EXTEND-IV: Randomization to Extend Stroke Intravenous ThromboLysis In Evolving Non-Large Vessel Occlusion With TNK (RESILIENT

Sponsor
Hospital Moinhos de Vento (Other)
Overall Status
Recruiting
CT.gov ID
NCT05199662
Collaborator
Ministry of Health, Brazil (Other), Boehringer Ingelheim (Industry), Brainomix Limited (Industry)
642
6
2
27.3
107
3.9

Study Details

Study Description

Brief Summary

A phase III, randomized, multi-center clinical trial that will examine whether treatment with intravenous TNK is superior to placebo in patients who suffer a non-large vessel occlusion ischemic stroke within 4.5-12 hours from time last seen well. The randomization employs a 1:1 ratio of intravenous thrombolysis with Tenecteplase (TNK) versus placebo in patients who suffer a non-large vessel occlusion ischemic stroke between 4.5 and 12 hours from time last seen well (TLSW) and have evidence of salvageable brain tissue on perfusion imaging.

Condition or Disease Intervention/Treatment Phase
  • Drug: Intravenous tenecteplase
  • Drug: Placebo
Phase 3

Detailed Description

Prospective, multi-center, randomized, controlled, double blinded trial with an adaptive design and population enrichment. The randomization employs a 1:1 ratio of intravenous thrombolysis with Tenecteplase (TNK) versus placebo in patients who suffer a non-large vessel occlusion ischemic stroke between 4.5 and 12 hours from time last seen well (TLSW) and have evidence of salvageable brain tissue on perfusion imaging. Randomization will be done under a minimization process using age (≤70 vs. >70 years), baseline NIHSS (≤10 vs. >10), baseline infarct volume (≤15mL vs. >15-30mL vs. >30-50mL), perfusion mismatch volume (≤15mL vs.

15-30mL vs. >30-50mL), therapeutic window (4.5-9 or 9-12 hours after TLKW), and clinical site. The candidate enriched populations that the trial considers are based on time last known well (TLKW) to randomization (4.5-9 vs. 9-12 hours) and mismatch volumes as measured using Mismatch on MRP-DWI or CTP-rCBF maps (>40 cc vs. >30cc vs. >20cc vs. >10cc). For the primary endpoint, subjects will be followed for 90 days post-randomization.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
642 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase III, Randomized, Multi-center Clinical Trial That Will Examine Whether Treatment With Intravenous TNK is Superior to Placebo in Patients Who Suffer a Non-large Vessel Occlusion Ischemic Stroke Within 4.5-12 Hours From Time Last Seen Well
Actual Study Start Date :
Jan 20, 2022
Anticipated Primary Completion Date :
Jan 1, 2024
Anticipated Study Completion Date :
May 1, 2024

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Control group

Placebo administered as a single bolus injection over 5 seconds

Drug: Placebo
Placebo matching IV TNK

Experimental: Intravenous tenecteplase (TNK)

Intravenous thrombolysis with Tenecteplase (TNK) at a dose of 0.25 mg/Kg (maximum 25mg, administered as a bolus over 5 seconds)

Drug: Intravenous tenecteplase
Intravenous tenecteplase (TNK). Patients will receive intravenous TNK (0.25mg/kg, maximum 25mg, administered as a bolus over 5 seconds).
Other Names:
  • TNK
  • Metalyse
  • Outcome Measures

    Primary Outcome Measures

    1. Distribution of the modified Rankin Scale scores at 90 days (shift analysis) as evaluated by two separate assessors at the central core lab) who are blinded to treatment. [90 days]

      Distribution of the modified Rankin Scale scores at 90 days (shift analysis) as evaluated by two separate assessors at the central core lab) who are blinded to treatment. Primary Endpoint will consider central core lab readings only (video interview with RFA method) with local reading as a back-up mechanism

    Secondary Outcome Measures

    1. Rates of Good Functional Outcomes adjusted for the baseline mRS and stroke severity (NIHSS) according to the modified Rankin Scale scores at 90 days [90 days]

      Rates of Good Functional Outcomes adjusted for the baseline mRS and stroke severity (NIHSS) according to the modified Rankin Scale scores at 90 days as following: If NIHSS <10 and Baseline mRS 0 or 1: 90-day mRS ≤1 If NIHSS <10 and Baseline mRS 2: 90-day mRS ≤2 If NIHSS ≥10 and Baseline mRS 0 or 1: 90-day mRS ≤2 If NIHSS ≥10 and Baseline mRS 2: 90-day mRS ≤3

    2. Rates of Excellent Outcome defined as mRS ≤ 1 and/ or equal to Baseline mRS at 90 days [90 days]

      Rates of Excellent Outcome defined as mRS ≤ 1 and/ or equal to Baseline mRS at 90 days

    3. Rates of Independent Outcome defined as mRS ≤ 2 and/ or equal to Baseline mRS at 90 days [90 days]

      Rates of Independent Outcome defined as mRS ≤ 2 and/ or equal to Baseline mRS at 90 days

    4. Mean score for disability on the utility-weighted modified Rankin scale (UW-mRS) at 90 days [90 days]

      Mean score for disability on the utility-weighted modified Rankin scale (UW-mRS) at 90 days

    5. Final infarct volume (FIV) and infarct growth (FIV - baseline infarct on CTP or DWI) evaluated on CT or MRI at 3-5 days (if available) [3-5 days]

      Final infarct volume (FIV) and infarct growth (FIV - baseline infarct on CTP or DWI) evaluated on CT or MRI at 3-5 days (if available)

    6. Final infarct volume (FIV) and infarct growth (FIV - baseline infarct on CTP or DWI) evaluated on CT or MRI at 24 hours (-2/+12 hours) [24 hours (-2/+12 hours)]

      Final infarct volume (FIV) and infarct growth (FIV - baseline infarct on CTP or DWI) evaluated on CT or MRI at 24 hours (-2/+12 hours)

    7. Dramatic early favorable response as determined by an NIHSS of 0-2 or NIHSS improvement ≥ 4 points at 24 (-2/+12 hours) hours [24 (-2/+12 hours) hours]

      Dramatic early favorable response as determined by an NIHSS of 0-2 or NIHSS improvement ≥ 4 points at 24 (-2/+12 hours) hours

    8. Quality of life analysis as measured by EuroQol/EQ5D at 3 month, 6 months and one year, between interventional therapy vs medical therapy alone [3 month, 6 months and one year]

      Quality of life analysis as measured by EuroQol/EQ5D at 3 month, 6 months and one year, between interventional therapy vs medical therapy alone

    9. Brain tissue reperfusion evaluated by CT or MRI perfusion at 24 hours in both treatment groups (if available) [24 hours]

      Brain tissue reperfusion evaluated by CT or MRI perfusion at 24 hours in both treatment groups (if available)

    10. Mortality at 90 days ( safety outcome) [90 days]

      Mortality at 90 days ( safety outcome)

    11. Clinically significant ICH rates at 24 (-2/+12) hours. [24 (-2/+12) hours]

      Clinically significant ICH rates at 24 (-2/+12) hours. All intracerebral hemorrhages will be classified by a central core-lab using the ECASS criteria. Symptomatic ICH will be defined as per the modified SITS-MOST definition: local or remote parenchymal hemorrhage type 2, subarachnoid hemorrhage, and/or intraventricular hemorrhage on the post-treatment imaging scan, combined with a neurological deterioration of 4 points or more on the NIHSS from baseline, or from the lowest NIHSS value between baseline and 24 h, or leading to death that the CEC/DSMB judges is causative of the deterioration.

    12. Incidence of any intracranial hemorrhage (Heidelberg criteria) measured at 24 (-2/+12) [24 (-2/+12)]

      Incidence of any intracranial hemorrhage (Heidelberg criteria) measured at 24 (-2/+12) hours

    Other Outcome Measures

    1. Cost effectiveness analysis of IV TNK vs standard medical therapy [12 months]

      Cost effectiveness analysis of IV TNK vs standard medical therapy

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
      1. Acute ischemic stroke where patient is ineligible for IV thrombolytic treatment with Alteplase due to onset >4.5 hours and is ineligible for endovascular treatment under standard of care due to absence of proximal arterial occlusion (e.g. intracranial ICA, MCA-M1 and dominant M2 segments, and vertebrobasilar arteries).
    • Dominant M2 segment is defined is a division supplying >50% of the MCA territory vs co-dominant supplying 50% of the MCA territory vs non-dominant supplying <50% of the MCA territory.

    1. No significant pre-stroke functional disability (mRS ≤2). 3. Evidence of a disabling deficit including significant aphasia, neglect, hemianopsia, or hemiparesis and/or baseline NIHSS score ≥4 points (obtained prior to randomization).

    2. Age ≥18 years (no upper age limit). 5. The presence of a Target Mismatch defined as:

    1. Ischemic Core < 50cc) (defined on NCCT/CTP* or DWI-MRI)
    • e-volume NCCT can be used to exclude patients if the investigator believes that its volume assessment is more reliable than the CTP volume in any particular case.
    1. Mismatch Volume (TMax >6sec lesion - Core volume lesion) >10cc c. Mismatch Ratio >1.4 6. Patient treatable within 4.5-12 hours of symptom onset. Symptoms onset is defined as point in time the patient was last seen well (at baseline). Treatment start is defined as initiation of IV TNK or placebo infusion.
    1. Informed consent obtained from patient or acceptable patient surrogate.
    Exclusion Criteria:
    1. Intracranial hemorrhage (ICH) identified by CT or MRI.

    2. Rapidly improving symptoms, particularly if in the judgment of the managing clinician that the improvement is likely to result in the patient having an NIHSS score of < 4 at randomization.

    3. Pre-stroke mRS score of ≥ 2 (indicating previous disability)

    4. Contra indication to imaging with MR or CT with contrast agents.

    5. Infarct core >1/3 MCA territory qualitatively or >50 mL quantitatively (determined by DWI lesion on MR).

    6. Participation in any investigational study in the previous 30 days

    7. Any terminal illness such that patient would not be expected to survive more than 1 year).

    8. Baseline platelet count < 100.000/µL

    9. Woman of childbearing potential who is known to be pregnant or who has a positive pregnancy test on admission.

    10. Previous stroke within last three months.

    11. Recent past history or clinical presentation of ICH, subarachnoid hemorrhage (SAH), arterio-venous (AV) malformation, aneurysm, or cerebral neoplasm other than meningioma.

    12. Current use of oral anticoagulants and a prolonged prothrombin time (INR > 1.6).

    13. Use of heparin, except for low dose subcutaneous heparin, in the previous 48 hours and a prolonged partial thromboplastin time exceeding the upper limit of the local laboratory normal range

    14. Use of glycoprotein IIb - IIIa inhibitors within the past 72 hours. Use of single agent oral platelet inhibitors (clopidogrel or low-dose aspirin) prior to study entry is permitted.

    15. Clinically significant hypoglycemia.

    16. Uncontrolled hypertension defined by a blood pressure > 185 mmHg systolic or >110 mmHg diastolic on at least 2 separate occasions at least 10 minutes apart, or requiring aggressive treatment to reduce the blood pressure to within these limits. The definition of "aggressive treatment" is left to the discretion of the responsible Investigator.

    17. Hereditary or acquired hemorrhagic diathesis.

    18. Gastrointestinal or urinary bleeding within the preceding 21 days.

    19. Major surgery within the preceding 14 days which poses risk in the opinion of the Investigator.

    20. Exposure to a thrombolytic agent within the previous 72 hours.

    21. Subject participating in a study involving an investigational drug or device that would impact this study.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Hospital Moinhos de Vento Porto Alegre Rio Grande Do Sul Brazil 90035000
    2 Instituto Hospitalar de Base Do Distrito Federal Brasília Brazil 70335900
    3 Hospital Geral de Fortaleza Fortaleza Brazil 60175-295
    4 Hospital de Clínicas de Porto Alegre Porto Alegre Brazil 90035-007
    5 Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - Universidade de São Paulo Ribeirão Preto Brazil 14015-010
    6 Hospital São Paulo São Paulo Brazil 04037-002

    Sponsors and Collaborators

    • Hospital Moinhos de Vento
    • Ministry of Health, Brazil
    • Boehringer Ingelheim
    • Brainomix Limited

    Investigators

    • Principal Investigator: Gisele Sampaio Silva, MD, MPH, PhD, Universidade Federal de São Paulo
    • Principal Investigator: Raul G Nogueira, MD, Emory University
    • Principal Investigator: Sheila CO Martins, MD, PhD, Hospital Moinhos de Vento

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Hospital Moinhos de Vento
    ClinicalTrials.gov Identifier:
    NCT05199662
    Other Study ID Numbers:
    • RESILIENT EXTEND-IV
    First Posted:
    Jan 20, 2022
    Last Update Posted:
    Apr 19, 2022
    Last Verified:
    Dec 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Hospital Moinhos de Vento
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Apr 19, 2022