protocolSection identificationModule nctId: NCT06320431, orgStudyIdInfo id: ACT-WHEN-001, briefTitle: ACT-GLOBAL THROMBOLYSIS (ACT-WHEN-001) Domain Within the ACT-GLOBAL Adaptive Platform Trial-NCT06352632, acronym: ACT-WHEN, statusModule overallStatus: NOT_YET_RECRUITING, startDateStruct date: 2024-04-15, primaryCompletionDateStruct date: 2030-09-30, completionDateStruct date: 2030-12-31, studyFirstPostDateStruct date: 2024-03-20, lastUpdatePostDateStruct date: 2024-04-25, sponsorCollaboratorsModule leadSponsor name: University of Calgary, class: OTHER, collaborators name: The George Institute for Global Health, Australia, descriptionModule briefSummary: This domain has a prospective, randomized, controlled, open-label, parallel group with blinded endpoint assessment (PROBE) design. Up to 4,000 patients with presumed acute ischemic stroke (AIS) will be followed for 90 days (or until death, if prior to 90 days). The end of the trial is defined as the date that all participants have completed their Day 90 assessment.This domain aim is to efficiently, reliably, and simultaneously, determine the comparative effectiveness of intravenous thrombolysis (IVT) using standard-dose intravenous tenecteplase (0.25 mg/kg body weight), vs. low-dose intravenous tenecteplase (0.18 mg/kg body weight) in all patients who present to hospital with acute ischemic stroke and are considered for intravenous thrombolysis. In addition, this domain also seeks to study standard-dose intravenous tenecteplase (0.25 mg/kg body weight), vs. low-dose intravenous tenecteplase (0.18 mg/kg body weight) vs. no TNK upfront with rescue IA TNK if necessary (in those eligible for emergency EVT) and no TNK upfront in those who have taken DOACs during the preceding 24 hours. This domain therefore seeks to generate more robust randomized evidence to guide clinicians in their decisions over the balance of risks and treatment with intravenous thrombolysis with tenecteplase wherever such evidence is currently insufficient.This domain will currently evaluate four research questions in relation to the use of IVT with tenecteplase:1. In patients with recent (24 hours) intake of a standard-dose direct oral anticoagulant (DOAC), how should IVT be used? - Use standard-dose (0.25 mg/kg body weight) or low-dose tenecteplase (0.18 mg/kg) or not at all.2. In patients planned to be treated with endovascular thrombectomy, how should tenecteplase be used? -Treat with IV tenecteplase (standard- or low-dose) or not at all.3. In any patient receiving IVT, what is the optimal dose of tenecteplase? - use standard-dose (0.25 mg/kg body weight) or low-dose tenecteplase (0.18 mg/kg).4. To what extent is the treatment effect of standard- vs. low-dose tenecteplase modified by key patient characteristics, such as diabetes, prior antiplatelet therapy, renal failure, or frailty, old age or having a heavy burden of cerebral small vessel disease on brain imaging., conditionsModule conditions: Acute Ischemic Stroke AIS, conditions: Stroke Acute, conditions: Stroke, Acute, Stroke Ischemic, designModule studyType: INTERVENTIONAL, phases: PHASE3, designInfo allocation: RANDOMIZED, interventionModel: PARALLEL, interventionModelDescription: Randomization will be stratified by: (1) planned emergency endovascular thrombectomy (EVT) and (2) known use or history to suggest use of a standard-dose direct oral anticoagulant (DOAC) within the last 24 hours. Randomization will be centralized, secure and concealed, using a web-based server and permuted blocks of varying sizes will be used.This will result in four pre-defined strata: (i) EVT+ / DOAC+ (ii) EVT+ / DOAC- (iii) EVT- / DOAC+ and (iv) EVT- / DOAC-.Patients in strata 1, 2 and 3 will be randomized to standard-dose IV tenecteplase (0.25 mg/kg body weight) vs. Low-dose tenecteplase (0.18 mg/kg body weight) or no IV thrombolysis (1:1:1 randomization). Patients in strata 4 will be randomized to standard-dose intravenous (IV) tenecteplase (0.25 mg/kg body weight) vs. Low-dose IV tenecteplase (0.18 mg/kg body weight) only (1:1 randomization).Emergency EVT is defined as anticipated arterial puncture time in the enrolling hospital ≤ 60 minutes from randomization., primaryPurpose: TREATMENT, maskingInfo masking: SINGLE, maskingDescription: The trial will have allocation concealment and blinded endpoint assessment, but open-label treatment. Given the time sensitive nature of acute stroke treatment, blinding the enrolling personnel to treatment assignment is not practical. Clinical site staff, including the Principal Investigator (PI), sub-investigators, clinic site staff, and the Sponsor will not be blinded to treatment allocated or received. In the event of an emergency the PI will be already unblinded.The trial will have blinded endpoint assessment on Day 90, with central blinded assessors contacting the participants., whoMasked: OUTCOMES_ASSESSOR, enrollmentInfo count: 4000, type: ESTIMATED, armsInterventionsModule interventions name: Tenecteplase, outcomesModule primaryOutcomes measure: A reduction of functional dependence analyzed across the whole distribution of outcomes assessed on the modified Rankin Scale (mRS),, secondaryOutcomes measure: 90-day mortality, secondaryOutcomes measure: Proportion of participants with a Modified Rankin Scale (mRS) of 0-1 at Day 90., secondaryOutcomes measure: Proportion of participants with a Modified Rankin Scale (mRS) of 0-2 at Day 90., secondaryOutcomes measure: Health-related quality of life, as measured by the EQ-5D-5L at Day 90., secondaryOutcomes measure: The frequencies of Serious Adverse Events (SAEs) from enrollment up to Day 4, secondaryOutcomes measure: Symptomatic intracranial hemorrhage, secondaryOutcomes measure: Large parenchymal hemorrhage (PH-2), secondaryOutcomes measure: Ordinal shift of 7 levels of mRS at 90 days, secondaryOutcomes measure: Proportion of participants achieving first pass (eTICI 2c or higher) reperfusion (when treated with EVT)., secondaryOutcomes measure: Proportion of participants achieving successful recanalization (revised arterial occlusive lesion [rAOL] score of 2b-3) at first angiographic acquisition (when treated with EVT)., secondaryOutcomes measure: Ambulatory status at discharge, secondaryOutcomes measure: Place of residence at 90 days, secondaryOutcomes measure: Imaging assessment (e.g., infarct size and edema volume), secondaryOutcomes measure: Summative total length of hospital stay in the first 90-days after stroke onset, eligibilityModule sex: ALL, minimumAge: 18 Years, stdAges: ADULT, stdAges: OLDER_ADULT, contactsLocationsModule locations facility: The George Institute for Global Health, city: Sydney, state: Barangaroo, zip: NSW 2000, country: Australia, contacts name: Xiaoying Chen, PHD, role: CONTACT, email: xchen@georgeinstitute.org.au, contacts name: Craig Anderson, MD, role: PRINCIPAL_INVESTIGATOR, geoPoint lat: -33.86785, lon: 151.20732, locations facility: University of Calgary, city: Calgary, state: Alberta, zip: T2N 1N4, country: Canada, contacts name: Carol C Kenney, RN, role: CONTACT, phone: 4039444286, email: ckenney@ucalgary.ca, contacts name: Michael D Hill, MD, role: CONTACT, email: michael.hill@ucalgary.ca, contacts name: Michael D Hill, MD, role: PRINCIPAL_INVESTIGATOR, geoPoint lat: 51.05011, lon: -114.08529, hasResults: False