Stroke, Acute
Conditions
Keywords
Acute Ischemic Stroke, Endovascular Thrombectomy, Neuroprotection, Tat-NR2B9c, NA-1, Nerinetide
Brief summary
The ESCAPE-NA-1 study is designed to determine the safety and efficacy of the neuroprotectant, Nerinetide (NA-1), in reducing global disability in subjects with major acute ischemic stroke (AIS) with a small established infarct core and with good collateral circulation who are selected for endovascular revascularization.
Detailed description
Trial Objectives: The primary objective is to determine the efficacy of the neuroprotectant, Nerinetide, in reducing global disability in subjects with major acute ischemic stroke (AIS) with a small established infarct core and with good collateral circulation selected for rapid endovascular revascularization. The secondary objectives are to determine the efficacy of Nerinetide in: * Reducing functional dependence * Improving neurological outcome * Improving activities of daily living * Reducing mortality rate The leading safety objectives are to determine the effect of administering a dose of 2.6 mg/kg (up to a maximum dose of 270 mg) intravenous (IV) infusion of Nerinetide to subject with acute stroke who are selected for endovascular revascularization on serious adverse events (SAEs) and 90-day mortality. Trial Design: This study is a Phase 3, randomized, multicentre, blinded, placebo-controlled, parallel group, single-dose design. Subjects harboring an acute ischemic stroke and who are selected for endovascular revascularization in accordance with local institutional practices and who harbor a small established infarct core and with good collateral circulation will be given a single, 2.6 mg/kg (up to a maximum dose of 270 mg) intravenous dose of Nerinetide (NA-1) or placebo as soon as they are deemed to have met the enrollment criteria and with the intention of starting administration within 30 minutes of randomization. The randomization will be by stochastic minimization to balance baseline factors.
Interventions
DRUGNerinetide (NA-1), 2.6 mg/kg
Single intravenous infusion of nerinetide over 10 ± 1 minutes
DRUGPlacebo
Placebo Comparator: Placebo
Sponsors
University of Calgary
NoNO Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Acute ischemic stroke (AIS) for immediate endovascular treatment 2. Age 18 or greater. 3. Onset (last-seen-well) time to randomization time within 12 hours. 4. Disabling stroke defined as a baseline National Institutes of Health Stroke Score (NIHSS) \> 5 at the time of randomization. 5. Pre-stroke (24 hours prior to stroke onset) independent functional status in activities of daily living with modified Barthel Index (BI) \> 90 (95 or 100). Patient must be living in their own home, apartment or seniors lodge where no nursing care is required. 6. Confirmed symptomatic intracranial occlusion, based on multiphase or dynamic computerized tomographic angiography (CTA), at one or more of the following locations: Intracranial carotid T/L, M1 middle cerebral artery (MCA). Functionally, when defining the M1 or the M2, the bulk of the MCA territory must be ischemic. 7. Non-contrast computed tomography (NCCT) and CTA (multiphase or dynamic) for trial eligibility performed or repeated at ESCAPE-NA1 stroke centre with endovascular suite on-site. 8. Endovascular treatment with declared first endovascular approach as either stent retriever or aspiration device, and intended to be initiated (arterial access) within 60 minutes of baseline/qualifying NCCT and to first recanalization of 90 minutes. Study drug intended to be administered within 60 minutes of the baseline/qualifying NCCT. 9. Signed informed consent from subject or legally authorized representative or, if required to enable inclusion by applicable national laws and regulations and the applicable independent review boards/Ethics Committee requirements for obtaining consent, from the investigator after consultation with an independent physician who is not otherwise participating in the trial.
Exclusion criteria
1. Evidence of a large core of established infarction defined as ASPECTS 0-4. 2. Evidence of absence of collateral circulation on CTA (Collateral score of 0 or 1). 3. Intent to use any endovascular device other than a stent retriever or clot aspiration device or intra-arterial medications as the initial thrombectomy approach. 4. Intent to use any intravenous thrombolytic other than alteplase if intravenous thrombolysis is planned. 5. No femoral pulses, very difficult endovascular access or extreme tortuosity of great vessels that is predicted to result in an inability to deliver timely endovascular therapy. Direct common carotid or radial/brachial/axillary access is permissible. 6. Estimated or known weight \> 120 kg or \< 45 kg. 7. Pregnancy; if a woman is of childbearing potential a urine or serum beta human chorionic gonadotropin (β-hCG) test is positive, or breastfeeding. 8. Severe contrast allergy or absolute contraindication to iodinated contrast preventing endovascular intervention, including any contraindications listed in the prescribing information approved by local authorities (e.g., patients with decompensated heart failure as a contraindication for the use of VISIPAQUE™ 270 in Germany). 9. Clinical history, past imaging or clinical judgment suggests that the intracranial occlusion is chronic or there is suspected intracranial dissection such that there is a predicted lack of success with endovascular intervention. 10. Prior enrolment in the ESCAPE-NA1 trial or prior receipt of NA-1 for any reason. 11. Severe known renal impairment defined as requiring dialysis (hemo- or peritoneal) or if known a creatinine clearance \< 29 mL/min. 12. Patient has a severe or fatal comorbid illness that will prevent improvement or follow-up. 13. Patient cannot complete follow-up treatment due to co-morbid non-fatal illness or they are known to be a visitor to the city or any other known reason for which follow-up would be impossible (e.g. incarcerated in a federal prison). 14. Participation in another clinical trial investigating a drug, medical device, or a medical procedure in the 30 days preceding study inclusion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With mRS Score of 0 to 2 | 90 Days | Overall number of subjects experiencing a favorable functional outcome 90 days post-randomization, defined as 0 to 2 on the mRS. The modified Rankin Scale (mRS) is a valid and reliable clinician-reported measure of global disability that has been widely applied for evaluating recovery from stroke. It is a scale used to measure functional recovery (the degree of disability or dependence in daily activities) of people who have suffered a stroke. mRS scores range from 0 (best outcome) to 6 (worst outcome), with 0 indicating no residual symptoms; 5 indicating bedbound, requiring constant care; and 6 indicating death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With NIHSS Score of 0 to 2 | 90 Days or the last rating | Number of subjects with good neurological outcome, as defined by a score of 0 to 2 on the NIHSS at Day 90 or the last rating. The National Institutes of Health Stroke Scale (NIHSS) is a standardized neurological examination score that is a valid and reliable measure of disability and recovery after acute stroke. Scores range from 0 to 42, with higher scores indicating increasing severity. |
| Mortality Rate | 90 Days | Mortality rate, as defined by event rate (%) for mortality over the 90-day study period |
Countries
Australia, Canada, Germany, Ireland, South Korea, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Patients with acute ischaemic stroke who were selected to undergo EVT (endovascular thrombectomy) were enrolled. The trial was done at acute care hospitals. Patients were randomly assigned (1:1) to receive a single intravenous dose of nerinetide (NA-1) or placebo. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated.
Pre-assignment details
The trial drug was administered as soon as possible after randomisation.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Drug vehicle only
Placebo: Placebo Comparator: Placebo | 556 |
| Nerinetide (NA-1), 2.6 mg/kg Single intravenous infusion of nerinetide over 10 ± 1 minutes | 549 |
| Total | 1,105 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 2 |
Baseline characteristics
| Characteristic | Nerinetide (NA-1), 2.6 mg/kg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 71.0 years | 70.0 years | 70.0 years |
| Alteplase Treatment Participants not treated with alteplase | 219 Participants | 227 Participants | 446 Participants |
| Alteplase Treatment Participants treated with alteplase | 330 Participants | 329 Participants | 659 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 15 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 541 Participants | 540 Participants | 1081 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Asian | 55 Participants | 52 Participants | 107 Participants |
| Race (NIH/OMB) Black or African American | 45 Participants | 31 Participants | 76 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 | 3 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 15 Participants | 26 Participants |
| Race (NIH/OMB) White | 436 Participants | 453 Participants | 889 Participants |
| Region of Enrollment Australia | 18 Participants | 25 Participants | 43 Participants |
| Region of Enrollment Canada | 253 Participants | 252 Participants | 505 Participants |
| Region of Enrollment Germany | 34 Participants | 42 Participants | 76 Participants |
| Region of Enrollment Ireland | 4 Participants | 5 Participants | 9 Participants |
| Region of Enrollment South Korea | 22 Participants | 20 Participants | 42 Participants |
| Region of Enrollment Sweden | 6 Participants | 8 Participants | 14 Participants |
| Region of Enrollment United Kingdom | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United States | 211 Participants | 203 Participants | 414 Participants |
| Sex: Female, Male Female | 268 Participants | 281 Participants | 549 Participants |
| Sex: Female, Male Male | 281 Participants | 275 Participants | 556 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 74 / 556 | 64 / 549 |
| other Total, other adverse events | 472 / 554 | 474 / 547 |
| serious Total, serious adverse events | 198 / 554 | 181 / 547 |
Outcome results
Primary
Number of Subjects With mRS Score of 0 to 2
Overall number of subjects experiencing a favorable functional outcome 90 days post-randomization, defined as 0 to 2 on the mRS. The modified Rankin Scale (mRS) is a valid and reliable clinician-reported measure of global disability that has been widely applied for evaluating recovery from stroke. It is a scale used to measure functional recovery (the degree of disability or dependence in daily activities) of people who have suffered a stroke. mRS scores range from 0 (best outcome) to 6 (worst outcome), with 0 indicating no residual symptoms; 5 indicating bedbound, requiring constant care; and 6 indicating death.
Time frame: 90 Days
Population: Intent-to-Treat Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Subjects With mRS Score of 0 to 2 | 329 Participants |
| Nerinetide, 2.6 mg/kg | Number of Subjects With mRS Score of 0 to 2 | 337 Participants |
Comparison: The primary hypothesis was that administration of nerinetide (NA-1) would result in an increase in the proportion of responders. The primary analysis was a Wald test for treatment group difference in the primary outcome from a logistic regression adjusted for the 2 stratification variables (alteplase use, first declared thrombectomy device), and the 6 covariates used in the minimization. The trial was designed to have 80% power to detect an 8.7% absolute difference between groups.p-value: 0.33595% CI: [0.869, 1.511]Regression, Logistic
Secondary
Mortality Rate
Mortality rate, as defined by event rate (%) for mortality over the 90-day study period
Time frame: 90 Days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Mortality Rate | 74 Participants |
| Nerinetide, 2.6 mg/kg | Mortality Rate | 64 Participants |
p-value: 0.19995% CI: [0.527, 1.143]Regression, Logistic
Secondary
Number of Subjects With NIHSS Score of 0 to 2
Number of subjects with good neurological outcome, as defined by a score of 0 to 2 on the NIHSS at Day 90 or the last rating. The National Institutes of Health Stroke Scale (NIHSS) is a standardized neurological examination score that is a valid and reliable measure of disability and recovery after acute stroke. Scores range from 0 to 42, with higher scores indicating increasing severity.
Time frame: 90 Days or the last rating
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Subjects With NIHSS Score of 0 to 2 | 320 Participants |
| Nerinetide, 2.6 mg/kg | Number of Subjects With NIHSS Score of 0 to 2 | 320 Participants |
p-value: 0.86695% CI: [0.781, 1.342]Regression, Logistic
Post Hoc
Mortality Rate in the Alteplase Sub-group
Mortality rate, as defined by event rate (%) for mortality over the 90-day study period in the sub-group of participants treated with alteplase as part of standard-of-care
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Mortality Rate in the Alteplase Sub-group | 31 Participants |
| Nerinetide, 2.6 mg/kg | Mortality Rate in the Alteplase Sub-group | 39 Participants |
p-value: 0.86995% CI: [0.588, 1.874]Regression, Logistic
Post Hoc
Mortality Rate in the No-Alteplase Sub-group
Mortality rate, as defined by event rate (%) for mortality over the 90-day study period in the sub-group of participants not treated with alteplase as part of standard-of-care
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Mortality Rate in the No-Alteplase Sub-group | 43 Participants |
| Nerinetide, 2.6 mg/kg | Mortality Rate in the No-Alteplase Sub-group | 25 Participants |
p-value: 0.05595% CI: [0.323, 1.013]Regression, Logistic
Post Hoc
Number of Subjects With mRS Score of 0 to 2 in the Alteplase Sub-group
Overall proportion of subjects experiencing a favorable functional outcome 90 days post-randomization, defined as 0 to 2 on the mRS in the sub-group of participants treated with alteplase as part of standard-of-care. The modified Rankin Scale (mRS) is a valid and reliable clinician-reported measure of global disability that has been widely applied for evaluating recovery from stroke. It is a scale used to measure functional recovery (the degree of disability or dependence in daily activities) of people who have suffered a stroke. mRS scores range from 0 (best outcome) to 6 (worst outcome), with 0 indicating no residual symptoms; 5 indicating bedbound, requiring constant care; and 6 indicating death.
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Subjects With mRS Score of 0 to 2 in the Alteplase Sub-group | 216 Participants |
| Nerinetide, 2.6 mg/kg | Number of Subjects With mRS Score of 0 to 2 in the Alteplase Sub-group | 207 Participants |
p-value: 0.52995% CI: [0.612, 1.286]Regression, Logistic
Post Hoc
Number of Subjects With mRS Score of 0 to 2 in the No-alteplase Sub-group
Overall number of subjects experiencing a favorable functional outcome 90 days post-randomization, defined as 0 to 2 on the mRS in the sub-group of participants not treated with alteplase as part of standard-of-care. The modified Rankin Scale (mRS) is a valid and reliable clinician-reported measure of global disability that has been widely applied for evaluating recovery from stroke. It is a scale used to measure functional recovery (the degree of disability or dependence in daily activities) of people who have suffered a stroke. mRS scores range from 0 (best outcome) to 6 (worst outcome), with 0 indicating no residual symptoms; 5 indicating bedbound, requiring constant care; and 6 indicating death.
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Subjects With mRS Score of 0 to 2 in the No-alteplase Sub-group | 113 Participants |
| Nerinetide, 2.6 mg/kg | Number of Subjects With mRS Score of 0 to 2 in the No-alteplase Sub-group | 130 Participants |
p-value: 0.02895% CI: [1.055, 2.603]Regression, Logistic
Post Hoc
Number of Subjects With NIHSS Score of 0 to 2 in the Alteplase Sub-group
Number of subjects with good neurological outcome, as defined by a score of 0 to 2 on the NIHSS at Day 90 or the last rating in the sub-group of participants treated with alteplase as part of standard-of-care. The National Institutes of Health Stroke Scale (NIHSS) is a standardized neurological examination score that is a valid and reliable measure of disability and recovery after acute stroke. Scores range from 0 to 42, with higher scores indicating increasing severity.
Time frame: 90 days or last rating
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Subjects With NIHSS Score of 0 to 2 in the Alteplase Sub-group | 207 Participants |
| Nerinetide, 2.6 mg/kg | Number of Subjects With NIHSS Score of 0 to 2 in the Alteplase Sub-group | 191 Participants |
p-value: 0.18195% CI: [0.545, 1.121]Regression, Logistic
Post Hoc
Number of Subjects With NIHSS Score of 0 to 2 in the No-Alteplase Sub-group
Number of subjects with good neurological outcome, as defined by a score of 0 to 2 on the NIHSS at Day 90 or the last rating in the sub-group of participants not treated with alteplase as part of standard-of-care. The National Institutes of Health Stroke Scale (NIHSS) is a standardized neurological examination score that is a valid and reliable measure of disability and recovery after acute stroke. Scores range from 0 to 42, with higher scores indicating increasing severity.
Time frame: 90 days or last rating
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Subjects With NIHSS Score of 0 to 2 in the No-Alteplase Sub-group | 113 Participants |
| Nerinetide, 2.6 mg/kg | Number of Subjects With NIHSS Score of 0 to 2 in the No-Alteplase Sub-group | 129 Participants |
p-value: 0.08895% CI: [0.943, 2.329]Regression, Logistic