EndoVascular Treatment With Stent-retriever and/or Thromboaspiration vs. Best Medical Therapy in Acute Ischemic Stroke

Phase 3

Completed

• Conditions: Ischemic Stroke; Stroke
• Interventions: Procedure: Thrombectomy; Device: Stentriever Solitaire FR® or Penumbra System®

• Registration Number: NCT02216643
• Lead Sponsor: Hospital de Clinicas de Porto Alegre

Brief Summary

Prospective, multi-center, randomized, controlled, open, blinded-endpoint trial with a sequential design. The randomization employs a 1:1 ratio of mechanical thrombectomy with stentriever and/or Thromboaspiration versus medical management alone. Randomization will be done under a minimization process using age, baseline NIHSS, use of IV tpa, vessel occlusion site and hospital. To evaluate the hypothesis that mechanical thrombectomy is superior to medical management alone in achieving more favorable outcomes in the distribution of the modified Rankin Scale scores at 90 days in subjects presenting with acute large vessel ischemic stroke \<8 hours from symptom onset. Subjects are either ineligible for IV alteplase or have received IV alteplase therapy without recanalization. Sample size is projected to be 690 patients for a difference in treatment effect of 10%.

Detailed Description

Patients with acute ischemic stroke related to anterior circulation large vessel occlusion will be randomized up to 8 hours from symptoms onset in both arms (mechanical thrombectomy versus medical management alone). Subjects are either ineligible for IV alteplase or have received IV alteplase therapy without recanalization. They will be admitted at acute stroke units in Brazil (or ICU if needed) and treated following international guidelines. Concomitant medications and non-pharmacological therapies will be recorded. A maximum of six attempts to retrieve the thrombus in a single vessel can be made. No additional treatment will be allowed either with Intrarterial tPA, mechanical devices or angioplasty/stenting.

The primary endpoint will be distribution of the modified Rankin Scale scores at 90 days (shift analysis) as evaluated by two separate assessors who are blinded to treatment

Interim Analysis The sample size for this Phase III Trial is projected to be 690 subjects. For interim analyses, the method of Lan and DeMets will be used to allocate alpha via the power family method with φ (phi) equal to 1 for the assessment of efficacy and futility, respectively after the first 174, 346 and 518 patients enrolled have completed the 90-day follow-up. The interval may be more frequent if requested by the Data and Safety Monitoring Board (DSMB). At interim analysis, in case the stopping boundaries are crossed the DSMB may recommend stopping the study either for better efficacy of the tested treatment either for futility. Other factors, such as safety, will be taken into consideration by the DSMB in the decision to stop the study. When considering stopping the trial for safety reasons, the DSMB will be instructed to consider both mortality (mRS=6) and severe dependency (mRS=5) at 3 months as one single outcome.

Study Timeline

• Study First Submitted: 2014-08-13
• Study First Submitted QC: 2014-08-13
• Study First Posted: 2014-08-15
• Study Start: 2017-02-08
• Primary Completion: 2019-06-30
• Study Completion: 2019-06-30
• Status Verified: 2020-02
• Last Update Submitted: 2020-02-16
• Last Update Posted: 2020-02-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 221

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 ≤ 1)
3. Baseline NIHSS score obtained prior to randomization must be equal or higher than 8 points
4. Age ≥18 years
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. Patient treatable within eight 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 groin puncture.
7. Informed consent obtained from patient or acceptable patient surrogate

Exclusion 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 or > 400mg/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 (NIHSS item of consciousness >1) (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 lactating 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 ≤1. 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).
15. Hypodensity on CT or restricted diffusion amounting to an ASPECTS score of <6 on NCCT, or <5 on DWI MRI. The use of CTP or MRI perfusion is optional.
16. Collaterals with malignant profile on CTA (without colateral circulation on CTA)
17. CT or MR evidence of hemorrhage (the presence of GRE microbleeds is allowed).
18. Significant mass effect with midline shift.
19. 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
20. Subjects with occlusions in multiple vascular territories (e.g., bilateral anterior circulation, or anterior/posterior circulation)
21. Evidence of intracranial tumor (except small meningioma).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
thrombectomy	Stentriever Solitaire FR® or Penumbra System®	mechanical thrombectomy with stentriever Solitaire FR® and/or thromboaspiration with Penumbra System® in patients with large vessel occlusion in cerebral anterior circulation vessels
thrombectomy	Thrombectomy	mechanical thrombectomy with stentriever Solitaire FR® and/or thromboaspiration with Penumbra System® in patients with large vessel occlusion in cerebral anterior circulation vessels

Primary Outcome Measures

Name	Time	Method
Distribution of the modified Rankin Scale scores (shift analysis)	90 days	Distribution of the modified Rankin Scale scores at 90 days (shift analysis) as evaluated by two separate assessors who are blinded to treatment

Secondary Outcome Measures

Name	Time	Method
Mortality	90 days	Mortality at 90 days
Functional independence (modified Rankin Score ≤ 2)	90 days	Functional independence measured by modified Rankin Score ≤ 2 in 90 days in both groups
Infarct Burden at 24 hours	24 hours	ASPECTS change from baseline to 24 hours on CT or MRI
Dramatic early favorable response	24 hours	defined as an NIHSS score 0-2 or a NIHSS score decrease of ≥8 from baseline at 24 hours
Cost effectiveness	Life-time horizon perspective	Cost effectiveness analysis of interventional therapy vs medical therapy alone
Quality of life analysis	3 months, 6 months, 1 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
Vessel recanalization at 24 hours	24 hours	Vessel recanalization evaluated by CT angiography (CTA) or MR angiography (MRA) at 24 hours in both treatment groups
Successful recanalization at the end of procedure	immediatelly after procedure (only thrombectomy arm)	defined as a grade of 2b or 3 (indicating reperfusion of \>50% of the affected territory) on the modified Thrombolysis in Cerebral Infarction (mTICI) scale
Symptomatic Intracranial hemorrhage	24 hours	Clinically significant Intracranial hemorrhage (ICH) rates at 24 (-2/+12) hours. All intracerebral hemorrhages will be classified by a central core-lab using the ECASS criteria for CT evaluation. 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. The incidence of any asymptomatic hemorrhage measured at 24 (-2/+12) hours will also be compared
Procedure related complications	During the procedure	Complications occurring during the procedure will be evaluated: distal embolization in a new territory, arterial dissection, arterial perfuration, groin hematoma

Trial Locations

Locations (15)

Hospital Estadual Central; 🇧🇷 Vitória, Espírito Santo, Brazil

Hospital São José do Avaí; 🇧🇷 Itaperuna, Rio De Janeiro, Brazil

Hospital de Clínicas - UNICAMP; 🇧🇷 Campinas, São Paulo, Brazil

Clinica Neurologica e Neurocirurgica de Joinville S/S Ltda; 🇧🇷 Joinville, Santa Catarina, Brazil

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

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

Hospital Geral de Fortaleza/SUS; 🇧🇷 Fortaleza, Ceará, Brazil

UNIÃO BRASILEIRA DE EDUCAÇÃO E ASSISTENCIA, Hospital São Lucas PUCRS; 🇧🇷 Porto Alegre, Rio Grande Do Sul, Brazil

Hospital Geral Roberto Santos; 🇧🇷 Salvador, Bahia, Brazil

Hospital de Clínicas de Porto Alegre; 🇧🇷 Porto Alegre, Rio Grande Do Sul, Brazil

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

Hospital Governador Celso Ramos; 🇧🇷 Florianópolis, SC, Brazil

Hospital de Clínicas de Ribeirão Preto; 🇧🇷 Ribeirão Preto, São Paulo, Brazil

Hospital de Base do Distrito Federal; 🇧🇷 Brasília, DF, Brazil

Irmandade da Santa Casa de Misericórdia; 🇧🇷 São Paulo, SP, Brazil