ACT-42 is a domain of the ACT-GLOBAL platform (NCT06352632).

This trial is a Phase 2b, multicenter, prospective, randomized, open label, blinded-endpoint (PROBE) controlled single-dose adaptive trial.

A total of up to 600 male and female participants aged ≥ 18 to ≤ 90 years harboring an acute ischemic stroke who are eligible for an intravenous thrombolytic with or without endovascular thrombectomy therapy will be enrolled within 4.5 hours of stroke onset/last known well.

Because AIS is a medical emergency, the trial is designed to enable the administration of standard-of-care treatments in order to save the life of the person concerned, restore good health and alleviate suffering.

A total of up to 600 male and female participants aged ≥ 18 to ≤ 90 years harboring an acute ischemic stroke who are eligible for an intravenous thrombolytic with or without endovascular thrombectomy therapy will be enrolled within 4.5 hours of stroke onset/last known well. Randomization will be 1:1 drug/placebo. Randomization will be stratified by large vessel occlusion (LVO) (yes/no) and a minimization algorithm to minimize the contribution of imbalances in baseline factors (age, sex, baseline NIHSS score). The design is adaptive with prospective rules for adaptive enrichment, in which enrollment may be restricted to participants without an LVO. LVO is defined as an occlusion of the intracranial ICA, M1 or proximal M2.

Randomized participants will receive/received an intravenous thrombolytic and be allocated to:

• the investigational group, a single, 2.6 mg/kg (up to a maximum of 300 mg) 20-minute intravenous dose of NoNO-42, with a target start time of less than 10 minutes from randomization or
• the control group, no trial specific intervention.

Day 90: All participants will be followed for 90 days (or until death if prior to 90 days) for efficacy and 30 days for safety. The end of the trial is defined as the date that all participants have completed their Day 90 contact.

1-Year follow Up: participants who completed the trial to Day 90 may be followed at 1 year for long-term efficacy.

One database lock and corresponding report for the trial to Day 90 and a separate database lock and analysis for the 1-year follow up are planned.

Inclusion Criteria:

1. Confirmed or suspected acute ischemic stroke (AIS) selected for intravenous thrombolysis.
2. Onset (last-known-well) time to randomization time within 4.5 hours.
3. Ages ≥ 18 to ≤ 90 years.
4. Disabling stroke defined as a baseline National Institutes of Health Stroke Score (NIHSS) >5.
5. Confirmed or suspected symptomatic anterior circulation intracranial occlusion. Tandem extracranial carotid and intracranial occlusions are permitted.
6. Pre-stroke independent functional status in activities of daily living as judged by the enrolling physician. Patient must be living without requiring nursing care.
7. Consent process completed as per national laws and regulation and the applicable ethics committee requirements.

Exclusion Criteria:

1. Large extent early ischemic changes/infarct in the ischemic territory on qualifying imaging.
2. Any intracranial hemorrhage on qualifying imaging.
3. Unlikely to initiate study drug administration before arterial puncture in those selected for EVT.
4. Known/suspected pregnancy and/or lactation.
5. Systolic blood pressure < 90 mmHg
6. Known prior receipt of NoNO-42 for any reason, including prior enrolment in this trial.

8) Severe comorbid illness with life expectancy less than 90 days, or likely to prevent completing 90-day follow-up.

9) Long term care facility resident or prisoner 10) Participation in another clinical trial outside of the ACT-GLOBAL platform investigating a drug or medical device or a neuro-interventional or surgical procedure that is not considered as standard care in the 30 days preceding trial enrolment.

Potential bias will be reduced by the following steps:

• allocation concealment: via online central randomization
• trial participants will remain blinded to dose and treatment allocation and will not be informed until after database lock.
• blinded endpoint assessment, at Days 30 and 90 central blinded assessors will contact the participants for mRS and EQ-5D-5L assessments.

Clinical site staff, including the Principal Investigator (PI), sub-investigators, clinic site staff, and the Sponsor will not be blinded