Brain Edema, Stroke, Acute
Conditions
Keywords
Infarction, Cerebrovascular Disorders, Brain Diseases, Pathological Processes Necrosis, Central Nervous System Diseases, Vascular Diseases, Cardiovascular Diseases, Glyburide, Hypoglycemic Agents, Physiological Effects of Drugs
Brief summary
The primary objective of Part 1 of the study is to determine if BIIB093 improves functional outcome at Day 90 as measured by the modified Rankin Scale (mRS) when compared with placebo in participants with Large Hemispheric Infarction (LHI). The secondary objectives of Part 1 of the study are to determine if BIIB093 improves overall survival at Day 90 when compared with placebo, if BIIB093 improves functional outcome at Day 90 on the mRS dichotomized 0-4 vs. 5-6 when compared with placebo, if BIIB093 reduces midline shift at 72 hours (or at time of decompressive craniectomy \[DC\] or comfort measures only \[CMO\], if earlier) when compared with placebo, and to evaluate the safety and tolerability of BIIB093 in participants with LHI. The objectives of Part 2 of the study are to evaluate long-term disability following LHI, to evaluate long-term outcome measures of clinical function, quality of life, and healthcare utilization, and to assess the safety of BIIB093 in subjects with LHI during the follow-up period.
Interventions
DRUGBIIB093
Administered as specified in the treatment arm.
DRUGPlacebo
Administered as specified in the treatment arm.
Sponsors
Remedy Pharmaceuticals, 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 85 Years
Healthy volunteers
No
Inclusion criteria
1. A clinical diagnosis of acute ischemic stroke in the middle cerebral artery (MCA) territory. 2. A large hemispheric infarction defined as; lesion volume of 80 to 300 centimeters cubed (cm\^3) on magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI), or computed tomography perfusion (CTP), or an Alberta Stroke Program Early CT Score (ASPECTS) of 1 to 5 with involvement of at least 2 defined cortical regions. 3. Screening National Institutes of Health Stroke Scale (NIHSS) \>=10. 4. At the time of randomization, and in the Investigator's judgement, it must be feasible for study drug treatment infusion to be initiated no later than 10 hours after time of symptom onset, if known, or the time last known normal. * Participants who wake with stroke may be included if neurological and other
Exclusion criteria
are satisfied. The time of stroke onset is to be taken as the midpoint between sleep onset (or last known to be normal) and time of waking. 5. For participants who receive thrombectomy, inclusion into the study must be based on post-thrombectomy MRI-DWI.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Percentage of Participants With Improvement in Functional Outcome at Day 90 Assessed Via the Modified Rankin Scale (mRS) | Day 90 | The mRS measures the degree of functional independence following stroke. In this study, 7-category ordinal mRS scale was condensed to the following 5-categories: 0/1, 2, 3, 4, 5/6 where 0 and 1 reflect no disability and near-normal functioning while 5 and 6 represent severe disability and death, respectively. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Time to All-Cause Death Through Day 90 | Randomization up to Day 90 | Time to all-cause death is defined as the time from randomization to the time of death. |
| Part 1: Percentage of Participants Who Achieved mRS 0-4 at Day 90 | Day 90 | The mRS measures the degree of functional independence following stroke. In this study, the 7-category ordinal mRS scale was condensed to the following 5-categories: 0/1, 2, 3, 4, 5/6 where 0 and 1 reflect no disability and near-normal functioning while 5 and 6 represent severe disability and death, respectively. |
| Part 1: Midline Shift at 72 Hours as Assessed by Non-contrast Computed Tomography (NCCT) or Magnetic Resonance Imaging (MRI) | At 72 hours | Midline shift is the perpendicular distance between the septum pellucidum and the line drawn between the anterior and posterior attachments of the falx to the inner table of the skull. |
| Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From the signing of informed consent up to the last follow-up visit (up to 4 years 11 months) | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly. |
Countries
Australia, Belgium, Brazil, Canada, China, Croatia, Czechia, Denmark, Finland, France, Germany, Hungary, Israel, Italy, Japan, Lithuania, Portugal, Russia, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at investigative sites in the United States, Brazil, China, Spain, Japan, Australia, Portugal, Germany, United Kingdom, Finland, Canada, Israel, France, Taiwan, Hungary, Czech Republic, Italy, Belgium, Lithuania, Russia and South Korea from 29 August 2018 to 18 August 2023.
Pre-assignment details
A total of 535 participants were enrolled and randomised, out of which 518 participants were dosed with BIIB093 or a matching placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were administered with BIIB093 matching placebo as an IV bolus on Day 1 followed by a continuous IV infusion for over 72 hours. | 268 |
| BIIB093 Participants were administered with BIIB093 as an IV bolus on Day 1 followed by continuous IV infusion for over 72 hours. | 267 |
| Total | 535 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 22 | 19 |
| Overall Study | Death | 3 | 13 |
| Overall Study | Physician Decision | 4 | 2 |
| Overall Study | Reason not specified | 14 | 12 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
| Overall Study | Withdrew Prior to Dosing | 9 | 8 |
Baseline characteristics
| Characteristic | BIIB093 | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 60.5 years STANDARD_DEVIATION 11.17 | 61.1 years STANDARD_DEVIATION 11 | 61.6 years STANDARD_DEVIATION 10.81 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 41 Participants | 77 Participants | 36 Participants |
| Race/Ethnicity, Customized Ethnicity Missing | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 223 Participants | 451 Participants | 228 Participants |
| Race/Ethnicity, Customized Ethnicity Not reported | 1 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 51 Participants | 104 Participants | 53 Participants |
| Race/Ethnicity, Customized Race Black or African American | 19 Participants | 40 Participants | 21 Participants |
| Race/Ethnicity, Customized Race Missing | 2 Participants | 5 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Not reported due to confidentiality regulations | 1 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Other | 16 Participants | 28 Participants | 12 Participants |
| Race/Ethnicity, Customized Race White | 177 Participants | 350 Participants | 173 Participants |
| Sex: Female, Male Female | 98 Participants | 202 Participants | 104 Participants |
| Sex: Female, Male Male | 169 Participants | 333 Participants | 164 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 97 / 259 | 103 / 259 |
| other Total, other adverse events | 199 / 259 | 201 / 259 |
| serious Total, serious adverse events | 177 / 259 | 199 / 259 |
Outcome results
Primary
Part 1: Percentage of Participants With Improvement in Functional Outcome at Day 90 Assessed Via the Modified Rankin Scale (mRS)
The mRS measures the degree of functional independence following stroke. In this study, 7-category ordinal mRS scale was condensed to the following 5-categories: 0/1, 2, 3, 4, 5/6 where 0 and 1 reflect no disability and near-normal functioning while 5 and 6 represent severe disability and death, respectively.
Time frame: Day 90
Population: The modified intent to treat (mITT) population included participants aged 18 to 70 years (inclusive) at the time of randomization, who had received any study drug, and who had at least 1 post-baseline mRS before or at Day 90 visit. Here, 'Overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Part 1: Percentage of Participants With Improvement in Functional Outcome at Day 90 Assessed Via the Modified Rankin Scale (mRS) | Score: 0/1 | 1.4 percentage of participants |
| Placebo | Part 1: Percentage of Participants With Improvement in Functional Outcome at Day 90 Assessed Via the Modified Rankin Scale (mRS) | Score: 3 | 12.6 percentage of participants |
| Placebo | Part 1: Percentage of Participants With Improvement in Functional Outcome at Day 90 Assessed Via the Modified Rankin Scale (mRS) | Score: 2 | 2.8 percentage of participants |
| Placebo | Part 1: Percentage of Participants With Improvement in Functional Outcome at Day 90 Assessed Via the Modified Rankin Scale (mRS) | Score: 4 | 25.2 percentage of participants |
| Placebo | Part 1: Percentage of Participants With Improvement in Functional Outcome at Day 90 Assessed Via the Modified Rankin Scale (mRS) | Score: 5/6 | 57.9 percentage of participants |
| BIIB093 | Part 1: Percentage of Participants With Improvement in Functional Outcome at Day 90 Assessed Via the Modified Rankin Scale (mRS) | Score: 4 | 23.5 percentage of participants |
| BIIB093 | Part 1: Percentage of Participants With Improvement in Functional Outcome at Day 90 Assessed Via the Modified Rankin Scale (mRS) | Score: 5/6 | 56.2 percentage of participants |
| BIIB093 | Part 1: Percentage of Participants With Improvement in Functional Outcome at Day 90 Assessed Via the Modified Rankin Scale (mRS) | Score: 0/1 | 3.2 percentage of participants |
| BIIB093 | Part 1: Percentage of Participants With Improvement in Functional Outcome at Day 90 Assessed Via the Modified Rankin Scale (mRS) | Score: 2 | 5.1 percentage of participants |
| BIIB093 | Part 1: Percentage of Participants With Improvement in Functional Outcome at Day 90 Assessed Via the Modified Rankin Scale (mRS) | Score: 3 | 12.0 percentage of participants |
p-value: =0.41595% CI: [0.8, 1.71]Regression, Logistic
Secondary
Part 1: Midline Shift at 72 Hours as Assessed by Non-contrast Computed Tomography (NCCT) or Magnetic Resonance Imaging (MRI)
Midline shift is the perpendicular distance between the septum pellucidum and the line drawn between the anterior and posterior attachments of the falx to the inner table of the skull.
Time frame: At 72 hours
Population: The mITT population included participants aged 18 to 70 years (inclusive) at the time of randomization, who received any study drug, and who had at least 1 post-baseline mRS before or at the Day 90 visit. Here, 'Overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Part 1: Midline Shift at 72 Hours as Assessed by Non-contrast Computed Tomography (NCCT) or Magnetic Resonance Imaging (MRI) | 6.32 millimeters (mm) | Standard Deviation 4.76 |
| BIIB093 | Part 1: Midline Shift at 72 Hours as Assessed by Non-contrast Computed Tomography (NCCT) or Magnetic Resonance Imaging (MRI) | 7.02 millimeters (mm) | Standard Deviation 4.565 |
p-value: =0.124295% CI: [-0.23, 1.87]ANOVA
Secondary
Part 1: Percentage of Participants Who Achieved mRS 0-4 at Day 90
The mRS measures the degree of functional independence following stroke. In this study, the 7-category ordinal mRS scale was condensed to the following 5-categories: 0/1, 2, 3, 4, 5/6 where 0 and 1 reflect no disability and near-normal functioning while 5 and 6 represent severe disability and death, respectively.
Time frame: Day 90
Population: The mITT population included participants aged 18 to 70 years (inclusive) at the time of randomization, who received any study drug, and who had at least 1 post-baseline mRS before or at the Day 90 visit. Here, 'Overall number of participants analyzed' signifies number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Part 1: Percentage of Participants Who Achieved mRS 0-4 at Day 90 | 41.6 percentage of participants |
| BIIB093 | Part 1: Percentage of Participants Who Achieved mRS 0-4 at Day 90 | 42.9 percentage of participants |
p-value: =0.741395% CI: [0.72, 1.6]Regression, Logistic
Secondary
Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly.
Time frame: From the signing of informed consent up to the last follow-up visit (up to 4 years 11 months)
Population: The safety population included all participants who were enrolled and had received any portion of the infusion of study treatment (placebo or BIIB093). Here, 'Overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 95.4 percentage of participants |
| Placebo | Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 68.3 percentage of participants |
| BIIB093 | Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 76.8 percentage of participants |
| BIIB093 | Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 97.3 percentage of participants |
Secondary
Part 1: Time to All-Cause Death Through Day 90
Time to all-cause death is defined as the time from randomization to the time of death.
Time frame: Randomization up to Day 90
Population: The mITT population included participants aged 18 to 70 years (inclusive) at the time of randomization, who received any study drug, and who had at least 1 post-baseline mRS before or at the Day 90 visit. Here, 'Overall number of participants analyzed' signifies number of participants with data available for outcome measure analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Part 1: Time to All-Cause Death Through Day 90 | NA days |
| BIIB093 | Part 1: Time to All-Cause Death Through Day 90 | NA days |