Randomization of Endovascular Treatment in Acute Ischemic Stroke in the Extended Time Window (RESILIENTExt)

Randomization of Endovascular Treatment With Stent-retriever and/or Thromboaspiration vs. Best Medical Therapy in Acute Ischemic Stroke Due to Large VEssel OcclusioN Trial in the Extended Time Window

A phase III, randomized, multi-center, open label clinical trial that will examine whether endovascular treatment is superior to standard medical therapy alone in patients who suffer a large vessel anterior circulation ischemic stroke within 8-24 hours from time last seen well

Study Overview

• Status: Unknown
• Conditions: Stroke, Ischemic
• Intervention / Treatment: Device: Thrombectomy

Detailed Description

Prospective, multi-center, randomized, controlled, open-label, blinded-endpoint trial with a sequential design. The randomization employs a 1:1 ratio of mechanical thrombectomy with stent-retriever and/or thromboaspiration versus medical management alone in patients who suffer a large vessel anterior circulation ischemic stroke between 8 and 24 hours from time last seen well. Randomization will be done under a minimization process using age (≤68 vs. >68 years), baseline NIHSS (<17 v. ≥17), ASPECTS (5-7 vs. 8-10), therapeutic window (6-12 or 12-24 hours after TLKW), occlusion site (Intracranial ICA or M1), and clinical site. For the primary endpoint, subjects will be followed for 90 days post-randomization. Sham endovascular procedure has been rejected due to the medical risk of the angiography and practical issues that difficult to maintain blindness of investigators.

• Study Type: Interventional
• Enrollment (Anticipated): 376
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Ceara
    • Fortaleza, Ceara, Brazil
      • Recruiting
      • Hospital Geral de Fortaleza
      • Contact: Fabricio Lima, PhD; Phone Number: 85999982150; Email: fabricio.lima.neuro@gmail.com
  • DF
    • Brasília, DF, Brazil
      • Recruiting
      • Hospital de Base
      • Contact: Leticia C Rebello, MD; Phone Number: 61999150626; Email: letirebello@gmail.com
  • Espirito Santo
    • Vitória, Espirito Santo, Brazil, 29050-335
      • Recruiting
      • Associacao Congregacao de Santa Catarina
      • Contact: Jose A Fiorot Jr, PhD; Phone Number: 27992778579; Email: fiorotjr@gmail.com
  • Minas Gerais
    • Uberlândia, Minas Gerais, Brazil
      • Recruiting
      • Hospital das Clínicas de Uberlândia
      • Contact: Jullyanna Shinosaki, MD; Phone Number: +553491161478; Email: jsm_shinosaki@yahoo.com.br
  • Parana
    • Curitiba, Parana, Brazil
      • Not yet recruiting
      • Hospital de Clínicas da Universidade Federal do Paraná
      • Contact: Viviane F Zetola; Phone Number: 0154199761660; Email: viviane.zetola@gmail.com
  • RJ
    • Itaperuna, RJ, Brazil
      • Not yet recruiting
      • Conferencia Sao jose do Avai
      • Contact: Ivete itaperuna P Goncalves; Phone Number: 22988315201; Email: ipilloster@gmail.com
  • RS
    • Porto Alegre, RS, Brazil, 90035007
      • Recruiting
      • Hospital de Clínicas de Porto Alegre
      • Contact: Natacha Fleck; Phone Number: 51992699829; Email: pesquisaneurovascular@gmail.com
      • Contact: Ana Julia Lehnen; Phone Number: 51992870762; Email: anajlehnen@gmail.com
    • Porto Alegre, RS, Brazil
      • Not yet recruiting
      • Irmandade Da Santa Casa de Misericordia de Porto Alegre - ISCMPA
      • Contact: Alexandre Maulaz; Phone Number: 51992826915; Email: maulaz@terra.com.br
  • SP
    • Botucatu, SP, Brazil
      • Not yet recruiting
      • Hospital das Clínicas da Faculdade de Medicina de Botucatu
      • Contact: Rodrigo Bazan, PhD; Phone Number: 14981157727; Email: bazan.r@terra.com.br
    • Campinas, SP, Brazil
      • Not yet recruiting
      • Hospital de Clínicas - UNICAMP
      • Contact: Fabricio B Cardoso, MD; Phone Number: 019981254952; Email: fabriciobuchdid@hotmail.com
    • Ribeirão Preto, SP, Brazil
      • Recruiting
      • Hospital das Clinicas de Ribeirao Preto
      • Contact: Octavio M Pontes-Neto, PhD; Phone Number: 16981013465; Email: ompneto@gmail.com
    • São José Do Rio Preto, SP, Brazil
      • Not yet recruiting
      • Fundacao Faculdade Regional de Medicina S J Rio Preto
      • Contact: Raquel Hidalgo, MD; Phone Number: 17997640004; Email: draquelhidalgo@gmail.com
    • São Paulo, SP, Brazil
      • Not yet recruiting
      • Instituto de Assistência Médica ao Servidor Público Estadual de São Paulo
      • Contact: André Rezende, MD; Phone Number: +5511981359842; Email: andrerezende@neurointervencao.com.br
    • São Paulo, SP, Brazil
      • Not yet recruiting
      • Universidade Federal de Sao Paulo - UNIFESP/EPM
      • Contact: Gisele S Silva, PhD; Email: giselesampaio@hotmail.com

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. Acute ischemic stroke where patient is ineligible for IV thrombolytic treatment or the treatment is contraindicated (e.g., subject presents beyond recommended time from symptom onset), or where patient has received IV thrombolytic therapy without clinical improvement.
2. No significant pre-stroke functional disability (mRS ≤2)
3. Baseline NIHSS score obtained prior to randomization must be equal or higher than 8 points (assessed within one hour prior to qualifying imaging)
4. Age ≥18 years (no upper age limit)
5. Occlusion (TICI 0-1) of the intracranial ICA (distal ICA or T occlusions) and/or MCA-M1 segment suitable for endovascular treatment, as evidenced by CTA, MRA or angiogram, with or without concomitant cervical carotid occlusion or stenosis.

6. The presence of Age-Adjusted modified Clinical ASPECTS Mismatch (mCAM) defined as ASPECTS 5-10 and one of the following criteria:

   1. NIHSS ≥ 8 and >50% involvement in 0-1 Cortical (e.g. M1-6) ASPECTS areas (any age);
   2. NIHSS ≥ 8 and >50% involvement in 0-2 Cortical (e.g. M1-6) ASPECTS areas (and age < 80 years old);
   3. NIHSS ≥ 15 and >50% involvement in 0-3 Cortical (e.g. M1-6) ASPECTS areas (and age < 80 years old).
7. Patient treatable within 6-24 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 arterial puncture.
8. Informed consent obtained from patient or acceptable patient surrogate

Exclusion Criteria:

-Clinical criteria

1. Known hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR > 3.0
2. Baseline platelet count < 30.000/µL
3. Baseline blood glucose of < 50mg/dL
4. Severe, sustained hypertension (SBP > 185 mm Hg or DBP > 110 mm Hg) NOTE: If the blood pressure can be successfully reduced and maintained at the acceptable level using AHA guidelines recommended medication (including iv antihypertensive drips), the patient can be enrolled.
5. Patients in coma defined as totally unresponsive; responding only with reflexes or being areflexic (Intubated patients for transfer could be randomized only in case an NIHSS is obtained by a neurologist prior transportation).
6. Seizures at stroke onset which would preclude obtaining a baseline NIHSS
7. Serious, advanced, or terminal illness with anticipated life expectancy of less than one year.
8. History of life-threatening allergy (more than rash) to contrast medium
9. Subjects who has received IV t-PA treatment beyond 4.5 hours from the beginning of the symptoms
10. Woman of childbearing potential who is known to be pregnant or who has a positive pregnancy test on admission.
11. Subject participating in a study involving an investigational drug or device that would impact this study.
12. Cerebral vasculitis
13. Patients with a pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations, mRS score at baseline must be ≤2. This excludes patients who are severely demented, require constant assistance in a nursing home type setting or who live at home but are not fully independent in activities of daily living (toileting, dressing, eating, cooking and preparing meals, etc.)

14. Unlikely to be available for 90-day follow-up (e.g. no fixed home address, visitor from overseas).

    - Neuroimaging criteria

15. Hypodensity on CT or restricted diffusion on MRI amounting to an ASPECTS score of <5.
16. Complete involvement of more than 3 cortical ASPECTS areas (e.g. M1, M2, M3, M4, M5, or M6).
17. Complete absence of leptomeningeal collaterals on CT angiography (e.g. Malignant CTA pattern or score 0).
18. CT or MR evidence of hemorrhage (the presence of GRE microbleeds is allowed).
19. Significant mass effect with midline shift.
20. Evidence of ipsilateral carotid occlusion, high grade stenosis or arterial dissection in the extracranial or petrous segment of the internal carotid artery that cannot be treated or will prevent access to the intracranial clot or excessive tortuosity of cervical vessels precluding device delivery/deployment
21. Subjects with occlusions in multiple vascular territories (e.g., bilateral anterior circulation, or anterior/posterior circulation)
22. Evidence of intracranial tumor (except small meningioma).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: thrombectomy; mechanical thrombectomy with stent-retriever and/or thromboaspiration	Device: Thrombectomy; Endovascular treatment of large vessel occlusion (mechanical thrombectomy) with stent-retriever and/or thromboaspiration (neurointerventionalist choice); Other Names: Endovascular treatment
ACTIVE_COMPARATOR: Clinical treatment; Best Medical treatment	Device: Thrombectomy; Endovascular treatment of large vessel occlusion (mechanical thrombectomy) with stent-retriever and/or thromboaspiration (neurointerventionalist choice); Other Names: Endovascular treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Rankin Scale scores	Distribution of the modified Rankin Scale scores at 90 days (shift analysis). The score range from zero to 6 with higher values indicating a worst functional outcome at 90 days	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality at 90 days	Mortality at 90 days	90 days
Proportion of Patients with Functional independence in 90 days	Functional independence defined as mRS ≤2	90 days
Disability on the utility-weighted modified Rankin scale (UW-mRS)	Mean score for disability on the utility-weighted modified Rankin scale (UW-mRS). The score range from 1 to zero with higher values indicating a better functional outcome at 90 days	90 days
Quality of life measured by EuroQol Group 5-Dimension Self-Report Questionnaire (EuroQol / EQ5D)	Quality of life analysis as measured by EuroQol/EQ5D 5-Dimension Self-Report Questionnaire, on which scores range from -0.176 to 1, with higher values indicating a better quality of life]) at 90 days	90 days and 1 year
Proportion of patients with Intracranial Hemorrhage at 24 hours	Clinically significant ICH rates at 24 (-2/+12) hours. All intracerebral hemorrhages will be classified by a central core-lab using the Heidelberg criteria. Symptomatic ICH will be defined as per the SITS-MOST definition: deterioration in NIHSS score of ≥4 points within 24 hours from treatment and evidence of intraparenchymal hemorrhage type 2 in the 22 to 36 hours follow-up imaging scans.	24 hours
Procedural related complications	Procedural related complications: arterial perforation, arterial dissection, and embolization in a previously uninvolved vascular territory	immediately after procedure

Collaborators and Investigators

• Sponsor: Hospital de Clinicas de Porto Alegre
• Collaborators: University of Campinas, Brazil; Federal University of São Paulo; UPECLIN HC FM Botucatu Unesp; Hospital de Base; Irmandade Santa Casa de Misericórdia de Porto Alegre; Universidade Federal do Paraná; Irmandade da Santa Casa de Misericordia de Sao Paulo; Federal University of Uberlandia; Hospital das Clínicas de Ribeirão Preto; Hospital Geral de Fortaleza; Instituto de Assistencia Medica ao Servidor Publico Estadual, Sao Paulo; Fundação Faculdade Regional de Medicina de São José do Rio Preto; Hospital Estadual Central; Hospital Sao Jose do Avai
• Investigators: Principal Investigator: Sheila CO Martins, MD, PhD, Hospital de Clínicas de Porto Alegre

Publications and helpful links

General Publications

• Roaldsen MB, Lindekleiv H, Mathiesen EB. Intravenous thrombolytic treatment and endovascular thrombectomy for ischaemic wake-up stroke. Cochrane Database Syst Rev. 2021 Dec 1;12(12):CD010995. doi: 10.1002/14651858.CD010995.pub3.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 9, 2020
• Primary Completion (ANTICIPATED): February 1, 2022
• Study Completion (ANTICIPATED): May 1, 2022

Study Registration Dates

• First Submitted: February 3, 2020
• First Submitted That Met QC Criteria: February 4, 2020
• First Posted (ACTUAL): February 5, 2020

Study Record Updates

• Last Update Posted (ACTUAL): February 10, 2021
• Last Update Submitted That Met QC Criteria: February 7, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: treatment; stroke; ischemic stroke; thrombectomy; acute stroke
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke; Ischemia
• Other Study ID Numbers: 17877519.6.1001.5327

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Because of the sensitive nature of the data collected for this study, requests to access the dataset from qualified researchers trained in human subject confidentiality protocols may be sent to the principal investigators
• IPD Sharing Time Frame: after de publication for 6 months
• IPD Sharing Access Criteria: Because of the sensitive nature of the data collected for this study, requests to access the dataset from qualified researchers trained in human subject confidentiality protocols may be sent to the principal investigators
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No