Stroke, Ischemic
Conditions
Keywords
Endovascular Thrombectomy
Brief summary
A Phase II, randomized, blinded, placebo-controlled, parallel group study with patients experiencing a large vessel occlusion acute ischemic stroke who are selected for endovascular revascularization. Participants will be given a 48 h infusion of either 0.5 mL/kg/h RNS60 (up to a maximum of 65 mL/h), 1.0 mL/kg/h RNS60 (up to a maximum of 130 mL/h), or 1.0 mL/kg/h (up to a maximum of 130 mL/h) placebo (normal saline) starting within 30 minutes of consent after confirmation of candidacy for endovascular thrombectomy.
Detailed description
This study is a Phase II, randomized, blinded, placebo-controlled, parallel group design. Participants experiencing a large vessel occlusion acute ischemic stroke who are selected for endovascular revascularization will be given a 48 h infusion of either 0.5 mL/kg/h RNS60 (up to a maximum of 65 mL/h), 1.0 mL/kg/h RNS60 (up to a maximum of 130 mL/h), or 1.0 mL/kg/h (up to a maximum of 130 mL/h) placebo (normal saline) starting within 30 minutes of consent after confirmation of candidacy for endovascular thrombectomy and prior to arterial closure. Outcomes of the main trial will be evaluated throughout a 90 day observation period.
Interventions
DRUGRNS60
RNS60 injection solution
DRUGPlacebo
Placebo injection solution
Sponsors
Revalesio Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, 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 older. 3. Onset (last-known-well) time to randomization time within 24 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) historical modified Rankin Scale (mRS) ≤2. Patient must be living independently without requiring nursing care. 7. Qualifying imaging performed less than 2 hours prior to randomization. 8. Consent process completed as per applicable laws and regulation and the IRB requirements.
Exclusion criteria
1. Evidence of a large core of established infarction defined as Alberta Stroke Program Early Computerized Tomography Score (ASPECTS) 0-4. 2. Evidence of absence of collateral circulation on qualifying imaging (collateral score of 0 or 1 if multiphase computed tomography angiography (mCTA) is used, or absence of adequate ischemic penumbra in the judgment of the Investigator if computed tomographic perfusion (CTP) is used). 3. Any evidence of intracranial hemorrhage or mass lesion on the qualifying imaging. 4. Planned use of an endovascular device not having approval or clearance by the relevant regulatory authority. 5. Endovascular thrombectomy procedure is completed as defined by the presence of arterial access closure. 6. 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. 7. Estimated or known weight \> 130 kg (287 lbs). 8. Known pregnant/lactating female. 9. Myocardial infarction (MI) within 6 months prior to Screening including non-Q wave MI; Diagnosis of congestive heart failure (CHF) with either: 1. current clinical signs and symptoms of ventricular dysfunction (e.g., edema, shortness of breath), 2. CHF medication adjustment within the prior 30 days or 3. ejection fraction (if report available) of 30% or less measured in the 6 months prior to Screening; as either medically documented or reported by patient or another person considered by the Investigator to be reasonably reliable. 10. Known renal impairment defined as requiring renal replacement therapy (hemo- or peritoneal dialysis). 11. Inability to have magnetic resonance imaging (MRI) (Non-magnetic resonance \[MR\] compatible implants or any other foreseeable reason, including claustrophobia) 12. Severe or fatal comorbid illness that will prevent improvement or follow up. 13. Inability to complete follow-up treatment to Day 90. 14. Participation in another clinical trial investigating a drug, medical device, or a medical procedure in the 30 days preceding trial inclusion and throughout the duration of the trial. 15. Reported known seizure at time of stroke onset. 16. Ischemic stroke within previous 30 days. 17. Patients in normal sinus rhythm with a known QTcF \> 460 ms at Screening. 18. Any other symptom that in the investigator's opinion may complicate or preclude the subject from participating in this trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Events (SAEs) | From start of study drug administration up to Day 90 | An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or resulted in a congenital anomaly/birth defect. An SAE could also be an important medical event that may not have resulted in death, was life-threatening, or required hospitalization, but jeopardized the participant and required medical or surgical intervention to prevent one of the outcomes listed above. Treatment-emergent SAEs were defined as SAEs that started after the start of study drug infusion and are reported here. |
| Mortality: Proportion of Participants Alive at Day 90 | Day 90 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| National Institutes of Health Stroke Scale (NIHSS) at 24 Hours | 24 hours | The NIHSS is a standardized neurological examination scale that is a measure of disability and recovery after acute stroke. The NIHSS assessment is a standardized 15-item impairment scale intended to evaluate neurologic outcome and degrees of recovery for subjects with stroke. The scale assesses levels of consciousness, extraocular movements, visual fields, facial muscle function, extremity strength, sensory function, coordination (ataxia), language (aphasia), speech (dysarthria), and hemi-inattention (neglect). The NIHSS was scored by those trained in the use of this scale. Each item was scored in ranges 0-2, 0-3, or 0-4. A score of 0 indicates normal performance. Total scores on the NIHSS ranged from 0-42, with higher values reflecting increasing severity. Stroke severity was further stratified in the following way: \> 25: Very severe; 15-24: Severe; 5-14: Mild to moderately severe; \< 5: Mild. |
| Proportion of Participants With Worsening of Stroke | Up to Day 90 | Worsening of stroke was defined as progression, or hemorrhagic transformation of the index stroke, as documented by brain imaging, which is (a) life-threatening requiring intervention and/or (b) results in increased disability as gauged by a ≥ 4-point increase from lowest NIHSS pre-decline and/or (c) results in death. Proportion of participants with worsening of stroke was calculated as number of participants with worsening of stroke divided by the total number of participants observed over the 90-day period in each arm. |
| Number of Participants With Non-disability Based on Modified Rankin Scale (mRS ) Score at Day 90 | Day 90 | The mRS is a clinician-reported outcome measure for participants who have suffered a stroke. It measures functional recovery as the degree of disability or dependence in daily activities in a 6-point disability scale with possible scores ranging from 0 to 5: 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; 3-moderate disability: requiring some help, but able to walk without assistance; 4-moderately severe disability: unable to walk without assistance and unable to attend to own bodily needs without assistance; 5-severe disability; bedridden, incontinent, requiring constant nursing care and attention. A score of 6 is used for participants who expire (death). Non-disability was defined as a score ranging from 0 to 2. Disability was defined as a score ranging from 3-6. |
| Health-related Quality of Life as Measured by 5-Level EuroQoL 5D Index (EQ-5D-5L) at Day 90 | Day 90 | EQ-5D-5L is a generic instrument for measuring health-related quality of life. It consists of a 5-item questionnaire, which was interviewer administered by study staff. The 5-item questionnaire comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and each dimension has 5 response levels (1-no problems, 2-slight problems, 3-moderate problems, 4-severe problems, 5-unable to/extreme problems). The health state is then summarized to be a single number, EQ-5D-5L Index score, by applying a country-specific standard value set. EQ-5D-5L Index score for the United States ranges from -0.59 to 1, where 1 indicates a better health condition. |
| Percentage of Participants With Barthel Index (BI) Score ≥95 at Day 90 | Day 90 | The BI is an index of functional independence. Its values range from 0 to 100, with higher scores indicating greater independence. Score range in BI items: Feeding 0-10; Bathing 0-5; Grooming 0-5; Dressing 0-10; Bowels 0-10; Bladder 0-10; Toilet use 0-10; Transfers (bed to chair and back) 0-15; Mobility (on level surfaces) 0-15; Stairs 0-10. Item scores vary in increments of 5 points. Functional independence at Day 90 was evaluated. Participants having a score ≥95 on the BI Score were deemed to have achieved functional independence, whereas those scoring \<95 at Day 90 were deemed to have failed to achieve functional independence. |
| Change From Baseline in Infarct Volume of Stroke at 48 Hours | Baseline, 48 hours | Infarct progression/regression was measured by Magnetic Resonance Imaging (MRI) of the brain. The mean change from post-EVT baseline in the volume of injured tissue was calculated at 48 hours. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 5 sites in the United States.
Pre-assignment details
Participants experiencing a large vessel occlusion (LVO) acute ischemic stroke (AIS) who were selected for endovascular thrombectomy (EVT) were randomized in a 1:1:1 ratio to one of three arms in the study. Participants were given a 48-hour infusion of either 0.5 milliliter/kilogram/hour (mL/kg/h) RNS60, 1.0 mL/kg/h RNS60, or 1.0 mL/kg/h placebo (normal saline).
Participants by arm
| Arm | Count |
|---|---|
| RNS60 1.0 mL/kg/h Participants received RNS60 1.0 mL/kg/h infusion for 48 hours (up to a maximum of 130 mL/h) starting within 30 min of randomization (but prior to arterial access closure). | 24 |
| RNS60 0.5 mL/kg/h Participants received RNS60 0.5 mL/kg/h infusion for 48 hours (up to a maximum of 65 mL/h) starting within 30 min of randomization (but prior to arterial access closure). | 30 |
| Placebo 1.0 mL/kg/h Participants received placebo (normal saline) 1.0 mL/kg/h infusion for 48 hours (up to a maximum of 130 mL/h) starting within 30 min of randomization (but prior to arterial access closure). | 28 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Events Leading to Death | 2 | 2 | 4 |
| Overall Study | Lost to Follow-up | 0 | 2 | 2 |
| Overall Study | Physician Decision | 0 | 1 | 0 |
| Overall Study | Withdrawal by Legal Authorized Representative | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | RNS60 1.0 mL/kg/h | Total | Placebo 1.0 mL/kg/h | RNS60 0.5 mL/kg/h |
|---|---|---|---|---|
| Age, Continuous | 67.8 years STANDARD_DEVIATION 10.65 | 67.2 years STANDARD_DEVIATION 11.88 | 66.0 years STANDARD_DEVIATION 12.5 | 68.0 years STANDARD_DEVIATION 12.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 77 Participants | 27 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 4 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 9 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 21 Participants | 68 Participants | 24 Participants | 23 Participants |
| Sex: Female, Male Female | 7 Participants | 31 Participants | 11 Participants | 13 Participants |
| Sex: Female, Male Male | 17 Participants | 51 Participants | 17 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 24 | 2 / 30 | 4 / 28 |
| other Total, other adverse events | 21 / 24 | 28 / 30 | 27 / 28 |
| serious Total, serious adverse events | 6 / 24 | 10 / 30 | 8 / 28 |
Outcome results
Primary
Mortality: Proportion of Participants Alive at Day 90
Time frame: Day 90
Population: ITT Population: All randomized participants who received study drug regardless of treatment actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RNS60 1.0 mL/kg/h | Mortality: Proportion of Participants Alive at Day 90 | 0.917 proportion of participants |
| RNS60 0.5 mL/kg/h | Mortality: Proportion of Participants Alive at Day 90 | 0.933 proportion of participants |
| Placebo 1.0 mL/kg/h | Mortality: Proportion of Participants Alive at Day 90 | 0.857 proportion of participants |
Primary
Number of Participants With Serious Adverse Events (SAEs)
An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or resulted in a congenital anomaly/birth defect. An SAE could also be an important medical event that may not have resulted in death, was life-threatening, or required hospitalization, but jeopardized the participant and required medical or surgical intervention to prevent one of the outcomes listed above. Treatment-emergent SAEs were defined as SAEs that started after the start of study drug infusion and are reported here.
Time frame: From start of study drug administration up to Day 90
Population: Safety Population: All randomized participants who received any volume of study drug based on the actual treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RNS60 1.0 mL/kg/h | Number of Participants With Serious Adverse Events (SAEs) | 6 Participants |
| RNS60 0.5 mL/kg/h | Number of Participants With Serious Adverse Events (SAEs) | 10 Participants |
| Placebo 1.0 mL/kg/h | Number of Participants With Serious Adverse Events (SAEs) | 8 Participants |
Secondary
Change From Baseline in Infarct Volume of Stroke at 48 Hours
Infarct progression/regression was measured by Magnetic Resonance Imaging (MRI) of the brain. The mean change from post-EVT baseline in the volume of injured tissue was calculated at 48 hours.
Time frame: Baseline, 48 hours
Population: ITT Population: All randomized participants who received study drug regardless of treatment actually received. Number of participants analyzed is the number of participants with data available at the specific time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RNS60 1.0 mL/kg/h | Change From Baseline in Infarct Volume of Stroke at 48 Hours | Baseline | 43.6 mL | Standard Deviation 40.26 |
| RNS60 1.0 mL/kg/h | Change From Baseline in Infarct Volume of Stroke at 48 Hours | Change From Baseline at 48 Hours | 21.4 mL | Standard Deviation 23.16 |
| RNS60 0.5 mL/kg/h | Change From Baseline in Infarct Volume of Stroke at 48 Hours | Baseline | 37.9 mL | Standard Deviation 41.82 |
| RNS60 0.5 mL/kg/h | Change From Baseline in Infarct Volume of Stroke at 48 Hours | Change From Baseline at 48 Hours | 27.1 mL | Standard Deviation 30 |
| Placebo 1.0 mL/kg/h | Change From Baseline in Infarct Volume of Stroke at 48 Hours | Baseline | 49.0 mL | Standard Deviation 55.93 |
| Placebo 1.0 mL/kg/h | Change From Baseline in Infarct Volume of Stroke at 48 Hours | Change From Baseline at 48 Hours | 40.6 mL | Standard Deviation 42.2 |
Secondary
Health-related Quality of Life as Measured by 5-Level EuroQoL 5D Index (EQ-5D-5L) at Day 90
EQ-5D-5L is a generic instrument for measuring health-related quality of life. It consists of a 5-item questionnaire, which was interviewer administered by study staff. The 5-item questionnaire comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and each dimension has 5 response levels (1-no problems, 2-slight problems, 3-moderate problems, 4-severe problems, 5-unable to/extreme problems). The health state is then summarized to be a single number, EQ-5D-5L Index score, by applying a country-specific standard value set. EQ-5D-5L Index score for the United States ranges from -0.59 to 1, where 1 indicates a better health condition.
Time frame: Day 90
Population: ITT Population: All randomized participants who received study drug regardless of treatment actually received. Number of participants analyzed is the number of participants with available data on Day 90.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RNS60 1.0 mL/kg/h | Health-related Quality of Life as Measured by 5-Level EuroQoL 5D Index (EQ-5D-5L) at Day 90 | 0.77 score on a scale | Standard Deviation 0.29 |
| RNS60 0.5 mL/kg/h | Health-related Quality of Life as Measured by 5-Level EuroQoL 5D Index (EQ-5D-5L) at Day 90 | 0.60 score on a scale | Standard Deviation 0.33 |
| Placebo 1.0 mL/kg/h | Health-related Quality of Life as Measured by 5-Level EuroQoL 5D Index (EQ-5D-5L) at Day 90 | 0.66 score on a scale | Standard Deviation 0.28 |
Secondary
National Institutes of Health Stroke Scale (NIHSS) at 24 Hours
The NIHSS is a standardized neurological examination scale that is a measure of disability and recovery after acute stroke. The NIHSS assessment is a standardized 15-item impairment scale intended to evaluate neurologic outcome and degrees of recovery for subjects with stroke. The scale assesses levels of consciousness, extraocular movements, visual fields, facial muscle function, extremity strength, sensory function, coordination (ataxia), language (aphasia), speech (dysarthria), and hemi-inattention (neglect). The NIHSS was scored by those trained in the use of this scale. Each item was scored in ranges 0-2, 0-3, or 0-4. A score of 0 indicates normal performance. Total scores on the NIHSS ranged from 0-42, with higher values reflecting increasing severity. Stroke severity was further stratified in the following way: \> 25: Very severe; 15-24: Severe; 5-14: Mild to moderately severe; \< 5: Mild.
Time frame: 24 hours
Population: ITT Population: All randomized participants who received study drug regardless of treatment actually received. The number of participants analyzed is the number of participants with data available at the 24 hour time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RNS60 1.0 mL/kg/h | National Institutes of Health Stroke Scale (NIHSS) at 24 Hours | 8.3 score on a scale | Standard Deviation 6.77 |
| RNS60 0.5 mL/kg/h | National Institutes of Health Stroke Scale (NIHSS) at 24 Hours | 10.4 score on a scale | Standard Deviation 7.67 |
| Placebo 1.0 mL/kg/h | National Institutes of Health Stroke Scale (NIHSS) at 24 Hours | 10.9 score on a scale | Standard Deviation 7.88 |
Secondary
Number of Participants With Non-disability Based on Modified Rankin Scale (mRS ) Score at Day 90
The mRS is a clinician-reported outcome measure for participants who have suffered a stroke. It measures functional recovery as the degree of disability or dependence in daily activities in a 6-point disability scale with possible scores ranging from 0 to 5: 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; 3-moderate disability: requiring some help, but able to walk without assistance; 4-moderately severe disability: unable to walk without assistance and unable to attend to own bodily needs without assistance; 5-severe disability; bedridden, incontinent, requiring constant nursing care and attention. A score of 6 is used for participants who expire (death). Non-disability was defined as a score ranging from 0 to 2. Disability was defined as a score ranging from 3-6.
Time frame: Day 90
Population: ITT Population: All randomized participants who received study drug regardless of treatment actually received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RNS60 1.0 mL/kg/h | Number of Participants With Non-disability Based on Modified Rankin Scale (mRS ) Score at Day 90 | 15 Participants |
| RNS60 0.5 mL/kg/h | Number of Participants With Non-disability Based on Modified Rankin Scale (mRS ) Score at Day 90 | 13 Participants |
| Placebo 1.0 mL/kg/h | Number of Participants With Non-disability Based on Modified Rankin Scale (mRS ) Score at Day 90 | 13 Participants |
Secondary
Percentage of Participants With Barthel Index (BI) Score ≥95 at Day 90
The BI is an index of functional independence. Its values range from 0 to 100, with higher scores indicating greater independence. Score range in BI items: Feeding 0-10; Bathing 0-5; Grooming 0-5; Dressing 0-10; Bowels 0-10; Bladder 0-10; Toilet use 0-10; Transfers (bed to chair and back) 0-15; Mobility (on level surfaces) 0-15; Stairs 0-10. Item scores vary in increments of 5 points. Functional independence at Day 90 was evaluated. Participants having a score ≥95 on the BI Score were deemed to have achieved functional independence, whereas those scoring \<95 at Day 90 were deemed to have failed to achieve functional independence.
Time frame: Day 90
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RNS60 1.0 mL/kg/h | Percentage of Participants With Barthel Index (BI) Score ≥95 at Day 90 | 70.8 percentage of participants |
| RNS60 0.5 mL/kg/h | Percentage of Participants With Barthel Index (BI) Score ≥95 at Day 90 | 40.0 percentage of participants |
| Placebo 1.0 mL/kg/h | Percentage of Participants With Barthel Index (BI) Score ≥95 at Day 90 | 42.9 percentage of participants |
Secondary
Proportion of Participants With Worsening of Stroke
Worsening of stroke was defined as progression, or hemorrhagic transformation of the index stroke, as documented by brain imaging, which is (a) life-threatening requiring intervention and/or (b) results in increased disability as gauged by a ≥ 4-point increase from lowest NIHSS pre-decline and/or (c) results in death. Proportion of participants with worsening of stroke was calculated as number of participants with worsening of stroke divided by the total number of participants observed over the 90-day period in each arm.
Time frame: Up to Day 90
Population: ITT Population: All randomized participants who received study drug regardless of treatment actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RNS60 1.0 mL/kg/h | Proportion of Participants With Worsening of Stroke | 0.208 proportion of participants |
| RNS60 0.5 mL/kg/h | Proportion of Participants With Worsening of Stroke | 0.400 proportion of participants |
| Placebo 1.0 mL/kg/h | Proportion of Participants With Worsening of Stroke | 0.286 proportion of participants |