Clinical trial NCT06320431: ACT-GLOBAL THROMBOLYSIS (ACT-WHEN-001) Domain Within the ACT-GLOBAL Adaptive Platform Trial-NCT06352632
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Acute Ischemic Stroke AIS
Stroke Acute
Stroke, Acute, Stroke Ischemic
Keywords: Stroke
Thrombolysis
Platform
Tenecteplase
Endovascular thrombectomy
EVT
Domain
Lead sponsor: University of Calgary
Sponsor class: OTHER
Collaborators: name: The George Institute for Global Health, Australia
First posted: 2024-03-20
Enrollment: 4000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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:

This is now one of the most frequent reasons why IVT is not administered, being present in \~6% of all patients presenting with AIS. The large prospective multi-site national Swiss Stroke Registry conducted in 2014-2019 indicates that of all patients with AIS and known atrial fibrillation (AF) who were potentially eligible for IVT, 466 (18%) were on a DOAC and 247 (9.5%) were on prior warfarin anticoagulation, and the number and age of patients, and indications for DOAC use, has rapidly increased over time. Separately, a recently published large international registry and a meta-analysis of other observational studies show that prior intake of DOACs within 48 hours of alteplase is not associated with an increased risk of ICH. No study until now, has compared IVT with tenecteplase standard-dose vs. low-dose tenecteplase vs. no tenecteplase in a randomized manner in these patients.

EVT eligibility:

EVT is the biggest advance in AIS treatment in the last decade, used in patients with target intracranial occlusions typically in proximal large-vessels of the cerebral circulation. Reperfusion rates as high as 90% are achieved in such patients, with the number-needed-to-treat to achieve improved outcomes being as low as 2.6. Reperfusion rates continue to improve with better technology, techniques, and operator experience. Conversely, data indicate lower rates of recanalization with IVT where there are large-vessel occlusions (a third of the EVT rates and at a later time), raising concerns over the utility of IVT in these patients. A meta-analysis of recent data concluded EVT alone is non-inferior to IVT with standard-dose alteplase followed by EVT; with the lower boundary of the 95% confidence interval (CI) being -2%;34 and rates of symptomatic intracerebral hemorrhage were 1% higher in patients offered IVT+EVT vs. EVT alone. The recent IRIS collaboration patient level meta-analysis did not however establish the non-inferiority of EVT alone compared with IVT (with alteplase) plus EVT in patients presenting directly at EVT centers. No study has compared IVT with tenecteplase before EVT vs. EVT alone (with rescue IA tenecteplase if EVT fails), nor of standard-dose vs. low-dose tenecteplase, in these patients. Our survey shows physicians persist in their uncertainty over how and when to use thrombolysis with tenecteplase in EVT-eligible patients.

The elderly, frail and those with comorbidities:

Age is one of the most important prognostic factors for outcomes in AIS. Multiple studies have shown that older age is associated with poor outcome and an increased risk of ICH with IVT. Underlying conditions such as renal failure, diabetes, cerebral small vessel disease, and remote cerebral infarcts, which increase the risks of ICH, are more frequently detected with modern brain imaging and are more common in the elderly. However, the elderly have often been excluded from acute stroke trials, such as in the original NINDS trial of alteplase where only 69 subjects over the age of 80 years were included, and similar figures in the subsequent ECASS III trial that sought to establish the efficacy of IVT in the 3-4.5-hour time window. Most of the randomized data for IVT in this age group have come from the IST-3 trial, which included 1,711 elderly patients; the rest of the data on the effectiveness of IVT in the elderly comes from registry studies (e.g. SITS, VISTA and SPOTRIAS), all on alteplase. In the ENCHANTED and AcT trials, there was no significant heterogeneity in the treatment effect by age. Although guidelines recommend the use of IVT in the elderly, they qualify this with caution over the risks of ICH and assign lower grades of evidence on efficacy in patients presenting late from symptom onset. A lower dose of tenecteplase could offer a safer and potentially more effective strategy in the elderly with AIS.

Patients with sub-acute looking infarcts, small intraarterial thrombi or no visible occlusions on baseline imaging:

Modern stroke imaging techniques are better able to characterize risk of ICH with IVT as compared to clinical judgement alone. Sub-acute looking infarcts (regions of the brain with moderate to severe hypoattenuation on non-contrast CT) can be seen early after stroke onset and signify severe ischemia. They are associated with higher risk of ICH; other studies show that benefit of IVT remains even with this higher ICH risk. Patients with small intra-arterial thrombi recanalize better with IVT than those with larger thrombi. In the ENCHANTED trial, patients with small or no visible occlusions on CT Angiography did better with low-dose vs. standard-dose alteplase. In subgroup analyses of the IST-3 trial, patients with no visible occlusions on baseline CT or MR angiography fared worst with standard-dose alteplase than when treated conservatively. There are no studies that assess risks and benefits of thrombolysis with tenecteplase (standard vs. low dose tenecteplase) when imaging assessed risks are potentially high or when thrombus burden itself is low.

Patients with dementia:

Although dementia itself is not a contraindication for IVT in patients presenting with acute ischemic stroke, these patients have not been included in most clinical trials on thrombolysis because dementia may confound neurological assessments, or their prognosis is so poor that discriminating a treatment effect would not be possible. Moreover, common conditions causally related to dementia include previous strokes and microbleeds associated with amyloid angiopathy, thus raising concerns about risk of ICH with thrombolysis. A propensity score matched analysis of data from the registry of the Canadian Stroke Network showed no differences between those with and without dementia in the risk of intracerebral hemorrhage, in mortality or in disability at discharge when administered IVT. In the Nationwide Inpatient Sample study however, dementia was associated with increased risk of symptomatic ICH in patients administered IVT. Randomized data on optimal dose of IVT with tenecteplase, especially in the context of pre-existing dementia/cognitive impairment is lacking.

Other patient groups:

There are many other patient groups where evidence gaps exist, guidelines offer some recommendations regarding IVT, but physicians continue to have uncertainties. These include those with high blood sugar or blood pressure at presentation, those with pre-existing severe renal dysfunction or those with functional disabilities. Some of these conditions are more prevalent than others; some patients have more than one of these conditions. With many of these patients, physician uncertainties vary around the degree/extent of these conditions and not just their presence or absence. Race and ethnic differences have also been noted with risk of ICH post IVT. Blacks and Asians likely have higher risk of ICH than Hispanics and Whites. Sex differences exist with women being offered less IVT (10% less than men in some studies) even after adjusting for all other variables.

Data from a large adaptive randomized clinical trial on thrombolysis dose and safety with tenecteplase, in the various patient conditions described above, will increase physician confidence and potentially result in better and faster utilization of intravenous thrombolysis, thus helping improve patient outcomes overall.

Eligibility criteria: Inclusion Criteria:

1. 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.
2. Consent process completed as per national laws and regulation and the applicable ethics committee requirements.

Exclusion Criteria:

1. 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.
2. Minor stroke patients with non-disabling symptoms.

Primary outcomes:
measure: A reduction of functional dependence analyzed across the whole distribution of outcomes assessed on the modified Rankin Scale (mRS),
timeFrame: From enrollment to the Day 90 assessment - Day 90 outcomes are assessed in a blinded manner
Secondary outcomes:
measure: 90-day mortality
timeFrame: From enrollment to the Day 90 assessment.
measure: Proportion of participants with a Modified Rankin Scale (mRS) of 0-1 at Day 90.
timeFrame: Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner)
measure: Proportion of participants with a Modified Rankin Scale (mRS) of 0-2 at Day 90.
timeFrame: Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner)
measure: Health-related quality of life, as measured by the EQ-5D-5L at Day 90.
timeFrame: Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner)
measure: The frequencies of Serious Adverse Events (SAEs) from enrollment up to Day 4
timeFrame: From enrollment ( randomization) to the Day 4
measure: Symptomatic intracranial hemorrhage
timeFrame: Up to 36 hours from randomization
measure: Large parenchymal hemorrhage (PH-2)
timeFrame: up to 36 hours from randomization
measure: Ordinal shift of 7 levels of mRS at 90 days
timeFrame: Done by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner)
measure: Proportion of participants achieving first pass (eTICI 2c or higher) reperfusion (when treated with EVT).
timeFrame: 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.
measure: Proportion of participants achieving successful recanalization (revised arterial occlusive lesion [rAOL] score of 2b-3) at first angiographic acquisition (when treated with EVT).
timeFrame: 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.
measure: Ambulatory status at discharge
timeFrame: Completed the day the patient is discharged from hospital.
measure: Place of residence at 90 days
timeFrame: Completed at the Day 90 follow-up visit
measure: Imaging assessment (e.g., infarct size and edema volume)
timeFrame: 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.
measure: Summative total length of hospital stay in the first 90-days after stroke onset
timeFrame: Completed at the Day 90 follow-up visit.
Other outcomes:
Locations:
city: Sydney
country: Australia
facility: The George Institute for Global Health
state: Barangaroo
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: A
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
city: Ottawa
country: Canada
facility: University of Ottawa
state: Ontario
Study officials:
affiliation: University of Calgary
name: Bijoy K Menon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The George Institute
name: Craig Anderson, MD
role: PRINCIPAL_INVESTIGATOR
References: