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DIRECT-SAFE: A Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval Versus Standard Bridging Thrombolysis With Endovascular Clot Retrieval

Primary Purpose

Ischemic Stroke

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Direct endovascular clot retrieval
Bridging thrombolysis followed by ECR
Sponsored by
Neuroscience Trials Australia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ischemic Stroke focused on measuring Stroke, Ischemia, Cerebral Infarction, Cerebrovascular Disorders, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Vascular Diseases, Cardiovascular Diseases, Pathologic Processes, Brain Infarction, Brain Ischemia, Tissue Plasminogen Activator, Plasminogen, Fibrinolytic Agents, Fibrin Modulating Agents, Molecular Mechanisms of Pharmacological Action

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients presenting with acute ischemic stroke eligible using standard criteria to receive IV thrombolysis within 4.5 hours of stroke onset
  2. Patient's age is ≥18 years
  3. Intra-arterial clot retrieval treatment can commence (groin puncture) within 6 hours of stroke onset.
  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 on non-contrast CT
  5. Contra indication 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 women

Sites / Locations

  • Liverpool Hospital
  • John Hunter Hospital
  • Royal North Shore Hospital
  • Royal Brisbane & Women's Hospital
  • Gold Coast University Hospital
  • Princess Alexandra Hospital
  • Royal Adelaide Hospital
  • Monash Medical Centre
  • Mobile Stroke Unit
  • Royal Melbourne Hospital
  • Fiona Stanley Hospital
  • Sir Charles Gairdner Hospital
  • Shantou Central Hospital
  • Cangzhou Central Hospital
  • Wuhan Central Hospital
  • The 4th Affiliated Hospital of CMU
  • Linyi People's Hospital
  • Shanxi People's Hospital
  • Beijing Fengtai Youanmen Hospital
  • Beijing Tiantin Hospital
  • Yunfu People's Hospital
  • Shiyan Taihe Hospital
  • Ningxiang People's Hospital
  • China-Japan Union Hospital of Jilin University
  • Maoming People's Hospital
  • Binzhou People's Hospital
  • Shunde Hospital of Southern Medical University
  • Jingjiang People's Hospital
  • Tianjin TEDA Hospital
  • Singapore General Hospital
  • Bach Mai Hospital
  • Military Hospital 103
  • 115 People's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

Direct endovascular clot retrieval

Bridging thrombolysis followed by ECR

Arm Description

Endovascular clot retrieval (ECR) within 4.5 hours stroke

Intravenous tPA (at the standard licensed dose of 0.9 mg/kg up to a maximum of 90mg, 10% as bolus and the remainder over 1 hour) followed by ECR

Outcomes

Primary Outcome Measures

Modified Rankin Scale (mRS)- ordinal analysis
Modified Rankin Scale (mRS) 0-2 or no change from baseline

Secondary Outcome Measures

modified Rankin Scale (mRS)- ordinal analysis
mRS 0-1 or no change from baseline
Death
Death due to any cause
Angiographic reperfusion
Proportion of patients with good angiographic reperfusion (mTICI 2b-3)
Symptomatic intracranial haemorrhage (sICH)
Proportion of patients with sICH

Full Information

First Posted
April 4, 2018
Last Updated
June 14, 2022
Sponsor
Neuroscience Trials Australia
Collaborators
The Florey Institute of Neuroscience and Mental Health
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1. Study Identification

Unique Protocol Identification Number
NCT03494920
Brief Title
DIRECT-SAFE: A Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval Versus Standard Bridging Thrombolysis With Endovascular Clot Retrieval
Official Title
DIRECT-SAFE: A Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval Versus Standard Bridging Thrombolysis With Endovascular Clot Retrieval Within 4.5 Hours of Stroke Onset
Study Type
Interventional

2. Study Status

Record Verification Date
July 2021
Overall Recruitment Status
Completed
Study Start Date
April 27, 2018 (Actual)
Primary Completion Date
September 8, 2021 (Actual)
Study Completion Date
September 8, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Neuroscience Trials Australia
Collaborators
The Florey Institute of Neuroscience and Mental Health

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The study will be a multicentre, prospective, randomized, open label, blinded endpoint (PROBE) phase 3 trial (2 arm with 1:1 randomization) in ischemic stroke patients within 4.5 hours of stroke onset. Randomised patients will be stratified for site of baseline arterial occlusion into one of three groups: 1. internal carotid artery (ICA) 2. middle cerebral artery (MCA) 3. basilar artery (BA). Patients will be randomised to either bridging intravenous thrombolysis with endovascular clot retrieval (ECR), or direct endovascular clot retrieval.
Detailed Description
The DIRECT-SAFE trial will include patients with acute ischemic stroke, who are ≥18 years of age and are eligible for standard intravenous tPA therapy within 4.5 hours of stroke onset. Patients will be assessed for large vessel occlusion to determine their eligibility for randomization into the trial. Eligible vessel occlusions include the internal carotid artery, basilar artery or middle cerebral artery (M1 or M2). Patients will be consented after large vessel occlusion is confirmed based on standard care multimodal imaging. Patients will be recruited in Australia, New Zealand, China, Taiwan, Vietnam, Singapore and Europe. Randomisation either direct to ECR or standard thrombolytic therapy and ECR shall be in a 1:1 ratio. All patients will have a multimodal MR (or CT/CTP at investigator's discretion if MRI not possible) at 18 to 30 hours post treatment to assess reperfusion, recanalization, ischemic core growth and hemorrhagic transformation. Final follow up will occur at Day 90.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ischemic Stroke
Keywords
Stroke, Ischemia, Cerebral Infarction, Cerebrovascular Disorders, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Vascular Diseases, Cardiovascular Diseases, Pathologic Processes, Brain Infarction, Brain Ischemia, Tissue Plasminogen Activator, Plasminogen, Fibrinolytic Agents, Fibrin Modulating Agents, Molecular Mechanisms of Pharmacological Action

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Patients will be randomised to either direct endovascular clot retrieval or to bridging intravenous thrombolysis with endovascular clot retrieval.
Masking
Outcomes Assessor
Masking Description
Blinded core laboratory adjudications of the primary outcome. NIHSS and mRS (secondary outcomes) performed by blinded assessor.
Allocation
Randomized
Enrollment
295 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Direct endovascular clot retrieval
Arm Type
Other
Arm Description
Endovascular clot retrieval (ECR) within 4.5 hours stroke
Arm Title
Bridging thrombolysis followed by ECR
Arm Type
Other
Arm Description
Intravenous tPA (at the standard licensed dose of 0.9 mg/kg up to a maximum of 90mg, 10% as bolus and the remainder over 1 hour) followed by ECR
Intervention Type
Other
Intervention Name(s)
Direct endovascular clot retrieval
Intervention Description
Direct endovascular clot retrieval within 4.5 hours of stroke onset
Intervention Type
Other
Intervention Name(s)
Bridging thrombolysis followed by ECR
Intervention Description
Bridging thrombolysis followed by ECR within 4.5 hours of stroke onset
Primary Outcome Measure Information:
Title
Modified Rankin Scale (mRS)- ordinal analysis
Description
Modified Rankin Scale (mRS) 0-2 or no change from baseline
Time Frame
3 months
Secondary Outcome Measure Information:
Title
modified Rankin Scale (mRS)- ordinal analysis
Description
mRS 0-1 or no change from baseline
Time Frame
3 months
Title
Death
Description
Death due to any cause
Time Frame
3 months
Title
Angiographic reperfusion
Description
Proportion of patients with good angiographic reperfusion (mTICI 2b-3)
Time Frame
Baseline
Title
Symptomatic intracranial haemorrhage (sICH)
Description
Proportion of patients with sICH
Time Frame
24 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients presenting with acute ischemic stroke eligible using standard criteria to receive IV thrombolysis within 4.5 hours of stroke onset Patient's age is ≥18 years Intra-arterial clot retrieval treatment can commence (groin puncture) within 6 hours of stroke onset. Arterial occlusion on CTA or MRA of the ICA, M1, M2 or basilar artery Exclusion Criteria: Intracranial hemorrhage (ICH) identified by CT or MRI Rapidly improving symptoms at the discretion of the investigator Pre-stroke mRS score of ≥ 4 (indicating previous disability) Hypodensity in >1/3 MCA territory on non-contrast CT Contra indication to imaging with contrast agents Any terminal illness such that patient would not be expected to survive more than 1 year 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. Pregnant women
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter Mitchell, MD
Organizational Affiliation
Melbourne Health
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Bernard Yan, MD
Organizational Affiliation
Melbourne Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Liverpool Hospital
City
Liverpool
State/Province
New South Wales
ZIP/Postal Code
2170
Country
Australia
Facility Name
John Hunter Hospital
City
New Lambton
State/Province
New South Wales
ZIP/Postal Code
2305
Country
Australia
Facility Name
Royal North Shore Hospital
City
St Leonards
State/Province
New South Wales
ZIP/Postal Code
2605
Country
Australia
Facility Name
Royal Brisbane & Women's Hospital
City
Brisbane
State/Province
Queensland
Country
Australia
Facility Name
Gold Coast University Hospital
City
Gold Coast
State/Province
Queensland
ZIP/Postal Code
4215
Country
Australia
Facility Name
Princess Alexandra Hospital
City
Woolloongabba
State/Province
Queensland
ZIP/Postal Code
4102
Country
Australia
Facility Name
Royal Adelaide Hospital
City
Adelaide
State/Province
South Australia
ZIP/Postal Code
5000
Country
Australia
Facility Name
Monash Medical Centre
City
Clayton
State/Province
Victoria
ZIP/Postal Code
3168
Country
Australia
Facility Name
Mobile Stroke Unit
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3050
Country
Australia
Facility Name
Royal Melbourne Hospital
City
Melbourne
State/Province
Victoria
Country
Australia
Facility Name
Fiona Stanley Hospital
City
Murdoch
State/Province
Western Australia
ZIP/Postal Code
6150
Country
Australia
Facility Name
Sir Charles Gairdner Hospital
City
Nedlands
State/Province
Western Australia
ZIP/Postal Code
6009
Country
Australia
Facility Name
Shantou Central Hospital
City
Shantou
State/Province
Guangdong
Country
China
Facility Name
Cangzhou Central Hospital
City
Cangzhou
State/Province
Hebei
Country
China
Facility Name
Wuhan Central Hospital
City
Wuhan
State/Province
Hubei
Country
China
Facility Name
The 4th Affiliated Hospital of CMU
City
Shenyang
State/Province
Liaoning
Country
China
Facility Name
Linyi People's Hospital
City
Linyi
State/Province
Shandong
Country
China
Facility Name
Shanxi People's Hospital
City
Shanxi
State/Province
Taiyuan
Country
China
Facility Name
Beijing Fengtai Youanmen Hospital
City
Beijing
Country
China
Facility Name
Beijing Tiantin Hospital
City
Beijing
Country
China
Facility Name
Yunfu People's Hospital
City
Guangdong
Country
China
Facility Name
Shiyan Taihe Hospital
City
Hubei
Country
China
Facility Name
Ningxiang People's Hospital
City
Hunan
Country
China
Facility Name
China-Japan Union Hospital of Jilin University
City
Jilin
Country
China
Facility Name
Maoming People's Hospital
City
Maoming
Country
China
Facility Name
Binzhou People's Hospital
City
Shandong
Country
China
Facility Name
Shunde Hospital of Southern Medical University
City
Shunde
Country
China
Facility Name
Jingjiang People's Hospital
City
Taizhou
Country
China
Facility Name
Tianjin TEDA Hospital
City
Tianjin
Country
China
Facility Name
Singapore General Hospital
City
Singapore
ZIP/Postal Code
169608
Country
Singapore
Facility Name
Bach Mai Hospital
City
Hanoi
Country
Vietnam
Facility Name
Military Hospital 103
City
Hanoi
Country
Vietnam
Facility Name
115 People's Hospital
City
Ho Chi Minh City
Country
Vietnam

12. IPD Sharing Statement

Citations:
PubMed Identifier
35810757
Citation
Mitchell PJ, Yan B, Churilov L, Dowling RJ, Bush SJ, Bivard A, Huo XC, Wang G, Zhang SY, Ton MD, Cordato DJ, Kleinig TJ, Ma H, Chandra RV, Brown H, Campbell BCV, Cheung AK, Steinfort B, Scroop R, Redmond K, Miteff F, Liu Y, Duc DP, Rice H, Parsons MW, Wu TY, Nguyen HT, Donnan GA, Miao ZR, Davis SM; DIRECT-SAFE Investigators. Endovascular thrombectomy versus standard bridging thrombolytic with endovascular thrombectomy within 4.5 h of stroke onset: an open-label, blinded-endpoint, randomised non-inferiority trial. Lancet. 2022 Jul 9;400(10346):116-125. doi: 10.1016/S0140-6736(22)00564-5.
Results Reference
derived
PubMed Identifier
35135060
Citation
Mitchell PJ, Yan B, Churilov L, Dowling RJ, Bush S, Nguyen T, Campbell BCV, Donnan GA, Miao Z, Davis SM; DIRECT-SAFE Investigators. DIRECT-SAFE: A Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval versus Standard Bridging Therapy. J Stroke. 2022 Jan;24(1):57-64. doi: 10.5853/jos.2021.03475. Epub 2022 Jan 31.
Results Reference
derived

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DIRECT-SAFE: A Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval Versus Standard Bridging Thrombolysis With Endovascular Clot Retrieval

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