Phase II Randomized, Double-Blind, Placebo-Controlled Study of Intravenous Alteplase Post-Andexanet Alfa Reversal in Acute Ischemic Stroke on DOAC Therapy
- Trial ID
- 2024-518509-17-00
- Protocol
- NBK241/1/2020
- Sponsor
- Medical University Of Gdansk
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** and **safety** of intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) in patients with acute ischemic stroke who are on chronic direct oral anticoagulant (DOAC) treatment. This evaluation occurs after the neutralization of anticoagulant activity through the administration of a specific reversal agent. The clinical relevance of this objective lies in determining the potential benefits and risks of rtPA therapy in this specific patient population, which could inform treatment protocols and improve outcomes for patients experiencing acute ischemic stroke while on DOACs.
Secondary objectives focus on the interventional part of the study and include:
- Assessing the efficacy of the investigational therapy in patients with acute ischemic stroke on non-vitamin K antagonist oral anticoagulants compared to placebo using the modified Rankin Scale (mRS).
- Evaluating the safety by assessing the incidence of fatal and non-fatal events, as well as the overall safety profile of the investigational therapy compared to placebo.
- Evaluating safety through neuroimaging assessments and characterizing major clinically significant extracranial bleedings.
Participants
The clinical trial involves participants diagnosed with **acute ischemic stroke**. The study population includes both male and female subjects, aged 18 years and older. Participants are selected based on their clinical diagnosis of acute ischemic stroke and are currently undergoing therapy with non-vitamin K antagonist oral anticoagulants such as apixaban or rivaroxaban. The trial includes individuals with a confirmed therapeutic anti-Xa activity, measured as a plasma concentration greater than 50 ng/mL. The study population is characterized by a vulnerable group, as it includes individuals with severe neurological deficits. The sponsor has not provided information regarding the total number of participants. Participants' lifestyle factors such as diet, physical activity, or habits are not specified in the available data.
Plans and Procedures
The clinical trial is a multicentre, parallel group, randomized, double-blind, placebo-controlled, phase II study designed to evaluate the efficacy and safety of reperfusion thrombolytic therapy with intravenous recombinant tissue **plasminogen activator** (rtPA) for patients with acute ischemic stroke who are on non-vitamin K antagonist oral anticoagulants. The trial involves the administration of a specific antidote to reverse anticoagulant activity prior to the intervention. The study is expected to run from September 2021 to June 2026, with participant involvement lasting up to 90 days post-admission.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, clinical diagnosis of acute ischemic stroke, and current anticoagulant therapy. The primary intervention involves the administration of intravenous thrombolysis with **alteplase** or a placebo, which must commence within 4.5 hours of symptom onset, extendable to 6.0 hours under specific conditions. Follow-up visits will occur at 7 days and 90 days post-admission to assess outcomes using the modified Rankin Scale (mRS) and the National Institutes of Health Stroke Scale (NIHSS). The end-of-study visit will evaluate the transition from disabling to non-disabling deficits and overall functional outcomes.
Participant involvement is expected to last for the duration of the study, with early termination possible if the participant experiences adverse events, withdraws consent, or if the investigator deems it necessary for safety reasons. The trial's primary endpoints include the transition from disabling to non-disabling deficits and changes in NIHSS scores, while secondary endpoints focus on functional outcomes assessed by mRS at 90 days. The study aims to provide valuable insights into the therapeutic potential of rtPA in this specific patient population.
Treatment
The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. The primary experimental medication is **Actilyse**, which is available in three different dosages: 10 mg, 20 mg, and 50 mg. Actilyse is formulated as a powder and solvent for the preparation of a solution for infusion. The active substance in Actilyse is **alteplase**, a recombinant tissue plasminogen activator. The medication is administered intravenously, with a maximum daily and total dose of 90 mg. The treatment period is limited to one day. Actilyse is manufactured by Boehringer Ingelheim International GmbH and is not a paediatric formulation.
Another experimental medication used in the trial is **Ondexxya**, which contains the active substance **andexanet alfa**. Ondexxya is provided as a 200 mg powder for solution for infusion and is administered intravenously. The maximum daily and total dose for Ondexxya is 1760 mg, with a treatment period of one day. This medication is produced by AstraZeneca AB and is also not a paediatric formulation.
The non-experimental treatment in the study is **Natrium Chloratum 0.9% Baxter**, a solution for infusion containing **sodium chloride** as the active substance. This solution is used as a placebo or comparator treatment and is administered as a solution for infusion. The maximum daily and total dose is 0.9%, with a treatment period of one day. Natrium Chloratum is manufactured by Baxter Polska Sp. z o.o. and is classified as a chemical substance.
All medications are administered intravenously, and participant compliance is monitored throughout the study. The trial aims to evaluate the efficacy and safety of these treatments in patients with acute ischemic stroke who are on chronic direct oral anticoagulant (DOAC) treatment, following the neutralization of anticoagulant activity by a specific reversal agent.
Efficacy
The efficacy of the investigational therapy in the clinical trial will be assessed using specific endpoints. For the interventional part of the study, the primary endpoints include the transition from a disabling to a non-disabling deficit, evaluated as a binary outcome (0-yes, 1-no), and the change in the National Institutes of Health Stroke Scale (NIHSS) score between admission and a 7-day follow-up. The observational part of the study will assess the outcome using the modified Rankin Scale (mRS) at 90 days, with the proportion of patients achieving an excellent or good functional outcome (mRS 0-1 and 0-2, respectively) being measured at 90 days (+/- 3 days) post-admission.
The efficacy parameters will be collected and analyzed at specified timepoints, including admission, 7-day follow-up, and 90 days post-admission. The modified Rankin Scale (mRS) and the NIHSS are the primary tools used for these assessments. These scales are validated instruments commonly used in clinical trials to evaluate functional outcomes and neurological deficits in patients with acute ischemic stroke. The study aims to provide a comprehensive evaluation of the investigational therapy's efficacy in improving patient outcomes following acute ischemic stroke in the context of non-vitamin K antagonist oral anticoagulant treatment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- INTERVENTIONAL PART OF THE STROACT STUDY: 1. Obtaining informed consent to participate in the trial. NOTE: Patients whose neurological deficit is severe enough to make it impossible to sign the consent form are allowed to give only their oral consent to participate in the study. However, this consent should be additionally certified by the signature of two independent witnesses (who are neither family members of the patient nor the STROACT study staff) or by the signature of his/her legal representative. Patients with aphasia and/or other speech disorders may be included into the study if following neurological assessment of the recruiting stroke physician, they are able to understand all important information about the study. 2. Age >18 years. 3. Clinical diagnosis of acute ischemic stroke (sharply defined onset of first symptoms) resulting in a disabling neurological deficit. 4. Therapy with an oral anticoagulant that is the non-vitamin K antagonist oral anticoagulant (apixaban or rivaroxaban) with laboratory confirmed therapeutic anti-Xa activity measured as a plasma concentration > 50 ng/mL. 5. Administration of study intervention (intravenous thrombolysis with alteplase) should be possible to start within 4.5 hours from AIS symptoms onset or the last time the patient was seen without symptoms, as per investigator’s judgment. NOTE: If a patient was enrolled and there was a clear clinical reason for delaying the start of the study intervention within the 4.5-hour window, the patient may still be included in the study if rtPA can be given within 6.0 hours of the onset of acute ischemic stroke. NOTE: In patients recruited to STROACT study, in addition to the inclusion / exclusion criteria, apply all standard clinical practice indications and contraindications for rtPA administration in acute ischemic stroke unless stated otherwise in this protocol.
- OBSERVATIONAL PART OF THE STROACT STUDY: 1. Age ≥ 18 years. 2. Clinical diagnosis of acute ischemic stroke (with sharply defined onset of first symptoms or last known well within 24 hours with laboratory confirmed therapeutic anti-IIa/Xa activity measured as a plasma concentration >50 ng/mL). 3. Therapy with an oral anticoagulant that is the non-vitamin K antagonist oral anticoagulant (dabigatran, apixaban or rivaroxaban) with laboratory confirmed therapeutic anti-IIa/Xa activity measured as a plasma concentration >50 ng/mL. 4. The neurological deficit rapidly improved to the point of a non-disabling deficit before obtaining the ICF to participate in the interventional part of the STROACT study. 5. Obtaining the ICF to participate in the observational part of the STROACT study.
Exclusion Criteria
- INTERVENTIONAL PART OF THE STROACT STUDY: 1. Occlusion of a large intracranial vessel in CT/MR angiography (CTA/MRA), corresponding to the current acute neurological deficit being an indication for primary mechanical thrombectomy. 2. Significant disability prior to the current stroke event defined as >2 points on the modified Rankin Scale (mRS) and/or significant impairment of the cognitive function prior to AIS (the latter documented in patient’s medical records). 3. Mild and rapidly improving neurological deficit with high probability of complete recovery. 4. Clinically severe stroke with >18 points in NIHSS. 5. Neuroimaging findings that might be responsible for acute neurological deficit (“stroke mimics”) and/or are contraindications for standard thrombolytic treatment: such as intracranial and/or intracerebral bleeding, tumours, abscesses and other. 6. Treatment with the following anticoagulants: a. Oral vitamin K antagonist (warfarin, acenocumarol), b. Unfractionated heparin, c. Low molecular weight heparin, or d. Inhibitors of coagulation factor IIa (dabigatran) and Xa other than rivaroxaban or apixaban 7. Whole blood, and/or blood clotting factors (such as: prothrombin complex concentrate [PCC], recombinant factor VIIa [rVIIa], fresh frozen plasma [FFP]) administered within 7 days before study treatment initiation. 8. Anti-Xa activity (which is assumed to be directly proportional to the DOAC plasma concentration) is <50 ng/mL. 9. CT or MRI initial lesion volume >1/2 of the anatomical perfusion area of the middle cerebral artery (MCA), or anterior cerebral artery (ACA), or posterior cerebral artery (PCA). 10. Suspected subarachnoid haemorrhage based on specific symptomatology and/or physical examination (even if CT/MRI is normal). 11. Any history of subarachnoid or intracerebral haemorrhage, so not including previous (currently normal in neuroimaging) traumatic sub-or epidural hematomas > 6 months before the current acute stroke. 12. Any past (chronic) medical illnesses that significantly impair patient’s functional status down to mRS 3 points or more (thus not only related to CNS pathologies and including cognitive impairment), and/or with a poor prognosis (e.g., neoplasms individually assessed to be of poor prognosis). NOTE: Patients after treatment of intracranial aneurysm may be considered for recruitment into the STROACT trial if the procedure was performed > 3 months prior to enrollment. 13. History of major surgery / trauma within 2 months before the current acute stroke. 14. History of acute ischemic stroke or any other medical condition treated with intravenous thrombolysis, or ischemic stroke treated with mechanical thrombectomy, within the 72 hours preceding the current patient’s stroke symptoms. 15. Recent (within 10 preceding days) traumatic external heart massage, obstetrical delivery, lumbar puncture, any puncture of a non-compressible blood vessel. 16. Recent (within 4 preceding weeks) myocardial infarction. 17. Severe trauma at the onset of acute ischemic stroke (e.g., skull fracture, long bone fracture, pelvic fracture). 18. Expected need for major surgery within 72 hours after enrollment (e.g., laparotomy, hip femoral/pelvic fracture surgery, endarterectomy). 19.Cerebral venous sinus thrombosis (CVST). 20.Pulmonary embolism. 21.Suspected infective endocarditis and/or pericarditis. 22.Acute pancreatitis. 23.Systemic or suspected cerebral vasculitis.
- OBSERVATIONAL PART OF THE STROACT STUDY: 1.Occlusion of a large intracranial vessel in CT/MR angiography (CTA/MRA), corresponding to the current acute neurological deficit being an indication for primary mechanical thrombectomy. NOTE 1: Patients who qualified to the mechanical thrombectomy cannot be enrolled to the observational part of the STROACT study. 2. Significant disability prior to the current stroke event defined as >2 points on the modified Rankin Scale (mRS) and/or significant impairment of the cognitive function prior to AIS (the latter documented in patient’s medical records). 3. Neuroimaging findings that might be responsible for acute neurological deficit (“stroke mimics”). 4. Treatment with the following anticoagulants: a. Oral vitamin K antagonist (warfarin, acenocumarol), b. Unfractionated heparin, c. Low molecular weight heparin, or d. Inhibitors of coagulation factor IIa/Xa other than dabigatran, rivaroxaban or apixaban 5. Whole blood, and/or blood clotting factors (such as: prothrombin complex concentrate [PCC], recombinant factor VIIa [rVIIa], fresh frozen plasma [FFP]) administered within 7 days before enrollment to the study. 6. Anti-IIa/Xa activity (which is assumed to be directly proportional to the DOAC plasma concentration) is <50 ng/. 7. Suspected subarachnoid haemorrhage based on specific symptomatology and/or physical examination (even if CT/MRI is normal). 8. Any past (chronic) medical illnesses that significantly impairs patient’s functional status down to mRS 3 points or more (thus not only related to CNS pathologies and including cognitive impairment), and/or with a poor prognosis (e.g., neoplasms individually assessed to be of poor prognosis). 9. Cerebral venous sinus thrombosis (CVST). 10. Pulmonary embolism. 11. Systemic or suspected cerebral vasculitis. 12. Congenital or acquired coagulopathy presenting with: a. Prolonged aPTT above 30% of the upper limit of normal (local laboratory reference range), b. Increased INR ≥1.7 13. Severe liver disease including acute hepatic failure, cirrhosis with/or without portal hypertension. 14. Pregnancy. 15. Predicted life expectancy <3 months. 16. Participation in another clinical trial at the time of enrollment or planned inclusion in another clinical trial within less than 90 days of enrollment, provided that protocols of these trials interfere pathophysiologicaly or formally and administratively with the STROACT study. 17. Previous participation in the current clinical trial. 18. Advanced renal failure (eGFR <30 mL/min/1.73m2). 19. Active infection with SARS-CoV-2 (up to 10 days from the first positive testing with any recommended assay or from the first symptoms of infection or severe “long” COVID-19 / severe Post-COVID Neurological Syndrome).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Recruiting | 30 Sept 2021 | 215 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Actilyse 50, 50 mg, proszek i rozpuszczalnik do sporządzania roztworu do infuzji | Test | PROSZEK I ROZPUSZCZALNIK DO SPORZĄDZANIA ROZTWORU DO INFUZJI | INTRAVENOUS USE | 90 | 1 | PRD329947 |
Actilyse 20, 20 mg, proszek i rozpuszczalnik do sporządzania roztworu do infuzji | Test | PROSZEK I ROZPUSZCZALNIK DO SPORZĄDZANIA ROZTWORU DO INFUZJI | INTRAVENOUS USE | 90 | 1 | PRD329235 |
Ondexxya 200 mg powder for solution for infusion | Test | POWDER FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1760 | 1 | PRD9745324 |
Actilyse 10, 10 mg, proszek i rozpuszczalnik do sporządzania roztworu do infuzji | Test | PROSZEK I ROZPUSZCZALNIK DO SPORZĄDZANIA ROZTWORU DO INFUZJI | INTRAVENOUS USE | 90 | 1 | PRD329218 |