Evaluation of Intravenous Thrombolysis with Alteplase or Tenecteplase in Acute Ischemic Stroke Patients on Direct Oral Anticoagulants

The primary objective of the DO-IT trial is to evaluate the **safety** and **efficacy** of intravenous thrombolysis (IVT) using either **alteplase** or **tenecteplase** in patients with acute ischemic stroke who have recently ingested direct oral anticoagulants (DOACs). The trial aims to determine if this strategy is superior to the standard of care in achieving a better functional outcome, as quantified by a shift on the modified Rankin Scale (mRS) at 90 days. This is clinically relevant as it addresses the challenge of managing acute ischemic stroke in patients on DOACs, where the risk of bleeding complications is a significant concern. The study seeks to provide evidence on whether IVT can be safely administered in this patient population, potentially expanding treatment options and improving outcomes.

The clinical trial involves a total of **200 participants** diagnosed with **acute ischemic stroke** who have recently ingested direct oral anticoagulants. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on their eligibility to receive intravenous thrombolytic therapy, such as alteplase or tenecteplase, as per standard care protocols. The trial population includes individuals who have ingested direct oral anticoagulants within 48 hours prior to enrollment or those with an ongoing prescription where the exact time of last intake is unknown. The study considers a vulnerable population, ensuring that informed consent is obtained, with deferred consent applied when possible according to national legislation. Lifestyle factors such as diet and physical activity are not specified, but the inclusion criteria focus on the timing of anticoagulant ingestion and the ability to initiate treatment within a specific timeframe following symptom recognition.

The clinical trial is designed to evaluate the **safety** and **efficacy** of intravenous thrombolysis in patients with acute ischemic stroke who have recently ingested direct oral anticoagulants. The trial employs a randomized, double-blind, controlled design to compare the outcomes of treatment with either **alteplase** or **tenecteplase** against the standard of care. The primary objective is to assess the functional outcome at 90 days, measured by a shift on the modified Rankin Scale (mRS). The trial is expected to commence recruitment on April 1, 2025, and conclude by April 30, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as recent ingestion of direct oral anticoagulants within 48 hours and the ability to be randomized and treated within specific time frames. Follow-up visits will be scheduled to monitor changes in stroke severity, health-related quality of life, and any adverse events such as symptomatic intracranial hemorrhage or major extracranial bleeding. The end-of-study visit will occur at 90 days ± 2 weeks to evaluate the primary and secondary endpoints, including all-cause mortality up to 7 days after admission or until discharge.

Participant involvement is expected to last approximately 90 days, with conditions for early termination including withdrawal of consent or the occurrence of significant adverse events. The trial will adhere to rigorous ethical standards, ensuring informed consent is obtained, and will follow national legislation for deferred consent where applicable. The study aims to provide definitive evidence on the use of intravenous thrombolysis in this specific patient population, potentially influencing future treatment guidelines for acute ischemic stroke.

The clinical trial involves the administration of two experimental medications, **alteplase** and **tenecteplase**, both of which are used in the treatment of acute ischemic stroke. The first experimental medication, Actilyse®, contains the active substance **alteplase**. It is provided as a powder and solvent for the preparation of a solution for injection or infusion. The pharmaceutical form is a solution for injection/infusion, and it is administered via **intravenous administration**. The dosage is calculated based on the patient's weight, with a maximum daily and total dose of 90 mg/kg. The treatment period is limited to a single day. Compliance with the dosing schedule is monitored to ensure adherence to the protocol.

The second experimental medication, Metalyse, contains the active substance **tenecteplase**. It is also provided as a powder and solvent for the preparation of a solution for injection. The pharmaceutical form is a solution for injection, and it is administered via **intravenous administration**. The dosage is similarly weight-based, with a maximum daily and total dose of 25 mg/kg. The treatment period is restricted to one day. Participant compliance is monitored to ensure the correct administration of the medication according to the study protocol.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The primary objective of the trial is to evaluate the safety and efficacy of intravenous thrombolysis with either alteplase or tenecteplase in patients with ischemic stroke who are on treatment with direct oral anticoagulants. The trial aims to determine if this strategy is superior to the standard of care in achieving better functional outcomes, as measured by a shift on the modified Rankin Scale at 90 days post-treatment.

The efficacy of the DO-IT trial will be assessed using several primary and secondary endpoints. The primary endpoint is the functional outcome measured by a shift on the **modified Rankin Scale (mRS)** at 90 days, with a permissible variation of ±2 weeks. This scale is a widely recognized tool for evaluating the degree of disability or dependence in daily activities of people who have suffered a stroke.

Secondary endpoints include a dichotomized good functional outcome, defined as an mRS score of 0-2 or a return to baseline at day 90 (±2 weeks). Additionally, changes in stroke severity will be evaluated using the National Institutes of Health Stroke Scale and ischemic stroke volume between baseline and 24 ± 12 hours. Health-related quality of life will be assessed using the EuroQol 5D-3L at 90 days (±2 weeks). Other secondary endpoints include the incidence of symptomatic intracranial hemorrhage within the first 36 hours, as defined by the European Co-operative Acute Stroke Study-II, major extracranial bleeding up to 24 ± 12 hours, and all-cause mortality up to 7 days after admission or until discharge.