Evaluation of Peri-Operative Acetylsalicylic Acid Versus Placebo in Elective Endovascular Coiling of Unruptured Intracranial Aneurysms

The primary objective of this study is to demonstrate a lower incidence of **stroke** in patients receiving **acetylsalicylic acid** (ASA) compared to those receiving a placebo following endovascular coiling of unruptured brain aneurysms. This is clinically relevant as it aims to establish ASA as a potential preventive measure against stroke in this specific patient population, potentially improving patient outcomes and reducing the burden of post-procedural complications.

Secondary objectives include:

• Determining if ASA is associated with lower risks of embolic or cognitive sequelae.
• Testing whether ASA use is associated with comparable safety to placebo in terms of all-cause mortality and bleeding risks.
• Assessing whether treatment with ASA is associated with better short- and long-term cognitive and neuropsychiatric outcomes up to 1-year post-procedure.
• Examining these outcomes in patients with different burdens of iatrogenic brain infarcts and assessing how any treatment effects of ASA are mediated by this infarct burden.
• Assessing whether ASA is associated with better cognitive-related activities of daily living (ADLs) and health-related quality of life up to 1-year post-procedure.

The clinical trial involves **subjects undergoing elective endovascular coiling-only repair of unruptured brain aneurysms**. The study population includes both male and female participants aged 18 years and older, who are functionally independent at baseline, as indicated by a modified Rankin scale score of less than 3. Participants must have an unruptured intracranial aneurysm suitable for coiling-only as a primary treatment. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants are required to provide informed consent and be available for the entire study period. Lifestyle considerations such as diet, physical activity, or habits are not specified. The selection criteria ensure that participants are in a general state of health that allows for the elective procedure and subsequent study participation.

The clinical trial is designed as a **randomized**, double-blind, placebo-controlled study to evaluate the efficacy of **acetylsalicylic acid** (ASA) in reducing the incidence of stroke in patients undergoing endovascular coiling-only for unruptured brain aneurysms. The trial will span approximately four years, with an estimated recruitment start date of May 5, 2023, and an estimated end date of May 5, 2027. Participants will be randomly assigned to receive either ASA or a placebo, with the primary objective being to demonstrate a lower incidence of stroke in the ASA group compared to the placebo group following the coiling procedure.

The study will include several key visits: an initial screening visit, follow-up visits, and an end-of-study visit. During the **screening visit**, eligibility criteria will be assessed, including age (≥18 years), the suitability of the aneurysm for coiling, functional independence at baseline, and informed consent. Participants will be required to be available for the entire study period. Follow-up visits will occur at specified intervals to monitor the incidence of embolic strokes, clinical thromboembolic events, and other secondary endpoints such as cognitive decline and thrombus formation. The **end-of-study visit** will conclude the participant's involvement, assessing long-term outcomes up to one year post-procedure.

Participant involvement is expected to last up to 90 days post-coiling, with additional assessments for cognitive and neuropsychiatric outcomes extending up to one year. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial aims to provide valuable insights into the potential benefits of ASA in preventing stroke and improving cognitive outcomes in this patient population.

The clinical trial involves the administration of **acetylsalicylic acid** as the experimental medication. The product, marketed under the name SALOSPIR® 325 mg, is provided in tablet form. Each tablet contains 325 mg of acetylsalicylic acid, a chemical substance, and is encapsulated in an opaque red-orange gelatin capsule to prevent rattling. Microcrystalline cellulose is used as a filler within the capsule. The route of administration is oral, with a maximum daily dose of 325 mg and a total maximum dose of 1625 mg over a treatment period of up to 5 days. The encapsulation ensures the integrity of the tablet during administration.

The study also includes a **placebo** treatment, which is composed of lactose monohydrate. The placebo is also in tablet form and is administered orally. To ensure the placebo tablets have a weight similar to the active treatment, two placebo tablets are placed inside a capsule and filled with microcrystalline cellulose. The placebo is designed to mimic the appearance and administration of the active treatment, maintaining the study's blinding. The dosing schedule for the placebo mirrors that of the active treatment, with a maximum daily dose of 325 mg and a total maximum dose of 1625 mg over a 5-day period.

Efficacy in this clinical trial will be assessed by evaluating the incidence of **embolic strokes** in subjects receiving acetylsalicylic acid (ASA) compared to those receiving a placebo. The primary endpoint is the incidence of embolic strokes, either clinically or detected on DWI-MRI, on Day 5 of the study, which is 12-48 hours following the coiling procedure. Secondary endpoints include the assessment of clinical thromboembolic events by Day 90 following coiling, the count of new DWI lesions on post-coiling MRI, and the frequency of large strokes (> 10 cc volume) on DWI MR. Additional secondary endpoints involve the incidence of cognitive decline from baseline to 90-day follow-up, visible thrombus formation during the coiling procedure, and the total volume of embolic strokes on DWI MR imaging. The study will also evaluate the death rate within 90 days following coiling in the ASA vs. placebo group and any peri-operative hemorrhagic complications, including intracranial hemorrhage, retroperitoneal hematoma, and gastrointestinal bleeding, stratified as major according to TIMI criteria.

Further assessments will determine whether treatment with ASA is associated with improved short- and long-term cognitive and neuropsychiatric outcomes up to one year post-procedure. The trial will also examine these outcomes in patients with varying burdens of iatrogenic brain infarcts and assess how any treatment effects of ASA are mediated by this infarct burden. Additionally, the study will assess whether ASA is associated with better cognitive-related activities of daily living (ADLs) and health-related quality of life up to one year post-procedure. The efficacy parameters will be measured and collected at specified timepoints, including Day 5 and Day 90, using clinical evaluations and imaging techniques such as DWI-MRI. The analysis will focus on comparing the outcomes between the ASA and placebo groups to determine the efficacy of ASA in reducing the incidence of stroke and improving cognitive and neuropsychiatric outcomes.