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Endovascular Therapy for Low NIHSS Ischemic Strokes (ENDOLOW)

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ClinicalTrials.gov Identifier: NCT04167527
Recruitment Status : Recruiting
First Posted : November 19, 2019
Last Update Posted : February 8, 2021
Sponsor:
Collaborators:
University of Calgary
University of Cincinnati
Heidelberg University
Children's Hospital Medical Center, Cincinnati
Information provided by (Responsible Party):
Raul Gomes Nogueira, Emory University

Brief Summary:
This study will test the hypothesis that patients presenting within 8 hours of onset with cerebral ischemia in the setting of proximal large vessel occlusions (LVO) and low baseline NIHSS scores (0-5) will have better 90-day clinical outcomes (mRS distribution) with immediate mechanical thrombectomy (iMT) compared to initial medical management (iMM).

Condition or disease Intervention/treatment Phase
Cerebral Ischemia Device: Immediate mechanical thrombectomy(iMT) using EmboTrap II Revascularization Device Combination Product: Initial medical management (iMM) Phase 2 Phase 3

Detailed Description:

Currently, the vast majority of these patients do not receive immediate vessel imaging with either CT- or MR-angiography. However, acute ischemic stroke patients with low NIHSS who harbor a large vessel occlusion (LVO) later decline in 20-40% of cases, and/or have underappreciated impairments related to their relatively mild strokes. Similarly, LVO patients presenting with a transient ischemic attack (TIA) are under increased risk of clinical deterioration. Such patients with apparent good collateral circulation, and hence a substantial perfusion of the vascular territory of the occluded large artery, likely have the most to gain from endovascular revascularization. At the same time, this collateral perfusion may allow for more frequent recanalization, either spontaneously or by intravenous (IV) rtPA. Experience with immediate mechanical thrombectomy (iMT) in the LVO mild stroke target population is limited.

This study will test the hypothesis that patients presenting within 8 hours of onset with cerebral ischemia in the setting of proximal large vessel occlusions (LVO) and low baseline NIHSS scores (0-5) will have better 90-day clinical outcomes (mRS distribution) with immediate mechanical thrombectomy (iMT) compared to initial medical management (iMM).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Endovascular Therapy for Low NIHSS Ischemic Strokes
Actual Study Start Date : September 5, 2020
Estimated Primary Completion Date : January 2023
Estimated Study Completion Date : January 2023

Arm Intervention/treatment
Experimental: Immediate mechanical thrombectomy(iMT)
Treatment initiation within 8 hours of symptom onset. Arterial puncture and revascularization will be performed using EmboTrap II Retriever. The procedure will be completed within two hours of arterial access.
Device: Immediate mechanical thrombectomy(iMT) using EmboTrap II Revascularization Device
Treatment initiation is defined as the date and time of arterial puncture. Femoral artery puncture will occur within 45 minutes of randomization and no longer than 90 minutes after the completion of the qualifying imaging. It must occur before 8 hours since the subject was last known well.The initial procedure will be performed using only the EmboTrap II Retriever for the first two passes, and a third pass is encouraged. Date and time of arterial puncture, revascularization, and procedure end will be recorded. It is expected that the interventional procedure will be completed within two hours of arterial access.
Other Name: EmboTrap II

Active Comparator: Initial medical management (iMM)
Standard medical therapy based on current AHA (American Heart Association) guidelines. Rescue mechanical thrombectomy (rMT) is allowed for patients initially assigned to iMM if they suffer major neurological worsening that clearly requires an intra-arterial intervention in the judgment of the treating team.
Combination Product: Initial medical management (iMM)
Patients will receive standard medical therapy based on current AHA guidelines. For patients who are treated with intravenous tissue plasminogen activator (rtPA), the sites' post-rtPA protocol will be followed. Rescue mechanical thrombectomy (rMT) is allowed for patients initially assigned to iMM if they suffer major neurological worsening that clearly requires an intra-arterial intervention in the judgment of the treating team.




Primary Outcome Measures :
  1. 90-day Global Disability Assessed Via the Blinded Evaluation of Modified Rankin Score (Ordinal Shift Analysis). [ Time Frame: 90-day ]
    The distribution of the modified Rankin Scale (mRS) is assessed by structured interview. The Modified Rankin Score (mRS) is a 6 point disability scale with possible scores ranging from 0 to 5. A separate category of 6 is usually added for patients who expire.

  2. Symptomatic intracranial hemorrhage (sICH) within 36 hours comparing the two treatment arms [ Time Frame: 36 hours ]
    Symptomatic intracranial hemorrhage (sICH) within 36 hours using SITS-MOST criteria, consisting of the presence of parenchymal hematoma type 2 (PH2) on neuroimaging associated with 4-point decline in NIHSS from baseline to 24 hours


Secondary Outcome Measures :
  1. Shift in distribution of the 90-day mRS with levels 5-6 combined (0;1;2;3;4;5-6) comparing the two treatment arms [ Time Frame: 90-day ]
    The distribution of the 90-day modified Rankin Scale (mRS) with levels 5-6 combined (0;1;2;3;4;5-6) is assessed by structured interview. The Modified Rankin Score (mRS) is a 6 point disability scale with possible scores ranging from 0 to 5. A separate category of 6 is usually added for patients who expire.

  2. Number of patients with good outcome comparing the two treatment arms [ Time Frame: 90-day ]
    Good outcome is defined by a score of 0-2 on the 90-day mRS. The Modified Rankin Score (mRS) is a 6 point disability scale with possible scores ranging from 0 to 5. A separate category of 6 is usually added for patients who expire.

  3. Number of patients with excellent outcome comparing the two treatment arms arms [ Time Frame: 90-day ]
    Excellent outcome is defined by a score 0-1 on the 90-day mRS. The Modified Rankin Score (mRS) is a 6 point disability scale with possible scores ranging from 0 to 5. A separate category of 6 is usually added for patients who expire.

  4. Number of patients with early Neurologic Deterioration (END) comparing the two treatment arms [ Time Frame: 24 hours post randomization ]
    Early Neurologic Deterioration (END) is defined as an increase in NIHSS of ≥4 points. NIH Stroke Scale/Score (NIHSS) is a 15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patent's ability to answer questions and perform activities. Ratings for each item are scored with 3 to 5 grades with 0 as normal, and there is an allowance for untestable items.

  5. Health-related quality of life EQ-5D score comparing the two treatment arms [ Time Frame: 90-day ]

    EQ-5D is a standardized instrument measuring health-related quality of life. The EQ-5D consists of a descriptive system and the EQ VAS.

    The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale. The scores on these five dimensions can be presented as a health profile or can be converted to a single summary index number.


  6. Infarct volume [ Time Frame: 24 hours post randomization ]
    Infarct volume is a direct measurement of one of the final pathologic steps leading to the clinical deficits caused by an ischemic stroke.Final infarct volume derived from MR imaging.

  7. Self-reported mental and physical health PROMIS Global-10 score [ Time Frame: 90-day ]
    Mental and physical health will be assessed using PROMIS Global-10. The PROMIS Global-10 short form consists of 10 items that assess general domains of health and functioning including overall physical health, mental health, social health, pain, fatigue, and overall perceived quality of life.Scores are converted to a T-Score metric.

  8. Self-reported PROMIS Fatigue score [ Time Frame: 90-day ]

    The PROMIS Fatigue assesses a range of self-reported symptoms, from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one's ability to execute daily activities and function normally in family or social roles. Fatigue is divided into the experience of fatigue (frequency, duration, and intensity) and the impact of fatigue on physical, mental, and social activities.

    Each question has five response options ranging in value from one to five.To find the total raw score, values of the response to each question will be summed up. Total raw score will be transformed into a T-score for each participant. The T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10. Therefore, a person with a T-score of 40 is one SD below the mean.


  9. Number of patients with intracranial hemorrhages using the Heidelberg Bleeding definition comparing the two treatment arms [ Time Frame: 90-day ]
    Intracranial hemorrhages will be defined using the Heidelberg Bleeding criteria.

  10. Mortality rate within 90 days comparing the two treatment arms [ Time Frame: 90-day ]
    Mortality rate will be calculated.

  11. Instrumental Activities of Daily Living (IADL) [ Time Frame: 90-day ]
    Instrumental Activities of Daily Living (IADLs) are activities related to independent living. The IADL scale covers eight functional domains: using the telephone, shopping, food preparation, housekeeping, laundry, transport, medication, and finances. Participants are scored according to their highest level of functioning in categories, and summary score ranges from 0 (low function, dependent) to 8 (high function, independent).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18 years or older
  2. Acute ischemic stroke based on clinical diagnosis (NIHSS 0-5) and presence of an objective neurological deficit
  3. Patients eligible for intravenous rt-PA should receive this therapy as soon as possible and no later than 4.5 hours from symptom onset
  4. Proximal Intracranial Artery Occlusion on Imaging by NCCT/CTA or MRI/MRA showing complete occlusion of the intracranial ICA, M1, or an "M1-like" M2 vessel with or without tandem cervical lesion. Notably, "M1-like" M2 vessel occlusions are defined functionally for the trial as following:

    1. Occlusion of both branches after MCA division (both M2s occluded) or
    2. Dominant M2 occlusion which is the larger diameter M2 and supplies the bulk of the MCA territory and/or
    3. If multi-phase CTA is performed, "M1-like" M2 occlusion such that the bulk (>2/3) of the MCA territory has evidence of delayed washout and/or
    4. If CT perfusion is performed, "M1-like" M2 occlusion such that Perfusion imaging shows a hypoperfusion lesion volume (Tmax >6 sec) of ≥100 mL
  5. Baseline Infarct Core of either:

    1. Baseline ASPECTS ≥6 on non-contrast CT (NCCT), or
    2. Baseline Infarct Core Volume of < 70cc on either CTP (Volume of rCBF <30%) or DWI if quantitative software tools are available (neither test is mandatory for study)

Exclusion Criteria:

  1. NIHSS ≥6
  2. Any sign of intracranial hemorrhage on baseline CT/MR (SDH/SAH/ICH)
  3. Any imaging findings suggestive of futile recanalization in the judgment of the local investigator
  4. High degree suspicion of intracranial arterial disease (ICAD), such as evidence of multifocal ICAD
  5. Premorbid disability (mRS ≥3)
  6. Inability to perform arterial puncture within 8 hours of last known well
  7. Seizures at stroke onset if it precludes obtaining an accurate baseline NIHSS
  8. Baseline blood glucose of <50 mg/dL (2.78 mmol) or >400 mg/dL (22.20 mmol)
  9. Baseline platelet count < 100,000/uL
  10. Serum creatinine levels > 3.0 mg/dL
  11. Presumed septic embolus or suspicion of bacterial endocarditis
  12. Any other condition that, in the opinion of the investigator, precludes an endovascular procedure or poses a significant hazard to the subject if an endovascular procedure was performed.
  13. Participation in another investigational treatment study in the previous 30 days
  14. Intubation and mechanical ventilation prior to study enrollment is medically indicated
  15. History of drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
  16. Site investigator does not have equipoise towards the ideal treatment concept (i.e. thrombectomy vs. best medical management)
  17. Known pregnancy
  18. Prisoner or incarceration

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04167527


Contacts
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Contact: David Wright, MD 404-778-1709 dwwrigh@emory.edu
Contact: Alex Hall, MS, RN, CEN 404-778-1585 alex.hall@emory.edu

Locations
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United States, Georgia
Grady Health System (non-CRN) Recruiting
Atlanta, Georgia, United States, 30322
Contact: David Wright, MD    404-778-1709    dwwrigh@emory.edu   
Contact: Shannon Doppelheuer, CCRC    404-778-1034    sdoppelheuer@emory.edu   
United States, Iowa
University of Iowa Recruiting
Iowa City, Iowa, United States, 52241
Contact: Edgar Samaniego, MD Ms       edgar-samaniego@uiowa.edu   
Sponsors and Collaborators
Emory University
University of Calgary
University of Cincinnati
Heidelberg University
Children's Hospital Medical Center, Cincinnati
Investigators
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Principal Investigator: Raul G Nogueira, MD Emory University
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Responsible Party: Raul Gomes Nogueira, Professor, Emory University
ClinicalTrials.gov Identifier: NCT04167527    
Other Study ID Numbers: IRB00107210
First Posted: November 19, 2019    Key Record Dates
Last Update Posted: February 8, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie the results reported in this article will be available after de-identification and in accordance with applicable laws and regulations. Other limited data sets may be provided as governed by ENDOLOW Publications SOP and in accordance with ICMJE.
Supporting Materials: Study Protocol
Time Frame: Data will become available beginning 1 year after publication of the primary analysis.
Access Criteria: After primary analysis publication, site investigators will have the opportunity to contribute to secondary, tertiary and quaternary analysis of the data and publication. Additionally, after 1 year, non-investigator researchers may submit requests to the publications committee for additional analysis after providing a methodologically sound proposal. Proposals can be sent to ENDOLOW-CCC@emory.edu. Data Transfer Agreements may apply.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Raul Gomes Nogueira, Emory University:
Immediate Mechanical Thrombectomy
Initial medical management
Large vessel occlusion
Efficacy
Safety
Additional relevant MeSH terms:
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Brain Ischemia
Cerebral Infarction
Ischemia
Pathologic Processes
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Brain Infarction
Stroke