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

Phase 3

• Conditions: Stroke, Ischemic
• Interventions: Device: Thrombectomy

• Registration Number: NCT04256096
• Lead Sponsor: Hospital de Clinicas de Porto Alegre

Brief Summary

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

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 Timeline

• Study First Submitted: 2020-02-03
• Study First Submitted QC: 2020-02-04
• Study First Posted: 2020-02-05
• Study Start: 2020-03-09
• Status Verified: 2021-02
• Last Update Submitted: 2021-02-07
• Last Update Posted: 2021-02-10
• Primary Completion: 2022-02-01
• Study Completion: 2022-05-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 376

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
thrombectomy	Thrombectomy	mechanical thrombectomy with stent-retriever and/or thromboaspiration
Clinical treatment	Thrombectomy	Best Medical treatment

Primary Outcome Measures

Name	Time	Method
Modified Rankin Scale scores	90 days	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

Secondary Outcome Measures

Name	Time	Method
Procedural related complications	immediately after procedure	Procedural related complications: arterial perforation, arterial dissection, and embolization in a previously uninvolved vascular territory
Proportion of patients with Intracranial Hemorrhage at 24 hours	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.
Proportion of Patients with Functional independence in 90 days	90 days	Functional independence defined as mRS ≤2
Disability on the utility-weighted modified Rankin scale (UW-mRS)	90 days	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
Quality of life measured by EuroQol Group 5-Dimension Self-Report Questionnaire (EuroQol / EQ5D)	90 days and 1 year	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
Mortality at 90 days	90 days	Mortality at 90 days

Trial Locations

Locations (14)

Hospital Geral de Fortaleza; 🇧🇷 Fortaleza, Ceara, Brazil

Hospital de Base; 🇧🇷 Brasília, DF, Brazil

Associacao Congregacao de Santa Catarina; 🇧🇷 Vitória, Espirito Santo, Brazil

Hospital de Clínicas da Universidade Federal do Paraná; 🇧🇷 Curitiba, Parana, Brazil

Conferencia Sao jose do Avai; 🇧🇷 Itaperuna, RJ, Brazil

Hospital de Clinicas de Porto Alegre; 🇧🇷 Porto Alegre, RS, Brazil

Hospital das Clínicas da Faculdade de Medicina de Botucatu; 🇧🇷 Botucatu, SP, Brazil

Hospital de Clínicas - UNICAMP; 🇧🇷 Campinas, SP, Brazil

Fundacao Faculdade Regional de Medicina S J Rio Preto; 🇧🇷 São José Do Rio Preto, SP, Brazil

Instituto de Assistência Médica ao Servidor Público Estadual de Sao Paulo; 🇧🇷 São Paulo, SP, Brazil

Universidade Federal de São Paulo - UNIFESP/EPM; 🇧🇷 São Paulo, SP, Brazil

Hospital das Clínicas de Uberlândia; 🇧🇷 Uberlândia, Minas Gerais, Brazil

Hospital das Clinicas de Ribeirao Preto; 🇧🇷 Ribeirão Preto, SP, Brazil

Irmandade da Santa Casa de Misericordia de Porto Alegre - ISCMPA; 🇧🇷 Porto Alegre, RS, Brazil