Patients presenting to the emergency department with acute ischemic stroke, who are are eligible for standard intravenous thrombolytic therapy within 4.5 hours of stroke onset will be assessed for major vessel occlusion to determine their eligibility for the trial. All participants will receive intravenous tenecteplase (or alteplase due to manufacturer shortage) and endovascular thrombectomy as standard care. The trial is a Bayesian Optimised Phase 2 dose-finding umbrella trial (single arm versus objective performance criterion of 20% substantial reperfusion prior to endovascular thrombectomy based on the EXTEND-IA TNK trials NCT02388061, NCT03340493). The aim is to determine the optimal dose of intravenous dornase alfa (recombinant human DNase 1) with sufficient promise to take forward in a seamless phase 2b/3 design.

Inclusion Criteria:

1. Patients presenting with acute ischemic stroke eligible, using standard criteria, to receive IV thrombolytics within 4.5 hours of stroke onset
2. Patient's age is ≥18 years
3. Intention to perform endovascular thrombectomy Imaging inclusion criteria
4. Arterial occlusion on CTA or MRA of the ICA, M1, M2 or basilar artery

Exclusion Criteria:

1. Intracranial hemorrhage (ICH) identified by CT or MRI
2. Rapidly improving symptoms at the discretion of the investigator
3. Pre-stroke mRS score of ≥ 4 (indicating previous disability)
4. Hypodensity in >1/3 MCA territory or equivalent proportion of basilar artery territory on non-contrast CT
5. Contraindication to imaging with contrast agents
6. Any terminal illness such that patient would not be expected to survive more than 1 year
7. Any condition that, in the judgment of the investigator could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study.
8. Pregnant or lactating women

Anonymized individual patient data will be uploaded to the Virtual Stroke Trials Archive (http://www.virtualtrialsarchives.org/vista/) 2 years after the publication of the primary manuscript. Qualified investigators can access data after submission of a project proposal that has been approved by the VISTA steering committee.

2 years after the publication of the primary manuscript

Qualified investigators can access data after submission of a project proposal that has been approved by the VISTA steering committee.

No blinding given single arm study but Independent core laboratory adjudication of the primary outcome, mRS (secondary outcome) performed by central assessor.