Glucagon-like Peptide-1 Receptor Agonists for Endovascular Stroke Thrombectomy

Official title

A Multicentre, Prospective, Randomized, Open-label, Blinded Endpoint, Clinical Trial Evaluating Subcutaneous Semaglutide in Patients With Acute Ischaemic Stroke Due to Anterior Circulation Large Vessel Occlusion Treated With Endovascular Thrombectomy

Overview

Endovascular thrombectomy (EVT) is a procedure that improves recovery for people who suffer from a stroke by removing blood clots from large blood vessels in the brain. However, even with this treatment, over half of the patients either pass away or are left with serious disabilities within three months. This is partly because, even in cases of a successful EVT, brain tissue damage continues to grow. Extent of brain damage is a major factor in how well a patient recovers. Studies in animals have shown that a drug called semaglutide might help protect the brain and improve recovery after a stroke. Semaglutide is currently used for the treatment of diabetes and obesity and is given as a weekly injection under the skin. The investigators are hoping to test whether giving semaglutide to stroke patients undergoing EVT can improve their recovery. A very large study at many hospitals is needed to answer this question. The investigators are starting with a vanguard phase of 100 patients with stroke who are scheduled for EVT in approximately 10 stroke centers across Canada. Once complete the full-scale phase III study of 826 patients (including 100 patients from the vanguard phase) at 52 global stroke centers will start. These patients will be randomly divided (like flipping a coin) into two groups: one will receive weekly semaglutide injections for 12 weeks, while the other will not receive the drug. During the vanguard phase, the investigators will track how many patients agree to participate, how many stay in the study, and how well they follow the treatment plan. The full trial will establish the benefit of semaglutide to improve the outcomes of patients with LVO treated with EVT.

Detailed description

Background/Importance:

Endovascular thrombectomy (EVT) has substantially improved functional outcomes and decreased mortality in acute ischemic stroke patients with large vessel occlusions (LVOs). However, more than half of the patients die or have significant disability at 90 days after EVT. Studies suggest considerable infarct growth despite successful EVT and infarct volume predicts survival and functional outcome after EVT. There is an unmet need for interventions to reduce infarct growth and improve the functional outcomes of patients with an acute LVO who undergo EVT. Glucagon-Like Peptide-1 receptor agonists (GLP-1 RAs) have been suggested to decrease infarct growth and improve motor and sensory impairments in both diabetic and non-diabetic animal models of stroke. GLP-1 RAs also consistently decreased the risk of major adverse cardiovascular events (MACE), with the most profound effect in stroke prevention, in large-scale randomized clinical trials (RCTs) of patients with and without history of diabetes.

Research Aims:

The overall goal of this study is to test whether semaglutide can improve the functional outcomes of adults with acute ischemic stroke attributed to an intracranial LVO who are planned for treatment with EVT. We are performing a vanguard phase to obtain factual feasibility and will then move into the full phase trial.

Methods:

Glucagon-like peptide-1 receptor agonists for Endovascular Stroke Thrombectomy (LEAST) is a multicentre, prospective, randomized, open label, blinded endpoint (PROBE) clinical trial. For the vanguard phase, LEAST will recruit a total of 100 adult patients scheduled to receive EVT at approximately 10 high-volume stroke research centres in Canada over 1.5 to 2 years. For the full trial, LEAST will recruit an additional 726 patients from approximately 52 global stroke research centres, for a total of 826 participants. Participants fulfilling the inclusion and exclusion criteria will be randomly assigned up to 6 hours from the end of the EVT procedure, defined as the time of the last angiographic run, to either receive semaglutide (0.25 mg subcutaneous \[SC\] weekly for 4 weeks followed by 0.5 mg SC weekly for another 8 weeks) or to no semaglutide treatment.

Outcomes:

For the vanguard phase the primary endpoint is recruitment rate (target \>6 participants per centre per year).

For the full trial, the primary endpoint is the proportion of participants with functional independence (mRS 0-2) at 90 (±14) days.

For the vanguard phase the secondary endpoints are retention rate (target \>90% of study participants remaining in the trial) and medication adherence (target \>75%).

For the full trial, the secondary endpoints are the difference between groups in the proportion of participants with functional independence (mRS 0-2) at 7 (±2) and 30 (±7) days; the difference between groups in mRS scores at 7 (±2), 30 (±7) and 90 (±14) days; the difference between groups in NIHSS scores at 36 (±12) hours; the difference between groups in EQ-5D-5L scores at 90 (±14) days; and the difference between groups in incident cerebrovascular and cardiovascular events at 90 (±14) days.

Interventions

• Drug Semaglutide
  Glucagon-like peptide-1 (GLP-1) receptor agonist

Primary outcome measures

• Vanguard phase: Feasibility - Recruitment [Time frame: From site activation until the end of recruitment (approximately 24 months)]
• Full trial: Functional Independenc [Time frame: From randomization to day 90±14]

Secondary outcome measures (7)

• Vanguard phase: Medication Adherence [Time frame: From randomization to day 90±14]
• Vanguard phase: Retention Rate [Time frame: From randomization to day 90±14]
• Full trial: Functional Independence [Time frame: At 7 (±2) and 30 (±7) days]
• Full trial: Functional Outcome [Time frame: At 7 (±2), 30 (±7) and 90 (±14) days.]
• Full trial: Early Neurological Recovery [Time frame: At 36 (±12) hours.]
• Full trial: Quality of Life [Time frame: At 90 (±14) days.]
• Full trial: Incident Cerebrovascular and Cardiovascular events [Time frame: At 90 (±14) days.]

Eligibility criteria

Inclusion criteria

• Age 18 years or above on the date of randomization.
• EVT for an LVO in the anterior circulation, defined as the intracranial segment of the internal carotid artery (ICA) and/or the M1 or proximal M2 segment of the middle cerebral artery (MCA).
• National Institutes of Health Stroke Scale (NIHSS) ≥ 6 points at the time of randomization.
• Pre-stroke modified Rankin Scale (mRS) 0 or 1.
• Ability to randomize within 6 hours from the end of EVT.
• Capable of giving signed informed consent either independently, or by a legally authorized representative (LAR).

Exclusion criteria

• Pregnancy or breast-feeding.
• Renal insufficiency (creatinine clearance < 30mL/min).
• Cirrhosis or severe hepatic dysfunction, characterized by jaundice, encephalopathy or coagulopathy.
• History of pancreatitis in the year prior to randomization or evidence of acute pancreatitis on randomization.
• Active sepsis on randomization.
• Cancer, regionally advanced or metastatic, or for which treatment had been administered within 6 months from randomization, or hematological cancer that is not in complete remission.
• Any terminal medical condition with life expectancy of less than 3 months.
• Personal or family history of medullary thyroid carcinoma (MTC) or patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).
• Body mass index (BMI) less than 19.
• Known hypersensitivity to GLP-1 RAs.
• Active treatment with an GLP-1RA prior to randomization.
• Refusal or inability to administer subcutaneous (SC) injections by the patient or a caregiver.
• Close affiliation with the investigational site.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07511543 · LEAST

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗