Evaluation of Intravenous Thrombolysis with Tenecteplase in Acute Ischemic Stroke Patients on Factor Xa Inhibitors: A Comparative Study

The primary objective of this study is to compare early neurological improvement (**ENI**) between patients with **acute ischemic stroke** (AIS) who are treated with intravenous thrombolysis (IVT) within 4.5 hours after stroke onset and those treated with the current standard of care. This is particularly focused on AIS patients who have recently ingested Factor Xa inhibitors. The clinical relevance of this objective lies in determining the efficacy of IVT in improving early neurological outcomes in this specific patient population, which could potentially influence treatment protocols and improve patient prognosis.

Secondary objectives include:

• Comparing clinical neurological improvement using the National Institutes of Health Stroke Scale (NIHSS) at 24 hours ± 12 hours between patients treated with IVT and those receiving standard care.
• Assessing infarct volume via CT/MRI at 24 hours ± 12 hours between the two treatment groups.
• Evaluating functional outcomes using the modified Rankin Scale at day 90 (± 2 weeks) between the treatment groups.
• Comparing the rate of symptomatic intracerebral hemorrhage (sICH) in AIS patients who ingested Factor Xa inhibitors within the last 48 hours and were treated with IVT within 4.5 hours after stroke onset, against the expected sICH rate in Norway for patients not on Factor Xa inhibitors prior to IVT.
• Determining the rate of any intracerebral hemorrhage (ICH) after IVT in the treatment arm.
• Comparing the number of deaths among participants in the treatment arms.

The clinical trial involves participants diagnosed with **acute ischemic stroke** (AIS) who are 18 years of age or older. The study population includes both male and female subjects, with no specific age range provided beyond the minimum age requirement. Participants must have ingested FXa inhibitors within the last 48 hours of symptom onset or have an ongoing prescription if the exact timing is unknown. The trial targets individuals presenting with a disabling neurological deficit due to AIS, who arrive within 4.5 hours of symptom onset or after awakening with symptoms, confirmed by FLAIR-DWI mismatch on MRI as assessed by a (neuro-) radiologist. The sponsor has not provided the total number of participants. The trial population was selected based on these criteria, and informed consent is required. The study does not specify any particular lifestyle considerations such as diet or physical activity. Both vulnerable and non-vulnerable populations are included in the study.

The clinical trial is designed to evaluate the efficacy and safety of **intravenous thrombolysis** in patients with **acute ischemic stroke** who have recently ingested **Factor Xa-inhibitors**. This is a randomized, double-blind, controlled trial with an estimated duration extending until December 31, 2032. The trial will commence recruitment on November 1, 2024, with the active trial period starting on March 10, 2025. Participants will be randomly assigned to receive either the investigational treatment or the current standard of care. The primary objective is to compare early neurological improvement between the two groups within 4.5 hours of stroke onset.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age (18 years or older), recent ingestion of FXa inhibitors, and clinical diagnosis of acute ischemic stroke with a disabling neurological deficit. Participants must present within 4.5 hours of symptom onset or after awakening with symptoms, with MRI confirmation. Informed consent is required. Follow-up visits will assess primary and secondary endpoints, including early neurological improvement and functional outcomes at 90 days. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any adverse events are addressed.

The expected length of participant involvement is up to 500 days, depending on the treatment group. 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 robust data on the safety and efficacy of thrombolysis in this specific patient population, contributing to improved treatment strategies for acute ischemic stroke.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Rivaroxaban** is utilized in the form of a film-coated tablet. It is administered orally with a maximum daily dose of 30 mg. The treatment period for rivaroxaban can extend up to 500 days. This medication is classified as a Factor Xa-inhibitor and is not a pediatric formulation.

**Apixaban** is another experimental medication used in this trial. It is provided in tablet form and administered orally. The maximum daily dose for apixaban is 20 mg, with a treatment period also extending up to 500 days. Apixaban is categorized as a FXa inhibitor and is not formulated for pediatric use.

**Tenecteplase** is administered as a solution for injection. The route of administration is intravenous, with a maximum daily dose of 25 mg. The treatment period for tenecteplase is limited to a single day. This medication is not a pediatric formulation and serves as a comparator in the trial.

**Alteplase** is provided as a solution for injection or infusion, administered intravenously. The maximum daily dose is 90 mg, and similar to tenecteplase, the treatment period is restricted to one day. Alteplase is not a pediatric formulation and is used as a comparator in the study.

**Edoxaban** is administered in the form of a film-coated tablet, taken orally. The maximum daily dose is 60 mg, with a treatment period of up to 500 days. Edoxaban is classified as a FXa inhibitor and is not intended for pediatric use.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy and safety of these medications in patients with acute ischemic stroke who have recently ingested Factor Xa-inhibitors.

The efficacy of the clinical trial titled "The efficacy and Safety of Intravenous thrombolysis in acute ischemic stroke patients with recent ingestion of Factor Xa-inhibitors Trial (SIFT)" will be assessed using both primary and secondary endpoints. The primary endpoint is **early neurological improvement**, defined as a reduction of ≥8 points on the National Institutes of Health Stroke Scale (NIHSS), or achieving an NIHSS score of 0-1 at 24 hours ± 12 hours post-treatment. Secondary endpoints include the percentage change in NIHSS from baseline to 24 hours ± 12 hours, percent change in infarct volume at 24 hours ± 12 hours, and the proportion of patients achieving a good functional outcome (modified Rankin Scale [mRS] 0-2) or an excellent functional outcome (mRS 0-1) at day 90 ± 2 weeks. Additional secondary endpoints include the occurrence of symptomatic intracerebral hemorrhage (sICH) on CT/MRI within 36 hours post-intravenous thrombolysis (IVT) that is causally related to an increase of 4 points or more on the NIHSS, any intracerebral hemorrhage (ICH) on CT/MRI within 36 hours post-IVT, and the occurrence of death within 90 days.

The efficacy parameters will be measured and collected at specified timepoints, including 24 hours ± 12 hours and day 90 ± 2 weeks, using validated scales such as the NIHSS and mRS. Imaging assessments will be conducted using CT/MRI to evaluate infarct volume and the presence of ICH. The analysis of these parameters will provide insights into the efficacy of intravenous thrombolysis in acute ischemic stroke patients who have recently ingested Factor Xa inhibitors.