Reperfusion thrombolytic therapy for ischemic stroke in patients on non-vitamin K antagonist oral anticoagulants: study protocol of a phase II randomized clinical trial

Reperfusion thrombolytic therapy for ischemic stroke in patients on non-vitamin K antagonist oral anticoagulants: study protocol of a phase II randomized clinical trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Reperfusion thrombolytic therapy for ischemic stroke in patients on non-vitamin K antagonist oral anticoagulants: study protocol of a phase II randomized clinical trial Bartosz Karaszewski, Bartosz Jabłoński, Dariusz Gąsecki, Sebastian Szczyrba, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5288990/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background Cardioembolic stroke accounts for more than 20% of all acute ischemic strokes (AIS) and is mainly caused by cardiac arrhythmias, particularly atrial fibrillation (AF). The presence of specific or multiple additional vascular risk factors indicates the need for oral anticoagulant (OAC) therapy in AF patients (according to the CHA2DS2-VASc classification). While OAC treatment significantly reduces the risk of AIS by over 80% in this population, the risk remains higher compared to the general population. Approximately half of AF patients on OAC therapy who experience AIS do not meet the criteria for thrombolytic (high blood activity of OAC) or mechanical thrombectomy (non-large vessel occlusion stroke) treatment. Aim This study aims to assess the efficacy and safety of recombinant tissue plasminogen activator (rtPA) in AIS patients who have been on chronic non-vitamin K antagonist oral anticoagulant (DOAC) therapy after receiving a specific reversal agent. Methods and design Patients with acute ischemic stroke (AIS) who are treated with specific oral anticoagulants (OACs) with anti-Xa activity ≥50 ng/ml and are not eligible for mechanical thrombectomy will be included in the study. The protocol involves administering a fast-acting antidote (andexanet alfa for rivaroxaban or apixaban) or a placebo, followed by intravenous thrombolytic therapy with rtPA or a placebo. The study arms for rivaroxaban and apixaban are designed as prospective, randomized, placebo-controlled interventional trials that meet phase II trial criteria. Discussion The STRoke on Oral AntiCoagulants for Thrombolysis (STROACT) trial is the first randomized clinical trial investigating the impact of intravenous thrombolysis with rtPA in AIS patients on chronic DOAC therapy. Trial registration www.clinicaltrialsregister.eu; EudraCT Nr: 2020-004898-41; March 31, 2021. ischemic stroke intravenous thrombolysis non-vitamin K antagonist oral anticoagulant andexanet alfa randomized trial Figures Figure 1 Figure 2 Administrative information Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/). Title {1} Reperfusion thrombolytic therapy for ischemic stroke in patients on non-vitamin K antagonist oral anticoagulants: study protocol of a phase II randomized clinical trial Trial registration {2a and 2b} www.clinicaltrialsregister.eu; EudraCT Nr: 2020-004898-41 Protocol version {3} 28 August 2024, v.6.0 Funding {4} Funding type: Grant Name of Funding agency: Medical Research Agency, Poland Grant Number: 2019/ABM/01/00084 Author details {5a} Bartosz Karaszewski a,b,c , Bartosz Jabłoński a,b , Dariusz Gąsecki a,b , Sebastian Szczyrba a,b , Adam Wyszomirski c a Department of Adult Neurology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland b Department of Adult Neurology, University Clinical Center, Gdańsk, Poland c Brain Diseases Centre, Medical University of Gdańsk, Gdańsk, Poland Name and contact information for the trial sponsor {5b} The trial sponsor is the Medical University of Gdańsk. Marii Sklodowskiej-Curie 3a street, 80-210 Gdansk, Poland Role of sponsor {5c} The sponsor had no role in the study design; collection, management, analysis, interpretation, or reporting of the data; report preparation; or publication decisions. Introduction Background and rationale {6a} The burden of cardiovascular and cerebrovascular diseases has been steadily increasing over the past decade and is expected to rise further as the global population ages [ 1 ]. Among these diseases, stroke remains the leading cause of permanent complex disability in adults. Currently, intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) within 4.5 hours of onset (or up to 9.0 hours with advanced neuroimaging methods) [ 2 , 3 ] and mechanical thrombectomy [ 4 ] with extended protocols (such as DAWN, DEFUSE 3, large core RCTs and posterior circulation protocols BAOCHE and ATTENTION)[ 5 – 12 ] have significantly improved outcomes for stroke patients. These interventions, combined with comprehensive interdisciplinary care in stroke units, significantly increase the likelihood of excellent and good functional outcomes (modified Rankin Scale [mRS] 0–1 and 0–2, respectively). However, there is still a lack of high-quality scientific evidence for specific treatments in certain acute ischemic stroke (AIS) subgroups. Non-LVO stroke patients who are on oral anticoagulants represent a significant portion of those who may not be eligible for reperfusion therapy, even if they present at the hospital shortly after the onset of symptoms. Objectives {7} The purpose of this study is to assess the effectiveness and safety of intravenous thrombolysis with rtPA in patients with acute ischemic stroke (AIS) who are on chronic non-vitamin K antagonist oral anticoagulant (DOAC) therapy, following the administration of a specific reversal agent. Trial design {8} STROACT (STRoke on Oral AntiCoagulants for Thrombolysis) is a multicenter, prospective, parallel-group, randomized, double-blind, placebo-controlled, superiority, non-commercial clinical trial with a 1:1 allocation ratio supported by a grant from the Polish Medical Research Agency. The trial aims to evaluate the efficacy and safety of a new intervention involving the sequential intravenous administration of DOAC-specific antidotes (andexanet alfa for apixaban and rivaroxaban) followed by thrombolysis with rtPA. A flowchart of the study is shown in Fig. 1. Methods: Participants, interventions, and outcomes Study setting {9} This study is being conducted at seven comprehensive stroke centers (CSCs) in Poland. All participating centers have extensive experience in specific acute ischemic stroke treatments. The main center is the Medical University of Gdansk, Department of Adult Neurology. Eligibility criteria {10} Patients with symptoms of AIS who were previously functionally independent (0–2 points on the modified Rankin Scale) will be considered for the STROACT study after exclusion of intracranial hemorrhage (ICH) and large vessel occlusion (LVO) using computed tomography (CT) or magnetic resonance imaging (MRI) with angiography sequences. Patients with LVO may be eligible for primary mechanical thrombectomy (MT) and will not be included in the study. Patients on DOACs (apixaban, rivaroxaban) mainly for the prevention of cardioembolic events will undergo standard diagnostic procedures (see Participant timeline {13}) and may be recruited into the study. Inclusion criteria Obtaining informed consent to participate in the trial prior to randomization. NOTE: Patients with severe neurological deficits that prevent them from signing the consent form may provide oral consent to participate in the study. This oral consent must be validated by the signatures of two independent witnesses (who are not family members or study staff) or by the patient’s legal representative. Patients with aphasia or other speech disorders may be enrolled in the study if, after a neurological assessment by the recruiting stroke physician, they demonstrate the ability to comprehend all essential information about the study. Age >18 years. Clinical diagnosis of acute ischemic stroke (sharply defined onset of first symptoms) leading to a disabling neurological deficit. Therapy with an oral anticoagulant that is a non-vitamin K antagonist oral anticoagulant (apixaban or rivaroxaban) with laboratory-confirmed therapeutic anti-Xa activity measured as a plasma concentration >50 ng/mL. The administration of the study intervention (intravenous thrombolysis with alteplase or a placebo) should be possible to start within 4.5 hours from the onset of acute ischemic stroke (AIS) symptoms or the last time the patient was seen without symptoms, as determined by the investigator. NOTE: If a patient has been randomized and there is a clear clinical justification for a delay in starting the study intervention within the 4.5-hour window, the patient may continue in the study if rtPA (or rtPA placebo) can be administered within 6.0 hours from the onset of AIS. For patients enrolled in the STROACT study, in addition to the inclusion/exclusion criteria, all standard clinical practice indications and contraindications for rtPA administration in acute ischemic stroke should be followed unless otherwise specified in this protocol. Exclusion criteria: Occlusion of a large intracranial vessel in CT/MR angiography (CTA/MRA), corresponding to the current acute neurological deficit, is an indication for primary mechanical thrombectomy. NOTE: Patients who qualify for mechanical thrombectomy cannot be enrolled in the STROACT study. Significant disability prior to the current stroke event is defined as having more than 2 points on the modified Rankin Scale (mRS) and/or significant impairment of cognitive function prior to AIS, with the latter documented in the patient’s medical records. Mild and rapidly improving neurological deficit with a high probability of complete recovery. Clinically severe stroke with >18 points in NIHSS. Neuroimaging findings that may cause acute neurological deficit (“stroke mimics”) and/or are contraindications for standard thrombolytic treatment: such as intracranial and/or intracerebral bleeding, tumors, abscesses, etc. Treatment with the following anticoagulants: Oral vitamin K antagonists (warfarin, acenocoumarol), Unfractionated heparin, Low molecular weight heparin, or Inhibitors of coagulation factor Xa other than rivaroxaban or apixaban. Administration of whole blood, and/or blood clotting factors (such as: prothrombin complex concentrate [PCC], recombinant factor VIIa [rVIIa], fresh frozen plasma [FFP]) within 7 days before starting the study treatment. Anti-Xa activity (which is assumed to be directly proportional to the DOAC plasma concentration) 1/2 of the anatomical perfusion area of the middle cerebral artery (MCA), or anterior cerebral artery (ACA), or posterior cerebral artery (PCA). Suspected subarachnoid hemorrhage based on specific symptomatology and/or physical examination (even if CT/MRI is normal). History of subarachnoid or intracerebral hemorrhage, excluding previous (currently normal in neuroimaging) traumatic sub-or epidural hematomas >6 months before the current acute stroke. Any chronic medical illnesses that significantly impair the patient’s functional status to a score of 3 or higher on the modified Rankin Scale (mRS), not limited to CNS pathologies and including cognitive impairment, and/or with a poor prognosis (e.g., neoplasms individually assessed to have a poor prognosis)). NOTE: Patients who have undergone treatment for intracranial aneurysm may be eligible for recruitment into the STROACT trial if the procedure was performed more than 3 months before randomization. History of major surgery/trauma within 2 months before the current acute ischemic stroke. History of acute ischemic stroke or any other medical condition treated with intravenous thrombolysis, or ischemic stroke treated with mechanical thrombectomy, within 72 hours before the current patient’s stroke symptoms. Recent (within the last 10 days) traumatic external heart massage, obstetrical delivery, lumbar puncture, or any puncture of a non-compressible blood vessel. Recent myocardial infarction (within the past 4 weeks). Severe trauma at the onset of acute ischemic stroke (e.g., skull fracture, long bone fracture, pelvic fracture). Expected need for major surgery within 72 hours after randomisation (e.g., laparotomy, hip femoral/pelvic fracture surgery, endarterectomy). Cerebral venous sinus thrombosis (CVST). Pulmonary embolism. Suspected infective endocarditis and/or pericarditis. Acute pancreatitis. Systemic or suspected cerebral vasculitis. Documented active ulcerative gastrointestinal disease during the last 3 months, documented oesophageal varices. Neoplasm with increased bleeding risk. Severe liver disease including acute hepatic failure, cirrhosis with/or without portal hypertension. Haemorrhagic retinopathy. Haemorrhagic diathesis (e.g., von Willebrand disease, haemophilia, and similar inherited coagulopathies). Platelet count <100,000/mm3. Active or recent severe, life-threatening bleeding. Congenital or acquired coagulopathy presenting with: Prolonged aPTT above 30% of the upper limit of normal (local laboratory reference range), Increased INR ≥1.7. Blood glucose 400 mg/dl (22.2 mmol/l) NOTE: Patients meeting the criteria may be enrolled in the STROACT trial if the CT or MRI lesion corresponds to a persisting acute neurological deficit even after blood glucose levels have been restored to 250 mg/dL or lower. Severe high blood pressure, defined as systolic blood pressure (SBP) > 185 mmHg or diastolic blood pressure (DBP) > 110 mmHg just before the study treatment administration or if there is a suspected requirement for aggressive medication use (such as labetalol, urapidil) to keep blood pressure below these values during subsequent reversal and/or thrombolytic treatment. Pregnancy. Predicted life expectancy <3 months. Participation in another clinical trial at the time of randomisation or planned inclusion in another clinical trial within less than 90 days of randomisation, provided that protocols of these trials interfere pathophysiologicaly or formally and administratively with the STROACT study. Previous participation in the current clinical trial. Advanced renal failure (eGFR <30 mL/min/1.73m2). Active infection with SARS-CoV-2 (up to 10 days from the first positive test result with any recommended assay or from the onset of symptoms of infection or severe “long” COVID-19 / severe Post-COVID Neurological Syndrome). Who will take informed consent? {26a} The investigator or their representative will explain the nature of the study to the participant or their legal representative and answer all questions regarding the study. The participant must be informed that participation in the clinical trial is voluntary, and they are free to refuse to participate and may withdraw their consent at any time and for any reason during the study. Participants or their legally authorized representative or two independent witnesses will be required to sign a statement of informed consent that meets applicable laws and regulations. Patients whose worsening neurological deficit makes it impossible to sign the consent form may give their oral consent to participate in the study. 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 the patient’s legal representative. Patients with aphasia and/or speech disorders may be included in the study if, in the opinion of the qualifying physician, they are able to understand the idea of the study. Informed consent to participate in the study from the patient or their legal representative must be obtained before performing any study-specific/study-related procedures. Additional consent provisions for collection and use of participant data and biological specimens {26b} No biological specimens will be stored. Participant data, including clinical and demographic information will be collected for research purposes. The data may be shared with other researchers for future studies in an anonymized format. Participants will provide consent for the use of their data and may withdraw at any time. If a participant withdraws, no further data will be collected, but anonymized data already gathered will be retained. Interventions Explanation for the choice of comparators {6b} The STROACT clinical trial is a randomized, double-blind, placebo-controlled study that aims to evaluate the efficacy and safety of a new intervention involving sequential intravenous administration of a DOAC-specific antidote and thrombolysis with rtPA for patients with acute ischemic stroke (AIS) who are actively treated with DOACs and do not have large vessel occlusion (LVO). The study will compare the new intervention to a placebo to determine its effectiveness and safety. We selected the comparator due to the absence of a specific treatment for this patient group. The STROACT study is the first initiative to establish a new therapeutic standard. Intervention description {11a} STROACT is a multicenter, parallel-group, randomized, double-blind, placebo-controlled clinical trial designed to assess the effectiveness and safety of reperfusion thrombolytic therapy using intravenous rtPA (alteplase) in patients with acute ischemic stroke (AIS) who are on non-vitamin K antagonist anticoagulants (DOAC anti-Xa inhibitors: apixaban and rivaroxaban) and have received a specific antidote/reversal agent (andexanet alfa). The study interventions for each study group are as follows: Study group A (patients on apixaban with high plasma anti-Xa activity): intravenous administration of andexanet alfa followed by an infusion of rtPA (or corresponding placebo for each component of the intervention). Study group B (patients on rivaroxaban with high plasma anti-Xa activity): intravenous administration of andexanet alfa followed by an infusion of rtPA (or corresponding placebo for each component of the intervention). Participants in groups A and B will be randomized in a 1:1 ratio to receive either active treatment or placebo. Placebo for the antidote and rtPA (0.9% NaCl solution) will be prepared immediately after randomization. All components of the study intervention (sequential therapy) are commercially available medications, and dosages and administration will adhere to local prescribing guidelines. In the STROACT study, rtPA (both bolus and infusion) will be administered in a vein of the arm contralateral to the ischemic lesion, while the antidote (andexanet alfa) will be administered in a vein of the arm on the same side as the ischemic lesion. During the recruitment process for the STROACT trial, we observed that patients with AIS who had high plasma levels of anticoagulants and were initially eligible for the study showed significantly improved clinical and neuroimaging outcomes compared to typical stroke cases. Many of these patients experienced rapid neurological recovery to a non-disabling status even before consenting to participate in the trial. Based on these findings, we hypothesized that AIS patients receiving direct oral anticoagulants (DOACs) therapy with therapeutic plasma concentrations (>50 ng/mL) have a more favorable prognosis than those not on this treatment or with suboptimal anticoagulation. To investigate this hypothesis, we expanded the STROACT study with an observational arm to monitor and assess this specific patient population during their hospitalization. For this portion of the project we plan to recruit 200 patients. Criteria for discontinuing or modifying allocated interventions {11b} It may be necessary for a participant to permanently discontinue the study intervention. If the study intervention is permanently discontinued, the participant will remain in the study to be evaluated for efficacy and safety parameters as appropriate. Study treatment may be permanently discontinued due to: Informed decision of the patient. The investigator's decision resulting from: Finding of incorrect randomization of the patient, posing a risk to the patient's health or life (non-compliance with inclusion/exclusion criteria). Adverse reactions that the investigator believes may harm the patient's health (regardless of their relation to the treatment). Temporary suspension of study treatment administration should occur if, during the second phase of treatment (rtPA or placebo), systolic blood pressure rises above 185 mmHg and/or diastolic blood pressure rises above 110 mmHg. If blood pressure cannot be lowered below 185/110 mmHg within 15 minutes, the study treatment should be permanently discontinued. Premature termination of the study treatment for any reason does not mean termination of the patient's participation in the study. The patient should be further evaluated according to the study protocol (at day 2, 7, 30, and 90). The patient (or their legally authorized representative) has the right to withdraw consent to participate in the study at any time. Discontinuation of acute phase therapy (intravenous thrombolysis/placebo) does not automatically terminate participation in the study. If a participant (or their legally authorized representative) withdraws consent, they will be asked if they are withdrawing consent for all further participation in the study (treatment, assessments, and follow-up) or only from treatment/assessments, allowing further follow-up. Strategies to improve adherence to interventions {11c} To ensure adherence to the trial protocol and effective preparation and administration of the intervention, all neurologists, nurses, pharmacists, and other healthcare professionals involved in the trial will undergo comprehensive training. This training will focus on the intervention protocol, patient assessment procedures, and adherence to standardized guidelines to ensure consistency across all clinical sites. Relevant concomitant care permitted or prohibited during the trial {11d} Concomitant therapy refers to any medical procedure or medication that is administered in addition to the study intervention, or standard diagnostic and management procedures for the condition under investigation. Concomitant medications include all prescription or over-the-counter drugs, vaccines, vitamins, and herbal supplements that a participant is using at the time of enrollment or begins taking during the course of the study. All concomitant therapies, especially those that may significantly influence hemostatic parameters, such as heparins, antiplatelet agents, anticoagulants, or drugs that interfere with anticoagulants (if anticoagulants are administered), must be carefully recorded. This information should be documented in the participant’s medical records and entered into the electronic Case Report Form (eCRF). The following details must be recorded for each concomitant therapy: Reason for use. Dates of administration, including both the start and end dates. Dosage details, including the dose and frequency of administration. There are no specific protocol restrictions regarding concomitant therapies or medications, other than those outlined in the study’s exclusion criteria. However, it is essential to monitor and document any new therapies that could potentially interact with the study intervention. Provisions for post-trial care {30} Patients who have had an acute ischemic stroke (AIS) are at a higher risk of venous thromboembolism (VTE) during the first one to three months post-stroke, mainly due to stroke-related immobility. Given the increased thrombotic risk during this period, it is important to consider restarting anticoagulant therapy or implementing of thromboembolism prophylaxis as soon as medically appropriate. The timing of post-stroke care, including the initiation of anticoagulation or other preventive measures, will be personalized based on each patient’s clinical condition and risk profile, with a careful assessment of the balance between thromboembolic and hemorrhagic risks. Outcomes {12} Primary outcomes The primary outcome is the transition from a disabling deficit at admission to a non-disabling deficit (up to two points on the modified Rankin Scale). This will be measured as the proportion of participants achieving this transition from admission to 90 days after receiving the investigational treatment, with a comparison between the treatment and control groups. The second primary outcome is the change in neurological status, assessed by the National Institutes of Health Stroke Scale (NIHSS) score, from admission to the 7-day follow-up. The outcome will be presented as the least squares (LS) mean difference in NIHSS score between admission and 7 days post-intervention for each study group. To address the issue of multiple primary endpoints, additional p-values will be provided using the Benjamini-Hochberg procedure. Secondary outcomes Efficacy Proportion of patients with excellent functional status, as assessed by the modified Rankin Scale (mRS) (mRS 0-1 points), at 90 days (+/- 3 days) after receiving the investigational treatment. Safety Incidence of deaths: Deaths from any cause Deaths subdivided by cause at 7 (+/-1 day), 30 (+/-2 days) and 90 days (+/- 3 days) after the investigational treatment administration. Incidence of non-fatal events is defined as Recurrent ischaemic stroke Haemorrhagic stroke (ICH or SAH) Neurological deterioration (NIHSS) at 7 (+/-1 day), and 90 days (+/- 3 days) after the administration of investigational treatment. Rate and severity of early intracranial hemorrhage (symptomatic and asymptomatic) detected by neuroimaging: CT or MRI at 24 hours (+/- 4 hours) after investigational treatment administration CT or MRI at 7 days (+/- 1 day) after investigational treatment infusion and assessed according to the European Cooperative Acute Stroke Study (ECASS III) classification. Note: Symptomatic Intracranial Hemorrhage (sICH) is defined as a deterioration of stroke severity in NIHSS of ≥ 4 points with parenchymal hemorrhage type 2 in neuroimaging. Incidence and severity of major extracranial hemorrhages defined as follows: Fatal Severe enough to require transfusion or surgery An absolute decrease in hemoglobin >5 g/dL A decrease in hematocrit >15% Bleeding resulting in persistent or temporary serious disability Incidence and categories of adverse events reported during the study. Exploratory Change in BNP or NT-proBNP plasma concentration at Day 7 compared to pre-treatment levels. Change in Barthel Index score measured at Day 90 compared to Day 7. Change on MoCA scale measured at Day 90 compared to Day 7. Assessment of pre-stroke cognitive impairment measured by IQCODE scale at Day 7. Change on HADS scale measured at Day 90 compared to Day 7. Number of days from hospital admission to discharge. Participant timeline {13} The participant timeline is presented in Fig. 2. Sample size {14} The null hypothesis (H0) assumes that the proportion of subjects randomized to the study treatment achieving the first primary endpoint – transition from disabling (at admission) to a non-disabling deficit (p1) is equal to the proportion in the placebo group (p2), H0: p1 = p2. The alternative hypothesis (Ha) assumes that the proportion of subjects achieving the first primary endpoint differs between the treatment group and the placebo group, Ha: p1 ≠ p2. The following assumptions were made: The primary endpoint is the transition from disabling (at admission) to a non-disabling deficit. The estimated proportion of subjects randomized to receive the investigational medicinal product (IMP) achieving the primary endpoint is 75% compared to 50% in the placebo group. These estimates are not derived from existing literature, but reflect the expert clinical judgment of the neurology team based on their experience, acknowledging the nature of this proof-of-concept trial. A 1:1 allocation ratio. A two-sided significance level of 0.05. Statistical power of 70%, given the limited number of participants available for recruitment. One interim analysis will be conducted using the Hwang-Shih-DeCani alpha spending function after half of the randomized subjects have provided data on the primary endpoint. A drop-out rate of 5%. Considering these assumptions, the minimum required sample size is 100 participants (rounded up from 97). Sample size calculation was performed using the R statistical program (version 4.3) with the rpact library (version 3.3.4). The statistical code to reproduce the results is provided below: # Load the rpact library for group sequential design and sample size calculations library(rpact) # Define the group sequential design using the Hwang-Shih-DeCani alpha spending function design <- getDesignGroupSequential( sided = 2, # Specify a two-sided hypothesis test alpha = 0.05, # Set the significance level (Type I error) beta = 0.3, # Set the Type II error (power = 1 - beta, 70%) informationRates = c(0.5, 1), # Define the proportion of information at each analysis (50% and 100%) typeOfDesign = "asHSD", # Use Hwang-Shih-DeCani spending function for interim analysis gammaA = -4 # Specify the gamma parameter for the spending function (-4 is a common choice) ) # Calculate the sample size required for a two-proportion comparison # pi2 = Control group proportion (expected to be 50%) # pi1 = Treatment group proportion (expected to be 75%) sampleSize <- getSampleSizeRates( design = design, pi2 = 0.5, # Expected proportion of transition in the control group pi1 = 0.75 # Expected proportion of transition in the treatment group ) # Adjust the fixed sample size to account for a 5% dropout rate # The calculated fixed sample size is increased to compensate for participant dropouts sampleSize$nFixed * 1/(1-0.05) # Multiply by the factor to account for the dropout rate Recruitment {15} The STROACT study will enroll patients admitted to the hospital under emergency conditions with suspected acute ischemic stroke (AIS) through the neurological emergency unit. All enrolled patients will be managed according to local acute stroke care protocols within the same clinical environment. These protocols must comply with current clinical guidelines for effective stroke unit care. Each clinical center participating in the STROACT study must have a stroke care unit and qualified staff trained to provide high-quality, standardized specialty care for acute stroke patients. This includes: Written protocols for rapid diagnosis and treatment of suspected acute stroke patients. 24/7 access to brain imaging (CT or MRI) and laboratory services. A specialized facility capable of administering thrombolysis and monitoring patients as per the study protocol, preferably within an acute stroke unit. Upon admission, standard procedures such as establishing intravenous access, monitoring physiological variables, correcting abnormalities, and initiating intravenous fluid therapy as needed should be followed. Recruitment of participants is expected to take place from 2022 to 2026 across seven study sites. Assignment of interventions: allocation Sequence generation {16a} Participants in each study group (based on the DOAC taken) will be randomized using a computer-generated randomization schedule. The allocation ratio is set at 1:1, randomizing participants to either the active treatment group or the control group. Stratification will be based on the National Institutes of Health Stroke Scale (NIHSS) score (<6 points/≥6 points) to ensure balanced generated distribution across the groups. A stratified variable block length randomization, based on a computer-generated randomization schedule integrated into the eCRF software, will be used to ensure consistent and unbiased assignment of participants. The randomization schedule will be incorporated into the electronic Case Report Form (eCRF) system, ensuring consistent and unbiased assignment of participants. Concealment mechanism {16b} The randomization process will be concealed through the eCRF system to prevent any influence on group allocation. The randomization algorithm is integrated into the eCRF software, ensuring that allocation remains hidden from both the investigator and participants until the appropriate point in the process. Upon entering the required patient information, the system will generate a unique randomization number automatically and notify unblinded personnel responsible for preparing the allocated treatment. The blinding mechanism will uphold the integrity of the randomization process. Implementation {16c} The investigator or a trained designee will conduct randomization using the predefined algorithm embedded in the eCRF system. The system is accessible 24/7 for randomization at any time. Prior to randomization, the investigator must verify that all eligibility criteria are met, the patient can receive study treatment (thrombolysis) within the specified time frame (4.5 to 6 hours from AIS onset), and the anti-Xa activity results (based on the DOAC taken prior to AIS) are available. The patient's NIHSS score, used for stratification, must also be provided before randomization. Detailed instructions for randomization will be provided in the eCRF completion manual for each study site. Discussion STROACT is the only ongoing therapeutic randomized clinical trial for ischemic stroke in patients on active DOAC treatment. In the STROACT trial, based on pharmaceutical characteristics and clinical research, we introduce a sequential therapy composed of a specific, fast-acting antidote and rtPA or corresponding placebos. Note that the anti-Xa arms of the study dedicated to patients on rivaroxaban/apixaban therapy include a long bolus of andexanet alpha, a bolus of alteplase, and simultaneous infusion of the antidote and thrombolytic (into opposite arms) for 60 minutes, and finally, the continued infusion of the remaining dose of the antidote. The whole process requires a high level of cooperation from different members of the stroke team, as well as advanced logistic solutions to administer the investigational medicinal product before 4.5 hours from the stroke onset. The first blood sample for determination of anti-Xa activity (corresponding to DOAC plasma concentration) is collected and processed immediately. Additionally, we are collecting blood at multiple time-points during and after the therapy, but the follow-up samples will be measured only during the first interim analysis (i.e, for a major patient sample). This work addresses the European Stroke Organization’s concern that “a randomized-controlled trial on this topic is unlikely to ever be planned for financial and logistical reasons” ( https://eso-stroke.org/can-we-apply-thrombolysis-for-stroke-in-patients-on-non-vitamin-k-oral-anticoagulants/ ). We have successfully applied for, registered in the EU, and are recruiting patients for the clinical trial investigating the potential causative (reperfusion) therapy based on combined anticoagulant reversal and fibrinolytic agents. The topic might be of interest due to its epidemiological significance, as non-LVO stroke patients on DOACs are the largest group among those who cannot receive any potential reperfusion therapy even if they arrive at the hospital shortly after the first stroke symptoms. Conclusion STROACT is the only ongoing therapeutic randomized clinical trial for ischemic stroke in patients on active DOAC treatment with aim to develop the first causative therapy for this group of patients; the results may make a significant contribution to the field of acute ischemic stroke therapies. Trial status Currently, the protocol is version 6.0 of August 28, 2024. The first patient was recruited in 2022. The enrollment of new patients will be terminated when the minimum number of patients assumed in the sample size analysis for the primary endpoint is achieved. According to the study schedule, the last patient will be recruited in 2026. All hospitals participating in the STROACT study are Polish Comprehensive Stroke Centers (CSCs) and academic hospitals with extensive experience in specific acute ischemic stroke treatments. Abbreviations ACA Anterior Cerebral Artery AE Adverse Event AF Atrial Fibrillation AIS Acute Ischemic Stroke ANCOVA Analysis of Covariance AR Adverse Reaction BNP Brain Natriuretic Peptide CBC Complete Blood Count CI Confidence Interval CNS Central Nervous System CRP C-Reactive Protein CSC Comprehensive Stroke Center CT Computed Tomography CTA CT Angiography CT/MRI CT or MRI Imaging CTA/MRA CT or MR Angiography CTCAE Common Terminology Criteria for Adverse Events CVST Cerebral Venous Sinus Thrombosis DBP Diastolic Blood Pressure DMP Data Management Plan DOAC Non-vitamin K Antagonist Oral Anticoagulant DSMB Data Safety Monitoring Board DUS Doppler Ultrasound Scan EC Executive Committee ECASS European Cooperative Acute Stroke Study ECG Electrocardiogram eCRF Electronic Case Report Form eGFR Estimated Glomerular Filtration Rate EU European Union FFP Fresh Frozen Plasma GCP Good Clinical Practice Ha Alternative Hypothesis H0 Null Hypothesis HADS Hospital Anxiety and Depression Scale ICH Intracranial Hemorrhage / International Council for Harmonisation IDMC Independent Data Monitoring Committee IEC Independent Ethics Committee IMP Investigational Medicinal Product INR International Normalized Ratio IRB Institutional Review Board IS Ischaemic Stroke ITT Intention to Treat IVT Intravenous Thrombolysis LVO Large Vessel Occlusion LS Least Squares MCA Middle Cerebral Artery MoCA Montreal Cognitive Assessment MRI Magnetic Resonance Imaging MRA MR Angiography mRS Modified Rankin Scale MT Mechanical Thrombectomy NA Not Available NIHSS NIH Stroke Scale NT-proBNP N-terminal Pro B-type Natriuretic Peptide OAC Oral Anticoagulant PCA Posterior Cerebral Artery PCC Prothrombin Complex Concentrate PI Principal Investigator PP Per Protocol rtPA Recombinant Tissue Plasminogen Activator SAE Serious Adverse Event SAF Safety Analysis SAP Statistical Analysis Plan SAH Subarachnoid Hemorrhage SBP Systolic Blood Pressure SC Steering Committee SOP Standard Operating Procedures SPIRIT Standard Protocol Items: Recommendations for Interventional Trials SUSAR Suspected Unexpected Serious Adverse Reaction VTE Venous Thromboembolism Declarations Acknowledgements Not applicable. Authors’ contributions {31b} BK conceptualized the trial and obtained funding. BK, BJ, DG, SSz, and AW designed the trial. BK, BJ, DG, and SSz were involved in patient recruitment and study coordination. BJ and AW wrote the first draft of the manuscript. All authors reviewed and approved the final version of the manuscript. Funding {4} The STROACT study (acronym: STRoke on Oral AntiCoagulants for Thrombolysis; short title: Reperfusion thrombolytic therapy for ischemic stroke in patients on nonvitamin K antagonist oral anticoagulants; full title: A multicenter, parallel group, randomized, double-blind, placebo-controlled, phase II study evaluating the efficacy and safety of reperfusion thrombolytic therapy with intravenous recombinant tissue plasminogen activator [rtPA] for ischemic stroke in patients on non-vitamin K antagonist oral anticoagulants after reversing anticoagulant activity with a specific antidote) is funded by the Medical Research Agency, Stanisława Moniuszki Street 1A, 00-014 Warszawa (Grant number: 2019/ABM/01/00084) and carried out in accordance with the International Conference on Harmonization Good Clinical Practice rules (ICH GCP E6 (R2); protocol number: NBK241/1/2020; principal investigator: BK. Availability of data and materials {29} The datasets generated and analyzed during the current study will not be publicly available to protect participant privacy. However, they can be obtained from the corresponding author upon reasonable request. Ethics approval and consent to participate {24} The study protocol was approved by the Independent Bioethics Committee for Scientific Research at the Medical University of Gdańsk (Number NKBBN/75-702/2021). This trial is being conducted in accordance with local legislation and institutional requirements. Consent for publication {32} The participant information materials and informed consent form can be obtained from the corresponding author upon request. Competing interests {28} BK has been a member of an AstraZeneca Advisory Board regarding the unrelated use of andexanet alfa. This membership occurred after the initiation of the STROACT study. AstraZeneca had no involvement in the STROACT study. The remaining authors declare that this research is being conducted without any commercial or financial relationships that could be perceived as a potential conflict of interest. References GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021;20(10):795–820. Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;384(9958):1929–35. Ma H, Campbell BCV, Parsons MW, Churilov L, Levi CR, Hsu CY et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke [published correction appears in N Engl J Med. 2021;384(13):1278]. N Engl J Med. 2019;380(19):1795–1803. Goyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723–31. Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378(1):11–21. Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378(8):708–18. Yoshimura S, Sakai N, Yamagami H, Uchida K, Beppu M, Toyoda K, et al. Endovascular therapy for acute stroke with a large ischemic region. N Engl J Med. 2022;386(14):1303–13. Sarraj A, Hassan AE, Abraham MG, Ortega-Gutierrez S, Kasner SE, Hussain MS et al. Trial of endovascular thrombectomy for large ischemic strokes [published correction appears in N Engl J Med. 2024;390(4):388]. N Engl J Med. 2023;388(14):1259–1271. Huo X, Ma G, Tong X, Zhang X, Pan Y, Nguyen TN, et al. Trial of endovascular therapy for acute ischemic stroke with large infarct. N Engl J Med. 2023;388(14):1272–83. Bendszus M, Fiehler J, Subtil F, Bonekamp S, Aamodt AH, Fuentes B et al. Endovascular thrombectomy for acute ischaemic stroke with established large infarct: multicentre, open-label, randomised trial. Lancet. 2023;402(10414):1753–1763. Profesoor Professor Tianjing Li PhD, Professor Shaun Treweek PhD, Professor Bartosz Karaszewski MD, PhD 1,* 1 Dept of Neurology, Dept of Adult Neurology, Head Brain Diseases Center, Research director Section of Cerebrovascular Diseases, Polish Neurological Society, Medical Univ of Gdańsk, University Clinical Center in Gdańsk, Medical Univ of Gdańsk, Head, President Elect * [email protected] , +48 585844820. Jovin TG, Li C, Wu L, Wu C, Chen J, Jiang C, et al. Trial of thrombectomy 6 to 24 hours after stroke due to basilar-artery occlusion. N Engl J Med. 2022;387(15):1373–84. Tao C, Nogueira RG, Zhu Y, Sun J, Han H, Yuan G, et al. Trial of endovascular treatment of acute basilar-artery occlusion. N Engl J Med. 2022;387(15):1361–72. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Minor revision 20 Mar, 2026 Reviewers agreed at journal 19 Sep, 2025 Reviewers invited by journal 16 Sep, 2025 Editor invited by journal 04 Mar, 2025 Editor assigned by journal 20 Feb, 2025 First submitted to journal 19 Feb, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5288990","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":515769415,"identity":"f74b959f-cab2-456e-b3ea-44d6b39d551e","order_by":0,"name":"Bartosz Karaszewski","email":"","orcid":"","institution":"Medical University of Gdansk: Gdanski Uniwersytet Medyczny","correspondingAuthor":false,"prefix":"","firstName":"Bartosz","middleName":"","lastName":"Karaszewski","suffix":""},{"id":515769416,"identity":"53f01443-eb72-4c19-bc0a-749e29fef090","order_by":1,"name":"Bartosz Jabłoński","email":"","orcid":"","institution":"Medical 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1","display":"","copyAsset":false,"role":"figure","size":48242,"visible":true,"origin":"","legend":"\u003cp\u003eStudy diagram\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5288990/v1/254c15c9ab0d98a63b9aa005.png"},{"id":92086907,"identity":"c4f74dc5-a0a6-4261-8ef4-4a1a004fcd2c","added_by":"auto","created_at":"2025-09-24 13:05:57","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":291647,"visible":true,"origin":"","legend":"\u003cp\u003eSchedule of study procedures\u003c/p\u003e\n\u003cp\u003eLaboratory examinations* - haematology (CBC and platelet count), coagulation parameteres (INR, aPTT, fibrinogen), biochemistry panel (electrolytes, glucose, creatinine, eGFR, AlAT, AspAT, bilirubin, albumin, CRP, troponin-I, BNP/NT-proBNP).\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5288990/v1/eec2f9d8ab13ca2468460af6.jpg"},{"id":92090593,"identity":"934f877d-f85e-4828-8dd5-3fd25b3d95f7","added_by":"auto","created_at":"2025-09-24 13:37:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1376466,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5288990/v1/46dd60b2-c15d-4c29-88c4-31127e03bcf2.pdf"}],"financialInterests":"","formattedTitle":"Reperfusion thrombolytic therapy for ischemic stroke in patients on non-vitamin K antagonist oral anticoagulants: study protocol of a phase II randomized clinical trial","fulltext":[{"header":"Administrative information","content":"\u003cp\u003eNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eTitle {1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 463px;\"\u003e\n \u003cp\u003eReperfusion thrombolytic therapy for ischemic stroke in patients on non-vitamin K antagonist oral anticoagulants: study protocol of a phase II randomized clinical trial\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 463px;\"\u003e\n \u003cp\u003ewww.clinicaltrialsregister.eu; EudraCT Nr: 2020-004898-41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eProtocol version {3}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 463px;\"\u003e\n \u003cp\u003e28 August 2024, v.6.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 463px;\"\u003e\n \u003cp\u003eFunding type: Grant\u003cbr\u003e\u0026nbsp;Name of Funding agency: Medical Research Agency, Poland\u003cbr\u003e\u0026nbsp;Grant Number: 2019/ABM/01/00084\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 463px;\"\u003e\n \u003cp\u003eBartosz Karaszewski\u003csup\u003ea,b,c\u003c/sup\u003e, Bartosz Jabłoński\u003csup\u003ea,b\u003c/sup\u003e, Dariusz Gąsecki\u003csup\u003ea,b\u003c/sup\u003e, Sebastian Szczyrba\u003csup\u003ea,b\u003c/sup\u003e, Adam Wyszomirski\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ea\u003c/sup\u003eDepartment of Adult Neurology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland\u003c/p\u003e\n \u003cp\u003e\u003csup\u003eb\u003c/sup\u003eDepartment of Adult Neurology, University Clinical Center, Gdańsk, Poland\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ec\u003c/sup\u003eBrain Diseases Centre, Medical University of Gdańsk, Gdańsk, Poland\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eName and contact information for the trial sponsor {5b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 463px;\"\u003e\n \u003cp\u003eThe trial sponsor is the Medical University of Gdańsk. Marii Sklodowskiej-Curie 3a street, \u0026nbsp;80-210 Gdansk, Poland\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eRole of sponsor {5c}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 463px;\"\u003e\n \u003cp\u003eThe sponsor had no role in the study design; collection, management, analysis, interpretation, or reporting of the data; report preparation; or publication decisions.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Introduction","content":"\n\u003ch3\u003eBackground and rationale {6a}\u003c/h3\u003e\n\u003cp\u003eThe burden of cardiovascular and cerebrovascular diseases has been steadily increasing over the past decade and is expected to rise further as the global population ages [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Among these diseases, stroke remains the leading cause of permanent complex disability in adults. Currently, intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) within 4.5 hours of onset (or up to 9.0 hours with advanced neuroimaging methods) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] and mechanical thrombectomy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] with extended protocols (such as DAWN, DEFUSE 3, large core RCTs and posterior circulation protocols BAOCHE and ATTENTION)[\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10 CR11\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] have significantly improved outcomes for stroke patients. These interventions, combined with comprehensive interdisciplinary care in stroke units, significantly increase the likelihood of excellent and good functional outcomes (modified Rankin Scale [mRS] 0\u0026ndash;1 and 0\u0026ndash;2, respectively). However, there is still a lack of high-quality scientific evidence for specific treatments in certain acute ischemic stroke (AIS) subgroups. Non-LVO stroke patients who are on oral anticoagulants represent a significant portion of those who may not be eligible for reperfusion therapy, even if they present at the hospital shortly after the onset of symptoms.\u003c/p\u003e\n\u003ch3\u003eObjectives {7}\u003c/h3\u003e\n\u003cp\u003eThe purpose of this study is to assess the effectiveness and safety of intravenous thrombolysis with rtPA in patients with acute ischemic stroke (AIS) who are on chronic non-vitamin K antagonist oral anticoagulant (DOAC) therapy, following the administration of a specific reversal agent.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eTrial design {8}\u003c/h2\u003e\u003cp\u003eSTROACT (STRoke on Oral AntiCoagulants for Thrombolysis) is a multicenter, prospective, parallel-group, randomized, double-blind, placebo-controlled, superiority, non-commercial clinical trial with a 1:1 allocation ratio supported by a grant from the Polish Medical Research Agency. The trial aims to evaluate the efficacy and safety of a new intervention involving the sequential intravenous administration of DOAC-specific antidotes (andexanet alfa for apixaban and rivaroxaban) followed by thrombolysis with rtPA. A flowchart of the study is shown in Fig.\u0026nbsp;1.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Methods: Participants, interventions, and outcomes","content":"\u003cp\u003e\u003cstrong\u003eStudy setting {9}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is being conducted at seven comprehensive stroke centers (CSCs) in Poland. All participating centers have extensive experience in specific acute ischemic stroke treatments. The main center is the Medical University of Gdansk, Department of Adult Neurology.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria {10}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with symptoms of AIS who were previously functionally independent (0\u0026ndash;2 points on the modified Rankin Scale) will be considered for the STROACT study after exclusion of intracranial hemorrhage (ICH) and large vessel occlusion (LVO) using computed tomography (CT) or magnetic resonance imaging (MRI) with angiography sequences. Patients with LVO may be eligible for primary mechanical thrombectomy (MT) and will not be included in the study. Patients on DOACs (apixaban, rivaroxaban) mainly for the prevention of cardioembolic events will undergo standard diagnostic procedures (see Participant timeline {13}) and may be recruited into the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eInclusion criteria\u003c/u\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eObtaining informed consent to participate in the trial prior to randomization.\u003cbr\u003eNOTE: Patients with severe neurological deficits that prevent them from signing the consent form may provide oral consent to participate in the study. This oral consent must be validated by the signatures of two independent witnesses (who are not family members or study staff) or by the patient\u0026rsquo;s legal representative. Patients with aphasia or other speech disorders may be enrolled in the study if, after a neurological assessment by the recruiting stroke physician, they demonstrate the ability to comprehend all essential information about the study.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"2\"\u003e\n \u003cli\u003eAge \u0026gt;18 years.\u003c/li\u003e\n \u003cli\u003eClinical diagnosis of acute ischemic stroke (sharply defined onset of first symptoms) leading to a disabling neurological deficit.\u003c/li\u003e\n \u003cli\u003eTherapy with an oral anticoagulant that is a non-vitamin K antagonist oral anticoagulant (apixaban or rivaroxaban) with laboratory-confirmed therapeutic anti-Xa activity measured as a plasma concentration \u0026gt;50 ng/mL.\u003c/li\u003e\n \u003cli\u003eThe administration of the study intervention (intravenous thrombolysis with alteplase or a placebo) should be possible to start within 4.5 hours from the onset of acute ischemic stroke (AIS) symptoms or the last time the patient was seen without symptoms, as determined by the investigator.\u003cbr\u003eNOTE:\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e\n\u003cul\u003e\n \u003cli\u003eIf a patient has been randomized and there is a clear clinical justification for a delay in starting the study intervention within the 4.5-hour window, the patient may continue in the study if rtPA (or rtPA placebo) can be administered within 6.0 hours from the onset of AIS.\u003c/li\u003e\n \u003cli\u003eFor patients enrolled in the STROACT study, in addition to the inclusion/exclusion criteria, all standard clinical practice indications and contraindications for rtPA administration in acute ischemic stroke should be followed unless otherwise specified in this protocol.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cu\u003eExclusion criteria:\u003c/u\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eOcclusion of a large intracranial vessel in CT/MR angiography (CTA/MRA), corresponding to the current acute neurological deficit, is an indication for primary mechanical thrombectomy.\u003cbr\u003eNOTE: Patients who qualify for mechanical thrombectomy cannot be enrolled in the STROACT study.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"2\"\u003e\n \u003cli\u003eSignificant disability prior to the current stroke event is defined as having more than 2 points on the modified Rankin Scale (mRS) and/or significant impairment of cognitive function prior to AIS, with the latter documented in the patient\u0026rsquo;s medical records.\u003c/li\u003e\n \u003cli\u003eMild and rapidly improving neurological deficit with a high probability of complete recovery.\u003c/li\u003e\n \u003cli\u003eClinically severe stroke with \u0026gt;18 points in NIHSS.\u003c/li\u003e\n \u003cli\u003eNeuroimaging findings that may cause acute neurological deficit (\u0026ldquo;stroke mimics\u0026rdquo;) and/or are contraindications for standard thrombolytic treatment: such as intracranial and/or intracerebral bleeding, tumors, abscesses, etc.\u003c/li\u003e\n \u003cli\u003eTreatment with the following anticoagulants:\u003col style=\"list-style-type: lower-alpha;\"\u003e\n \u003cli\u003eOral vitamin K antagonists (warfarin, acenocoumarol),\u003c/li\u003e\n \u003cli\u003eUnfractionated heparin,\u003c/li\u003e\n \u003cli\u003eLow molecular weight heparin, or\u003c/li\u003e\n \u003cli\u003eInhibitors of coagulation factor Xa other than rivaroxaban or apixaban.\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n \u003cli\u003eAdministration of whole blood, and/or blood clotting factors (such as: prothrombin complex concentrate [PCC], recombinant factor VIIa [rVIIa], fresh frozen plasma [FFP]) within 7 days before starting the study treatment.\u003c/li\u003e\n \u003cli\u003eAnti-Xa activity (which is assumed to be directly proportional to the DOAC plasma concentration) \u0026lt;50 ng/mL.\u003c/li\u003e\n \u003cli\u003eInitial lesion volume on CT or MRI \u0026gt;1/2 of the anatomical perfusion area of the middle cerebral artery (MCA), or anterior cerebral artery (ACA), or posterior cerebral artery (PCA).\u003c/li\u003e\n \u003cli\u003eSuspected subarachnoid hemorrhage based on specific symptomatology and/or physical examination (even if CT/MRI is normal).\u003c/li\u003e\n \u003cli\u003eHistory of subarachnoid or intracerebral hemorrhage, excluding previous (currently normal in neuroimaging) traumatic sub-or epidural hematomas \u0026gt;6 months before the current acute stroke.\u003c/li\u003e\n \u003cli\u003eAny chronic medical illnesses that significantly impair the patient\u0026rsquo;s functional status to a score of 3 or higher on the modified Rankin Scale (mRS), not limited to CNS pathologies and including cognitive impairment, and/or with a poor prognosis (e.g., neoplasms individually assessed to have a poor prognosis)).\u003cbr\u003eNOTE: Patients who have undergone treatment for intracranial aneurysm may be eligible for recruitment into the STROACT trial if the procedure was performed more than 3 months before randomization.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"13\"\u003e\n \u003cli\u003eHistory of major surgery/trauma within 2 months before the current acute ischemic stroke.\u003c/li\u003e\n \u003cli\u003eHistory of acute ischemic stroke or any other medical condition treated with intravenous thrombolysis, or ischemic stroke treated with mechanical thrombectomy, within 72 hours before the current patient\u0026rsquo;s stroke symptoms.\u003c/li\u003e\n \u003cli\u003eRecent (within the last 10 days) traumatic external heart massage, obstetrical delivery, lumbar puncture, or any puncture of a non-compressible blood vessel.\u003c/li\u003e\n \u003cli\u003eRecent myocardial infarction (within the past 4 weeks).\u003c/li\u003e\n \u003cli\u003eSevere trauma at the onset of acute ischemic stroke (e.g., skull fracture, long bone fracture, pelvic fracture).\u003c/li\u003e\n \u003cli\u003eExpected need for major surgery within 72 hours after randomisation (e.g., laparotomy, hip femoral/pelvic fracture surgery, endarterectomy).\u003c/li\u003e\n \u003cli\u003eCerebral venous sinus thrombosis (CVST).\u003c/li\u003e\n \u003cli\u003ePulmonary embolism.\u003c/li\u003e\n \u003cli\u003eSuspected infective endocarditis and/or pericarditis.\u003c/li\u003e\n \u003cli\u003eAcute pancreatitis.\u003c/li\u003e\n \u003cli\u003eSystemic or suspected cerebral vasculitis.\u003c/li\u003e\n \u003cli\u003eDocumented active ulcerative gastrointestinal disease during the last 3 months, documented oesophageal varices.\u003c/li\u003e\n \u003cli\u003eNeoplasm with increased bleeding risk.\u003c/li\u003e\n \u003cli\u003eSevere liver disease including acute hepatic failure, cirrhosis with/or without portal hypertension.\u003c/li\u003e\n \u003cli\u003eHaemorrhagic retinopathy.\u003c/li\u003e\n \u003cli\u003eHaemorrhagic diathesis (e.g., von Willebrand disease, haemophilia, and similar inherited coagulopathies).\u003c/li\u003e\n \u003cli\u003ePlatelet count \u0026lt;100,000/mm3.\u003c/li\u003e\n \u003cli\u003eActive or recent severe, life-threatening bleeding.\u003c/li\u003e\n \u003cli\u003eCongenital or acquired coagulopathy presenting with:\u003col style=\"list-style-type: lower-alpha;\"\u003e\n \u003cli\u003eProlonged aPTT above 30% of the upper limit of normal (local laboratory reference range),\u003c/li\u003e\n \u003cli\u003eIncreased INR\u0026nbsp;\u0026ge;1.7.\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/li\u003e\n \u003cli\u003eBlood glucose \u0026lt;50 mg/dl (2.8 mmol/l) or \u0026gt;400 mg/dl (22.2 mmol/l)\u003cbr\u003eNOTE: Patients meeting the criteria may be enrolled in the STROACT trial if the CT or MRI lesion corresponds to a persisting acute neurological deficit even after blood glucose levels have been restored to 250 mg/dL or lower.\u003c/li\u003e\n\u003c/ol\u003e\n\u003col start=\"33\"\u003e\n \u003cli\u003eSevere high blood pressure, defined as systolic blood pressure (SBP) \u0026gt; 185 mmHg or diastolic blood pressure (DBP) \u0026gt; 110 mmHg just before the study treatment administration or if there is a suspected requirement for aggressive medication use (such as labetalol, urapidil) to keep blood pressure below these values during subsequent reversal and/or thrombolytic treatment.\u003c/li\u003e\n \u003cli\u003ePregnancy.\u003c/li\u003e\n \u003cli\u003ePredicted life expectancy \u0026lt;3 months.\u003c/li\u003e\n \u003cli\u003eParticipation in another clinical trial at the time of randomisation or planned inclusion in another clinical trial within less than 90 days of randomisation, provided that protocols of these trials interfere pathophysiologicaly or formally and administratively with the STROACT study.\u003c/li\u003e\n \u003cli\u003ePrevious participation in the current clinical trial.\u003c/li\u003e\n \u003cli\u003eAdvanced renal failure (eGFR \u0026lt;30 mL/min/1.73m2).\u003c/li\u003e\n \u003cli\u003eActive infection with SARS-CoV-2 (up to 10 days from the first positive test result with any recommended assay or from the onset of symptoms of infection or severe \u0026ldquo;long\u0026rdquo; COVID-19 / severe Post-COVID Neurological Syndrome).\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eWho will take informed consent? {26a}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe investigator or their representative will explain the nature of the study to the participant or their legal representative and answer all questions regarding the study. The participant must be informed that participation in the clinical trial is voluntary, and they are free to refuse to participate and may withdraw their consent at any time and for any reason during the study. Participants or their legally authorized representative or two independent witnesses will be required to sign a statement of informed consent that meets applicable laws and regulations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients whose worsening neurological deficit makes it impossible to sign the consent form may give their oral consent to participate in the study. 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 the patient\u0026rsquo;s legal representative. Patients with aphasia and/or speech disorders may be included in the study if, in the opinion of the qualifying physician, they are able to understand the idea of the study.\u003c/p\u003e\n\u003cp\u003eInformed consent to participate in the study from the patient or their legal representative must be obtained before performing any study-specific/study-related procedures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo biological specimens will be stored. Participant data, including clinical and demographic information will be collected for research purposes. The data may be shared with other researchers for future studies in an anonymized format. Participants will provide consent for the use of their data and may withdraw at any time. If a participant withdraws, no further data will be collected, but anonymized data already gathered will be retained.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExplanation for the choice of comparators {6b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe STROACT clinical trial is a randomized, double-blind, placebo-controlled study that aims to evaluate the efficacy and safety of a new intervention involving sequential intravenous administration of a DOAC-specific antidote and thrombolysis with rtPA for patients with acute ischemic stroke (AIS) who are actively treated with DOACs and do not have large vessel occlusion (LVO). The study will compare the new intervention to a placebo to determine its effectiveness and safety.\u003c/p\u003e\n\u003cp\u003eWe selected the comparator due to the absence of a specific treatment for this patient group. The STROACT study is the first initiative to establish a new therapeutic standard.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention description {11a}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSTROACT is a multicenter, parallel-group, randomized, double-blind, placebo-controlled clinical trial designed to assess the effectiveness and safety of reperfusion thrombolytic therapy using intravenous rtPA (alteplase) in patients with acute ischemic stroke (AIS) who are on non-vitamin K antagonist anticoagulants (DOAC anti-Xa inhibitors: apixaban and rivaroxaban) and have received a specific antidote/reversal agent (andexanet alfa). The study interventions for each study group are as follows: Study group A (patients on apixaban with high plasma anti-Xa activity): intravenous administration of andexanet alfa followed by an infusion of rtPA (or corresponding placebo for each component of the intervention). Study group B (patients on rivaroxaban with high plasma anti-Xa activity): intravenous administration of andexanet alfa followed by an infusion of rtPA (or corresponding placebo for each component of the intervention).\u003c/p\u003e\n\u003cp\u003eParticipants in groups A and B will be randomized in a 1:1 ratio to receive either active treatment or placebo.\u003c/p\u003e\n\u003cp\u003ePlacebo for the antidote and rtPA (0.9% NaCl solution) will be prepared immediately after randomization. All components of the study intervention (sequential therapy) are commercially available medications, and dosages and administration will adhere to local prescribing guidelines.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the STROACT study, rtPA (both bolus and infusion) will be administered in a vein of the arm contralateral to the ischemic lesion, while the antidote (andexanet alfa) will be administered in a vein of the arm on the same side as the ischemic lesion.\u003c/p\u003e\n\u003cp\u003eDuring the recruitment process for the STROACT trial, we observed that patients with AIS who had high plasma levels of anticoagulants and were initially eligible for the study showed significantly improved clinical and neuroimaging outcomes compared to typical stroke cases. Many of these patients experienced rapid neurological recovery to a non-disabling status even before consenting to participate in the trial. Based on these findings, we hypothesized that AIS patients receiving direct oral anticoagulants (DOACs) therapy with therapeutic plasma concentrations (\u0026gt;50 ng/mL) have a more favorable prognosis than those not on this treatment or with suboptimal anticoagulation. To investigate this hypothesis, we expanded the STROACT study with an observational arm to monitor and assess this specific patient population during their hospitalization. For this portion of the project we plan to recruit 200 patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt may be necessary for a participant to permanently discontinue the study intervention. If the study intervention is permanently discontinued, the participant will remain in the study to be evaluated for efficacy and safety parameters as appropriate. Study treatment may be permanently discontinued due to:\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eInformed decision of the patient.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe investigator\u0026apos;s decision resulting from:\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eFinding of incorrect randomization of the patient, posing a risk to the patient\u0026apos;s health or life (non-compliance with inclusion/exclusion criteria).\u003c/p\u003e\n\u003cp\u003eAdverse reactions that the investigator believes may harm the patient\u0026apos;s health (regardless of their relation to the treatment).\u003c/p\u003e\n\u003cp\u003eTemporary suspension of study treatment administration should occur if, during the second phase of treatment (rtPA or placebo), systolic blood pressure rises above 185 mmHg and/or diastolic blood pressure rises above 110 mmHg. If blood pressure cannot be lowered below 185/110 mmHg within 15 minutes, the study treatment should be permanently discontinued.\u003c/p\u003e\n\u003cp\u003ePremature termination of the study treatment for any reason does not mean termination of the patient\u0026apos;s participation in the study. The patient should be further evaluated according to the study protocol (at day 2, 7, 30, and 90).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe patient (or their legally authorized representative) has the right to withdraw consent to participate in the study at any time. Discontinuation of acute phase therapy (intravenous thrombolysis/placebo) does not automatically terminate participation in the study. If a participant (or their legally authorized representative) withdraws consent, they will be asked if they are withdrawing consent for all further participation in the study (treatment, assessments, and follow-up) or only from treatment/assessments, allowing further follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrategies to improve adherence to interventions {11c}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo ensure adherence to the trial protocol and effective preparation and administration of the intervention, all neurologists, nurses, pharmacists, and other healthcare professionals involved in the trial will undergo comprehensive training. This training will focus on the intervention protocol, patient assessment procedures, and adherence to standardized guidelines to ensure consistency across all clinical sites.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConcomitant therapy refers to any medical procedure or medication that is administered in addition to the study intervention, or standard diagnostic and management procedures for the condition under investigation. Concomitant medications include all prescription or over-the-counter drugs, vaccines, vitamins, and herbal supplements that a participant is using at the time of enrollment or begins taking during the course of the study.\u003c/p\u003e\n\u003cp\u003eAll concomitant therapies, especially those that may significantly influence hemostatic parameters, such as heparins, antiplatelet agents, anticoagulants, or drugs that interfere with anticoagulants (if anticoagulants are administered), must be carefully recorded. This information should be documented in the participant\u0026rsquo;s medical records and entered into the electronic Case Report Form (eCRF). The following details must be recorded for each concomitant therapy:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eReason for use.\u003c/li\u003e\n \u003cli\u003eDates of administration, including both the start and end dates.\u003c/li\u003e\n \u003cli\u003eDosage details, including the dose and frequency of administration.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThere are no specific protocol restrictions regarding concomitant therapies or medications, other than those outlined in the study\u0026rsquo;s exclusion criteria. However, it is essential to monitor and document any new therapies that could potentially interact with the study intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProvisions for post-trial care {30}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients who have had an acute ischemic stroke (AIS) are at a higher risk of venous thromboembolism (VTE) during the first one to three months post-stroke, mainly due to stroke-related immobility. Given the increased thrombotic risk during this period, it is important to consider restarting anticoagulant therapy or implementing of thromboembolism prophylaxis as soon as medically appropriate.\u003c/p\u003e\n\u003cp\u003eThe timing of post-stroke care, including the initiation of anticoagulation or other preventive measures, will be personalized based on each patient\u0026rsquo;s clinical condition and risk profile, with a careful assessment of the balance between thromboembolic and hemorrhagic risks.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes {12}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome is the transition from a disabling deficit at admission to a non-disabling deficit (up to two points on the modified Rankin Scale). This will be measured as the proportion of participants achieving this transition from admission to 90 days after receiving the investigational treatment, with a comparison between the treatment and control groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe second primary outcome is the change in neurological status, assessed by the National Institutes of Health Stroke Scale (NIHSS) score, from admission to the 7-day follow-up. The outcome will be presented as the least squares (LS) mean difference in NIHSS score between admission and 7 days post-intervention for each study group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo address the issue of multiple primary endpoints, additional p-values will be provided using the Benjamini-Hochberg procedure.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcomes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eEfficacy\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eProportion of patients with excellent functional status, as assessed by the modified Rankin Scale (mRS) (mRS 0-1 points), at 90 days (+/- 3 days) after receiving the investigational treatment.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eSafety\u003c/u\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eIncidence of deaths:\u003cul style=\"list-style-type: circle;\"\u003e\n \u003cli\u003eDeaths from any cause\u003c/li\u003e\n \u003cli\u003eDeaths subdivided by cause\u003cbr\u003eat 7 (+/-1 day), 30 (+/-2 days) and 90 days (+/- 3 days) after the investigational treatment administration.\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003eIncidence of non-fatal events is defined as\u003cul style=\"list-style-type: circle;\"\u003e\n \u003cli\u003eRecurrent ischaemic stroke\u003c/li\u003e\n \u003cli\u003eHaemorrhagic stroke (ICH or SAH)\u003c/li\u003e\n \u003cli\u003eNeurological deterioration (NIHSS)\u003cbr\u003eat 7 (+/-1 day), and 90 days (+/- 3 days) after the administration of investigational treatment.\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003eRate and severity of early intracranial hemorrhage (symptomatic and asymptomatic) detected by neuroimaging:\u003cul style=\"list-style-type: circle;\"\u003e\n \u003cli\u003eCT or MRI at 24 hours (+/- 4 hours) after investigational treatment administration\u003c/li\u003e\n \u003cli\u003eCT or MRI at 7 days (+/- 1 day) after investigational treatment infusion\u003cbr\u003eand assessed according to the European Cooperative Acute Stroke Study (ECASS III) classification.\u003cbr\u003eNote: Symptomatic Intracranial Hemorrhage (sICH) is defined as a deterioration of stroke severity in NIHSS of \u0026ge; 4 points with parenchymal hemorrhage type 2 in neuroimaging.\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003eIncidence and severity of major extracranial hemorrhages defined as follows:\u003cul style=\"list-style-type: circle;\"\u003e\n \u003cli\u003eFatal\u003c/li\u003e\n \u003cli\u003eSevere enough to require transfusion or surgery\u003c/li\u003e\n \u003cli\u003eAn absolute decrease in hemoglobin \u0026gt;5 g/dL\u003c/li\u003e\n \u003cli\u003eA decrease in hematocrit \u0026gt;15%\u003c/li\u003e\n \u003cli\u003eBleeding resulting in persistent or temporary serious disability\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003eIncidence and categories of adverse events reported during the study.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cu\u003eExploratory\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eChange in BNP or NT-proBNP plasma concentration at Day 7 compared to pre-treatment levels.\u003c/li\u003e\n \u003cli\u003eChange in Barthel Index score measured at Day 90 compared to Day 7.\u003c/li\u003e\n \u003cli\u003eChange on MoCA scale measured at Day 90 compared to Day 7.\u003c/li\u003e\n \u003cli\u003eAssessment of pre-stroke cognitive impairment measured by IQCODE scale at Day 7.\u003c/li\u003e\n \u003cli\u003eChange on HADS scale measured at Day 90 compared to Day 7.\u003c/li\u003e\n \u003cli\u003eNumber of days from hospital admission to discharge.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline {13}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe participant timeline is presented in Fig. 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size {14}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe null hypothesis (H0) assumes that the proportion of subjects randomized to the study treatment achieving the first primary endpoint \u0026ndash; transition from disabling (at admission) to a non-disabling deficit (p1) is equal to the proportion in the placebo group (p2), H0: p1 = p2. The alternative hypothesis (Ha) assumes that the proportion of subjects achieving the first primary endpoint differs between the treatment group and the placebo group, Ha: p1 \u0026ne; p2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe following assumptions were made:\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eThe primary endpoint is the transition from disabling (at admission) to a non-disabling deficit.\u003c/li\u003e\n \u003cli\u003eThe estimated proportion of subjects randomized to receive the investigational medicinal product (IMP) achieving the primary endpoint is 75% compared to 50% in the placebo group. These estimates are not derived from existing literature, but reflect the expert clinical judgment of the neurology team based on their experience, acknowledging the nature of this proof-of-concept trial.\u003c/li\u003e\n \u003cli\u003eA 1:1 allocation ratio.\u003c/li\u003e\n \u003cli\u003eA two-sided significance level of 0.05.\u003c/li\u003e\n \u003cli\u003eStatistical power of 70%, given the limited number of participants available for recruitment.\u003c/li\u003e\n \u003cli\u003eOne interim analysis will be conducted using the Hwang-Shih-DeCani alpha spending function after half of the randomized subjects have provided data on the primary endpoint.\u003c/li\u003e\n \u003cli\u003eA drop-out rate of 5%.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eConsidering these assumptions, the minimum required sample size is 100 participants (rounded up from 97).\u003c/p\u003e\n\u003cp\u003eSample size calculation was performed using the R statistical program (version 4.3) with the rpact library (version 3.3.4). The statistical code to reproduce the results is provided below:\u003c/p\u003e\n\u003cp\u003e# Load the rpact library for group sequential design and sample size calculations\u003c/p\u003e\n\u003cp\u003elibrary(rpact)\u003c/p\u003e\n\u003cp\u003e# Define the group sequential design using the Hwang-Shih-DeCani alpha spending function\u003c/p\u003e\n\u003cp\u003edesign \u0026lt;- getDesignGroupSequential(\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; sided = 2, \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;# Specify a two-sided hypothesis test\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; alpha = 0.05, \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; # Set the significance level (Type I error)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; beta = 0.3, \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; # Set the Type II error (power = 1 - beta, 70%)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;informationRates = c(0.5, 1), \u0026nbsp;# Define the proportion of information at each analysis (50% and 100%)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; typeOfDesign = \u0026quot;asHSD\u0026quot;, \u0026nbsp; \u0026nbsp;# Use Hwang-Shih-DeCani spending function for interim analysis\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; gammaA = -4 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; # Specify the gamma parameter for the spending function (-4 is a common choice)\u003c/p\u003e\n\u003cp\u003e)\u003c/p\u003e\n\u003cp\u003e# Calculate the sample size required for a two-proportion comparison\u003c/p\u003e\n\u003cp\u003e# pi2 = Control group proportion (expected to be 50%)\u003c/p\u003e\n\u003cp\u003e# pi1 = Treatment group proportion (expected to be 75%)\u003c/p\u003e\n\u003cp\u003esampleSize \u0026lt;- getSampleSizeRates(\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; design = design,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; pi2 = 0.5, \u0026nbsp; # Expected proportion of transition in the control group\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; pi1 = 0.75 \u0026nbsp; # Expected proportion of transition in the treatment group\u003c/p\u003e\n\u003cp\u003e)\u003c/p\u003e\n\u003cp\u003e# Adjust the fixed sample size to account for a 5% dropout rate\u003c/p\u003e\n\u003cp\u003e# The calculated fixed sample size is increased to compensate for participant dropouts\u003c/p\u003e\n\u003cp\u003esampleSize$nFixed * 1/(1-0.05) \u0026nbsp;# Multiply by the factor to account for the dropout rate\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment {15}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe STROACT study will enroll patients admitted to the hospital under emergency conditions with suspected acute ischemic stroke (AIS) through the neurological emergency unit. All enrolled patients will be managed according to local acute stroke care protocols within the same clinical environment. These protocols must comply with current clinical guidelines for effective stroke unit care. Each clinical center participating in the STROACT study must have a stroke care unit and qualified staff trained to provide high-quality, standardized specialty care for acute stroke patients. This includes:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eWritten protocols for rapid diagnosis and treatment of suspected acute stroke patients.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e24/7 access to brain imaging (CT or MRI) and laboratory services.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eA specialized facility capable of administering thrombolysis and monitoring patients as per the study protocol, preferably within an acute stroke unit.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eUpon admission, standard procedures such as establishing intravenous access, monitoring physiological variables, correcting abnormalities, and initiating intravenous fluid therapy as needed should be followed. Recruitment of participants is expected to take place from 2022 to 2026 across seven study sites.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: allocation\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSequence generation {16a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants in each study group (based on the DOAC taken) will be randomized using a computer-generated randomization schedule. The allocation ratio is set at 1:1, randomizing participants to either the active treatment group or the control group. Stratification will be based on the National Institutes of Health Stroke Scale (NIHSS) score (\u0026lt;6 points/\u0026ge;6 points) to ensure balanced generated distribution across the groups. A stratified variable block length randomization, based on a computer-generated randomization schedule integrated into the eCRF software, will be used to ensure consistent and unbiased assignment of participants. The randomization schedule will be incorporated into the electronic Case Report Form (eCRF) system, ensuring consistent and unbiased assignment of participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConcealment mechanism {16b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe randomization process will be concealed through the eCRF system to prevent any influence on group allocation. The randomization algorithm is integrated into the eCRF software, ensuring that allocation remains hidden from both the investigator and participants until the appropriate point in the process. Upon entering the required patient information, the system will generate a unique randomization number automatically and notify unblinded personnel responsible for preparing the allocated treatment. The blinding mechanism will uphold the integrity of the randomization process.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplementation {16c}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe investigator or a trained designee will conduct randomization using the predefined algorithm embedded in the eCRF system. The system is accessible 24/7 for randomization at any time. Prior to randomization, the investigator must verify that all eligibility criteria are met, the patient can receive study treatment (thrombolysis) within the specified time frame (4.5 to 6 hours from AIS onset), and the anti-Xa activity results (based on the DOAC taken prior to AIS) are available. The patient\u0026apos;s NIHSS score, used for stratification, must also be provided before randomization. Detailed instructions for randomization will be provided in the eCRF completion manual for each study site.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSTROACT is the only ongoing therapeutic randomized clinical trial for ischemic stroke in patients on active DOAC treatment. In the STROACT trial, based on pharmaceutical characteristics and clinical research, we introduce a sequential therapy composed of a specific, fast-acting antidote and rtPA or corresponding placebos. Note that the anti-Xa arms of the study dedicated to patients on rivaroxaban/apixaban therapy include a long bolus of andexanet alpha, a bolus of alteplase, and simultaneous infusion of the antidote and thrombolytic (into opposite arms) for 60 minutes, and finally, the continued infusion of the remaining dose of the antidote. The whole process requires a high level of cooperation from different members of the stroke team, as well as advanced logistic solutions to administer the investigational medicinal product before 4.5 hours from the stroke onset.\u003c/p\u003e\u003cp\u003eThe first blood sample for determination of anti-Xa activity (corresponding to DOAC plasma concentration) is collected and processed immediately. Additionally, we are collecting blood at multiple time-points during and after the therapy, but the follow-up samples will be measured only during the first interim analysis (i.e, for a major patient sample).\u003c/p\u003e\u003cp\u003eThis work addresses the European Stroke Organization\u0026rsquo;s concern that \u0026ldquo;a randomized-controlled trial on this topic is unlikely to ever be planned for financial and logistical reasons\u0026rdquo; (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://eso-stroke.org/can-we-apply-thrombolysis-for-stroke-in-patients-on-non-vitamin-k-oral-anticoagulants/\u003c/span\u003e\u003cspan address=\"https://eso-stroke.org/can-we-apply-thrombolysis-for-stroke-in-patients-on-non-vitamin-k-oral-anticoagulants/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). We have successfully applied for, registered in the EU, and are recruiting patients for the clinical trial investigating the potential causative (reperfusion) therapy based on combined anticoagulant reversal and fibrinolytic agents.\u003c/p\u003e\u003cp\u003eThe topic might be of interest due to its epidemiological significance, as non-LVO stroke patients on DOACs are the largest group among those who cannot receive any potential reperfusion therapy even if they arrive at the hospital shortly after the first stroke symptoms.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSTROACT is the only ongoing therapeutic randomized clinical trial for ischemic stroke in patients on active DOAC treatment with aim to develop the first causative therapy for this group of patients; the results may make a significant contribution to the field of acute ischemic stroke therapies.\u003c/p\u003e\u003cp\u003e\u003cb\u003eTrial status\u003c/b\u003e\u003c/p\u003e\u003cp\u003eCurrently, the protocol is version 6.0 of August 28, 2024. The first patient was recruited in 2022. The enrollment of new patients will be terminated when the minimum number of patients assumed in the sample size analysis for the primary endpoint is achieved. According to the study schedule, the last patient will be recruited in 2026.\u003c/p\u003e\u003cp\u003eAll hospitals participating in the STROACT study are Polish Comprehensive Stroke Centers (CSCs) and academic hospitals with extensive experience in specific acute ischemic stroke treatments.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e\u003ccolgroup cols=\"2\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnterior Cerebral Artery\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAdverse Event\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAtrial Fibrillation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAIS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAcute Ischemic Stroke\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eANCOVA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnalysis of Covariance\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAdverse Reaction\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBNP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBrain Natriuretic Peptide\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCBC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eComplete Blood Count\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eConfidence Interval\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCentral Nervous System\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC-Reactive Protein\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCSC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eComprehensive Stroke Center\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eComputed Tomography\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCTA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCT Angiography\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCT/MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCT or MRI Imaging\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCTA/MRA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCT or MR Angiography\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCTCAE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCommon Terminology Criteria for Adverse Events\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCVST\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCerebral Venous Sinus Thrombosis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiastolic Blood Pressure\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDMP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eData Management Plan\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDOAC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNon-vitamin K Antagonist Oral Anticoagulant\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDSMB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eData Safety Monitoring Board\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDoppler Ultrasound Scan\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eExecutive Committee\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eECASS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEuropean Cooperative Acute Stroke Study\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eECG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eElectrocardiogram\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeCRF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eElectronic Case Report Form\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEstimated Glomerular Filtration Rate\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEU\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEuropean Union\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFFP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFresh Frozen Plasma\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGCP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGood Clinical Practice\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHa\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAlternative Hypothesis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eH0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNull Hypothesis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHADS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHospital Anxiety and Depression Scale\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eICH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIntracranial Hemorrhage / International Council for Harmonisation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIDMC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIndependent Data Monitoring Committee\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIEC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIndependent Ethics Committee\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIMP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInvestigational Medicinal Product\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eINR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInternational Normalized Ratio\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIRB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInstitutional Review Board\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIschaemic Stroke\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eITT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIntention to Treat\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIVT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIntravenous Thrombolysis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLVO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLarge Vessel Occlusion\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLeast Squares\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMCA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMiddle Cerebral Artery\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMoCA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMontreal Cognitive Assessment\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMagnetic Resonance Imaging\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMRA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMR Angiography\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003emRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eModified Rankin Scale\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMechanical Thrombectomy\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNot Available\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNIHSS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNIH Stroke Scale\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNT-proBNP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eN-terminal Pro B-type Natriuretic Peptide\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOAC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOral Anticoagulant\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePCA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePosterior Cerebral Artery\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePCC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eProthrombin Complex Concentrate\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePrincipal Investigator\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePer Protocol\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ertPA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRecombinant Tissue Plasminogen Activator\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSAE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSerious Adverse Event\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSAF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSafety Analysis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSAP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStatistical Analysis Plan\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSAH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSubarachnoid Hemorrhage\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSBP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSystolic Blood Pressure\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSteering Committee\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSOP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStandard Operating Procedures\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSPIRIT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStandard Protocol Items: Recommendations for Interventional Trials\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSUSAR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSuspected Unexpected Serious Adverse Reaction\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVTE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eVenous Thromboembolism\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions {31b}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBK conceptualized the trial and obtained funding. BK, BJ, DG, SSz, and AW designed the trial. BK, BJ, DG, and SSz were involved in patient recruitment and study coordination. BJ and AW wrote the first draft of the manuscript. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe STROACT study (acronym: STRoke on Oral AntiCoagulants for Thrombolysis; short title: Reperfusion thrombolytic therapy for ischemic stroke in patients on nonvitamin K antagonist oral anticoagulants; full title: A multicenter, parallel group, randomized, double-blind, placebo-controlled, phase II study evaluating the efficacy and safety of reperfusion thrombolytic therapy with intravenous recombinant tissue plasminogen activator [rtPA] for ischemic stroke in patients on non-vitamin K antagonist oral anticoagulants after reversing anticoagulant activity with a specific antidote) is funded by the Medical Research Agency, Stanisława Moniuszki Street 1A, 00-014 Warszawa (Grant number: 2019/ABM/01/00084) and carried out in accordance with the International Conference on Harmonization Good Clinical Practice rules (ICH GCP E6 (R2); protocol number: NBK241/1/2020; principal investigator: BK.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cimg 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wt9n1bSNNhsNcvDHqcZW3upDIkeLxirbntM5UZXywCQDg/Mfx8+K/w3/Z9/4K4/FT4j/Gz9nzUPHmg33hnT7CzsYdBhvVS6ax0txMBcDy+FikTcDuG/HQnH1H+wP+2F+zh8efG2u+APgr+zRqHw9vo9KTULtp/DNtYx38McojwWt+GZGnGA5ziRivRqAPmr/gjv8AsO/ssftMfsza547+OPwlg17VrTx5dWFveS6ldwlLdLKykVMQyoDh5JDkgn5sZwAB2cXhXXf+CV37engn4f8Aws166uvhL8cNaNmvhS7lMh0nUDLDBvhLNkBHuLbEhyzxFo33tGkleRf8E0f+CgXhT9iX4Aax8MfiD8FvG+q6jfeMLjVITpGlr5Yie2tYQCZGX5gYGz7EV7X4N8DftIf8FHf2wvh7+018TvhTqngT4V/Dub+0vC9jql0iXeoziRbm3uFTy9373Fn5gy0YS2dVcM2SAbPwI/5Tx/Gr/smdr/6I0GvNv2Ef2dPCX/BUTx34+/bX/a3gutcs28TPo/hjwv8A2xIsWn26Red9mcxLGTFEl1biMoyFnWZ5FLOS3p/wL0vVYf8Aguj8ZtXk0y4W0m+G1qkd0YWEbt5GhcBsYJ4PfsfSvOfgF45+IH/BHP4pa1+zn8Z/BOr+IPht4s1j+1fCfi7QbEytEf3UMzzRgEkrEIvMjBLq0S7FdZQ1AH1H8OP+CZn7Inwc+M3hv45/CLwHdeHdZ8NfbPs0Nlq00tvdG4t3t2MyztIx2pI+3YyctzuAAHin/BSSTXf20v2kvA//AATb+GurLDBbzf8ACTfEjWIo2lGlW6RkQxv5bfKxSQtskUK0lzZ/MoJNdron/BVzwX4++N0Pgf4YfB/xVqfhPTdD1DV/GHjG60me3XT7O2tTN5kcDJvk+ceWQQpJZQm8sBXiP7Dv7KP7Rn7Smv8Ai/8A4KAWP7QGvfC3xH448RanbWtqugxakzaWZoWEYa5YfIksXkqNgIW1XBCnFAHs3/BH74sa7ffBDWv2VviQ00fjT4Pa9caLqltcXjXDG1M0phYSHKlUdZrdVRmVEt4yMK6CuZ/4JUAD9sj9rvA/5qav/px1muI1L4MfGf8AYZ/4KYfDP4xeJvizqXxCj+Lk03h/xNqMegRWkxJ+zWyeckYMaRK72M29SrsbaTI67+T+DX7XK/sAftk/tGRfE/4GeNNU/wCEy8fSXem/2PpqYWFLy/mSQmRlyssV3E6EZyvJxkZAP1Korxr9jz9sHw3+2L4K1bxn4Y+HPibw7HpOqfYpLfxFYiIzMY1k3RurMj/e5AOV4JADKT7LQAUUUUAfD/7QepS/tWf8FXPhn+zJClveeFfg3pj+PfGUEkjFH1Vg0GmRHYMpPCzi4VWYK8crZDYAr7ajRY0CJ93tXxf/AMEqjefEr40ftNftK+JEZtb174z3XhtZoV228mmaNDHb2bIOctslcO4JDMOgwRX2gCrN97pXLhdYub3k2/ley/BX+bPe4g5aVenhYaKlCKfnJrmk/wDwJteiRX/tTT/7QbTPt8P2iONZHt/MG9UYsFYr1AJVgD0O0+hq0SGPHftXz7+3V+xjd/tM+FYvEPws+I2peB/iNobR3HhnxVpN08RaSFjJHb3SqcXFvvJOxwwQuzKOWVvzt8Bf8Fzv2zf2L/ibcfs/ft4/CCPXLrQmW3vryzxb3zIkLKk6/wDLK4Er7HMgKqVLEDPFcuLzKjgJr26ai9pbr0dtUetw/wAE5lxVhZyyuUalWCvKm2ozt3jfSS+d09Ox+ynU5NfPv/BTr9k66/bO/Yt8Z/BXRIrdteks1v8AwzJcRRsV1C2kE0SK7kCLzdhtzJkbUmfORkGn+y5/wVO/Yu/a2uZdJ+F/xZt4NUt2bdpOtKbO4dR5Q8xUkxuTdMigjq2QBwa+ileO7g3RShlZfvCuqNTD42i+VqUWrXTutTxZ4XOOG8zhKvTlSq05JpSi00079UfybfCz4t/E/wCBXje1+IPwm8bal4d1zT5lMN9p8xjcYcPsYdHUsq5RgVYgZBHFa/xq+Ovxc/aM8ezfE742+PL7xJrtxbxQyahfsu4RIoCRqqgKijnhVAJLNgsxJ+gP+C2/7Jln+yj+3br0Phu08nw/43i/4SXR444yEt3uJXW4gB2hRtuEkZUXISKWJfrhf8Env2TF/bH/AG1/C/w41iKOTQtH/wCJ94ojfDCSxtZI/wByVJBYSyvBC2OQsrNztr8vx+Fxjx0cFFuzla13bdWdtv8AgH908M59kNPhapxTVpwUoUlLnsuZO2sU7X1elk9Wftb/AMEef2Vbr9kz9hXwr4P8T+H10/xNrgk1zxRHtdZBc3BDJHIr/dkitxBC4AA3Qnr1P1MAAMAVCGt7K2VGkVVjTHzNXyv+1h/wWP8A2If2TnvdE8QfEyPxB4it7Z2j0Hw3i6kaXyVljjd1OyLzAygMxwM84wa/To/V8Bh4wbSjFJa6bH8OYj+2OLM6rYmFOVSrVlKTSTesnf5JdOyPqzcAuegqqmu6LLq/9gR6zatfC38/7H9oXzvK3bfM2Zzt3cbsYzxX4t+Nv+C3X7f/AO3p8R7P9nT9iD4bw+FLzWtQmisry0b7TffZhMjRzSu48u1CRofNbDLh2wRhSf0i/YD/AGENB/Y18CLq/jjxxeeMviPrNmieJ/G+tXck8zruMn2O2aUlorVHZmVBjcx3sMkBZw+Mp4uT9mm4reWy9F1Z0ZtwriuH8PF4+ajVltTWsrd5W0S7btn0XNGZkaF1+VlwfeviL9i4Wv7If/BRf4ufsM6doyWfhfxlZx/EjwJ5OxVt/OaO0v7bAwFXz0BiiVfkjjbJOQa+4N643ZzXxb/wUhS3+E/7Yf7LX7UdvbLLLafEmbwVdWcahZLldbtXgjkZ+6wGJnCHjLnGDmrxV48s1umvubs/uTv8kcuRyjWdbBzfu1IS/wDAopyi/Vtct+zZ9rUU2KTfEr/3lzXzX+3d+2t8R/2WvHfwv+HHwy+F+meJtU+JWr3Om2cepao1qsVwstnFCNwUjDPdcscABc11ngn0tjPJFFfF/wAVf+Ch37U37K2seGfEH7Xn7Lek6H4L1vWG0++17w14kOoSWb+WzrlAoBOAXC5yyxybckAHp/2ov24Pjd8LP2wfC/7IPwO+DGi+JtW8U+FTq1nNq2uNZgMGvS8edpXAjs2YEnknHpQB9U0V4T8H/iT+3pr/AMRdN0n40/s0+EtA8NS+d/aWr6X4yF3PBiFzHti2jdukCKeeAxPavCvE37an7e37Q/x2+IXwo/Yi+GXhW3sfhh4jk0jW77xNeK0t43mSQq4VmVVHmWtwRgk7WTdg5FAH3XRXz58N/wBoL9pHQv2SPH3xZ/aR+DNroXi7wDY6q66fDcH7NrS2NgswukYZ2xTSiRRjIAHBNecfAf8AbP8A+Cg37R/wp0v4y/C/9kbwXcaFrXn/AGGa68dGF28meSB8oyZH7yJh7jnvQB9lUVyvwe1j4p+IPhzp+rfGfwbYeH/E0vnf2lpGl6h9rggxM6x7ZcDduiCMeOCxHavlD4Bf8FZrL42/t1Xn7P1h4Vt18D6pcXWl+D/Eyzf8fd9aLJLJNvPytHOmwIg+Zcw5yZSAAfbNFeD/APBQX9sWb9iP4Cw/Fm08GLr15feILfS7GxkuPKjWSSOWVndgCdoSGTGASWK9smvLPjV+2/8At2/szeDF+Lfxz/Y88Ow+E7PVLWHW7zQfGP2q4toZZAm8JsAGSQgLHbvdQcZoA+y6K+ev2pf+Cg/wq/Zv/Zh0b9ouGGbVP+Ew0+3n8FaSy+VJfNPAJo2kzzHGqMrOTyMhR8zKD44fjb/wWg8Qt/wtrRf2bvCul+Ho/wDSZPBd9cA6lJHBxLCCzB98pjcoducSpgHuAfdFFfKH7RX7dPxb+CP7Lvwx+PPiT4PTeHdY8SePtP0jxZ4V1YbprW3IujOIzkfM4tg0bH+GRSRnIr3/AOO/xFu/g/8AA/xl8WbPTEvJvC/hXUtXgs5pCiztbW0kwjJHIDFMZHQGgDsKK8b/AGDvj54p/ae/ZM8HfHDxrp1tbatrVvcrfR2YIiaW3u5rYyKD90P5O/bzt3YyQM17JQB8bf8ABCaVp/8Agl58P9SuXZ7i4utcluJ5OXlc6xeZZieWYjueTXzF+x1/wUa+LXw5/wCCr3xi+DXxp8Rahqfw/wDFPxXk0DTNUv7oeToGrbbhLC2QdluYbMwKo6vCjcfOT9Pf8ELrZtL/AOCbXhPwLqJEOreH9Y13T9c09mHmWV0ur3bNDKOqOFZW2nswPQiuH8Ff8Ecb3xJ4r/agtfjT4vij0n4y+NLHV/B+paESt9pEltJNdxXasfuSpPcmPAxuWB8nbLgeDTp4iWDw0qd04pNro/d2fq9PI/VsdjMjw/E2dwx0U41JzjB2u1eqnzR81G7Suk0rbHmmk/tq/Gf48/8ABcD4ay+CfFt9a/B9tQ8UeDNItYZiLbXbnTdNNxqF0Uxh0F09tHHKpKsLTKkZcH6f/wCCmn/BMz4Y/t9fC6RZkh0nxto9u7+G/Eix/NGx5MEuOXgY9V6qfmXnIObD/wAE1dH+G/7Qv7MutfAmG00XwH8CdM8Ux3lnNI0lxdS6jbwwpg/xO8rTzSOeMg8ZYY5X/grl/wAFcfB/7C3hCb4V/C+6tNY+KOrWebKxYiSHRoWHF1cgd8cpEeXIycL96pUqcMLWWM1jJ3121S0Xo7pHPSx2KxWfZdLhlOFWnDl91Wd41J2lPfVwcXLVrWx+DPjLwv4m+E/xC1XwPr/+ha34a1qaxvRBN81vdW8rRuAw7q6HkenFfRv7K/8AwWQ/bc/ZYgtdA0j4lf8ACS6BDcQu2j+Js3WIhK8ksccxO+MyGRgzZbHy4A2gV8wa3rPjP4p+OLzX9YuLzWfEHiPVpJ7mRYzJcX15cS7mOFGWd5HPAHJbgV9Wfskf8EQ/23v2ppodW1DwV/wg3h2aFZf7b8URtG0iukhQxwD94/zIFYHaV8xTyK+BwODzCOIvgpSXp28+h/XHE3EXB+IyeMOJaVOT5Ve9r81teXqrva2p6F/wU0/4Kc/s/f8ABSP9lfw6mr+Cbrwz8UPCGtRzWcLQG4huraaEJeRQzKcRo0ohkG8biLUDgtXH/wDBOP8A4KUfC3/gnL8H/FXiDwv8KZvE/wAT/FOqLbpcXkvlWdjplv5BjQvgvmRpbokJwTDFu4ArS/4Kb/8ABPb4H/8ABNn4U+Cvh5Y+Ip/FnxF8YyTXWsaxNKiQ6bZwR24eKKAfMvmTsTHK3OxZkOe3Vf8ABLL/AIJ7fsxf8FN/gBqnhbV9Q1Twj8QPh5qUUepazpAEkeraddNcy27yRyfL5vmCaMsuCI7aH+8a9b/hTnmrXuurGO/m1917fKx8D/xgmF4BU+StHLqtW9tXZJ27qXI5dNXfXY+f/wBqr/gq7+21+1rqUb+Nfi1faNpdvcedZ6L4YmexgjZfNCuxjId32TMhJOCAvGQDXhfw1+HviX4rfETQPhf4Pt45NV8Sa1a6XpiTSBEa4uJVijDMeFXc6gt2HNfW37VP/BD/APbe/Zpe71nS/BsfjbQLWGSVtW8N5aRY44leR3gb51wdygDcW2ZA5Ar5V8M+IPGPwk+Iun+KtHE2l+IPDGuQ3dr59uUltL22lDpuRuQyyIMqRwRgivJxmIzCniEsZGW+u+3Wz29D9A4dyfg/H5NN8M16blyaJJL3rO11vvvfU/oo/wCCZv8AwTP+FH/BPj4ULYaWkOseNdYgjfxR4qkhw9w4wfIhzzHAp6L1Y/M2TgDwH/gqO/xq/bv/AGg7r9hv9mP4jXnh/wD4Vp4RuPFXjDVtOvmt/N1maBk0nSWmVlMRcNJM+7KmNgw+aMCvXP8Aglp/wVI8C/t7/DkeGtfnt9H+IWj2aprGjmQKLoAY+0wDuhOcr1U+2Kz/ANlv/gkP4I8JaX4m8dftYauvjj4jeNfFV5rHiLXrG4uLOECRz5VvEiSA+UicqrE7DIyjCgV+gR9nisHTjhdYPV2dtF07p3tf5n8gVPrmQ8R4qvn7axUNIqUVK8m7c1nZOKje1urVtj2X/gnn+02f2tv2RfB/xj1JlXXLnTxZ+KbMw+U9pqtsfJu4mj6x/vkdlVsHYyHoRXlH/BcGCPw1+xIfj/ZRbte+Fnjzw94n8L+Y37o30eowwKJF/jTZcSZHHOD2roP2L/2JfHv7HX7TvxZn8Fatp8fwh8ayafq3h/w+JZXutO1YQiG8fLEgiXYHZiST+6Axscnn/wDgtfew+Jf2UtD/AGcHWSKf4vfFDw54Ss9Q4K6fJLfJc+ey/wAQAtWXaOcuD0BrplKtLL2pq0rNerWifzdmeNhY5fHjClPDSvRlOMrdoNpyi/NJtP0PsLTHMljDIf4oVP6V8F/8Fh7fxXe/tL/st2XgPVLWy1ybx1dJo15fQmSGC6N5pAieRRyyLJtLKOo4r7005PLsYYv7sSj9K8b/AGmP2OdA/aS+Lnwr+KureMLzTZvhd4lbVrW1t4VZb4mW2m2MT90b7SMcdnbvivRWx8lP4nY+MfE2gfH/APaa/br0r9jX/gol8VtN07RtF8rXvDWmaRYpBY+K5I59kQXJyGlge7TGQy7HUAsOdn/goL4L+LHxF/4K9fC/wh8D/iLH4S8UXnwzb+y/EEkZdbXa2svJwAc7olkTp1evqf8AbI/Yc8Lfta6h4P8AF6+Mr7wr4q8E6zHe6J4k0mFGnjUOrlPmHOHRJEJztZT2Zqy/2lf+Cf8AH8fv2idD/ac8PfHjxJ4L8SeHvD/9k6fcaDbwsUTddFnBkBIZlu5EPbFBBU/ZT/Z0/bt+F3xTPiT9oP8AbBt/GXh3+z5ojokelkM8zFdj72A2bcE5GScYxgkjhfiZ/wAE8v2jPhl8YvFn7QX7Df7RTaDeeLtYm13xF4V1qAPbajdqzTxwb8f6uSaW4zuwFWUDJAzXrfwe/ZR+Mfw1+I+m+M/FX7bHjzxdY2XnfaPDutQ2y211vhdBvKKG+VnWQY/iQe9eT3v/AATW/aX+H2qLp37OH7e3i7QfDd5rM95qWl6sxuZIY3ZAqQyHJYrEu3c/UqDjk0AZnwu/bT8W/tdf8E//AI+6R8U/C8Ok+MvA/gnWtM1+3tVPkzE6XOomB5UM0sVwGRSQu1cEhhXjf7AP7MH/AAUG+IX7JXhXxd8Dv20bfwn4XvG1A6XoElkztabdQuUkG4IQd0qyP16OK+w/gX/wT5+G3wH/AGUvFn7LfhzxTqd1D40tdSi1rxDdRp9pd7y2NvvCj5QI4tgC9Cyljyxri/ht/wAEzPiR8H/BNn8Ovhl+3v8AEbRdD05pPsOm2draCOLzJGlfAK93d2PuTQBe/wCChXx98T/sv/sEyaV4n8RpqXxA8TaHB4Ys7rTleNrvUZoPLurqJVO9Aq+dIpHR/KU4LCvhv4leJ/hP4c/4J+/DXwb8NfD/AI20/wCKHww1RPEkOvXPgWe3WG7mlM94hn27NsTeSyyMDuWwjHAOK+89X/4Jzw+PviZ8L/iJ8Z/2gvFHjBvhj5s9na6tDCov7w3jXKzylR2/0eMqOGS0jB6tX0he2VpqVnNp2oWcdxb3EbR3FvPGGSRSMMrA8MCDgg8GgD84v+Cpfx6039p7/glZ8M/jnplmtv8A2940sZLy1j3bbe7js9RiuIlzyVWaORVY/eUA96z/ANu26/ba1T4heB/2QP2svjFodv8AD34javYpqHjDw34ZaC3EouDi0dnY4ZXWGXnCjKMTtR694sP+CRXwyX9kK5/ZG1v4r+ILyxbxp/wkmm6w0cay2M3lLB5Sx/dKGPzMj+9MzdQK9y/au/Zf+HX7XnwcvPg58SEkjt5rhbnT9Qt/9dp92gYJPHnjcFZ1IPBV2HegD4o/4Kf+BNJ+CPx1/ZTs9evbdfhZ4P1Ox0zy9StzKLOG1u7D7Q9zIQVkR7WOIbSOfs8pwQeP0lz3rx/4kfsafCj4zfs2aD+zR8Ynvte03QbGwit9VmuDHeNcWsAhW63jpIy793XIlcd6+f8ATv8Agmd+1voVz/wrTRP+ChXiiL4byW81vJp7RltRMMsbGVfMPy/NK7c54Q8YOKAK/wDwXF1Kx8V/sjeCdQ8I6/a3EV18WLBbPULOdZY94s9RXcGUkHawxx0IIrkf2jP2R/8Agph4Z/Z98deJPiD+3lbazoOn+DdUudc0ddPdTfWcdpK00GdnG+MMuf8Aar6E8Rf8E1vhHr/7L/w+/ZUPijWIfD/gPxRb60sylfO1GVTctMjnH7tZGupW+XlOAOle1/F/4d2Xxf8AhP4o+E2qahNZ2vijw/faRcXVuoZ4Y7mB4WdQeCwD5GeM0AeG/wDBHc/8a5Ph1/3F/wD073tfTNea/sofs+aZ+yv8AfD/AMBdE1+41S30Jbnbf3Uaq8rTXMtw2QvGA0xUewFelUAfEv8AwTIEfwi/ap/ah/ZV1S5jm1Cx+KX/AAmdvdq2xbi21u2jmWJYz82YBEqO/KlnXGOlfavO/p/9avib9tHT5f2Vv+ChHwl/buFzJa+EvEFvJ8P/AIm3Sxhktoblml065kJAWKIXe0Szsw2KI1Gd5B+2YZFliEinhxkVyYX3E6b3i39zd1/l8me9n3LWnRxlParCN/KUUoyXq2ua3aSPlP8A4KMfts/Fj4KwQ/s+fsk/CfVPGnxe8SaaZ9LtLOxMlrotq/nBb26dsRjJt5xFGzDzGhbPC7W+CfgF/wAG8n7Sv7RetzfGf9uL4zXOh6h4gma+1SztmF3qkkksaSBppXzGjh2dGjAYLs4bGMfsyun2yXsmpLaRi4mjWOS48sb2RSxVSepA3sQOxY+pqx83SssRgaeMqXrNtLZbL/gs7cq4sx2Q4N0sujGE5L3p7zfkm9EvkeBfs0/8Eyv2Lf2Tza3/AMJfglpkerWcMkS6/qUf2q+ZWmE/MsmTlXVNp4KhFAPFe8yvDZ2jSEBAiE1KBzuNfIX/AAWz/aph/Zi/YQ8SRWAc6344U+GNF2ZHlNdRSCaYlWDJst1nZGGcSCMEYJrStUw+X4WVS1oxTbsuxxZfh814qzyjhXOVSpVkopybbu3a+vRb+h+LP/BT39qZP2wP21vGfxZ0rVnu9BhvBpfhdvMLRrp9v+7R48gFUlfzLjaRkG4bNbP/AARu/azuf2TP27PCes6jqi2/hzxZcr4c8TrNMqRCC5kVYp2ZztjEVwIZC/UIsgyAxrxT4K/A34uftF+Oofhl8EvAd94i16a3knj0/T1XKxIMu7MxCooyBuYgZZVHJANH42/Ab4v/ALOPj24+F/xv8BX3h3XobeOaSx1BRlopBlJFZSUdTz8ykjcGU8qwH5jgcRipYuWOaesr36el/wAD+6eKMnyCnw5S4VhUjzRpcvJdcyskk7b3vrfvqf1gjy7qBThWV1714d+05/wTo/ZE/a00STTfi38INOlumZ3h1bT4xa3kLPIkjss0YDZcxruJySMjua5n/gkl+1laftffsO+D/HdzrNxe+INEs10Hxc93M0s51K0jRHlkcqNzTIY7jjOBcAEkg19Nc9c1+pctHGYdNpOMlfVX3P4Q9pmnDeaThSnKnVpyavFtNNO26t/wx+QXxI/4ID/tL/s0/EvRvjT/AME/vjj9p1LSrpJY7fXZhbTwn96XIkRSkkZAij8tly29iTgYr9Af2EP2m/id8f8AwPe+HPj18HtY8E+PvCv2eDxNpeoWjLbyvJGHjnt5hlJEdeSqsShypxXvQwFytCxqjZRF/wAa5cLltDBVHKheKe8enrrsz2s+42zTijBwp5qo1KkNI1LWmlfVNrSSt3XncefXFfFX7fstt8af2+v2Zv2VEmM1nY+KLvx/4iWzUtPY/wBlwN9gkc9EhluGkhJPU4HXFfaF1MLe3eZnwFUmviL/AIJ0f2d+15+1x8XP+CkUkl5Lo9xcf8IJ8Mmm8xY20azMUlzdRZCh4ri7AkXK7o2WVCSS1bYr95KNJbtp/JO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alt=\"image\"\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials {29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study will not be publicly available to protect participant privacy. However, they can be obtained from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Independent Bioethics Committee for Scientific Research at the Medical University of Gdańsk (Number NKBBN/75-702/2021). This trial is being conducted in accordance with local legislation and institutional requirements.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe participant information materials and informed consent form can be obtained from the corresponding author upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBK has been a member of an AstraZeneca Advisory Board regarding the unrelated use of andexanet alfa. This membership occurred after the initiation of the STROACT study. AstraZeneca had no involvement in the STROACT study. The remaining authors declare that this research is being conducted without any commercial or financial relationships that could be perceived as a potential conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990\u0026ndash;2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021;20(10):795\u0026ndash;820.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEmberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;384(9958):1929\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMa H, Campbell BCV, Parsons MW, Churilov L, Levi CR, Hsu CY et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke [published correction appears in N Engl J Med. 2021;384(13):1278]. N Engl J Med. 2019;380(19):1795\u0026ndash;1803.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGoyal M, Menon BK, van Zwam WH, Dippel DW, Mitchell PJ, Demchuk AM, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387(10029):1723\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378(1):11\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlbers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378(8):708\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYoshimura S, Sakai N, Yamagami H, Uchida K, Beppu M, Toyoda K, et al. Endovascular therapy for acute stroke with a large ischemic region. N Engl J Med. 2022;386(14):1303\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSarraj A, Hassan AE, Abraham MG, Ortega-Gutierrez S, Kasner SE, Hussain MS et al. Trial of endovascular thrombectomy for large ischemic strokes [published correction appears in N Engl J Med. 2024;390(4):388]. N Engl J Med. 2023;388(14):1259\u0026ndash;1271.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHuo X, Ma G, Tong X, Zhang X, Pan Y, Nguyen TN, et al. Trial of endovascular therapy for acute ischemic stroke with large infarct. N Engl J Med. 2023;388(14):1272\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBendszus M, Fiehler J, Subtil F, Bonekamp S, Aamodt AH, Fuentes B et al. Endovascular thrombectomy for acute ischaemic stroke with established large infarct: multicentre, open-label, randomised trial. Lancet. 2023;402(10414):1753\u0026ndash;1763. Profesoor Professor Tianjing Li PhD, Professor Shaun Treweek PhD, Professor Bartosz Karaszewski MD, PhD\u003csup\u003e1,* 1\u003c/sup\u003eDept of Neurology, Dept of Adult Neurology, Head Brain Diseases Center, Research director Section of Cerebrovascular Diseases, Polish Neurological Society, Medical Univ of Gdańsk, University Clinical Center in Gdańsk, Medical Univ of Gdańsk, Head, President Elect \u003csup\u003e*\u003c/sup\[email protected], +48 585844820.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJovin TG, Li C, Wu L, Wu C, Chen J, Jiang C, et al. Trial of thrombectomy 6 to 24 hours after stroke due to basilar-artery occlusion. N Engl J Med. 2022;387(15):1373\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTao C, Nogueira RG, Zhu Y, Sun J, Han H, Yuan G, et al. Trial of endovascular treatment of acute basilar-artery occlusion. N Engl J Med. 2022;387(15):1361\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"ischemic stroke, intravenous thrombolysis, non-vitamin K antagonist oral anticoagulant, andexanet alfa, randomized trial","lastPublishedDoi":"10.21203/rs.3.rs-5288990/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5288990/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCardioembolic stroke accounts for more than 20% of all acute ischemic strokes (AIS) and is mainly caused by cardiac arrhythmias, particularly atrial fibrillation (AF). The presence of specific or multiple additional vascular risk factors indicates the need for oral anticoagulant (OAC) therapy in AF patients (according to the CHA2DS2-VASc classification). While OAC treatment significantly reduces the risk of AIS by over 80% in this population, the risk remains higher compared to the general population. Approximately half of AF patients on OAC therapy who experience AIS do not meet the criteria for thrombolytic (high blood activity of OAC) or mechanical thrombectomy (non-large vessel occlusion stroke) treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study aims to assess the efficacy and safety of recombinant tissue plasminogen activator (rtPA) in AIS patients who have been on chronic non-vitamin K antagonist oral anticoagulant (DOAC) therapy after receiving a specific reversal agent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods and design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with acute ischemic stroke (AIS) who are treated with specific oral anticoagulants (OACs) with anti-Xa activity ≥50 ng/ml and are not eligible for mechanical thrombectomy will be included in the study. The protocol involves administering a fast-acting antidote (andexanet alfa for rivaroxaban or apixaban) or a placebo, followed by intravenous thrombolytic therapy with rtPA or a placebo. The study arms for rivaroxaban and apixaban are designed as prospective, randomized, placebo-controlled interventional trials that meet phase II trial criteria.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe STRoke on Oral AntiCoagulants for Thrombolysis (STROACT) trial is the first randomized clinical trial investigating the impact of intravenous thrombolysis with rtPA in AIS patients on chronic DOAC therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ewww.clinicaltrialsregister.eu; EudraCT Nr: 2020-004898-41; March 31, 2021.\u003c/p\u003e","manuscriptTitle":"Reperfusion thrombolytic therapy for ischemic stroke in patients on non-vitamin K antagonist oral anticoagulants: study protocol of a phase II randomized clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-24 13:05:53","doi":"10.21203/rs.3.rs-5288990/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2026-03-20T15:14:43+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-09-19T05:59:52+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-16T07:54:14+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Trials","date":"2025-03-04T11:07:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-02-20T05:35:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-02-19T16:44:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6790a1f8-a9a5-4f9e-a373-32fb2ceb3637","owner":[],"postedDate":"September 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-31T21:54:24+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-24 13:05:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5288990","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5288990","identity":"rs-5288990","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}