EGRABIS1: The Effect of GLP-1 Receptor Agonist on Cerebral Blood Flow Velocity in Stroke

Sponsor

Christina Kruuse (Other)

Overall Status

Recruiting

CT.gov ID

NCT02829502

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This randomized controlled trial investigates the effect of a single dose of glucagon-like peptide-1 (GLP-1) receptor agonist in the subacute phase of stroke in humans. The primary endpoint is the mean flow velocity in the middle cerebral arteries measured by transcranial doppler and cortical oxygination measured by near infrared spectroscopy (NIRS). The secondary endpoints are changes in endothelial/inflammatory biomarkers in the blood, changes in the ankle-brachial index and changes in the reactive hyperaemia index measured by EndoPAT2000.

Condition or Disease	Intervention/Treatment	Phase
Ischemic Stroke	Drug: Byetta Drug: Normosaline	Phase 2

Detailed Description

Glucagon-like peptide 1 (GLP-1) receptor agonists are widely used in the treatment of type 2 diabetes because of their ability to mimic the incretin hormone, GLP-1. GLP-1 increases glucose-dependent insulin secretion and thereby reduces the glucose level. Over the past few years, GLP-1 receptor agonists have been investigated as possible therapies for neurological disorders, due to their ability to cross the blood-brain-barrier. Evidence of the treatment of cerebrovascular diseases has been growing especially in animal stroke models. GLP-1 receptors, which are located in the central nervous system on neurons and endothelium, are upregulated in the brain due to ischemia. GLP-1 receptor agonists have shown anti-inflammatory and anti-apoptotic properties, and they may protect the cell from oxidative stress and may protect the endothelium. The inner lining of blood vessels, the endothelium, is an active component of the endocrine function. It affects the formation of blood clots and plays a role in the disease mechanisms of stroke. The current acute and prophylactic treatments of stroke mainly target platelet function, but not endothelial function.

This double-blinded, randomized, controlled, pilot trial investigates the effect of a single dose of the GLP-1 receptor agonist, exenatide, on cerebral blood flow velocity in the subacute phase of stroke in humans. The primary endpoint is the mean flow velocity in the middle cerebral arteries measured by transcranial doppler and cortical oxygination measured by near infrared spectroscopy (NIRS). The secondary endpoints are the effects on the peripheral endothelium, hereby: 1) changes in the reactive hyperaemia index measured by EndoPAT2000, 2) changes in the ankle-brachial index, and 3) changes in endothelial/inflammatory biomarkers in the blood. The primary and secondary endpoints are measured before and up till three hours after administration of exenatide.

The overall hypothesis is that GLP-1 receptor agonists may represent a novel potential neuroprotective treatment in stroke. Parallel to this study we investigate the effect of GLP-1 receptor agonist on people free of cerebrovascular diseases (ref. to EGRABINS1).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

The Effect of Glucagon-like Peptide 1 (GLP-1) Receptor Agonist on Cerebral Blood Flow Velocity in Stroke Patients

Study Start Date :

Aug 1, 2016

Anticipated Primary Completion Date :

Jan 1, 2022

Anticipated Study Completion Date :

May 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Byetta Pre- and post treatment investigations: Mean flow velocity of the middle cerebral arteries bilateral by transcranial doppler Cerebral cortical oxygination by near infrared spectroscopy (NIRS) Endothelial function/response by the methods: Biomarkers in blood (eg. e-selectin, VCAM, ICAM, endothelin, ADMA, miRNA) EndoPAT2000 Ankle-brachial index	Drug: Byetta Single dose of subcutaneous injection of 5 μg exenatide (Byetta). Other Names: Exenatide GLP-1 receptor analogue GLP-1 receptor agonist
Placebo Comparator: Normosaline Pre- and post treatment investigations: Mean flow velocity of the middle cerebral arteries bilateral by transcranial doppler Cerebral cortical oxygination by near infrared spectroscopy (NIRS) Endothelial function/response by the methods: Biomarkers in blood (eg. e-selectin, VCAM, ICAM, endothelin, ADMA, miRNA) EndoPAT2000 Ankle-brachial index	Drug: Normosaline Single dose of subcutaneous injection of 20 μL normosaline (placebo). Other Names: Isotonic saline

Arm

Intervention/Treatment

Active Comparator: Byetta

Pre- and post treatment investigations: Mean flow velocity of the middle cerebral arteries bilateral by transcranial doppler Cerebral cortical oxygination by near infrared spectroscopy (NIRS) Endothelial function/response by the methods: Biomarkers in blood (eg. e-selectin, VCAM, ICAM, endothelin, ADMA, miRNA) EndoPAT2000 Ankle-brachial index

Drug: Byetta

Single dose of subcutaneous injection of 5 μg exenatide (Byetta).

Other Names:

Exenatide

GLP-1 receptor analogue

GLP-1 receptor agonist

Placebo Comparator: Normosaline

Drug: Normosaline

Single dose of subcutaneous injection of 20 μL normosaline (placebo).

Other Names:

Isotonic saline

Outcome Measures

Primary Outcome Measures

Changes in the mean flow velocity in the middle cerebral arteries and in cortical oxigination. [Up till 3 hours]
Change in the mean flow velocity in the middle cerebral arteries will be measured with transcranial doppler and cortical oxygination by near infrared spectroscopy (NIRS) before and up till tree hours after injection of exenatide/placebo.

Secondary Outcome Measures

Endothelial reactivity [3 hours]
Measurement of endothelial reactivity in fingers post occlusion by non-invasive plethysmography (EndoPAT2000) before and three hours after injection of exenatide/placebo.
Changes in endothelial biomarkers in blood [3 hours]
Venous blood samples to measure endothelial biomarkers (including V-CAM, I-CAM, endothelin, e-selectin, ADMA, hsCRP, miRNA) before and three hours after injection of exenatide/placebo.
Endothelial function/response in ankle-brachial index [3 hours]
Measuring of the blood pressure in the ankles and in the arm calculate the ankle-brachial index before and three hours after injection of exenatide/placebo.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients ≥ 18 years with newly symptoms of stroke
Able to receive exenatide/placebo within 21 days after onset of symptoms
Radiological confirmed diagnoses of ischemic stroke
NIHSS between 1-20 at the onset of symptoms
modified rankin scale (mRS) ≤ 2 prior to onset of symptoms
Has given written informed consent

Exclusion Criteria:

Intracerebral haemorrhage
Subdural / epidural hemorrhage
Subarachnoid haemorrhage
Previously major structural damage to the brain
Diabetes type 1
Diabetes type 2
Known atrial fibrillation
50% stenosis of internal carotid
Known allergy to GLP-1 receptor agonists
Hepatic impairment (ALT> 3 x upper normal limit)
Renal impairment (eGFR <30 ml / min)
Inflammatory bowel disease
Previous pancreatitis
Heart failure (NYHA class 3-4)
Pregnancy or lactation
Patient unable to co-operate to the investigation procedures
Visualization of the middle cerebral artery bilaterally by transcranial dopple not possible