Principal Investigator: Lee Chung
Keywords: Large Hemispheric Infarct , Acute Ischemic Stroke , Glibenclamide , Severe Cerebral Edema Department: Neurology
IRB Number: 00094516 Co Investigator: Nabeel Chauhan
Specialty: Neurology, Neurology
Sub Specialties: Neuro Critical Care, Stroke
Recruitment Status: Recruiting

Contact Information

Theodore Rock
theodore.rock@hsc.utah.edu
801-585-0541

Brief Summary

Primary Objective:
To determine if BIIB093 improves functional outcome at Day 90 as measured by modified Rankin Scale (mRS) when compared with placebo in subjects with LHI.
 
Secondary Objectives:
To determine if BIIB093 improves overall survival at Day 90 when compared with placebo in the modified intent-to-treat (mITT) population.

To determine if BIIB093 improves functional outcome at Day 90 on the mRS dichotomized 0-4
vs. 5-6, when compared with placebo in the mITT population.

To determine if BIIB093 reduces midline shift at 72 hours (or at time of DC or comfort measures
only [CMO], if earlier) when compared with placebo in the mITT population.

To evaluate the safety and tolerability of BIIB093 in subjects with LHI.

Detailed Description

This is a Phase 3, randomized, multicenter, placebo-controlled, double-blind, parallel-group study in subjects aged 18 to 85 years with a LHI and time from symptom onset to start of study treatment infusion of ≤10 hours. Standard of care (SOC) imaging (MRI and/or computed tomography perfusion [CTP] and/or non-contrast computed tomography [NCCT]) is performed at screening to assess lesion size. The lesion must meet the size criteria set forth in Section 8.1 for the subject to be eligible for this study.The study is a 2-part study: Part 1 is a safety and efficacy study that includes the time from screening/enrollment through the completion of the Day 90 assessments. Part 2 is a long-term functional outcome study and includes Day 91 through the completion of the Month 12 assessments.The study allows SOC therapy including IV rtPA, thrombectomy, mannitol, hypertonic saline, DC, and other treatments for LHI per local guidelines as determined by the Investigator. Study treatment is administered as a 3-stage continuous infusion over 72 hours in a 1:1 randomization allocation (BIIB093: placebo).In order to avoid any delays in administration of standard of care stroke therapies, IV thrombolysis and/or thrombectomy must be completed prior to randomization when they are planned for subjects who are being screened for the study. Given the limited experience with the use of thrombectomy in subjects with LHI, a post-thrombectomy MRI is required to determine study eligibility when thrombectomy occurs prior to randomization. In the event that IV thrombolysis or thrombectomy is required in subjects who have already been randomized into the trial, they are allowed per the study protocol.Since there is limited experience with thrombectomy in LHI patients, the number of subjects with thrombectomy performed prior to randomization is not to exceed approximately 8% in each of the ≤70 yrs and >70 yrs age subgroups of the study population.After the study treatment infusion is complete, imaging by NCCT or MRI for midline shift (method should be consistent with baseline imaging method whenever possible) should be performed between 72 to 96 hours and as close to 72 hours as possible. For those subjects designated for DC or CMO, the NCCT or MRI for midline shift should occur within 12 hours prior to DC or the initiation of CMO, respectively. In the event a SOC scan is taken that meets the foregoing requirements, the SOC scan will be collected and a study-specific scan need not be obtained. In the case of DC or CMO, if no SOC image within 12 hours prior to DC or CMO is available and taking a study-specific image would, in the opinion of the Investigator, be contrary to the best interest of the subject, a study-specific image will not be obtained.The efficacy endpoints (mRS and survival) will be recorded at Days 30 and 90 and midline shift at 72 hours. Database lock will take place at Day 90. Safety laboratory values will be assessed through Day 7 or hospital discharge (whichever is earlier). AEs will be collected through Day 90 and SAEs through Month 12. Patient outcome measures (EQ-5D-5L, BI, SIS-16, Health Care Resource Utilization Questionnaire, and Zaret Burden Interview) will be assessed at selectedtime points. The study has been designed to randomize approximately 600 subjects aged 18 to 70 years. In addition, approximately 80 subjects aged >70 years and up to 85 years (inclusive) will also be randomized for safety and exploratory efficacy evaluations.

Inclusion Criteria

Inclusion Criteria:
 
Ability to understand the purpose and risks of the study and provide signed and dated
informed consent and authorization to use confidential health information in accordance
with national and local subject privacy regulations or consent provided by an independent
physician where local regulation allows, and/or provision of informed consent by the
subject’s legally authorized representative (LAR) in accordance with all local and
national regulations or according to the local ethics committee’s guidelines or by another
process compliant with applicable national laws and regulations and ethics committee
requirements.

Have to have a clinical diagnosis of acute ischemic stroke in the MCA territory (PCA and/or ACA
territory involvement in addition to primary MCA territory stroke is acceptable).

Aged 18 to 85 years old, inclusive, at the time of informed consent.

Screening NIHSS ≥10.

Prior to the current stroke, no significant disability in the opinion of the Investigator (able
to independently perform all duties and activities of daily living without assistance from a
caregiver, spouse, or another person).

A large hemispheric infarction defined, in order of preference, as either:
a) a magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) lesion
volume of 80 to 300 cm3, or a computed tomography perfusion (CTP) core lesion volume of 80 to 300 cm3, or an Alberta Stroke Program Early computed tomography (CT) Score (ASPECTS) on
non-contrast computed tomography (NCCT) of 1 to 5 with involvement of at least 2
defined cortical regions, if lesion volume from MRI DWI or CTP is not available.
In the event that more than one scan is available for a particular subject resulting in
disagreement, the investigator should make the determination about eligibility
considering all patient information including but not limited to:
scan timing and scan modality that in the opinion of the investigator best represents the infarct size. The scan used for eligibility will be documented.

For subjects who receive thrombectomy prior to randomization, inclusion into the study
must be based on an infarct volume of 80 to 300 cm3 measured by post-thrombectomy
MRI-DWI.

Study drug treatment infusion should be initiated as soon as possible but no later than 10
hours after time of symptom onset, if known, or the time last known normal (if time to
symptom onset is unknown).

Exclusion Criteria

Exclusion Criteria:
 
1. In the judgment of the Investigator, the subject is likely to have supportive care
withdrawn in the first day.

2. Commitment to decompressive craniectomy (DC) prior to enrollment.

3. Evidence (clinical or imaging) of concurrent infarction in the contralateral hemisphere deemed by the Investigator to be sufficiently serious so as to affect functional outcome. This would include, for example, a contralateral ACA infarct that leads to bilateral leg
paralysis.

4. Clinical signs of herniation, e.g., 1 or 2 dilated, fixed pupils; unconsciousness related to
edema (i.e., ≥2 on item 1a on the NIHSS); and/or loss of other brain stem reflexes,
attributable to edema or herniation according to the Investigator’s judgment.

5. Brain hemorrhage (other than small petechial/punctate hemorrhages) on NCCT/MRI.

6.NCCT/MRI evidence of anteroseptal/pineal shift >2 mm prior to enrollment.

7. Use of intra-arterial thrombolytic agents, alone or in combination with thrombectomy.

8. Patients whoare currently being considered for thrombectomy and/or IV thrombolysis
may not be randomized into the study until these procedures have been completed OR the
decision not to perform them has been made. These treatments should not be delayed for
study screening procedures. When thrombectomy is performed prior to randomization,
study eligibility must be assessed using inclusion criterion #7.

9. Subjects with, in the opinion of the Investigator, life expectancy <3 months not related to
current LHI, or those unlikely to be compliant with follow up.

10. Subjects in whom a peripheral IV line cannot be placed.

11. Subjects with mental disability (prior to qualifying LHI) or wards of the state.

12. Subjects whose stroke symptoms are rapidly improving and are not expected in the opinion of the Investigator to have NIHSS≥10 at the time of randomization.

13. Known allergy to BIIB093 or to another sulfonylurea drug or any of the components of
the formulated BIIB093 or matching placebo.

14. Subjects who are known to have taken oral glibenclamide within the past 10 hours.

15. Known history of clinically significant severe form of renal or hepatic disorder, in the
Investigator's opinion (e.g., dialysis or cirrhosis, respectively).

16. Known history of chronic obstructive pulmonary disease that, in the judgment of the
Investigator, is severe (e.g., requiring home oxygen).

17. Known history of clinically significant hypoglycemia, in the Investigator's opinion based
on known medical history or local screening laboratory assessments (i.e. screening blood
glucose <70 mg/dL [~3.9 mmol/L]).

18. Subjects who have or have ever had diabetic ketoacidosis or diabetic coma/precoma.

19. Acute ST elevation myocardial infarction (MI), and/or acute decompensated heart failure,
and/or QTc >520 msec, and/or admission for an acute coronary syndrome, MI, cardiac
arrest, or non-voluntary coronary intervention (percutaneous coronary intervention or
coronary artery surgery) within the past 3 months.

20. New York Heart Association heart failure III/IV (class III: marked limitation in activity
due to symptoms, even during less-than-ordinary activity, e.g. walking short distances
(20-100 m); class IV: severe limitations. Experiences symptoms even while at rest.
Mostly bedbound patients).

21. Known cardiac ventricular tachycardia.

22. Subjects with known glucose-6-phosphate dehydrogenase enzyme deficiency.

23. Serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., septicemia)
that required hospitalization or was clinically significant in the opinion of the Investigator
within 3 days prior to Screening.

24. Females who are pregnant or women of childbearing potential with a positive pregnancy
test at time of admission.

25. Nursing women who are unable to stop breastfeeding during study treatment infusion and
for 7 days following the end of study treatment infusion.

26. Known current participation or known history of participation in any other investigational
study that involved treatment with an investigational drug within 14 days prior to
enrollment.

27. Inability to comply with study requirements.

28. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the
subject unsuitable for enrollment.