order to deliver oxygen to brain tissue by travelling through micro vessels with a diameter of just 2-3 μm. RBC's can carry nitric oxide as NO2-/s-nitrosylated proteins. These proteins improve RBC deformability and induce hypoxic vasodilation thereby improving passage through the microvasculature. RBC's also express Erythrocyte Nitric Oxide Synthase 3, which regulate the rheo-erythrocrine function. Erythrocyte Nitric Oxide Synthase 3 is activated by shear stress and provide an extra source of NO for hypoxic vasodilation. Preliminary data have shown that experimental stroke on mice seems to cause a rheo-erythrocrine dysfunction of the RBC's leading to a loss of deformability. The RBC's become rigid, which can lead to occlusion of micro vessels in the brain and further ischemic damage. Loss of deformability can be measured as a reduced Elongation Index (EI) by ektacytometry and may be attenuated by RIC.

Eligibility criteria: STROKE PATIENTS

Inclusion Criteria:

* Onset to randomization \< 48 hours
* Independent in daily living (mRS 0-2)
* Legal competent
* Ambulatory
* Documented ischemic stroke on baseline MRI

Exclusion Criteria:

* Prior stroke, dementia or other known neurological condition Pregnancy
* Contraindications to MRI
* Investigators discretion
* Known upper extremity peripheral arterial stenosis Diabetes

CONTROLS

Inclusion Criteria:

* Independent in daily living (mRS 0-2) Ambulatory
* Legal competent
* Non vascular diagnosis (e.g. epilepsy, migraine etc.)

Exclusion Criteria

* Prior stroke, dementia or other known neurological condition
* Pregnancy
* Contraindications to MRI
* Investigators discretion
* Known upper extremity peripheral arterial stenosis Diabetes

Primary outcomes:
measure: RBC deformability will serve as a biomarker of the conditioning response and predictor of the clinical outcome in stroke patients.
timeFrame: 1 week
measure: RBC deformability will serve as a biomarker of the conditioning response and predictor of the clinical outcome in stroke patients
timeFrame: 1 week
Secondary outcomes:
measure: Nitric oxide quantification using DAF-FM-Diacetate flowcytometry as a biomarker of the conditioning response
timeFrame: 1 week
measure: Nitric oxide quantification using DAF-FM-Diacetate flowcytometry as a predictor of the short term clinical outcome in stroke patients
timeFrame: 1 week
measure: RBC deformability presentation across stroke subtypes
timeFrame: 1 week
measure: RBC deformability in relation to infarct size/stroke severity
timeFrame: 1 week
measure: RBC erythrocrine dysfunction (NOS3) presentation across stroke subtypes
timeFrame: 9 months
measure: RBC erythrocrine dysfunction (nitric oxide) presentation across stroke subtypes
timeFrame: 9 months
measure: RBC erythrocrine dysfunction (NOS3) in relation to infarct size/stroke severity
timeFrame: 9 months
measure: RBC erythrocrine dysfunction (nitric) in relation to infarct size/stroke severity
timeFrame: 9 months
measure: Difference in 7 days cognitive impairment between treatment groups
timeFrame: 1 week
measure: RBC erythrocrine dysfunction and deformability as a marker for difference in 7 days cognitive impairment (MoCA scale)
timeFrame: 9 months
measure: Circulating microRNA profile of RIC-induced neuroprotection
timeFrame: 9 months
measure: Extracellular vesicle profile of RIC-induced neuroprotection
timeFrame: 9 months
measure: Circulating microRNA as a marker for difference in 7 days cognitive impairment (MoCA score)
timeFrame: 9 months
measure: Extracellular vesicle profile as a marker for RBC erythrocrine dysfunction and deformability
timeFrame: 9 months
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
Study officials:
affiliation: Aarhus University Hospital, Department of Neurology
name: Grethe Andersen, MD, DMSc
role: PRINCIPAL_INVESTIGATOR
References: