Ischemic Stroke
Conditions
Brief summary
Primary Endpoint: The primary objective is to show that AIS patients, ineligible for or refractory to treatment with IV-tPA, with appropriate image selection, treated with mechanical thrombectomy within 6-12 hours of symptom onset have less stroke related disability and improved good functional outcomes as compared to those treated with best MT with respect to endpoint defined as: • 90-day global disability assessed via the modified Rankin score (mRS), analyzed using raw mRS scores. Statistical details can be found in section 7.2. Secondary Endpoints: * 90-day global disability in the 6-12 hr cohort assessed via the overall distribution of mRS * Proportion of patients with good functional recovery for the 6-12 hr cohort as defined by mRS 0-2 at 90 days * Mortality at 30 and 90 days * Intracranial hemorrhage with neurological deterioration (NIHSS worsening \>4) within 24 hours of randomization * Procedure related serious adverse events (SAE's) * Arterial revascularization measured by TICI 2b or 3 following device use
Detailed description
Intravenous (IV) tissue plasminogen activator (tPA) administration has been shown to be safe and effective for treatment of AIS within 3 hours of symptom onset, and newer evidence has shown potential benefit out to 4.5 hours. Mechanical thrombectomy for AIS patients has been shown in clinical trials to be safe up to 8 hours after symptom onset. The rapid progression of thrombectomy devices over the last several years has resulted in faster recanalization times while maintaining a high degree of safety. This has resulted in improved patient outcomes, similar to prior randomized trial data showing improved outcomes over medical therapy or earlier devices. Data from the MERCI trial suggests that patients \> 85 as well as those with a baseline NIHSS score \> 30 are unlikely to benefit from thrombectomy. Patients with rapidly improving neurologic deficits likely will have an excellent recovery with conventional care, precluding the ability to detect a beneficial treatment effect of thrombectomy. Pilot data incorporating physiologic imaging has shown that appropriate patients can be selected for thrombectomy. This selection methodology has shown the ability to maintain the same level of safety and efficacy as those patients treated in the highly selective environment of a clinical trial, despite presenting far beyond accepted time based standards. Vertebrobasilar occlusion patients are excluded to maintain a homogenous study population, particularly since no data currently is available addressing the comparability of imaging penumbral patterns in the anterior vs. posterior circulation. This has also been shown to be reproducible at multiple centers and with different imaging modalities. However, all prospective interventional stroke studies performed to date have been restricted by the 8-hour time window.
Interventions
DEVICEEndovascular Mechanical Thrombectomy
Endovascular intervention can be performed under either general anesthesia or conscious sedation based on best practices as determined by treating physician. Attempt should be made to expedite the transition from imaging to treatment in as rapid a fashion as possible. The subject should be prepared for the planned interventional procedure according to standard hospital procedures. Mechanical revascularization should be performed with the operators standard thrombectomy technique using aspiration or a stent retriever, separately or in combination.
Sponsors
Vanderbilt University
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Age 18 and older (i.e., candidates must have had their 18th birthday) 2. NIHSS ≥8 at the time of neuroimaging 3. Presenting or persistent symptoms within 6-12 hours of when groin puncture can be obtained 4. Neuroimaging demonstrates large vessel proximal occlusion (distal ICA through MCA M1 bifurcation) 5. The operator feels that the stroke can be appropriately treated with traditional endovascular techniques (endovascular mechanical thrombectomy without adjunctive devices such as stents) 6. Pts are within 6-12 hours of symptom onset, that have received IV-tPA without improvement in symptoms are eligible for this study. Patients presenting earlier than 6 hours should be treated according to local standard of care. 7. Pre-event Modified Rankin Scale score 0-1 8. Consenting requirements met according to local IRB
Exclusion criteria
1. Patient is less than 6-hours from symptom onset 2. Rapidly improving neurologic examination 3. Absence of large vessel occlusion on non-invasive imaging 4. Known or suspected pre-existing (chronic) large vessel occlusion in the symptomatic territory 5. Absence of an associated large penumbra as defined by physiologic imaging according to standard of practice at the participating institution 6. Any intracranial hemorrhage in the last 90 days 7. Known irreversible bleeding disorder 8. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR \> 2.5 or institutionally equivalent prothrombin time of 2.5 times normal 9. Platelet count \< 100 x 103 cells/mm3 or known platelet dysfunction 10. Inability to tolerate, clinically documented evidence in medical history of adverse reaction to, or contraindication to medications used in treatment of the stroke 11. Contraindication to CT and MRI (i.e., iodine contrast allergy or other condition that prohibits imaging from either CT or MRI) 12. Known allergy to contrast used in angiography that cannot be medically controlled 13. Relative contraindication to angiography (e.g., serum creatinine \> 2.5 mg/dL) 14. Women who are currently pregnant or breast-feeding (Women of child-bearing potential must have a negative pregnancy test prior to the study procedure (either serum or urine) 15. Evidence of active infection (indicated by fever at or over 99.9 °F and/or open draining wound) at the time of randomization 16. Current use of cocaine or other vasoactive substance 17. Any comorbid disease or condition expected to compromise survival or ability to complete follow-up assessments through 90 days 18. Patients who lack the necessary mental capacity to participate or are unwilling or unable to comply with the protocol's follow up appointment schedule (based on the investigator's judgment) Head CT or MRI Scan
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Good Functional Outcomes Measured by Modified Rankin Score (mRS) | 90 days | Modified rankin score measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The range is 0-6 (0 is highest function with no symptoms and 6 is death). This outcome measured percentage of subjects with a good functional outcome with a score ranging from 0-2. The primary objective is to show that AIS patients, ineligible for or refractory to treatment with IV-tPA, (patients seen within 6 hours of symptom onset will be immediately considered for endovascular therapy according to the site's standard of care. Likewise, patients presenting beyond 12 hours will be treated according to the site's standard of care), with appropriate image selection, treated with mechanical thrombectomy within 6-12 hours of symptom onset have less stroke related disability and improved good functional outcomes as compared to those treated with best MT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in the 6-12hr Cohort With Good Functional Recovery as Assessed by the Modified Rankin Scale (mRS) | 90 days | The 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. A score of 0-2 represents good functional recovery. The scores are defined as follows: (0) No symptoms at all; (1) No significant disability despite symptoms, able to carry out all usual duties and activities; (2) Slight disability, unable to carry out all previous activities, but able to look after own affairs without assistance. |
| Percentage of Participants Mortality at 30 Days | 30 days | Mortality at 30 days will be compared between randomized groups in an ITT fashion; with overall Type I error controlled using hierarchical testing. That is, if statistical significance is observed on the primary effectiveness endpoint, the secondary clinical efficacy endpoints will then be tested in sequential fashion each at a two-sided alpha level of 0.05, with testing ceasing once a null hypothesis cannot be rejected. |
| Percentage of Participants Mortality at 90 Days | 90 days | Mortality at 90 days will be compared between randomized groups in an ITT fashion; with overall Type I error controlled using hierarchical testing. That is, if statistical significance is observed on the primary effectiveness endpoint, the secondary clinical efficacy endpoints will then be tested in sequential fashion each at a two-sided alpha level of 0.05, with testing ceasing once a null hypothesis cannot be rejected. |
| Percentage of Participants in the 6-12 hr Cohort With Global Disability as Assessed by the Modified Rankin Score (mRS) | 90 day | The 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. A score of 3-6 represents global disability are defined as follows: (3) moderate disability (requiring some help, but able to walk without assistance); (4) moderate severe disability (unable to walk without assistance and unable to attend to own bodily needs without assistance); (5) severe disability (bedridden, incontinent and requiring constant nursing care and attention; and (6) dead. |
| Percentage of Participants With SAE's Related to a Thrombectomy Procedure | 90 days | A Thrombectomy is an interventional procedure to remove a blood clot (thrombus) from a blood vessel in the brain. Procedure related SAE's will be compared between randomized groups in an ITT fashion; with overall Type I error controlled using hierarchical testing. That is, if statistical significance is observed on the primary effectiveness endpoint, the secondary clinical efficacy endpoints will then be tested in sequential fashion each at a two-sided alpha level of 0.05, with testing ceasing once a null hypothesis cannot be rejected. |
| Arterial Revascularization Measured by TICI 2b or 3 Following Device Use | 90 days | Arterial revascularization measured by TICI 2b or 3 following device use will be compared between randomized groups in an ITT fashion; with overall Type I error controlled using hierarchical testing. That is, if statistical significance is observed on the primary effectiveness endpoint, the secondary clinical efficacy endpoints will then be tested in sequential fashion each at a two-sided alpha level of 0.05, with testing ceasing once a null hypothesis cannot be rejected. |
| Percentage of Patients With Serious Adverse Events (SAEs) Related to Thrombectomy Device. | 90 days | A Thrombectomy device is a device intended to restore blood flow in a vessel in the brain by removing a blood clot (thrombus). |
| Percentage of Participants With ICH (Intracranial Hemorrhage) With Neurological Deterioration (NIHSS Worsening >4). | 90 days | ICH with neurological deterioration (NIHSS worsening \>4) will be compared between randomized groups in an ITT fashion; with overall Type I error controlled using hierarchical testing. That is, if statistical significance is observed on the primary effectiveness endpoint, the secondary clinical efficacy endpoints will then be tested in sequential fashion each at a two-sided alpha level of 0.05, with testing ceasing once a null hypothesis cannot be rejected. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Best Medical Therapy Patients randomized to the control group will receive best conventional MT for acute ischemic stroke as determined by the attending stroke physician. Standardization of medical management in both arms will occur according to the following:
* General medical management according to AHA/ASA guidelines
* Admission to monitored or intensive care unit for at least 24 hours
* Aggressive hypertensive-hypervolemic therapy should be used only in the case of symptomatic blood pressure fluctuations or if blood pressure drops below the normal range for the patient
* Antithrombotics: ASA 325 mg PO qd for 7 days (clopidogrel may be used as adjunctive therapy if indicated for cardiac disease) then per discretion of treating physician
* Close monitoring of BP and glucose with treatment according to AHA/ASA guidelines
* Follow-up imaging study required in any patient with neurologic deterioration | 21 |
| Endovascular Treatment Endovascular intervention can be performed under either general anesthesia or conscious sedation based on best practices as determined by treating physician. Attempt should be made to expedite the transition from imaging to treatment in as rapid a fashion as possible. The subject should be prepared for the planned interventional procedure according to standard hospital procedures. Mechanical revascularization should be performed with the operators standard thrombectomy technique using aspiration or a stent retriever, separately or in combination.
Endovascular Mechanical Thrombectomy: Endovascular intervention can be performed under either general anesthesia or conscious sedation based on best practices as determined by treating physician. Attempt should be made to expedite the transition from imaging to treatment in as rapid a fashion as possible. The subject should be prepared for the planned interventional procedure according to standard hospital procedures. Mechanical r | 12 |
| Total | 33 |
Baseline characteristics
| Characteristic | Best Medical Therapy | Endovascular Treatment | Total |
|---|---|---|---|
| Age, Continuous | 65 years STANDARD_DEVIATION 13 | 70 years STANDARD_DEVIATION 10.1 | 67 years STANDARD_DEVIATION 12.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 12 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 21 participants | 12 participants | 33 participants |
| Sex: Female, Male Female | 8 Participants | 8 Participants | 16 Participants |
| Sex: Female, Male Male | 13 Participants | 4 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 21 | 1 / 12 |
| other Total, other adverse events | 10 / 21 | 9 / 12 |
| serious Total, serious adverse events | 12 / 21 | 4 / 12 |
Outcome results
Primary
Rate of Good Functional Outcomes Measured by Modified Rankin Score (mRS)
Modified rankin score measures the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The range is 0-6 (0 is highest function with no symptoms and 6 is death). This outcome measured percentage of subjects with a good functional outcome with a score ranging from 0-2. The primary objective is to show that AIS patients, ineligible for or refractory to treatment with IV-tPA, (patients seen within 6 hours of symptom onset will be immediately considered for endovascular therapy according to the site's standard of care. Likewise, patients presenting beyond 12 hours will be treated according to the site's standard of care), with appropriate image selection, treated with mechanical thrombectomy within 6-12 hours of symptom onset have less stroke related disability and improved good functional outcomes as compared to those treated with best MT.
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Best Medical Therapy | Rate of Good Functional Outcomes Measured by Modified Rankin Score (mRS) | 42.9 percentage of participants |
| Endovascular Treatment | Rate of Good Functional Outcomes Measured by Modified Rankin Score (mRS) | 75 percentage of participants |
Secondary
Arterial Revascularization Measured by TICI 2b or 3 Following Device Use
Arterial revascularization measured by TICI 2b or 3 following device use will be compared between randomized groups in an ITT fashion; with overall Type I error controlled using hierarchical testing. That is, if statistical significance is observed on the primary effectiveness endpoint, the secondary clinical efficacy endpoints will then be tested in sequential fashion each at a two-sided alpha level of 0.05, with testing ceasing once a null hypothesis cannot be rejected.
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Best Medical Therapy | Arterial Revascularization Measured by TICI 2b or 3 Following Device Use | 100 percentage of participants |
| Endovascular Treatment | Arterial Revascularization Measured by TICI 2b or 3 Following Device Use | 83 percentage of participants |
Secondary
Percentage of Participants in the 6-12 hr Cohort With Global Disability as Assessed by the Modified Rankin Score (mRS)
The 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. A score of 3-6 represents global disability are defined as follows: (3) moderate disability (requiring some help, but able to walk without assistance); (4) moderate severe disability (unable to walk without assistance and unable to attend to own bodily needs without assistance); (5) severe disability (bedridden, incontinent and requiring constant nursing care and attention; and (6) dead.
Time frame: 90 day
Population: There were only 12 participants total in the 6-12hr cohort
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Best Medical Therapy | Percentage of Participants in the 6-12 hr Cohort With Global Disability as Assessed by the Modified Rankin Score (mRS) | 62.5 percentage of participants |
| Endovascular Treatment | Percentage of Participants in the 6-12 hr Cohort With Global Disability as Assessed by the Modified Rankin Score (mRS) | 50 percentage of participants |
Secondary
Percentage of Participants in the 6-12hr Cohort With Good Functional Recovery as Assessed by the Modified Rankin Scale (mRS)
The 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. A score of 0-2 represents good functional recovery. The scores are defined as follows: (0) No symptoms at all; (1) No significant disability despite symptoms, able to carry out all usual duties and activities; (2) Slight disability, unable to carry out all previous activities, but able to look after own affairs without assistance.
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Best Medical Therapy | Percentage of Participants in the 6-12hr Cohort With Good Functional Recovery as Assessed by the Modified Rankin Scale (mRS) | 42.9 Percentage of particpants |
| Endovascular Treatment | Percentage of Participants in the 6-12hr Cohort With Good Functional Recovery as Assessed by the Modified Rankin Scale (mRS) | 75.0 Percentage of particpants |
Secondary
Percentage of Participants Mortality at 30 Days
Mortality at 30 days will be compared between randomized groups in an ITT fashion; with overall Type I error controlled using hierarchical testing. That is, if statistical significance is observed on the primary effectiveness endpoint, the secondary clinical efficacy endpoints will then be tested in sequential fashion each at a two-sided alpha level of 0.05, with testing ceasing once a null hypothesis cannot be rejected.
Time frame: 30 days
Population: The values for 4 subjects was not captured at this timepoint
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Best Medical Therapy | Percentage of Participants Mortality at 30 Days | 12 percentage of participants |
| Endovascular Treatment | Percentage of Participants Mortality at 30 Days | 0 percentage of participants |
Secondary
Percentage of Participants Mortality at 90 Days
Mortality at 90 days will be compared between randomized groups in an ITT fashion; with overall Type I error controlled using hierarchical testing. That is, if statistical significance is observed on the primary effectiveness endpoint, the secondary clinical efficacy endpoints will then be tested in sequential fashion each at a two-sided alpha level of 0.05, with testing ceasing once a null hypothesis cannot be rejected.
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Best Medical Therapy | Percentage of Participants Mortality at 90 Days | 19.1 percentage of participants |
| Endovascular Treatment | Percentage of Participants Mortality at 90 Days | 8.3 percentage of participants |
Secondary
Percentage of Participants With ICH (Intracranial Hemorrhage) With Neurological Deterioration (NIHSS Worsening >4).
ICH with neurological deterioration (NIHSS worsening \>4) will be compared between randomized groups in an ITT fashion; with overall Type I error controlled using hierarchical testing. That is, if statistical significance is observed on the primary effectiveness endpoint, the secondary clinical efficacy endpoints will then be tested in sequential fashion each at a two-sided alpha level of 0.05, with testing ceasing once a null hypothesis cannot be rejected.
Time frame: 90 days
Population: One patient had no NIHSS scores after baseline and was excluded from this analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Best Medical Therapy | Percentage of Participants With ICH (Intracranial Hemorrhage) With Neurological Deterioration (NIHSS Worsening >4). | 0 percentage of participants |
| Endovascular Treatment | Percentage of Participants With ICH (Intracranial Hemorrhage) With Neurological Deterioration (NIHSS Worsening >4). | 0 percentage of participants |
Secondary
Percentage of Participants With SAE's Related to a Thrombectomy Procedure
A Thrombectomy is an interventional procedure to remove a blood clot (thrombus) from a blood vessel in the brain. Procedure related SAE's will be compared between randomized groups in an ITT fashion; with overall Type I error controlled using hierarchical testing. That is, if statistical significance is observed on the primary effectiveness endpoint, the secondary clinical efficacy endpoints will then be tested in sequential fashion each at a two-sided alpha level of 0.05, with testing ceasing once a null hypothesis cannot be rejected.
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Best Medical Therapy | Percentage of Participants With SAE's Related to a Thrombectomy Procedure | 0.0 Percentage of participants |
| Endovascular Treatment | Percentage of Participants With SAE's Related to a Thrombectomy Procedure | 8.3 Percentage of participants |
Secondary
Percentage of Patients With Serious Adverse Events (SAEs) Related to Thrombectomy Device.
A Thrombectomy device is a device intended to restore blood flow in a vessel in the brain by removing a blood clot (thrombus).
Time frame: 90 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Best Medical Therapy | Percentage of Patients With Serious Adverse Events (SAEs) Related to Thrombectomy Device. | 0 percentage of participants |
| Endovascular Treatment | Percentage of Patients With Serious Adverse Events (SAEs) Related to Thrombectomy Device. | 0 percentage of participants |