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

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

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.

Study Overview

• Status: Completed
• Conditions: Ischemic Stroke
• Intervention / Treatment: Other: Direct endovascular clot retrieval; Other: Bridging thrombolysis followed by ECR

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.

• Study Type: Interventional
• Enrollment (Actual): 295
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Liverpool, New South Wales, Australia, 2170
      • Liverpool Hospital
    • New Lambton, New South Wales, Australia, 2305
      • John Hunter Hospital
    • St Leonards, New South Wales, Australia, 2605
      • Royal North Shore Hospital
  • Queensland
    • Brisbane, Queensland, Australia
      • Royal Brisbane & Women's Hospital
    • Gold Coast, Queensland, Australia, 4215
      • Gold Coast University Hospital
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre
    • Melbourne, Victoria, Australia
      • Royal Melbourne Hospital
    • Melbourne, Victoria, Australia, 3050
      • Mobile Stroke Unit
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Fiona Stanley Hospital
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
• China
  • Beijing, China
    • Beijing Fengtai Youanmen Hospital
  • Beijing, China
    • Beijing Tiantin Hospital
  • Guangdong, China
    • Yunfu People's Hospital
  • Hubei, China
    • Shiyan Taihe Hospital
  • Hunan, China
    • Ningxiang People's Hospital
  • Jilin, China
    • China-Japan Union Hospital of Jilin University
  • Maoming, China
    • Maoming People's Hospital
  • Shandong, China
    • Binzhou People's Hospital
  • Shunde, China
    • Shunde Hospital of Southern Medical University
  • Taizhou, China
    • Jingjiang People's Hospital
  • Tianjin, China
    • Tianjin TEDA Hospital
  • Guangdong
    • Shantou, Guangdong, China
      • Shantou Central Hospital
  • Hebei
    • Cangzhou, Hebei, China
      • Cangzhou Central Hospital
  • Hubei
    • Wuhan, Hubei, China
      • Wuhan Central Hospital
  • Liaoning
    • Shenyang, Liaoning, China
      • The 4th Affiliated Hospital of CMU
  • Shandong
    • Linyi, Shandong, China
      • Linyi People's Hospital
  • Taiyuan
    • Shanxi, Taiyuan, China
      • Shanxi People's Hospital
• Singapore
  • Singapore, Singapore, 169608
    • Singapore General Hospital
• Vietnam
  • Hanoi, Vietnam
    • Bach Mai Hospital
  • Hanoi, Vietnam
    • Military Hospital 103
  • Ho Chi Minh City, Vietnam
    • 115 PEOPLE's HOSPITAL

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 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Direct endovascular clot retrieval; Endovascular clot retrieval (ECR) within 4.5 hours stroke	Other: Direct endovascular clot retrieval; Direct endovascular clot retrieval within 4.5 hours of stroke onset
Other: Bridging thrombolysis followed by ECR; 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	Other: Bridging thrombolysis followed by ECR; Bridging thrombolysis followed by ECR within 4.5 hours of stroke onset

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Rankin Scale (mRS)- ordinal analysis	Modified Rankin Scale (mRS) 0-2 or no change from baseline	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
modified Rankin Scale (mRS)- ordinal analysis	mRS 0-1 or no change from baseline	3 months
Death	Death due to any cause	3 months
Angiographic reperfusion	Proportion of patients with good angiographic reperfusion (mTICI 2b-3)	Baseline
Symptomatic intracranial haemorrhage (sICH)	Proportion of patients with sICH	24 hours

Collaborators and Investigators

• Sponsor: Neuroscience Trials Australia
• Collaborators: The Florey Institute of Neuroscience and Mental Health
• Investigators: Principal Investigator: Peter Mitchell, MD, Melbourne Health; Principal Investigator: Bernard Yan, MD, Melbourne Health

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 27, 2018
• Primary Completion (Actual): September 8, 2021
• Study Completion (Actual): September 8, 2021

Study Registration Dates

• First Submitted: April 4, 2018
• First Submitted That Met QC Criteria: April 4, 2018
• First Posted (Actual): April 11, 2018

Study Record Updates

• Last Update Posted (Actual): June 16, 2022
• Last Update Submitted That Met QC Criteria: June 14, 2022
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Stroke; Pathologic Processes; Vascular Diseases; Cardiovascular Diseases; Nervous System Diseases; Ischemia; Central Nervous System Diseases; Brain Diseases; Cerebral Infarction; Cerebrovascular Disorders; Brain Infarction; Brain Ischemia; Molecular Mechanisms of Pharmacological Action; Tissue Plasminogen Activator; Plasminogen; Fibrinolytic Agents; Fibrin Modulating Agents
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke
• Other Study ID Numbers: NTA1601

Drug and device information, study documents

• 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