A Multicentre, Prospective, Randomized, Open Label, Blinded-endpoint Trial to Optimize the Use of Intravenous Tenecteplase in Participants With Acute Ischemic Stroke (ACT-GLOBAL THROMBOLYSIS (ACT WHEN-001) Within A Multi-faCtorial, mulTi-arm, Multi-staGe, Randomised, gLOBal Adaptive pLatform Trial for Stroke (ACT-GLOBAL) NCT06352632
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 4,000
- 试验地点
- 24
- 主要终点
- A reduction of functional dependence analyzed across the whole distribution of outcomes assessed on the modified Rankin Scale (mRS),
研究概览
简要总结
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 48 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:
- In patients with recent (48 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.
- 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.
- 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).
- 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.
详细描述
Background and Rationale:
Tenecteplase has become the first choice of IVT for patients with AIS in hospitals around the world: its mechanisms of action are well characterized; the single bolus administration has important practical advantages over alteplase (0.9 mg/kg, max. 90 mg; with 10% of the dose given as a bolus followed by an infusion over 60 mins); trials indicate it has non-inferior efficacy as compared to alteplase, potential superiority among patients with large-vessel occlusion; and it is endorsed by national and international guidelines. While alteplase remains the only regulatory-approved IVT for the treatment of AIS in some countries with tenecteplase (0.25 mg/kg body weight) recently approved by the European Medical Agency, it is anticipated that this will continue to change over the next year. Current evidence indicates tenecteplase is as safe, and potentially more efficacious than alteplase in AIS.
Optimal tenecteplase dosing:
Doses of tenecteplase ranging from 0.1 to 0.4mg/kg were tested in clinical trials of acute stroke with a dose of tenecteplase 0.25 mg/kg body weight showing comparable efficacy to standard dose alteplase (0.9 mg/kg body weight). When compared to standard dose alteplase, the large ENCHANTED trial that enrolled 3000 patients suggested that 2/3rd standard dose alteplase has better safety, with similar efficacy rates but failed to show statistical non-inferiority. This lower dose of alteplase is used as standard care in many Asian countries. With results from the recently completed AcT trial showing similar efficacy and safety of tenecteplase (0.25 mg/kg body weight) vs. standard dose alteplase (0.9 mg/kg body weight), tenecteplase at 0.25 mg/kg body weight is becoming the new global standard for intravenous thrombolysis. Dosing studies with intravenous tenecteplase have however not tested efficacy and safety of low dose (2/3rd standard dose) tenecteplase, like in the ENCHANTED trial, in a broad population of acute stroke patients. A network meta-analysis of five clinical trials suggested better efficacy with intravenous tenecteplase at 0.25mg/kg with better safety at 0.1mg/kg, as compared to 0.4mg/kg, the only three doses on which such data is available. While the Canadian Stroke Best Practices, European Stroke Organization Guidelines and multiple national guidelines recommend an intravenous tenecteplase dose of 0.25mg/kg to a maximum of 25mg for acute stroke under 4.5 hours, there are certain scenarios where thrombolysis may carry a higher theoretical risk of hemorrhagic complications, warranting a more cautious approach with a lower dose tenecteplase (0.18 mg/kg). This lower dose of tenecteplase (midway between 0.25 mg/kg and 0.1 mg/kg and approximately 2/3rd standard dose tenecteplase) may potentially offer an optimal balance of efficacy and safety in many patient risk groups.
Recent ingestion of DOACs:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •All patients with disabling AIS presenting within 4.5 hours of symptom onset or last known well who may benefit from intravenous thrombolysis (IVT) with tenecteplase. Patients potentially eligible for IVT with conditions described as relative contraindications in national guidelines where physician discretion is recommended are eligible. Patients who received a DOAC, and those planned for emergency EVT are eligible.
- •Consent process completed as per national laws and regulation and the applicable ethics committee requirements.
排除标准
- •Any absolute contraindication for IV thrombolysis per current national guidelines. Examples include those who are actively bleeding, had recent intracranial surgery, head trauma, intracranial or subarachnoid hemorrhage, or a bleeding diathesis.
- •Minor stroke patients with non-disabling symptoms.
研究组 & 干预措施
2) IVT with tenecteplase at low-dose: 0.18 mg/kg
The intervention group will receive intravenous tenecteplase as a single bolus as per the standard manufacturers' instructions for use. The dose administered will be 0.18 mg/kg body weight (maximum dose 18 mg) over 10-20 seconds as soon as possible after randomization.
干预措施: Tenecteplase (Drug)
3) No IV thrombolysis [(only in those undergoing EVT or those on DOACs)
No intravenous tenecteplase only applied to subjects on DOACs over the last 24 hours or those planned for emergency EVT
干预措施: Tenecteplase (Drug)
结局指标
主要结局
A reduction of functional dependence analyzed across the whole distribution of outcomes assessed on the modified Rankin Scale (mRS),
时间窗: From enrollment to the Day 90 assessment - Day 90 outcomes are assessed in a blinded manner
Modified Rankin Scale (mRS) -which scores of 0 to 1 indicate a favourable outcome without or with symptoms but no disability, scores of 2 to 5 indicate increasing levels of disability (and dependency), and a score of 6 indicates death.
次要结局
- Proportion of participants with a Modified Rankin Scale (mRS) of 0-1 at Day 90.(Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner))
- 90-day mortality(From enrollment to the Day 90 assessment.)
- Symptomatic intracranial hemorrhage(Up to 36 hours from randomization)
- Large parenchymal hemorrhage (PH-2)(up to 36 hours from randomization)
- Imaging assessment (e.g., infarct size and edema volume)(Assessed and evaluated by the Central Imaging Core lab by blinded radiologists/stroke neurologists. These imaging readings will be performed over the course of the trial through study completion.)
- Summative total length of hospital stay in the first 90-days after stroke onset(Completed at the Day 90 follow-up visit.)
- Proportion of participants with a Modified Rankin Scale (mRS) of 0-2 at Day 90.(Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner))
- The frequencies of Serious Adverse Events (SAEs) from enrollment up to Day 4(From enrollment ( randomization) to the Day 4)
- Ordinal shift of 7 levels of mRS at 90 days(Done by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner))
- Ambulatory status at discharge(Completed the day the patient is discharged from hospital.)
- Place of residence at 90 days(Completed at the Day 90 follow-up visit)
- Health-related quality of life, as measured by the EQ-5D-5L at Day 90.(Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner))
- Proportion of participants achieving first pass (eTICI 2c or higher) reperfusion (when treated with EVT).(Assessed and evaluated after the EVT procedure by the Central Imaging Core lab by blinded radiologists/stroke neurologists-the imaging reading will be done over the course of the trial through study completion.)
- Proportion of participants achieving successful recanalization (revised arterial occlusive lesion [rAOL] score of 2b-3) at first angiographic acquisition (when treated with EVT).(Assessed and evaluated after the EVT procedure by the Central Imaging Core lab by blinded radiologists/stroke neurologists. These imaging readings will be done over the course of the trial through study completion.)
研究者
Dr. Bijoy Menon
MD
University of Calgary