Evaluation of Tenecteplase Versus Alteplase in Acute Ischaemic Stroke Due to Basilar Artery Occlusion: A Randomized Controlled Trial

The primary objective of this study is to evaluate the efficacy of the thrombolytic agent **tenecteplase** (TNK, 0.25 mg/kg) administered within 24 hours after symptom onset, with or without thrombectomy, compared to the current best practice involving **alteplase** (rtPA, 0.9 mg/kg within 4.5 hours of stroke onset) or standard care/no lysis, with or without thrombectomy. The goal is to achieve an excellent functional outcome, defined as a modified Rankin Scale (mRS) score of 0-1 or a return to the premorbid mRS at 90 days, in patients with acute ischaemic stroke due to basilar artery occlusion. This is clinically relevant as it aims to improve recovery outcomes in a critical patient population.

Secondary objectives include:

• Good functional outcome, defined as mRS 0 to 2 or return to baseline at 3 months.
• Favourable functional outcome, defined as mRS 0 to 3 or return to baseline at 3 months.
• Improvement on the mRS score (ordinal analysis of the mRS, merging category 5-6) at 3 months.
• Early clinical improvement, indicated by a reduction in acute 72-hour NIHSS score of ≥8 or a 72-hour NIHSS score of 0-1.
• Basilar recanalization (eTICI 2B-3) on digital subtraction angiography run prior to thrombectomy.
• Occurrence of symptomatic intracerebral hemorrhage (sICH) defined as parenchymal hemorrhage type 2 (PH2), subarachnoid hemorrhage, and/or intraventricular hemorrhage within 36 hours of treatment, combined with a neurological deterioration of ≥4 points on the NIHSS from baseline, or leading to death.
• Reduction of severe disability or death (mRS 5-6) at 3 months.
• Reduction of mortality due to any cause at 3 and 12 months.
• Higher quality of life as assessed by the Quality-of-Life assessment (EQ-5D).

The clinical trial involves participants diagnosed with **acute ischaemic stroke** due to basilar artery occlusion. The study population includes both male and female subjects aged 18 years and older. Participants are required to present with posterior circulation ischaemic stroke symptoms due to partial or complete basilar artery occlusion within 24 hours from symptom onset. The trial population is selected based on the presence of a basilar artery occlusion confirmed by CT Angiography or MR Angiography, with the occlusion being potentially retrievable. Participants must have a premorbid modified Rankin Scale score of 3 or less, indicating independent function or requiring only minor domestic assistance. The trial includes a vulnerable population, and all participants must be affiliated with a French social security scheme or equivalent. Written informed consent is obtained from participants or their representatives. The sponsor has not provided the total number of participants involved in the study.

The clinical trial is a **randomized**, controlled study designed to evaluate the efficacy of **tenecteplase** in patients with **acute ischaemic stroke** due to basilar artery occlusion. The trial aims to determine whether tenecteplase, administered within 24 hours of symptom onset, is superior to the current best practice, which includes **alteplase** or standard care, in achieving excellent functional outcomes at 90 days. The study is structured as a **double-blind** trial to ensure unbiased results. The trial is expected to commence recruitment on January 1, 2025, and conclude by January 1, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), presence of basilar artery occlusion, and premorbid functional status. Following the screening, eligible participants will be randomized to receive either tenecteplase or the comparator treatment. The trial includes follow-up visits to monitor patient outcomes, with assessments conducted at 3 and 12 months post-treatment to evaluate the primary and secondary endpoints, including the Modified Rankin Scale (mRS) scores and quality of life measures.

The expected duration of participant involvement is approximately 12 months, with the possibility of early termination if adverse events occur or if the participant withdraws consent. The trial's primary endpoint is the proportion of patients achieving an mRS score of 0-1 or returning to baseline mRS at 3 months. Secondary endpoints include various mRS score analyses, early clinical improvement, and safety assessments such as the incidence of symptomatic intracerebral hemorrhage. The trial's design and procedures are meticulously planned to ensure the collection of robust and reliable data to support the study's objectives.

The clinical trial involves the administration of **tenecteplase**, marketed as Metalyse, which is provided in two formulations: Metalyse 10,000 units powder and solvent for solution for injection, and Metalyse 5,000 units (25 mg) powder for solution for injection. Both formulations are intended for **injection** and are manufactured by Boehringer Ingelheim International GmbH. The active substance, tenecteplase, is a protein of non-human origin. The maximum daily and total dose for the 10,000 units formulation is 90 mg, while for the 5,000 units formulation, it is 25 mg. The treatment period for both formulations is limited to one day. The dosing schedule is based on a weight-adjusted regimen, with a maximum dose of 0.25 mg/kg.

The comparator treatment in the study is **alteplase**, marketed as Actilyse, which is available in three formulations: Actilyse powder and solvent for solution injectable and perfusion, with marketing authorization numbers 34009 557 184 2 0, 34009 558 530 1 5, and 34009 558 529 3 3. All formulations are intended for **injection/infusion** and are produced by Boehringer Ingelheim France S.A.S. The active substance, alteplase, is also a protein of non-human origin. The maximum daily and total dose for the formulations is 90 mg, except for the formulation with marketing authorization number 34009 557 184 2 0, which has a maximum dose of 25 mg. The treatment period is restricted to one day. The dosing regimen for alteplase is 0.9 mg/kg, administered within 4.5 hours of stroke onset.

Participant compliance with the dosing schedule will be monitored throughout the trial. The trial aims to evaluate the efficacy of tenecteplase in comparison to alteplase in achieving excellent functional outcomes in patients with acute ischemic stroke due to basilar artery occlusion. The study will assess the return to the premorbid modified Rankin Scale at 90 days post-treatment.

Efficacy in the clinical trial titled "Extending the time window for Tenecteplase by Effective RecanalizatioN of bAsilar artery occLusion in patients with POSTerior circulation stroke (POST ETERNAL)" will be assessed using several parameters. The primary endpoint is the proportion of patients achieving a Modified Rankin Scale (mRS) score of 0-1, indicating no disability, or a return to baseline mRS at 3 months. Secondary endpoints include the proportion of patients with mRS scores of 0-2 or 0-3, ordinal analysis of the mRS, and early clinical improvement as measured by a reduction in the acute 72-hour NIHSS score of ≥8 or a 72-hour NIHSS score of 0-1.

Additional secondary endpoints involve the proportion of patients with complete occlusion at baseline achieving eTICI 2b/3 on initial digital subtraction angiography prior to thrombectomy, the incidence of symptomatic intracerebral hemorrhage (sICH) within 36 hours of treatment, and the proportion of patients with mRS scores of 5-6 at 90 days, indicating severe disability or death. All-cause mortality within 90 days and quality of life assessments using the EQ-5D at 3 and 12 months will also be evaluated. These efficacy parameters will be measured and analyzed at specified timepoints, including 3 months and 90 days post-treatment, to determine the effectiveness of **tenecteplase** in comparison to current best practices in patients with acute ischemic stroke due to basilar artery occlusion.