INTRA-ARTERIAL MeVO TREATMENT (IMP-ACT) Within the ACT-GLOBAL Adaptive Platform Trial-NCT06352632

Stroke, Acute Ischemic, Medium Vessel Occlusion

Intra-arterial thrombolysis, Mechanical Endovascular Thrombectomy, Angiography, Mevo, Tenecteplase, Alteplase, Platform, Domain, EVT

This domain will be conducted as part of ACT-GLOBAL platform trial and will have the nested domain name of IMP-ACT. Acute ischemic stroke (AIS) caused by intracranial arterial occlusion remains a major cause of disability and death. Medium vessel occlusion stroke (MeVO), involving distal medium-sized intracranial arteries, accounts for approximately 25-40% of all AIS cases. Despite best medical management, including intravenous thrombolysis, up to 40% of MeVO patients fail to regain functional independence, and mortality remains approximately 10%. These poor outcomes prompted several randomized trials evaluating endovascular thrombectomy (EVT) for MeVO stroke, including the CIHR-funded ESCAPE-MeVO trial. ESCAPE-MeVO, DISTAL, and DISCOUNT did not demonstrate overall benefit of EVT compared with best medical management, whereas ORIENTAL-MeVO reported benefit in an Asian population. These conflicting findings have resulted in uncertainty regarding optimal MeVO management and suggest that treatment benefit may depend on patient selection. A potential explanation for the neutral EVT trials is suboptimal reperfusion. In ESCAPE-MeVO, successful reperfusion was achieved in only 75% of patients, leaving substantial room for procedural improvement. At the same time, major procedural complications were infrequent, supporting the feasibility of exploring strategies to enhance reperfusion. Subgroup analyses from ESCAPE-MeVO suggested that treatment effect may vary according to time from symptom onset and collateral status. Patients treated early after stroke onset and those with favorable collaterals appeared to derive greater benefit from EVT than later presenters or patients with poor collateral circulation. These findings support a more targeted treatment approach in selected MeVO patients. Intra-arterial thrombolysis (IAT) has emerged as a promising adjunct to EVT. Local delivery of thrombolytic agents may dissolve residual distal thrombi that are inaccessible or unsafe to treat mechanically and may improve both macrovascular and microvascular reperfusion. Because thrombus burden is generally smaller in MeVO stroke, adjunctive IAT may be particularly effective in this population. However, no randomized trial has evaluated combined EVT and IAT for primary MeVO stroke. This study will address that evidence gap and determine whether adjunctive IAT can improve outcomes in carefully selected patients with MeVO stroke.

MeVO stroke is common and outcomes remain poor despite state-of-the-art treatment. Recent randomized trials identify a subgroup likely to benefit from EVT - patients with favourable collateral status treated early - and emerging evidence suggests that IAT can safely augment EVT reperfusion success. Equipoise in the stroke physician community has increased, and IMP-ACT shares common elements with other ACT-GLOBAL domains, allowing trial efficiency to be maximised and operational costs reduced by conducting the domain within the ACT-GLOBAL platform. This domain will be conducted as part of the ACT-GLOBAL adaptive platform trial and has the nested domain name IMP-ACT. It is a prospective, randomized, open-label, blinded-endpoint (PROBE), adaptive, phase 3, parallel-group, controlled trial. Up to 800 participants with acute ischemic stroke due to medium vessel occlusion will be enrolled globally. Male and female patients aged ≥18 years with acute ischemic stroke caused by a medium vessel occlusion (M2 or M3, A2 or A3, or P2 or P3 segment) confirmed on non-invasive neurovascular imaging, in whom the time from symptom onset (or last seen well) to randomization is ≤4.5 hours, with a baseline NIHSS score \>5, good or moderate collateral status, and limited early ischemic change (ASPECTS ≥9), who are clinically eligible for immediate EVT and IAT and in whom the occlusion has been assessed by the attending neurointerventionalist as safely accessible by endovascular means. Eligible patients are randomized to one of the following three arms: * Control arm: usual care - intravenous thrombolysis if eligible, plus usual stroke unit care. * Intervention arm 1: mechanical EVT, with tools and technique left to the discretion of the operator; intra-arterial thrombolytic drugs must not be administered. * Intervention arm 2: mechanical EVT followed by adjunctive intra-arterial thrombolysis - microcatheter injection of tenecteplase up to 0.0625 mg/kg (maximum 6.25 mg) or alteplase up to 0.225 mg/kg (maximum 22.5 mg) over 5-10 minutes from a proximal, safe microcatheter position in the affected arterial territory, with agent selected according to local availability. Randomization occurs immediately after baseline neuroimaging (NCCT/CTA), once clinical eligibility has been determined, via a centralized, secure, concealed, real-time web-based server, thereby ensuring allocation concealment. Participants are initially allocated 1:1:1. Once 150 participants have been enrolled, response-adaptive randomization (RAR) begins and allocation probabilities are updated with accumulating trial data at each adaptive interim analysis; enrolment to usual care will match the best-performing treatment arm. A minimal sufficient balance (covariate-adaptive) algorithm balances allocation by region, age, sex, baseline stroke severity (NIHSS), occlusion location, intravenous thrombolysis, time from last known well to randomization and calendar month. Treatment is open-label; blinding of enrolling staff is neither practical nor ethical in acute stroke, and sham endovascular procedures are not feasible. Endpoint assessment is blinded. EVT and IAT are one-time treatments administered on Day 1. The duration of an EVT procedure ranges from 20 minutes or less to 2 hours, with the majority completed within 90 minutes; IAT adds 5-10 minutes to the same angiographic procedure. Each participant is followed for one 90-day period and is hospitalized and treated according to current standard of care. At Day 30 and 90, a blinded qualified central assessor - with no access to treatment allocation, imaging information or safety data - contacts the participant for efficacy assessment. The end of the domain is defined as the date of last contact of the last participant at the Day 90 follow-up. Duration: Recruitment is expected to take 33 months. The End of Study Activity, defined as completion of data collection following the final follow-up visit of the last patient enrolled across all participating countries, will occur approximately 9 months after enrolment of the last patient. Visit 1 - Day 1 (Baseline): Eligibility, informed consent, demographics, medical history, frailty questionnaire, stroke-focused examination and stroke severity (NIHSS), weight, vital signs (blood pressure, heart rate, ECG), baseline imaging (non-contrast CT head and CTA arch-to-vertex, ± perfusion), baseline blood work, concomitant medications, randomization and administration of the allocated intervention (endovascular procedure or usual care - EVT, EVT + IAT or usual care), final MeVO-eTICI, and serious adverse event monitoring. Visit 2 - Day 2 (window 18-56 hours): Neurological assessment (NIHSS at 24 hours), ambulatory status, weight, laboratory (blood) tests, concomitant medications, stroke etiology, follow-up imaging including repeat CTA (arch to vertex), and serious adverse event monitoring. Follow-up imaging is used to assess infarct volume and hemorrhagic transformation; MRI (including at minimum axial DWI, FLAIR and a hemorrhage-sensitive sequence - gradient echo or susceptibility weighted imaging) is preferred and may be supplanted by non-contrast CT if MRI is unavailable. Follow-up imaging is considered a standard-of-care imaging procedure. Visit 3 - Day 4 (or discharge if earlier): Ambulatory status, stroke care, imaging (MR head), and continued serious adverse event monitoring. Neurovascular imaging beyond Day 2 is collected only when conducted as per standard of care. Visit 4 - Day 30 (window -5 to +5 days): Blinded central assessment of mRS (using the Rankin Focused Assessment tool) and EQ-5D-5L. Day 30 assessments are conducted by centralized telephone or online interview by central trial personnel blinded to treatment assignment and to treatment received; conventional blinded site-based personnel may undertake the assessment if necessary. Visit 5 - Day 90 (window -14 to +14 days): Blinded central assessment of the primary outcome (mRS using the Rankin Focused Assessment tool), EQ-5D-5L, COSMOS, ambulatory status and place of residence. Day 90 assessments are conducted by centralized telephone or online interview by central trial personnel blinded to treatment assignment and to treatment received; conventional blinded site-based personnel may undertake the assessment if necessary. Note: only serious adverse events are collected, from enrolment up to Day 4 (inclusive); simple adverse events are not collected.

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