Study Design and Duration:

This domain will be conducted as part of ACT-GLOBAL platform trial and will have the nested domain name of REACT. It has a prospective, randomised, controlled, open-label, parallel group with blinded endpoint assessment (PROBE) design of up to 1,500 subjects with Acute Ischemic Stroke (AIS) who undergo EVT. Randomisation will be stratified by country/ region, and the IA thrombolytic agent (tenecteplase or alteplase). Minimal sufficient balance algorithm will operate within each stratum to preserve balance on key covariates while maintaining allocation randomness.

Participants 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. Primary outcome data will be determined by simplified, structured method of assessment using the modified Rankin scale (mRS), conducted through centralized telephone interviews or online media performed by central trial personnel blinded to treatment assignment and received.

Domain Interventions:

The intervention group will receive a single dose of local intraarterial thrombolysis using either tenecteplase (at a dose of 0.0625mg/kg; maximum dose of 6.25mg) or alteplase (0.225 mg/kg; maximum dose, 20mg) at the end of EVT procedure plus standard of care while the control group will receive standard of care alone. The selection of the thrombolytic agent will be determined according to local availability. The dose of intraarterial thrombolysis will be increased if the above dose meets prespecified posterior probabilities at the first or second interims.

In all eligible patients:

1. Local intra-arterial thrombolysis using either tenecteplase at a dose of 0.0625mg/kg "maximum dose of 6.25mg" or alteplase "0.225 mg/kg; maximum dose, 20mg*

2. No intra-arterial thrombolysis.

   • The dose of IA thrombolysis may be doubled to 0.125 mg/kg tenecteplase or 0.45 mg/kg alteplase if this dose shows futility at pre-specified interims Randomization will be stratified by country/ region, the IA thrombolytic agent used (tenecteplase or alteplase). IA thrombolysis will be administered as a one-time treatment.

This is a domain within the ACT-GLOBAL platform trial to compare IA thrombolysis use (Yes vs No) following the completion of endovascular thrombectomy procedures among subjects who did not receive IV thrombolysis.

The key arguments for the proposed trial are:

• About 50% of patients treated with EVT are left with distal occlusions that cannot be reached with current devices. Even when reperfusion is considered complete, evidence suggests microthrombi persist in downstream cerebral circulation, contributing to poor outcomes.
• Other approved acute stroke treatments such as intravenous thrombolysis or antithrombotics do not address incomplete reperfusion. Approximately half of stroke patients treated with EVT are not concurrently or pre-treated with IV thrombolysis.
• Systemic antithrombotics used in conjunction with IV thrombolysis are unsafe or ineffective.
• Prospective cohorts and randomized controlled trials (RCTs) suggest that targeted intraarterial thrombolysis offered directly to the affected arterial territory is a promising approach to enhance reperfusion when thrombectomy with mechanical devices is complete. Recent meta-analyses from small pilot studies suggest safety of this approach.
• Recent RCTs showed mixed results but with overall potentially better clinical outcomes with intraarterial thrombolysis using either tenecteplase or alteplase.
• A high quality, large, pragmatic, and globally representative confirmatory trial is needed to generate definitive evidence and inform clinical practice on the safety and benefit of IA thrombolysis.

Modern endovascular thrombectomy (EVT) offered using mechanical devices like stent-retrievers and aspiration catheters has revolutionized acute stroke therapy and improved outcomes. Still, a significant gap exists between EVT procedural success and clinical recovery in patients with large vessel occlusion stroke. Less than half of patients receiving EVT achieve functional independence (modified Rankin Scale "mRS" 0-2) despite medical care and rehabilitation. Moreover, ~15% of all EVT procedures fail with subsequent dismal outcomes. Incomplete reperfusion is a major reason that explains why many patients fail to recover fully after thrombectomy. This phenomenon occurs either because of clot fragments that lodge in distal arteries (micro-embolization), or because of in-situ thrombus formation in the micro-circulation. These occlusions are too distal for current devices to reach. However, they can be reached in a targeted manner by administering chemical thrombolysis directly into target areas through catheters lodged in large arteries.

While the incidence and consequences of macrocirculatory obstruction are well-described, microcirculatory obstruction (also called no-reflow) has not been extensively studied in stroke. Nonetheless, it has been reported in 25% of patients post successful EVT with associated higher odds of infarct growth, and poor functional outcomes including death. In an imaging sub study of the CHOICE phase II RCT (comparing local intraarterial "IA" alteplase vs placebo following successful thrombectomy), 58% of patients enrolled to the control arm demonstrated persistent hypoperfusion on MRI at 48 hours after successful EVT. This hypoperfusion was postulated to result from microcirculatory obstruction and was associated with poor outcomes.

Intravenous thrombolysis given prior to EVT may have some effect on lysing downstream thrombi once endovascular recanalization is achieved. However, around half of EVT-treated patients do not receive IV thrombolysis due to contraindications or presenting outside IV thrombolysis treatment window. In addition, the short half-life of IV thrombolytic agents (plasma elimination half-life of ~ 3.5 minutes for alteplase and ~20 minutes for tenecteplase) means that they may not have any effect on thrombi that persist after EVT is completed. In a study of 1303 patients from the German stroke registry, patients in whom the IV alteplase infusion was still ongoing at the end of EVT had higher odds of achieving excellent recovery compared to those who completed the infusion prior to EVT completion. Recent RCTs exploring antithrombotics agents to enhance reperfusion either showed harm (IV ASA ( acetylsalicylic acid) with or without IV heparin) or lack of benefit (IV tirofiban).

Targeted intra-arterial (IA) thrombolysis is a promising adjunct therapy that can be offered to enhance reperfusion immediately after EVT. Thrombolysis administered directly in the affected vascular bed maximizes the fibrinolytic effect on the local cerebral circulation while reducing systemic uptake and side effects. Different thrombolytic agents have been used for IA stroke therapy. However, meta-analyses suggest low quality evidence of available studies given their observational nature and restrictive selection criteria. In one meta-analysis of five observational studies (n=269 patients), there was a suggestion of better functional independence with intraarterial alteplase or urokinase over controls (OR: 1.34; 95% CI: 1.00 to 1.80) without increased risk of symptomatic hemorrhage or death. In the INFINITY registry conducted in 10 European centers, IA alteplase was associated with improved reperfusion in 50% of patients who achieved incomplete reperfusion after EVT. The phase II RCT (CHOICE, n=121 subjects) of IA alteplase after successful EVT at a dose equivalent to 25% of the maximum IV alteplase dosing showed the safety and efficacy of this approach. This trial was stopped prematurely due to placebo supply constraints. Still, it showed an absolute risk difference of 18.4% (95%CI 0.3%-36.4%; P=0.047) in excellent outcome (mRS 0-1) favouring IA alteplase, without increased risk of symptomatic intracranial haemorrhage. In an imaging sub study of the trial, 58% of patients enrolled to the control arm demonstrated persistent hypoperfusion on MRI despite angiographically successful EVT. These results need to be interpreted with caution however given small sample size and premature closure of study. A phase III RCT (PEARL, n=324 subjects) with a similar design and IA alteplase dosing as CHOICE was presented recently (unpublished) and showed improved mRS 0-1 in the treatment arm compared to controls with an absolute risk difference of 15% (95%CI 3.7%-26.3%; P=0.01).

Tenecteplase is a promising agent for IA thrombolysis. It has superior pharmacokinetic properties over alteplase including its longer half-life (~20 minutes), and greater fibrin specificity. Our large CIHR (Canadian Institute of Health Research) funded AcT (Alteplase compared to Tenecteplase) RCT (n=1600 subjects) demonstrated the non-inferiority and comparable safety of IV tenecteplase (0.25 mg/kg) vs. alteplase for all ischemic stroke patients eligible for IV thrombolysis. In 520 patients treated with EVT in AcT, there was a suggestion of better recanalization with tenecteplase and similar safety. The EXTENDIA-TNK trial showed superior recanalization and better outcomes among patients treated with IV tenecteplase vs those treated with IV alteplase. Therefore, tenecteplase is now the standard for IV thrombolysis in acute ischemic stroke. The current Canadian Best Practice guidelines recommend tenecteplase as an alternative to alteplase in all eligible stroke patients. Tenecteplase can be administered intraarterially and may help reperfuse the brain better than but as safe as IA alteplase. While two prior RCTs using IA tenecteplase in patients with anterior circulation (POST-TNK, n=540 subjects), and posterior circulation (ATTENTION, N=208 subjects) strokes following endovascular reperfusion showed neutral results, a recent phase III RCT of IA tenecteplase in anterior circulation stroke patients following endovascular reperfusion showed positive results. The ANGEL-TNK trial (n= 255 subjects) was recently presented and showed that patients treated with IA tenecteplase at a dose equivalent to 50% of the IV tenecteplase dose had better 90-day mRS 0-1 compared to controls (40.5% vs 26.4%, OR 1.4, 95%CI 1.1 to 2) without safety concerns.

While these results suggest a potential benefit of IA thrombolysis following thrombectomy, the heterogeneity of existing trials, their narrow geographic scope (conducted primarily in China or Spain), and the inconsistent benefit across key functional outcomes (e.g., improvement in mRS 0-1 but not mRS 0-2 or ordinal shift) underscore the necessity for a globally representative, large-scale, pragmatic confirmatory trial to provide definitive evidence and guide clinical practice.

Domain Rationale:

The key arguments for the proposed trial are:

• About 50% of patients treated with EVT are left with distal occlusions that cannot be reached with current devices. Even when reperfusion is considered complete, evidence suggests microthrombi persist in downstream cerebral circulation, contributing to poor outcomes.
• Other approved acute stroke treatments such as intravenous thrombolysis or antithrombotics do not address incomplete reperfusion. Approximately half of stroke patients treated with EVT are not concurrently or pre-treated with IV thrombolysis.
• Systemic antithrombotics used in conjunction with IV thrombolysis are unsafe or ineffective.
• Prospective cohorts and randomized controlled trials (RCTs) suggest that targeted intraarterial thrombolysis offered directly to the affected arterial territory is a promising approach to enhance reperfusion when thrombectomy with mechanical devices is complete. Recent meta-analyses suggest safety of this approach.
• Recent RCTs showed mixed results but with overall potentially better clinical outcomes with intraarterial thrombolysis using either tenecteplase or alteplase. The combination of IV thrombolysis plus IA thrombolysis did not result in safety concerns.
• A high quality, large, pragmatic, and globally representative confirmatory trial is needed to generate definitive evidence and inform clinical practice on the safety and benefit of IA thrombolysis.

DOMAIN AIMS AND OBJECTIVES

This domain aim is to efficiently, reliably, and simultaneously, determine the effectiveness of targeted intraarterial (IA) thrombolysis using either tenecteplase at a dose of 0.0625mg/kg (maximum dose of 6.25mg) or alteplase (0.225 mg/kg; maximum dose, 20mg) vs. no IA thrombolysis in all patients who undergo EVT. For participants allocated to the IA thrombolysis arm, the selection of thrombolytic agent (tenecteplase or alteplase) will be determined according to local availability.

This domain of the ACT-GLOBAL platform is designed in such a way that the accrued data could be used to design and then ask a future research question on IA thrombolysis in a pertinent subgroup of patients

Inclusion Criteria:

1. Age ≥18 years
2. Clinical diagnosis of stroke

Exclusion Criteria:

There are no platform level exclusion criteria.

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.

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.