Among the treatments evaluated in ACT-GLOBAL, which is associated with the highest likelihood of improving important patient outcomes following stroke?

The study setting/ Study sites: Only the NTERACT5 Domain will be conducted in Sri Lanka.

Study sites: Sri Jayewardenepura General Hospital, National Hospital of Sri Lanka, Kandy National Hospital, National Hospital – Galle and Colombo South Teaching Hospital.

Randomization

The objective of randomization is to prevent possible selection bias and to balance confounding by both known and unknown factors, by providing random treatment assignment to each participant. A web-based central randomization system will be used. Randomization will occur after data necessary to implement the inclusion and exclusion criteria have been entered into the secure randomization website.

Depending on domain inclusion and exclusion criteria as well as the time point of randomisation in patient care flow, patients may be randomized into each domain sequentially. Randomization will be dynamic using random number generation and concealed. Stratification may be used in specific domains to ensure balance on key prognostic variables throughout the duration of the trial.

Detailed randomisation method and key prognostic variables used for stratification will be specified in Domain-Specific Appendices. Treatment assignment(s) will be obtained using a central, computer-based randomization program via the study-specific password protected website accessed by an authorized research coordinator or investigator at participating site. Upon randomization by the authorized person at each site, an email notification will be sent to the Site PI, Site Study Coordinator and relevant members from the project team. Sequential randomisation will be implemented according to the position of specific domain in patient care flow and domain specific prognostic covariates.

Intervention –

Current domains within the ACT-GLOBAL study, treatments will be provided on an open-label basis. However, the blinding of treatment status is not precluded for existing and future domains. If required, details related to blinding of interventions will be specified in the Domain-Specific Appendices

Participant Group/Arm and the Intervention –

1. Experimental: IV thrombolysis domain 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.

Treatment:

Arm 1: Standard-dose intravenous tenecteplase • Standard-dose intravenous tenecteplase (0.25 mg/kg body weight); one-time IV bolus injection soon after randomisation

Arm 2: Low-dose intravenous tenecteplase • Low-dose intravenous tenecteplase (0.18 mg/kg body weight); one-time IV bolus injection soon after randomisation

Arm 3: No intravenous tenecteplase • No intravenous tenecteplase only in subjects on direct oral anticoagulant (DOACs) or those planned for emergency endovascular thrombectomy (EVT)

1. Experimental: Blood Pressure domain 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.

Treatment: Arm 1: Conservative Blood Pressure Control • 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) Arm 2: Moderate Blood Pressure Control • 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) Arm 3: Intensive Blood Pressure Control • 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)

1. Experimental: ACT-42 domain 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. Arm 1: Placebo • 100 mL of 0.9% normal saline, administered as a single IV infusion with a 20-minute dosing duration. Arm 2 Drug: NoNO-42 • NoNO-42 at weight-based dosing - 2.6 mg/Kg, administered as a single IV infusion with a 20-minute dosing duration

2. Experimental: INTERACT5 Domain 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.

Arm1: No deferoxamine mesylate and no colchicine • No deferoxamine mesylate and no colchicine

Arm 2: Drug: Deferoxamine mesylate only • Deferoxamine mesylate at a dose of 32mg/kg/day via intravenous infusion immediately (within 1 hour) and continued for 2 consecutive days. Arm 3: Drug: Colchicine only • 0.5mg of oral colchicine daily for 30 days

Arm 4: Drug: Both deferoxamine mesylate and colchicine • 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

Platform Inclusion Criteria: 1. Age equal or greater than 18 years 2. Clinical diagnosis of stroke

Each state and domain will specify additional inclusion and exclusion criteria in the respective Domain-Specific Registration. Patients who fulfil the overall platform criteria will be assessed for enrollment into each active domain.