Cerebral Infarction, Stroke, Acute
Conditions
Keywords
endovascular, endovascular procedure, Mechanical Thrombectomy
Brief summary
This is a study to evaluate the hypothesis that FDA cleared thrombectomy devices plus medical management leads to superior clinical outcomes in acute ischemic stroke patients at 90 days when compared to medical management alone in appropriately selected subjects with the Target mismatch profile and an MCA (M1 segment) or ICA occlusion who can be randomized and have endovascular treatment initiated between 6-16 hours after last seen well.
Detailed description
DEFUSE 3 is a prospective randomized Phase III multicenter controlled trial of patients with acute ischemic anterior circulation strokes due to large artery occlusion treated between 6-16 hours of stroke onset with endovascular thrombectomy therapy vs. control. The primary endpoint, the modified Rankin Score, will be assessed at 3 months. The patients' participation in the study concludes at that time (3 months from stroke onset). The study will randomize up to 476 patients over 4 years. The purpose of DEFUSE 3 is to assess the safety and efficacy of thrombectomy in carefully selected patients in an extended time window. Only the devices listed in this protocol will be used. Selection of the specific device (or devices) is determined by the individual endovascular therapist. Patients who meet the inclusion criteria will undergo either CT Perfusion/CT Angiogram or MR DWI/PWI/MRA studies prior to randomization. Patients who have evidence of an ICA or MCA M1 occlusion and a Target Mismatch Profile will be randomized in a 1:1 ratio to treatment with one or more DEFUSE 3 approved thrombectomy devices (only the devices listed in this protocol are approved for use in DEFUSE 3) plus standard medical therapy versus standard medical therapy alone. Patients who are enrolled, but not randomized, will receive standard therapy according to local guidelines. Baseline data, and information about early stroke therapies, will be captured for this group of patients. Randomization of a maximum of 476 patients is planned. A novel adaptive design will identify, at interim analyses, the group with the best prospect for showing benefit from endovascular treatment, based on baseline core lesion volumes and the times since stroke onset. Interim analyses will be conducted at 200 and 340 patients, at which time the study may stop for efficacy/futility, or the inclusion criteria may be adjusted in the case of futility.
Interventions
PROCEDUREEndovascular Thrombectomy
Patients will be treated with thrombectomy devices (stent-retrievers) and/or suction thrombectomy systems currently cleared by the FDA for thrombus removal in patients experiencing an acute stroke following the published instructions for use for these devices. These devices will be used between 6 and 16 hours following symptom onset in DEFUSE 3 based on an FDA IDE. The devices which will be used are the Trevo Retriever, the Solitaire Revascularization Device and the Penumbra system thrombectomy system.
DEVICETrevo Retriever
Trevo Retriever is one of the interventional devices that is approved for use in DEFUSE 3 during the endovascular thrombectomy procedure. The device choice is at the discretion of the physician performing the procedure.
DEVICESolitaire™ FR Revascularization Device
Solitaire™ FR Revascularization Device is one of the interventional devices that is approved for use in DEFUSE 3 during the endovascular thrombectomy procedure. The device choice is at the discretion of the physician performing the procedure.
DEVICEPenumbra thrombectomy system
Penumbra thrombectomy system is one of the interventional devices that is approved for use in DEFUSE 3 during the endovascular thrombectomy procedure. The device choice is at the discretion of the physician performing the procedure. The Penumbra System includes: • Penumbra Aspiration Pump (1115V) Penumbra System 054 Penumbra System MAX Penumbra System 110 Aspiration Tubing Penumbra System \[026, 032, 041\] Penumbra System Separator Flex \[026, 032, 041, 054\] Penumbra Pump MAX Penumbra System Reperfusion Catheter ACE64 & ACE68
DEVICECovidien MindFrame Capture Revascularization Device
Covidien MindFrame Capture Revascularization Device is one of the interventional devices that is approved for use in DEFUSE 3 during the endovascular thrombectomy procedure. The device choice is at the discretion of the physician performing the procedure.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
University of Cincinnati
Medical University of South Carolina
NINDS Stroke Trials Network (StrokeNet)
Gregory W Albers
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
Clinical Inclusion Criteria: 1. Signs & symptoms consistent w/ the diagnosis of acute anterior circulation ischemic stroke 2. Age 18-90 years 3. Baseline NIHSSS is ≥ 6 and remains ≥6 immediately prior to randomization 4. Endovascular treatment can be initiated (femoral puncture) between 6 and 16 hours of stroke onset. Stroke onset is defined as the time the patient was last known to be at their neurologic baseline (wake-up strokes are eligible if they meet the above time limits). 5. modified Rankin Scale less than or equal to 2 prior to qualifying stroke (functionally independent for all ADLs) 6. Patient/Legally Authorized Representative has signed the Informed Consent form. Clinical
Exclusion criteria
1. Other serious, advanced, or terminal illness (investigator judgment) or life expectancy is less than 6 months. 2. Pre-existing medical, neurological or psychiatric disease that would confound the neurological or functional evaluations 3. Pregnant 4. Unable to undergo a contrast brain perfusion scan with either MRI or CT 5. Known allergy to iodine that precludes an endovascular procedure 6. Treated with tPA \>4.5 hours after time last known well 7. Treated with tPA 3-4.5 hours after last known well AND any of the following; age \>80, current anticoagulant use, history of diabetes or prior stroke, NIHSS \>25 8. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; recent oral anticoagulant therapy with INR \> 3 (recent use of one of the new oral anticoagulants is not an exclusion if estimated GFR \> 30 ml/min). 9. Seizures at stroke onset if it precludes obtaining an accurate baseline NIHSS 10. Baseline blood glucose of \<50mg/dL (2.78 mmol) or \>400mg/dL (22.20 mmol) 11. Baseline platelet count \< 50,000/uL 12. Severe, sustained hypertension (Systolic BP \>185 mmHg or Diastolic BP \>110 mmHg) 13. Current participation in another investigational drug or device study 14. Presumed septic embolus; suspicion of bacterial endocarditis 15. Clot retrieval attempted using a neurothrombectomy device prior to 6 hrs from symptom onset 16. Any other condition that, in the opinion of the investigator, precludes an endovascular procedure or poses a significant hazard to the subject if an endovascular procedure was performed. Neuroimaging Inclusion Criteria: 1. ICA or MCA-M1 occlusion (carotid occlusions can be cervical or intracranial; with or without tandem MCA lesions) by MRA or CTA AND 2. Target Mismatch Profile on CT perfusion or MRI (ischemic core volume is \< 70 ml, mismatch ratio is \>/= 1.8 and mismatch volume\* is \>/= 15 ml) Alternative neuroimaging inclusion criteria (if perfusion imaging or CTA/MRA is technically inadequate): A) If CTA (or MRA) is technically inadequate: Tmax\>6s perfusion deficit consistent with an ICA or MCA-M1 occlusion AND Target Mismatch Profile (ischemic core volume is \< 70 ml, mismatch ratio is \>1.8 and mismatch volume is \>15 ml as determined by RAPID software) B) If MRP is technically inadequate: ICA or MCA-M1 occlusion (carotid occlusions can be cervical or intracranial; with or without tandem MCA lesions) by MRA (or CTA, if MRA is technically inadequate and a CTA was performed within 60 minutes prior to the MRI) AND DWI lesion volume \< 25 ml C) If CTP is technically inadequate: Patient can be screened with MRI and randomized if neuroimaging criteria are met. Neuroimaging
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Distribution of Scores on the Modified Rankin Scale (mRS) at Day 90 | Day 90 | The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6 with 0 being perfect health without symptoms to 6 being death. 0 - No symptoms. 1. \- No significant disability. Able to carry out all usual activities, despite some symptoms. 2. \- Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3. \- Moderate disability. Requires some help, but able to walk unassisted. 4. \- Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5. \- Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6. \- Dead. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Count of Patients With mRS 0-2 at Day 90 as a Measure of Functional Independence | day 90 | The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6 with 0 being perfect health without symptoms to 6 being death. 0 - No symptoms. * No significant disability. Able to carry out all usual activities, despite some symptoms. * Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. * Moderate disability. Requires some help, but able to walk unassisted. * Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. * Severe disability. Requires constant nursing care and attention, bedridden, incontinent. * Dead. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Infarct Volume (Imaging Outcome) | 24 (+/- 6) hours | Infarct volume on diffusion-weighted MRI (or CT if MRI not feasible) at 24 (±6) hours after randomization |
| Lesion Growth (Imaging Outcome) | 24 hours (±6) | Lesion growth between the RAPID-identified ischemic core on baseline imaging and the infarct volume at 24 hours (±6) |
| Count of Participants With Symptomatic Intracranial Hemorrhage (Primary Safety Outcome) | 36 hours | Defined as NIHSS worsening of 4 or more points associated with brain hemorrhage within 36 hours of randomization |
| Recanalization (Imaging Outcome) | 24 hours (±6) | Recanalization of the primary arterial occlusive lesion at 24-hours on CTA/MRA |
| Reperfusion (Imaging Outcome) | between baseline and 24 hours (+/- 6 hours) | Successful reperfusion defined as a \>90% reduction in Tmax\>6sec lesion volume between baseline and 24 hours |
| Parenchymal Hematoma Type 2 (Safety Outcome) | 24 (±6) hours | PH 2 rates on the 24 hour scan (±6) |
Countries
United States
Participant flow
Recruitment details
From May 2016 through May 2017, a total of 182 patients underwent randomization (92 to the endovascular-therapy group and 90 to the medical-therapy group) at 38 centers in the United States.
Pre-assignment details
After obtaining written informed consent, participants were randomized if they met all clinical and imaging eligibility requirements and could undergo initiation of endovascular therapy between 6 and 16 hours after the time that they had last been known to be well.
Participants by arm
| Arm | Count |
|---|---|
| Endovascular Thrombectomy Therapy Treatment with one or more thrombectomy devices (only the devices listed in this protocol are approved for use in DEFUSE 3) plus standard medical therapy for patients who have evidence of an ICA or MCA M1 occlusion and a Target Mismatch Profile.
Devices approved for use in DEFUSE 3:
* Trevo Retriever
* Solitaire™ FR Revascularization Device
* Penumbra thrombectomy system
* Covidien MindFrame Capture Revascularization Device
Endovascular Thrombectomy: Patients will be treated with thrombectomy devices (stent-retrievers) and/or suction thrombectomy systems currently cleared by the FDA for thrombus removal in patients experiencing an acute stroke following the published instructions for use for these devices. These devices will be used between 6 and 16 hours following symptom onset in DEFUSE 3 based on an FDA IDE. The devices which will be used are the Trevo Retriever, the Solitaire Revascularization Device and the Penumbra system thrombectomy system. | 92 |
| Medical Management standard medical therapy alone | 90 |
| Total | 182 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 13 | 23 |
| Overall Study | Lost to Follow-up | 1 | 2 |
Baseline characteristics
| Characteristic | Endovascular Thrombectomy Therapy | Medical Management | Total |
|---|---|---|---|
| Age, Continuous | 70 years | 71 years | 70.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 10 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 77 Participants | 80 Participants | 157 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| NIHSS, continuous | 16 units on a scale | 16 units on a scale | 16 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 5 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 78 Participants | 80 Participants | 158 Participants |
| Sex: Female, Male Female | 46 Participants | 46 Participants | 92 Participants |
| Sex: Female, Male Male | 46 Participants | 44 Participants | 90 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 13 / 92 | 23 / 90 |
| other Total, other adverse events | 57 / 92 | 59 / 90 |
| serious Total, serious adverse events | 40 / 92 | 48 / 90 |
Outcome results
Primary
The Distribution of Scores on the Modified Rankin Scale (mRS) at Day 90
The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6 with 0 being perfect health without symptoms to 6 being death. 0 - No symptoms. 1. \- No significant disability. Able to carry out all usual activities, despite some symptoms. 2. \- Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3. \- Moderate disability. Requires some help, but able to walk unassisted. 4. \- Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5. \- Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6. \- Dead.
Time frame: Day 90
Population: intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Endovascular Thrombectomy Therapy | The Distribution of Scores on the Modified Rankin Scale (mRS) at Day 90 | 3 score on a scale |
| Medical Management | The Distribution of Scores on the Modified Rankin Scale (mRS) at Day 90 | 4 score on a scale |
p-value: <0.00195% CI: [1.63, 4.7]Cochran-Mantel-Haenszel
Secondary
Count of Patients With mRS 0-2 at Day 90 as a Measure of Functional Independence
The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6 with 0 being perfect health without symptoms to 6 being death. 0 - No symptoms. * No significant disability. Able to carry out all usual activities, despite some symptoms. * Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. * Moderate disability. Requires some help, but able to walk unassisted. * Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. * Severe disability. Requires constant nursing care and attention, bedridden, incontinent. * Dead.
Time frame: day 90
Population: intention to treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Endovascular Thrombectomy Therapy | Count of Patients With mRS 0-2 at Day 90 as a Measure of Functional Independence | 41 Participants |
| Medical Management | Count of Patients With mRS 0-2 at Day 90 as a Measure of Functional Independence | 15 Participants |
Other Pre-specified
Count of Participants With Symptomatic Intracranial Hemorrhage (Primary Safety Outcome)
Defined as NIHSS worsening of 4 or more points associated with brain hemorrhage within 36 hours of randomization
Time frame: 36 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Endovascular Thrombectomy Therapy | Count of Participants With Symptomatic Intracranial Hemorrhage (Primary Safety Outcome) | 6 Participants |
| Medical Management | Count of Participants With Symptomatic Intracranial Hemorrhage (Primary Safety Outcome) | 4 Participants |
Other Pre-specified
Infarct Volume (Imaging Outcome)
Infarct volume on diffusion-weighted MRI (or CT if MRI not feasible) at 24 (±6) hours after randomization
Time frame: 24 (+/- 6) hours
Other Pre-specified
Lesion Growth (Imaging Outcome)
Lesion growth between the RAPID-identified ischemic core on baseline imaging and the infarct volume at 24 hours (±6)
Time frame: 24 hours (±6)
Other Pre-specified
Parenchymal Hematoma Type 2 (Safety Outcome)
PH 2 rates on the 24 hour scan (±6)
Time frame: 24 (±6) hours
Other Pre-specified
Recanalization (Imaging Outcome)
Recanalization of the primary arterial occlusive lesion at 24-hours on CTA/MRA
Time frame: 24 hours (±6)
Other Pre-specified
Reperfusion (Imaging Outcome)
Successful reperfusion defined as a \>90% reduction in Tmax\>6sec lesion volume between baseline and 24 hours
Time frame: between baseline and 24 hours (+/- 6 hours)