Improving Early Reperfusion With Adjuvant Dornase Alfa in Large Vessel Ischemic Stroke (EXTEND-IA DNase)

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 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.

Study Overview

• Status: Recruiting
• Conditions: Ischemic Stroke
• Intervention / Treatment: Drug: Dornase Alfa

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Bruce CV Campbell, MBBS PhD; Phone Number: 0393427000; Email: bruce.campbell@mh.org.au

Study Locations

• Australia
  • Queensland
    • Brisbane, Queensland, Australia, 4102
      • Recruiting
      • Princess Alexandra Hospital
      • Contact: Carol Bendall; Phone Number: +61 7 3176 1499; Email: carol.bendall@health.qld.gov.au
      • Principal Investigator: Michael Devlin, MBBS
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Not yet recruiting
      • Royal Adelaide Hospital
      • Principal Investigator: Timothy Kleinig, MBBS PhD
  • Victoria
    • Melbourne, Victoria, Australia, 3050
      • Recruiting
      • Royal Melbourne Hospital
      • Principal Investigator: Bruce Campbell, MBBS PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intravenous Dornase alfa (DNase); Patients will receive a single intravenous dose of dornase alfa (at either 0.125mg/kg, 0.25mg/kg, or 0.5mg/kg in escalating tiers), administered as a bolus over ~30 seconds.	Drug: Dornase Alfa; Intravenous Dornase alfa; Other Names: Pulmozyme; DNase

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with substantial angiographic reperfusion or absence of retrievable intracranial thrombus at initial angiogram without symptomatic intracerebral hemorrhage	composite outcome of reperfusion on initial angiogram (day 0 - expanded Treatment In Cerebral Infarction [eTICI] 2b-3 or no retrievable intracranial thrombus) and assessment of symptomatic intracerebral hemorrhage on brain imaging 24h post-treatment. eTICI 2b-3 indicates reperfusion of >50% of the initially involved arterial territory.	24 hours post-treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
modified Rankin Scale (mRS) at 3 months	ordinal analysis versus EXTEND-IA TNK I & II historical control, adjusted for age and baseline National Institutes of Health Stroke Scale (NIHSS) score. mRS is a functional outcome/disability score from 0 (no disability) to 6 (death). NIHSS is a neurological impairment score from 0 (no deficit) to 42 (death)	3 months post stroke
modified Rankin Scale (mRS) 0-1 or no change from baseline at 3 months	versus EXTEND-IA TNK I & II historical control, adjusted for age and baseline NIHSS score	3 months post stroke
modified Rankin Scale (mRS) 0-2 or no change from baseline at 3 months	versus EXTEND-IA TNK I & II historical control, adjusted for age and baseline NIHSS score	3 months post stroke
Proportion of patients with 8 point reduction in NIHSS or reaching 0-1 at 3 days (early neurological improvement)	versus EXTEND-IA TNK I & II historical control, adjusted for age and baseline NIHSS score	3 days post stroke
Proportion of patients with near-complete reperfusion (eTICI 2c/3) at conclusion of the endovascular procedure	versus EXTEND-IA TNK I & II historical control	day 0 (end of endovascular thrombectomy)
Symptomatic intracranial hemorrhage (SICH)	Symptomatic intracranial hemorrhage includes any sub-arachnoid bleeding associated with clinical symptoms and symptomatic intracerebral hemorrhage (SICH). SICH is defined as "Intracerebral hemorrhage (parenchymal hematoma type 2 - PH2 within 36 hours of treatment) combined with neurological deterioration leading to an increase of ≥4 points on the NIHSS from baseline, or death"	36 hours post treatment
Death due to any cause	versus EXTEND-IA TNK I & II historical control, adjusted for age and baseline NIHSS	up to 3 months post stroke

Collaborators and Investigators

• Sponsor: University of Melbourne
• Investigators: Principal Investigator: Bruce CV Campbell, MBBS PhD, University of Melbourne

Study record dates

Study Major Dates

• Study Start (Actual): February 18, 2022
• Primary Completion (Anticipated): September 30, 2025
• Study Completion (Anticipated): December 31, 2025

Study Registration Dates

• First Submitted: January 10, 2022
• First Submitted That Met QC Criteria: January 10, 2022
• First Posted (Actual): January 24, 2022

Study Record Updates

• Last Update Posted (Actual): May 24, 2022
• Last Update Submitted That Met QC Criteria: May 22, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: thrombolysis; tenecteplase; thrombolytic; endovascular thrombectomy; DNase; dornase alfa
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction
• Other Study ID Numbers: MBC2101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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.
• IPD Sharing Time Frame: 2 years after the publication of the primary manuscript
• IPD Sharing Access Criteria: Qualified investigators can access data after submission of a project proposal that has been approved by the VISTA steering committee.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes