Stroke, Acute
Conditions
Brief summary
The primary purpose of this study is to determine if a single dose of nerinetide can reduce global disability in people who have had a stroke and are selected for endovascular therapy without the use of a tissue plasminogen activator (alteplase, tenecteplase, or equivalent).
Detailed description
This study is a Phase 3, randomized, multicentre, blinded, placebo-controlled, parallel group, single-dose with a single interim analysis. Because AIS (acute ischemic stroke) is a medical emergency, the trial is designed to enable the administration of standard-of-care treatments without delay in order to save the life of the person concerned, restore good health or alleviate suffering. Participants harboring an acute ischemic stroke who are selected for endovascular revascularization without intravenous or intra-arterial thrombolytic therapy will be given a single, 2.6 mg/kg (up to a maximum dose of 270 mg) intravenous dose of nerinetide or placebo. Outcomes of the main trial will be evaluated throughout a 90 day observation period. Participants will be followed at 1-Year for the analytic sub-trial for further outcome assessment by telemedicine or telephone interview conducted by individuals blinded to the outcome of the main trial. This sub-trial will be conducted to explore the independent functioning and quality of life at 1-Year.
Interventions
DRUGPlacebo
Vehicle only
DRUGNerinetide
Single intravenous infusion of nerinetide 2.6 mg/kg (up to a maximum dose of 270 mg) over 10 ± 1 minutes
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) selected for emergency endovascular treatment. 2. Age 18 years or greater. 3. Onset (last-known-well) time to randomization time within 12 hours. 4. Disabling stroke defined as a baseline National Institutes of Health Stroke Score (NIHSS): 1. NIHSS \> 5 for internal carotid artery (ICA) and M1-middle cerebral artery (MCA) occlusion; or 2. NIHSS \> 10 for M2-MCA occlusion. 5. Confirmed symptomatic intracranial occlusion at one or more of the following locations: Intracranial carotid I/T/L, M1 or M2 segment MCA. Tandem extracranial carotid and intracranial occlusions are permitted. 6. Pre-stroke (24 hours prior to stroke onset) independent functional status in activities of daily living with modified Barthel Index (BI) ≥ 95. Patient must be living without requiring nursing care. 7. Qualifying imaging performed less than 2 hours prior to randomization. 8. Consent process completed as per national laws and regulation and the applicable ethics committee requirements.
Exclusion criteria
1. Treated with a tissue plasminogen activator (e.g., alteplase or tenecteplase) within 24 hours before randomization. 2. Determination by the treating physician, based on current treatment guidelines and medical evidence, that treatment with a plasminogen activator is indicated. 3. Large core of established infarction defined as ASPECTS 0-4. 4. Absent or poor collateral circulation on qualifying imaging (e.g. collateral score of 0 or 1). 5. Any intracranial hemorrhage on the qualifying imaging. 6. Planned use of an endovascular device not having approval or clearance by the relevant regulatory authority. 7. Endovascular thrombectomy procedure is completed as defined by the presence of TICI 2c/3 reperfusion or completion of groin / arterial closure. 8. Clinical history, past imaging or clinical judgment suggesting that the intracranial occlusion is chronic or there is suspected intracranial dissection such that there is a predicted lack of success with endovascular intervention. 9. Estimated or known weight \> 120 kg (264 lbs). 10. Pregnancy/Lactation; female, with positive urine or serum beta human chorionic gonadotropin (β-hCG) test, or breastfeeding. 11. Known prior receipt of nerinetide for any reason, including prior enrolment in this ESCAPE-NEXT trial. 12. Severe known renal impairment defined as requiring renal replacement therapy (hemo- or peritoneal dialysis). 13. Severe or fatal comorbid illness that will prevent improvement or follow up. 14. Inability to complete follow-up treatment to Day 90. 15. Participation in another clinical trial investigating a drug, medical device, or a medical procedure in the 30 days preceding trial inclusion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Independent Functioning on the Modified Rankin Scale (mRS), as Defined by a Score of 0-2 | 90 days | 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 |
|---|---|---|
| Mortality Rate, as Defined by Event Rate (Percent) for Mortality Over the 90-day Study Period. | 90 days | The estimand of mortality rate was the adjusted unconditional population difference in the number of deaths observed divided by the number of participants observed over the 90-day study period (mortality proportions) between treatment conditions (nerinetide vs. placebo) in the target patient population at Day 90. Deaths occurring over the Day 90 period were considered as non-responses. |
| Number of Participants Exhibiting a Worsening of Their Index Stroke. | 90 days | Worsening of stroke is defined as (A) progression, or hemorrhagic transformation of the index stroke, as documented by medical imaging that is (a) life-threatening requiring intervention and/or (b) results in increased disability as gauged by a ≥4 point increase from lowest NIHSS during hospitalization or (B) results in death from the index stroke. |
| Number of Participants With Good Neurological Outcome, as Defined by a Score of 0-2 on the NIHSS at Day 90 Post Randomization. | 90 days | 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. |
Countries
Australia, Canada, Germany, Italy, Netherlands, Norway, Singapore, Switzerland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Vehicle only
Placebo: Vehicle only | 393 |
| Nerinetide Single intravenous infusion of nerinetide 2.6 mg/kg (up to a maximum dose of 270 mg) over 10 ± 1 minutes
Nerinetide: Single intravenous infusion of nerinetide 2.6 mg/kg (up to a maximum dose of 270 mg) over 10 ± 1 minutes | 451 |
| Total | 844 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 4 |
| Overall Study | Withdrawal by Subject | 3 | 9 |
Baseline characteristics
| Characteristic | Placebo | Nerinetide | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 299 Participants | 349 Participants | 648 Participants |
| Age, Categorical Between 18 and 65 years | 94 Participants | 102 Participants | 196 Participants |
| Age, Continuous | 75 years STANDARD_DEVIATION 12.56 | 76 years STANDARD_DEVIATION 13.29 | 76 years STANDARD_DEVIATION 12.96 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 24 Participants | 38 Participants | 62 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 18 Participants | 31 Participants |
| Race (NIH/OMB) More than one race | 15 Participants | 21 Participants | 36 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 14 Participants | 10 Participants | 24 Participants |
| Race (NIH/OMB) White | 323 Participants | 362 Participants | 685 Participants |
| Sex: Female, Male Female | 194 Participants | 223 Participants | 417 Participants |
| Sex: Female, Male Male | 199 Participants | 228 Participants | 427 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 70 / 396 | 87 / 454 |
| other Total, other adverse events | 329 / 393 | 393 / 451 |
| serious Total, serious adverse events | 148 / 393 | 182 / 451 |
Outcome results
Primary
Number of Participants With Independent Functioning on the Modified Rankin Scale (mRS), as Defined by a Score of 0-2
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: ITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Independent Functioning on the Modified Rankin Scale (mRS), as Defined by a Score of 0-2 | 181 Participants |
| Nerinetide | Number of Participants With Independent Functioning on the Modified Rankin Scale (mRS), as Defined by a Score of 0-2 | 206 Participants |
Secondary
Mortality Rate, as Defined by Event Rate (Percent) for Mortality Over the 90-day Study Period.
The estimand of mortality rate was the adjusted unconditional population difference in the number of deaths observed divided by the number of participants observed over the 90-day study period (mortality proportions) between treatment conditions (nerinetide vs. placebo) in the target patient population at Day 90. Deaths occurring over the Day 90 period were considered as non-responses.
Time frame: 90 days
Population: ITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Mortality Rate, as Defined by Event Rate (Percent) for Mortality Over the 90-day Study Period. | 70 Participants |
| Nerinetide | Mortality Rate, as Defined by Event Rate (Percent) for Mortality Over the 90-day Study Period. | 87 Participants |
Secondary
Number of Participants Exhibiting a Worsening of Their Index Stroke.
Worsening of stroke is defined as (A) progression, or hemorrhagic transformation of the index stroke, as documented by medical imaging that is (a) life-threatening requiring intervention and/or (b) results in increased disability as gauged by a ≥4 point increase from lowest NIHSS during hospitalization or (B) results in death from the index stroke.
Time frame: 90 days
Population: ITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Exhibiting a Worsening of Their Index Stroke. | 68 Participants |
| Nerinetide | Number of Participants Exhibiting a Worsening of Their Index Stroke. | 76 Participants |
Secondary
Number of Participants With Good Neurological Outcome, as Defined by a Score of 0-2 on the NIHSS at Day 90 Post Randomization.
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Good Neurological Outcome, as Defined by a Score of 0-2 on the NIHSS at Day 90 Post Randomization. | 251 Participants |
| Nerinetide | Number of Participants With Good Neurological Outcome, as Defined by a Score of 0-2 on the NIHSS at Day 90 Post Randomization. | 268 Participants |