Intra-Arterial Thrombolysis with Alteplase Post-Successful Reperfusion in Acute Anterior Circulation Ischemic Stroke: A Randomized Clinical Trial

The primary objective of this study is to demonstrate the superiority of adjunct **intra-arterial (IA) thrombolysis** versus no adjunct IA thrombolysis on the 90-day functional outcome rate in patients with acute anterior circulation large vessel occlusion (LVO) **ischemic stroke**. This is assessed by a shift in the 90-day modified Rankin Scale (mRS) toward a better functional outcome in patients who have achieved successful angiographic reperfusion (eTICI 2b-2c-3) following intravenous thrombolysis (IVT) alone, bridging therapy, or mechanical thrombectomy (MT) alone. The clinical relevance of this objective lies in potentially improving long-term functional outcomes for patients with acute ischemic stroke, thereby enhancing recovery and reducing disability.

Secondary objectives include: - Assessing the clinical efficacy and safety of adjunct IA thrombolysis after IVT alone, bridging therapy, or MT alone. - Evaluating the cost-effectiveness of adjunct IA thrombolysis in these scenarios. - Assessing the budget impact of a new stroke management strategy in cases of successful angiographic reperfusion. These objectives aim to provide a comprehensive understanding of the potential benefits and economic implications of adjunct IA thrombolysis in stroke management.

The clinical trial focuses on patients with **ischemic stroke**, specifically those experiencing acute anterior circulation large vessel occlusion (LVO) stroke. The study population includes both male and female participants, with an age range of 18 to 64 years. Participants are selected based on their health status, which includes a pre-stroke modified Rankin Scale (mRS) score of 0-2, and a National Institutes of Health Stroke Scale (NIHSS) score of 5 or higher at admission. The trial targets individuals who have achieved successful angiographic reperfusion, classified as eTICI 2b-2c-3, following intravenous thrombolysis (IVT) alone, bridging therapy, or mechanical thrombectomy (MT) alone. The sponsor has not provided the total number of participants. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified. Key inclusion criteria involve confirmation of intracranial internal carotid artery, M1, or M2 occlusion through CT or MRI imaging.

The clinical trial is designed to evaluate the efficacy and safety of **alteplase** in patients with acute ischemic stroke, specifically targeting those with anterior circulation large vessel occlusion (LVO) who have achieved successful angiographic reperfusion. This is a multicenter, randomized, double-blind, controlled trial. The primary objective is to demonstrate the superiority of adjunct intra-arterial (IA) thrombolysis over no adjunct IA thrombolysis in improving the 90-day functional outcome, as measured by the shift in the modified Rankin Scale (mRS). The trial is expected to commence recruitment on May 1, 2025, and conclude by May 31, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a pre-stroke mRS of 0-2, a National Institutes of Health Stroke Scale (NIHSS) score of ≥5, and successful reperfusion confirmed by catheter angiogram. Follow-up visits will be scheduled to assess both efficacy and safety endpoints, including early neurological improvement and any complications during endovascular treatment. The primary endpoint will be evaluated at 90 days post-treatment, with secondary endpoints including functional independence and cost-effectiveness analyses.

The expected duration of participant involvement is approximately 90 days, with the possibility of early termination if significant adverse events occur, such as symptomatic intracerebral hemorrhage or other serious complications. The trial will adhere to rigorous safety monitoring protocols to ensure participant well-being throughout the study period. The use of **Actilyse**, a solution for injection/infusion, will be administered via intra-arterial route, with a maximum daily dose of 20 mg. The trial will not include pediatric formulations and is not classified as a low-intervention study.

The clinical trial involves the use of the experimental medication **ACTILYSE**, which is a **poudre et solvant pour solution injectable et perfusion**. The active substance in this medication is **alteplase**, a protein classified under the ATC code B01AD02. **ACTILYSE** is administered as a **solution for injection/infusion** and is specifically used for **intraarterial use**. The maximum daily dose and total dose amount are both set at 20 mg, with a maximum treatment period of one day. The medication is not formulated for pediatric use and is not classified as an orphan drug. The pharmaceutical form of the product is a powder and solvent for injectable solution and infusion, manufactured by Boehringer Ingelheim France S.A.S.

In this trial, the experimental treatment is compared against a control group receiving no adjunct intraarterial thrombolysis. The primary objective is to assess the superiority of adjunct intraarterial thrombolysis in improving the 90-day functional outcome rate, as measured by the modified Rankin Scale (mRS), in patients with acute anterior circulation large vessel occlusion (LVO) stroke who have achieved successful angiographic reperfusion. The study does not involve any additional non-experimental treatments such as standard-of-care therapy or placebo. Participant compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol.

Efficacy in the clinical trial will be assessed using several parameters, primarily focusing on the functional outcomes of patients with acute anterior circulation large vessel occlusion (LVO) stroke. The primary endpoint is the shift in scores on the modified Rankin Scale (mRS) at 90 days, which measures the severity of disability. Secondary efficacy endpoints include the distribution of mRS scores at day 90, the achievement of an excellent functional outcome (mRS 0-1), and functional independence (mRS 0-2) at 90 days. Additionally, early neurological improvement will be evaluated by a reduction in the National Institutes of Health Stroke Scale (NIHSS) score by at least 8 points or achieving an NIHSS score of 0-1 at 24 hours. The efficacy of the endovascular procedure, including intra-arterial thrombolysis, will be assessed by the **eTICI** score at the end of the procedure. Infarct growth will be measured by the difference in ASPECTS scores and infarct core volume between 24 hours and baseline, using MRI DWI or CT perfusion.