ACT-GLOBAL THROMBOLYSIS (ACT-WHEN-001) Domain Within the ACT-GLOBAL Adaptive Platform Trial (ACT-WHEN)

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)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Ischemic Stroke AIS; Stroke, Acute, Stroke Ischemic; Stroke Acute
• Intervention / Treatment: Drug: Tenecteplase

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.

• Study Type: Interventional
• Enrollment (Estimated): 4000
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Bijoy K Menon, MD; Phone Number: 4039448107; Email: bkmmenon@ucalgary.ca
• Study Contact Backup: Name: Craig Anderson, MD; Phone Number: 4039448107; Email: canderson@georgeinstitute.org.au

Study Locations

• Australia
  • Barangaroo
    • Sydney, Barangaroo, Australia, NSW 2000
      • The George Institute for Global Health
      • Principal Investigator: Craig Anderson, MD
      • Contact: Xiaoying Chen, PHD; Email: xchen@georgeinstitute.org.au
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 1N4
      • University of Calgary
      • Principal Investigator: Michael D Hill, MD
      • Contact: Carol C Kenney, RN; Phone Number: 4039444286; Email: ckenney@ucalgary.ca
      • Contact: Michael D Hill, MD; Email: michael.hill@ucalgary.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Standard-dose intravenous tenecteplase (0.25 mg/kg body weight); The intervention group will receive intravenous tenecteplase as a single bolus as per the standard manufacturers' instructions for use. The dose administered will be 0.25 mg/kg body weight (maximum dose 25 mg) over 10-20 seconds as soon as possible after randomization.
Active Comparator: 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.	Drug: Tenecteplase; Thrombolytic; Other Names: TNKase; Metalyse
Active Comparator: 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	Drug: Tenecteplase; Thrombolytic; Other Names: TNKase; Metalyse

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
A reduction of functional dependence analyzed across the whole distribution of outcomes assessed on the modified Rankin Scale (mRS),	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.	From enrollment to the Day 90 assessment - Day 90 outcomes are assessed in a blinded manner

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
90-day mortality	Date and cause of death are collected from randomization until End of Study.	From enrollment to the Day 90 assessment.
Proportion of participants with a Modified Rankin Scale (mRS) of 0-1 at Day 90.	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.	Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner)
Proportion of participants with a Modified Rankin Scale (mRS) of 0-2 at Day 90.	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.	Completed by telephone at the Day 90 assessment (Day 90 outcomes are assessed in a blinded manner)
Health-related quality of life, as measured by the EQ-5D-5L at Day 90.	The EQ-5D-5L is a generic instrument for describing and valuing health. It is based on a descriptive system that defines health in terms of five dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has five response categories corresponding to: no problems, slight, moderate, severe and extreme problems. The version of the instrument selected for the trial is interviewer administered either in-person, or by telemedicine or by telephone. The respondents will also rate their overall health on the day of the interview on a 0-100 visual analogue scale (EQ-VAS).	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	Serious Adverse events include the following events :results in death, life threatening,Requires inpatient hospitalization or prolongation of existing hospitalization,Results in persistent disability/incapacity,Is a congenital anomaly/birth defect, an important medical event that may not result in death, be life-threatening, or require hospitalization, but may jeopardize the participant and may require medical or surgical intervention to prevent an outcome listed in the SAE selection.	From enrollment ( randomization) to the Day 4
Symptomatic intracranial hemorrhage	Any new intracranial hemorrhage detected by brain imaging associated with neuroligical worsening or deterioration of symptoms.	Up to 36 hours from randomization
Large parenchymal hemorrhage (PH-2)	PH-2:( hemorrhage grading scale) homogeneous hyperdensity occupying over 30% of the infarct zone, with significant mass effect	up to 36 hours from randomization
Ordinal shift of 7 levels of mRS at 90 days	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.	Done 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).	The thrombolysis in cerebral infarction (TICI) grading system was described in 2003 by Higashida et al. as a tool for determining the response of thrombolytic therapy for ischemic stroke. In neurointerventional radiology it is commonly used for patients post endovascular revascularization.	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).	The thrombolysis in cerebral infarction (TICI) grading system was described in 2003 by Higashida et al. as a tool for determining the response of thrombolytic therapy for ischemic stroke. In neurointerventional radiology it is commonly used for patients post endovascular revascularization.	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.
Ambulatory status at discharge	Assessing mobility of the patient at discharge	Completed the day the patient is discharged from hospital.
Place of residence at 90 days	Assessing the patient's residence at the Day 90 follow up. ( example: home,rehabilitation, long term care, remains hospitalized)	Completed at the Day 90 follow-up visit
Imaging assessment (e.g., infarct size and edema volume)	The total absolute infarct volume is the sum of infarct volumes calculated for each slice.	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	Calculating the total number of days the patient was hospitalized since their hospital admission.	Completed at the Day 90 follow-up visit.

Collaborators and Investigators

• Sponsor: University of Calgary
• Collaborators: The George Institute for Global Health, Australia
• Investigators: Principal Investigator: Bijoy K Menon, MD, University of Calgary; Principal Investigator: Craig Anderson, MD, The George Institute

Study record dates

Study Major Dates

• Study Start (Estimated): April 15, 2024
• Primary Completion (Estimated): September 30, 2030
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: February 5, 2024
• First Submitted That Met QC Criteria: March 12, 2024
• First Posted (Actual): March 20, 2024

Study Record Updates

• Last Update Posted (Actual): March 20, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Stroke; Thrombolysis; Endovascular thrombectomy; Tenecteplase; EVT; Platform; Domain
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke; Ischemia; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tenecteplase
• Other Study ID Numbers: ACT-WHEN-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Domain information and tabular trial results will be posted on the National Institutes of Health's website www.clinicaltrials.gov within one year of domain completion.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No