The safety and efficacy of acute subcutaneous administration of semaglutide in non-diabetic patients with acute ischemic stroke: a multicentre, phase 2, prospective, randomized, open-label, blinded endpoint trial (ASSET)

The primary objective of the study is to evaluate the **safety** and **efficacy** of administering subcutaneous **semaglutide** in the acute phase following an **ischemic stroke** in non-diabetic patients. This is clinically relevant as it aims to explore a potential therapeutic option that could improve outcomes in the acute management of ischemic stroke, a condition with significant morbidity and mortality. The study is designed as a multicentre, phase 2, prospective, randomized, open-label, blinded endpoint trial, which ensures a robust assessment of the intervention's impact on patient health.

The clinical trial focuses on evaluating the safety and efficacy of administering subcutaneous semaglutide in the acute phase following an **ischemic stroke**. The study population includes both male and female participants aged 18 years and older. Participants are required to have experienced an acute ischemic stroke with disabling neurological deficits, such as impairments in language, motor function, cognition, gaze, vision, neglect, or ataxia. The trial targets individuals who were last seen well to randomization within 4.5 hours or those with a DWI-FLAIR mismatch on MRI if the time of onset is unknown, provided it is less than 4.5 hours since symptoms were acknowledged. Prior to the stroke, participants should have had none to moderate disability in daily living, as indicated by a pre-stroke modified Rankin Scale score of 0-3. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, and both genders are represented. Specific lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data.

The clinical trial is designed to evaluate the **safety** and **efficacy** of subcutaneous administration of **semaglutide** in patients with acute ischemic stroke. This is a multicenter, phase 2, prospective, randomized, open-label, blinded endpoint trial. The trial is expected to run from December 2022 to December 2027. Participants will be randomly assigned to receive either semaglutide or a control treatment, with the primary endpoint being a shift toward better functional outcomes in the distribution of the modified Rankin Scale (mRS). Secondary endpoints include the proportion of patients with serious adverse events, 90-day and one-year mortality, and various measures of neurological and metabolic outcomes.

The study involves several key visits: an initial screening visit to confirm eligibility, followed by randomization within 4.5 hours of stroke onset or based on MRI findings. Participants will undergo regular follow-up visits to monitor safety and efficacy outcomes, with assessments at 90 days and 12 months post-randomization. The end-of-study visit will occur at the conclusion of the trial period. The expected length of participant involvement is up to 12 months, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety.

Inclusion criteria require participants to be adults aged 18 years or older with acute ischemic stroke and disabling neurological deficits. Exclusion criteria are not specified in the provided data. The trial aims to provide insights into the potential benefits of semaglutide in improving functional outcomes and reducing adverse events in non-diabetic stroke patients. The trial's design ensures rigorous assessment of both primary and secondary endpoints, contributing to the understanding of semaglutide's role in stroke management.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. The **experimental medication** is **semaglutide**, administered as a solution for injection in a pre-filled pen. Two formulations are used: Ozempic 0.5 mg and Ozempic 0.25 mg. The pharmaceutical form is a solution for injection, and the route of administration is subcutaneous injection. The maximum daily dose for the 0.5 mg formulation is 0.07 mg, with a total maximum dose of 2.0 mg over a treatment period of up to 4 weeks. For the 0.25 mg formulation, the maximum daily dose is 0.04 mg, with a total maximum dose of 1.0 mg over the same treatment period. Participant compliance is monitored through regular assessments and adherence checks.

Non-experimental treatments include **Imodium**, which contains the active substance **loperamide hydrochloride**. It is provided as a film-coated tablet for oral administration. The maximum daily dose is 16 mg, with a total maximum dose of 32 mg over a treatment period of up to 2 days. Another non-experimental treatment is **Hjertemagnyl**, containing **acetylsalicylic acid**. This is also a film-coated tablet for oral administration, with a maximum daily and total dose of 300 mg over a 1-day treatment period.

Additional non-experimental treatments include **Ondansetron Fresenius Kabi**, which contains **ondansetron**. It is administered as a solution for injection via intravenous slow bolus injection. The maximum daily dose is 16 mg, with a total maximum dose of 80 mg over a treatment period of up to 5 days. Lastly, **Actilyse**, containing **alteplase**, is administered as a solution for injection/infusion via intravenous bolus injection or IV infusion. The maximum daily and total dose is 90 mg over a 1-day treatment period. Compliance with these treatments is ensured through careful monitoring and documentation of administration schedules.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is a shift toward better functional outcomes in the distribution of the modified Rankin Scale (mRS), evaluated through ordinal logistic regression. Secondary endpoints include a variety of measures such as the proportion of patients experiencing serious adverse events within 90 days, 90-day and one-year mortality rates, and the frequency of predefined serious adverse events. Additional secondary endpoints involve the assessment of excellent functional outcomes (mRS 0-1) at 90 days, Major Adverse Cardiac and Cerebral Events (MACCE) and recurrent ischemic events at 3 and 12 months, and stroke recurrence at 12 months in patients with small vessel disease.

Further secondary endpoints include early neurological improvement measured by the National Institutes of Health Stroke Scale (NIHSS) at 24 hours compared to baseline, changes in body weight, fasting plasma glucose, body mass index (BMI), waist circumference, and HbA1c levels at week 12 compared to baseline. The trial will also evaluate changes in quality of life using the EQ5D scale, changes in Major Depression Inventory (MDI), and activities of daily living using the Multi Data Set – Home Care (MDS-HC) at week 12. Additional assessments include 24-hour infarct growth on DWI-MRI, acute and long-term platelet inhibition, and the effect of **semaglutide** on various biomarkers such as insulin, c-peptide, glucagon, leptin, cholecystokinin (CCK), and gastric inhibitory polypeptide (GIP). The proportion of patients diagnosed with dementia at 12 months and changes in TICS score from 12 months to 90 days will also be evaluated.