МНОГОФАКТОРИАЛЬНОЕ, МНОГОРУЧНОЕ, МНОГОЭТАПНОЕ, рандомизированное, ГЛОБАЛЬНОЕ АДАПТИВНОЕ ПЛАТФОРМНОЕ ИССЛЕДОВАНИЕ Инсульта

This domain has a prospective, randomized, controlled, open-label, parallel group with blinded endpoint assessment (PROBE) design to optimize the use of intravenous Tenecteplase in participants with Acute Ischemic Stroke.

Standard-dose intravenous tenecteplase (0.25 mg/kg body weight); one-time IV bolus injection soon after randomisation

Low-dose intravenous tenecteplase (0.18 mg/kg body weight); one-time IV bolus injection soon after randomisation

No intravenous tenecteplase only in subjects on direct oral anticoagulant (DOACs) or those planned for emergency endovascular thrombectomy (EVT)

Third Enhanced Control of Hypertension and Thrombectomy Stroke Study (ENCHANTED3/MT) as a domain of ACT-GLOBAL to compare three BP lowering management strategies, that of conservative, moderate and intensive BP lowering in patients with Acute Ischaemic Stroke admitted to participating hospitals who has an elevated SBP after reperfusion therapy via Endovascular Thrombectomy, and reliably determine, which approach leads to improved functional outcome.

Locally available and approved i.v. BP lowering agents can be used in this domain.

No or minimal Systolic Blood Pressure (SBP) control; SBP reduction by 5-10mmHg or a target of 175-180mmHg if very-high baseline SBP (≥180mmHg); the timing of administration of interventions is specified to be immediately after randomisation; the intervention target is to be achieved ideally at 1 hour after randomisation and maintained for 24 hours (or until hospital discharge or death if this should occur earlier)

SBP reduction by 10-20mmHg or a target of 160 ± 5, whichever is higher; no control if low-high baseline SBP (150-160mmHg); the timing of administration of interventions is specified to be immediately after randomisation; the intervention target is to be achieved ideally at 1 hour after randomisation and maintained for 24 hours (or until hospital discharge or death if this should occur earlier)

SBP reduction by 30-50mmHg or a target of 140±5 mmHg, whichever is higher after endovascular thrombectomy (EVT); the timing of administration of interventions is specified to be immediately after randomisation; the intervention target is to be achieved ideally at 1 hour after randomisation and maintained for 24 hours (or until hospital discharge or death if this should occur earlier)

This domain has a Phase 2b, multicenter, prospective, randomized, open label, blinded-endpoint (PROBE) controlled single-dose adaptive design and aim to determine the efficacy and safety of NoNO-42 in participants with Acute Ischaemic Stroke selected for thrombolysis with or without Endovascular Thrombectomy.

100 mL of 0.9% normal saline, administered as a single IV infusion with a 20-minute dosing duration.

NoNO-42 at weight-based dosing - 2.6 mg/Kg, administered as a single IV infusion with a 20-minute dosing duration

This is a domain within the Intracerebral Haemorrhage State of the ACT-GLOBAL adaptive platform trial for stroke.

The objective of this domain is to determine the efficacy of intravenous deferoxamine and low-dose oral colchicine, both individually and in combination, compared to standard of care alone, on improving functional outcome in patients with acute spontaneous supratentorial ICH.

No deferoxamine mesylate and no colchicine

Deferoxamine mesylate at a dose of 32mg/kg/day via intravenous infusion immediately (within 1 hour) and continued for 2 consecutive days

0.5mg of oral colchicine daily for 30 days

Deferoxamine mesylate at a dose of 32mg/kg/day via intravenous infusion immediately (within 1 hour) and continued for 2 consecutive days; plus 0.5mg of oral colchicine daily for 30 consecutive days

This domain will be conducted as part of ACT-GLOBAL platform trial and will have the nested domain name of REACT. This domain aims to efficiently, reliably, and simultaneously, determine the effectiveness of targeted intraarterial (IA) thrombolysis using either tenecteplase or alteplase vs. no IA thrombolysis in all patients who undergo EVT. It has a prospective, randomised, controlled, open-label, parallel group with blinded endpoint assessment (PROBE) design of up to 1,500 subjects with 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.

The duration of follow-up is 90 days. Primary outcome will be mRS, conducted through centralized telephone interviews or online media performed by central trial personnel blinded treatment assignment and received.

Participants randomised to the IA thrombolysis group will receive IA thrombolysis (tenecteplase or alteplase) at the time of completion of the mechanical thrombectomy part of the EVT procedure. Tenecteplase will be given at a dose of 0.0625mg/kg (maximum dose of 6.25mg) and alteplase at a dose of 0.225 mg/kg (maximum dose 22.5mg) intraarterially by the treating neuro-interventional staff. The selection of thrombolytic agent will be determined according to local availability.

The study drug dose will be increased to 0.125 mg/ kg (maximum dose 12.5mg) for tenecteplase or 0.45 mg/kg (maximum dose 40mg) for alteplase if above dose meet prespecified posterior probabilities at the first or second interims per adaptive design report.

Participants randomised to the No IA thrombolysis group will not receive IA thrombolysis.

This is a randomized, open-label, blinded-endpoint, phase 3 domain within the Acute Ischemic Stroke State. Up to 800 adults with stroke due to medium-vessel occlusion are randomized to usual care, mechanical endovascular thrombectomy (EVT) without intra-arterial (IA) thrombolysis, or mechanical EVT followed by adjunctive IA thrombolysis with tenecteplase or alteplase. Usual medical and stroke-unit care is provided in all groups; intravenous thrombolysis may be given when eligible. Participants are followed for 90 days. Treatment details are specified in the IMP-ACT domain registration (NCT07906275).

Usual medical and stroke-unit care, including intravenous thrombolysis when eligible. This is the usual-care strategy in IMP-ACT (NCT07906275), without assigned mechanical endovascular thrombectomy or adjunctive intra-arterial thrombolysis.

Mechanical endovascular thrombectomy (EVT) using tools and techniques selected by the treating neurointerventionalist. This procedure is used in both EVT strategies in IMP-ACT (NCT07906275); the EVT-alone strategy does not include intra-arterial thrombolysis.

Adjunctive intra-arterial tenecteplase or alteplase delivered by microcatheter into the affected arterial territory following mechanical endovascular thrombectomy. The agent is selected according to local availability. This intervention is used only in the EVT-plus-intra-arterial-thrombolysis strategy. Regimen details are specified in the IMP-ACT domain registration (NCT07906275).

CoPRIME is a planned phase 2a, multicentre, randomized, open-label, blinded-endpoint safety and feasibility domain within the Secondary Prevention State of ACT-GLOBAL. It will enrol 300 eligible adults with non-cardioembolic acute ischemic stroke treated with intravenous thrombolysis and/or endovascular thrombectomy. Eligible participants are randomized 1:1:1 within 30 hours after the end of acute reperfusion therapy, after a post-reperfusion non-contrast CT and with NIHSS <=10 at randomization, to aspirin alone, aspirin plus clopidogrel, or aspirin plus ticagrelor for 21 days. Study treatment starts within 60 minutes of randomization, and participants are followed for 90 days. As of 5 November 2026, the updated protocol has been submitted to Health Canada; the domain remains in the planning phase, with no enrolment under the updated protocol. Domain registration: NCT07844603.

Aspirin 160 mg on day 1, followed by 81 mg once daily on days 2-21. Study treatment starts within 60 minutes of randomization. This is the aspirin-alone strategy in CoPRIME.

Aspirin 160 mg plus clopidogrel 300 mg on day 1, followed by aspirin 81 mg once daily plus clopidogrel 75 mg once daily on days 2-21. Study treatment starts within 60 minutes of randomization. This is the aspirin-plus-clopidogrel strategy in CoPRIME.

Aspirin 160 mg plus ticagrelor 180 mg on day 1, followed by aspirin 81 mg once daily plus ticagrelor 90 mg twice daily on days 2-21. Study treatment starts within 60 minutes of randomization. This is the aspirin-plus-ticagrelor strategy in CoPRIME.

The mRS is a 7-outcome ordered categorical scale that assesses functional neurological status after stroke. It is not intended for use as a measure of historical functional status. It is well accepted as a standard outcome around the world in the stroke community, by patients and by regulatory authorities. The seven values and the clinical summary of the individual scores are summarized in the following:

0 = No symptoms

1. = No significant disability; able to carry out all usual activities
2. = Slight disability; can look after own affairs, but unable to carry out all previous activities
3. = Moderate disability; require some help
4. = Moderately severe disability; unable to attend to own bodily needs without assistance
5. = Severe disability; bedridden and requiring constant nursing care and attention
6. = Dead

Excellent functional neurological outcome means modified Rankin scale (mRS) scores 0-1. The minimum mRS is 0 (no symptoms) while the maximum mRS is 6 (death). The higher the mRS score is the worse outcome is.

Independent functional neurological outcome means modified Rankin scale (mRS) scores 0-2. The minimum mRS is 0 (no symptoms) while the maximum mRS is 6 (death). The higher the mRS score is the worse outcome is.

Health Related Quality of Life based on EuroQol 5 Dimension 5 Level (EQ-5D-5L).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.

Mortality status equals to death which will be collected at all visits during the trial period