Safety and Efficacy of Intravenous Thrombolysis in Patients With Ischemic Stroke and Direct Oral Anticoagulants Intake (DO-IT)

Safety and Efficacy of Intravenous Thrombolysis in Patients With Ischemic Stroke on Treatment With Direct Oral Anticoagulants: DO-IT - The DOAC Intravenous Thrombolysis Trial

DO-IT is an international, multicenter, prospective, two-arm, randomized, open label, blinded endpoint superiority trial determining the safety and efficacy of intravenous thrombolysis (IVT) in participants experiencing an acute ischemic stroke (AIS) with recent (within the last 48 hours) intake of direct oral anticoagulant (DOAC). For this purpose, 906 adult participants experiencing an AIS with recent DOAC intake will be enrolled at several high-volume international stroke centers and randomly assigned in a ratio of 1:1 to one of two treatment arms: (1) IVT and standard of care/best medical treatment or (2) standard of care/best medical treatment. The DO-IT trial is a definitive test of the hypothesis that IVT is superior to standard of care for achieving better outcome at 90 days in AIS participants with recent DOAC intake.

Study Overview

• Status: Recruiting
• Conditions: Ischemic Stroke
• Intervention / Treatment: Drug: Tenecteplase or Alteplase

• Study Type: Interventional
• Enrollment (Estimated): 906
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Thomas Meinel, MD, PhD; Phone Number: +41 31 66 4 25 67; Email: thomas.meinel@insel.ch
• Study Contact Backup: Name: Freschta Zipser-Mohammadzada, PhD; Phone Number: +41 31 63 2 60 83; Email: nctu@insel.ch

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Not yet recruiting
    • UZ Leuven
    • Principal Investigator: Robin Lemmens, MD
    • Contact: Annemie Devroye; Email: annemie.devroye@uzleuven.be
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Not yet recruiting
      • Hamilton Health Sciences
      • Principal Investigator: Luciana Catanese, MD
• France
  • Paris, France, 75014
    • Not yet recruiting
    • GHU Paris Psychiatrie et Neurosciences, Sainte Anne
    • Principal Investigator: Guillaume Turc, Dr. med.
• Germany
  • Heidelberg, Germany, 69120
    • Not yet recruiting
    • Heidelberg University Hospital
    • Principal Investigator: Jan C. Purrucker, MD
• Greece
  • Athens, Greece, 12462
    • Not yet recruiting
    • "Attikon" University Hospital
    • Principal Investigator: Georgios Tsivgoulis, MD, PhD
• Japan
  • Kansai
    • Osaka, Kansai, Japan, 565-8565
      • Not yet recruiting
      • National Cerebral and Cardiovascular Center Osaka
      • Principal Investigator: Masatoshi Koga, MD, PHD
• Netherlands
  • Amsterdam, Netherlands, 1105
    • Not yet recruiting
    • Academic Medical Center Amsterdam, Department of Neurology
    • Principal Investigator: Jonathan Coutinho, Dr. med.
• New Zealand
  • Christchurch, New Zealand, 8011
    • Not yet recruiting
    • Canterbury District Health Board
    • Principal Investigator: Teddy Wu, MD
• Norway
  • Oslo, Norway
    • Not yet recruiting
    • Akershus Hospital
    • Contact: Espen Kristoffersen, MD
    • Principal Investigator: Espen Kristoffersen
• Portugal
  • Lisbon, Portugal, 1150-199
    • Not yet recruiting
    • Lisbon Central University Hospital Centre
    • Principal Investigator: Diana Aguiar de Sousa, MD, PhD
• Spain
  • Barcelona, Spain, 08035
    • Not yet recruiting
    • Vall d'Hebron Stroke Center
    • Principal Investigator: Carlos A. Molina, MD, PhD
• Switzerland
  • Basel, Switzerland, 4031
    • Not yet recruiting
    • University Hospital Basel
    • Contact: Thomas Pokorny; Phone Number: +41 61 328 59 85; Email: thomas.pokorny@usb.ch
    • Principal Investigator: Mira Katan, Prof.
    • Sub-Investigator: Gerrit Grosse, MD
  • Bern, Switzerland, 3010
    • Recruiting
    • Inselspital Bern
    • Contact: Thomas Meinel, MD, PhD; Phone Number: 0041 31 63 2 91 86; Email: thomas.meinel@insel.ch
    • Principal Investigator: Thomas Meinel, MD, PhD
  • St. Gallen, Switzerland
    • Recruiting
    • Kantonsspital St. Gallen
    • Contact: Gian Marco De Marchis, Prof.
    • Principal Investigator: Gian Marco De Marchis, Prof.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Informed consent (deferred consent when possible according to national legislation)
• AIS eligible to receive intravenous alteplase/tenecteplase as per standard of care disabling according to the judgement of the treating physician
• DOAC ingestion within 48 hours prior to enrollment, or patient with an ongoing prescription of DOAC but exact time point of last intake is unknown.

• Either

  • Can be randomized within 4 hours 15 minutes and treated within 4 hours 30 minutes of last known well time OR
  • MRI showing a pattern of "DWI-FLAIR-mismatch", i.e. acute ischemic lesion visibly on DWI ("positive DWI") but no marked parenchymal hyperintensity visible on FLAIR ("negative FLAIR") indicative of an acute ischemic lesion ≤4.5 hours of age AND Treatment can be started within 4.5 hours of symptom recognition (e.g., awakening).

Exclusion Criteria:

• Contra-indications to IVT by the current standard of care of the treating physicians with the exception of recent DOAC intake as specified above.
• Intended reversal by specific or unspecific reversal agents

• Pregnancy or lactating women. To be reasonable sure to exclude women with ongoing pregnancy, women are not considered of childbearing potential if they fulfill the following criteria

  • Age > 55 years OR
  • Age < 55 years and at least 12 months since last menstrual period OR
  • Have had a documented surgical sterilization
• Patient < 18 years of age (since the benefit of IVT is unproven in this population)

Since the benefit of IVT might be smaller in patients in which additional endovascular treatment is planned, the investigators will cap patients with intended mechanical thrombectomy at 20% of the trial population. If this number is reached, the following additional exclusion criterion will be applied:

• Intended treatment with endovascular reperfusion strategies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Best Medical Treatment (standard of care); Patients will receive Standard of care/Best medical treatment according to local applicable guidelines, including the current American Heart Association/American Stroke Association (AHA/ASA) and European Stroke Organisation/ European Society of Minimally Invasive Neurological Therapy (ESO/ESMINT) guidelines.
Experimental: Intravenous Thrombolysis + Best medical treatment (standard of care); Patients will receive intravenous administration of Tenecteplase or Alteplase.	Drug: Tenecteplase or Alteplase; Patients randomized to intravenous thrombolysis (IVT) treatment will receive intravenous Tenecteplase or Alteplase.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Rankin Scale (mRS)	Modified Rankin Scale is a scale that runs from 0-6, running from perfect health without symptoms (0) to death (6).	90 days +/- 2 weeks after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dichotomized modified Rankin Scale (mRS) 0-2 (good functional outcome)	Modified Rankin Scale is a scale that runs from 0-6, running from perfect health without symptoms (0) to death (6).	90 days +/- 2 weeks post-randomization
Change from baseline in stroke severity (National Institutes of Health Stroke Scale, NIHSS)	The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. Thus, 0 (minimum score) means "no symptoms", whereas 42 (maximum score) means "severe stroke".	24 +/- 12 hours after Intervention
Health-related Quality of Life (EuroQol 5D-3L questionnaire)	The EuroQol 5D-3L (EuroQol 5 Dimensions with each 3 Levels) measures health-related Quality of Life.	90 days +/- 2 weeks post-randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Symptomatic intracranial hemorrhage	Observed in clinical imaging	Within the first 36 hours post-randomization
Rate of Major extracranial bleeding	Defined as clinically overt bleeding that is accompanied by one or more of the following (according to International Society on Thrombosis and Haemostasis definitions): Decrease in haemoglobin of ≥ 2g / dl over a 24-hour period; Transfusion of ≥ 2 units of packed red blood cells; Occurring in a critical part of the body (intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, retroperitoneal); In order for bleeding (e.g. gastrointestinal) in a critical area or organ to be classified as a major extracranial bleeding it must be associated with a symptomatic clinical presentation.	Within the first 24 hours post-randomization
All-cause mortality	Death from any cause	Up to 7 to 10 days after admission or until discharge, usually 2 weeks after admission

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Investigators: Study Director: Thomas Meinel, MD, PhD, Insel Gruppe AG, University Hospital Bern

Study record dates

Study Major Dates

• Study Start (Actual): March 14, 2025
• Primary Completion (Estimated): January 31, 2029
• Study Completion (Estimated): April 30, 2029

Study Registration Dates

• First Submitted: August 22, 2024
• First Submitted That Met QC Criteria: August 22, 2024
• First Posted (Actual): August 26, 2024

Study Record Updates

• Last Update Posted (Actual): March 30, 2025
• Last Update Submitted That Met QC Criteria: March 25, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Rivaroxaban; Anticoagulation; Alteplase; Apixaban; Dabigatran; Edoxaban; DOAC; Tenecteplase; r-tPA (tissue-type plasminogen activator); NOAC (Novel Oral Anticoagulants)
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Brain Infarction; Brain Ischemia; Infarction; Necrosis; Ischemic Stroke; Stroke; Cerebral Infarction; Ischemia; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Fibrinolytic Agents; Tenecteplase; Tissue Plasminogen Activator
• Other Study ID Numbers: 2024-01157

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPDMA (individual participant data meta-analysis) of similar interventional clinical studies is planned.
• IPD Sharing Time Frame: After publication of primary study results
• IPD Sharing Access Criteria: Ethics clearance, agreement with the DO-IT collaboration about terms of use and authorship
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No