Ischemic Stroke, Stroke
Conditions
Keywords
Stroke, Ischemic Stroke, Thrombectomy, Reperfusion Therapy, Treatment
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.
Interventions
PROCEDUREThrombectomy
Patients with acute ischemic stroke with anterior circulation large vessel occlusion will be randomized to receive mechanical thrombectomy with stent-retriever Solitaire FR® and/or thromboaspiration with Penumbra System® versus medical management alone versus medical management alone. A maximum of six attempts to retrieve the thrombus in a single vessel can be made . No additional treatment will be allowed either with IA tPA, other mechanical devices or angioplasty/stenting.
DEVICEStentriever Solitaire FR® or Penumbra System®
Patients with acute ischemic stroke with anterior circulation large vessel occlusion will be randomized to receive mechanical thrombectomy with stent-retriever and/or thromboaspiration versus medical management alone versus medical management alone. A maximum of six attempts to retrieve the thrombus in a single vessel can be made . No additional treatment will be allowed either with IA tPA, other mechanical devices or angioplasty/stenting.
Sponsors
Ministry of Health, Brazil
Medtronic
Penumbra Inc.
iSchemaView, Inc
Brainomix Limited
Hospital de Clinicas de Porto Alegre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Functional independence (modified Rankin Score ≤ 2) | 90 days | Functional independence measured by modified Rankin Score ≤ 2 in 90 days in both 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 |
| Mortality | 90 days | Mortality at 90 days |
| 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 |
| 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 |
Countries
Brazil
Outcome results
None listed