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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Best Medical Treatment (standard of care) | No Intervention | 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. | |
| Intravenous Thrombolysis + Best medical treatment (standard of care) | Experimental | Patients will receive intravenous administration of Tenecteplase or Alteplase. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tenecteplase or Alteplase | Drug | Patients randomized to intravenous thrombolysis (IVT) treatment will receive intravenous Tenecteplase or Alteplase. |
|
| 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 |
| 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) |
| 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):
|
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
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
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:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Thomas Meinel, MD, PhD | Contact | +41 31 66 4 25 67 | thomas.meinel@insel.ch | |
| Freschta Zipser-Mohammadzada, PhD | Contact | +41 31 63 2 60 83 | nctu@insel.ch |
| Name | Affiliation | Role |
|---|---|---|
| Thomas Meinel, MD, PhD | Insel Gruppe AG, University Hospital Bern | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| UZ Leuven | Not yet recruiting | Leuven | 3000 | Belgium |
IPDMA (individual participant data meta-analysis) of similar interventional clinical studies is planned.
After publication of primary study results
Ethics clearance, agreement with the DO-IT collaboration about terms of use and authorship
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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 |
| 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 |
| Hamilton Health Sciences | Not yet recruiting | Hamilton | Ontario | L8L 2X2 | Canada |
|
| GHU Paris Psychiatrie et Neurosciences, Sainte Anne | Not yet recruiting | Paris | 75014 | France |
|
| Heidelberg University Hospital | Not yet recruiting | Heidelberg | 69120 | Germany |
|
| "Attikon" University Hospital | Not yet recruiting | Athens | 12462 | Greece |
|
| National Cerebral and Cardiovascular Center Osaka | Not yet recruiting | Osaka | Kansai | 565-8565 | Japan |
|
| Academic Medical Center Amsterdam, Department of Neurology | Not yet recruiting | Amsterdam | 1105 | Netherlands |
|
| Canterbury District Health Board | Not yet recruiting | Christchurch | 8011 | New Zealand |
|
| Akershus Hospital | Not yet recruiting | Oslo | Norway |
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| Lisbon Central University Hospital Centre | Not yet recruiting | Lisbon | 1150-199 | Portugal |
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| Vall d'Hebron Stroke Center | Not yet recruiting | Barcelona | 08035 | Spain |
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| University Hospital Basel | Not yet recruiting | Basel | 4031 | Switzerland |
|
| Inselspital Bern | Recruiting | Bern | 3010 | Switzerland |
|
| Kantonsspital St. Gallen | Recruiting | Sankt Gallen | Switzerland |
|
| ID | Term |
|---|---|
| D000083242 | Ischemic Stroke |
| ID | Term |
|---|---|
| D020521 | Stroke |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D000077785 | Tenecteplase |
| D010959 | Tissue Plasminogen Activator |
| ID | Term |
|---|---|
| D012697 | Serine Endopeptidases |
| D010450 | Endopeptidases |
| D010447 | Peptide Hydrolases |
| D006867 | Hydrolases |
| D004798 | Enzymes |
| D045762 | Enzymes and Coenzymes |
| D057057 | Serine Proteases |
| D010960 | Plasminogen Activators |
| D001779 | Blood Coagulation Factors |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D001685 | Biological Factors |
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