Glucagon-like Peptide 1 Receptor Agonist in Acute Large Vessel Occlusion Stroke Treated by Reperfusion Therapies

NCT05920889 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: CREC 2023.026-T
• Study Type: interventional
• Target: 140
• Locations: 2 countries
• Sites: 2

Brief Summary

Endovascular thrombectomy (EVT) is a highly effective therapy for acute ischemic stroke with large vessel occlusion (LVO). EVT was proven efficacious in selected patients with symptoms onset or last-known-well time of up to 24 hours. With a number-needed-to-treat (NNT) of 2.3-2.8 to achieve functional independence, EVT had become the current state-of-the-art treatment for ischemic stroke with LVO. Nevertheless, more than half of LVO strokes suffered from functional dependence or death despite EVT. Futile EVTs were contributed by peri-procedural malignant brain edema (MBE) and symptomatic intracranial hemorrhage (sICH). Studies suggested that 26.9% of EVTs were complicated by MBE, whereas sICH was present in 6-9% of LVO patients who received EVT. The fundamental pathophysiology of MBE and sICH is blood-brain-barrier (BBB) disruption secondary to ischemia, mechanical and reperfusion injury. These pathological processes can result in increased tissue permeability, excess production of oxygen free radicals and inflammatory response that eventually lead to hemorrhage and edema. Poor collateral circulation, proximal LVOs, intravenous thrombolysis, blood pressure and glucose fluctuation had all been implicated to in MBE and sICH. However, these risk factors were either unmodifiable or not shown to improve EVT outcomes. The preliminary results of a recent randomized trial even suggested harmful effects of intensive blood pressure following EVT. With indications of EVT are expanding to patients with prolonged ischemia and large ischemic cores, enhancing BBB and neuronal tolerance to ischemia and reperfusion therapies may hugely impact on EVT outcomes. Recent animal models have shown that glucagon-like peptide peptide-1 receptor agonists (GLP-1RA) significantly reduced infarct volume and neurological deficits following temporary or permanent middle cerebral artery occlusion. These effects were likely due to the anti-oxidant, anti-inflammatory and anti-apoptotic properties of GLP-1RA that protected BBB integrity and ischemic neurons during induced LVO and/or reperfusion. Investigator hypothesizes that compared to standard reperfusion strategies, administration of GLP-1RA in LVO patients who receive EVT may prevent the development of MBE and sICH, and improve neurological outcomes. In this randomized, open-label pilot study, investigator aims to determine the effect of semaglutide, a GLP-1RA, on the radiological and clinical outcomes in LVO patients undergoing EVT.

Conditions

Stroke; Stroke, Acute; Stroke, Ischemic; Brain Diseases

Outcome Measures

Primary Outcomes (2)

• Change of Modified Rankin Score

  Change of Modified Rankin Score to measure degree of disability/dependence. Scores 0-2 is considered good outcome, while scores 3-6 is considered poor outcome.

  Day 90

• Composite Safety Outcome

  Composite of Death, Intracranial Hemorrhage (ICH) and Malignant Brain Edema (MBE)

  Day 90

Secondary Outcomes (9)

• Malignant brain edema (MBE)

  From Day 0 post treatment, up to 90 Days.

• Symptomatic intracranial hemorrhage (sICH)

  From Day 0 post treatment, up to 90 Days.

• Blood-brain-barrier (BBB) permeability

  From Day 0 post treatment, up to 90 Days.

• Hemorrhagic transformation and parenchymal hemorrhage

  From Day 0 post treatment, up to 90 Days.

• Modified Rankin Score (mRS) 0-3

  From Day 0 post treatment, up to 90 Days.

Study Arms (2)

Semaglutide Group

ACTIVE COMPARATOR

Prescribe study drug: Patients randomized into the semaglutide group will receive 0.5mg subcutaneous injection of the drug before or during EVT, and 7 days after the procedure. i.e. semaglutide group will receive a total of 2 injections.

Drug: Semaglutide

Standard of care

NO INTERVENTION

Standard medical therapy

Interventions

Semaglutide DRUG

0.5mg subcutaneous injection of the drug before or during EVT, and 7 days after the procedure. i.e. patient will receive a total of 2 injections.

Semaglutide Group

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• LVO stroke at terminal ICA or proximal M1 eligible for emergency endovascular treatment as per current treatment guideline.
• LKW-to-puncture time ≤ 12 hours.
• Age 18 years or greater.
• National Institute of Health Stroke Scale (NIHSS) ≥10
• LVO stroke due to thromboembolism or intracranial stenosis (acute or acute on chronic occlusion).
• Patients who received computer tomographic angiography and perfusion (CTA+P).
• Pre-stroke (24 hours prior to stroke onset) independent functional status with modified Rankin Scale (mRS) ≤ 2.
• Consent process completed as per national laws and regulation and the applicable ethics committee requirements.

You may not qualify if:

• ASPECT score ≤ 5.
• Intracranial hemorrhage on pre-EVT imaging.
• LVO etiologies other than thromboembolism or intracranial stenosis (acute or acute on chronic total occlusion), e.g. arterial dissection, infective endocarditis on initial diagnostic imaging.Estimated or known body mass index \< 18 kg/m2
• Estimated or known body mass index \< 18 kg/m2.
• Pregnancy/Lactation; female, with positive urine or serum beta human chorionic gonadotropin (β-hCG) test, or breastfeeding.
• Creatinine clearance \< 30mL/min.
• Severe or fatal comorbid illness, e.g. terminal malignancy.
• History of allergy to GLP-1RA.
• Family or personal history of multiple endocrine neoplasia, medullary thyroid carcinoma, pancreatic carcinoma, known proliferative diabetic retinopathy.
• Active sepsis on randomization.
• Patients with hypoglycaemia on presentation. Defined as capillary or serum glucose level of \<4mmol/L.
• Patients prone to severe hypoglycaemia, including chronic kidney disease of estimated glomerular filtration rate of 50ml/min/1.73m\^2; also those with chronic liver disease with Child's Pugh score C or above; patients with recurrent unexplained hypoglycemia.
• Patient already on GLP-1RA prior to screening.
• Contraindications to iodine-based CT contrast.

Sponsors & Collaborators

• Chinese University of Hong Kong: lead
• Linyi People's Hospital: collaborator

Study Sites (2)

Linyi People's Hospital

Linyi, Shangdong, 276000, China

Location

Chinese University of Hong Kong

Hong Kong, Hong Kong

Location

Related Publications (1)

• Wang H, Ko H, Leung TW, Huang J, Sai J, Liang Y, Li H, Zhang J, Cao Q, Zang W, Li Y, Ma SH, Lui WT, Choi J, Chan C, Wong J, Kwok AJ, Ma K, Fan F, Chan A, Ip V, Leung H, Soo Y, Wong KT, Lai B, Chu CM, Leung HS, Hui A, Cheung T, Abrigo J, Li SH, Chan L, Yeung J, Pan S, Yip T, Lui LT, Hung T, Tsang SF, Leng X, Lam B, Mok VCT, Chan RHM, Nguyen TN, Hu W, Che F, Ip BY. Glucagon-like peptide-1 receptor agonist in large vessel occlusion treated by reperfusion therapy-a phase 2 randomized trial. Nat Commun. 2025 Dec 14;16(1):11274. doi: 10.1038/s41467-025-66167-z.

  PMID: 41392086 DERIVED

MeSH Terms

Conditions

Stroke; Ischemic Stroke; Brain Diseases

Interventions

semaglutide

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Study Officials

• Bonaventure Yiu Ming IP, MB ChB

  Chinese University of Hong Kong

  PRINCIPAL INVESTIGATOR

• Fengyuan CHE, MD,PhD

  Linyi People's Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Model Details: 140 patients will be randomized to "treatment arm" with semaglutide and standard medical therapy, and "control arm" with standard medical therapy alone in a 1:1 ratio.

Study Record Dates

• First Submitted: June 16, 2023
• First Posted: June 27, 2023
• Study Start: August 1, 2023
• Primary Completion: October 25, 2024
• Study Completion: October 25, 2024
• Last Updated: March 7, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1); HK (1)