Clinical trial NCT02864953
Conditions: Brain Edema Stroke, Acute
Keywords: Infarction Cerebrovascular Disorders Brain Diseases Pathological Processes Necrosis Central Nervous System Diseases Vascular Diseases Cardiovascular Diseases Glyburide Hypoglycemic Agents Physiological Effects of Drugs
Sponsor: Remedy Pharmaceuticals, Inc.
Start date: 2018-08-29; Completion date: 2023-08-18
Enrollment: 535 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:

Arms: arm 1: BIIB093 administered as a bolus followed by continuous intravenous (IV) infusion over 72 hours. arm 2: Placebo administered as a bolus followed by continuous intravenous (IV) infusion over 72 hours.
Interventions: intervention 1: BIIB093 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered as specified in the treatment arm. intervention 2: Administered as specified in the treatment arm.

Protocol documents:
Prot_000.pdf: 
 
Oﬃcial Title: 
Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
MulƟcenter, Phase 3 Study to Evaluate the Eﬃcacy and Safety of 
Intravenous BIIB093 (Glibenclamide) for Severe Cerebral Edema Following 
Large Hemispheric InfarcƟon 
NCT Number: 
NCT02864953 
Document Date: 
Protocol Version 3.0: 11 Jun 2021 
COVER PAGE 


CONFIDENTIAL
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Biogen MA Inc.
1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
PROTOCOL NUMBER: 252LH301
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
PHASE OF DEVELOPMENT: 3
Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Phase 3 
Study to Evaluate the Efficacy and Safety of Intravenous BIIB093 (Glibenclamide) for 
Severe Cerebral Edema following Large Hemispheric Infarction
CHARM Study:  Glibenclamide for large hemispheric infarction 
analyzing mRS and mortality
IND NUMBER:                        128581
EUDRA CT NUMBER:           2017-004854-41 
DATE:
11 June 2021
Version 3
FINAL
Supersedes previous Version 2 dated 29 September 2020.




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TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ....................................................................................................2
1.
SYNOPSIS ...................................................................................................................9
2.
LIST OF ABBREVIATIONS.....................................................................................13
3.
SPONSOR INFORMATION .....................................................................................15
4.
INTRODUCTION......................................................................................................16
4.1.
Large Hemispheric Infarction Background ................................................................16
4.2.
Rationale for Glibenclamide in Reducing Edema Formation.....................................16
4.3.
Current Therapies for Edema Associated with LHI ...................................................17
4.4.
Profile of Previous Experience with Intravenous BIIB093........................................18
4.4.1.
Nonclinical Experience...............................................................................................18
4.4.2.
Clinical Experience.....................................................................................................19
4.4.3.
Benefit/Risk................................................................................................................19
4.5.
Study Rationale...........................................................................................................20
4.6.
Dosing Rationale ........................................................................................................20
5.
SCHEDULE OF ACTIVITIES ..................................................................................21
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................25
6.1.
PART 1 Objectives and Endpoints.............................................................................25
6.2.
PART 2 Objectives and Endpoints.............................................................................26
7.
STUDY DESIGN .......................................................................................................27
7.1.
Study Overview ..........................................................................................................27
7.2.
Study Duration for Subjects........................................................................................28
7.3.
Responsibilities of Study Site Personnel....................................................................28
7.4.
Study Stopping Rules .................................................................................................28
7.5.
End of Study ...............................................................................................................29
8.
SELECTION OF SUBJECTS ....................................................................................30
8.1.
Inclusion Criteria ........................................................................................................30
8.2.
Exclusion Criteria.......................................................................................................31
9.
SCREENING AND RANDOMIZATION .................................................................34
9.1.
Screening ....................................................................................................................34
9.2.
Randomization............................................................................................................34
9.3.
Blinding Procedures....................................................................................................35


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10.
DISCONTINUATION OF STUDY TREATMENT AND WITHDRAWAL 
OF SUBJECTS FROM THE STUDY........................................................................36
10.1.
Discontinuation of Study Treatment...........................................................................36
10.2.
Lost to Follow-Up.......................................................................................................37
10.3.
Withdrawal of Subjects from Study ...........................................................................38
11.
STUDY TREATMENT USE .....................................................................................39
11.1.
Regimen......................................................................................................................39
11.2.
Modification of Dose and/or Treatment Schedule......................................................39
11.3.
Precautions..................................................................................................................40
11.4.
Concomitant Therapy and Procedures........................................................................40
11.4.1.
Concomitant Therapy .................................................................................................40
11.4.1.1.
Allowed Concomitant Therapy...................................................................................40
11.4.1.2.
Disallowed Concomitant Therapy..............................................................................42
11.4.2.
Concomitant Procedures.............................................................................................42
11.4.2.1.
Thrombectomy............................................................................................................42
11.4.2.2.
Decompressive Craniectomy......................................................................................43
11.5.
Continuation of Treatment..........................................................................................43
12.
STUDY TREATMENT MANAGEMENT................................................................44
12.1.
BIIB093 ......................................................................................................................44
12.1.1.
BIIB093 Preparation...................................................................................................44
12.1.2.
BIIB093 Storage.........................................................................................................45
12.1.3.
BIIB093 Handling and Disposal.................................................................................45
12.1.4.
BIIB093 Accountability..............................................................................................45
12.2.
Placebo........................................................................................................................45
13.
EFFICACY ASSESSMENTS ....................................................................................46
13.1.
Clinical Efficacy Assessments....................................................................................46
13.1.1.
Functional Outcome (mRS)........................................................................................46
13.1.2.
Subject Disposition.....................................................................................................46
13.1.3.
Midline Shift...............................................................................................................46
13.1.4.
Patient Outcome Measures .........................................................................................47
13.1.4.1.
European Quality of Life Assessment (EQ-5D-5L)...................................................47
13.1.4.2.
Zarit Burden Interview ...............................................................................................47


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13.1.4.3.
Barthel Index ..............................................................................................................47
13.1.4.4.
Stroke Impact Scale 16...............................................................................................47
13.1.4.5.
HealthCare Resource Utilization Questionnaire.........................................................47
13.3.
Genetic and Pharmacogenetic Assessments...............................................................48
13.4.
Future Scientific Research Assessments ....................................................................48
14.
SAFETY ASSESSMENTS ........................................................................................49
14.1.
Clinical Safety Assessments.......................................................................................49
14.2.
Laboratory Safety Assessments..................................................................................49
14.3.
Product-Specific Safety Assessments.........................................................................50
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................51
15.1.
Definitions ..................................................................................................................51
15.1.1.
Adverse Event.............................................................................................................51
15.1.2.
Serious Adverse Event................................................................................................51
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................52
15.2.
Safety Classifications..................................................................................................52
15.2.1.
Investigator Assessment of Events.............................................................................52
15.2.2.
Relationship of Events to Study Treatment................................................................52
15.2.3.
Severity of Events.......................................................................................................53
15.2.4.
Expectedness of Events ..............................................................................................53
15.3.
Monitoring and Recording Events..............................................................................53
15.3.1.
Adverse Events...........................................................................................................53
15.3.2.
Adverse Events of Special Interest.............................................................................54
15.3.3.
Serious Adverse Events..............................................................................................54
15.3.4.
Immediate Reporting of Serious Adverse Events.......................................................54
15.3.4.1.
Deaths .........................................................................................................................54
15.3.5.
Suspected Unexpected Serious Adverse Reactions....................................................55
15.4.
Procedures for Handling Special Situations ...............................................................55
15.4.1.
Pregnancy ...................................................................................................................55
15.4.2.
Overdose.....................................................................................................................55
15.4.3.
Medical Emergency....................................................................................................55


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15.4.3.1.
Unblinding for Medical Emergency...........................................................................56
15.5.
Contraception Requirements ......................................................................................56
15.6.
Safety Responsibilities................................................................................................57
15.6.1.
The Investigator..........................................................................................................57
15.6.2.
Biogen.........................................................................................................................58
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........59
16.1.
Demography and Baseline Disease Characteristics....................................................59
16.2.
Efficacy.......................................................................................................................59
16.2.1.
Analysis Population....................................................................................................59
16.2.2.
Methods of Analysis...................................................................................................59
16.2.2.1.
General Considerations...............................................................................................59
16.2.2.2.
Analysis of the Primary Endpoint...............................................................................60
16.2.2.3.
Analysis of the Secondary Endpoints.........................................................................60
16.3.
Pharmacokinetics........................................................................................................60
16.3.1.
Analysis Population....................................................................................................60
16.3.2.
Methods of Analyses ..................................................................................................60
16.4.1.
Analysis Populations ..................................................................................................61
16.4.2.
Methods of Analyses ..................................................................................................61
16.6.
Safety..........................................................................................................................61
16.6.1.
Analysis Population....................................................................................................61
16.6.2.
Methods of Analysis...................................................................................................61
16.6.2.1.
Adverse Events...........................................................................................................61
16.6.2.2.
Clinical Laboratory Results........................................................................................62
16.6.2.3.
ECG ............................................................................................................................62
16.6.2.4.
Vital Signs ..................................................................................................................62
16.7.
Interim Analyses.........................................................................................................62
16.8.
Sample Size Considerations .......................................................................................63
17.
ETHICAL REQUIREMENTS ...................................................................................64
17.1.
Declaration of Helsinki...............................................................................................64
17.2.
Ethics Committee........................................................................................................64


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17.3.
Subject Information and Consent ...............................................................................64
17.4.
Subject Data Protection ..............................................................................................65
17.5.
Compensation for Injury.............................................................................................65
17.6.
Conflict of Interest......................................................................................................66
17.7.
Registration of Study and Disclosure of Study Results..............................................66
18.
ADMINISTRATIVE PROCEDURES.......................................................................67
18.1.
Study Site Initiation....................................................................................................67
18.2.
Quality Control and Quality Assurance......................................................................67
18.3.
Monitoring of the Study..............................................................................................67
18.4.
Study Funding.............................................................................................................68
18.5.
Publications.................................................................................................................68
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................69
19.1.
External Contract Organizations.................................................................................69
19.1.1.
Contract Research Organization.................................................................................69
19.1.2.
Interactive Response Technology...............................................................................69
19.1.3.
Electronic or Remote Data Capture............................................................................69
19.1.4.
Central Laboratories for PK, Biomarker, Pharmacogenetic (as applicable) 
Assessments................................................................................................................69
19.1.5.
Central Facility for Other Assessments......................................................................69
19.2.
Study Committees.......................................................................................................70
19.2.1.
Advisory Committee...................................................................................................70
19.2.2.
Independent Data Monitoring Committee..................................................................70
19.3.
Changes to Final Study Protocol ................................................................................70
19.4.
Ethics Committee Notification of Study Completion or Termination........................70
19.5.
Retention of Study Data..............................................................................................70
19.6.
Study Report Signatory...............................................................................................71
20.
REFERENCES ...........................................................................................................72
APPENDIX 1.
MEDICATIONS THAT MODULATE CYP2C9 AND CYP3A4.....................74
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................77


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LIST OF TABLES
Table 1:
Beneficial Effects of Glibenclamide in Rat Models of Large Hemispheric 
Infarction.....................................................................................................................17
Table 2: 
Schedule of Activities – Part 1 (Screening through Day 90)......................................21
Table 3:
 Schedule of Activities – Part 2 (Day 91 through Month 12).....................................24
Table 4:
Criteria to Determine Clinically Relevant Vital Signs Abnormalities .......................62


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1.
SYNOPSIS
Protocol Title:
Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
Multicenter, Phase 3 Study to Evaluate the Efficacy and Safety of 
Intravenous BIIB093 (Glibenclamide) for Severe Cerebral Edema 
following Large Hemispheric Infarction 
Protocol Number:
252LH301
Version Number:
3.0
Name of Study 
Treatment:
BIIB093
Study Phase:
3
Study Indication:
Large Hemispheric Infarction (LHI)
Study Rationale:
LHI is defined as an ischemic stroke affecting the total or sub-total 
territory of the middle cerebral artery (MCA), with or without 
involvement of the adjacent supratentorial territories (i.e., anterior 
cerebral artery [ACA] or posterior cerebral artery [PCA]).  LHI is 
frequently complicated by edema that ultimately may lead to 
transtentorial herniation.  In Study 203 (GAMES-RP), malignant 
edema complicated approximately 50% of LHI.  The prognosis for 
patients with malignant edema is frequently poor, with case fatality as 
high as 40% to 80%.
BIIB093 (also known as glibenclamide and/or glyburide) is a 
sulfonylurea that has its effect via antagonism of the sulfonylurea 
receptor 1 (SUR1).  BIIB093 specifically targets the SUR1-TRPM4 
channel, a mechanism involved in development of edema through 
inhibition of newly upregulated SUR1-TRPM4 channels, reducing the 
formation of edema and its sequalae in multiple models of LHI.  
Intravenous (IV) BIIB093 has been shown to be safe and well tolerated 
in patients with LHI at risk for cerebral edema. 
The current study (Study 252LH301) is a 2-part Phase 3 study to assess 
efficacy and safety of intravenous (IV) BIIB093 to improve functional 
outcomes in subjects with LHI.  Part 1 is a 90-day efficacy and safety 
evaluable period following a 72-hour infusion of BIIB093 or matching 
placebo, and Part 2 is a follow-up period with study visits at Month 6 
and Month 12.






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territory.  (Supratentorial PCA and/or ACA territory involvement in 
addition to primary MCA territory stroke is acceptable.)  
Detailed criteria are described in Section 8.
Treatment Groups:
Study subjects will be randomized in a 1:1 allocation to receive either 
BIIB093 IV 8.6 mg total dose or matching placebo administered as a 3-
stage continuous infusion over 72 hours. There are 2 age groups (18 to 
70 vs. >70-85). Within each age group, subjects will be stratified based 
on region, recombinant tissue plasminogen activator (yes, no), 
thrombectomy (yes, no), use of Alberta Stroke Program Early 
computed tomography (CT) Score (ASPECTS) for screening (yes, no), 
and baseline NIHSS (≤20 vs. >20). 
Since there is limited experience with thrombectomy in LHI patients, 
the number of subjects with thrombectomy performed prior to 
randomization is targeted at approximately 20% in the ≤ 70 year age 
group but may vary from this to reflect the evolving standard of care 
and stroke treatment guidelines. The number of subjects with 
thrombectomy performed prior to randomization is targeted at 
approximately 8% in the >70 year age group. 
Duration of 
Treatment and 
Follow-up:
The primary study outcome is at Day 90 (completion of Part 1).  All 
subjects will be followed for 1 year (completion of Part 2).


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2.LIST OF ABBREVIATIONS
ABCC8
ATP Binding Cassette Subfamily C Member 8 protein
ACA
anterior cerebral artery
AE
adverse event
AHA
American Heart Association
ALT
alanine aminotransferase
ASPECTS
Alberta Stroke Program Early CT Score
AST
aspartate aminotransferase
ATP
adenosine triphosphate
BG
blood glucose
BI
Barthel Index
CHW
Cui-Hung-Wang
CMO
comfort measures only
CRO
contract research organization
CTP
computed tomography perfusion
CYP
cytochrome P450
CYP2C9
cytochrome P450 2C9
D10NS
10% dextrose in normal saline
D50W
dextrose 50% in water
D5NS
5% dextrose in normal saline
DC
decompressive craniectomy
DHA
Directions for Handling and Administration
DWI
diffusion-weighted imaging
ECG
electrocardiogram
eCRF
electronic case report form
EQ-5D-5L
EuroQol 5-level assessment of health outcomes
G6PD
glucose-6-phosphate dehydrogenase
GCP
Good Clinical Practice
ICF
informed consent form
ICH
International Council for Harmonisation
ICL
imaging core laboratory
IDMC
independent data monitoring committee
IRT
interactive response technology
IV
intravenous
LAR
legally authorized representative
LHI
large hemispheric infarction
MCA
middle cerebral artery
MI
myocardial infarction
mITT
modified intent-to-treat
MRI
magnetic resonance imaging
mRS
modified Rankin Scale
NCCT
non-contrast computed tomography


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NIDDM
non-insulin-dependent diabetes mellitus
NIHSS
National Institutes of Health Stroke Scale
OATP1B1
organic-anion-transporting polypeptide 1B1
PCA
posterior cerebral artery
POC
point-of-care
PVC
polyvinyl chloride
QTc
corrected QT interval
rtPA
recombinant tissue plasminogen activator or thrombolysis
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SIS-16
Stroke Impact Scale 16 Questions
SOC
standard of care
SUR1
sulfonylurea receptor 1
SUR1-TRPM4
a nonselective cation channel formed by the sulfonylurea receptor-1 
(SUR1) regulatory unit in association with the transient receptor 
potential cation channel subfamily M member 4 (TRPM4) pore
SUSAR
Suspected Unexpected Serious Adverse Reaction
ULN
upper limit of normal


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3.SPONSOR INFORMATION
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead, Berkshire 
SL6 4AY
United Kingdom
Biogen Japan Ltd.
Nihonbashi 1-chome 
Mitsui Building 14F
4-1 Nihonbashi 1-chome
Chuo-ku, Tokyo
103-0027 Japan
Biogen Australia PTY Ltd.
Suite 1, Level 3 
123 Epping Road
North Ryde, NSW 2113
Australia
For urgent medical issues in which the Medical Monitor should be contacted, please refer to the 
Study Reference Guide’s Official Study Contact List for complete contact information.  
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization (CRO) and other third parties; however, Biogen retains overall accountability for 
these activities.


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4.
INTRODUCTION
BIIB093 is an investigational product under development for the treatment and prevention of 
severe cerebral edema in patients with large hemispheric infarction and for the treatment of brain 
contusion (refer to the Investigator’s Brochure).
4.1.
Large Hemispheric Infarction Background
Large hemispheric infarction (LHI) is defined as an ischemic stroke affecting the total or sub-
total territory of the middle cerebral artery (MCA), involving the basal ganglia at least partially, 
with or without involvement of the adjacent supratentorial territories (i.e., anterior cerebral artery 
[ACA] or posterior cerebral artery [PCA]).  LHI is frequently complicated by edema that 
ultimately leads to transtentorial herniation [Torbey 2015].
Life-threatening edema complicates LHI prognosis in approximately 50% of patients with LHI.  
Such swelling can compromise arterial inflow to surrounding tissues causing further ischemic 
damage and enlargement of the infarct, and frequently results in brain herniation and death.  
Clinical characteristics comprise secondary deterioration of neurological symptoms, particularly 
a disturbance of consciousness and further clinical signs of brain stem herniation.  The prognosis 
for these patients is frequently poor, with case fatality as high as 40% to 80% [Hacke 1996], 
[Berrouschot 1998].
Decompressive craniectomy (DC) has improved the outlook for LHI and did reduce mortality to 
22% in a pooled analysis of DC studies [Vahedi 2007].  However, numerous factors limit the 
usefulness of DC, including limited eligibility for surgery among patients who are gravely ill and 
have life-threatening co-morbidities [Arac 2009], and DC is not indicated for patients with LHI 
prior to development of clinically significant edema.
4.2. Rationale for Glibenclamide in Reducing Edema Formation
Glibenclamide (5-chloro-N-(4-[N-(cyclohexylcarbamoyl) sulfamoyl]phenethyl)-2-
methoxybenzamide; also known as glyburide) is an antidiabetic medication in a class of 
medications known as sulfonylureas.  Oral glibenclamide has been used successfully in the 
treatment of non-insulin-dependent diabetes mellitus (NIDDM) for >20 years.  In treating 
NIDDM, glibenclamide works by inhibiting adenosine triphosphate (ATP)-sensitive potassium 
channels in pancreatic beta cells by antagonism of sulfonylurea receptor 1 (SUR1).  This 
inhibition causes cell membrane depolarization, which causes voltage-dependent calcium 
channels to open, which in turn causes an increase in intracellular calcium in the beta cell, 
stimulating insulin release. 
The SUR1-TRPM4 channel is a nonselective cation channel that is expressed in the central 
nervous system only under conditions of ischemia, hypoxia, and trauma [Chen 2003; Chen and 
Simard 2001; Simard 2006].  Channel opening, which is triggered by depletion of ATP, results in 
cytotoxic edema, oncotic cell death, and vasogenic edema [Simard 2007].  If the cell involved in 
the above pathophysiological sequence is a microvascular endothelial cell, these mechanisms 
result in formation of space-occupying edema [Simard 2006; Simard 2007].  Brain edema 


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formation through this mechanism is a serious complication and can lead to mechanical 
compression of adjacent brain structures, herniation, and death.  Additionally, it can impair 
regional cerebral blood flow, resulting in further ischemia.
Like the ATP-sensitive potassium channels in pancreatic beta cells, the SUR1-TRPM4 channel is 
regulated by SUR1 and is blocked by sulfonylureas such as glibenclamide.  Glibenclamide thus 
specifically targets a mechanism involved in development of edema, reducing the formation of 
edema and secondary damage resulting from edema in multiple models of LHI with treatment 
delays of up to 10 hours following LHI (Table 1).
Table 1:
Beneficial Effects of Glibenclamide in Rat Models of Large Hemispheric 
Infarction
Publication
(Tx Delay)
Effects of Glibenclamide
(All effects listed were statistically significant: 0.001  P < 
0.05)
SLP1
[Simard 2006] 
(none)
reduced mortality from 65% to 24% at 7 d
reduced excess brain water by 42% at 8 h
YesA
[Simard 2010] 
(6 h)
reduced mortality from 67% to 5% at 24 h
reduced hemispheric swelling from 21% to 8% at 24 h
better preservation of watershed cortex and white matter, 
better neuroscores, Garcia scores, and the trajectory of 
weight gain compared with DC during 2 weeks post-insult
YesB
[Simard 2012a]
+ rtPA
(4.5 & 10 h)
reduced mortality from 53% to 17% or 12% at 48 h (Vehicle 
vs. Tx at 4.5 h or 10 h, respectively) 
reduced swelling from 14.7% to 8.1% or 8.8% at 24 h (same 
groups)
improved Garcia scores from 3.8 to 7.6 or 8.4 at 48 h (same 
groups)
YesB
[Simard 2012b] 
+ rtPA
(6 h)
reduced hemispheric swelling from 26% to 12% at 24 h
improved neuroscores from 7 to 3 at 2 weeks
YesA
d = days; DC = decompressive craniectomy; h = hours; rtPA = recombinant tissue plasminogen activator; SLP = STAIR laboratory 
practice; Tx = treatment.
1SLP, including monitoring laser doppler flowmetry and blood gases, temperature control, random treatment allocation, and blinded 
outcome assessment, were performed but not documented (YesA) or performed and documented (YesB).
4.3. Current Therapies for Edema Associated with LHI
Standard of care treatment for ischemic stroke is reperfusion using recombinant tissue 
plasminogen activator (rtPA).  A link between reperfusion and the development of life-
threatening edema has been proposed [Hallenbeck and Dutka 1990; Koudstaal 1988; Nielsen 
2012], and the use of rtPA may aggravate the development of edema [Rudolf 1998]. 
In addition to reperfusion therapy, thrombectomy, using a mechanical device for clot disruption 
for the treatment of stroke has increased in prevalence.  Although thrombectomy or other 
reperfusion therapies may be used in patients at risk for large infarction, these therapies are not 
always successful; therefore, some treated patients may remain at risk for life-threatening 
complications of edema.


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Mannitol and hypertonic saline are osmotic agents that are approved for reducing intracranial 
pressure and are used to reduce brain swelling in LHI after the swelling leads to neurological 
deterioration, although American Heart Association (AHA) guidelines [Jauch 2013; Wijdicks 
2014] state that the effects in patients with ischemic brain swelling is unknown.  
Furthermore, randomized controlled trials comparing mannitol with placebo or open control 
were reviewed and found there was not enough evidence to support the routine use of mannitol 
in all acute stroke patients [Bereczki 2007].  Glucocorticoids are similarly approved for the 
treatment of cerebral edema ([e.g., Decadron [dexamethasone]).  Randomized trials comparing 
corticosteroids with placebo or control in people with acute ischemic stroke were reviewed, 
determining there was not enough evidence to recommend corticosteroid treatment [Qizilbash 
2002].  AHA and Neurocritical Care Society/German Society for Neurocritical and Emergency 
Medicine guidelines recommend corticosteroids not be administered in acute stroke [Jauch 2013; 
Torbey 2015; Wijdicks 2014].
DC has improved the bleak outlook for malignant MCA infarction and reduced mortality to 22% 
in a pooled analysis of DC studies [Vahedi 2007].  However, numerous factors limit the 
usefulness of DC, including limited eligibility for surgery among patients who are gravely ill and 
have important co-morbidities [Arac 2009], and DC is not indicated for patients with LHI prior 
to development of clinically significant edema.
There are currently no therapeutic approaches targeted at reducing the development of edema 
early after the index LHI.  The ability to prevent the development of life-threatening edema 
would be a life-saving intervention that would meaningfully reduce mortality and morbidity.  
Thus, there is an unmet medical need for innovative medical strategies to treat LHI by reducing 
subsequent edema.
4.4. Profile of Previous Experience with Intravenous BIIB093
Glibenclamide administered as an intravenous (IV) formulation is being studied in LHI.  IV 
glibenclamide is known as BIIB093 and was formerly known as CIRARA or RP-1127 when 
under development by Remedy Pharmaceuticals.
See the BIIB093 Investigator’s Brochure for detailed information on relevant nonclinical and 
clinical studies.
4.4.1. Nonclinical Experience
The safety profile of 2 oral glibenclamide/glyburide products such as Micronase® and Glynase®, 
are considered supportive of BIIB093 as it relates to genotoxicity, carcinogenicity, and 
reproductive toxicity information.  Biogen’s nonclinical safety testing strategy for BIIB093 
includes a completed local irritation and systemic toxicity study in rats (Study No. 
0440RR31.001, Remedy No. RPI-TOX1), an in vitro hemolytic potential assay (Study No. 
0725XR31.001), and 2 planned studies: a 14-day continuous infusion rat study and an 
extravascular irritation rabbit study.  Further nonclinical information for glibenclamide is based 
on bibliographical data from peer-reviewed articles on genotoxicity, carcinogenicity, and 


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reproductive toxicity as well as the pharmacology of the substance published since the early 
1970s. 
4.4.2. Clinical Experience
A summary of results from the 2 LHI studies using the same dose of IV glibenclamide as 
proposed for the current study is provided below.
In Study 201 (GAMES-PILOT), 10 subjects with severe ischemic stroke and a baseline magnetic 
resonance imaging (MRI) diffusion-weighted imaging (DWI) lesion between 82 to 210 cc, age of 
18 to 80 years, and time from symptom onset to drug infusion of <10 hours were enrolled at 2 
clinical sites in the United States.  The primary objective of the study was to assess the safety 
and feasibility of enrolling, evaluating, and treating subjects with LHI with BIIB093, whether or 
not they were treated IV with rtPA.  Subjects who received intra-arterial reperfusion therapy, 
prophylactic DC, or were on sulfonylurea treatment at presentation were excluded.  Nine out of 
10 enrolled subjects received rtPA within 4.5 hours from onset of stroke.  Baseline National 
Institute of Health Stroke Scale (NIHSS) scores ranged from 11 to 31, with a median of 18.  The 
mean time from onset of stroke to treatment with BIIB093 was 8.7 hours, with a range of 6.8 to 
9.9 hours.  The incidence of malignant cerebral edema was 20%.  Other than those who 
developed malignant edema, subjects did not require osmotherapy, intubation, or DC.  Results 
from this study indicated that it was feasible to enroll, evaluate and treat subjects with severe 
stroke according to the protocol.  The regimen was well tolerated, and there were no reported 
cases of hypoglycemia.  
Study 203 (GAMES-RP) was a randomized, double-blind, placebo-controlled, multicenter study 
of BIIB093 in subjects with LHI.  The study enrolled subjects aged 18 to 80 years who had a 
clinical diagnosis of large anterior circulation ischemic stroke <10 hours from time last known to 
be neurologically normal, confirmed by a baseline DWI lesion volume of 82 to 300 cm3.  
Subjects who received intra-arterial reperfusion therapy, prophylactic DC, or were on 
sulfonylurea treatment at presentation were excluded.  The primary objective was to assess 
clinical efficacy of BIIB093 compared with placebo in subjects with a severe anterior circulation 
ischemic stroke likely to develop malignant edema.  In Study 203, malignant edema complicated 
approximately 50% of LHI.  This primary efficacy endpoint was the proportion of subjects who 
achieved a modified Rankin Scale (mRS) score of 0 to 4 at Day 90 without undergoing DC.  At 
Day 90, 17 subjects (41%) who received BIIB093 and 14 (39%) in the placebo group achieved 
the primary endpoint (adjusted odds ratio 0.87, 95% confidence interval 0.32 to 2.32; p=0.77); 
thus, the study did not achieve the primary endpoint.  However, BIIB093 administration was 
associated with a potential reduction in mortality, which was accompanied by evidence of 
reduced brain edema and improved functional outcomes (as measured with mRS).  Safety 
analysis suggested that BIIB093 was well tolerated in critically ill LHI participants [Sheth 2016]. 
4.4.3.
Benefit/Risk
BIIB093 was shown to potentially reduce mortality associated with LHI, reducing brain edema, 
and improving functional outcomes.  Currently, there is no therapy available to reduce brain 
swelling secondary to LHI and there is an unmet medical need for this life-threating condition.


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BIIB093 given intravenously in 3-stage dosing regimen over 72 hours was generally well 
tolerated in the population of subjects with LHI. The only adverse drug reaction identified was 
hypoglycemia which can be mitigated by frequent blood glucose measurement and dose 
adjustment.  The safety profile of BIIB093 observed in completed studies in LHI and TBI is 
detailed in the Investigator’s Brochure. Based on the observed benefit in Phase 2 studies of 
BIIB093 for treatment of LHI and the safety profile, Biogen considers that the benefit/risk 
profile of BIIB093 remains positive and supports the continued development of BIIB093 for the 
treatment of patients with LHI.
4.5. Study Rationale
At present, no pharmacotherapy is available to reduce brain swelling secondary to LHI, and no 
drug therapy has been rigorously investigated for patients at a high risk of developing 
life-threatening edema.  Given the promising results of the GAMES-PILOT and 
GAMES-RP studies, the current study will evaluate the efficacy and safety of BIIB093 in 
subjects with LHI.
4.6. Dosing Rationale
The total daily dose for the Phase 3 study (8.6 mg over 72 hours) was determined based on the 
maximum tolerated dose observed in healthy volunteers that did not produce persistent 
hypoglycemia in the Phase 1 study.  The IV infusion regimen was refined based on Phase 1 data 
and PK modeling to a 3-stage dosing regimen over a period of 72 hrs.  This dosing regimen was 
shown to be safe and well-tolerated in Phase 2, and systemic exposure is significantly lower than 
that from the approved therapeutic oral dose (maximum dose of 20 mg/day in in US and EU, and 
10 mg/day in Japan for non-micronized glibenclamide [Euglucon®]) taken chronically by 
patients with diabetes. Therefore, this dosing regimen is selected for Phase 3 as it rapidly 
achieves and maintains the desired steady-state concentration of BIIB093 while staying below 
the concentration threshold associated with hypoglycemia.  The 3-stage dosing regimen consists 
of an initial bolus loading dose (given over 2 mins), followed by constant IV infusion 
administered sequentially at two different flow rates (a rapid IV infusion for 6 hours followed by 
a maintenance IV infusion for the remaining 66 hours).  The treatment period of 72 hours has 
been selected because in humans with LHI, herniation peaks at 2-3 days; thus, this infusion 
duration allows for intervention prior to peak edema and treats through the period where patients 
are at risk for severe edema. 


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5.
SCHEDULE OF ACTIVITIES
Table 2:
Schedule of Activities – Part 1 (Screening through Day 90) 
Screening
/
Enroll-
ment
Hrs 
>0-12
Hr 24
(±12h)
Hr 48
(±12h)
Hr 72
(±12h)
Day 7
(±24h)/
Hospital
Discharge
Day 30
(±7 d)
Telephone/
Telemedicine
Visit
Day 90
(±14 d)1
In-person
Visit
Preferred
Craniectomy
/Comfort 
Care (if
Applicable)
Early
Term.
Visit2
Inclusion/exclusion 
criteria
X
-
-
-
-
-
-
-
-
-
Informed consent
X
-
-
-
-
-
-
-
-
-
Demographics, medical 
history, physical 
examination (including 
height and weight), 
rtPA/thrombectomy 
status3
X
-
-
-
-
-
-
-
-
-
Time of symptom onset 
or, if unknown, last 
known normal
X
-
-
-
-
-
-
-
-
-
Imaging 
(MRI/CTP/NCCT) for 
lesion size or ASPECTS 
estimation4
X
-
-
-
-
-
-
-
-
-
Pregnancy test
X
-
-
-
-
-
-
-
-
-
NIHSS5
X
Clinical laboratory 
samples (hematology, 
blood chemistry)6,7
X
-
X
X
X
X
-
-
-
X8
Vital signs9
X
-
X
X
X
X
-
-
-
X8
12-lead ECG7,10
X
Hrs 4-6
X
X
X
X
-
-
-
X8
Enrollment/
Randomization11
X
-
-
-
-
-
-
-
-
-
Craniectomy/comfort 
care/cranioplasty 
assessment form(s)
-
-
-
-
-
-
-
-
X
-






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Table 3:
 Schedule of Activities – Part 2 (Day 91 through Month 12)
Month 6 (± 30 days)
Telephone/Telemedicine Visit1
Month 12 (± 30 days)
Telephone/Telemedicine Visit1
mRS
X
X
Subject disposition2
X
 X
EQ-5D-5L, BI, SIS-16
X
X
HCRUQ, Zarit
-
X
SAEs
X
X
BI = Barthel Index; EQ-5D-5L = EuroQol 5-level assessment of health outcome; HCRUQ = HealthCare Resource Utilization Questionnaire; mRS = modified Rankin Scale; 
SIS-16 = Stroke Impact Scale 16 Questions, Zarit = Zarit Burden Interview.
1 In-person clinic visits may be conducted at the study subject’s/representative’s request.
2 Subject disposition: location (e.g., hospice, nursing home, rehabilitation facility, home), level of rehabilitation, and if death occurred, the primary cause of 
death and date and time of death will be recorded. Brain death and death associated with withdrawal of care must be documented. 


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6.
STUDY OBJECTIVES AND ENDPOINTS
6.1.
PART 1 Objectives and Endpoints
Primary Objective
Primary Endpoint
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.  
Day 90 mRS score as a 5-category ordinal scale 
(the 5-category mRS combines mRS categories 0 
and 1 and mRS categories 5 and 6).
Secondary Objectives
Secondary Endpoints
To determine if BIIB093 improves overall 
survival at Day 90 when compared with placebo 
in the modified intent-to-treat (mITT) population.
Time to all-cause death over the 90-day period. 
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.
Proportion of subjects who achieved mRS 0-4 at 
Day 90.
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.
Midline shift at 72 hours (or at time prior to DC or 
CMO, if earlier).
To evaluate the safety and tolerability of BIIB093 
in subjects with LHI.
Incidence of adverse events (AEs), serious 
adverse events (SAEs), and clinically significant 
abnormal vital signs, 12-lead electrocardiogram 
(ECG) findings, and laboratory results (including 
those associated with blood glucose (BG) levels). 




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7.
STUDY DESIGN
7.1.
Study Overview
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 targeted at approximately 20% in the 
≤70 year age group but may vary from this to reflect the evolving standard of care and stroke 
treatment guidelines. The number of subjects with thrombectomy performed prior to 
randomization is targeted at approximately 8% in the >70 year age group.
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.  


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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, HealthCare 
Resource Utilization Questionnaire, and Zaret Burden Interview) will be assessed at selected 
timepoints.  
The study has been designed to randomize approximately 688 subjects aged 18 to 70 years, 
inclusive.  In addition, approximately 80 subjects aged >70 years and up to 85 years (inclusive) 
will also be randomized for safety 
 evaluations.  
A flowchart of study activities is available in the Study Reference Guide.
7.2.
Study Duration for Subjects
The total duration of study participation for each subject will be approximately 12 months; this 
consists of a concurrent screening and enrollment period, a treatment period of 72 hours, and a 
follow-up period of 52 weeks.  Study Part 1 will be considered screening through Day 90, and 
Study Part 2 will be Day 91 through Month 12.
The primary study outcome is at Day 90 (the end of Part 1); however, all subjects will be 
consented for both study parts together and followed for 1 year. The end of the study is 
considered the final study assessment at Month 12 or in the event of early termination, death or 
study withdrawal. 
7.3. Responsibilities of Study Site Personnel
The attending clinician has ultimate responsibility and discretion for treating subjects.  The 
clinician will use his/her best judgment in treating subjects based upon the specific clinical 
situation and in accordance with Good Clinical Practice (GCP).
7.4. Study Stopping Rules
Biogen may terminate this study at any time after informing Investigators. Investigators will be 
notified by Biogen or designee if the study is placed on hold, completed or closed. An 
independent, external data monitoring committee (IDMC) will be formed and will review safety 
data regularly. The study may be terminated by the Sponsor at the recommendation of the 
IDMC, based exclusively on safety data. The Sponsor may perform an interim futility analysis 
based on the primary endpoint when approximately 30% of planned mITT subjects complete 
Day 90. Should the Sponsor elect to conduct unblinded interim futility analyses, the study may 
be terminated by the Sponsor at the recommendation of the IDMC. Details of the IDMC 
responsibilities will be provided in the IDMC charter. 


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7.5. End of Study
The end of study is last subject, last visit, i.e., when the last subject completes the 1-year visit or 
withdraws from the study.  


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8.
SELECTION OF SUBJECTS
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Screening, or at the timepoint specified in the individual eligibility criterion listed:
1. 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.
2. 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).
3. Aged 18 to 85 years old, inclusive, at the time of informed consent.
4. Screening NIHSS ≥10.
5. 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).
6. 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
b) a computed tomography perfusion (CTP) core lesion volume of 80 to 300 cm3, or
c) 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: 1) scan timing and 2) 
scan modality that in the opinion of the investigator best represents the infarct size.  The 
scan used for eligibility will be documented.
Note:  Automated image analysis software will be used whenever possible as a standard 
method to aid in estimating infarct core volume and/or ASPECTS.  The final ASPECTS 
determination for the purposes of inclusion will be made by the investigator or local 
reader.  In the event that a suitable baseline scan is not available as part of the SOC, a 
study-specific MRI DWI, CTP, or NCCT, in order of preference, will be obtained.  A 


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repeat scan for study inclusion purposes may be performed if deemed appropriate and 
would be achievable prior to infusion. 
7. 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. 
8. At the time of randomization and in the Investigator’s judgment, 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 (if time to symptom onset is unknown). 
Investigators should refer to Section 11.1.

Subjects who wake with stroke may be included if neurological and other exclusion 
criteria are satisfied. These “wake up” strokes are defined as having no symptoms at 
sleep onset and a known sleep onset time, but stroke symptoms on waking. The time 
of stroke onset is to be taken as the midpoint between sleep onset and time of waking. 
The maximum time window for initiation of study drug treatment infusion is then 
10 hours from the midpoint as described. If sleep onset time is unknown, then last 
known normal time must be used and the midpoint does not apply.
8.2. Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Screening, or at the timepoint specified in the individual criterion listed:
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 who are currently being considered for thrombectomy and/or IV thrombolysis 
may not be randomized into the study until these procedures have been completed OR the 


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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.
Medical History
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 (G6PD) enzyme deficiency.


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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.
 Other
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.


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9.
SCREENING AND RANDOMIZATION
The study will allow SOC therapy including IV thrombolysis, thrombectomy (see inclusion 
criteria #7), mannitol, hypertonic saline, DC, and other treatments for LHI per local guidelines as 
determined by the Investigator.
9.1.
Screening 
Subjects, their legally authorized representative (LAR), or physician per local requirements must 
provide informed consent before any screening tests are performed (see Section 17.3).  
Determination of whether consent by a LAR is required (and if so, determination of the LAR) as 
well as specific details of the consenting process will be determined by country law, state law, 
and local ethics committee requirements.  The study team is encouraged to use fax, telephone, 
and/or telemedicine consent if allowed by country law, state law, and local ethics committee 
rules.  Participating study sites are required to document all screened candidates initially 
considered for inclusion in the study.  
All subjects arriving at the recruiting site prior to 10 hours of symptom onset or last known 
normal, having the potential for a large lesion, with a NIHSS ≥10, and meeting all 
inclusion/exclusion criteria should be considered for potential inclusion in this study.
A screen failure log will be maintained at each site.  Subjects are eligible for rescreening (i.e., an 
additional study-specific imaging scan) provided they meet the protocol-specified time window 
and all non-lesion size-related inclusion/exclusion criteria.  Screen failures are defined as 
subjects who have been diagnosed with LHI, sign the informed consent form (ICF) but are not 
subsequently randomized.  If a subject is considered a screen failure, the reasons for exclusion 
must be documented in the subject’s source documents and on the screening log.  A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements and 
to respond to queries from regulatory authorities.  Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE.  
Because pertinent subject information will already be collected as part of SOC, and to reduce 
additional study-specific procedures, baseline information may be taken from the subject’s 
medical records prior to obtaining informed consent.  However, informed consent will be 
obtained prior to performing any study-specific procedures.
9.2. Randomization 
Enrollment and randomization will be concurrent.  Subjects will be randomized/enrolled after all 
screening assessments have been completed and after the Investigator has verified that the 
subjects are eligible per criteria in Section 8.  Subjects will be assigned a unique identification 
number that will be used on study-related documents pertaining to the subject.  Any subject 
identification numbers that are assigned will not be reused even if the subject does not receive 
treatment or continue in the study.  


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Randomization will be performed using interactive response technology (IRT).  Subjects will be 
randomized to receive study treatment or placebo in a 1:1 ratio.  As part of randomization, for 
each age group (18 to 70 years vs. >70 to 85 years), a minimization method will be used to 
achieve treatment group balance over the following baseline covariates:  region, rtPA (yes, no), 
thrombectomy (yes, no), use of ASPECTS for screening (yes, no), and baseline NIHSS (≤20 vs. 
>20). For details on enrollment of subjects with thrombectomy, see Section 7.1.
Refer to the Study Reference Guide for details on randomization/enrollment.
9.3.
Blinding Procedures
The investigators, study site staff, subjects, and caregivers will be blinded to the subject 
treatment assignments for the duration of the trial (Parts 1 and 2).  To ensure that efficacy and 
outcome assessors are blinded to study treatment, evaluators performing all efficacy and 
outcome evaluations will be blinded to knowledge of AEs and SAEs during the acute 
hospitalization phase of the study (should not have participated in the treatment during the acute 
hospitalization phase of the study nor review the subject’s hospital records from the acute 
hospitalization study period including BG levels, BG management, or carbohydrate intake).  
The study Sponsor and CRO study management team will be fully blinded for Part 1 of the 
study.  After Part 1 is completed and the clinical study database is locked, designated personnel 
at the Sponsor will be unblinded to the Part 1 data for the purposes of evaluating the Day 90 data.  
The Sponsor and CRO study management team responsible for all site interactions and data entry 
will remain blinded to individual treatment assignments during Part 2 of the study.  


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10.
DISCONTINUATION OF STUDY TREATMENT AND 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
10.1.
Discontinuation of Study Treatment
Note: Subjects who discontinue study treatment for any reason should not be withdrawn from the 
study and should continue protocol-required tests and assessments. 
A subject must permanently discontinue study treatment for any of the following reasons:

The subject/LAR withdraws consent to continue study treatment.  Subject withdrawal 
may occur any time the subject or LAR wishes to no longer continue with the study.  
Every attempt must be made to obtain information about the reason(s) for 
discontinuation, and any possible AEs.

The subject has a positive pregnancy test during the 72-hour time window of 
treatment.

The subject experiences an AE that necessitates permanent discontinuation of study 
treatment.

The subject experiences a medical emergency that necessitates unblinding of the 
subject’s treatment assignment.

The subject is unwilling or unable to comply with the protocol.

At the discretion of the Investigator for medical reasons.

Study drug must be discontinued if hypoglycemia cannot be rectified by the treating 
team, the severity and length of hypoglycemia is determined by the Investigator to be 
harmful to the subject, and the infusion rate has already been reduced to 0.0795 mg/h 
(refer to Directions for Handling and Administration [DHA] for corresponding mL/h 
rate) for >30 minutes.

Increases in QT/QTc (formula not specified) to >550 msec, if the measurement is 
obtained and confirmed with a second ECG reading within 15 minutes

The subject has confirmed alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >5×upper limit of normal (ULN), or confirmed ALT or AST 
>3×ULN and bilirubin >2×ULN.

The subject experiences a severe hypersensitivity to study treatment based on the 
Investigator’s assessment.
If the study treatment infusion is reduced or discontinued as a result of BG<55 mg/dL 
(~3.1 mmol/L), dextrose 50% in water (D50W; or another concentration of dextrose, if D50W is 


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not available) must be administered by bolus in order to achieve a BG level ≥80 mg/dL 
(~4.4 mmol/L). Multiple boluses may be administered, the timing and volume of which are at the 
discretion of the Investigator. BG monitoring is then required every 15 (±10) minutes until BG ≥ 
80 mg/dL (~4.4 mmol/L) for 3 consecutive readings without bolus glucose supplementation.
The primary reason for discontinuation of study treatment must be recorded in the subject’s 
electronic case report form (eCRF).  All subjects who discontinue study treatment, except for 
those who withdraw consent, will be followed to the end of study (i.e., end of Part 2).
If a site learns, while a subject is receiving study treatment, that the subject had taken 
sulfonylureas within 24 hours prior or during the hospital stay, this will not be a cause for 
discontinuation of study treatment or of withdrawal from the study.
If possible, the study Medical Monitor should be contacted before early discontinuation of study 
treatment.  The Medical Monitor must be informed within 24 hours of early study treatment 
discontinuation. 
Institution of Comfort Care/Palliative Care Measures
If a decision is made to move the subject to CMO/palliative care during the study, the 
Investigator should complete all assessments specified by the CMO (or palliative care)/DC visit 
(see Table 2) prior to CMO/palliative care (i.e., final imaging, NIHSS). In addition, the comfort 
care eCRF and NIHSS should be completed. If a brain imaging study has not been performed 
within the prior 12 hours of the decision, it should be obtained whenever possible. 
CMO/palliative care subjects do not need to be terminated early from the study unless informed 
consent is withdrawn or as determined by the Investigator. 
CMO/palliative care subjects are encouraged to remain in the study to enable the collection of 
protocol assessments if feasible; however, the minimum assessments required are collection of 
AEs/SAEs and mRS.
10.2.
Lost to Follow-Up
Potential sources of follow-up information will include subject medical records, the subject, 
LAR, family members, and personal physician.  In addition, information may be collected by 
contacting the rehabilitation facility/nursing home, accessing a shared healthcare database, 
or reviewing publicly available death records.  Subjects will be considered lost to follow-up if all 
attempts to collect the follow-up assessments are unsuccessful.  The subject should not be 
classified as “lost to follow-up” until the final assessment has been missed and a certified letter 
has been sent to both the LAR and subject with no response within 30 days of sending.
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit:

The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether the subject wishes to and/or should continue in the study.


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
In cases in which the subject is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the subject.  These contact attempts should 
be documented in the subject’s medical record.

Should the subject continue to be unreachable, that subject will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
10.3. Withdrawal of Subjects from Study
Early termination is defined as withdrawal from the study.  Subjects must be withdrawn from the 
study if the subject or LAR withdraws consent for any reason. Subjects who discontinue study 
treatment for any reason or who move to comfort care/palliative care should not be withdrawn 
from the study (see Section 10.1).
The primary reason for the subject’s withdrawal from the study must be recorded in the subject’s 
CRF.  If a subject is withdrawn due to pregnancy, early termination study procedures will be 
performed.  Subjects must undergo end-of-treatment assessments (Day 90 assessments if Part 1 
at the time of termination or Month 12 assessments if Part 2 at the time of termination) unless 
withdrawal is due to death or withdrawal of consent.  Subjects who withdraw from the study may 
not be replaced.  


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11.
STUDY TREATMENT USE
11.1. Regimen
Refer to and follow the DHA.
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) [refer to Section 8.1, inclusion criterion 8]. Study treatment administration will 
initiate with 0.13 mg administered as a bolus over approximately 2 minutes, followed by 
0.16 mg/h for 6 hours, followed by 0.11 mg/h for the remaining 66 hours (or 0 mg in all cases for 
placebo) [refer to DHA for corresponding mL/h rate]. The total volume of infusion will be 8.6 
mg over 72 hours. Infusion should be stopped 72 hours from the start of infusion whenever 
possible. If stopping at precisely 72 hours is not possible, a ±30-minute window is permitted. 
The infusion will be prepared in 1000 mL IV bags, which must be replaced every 24 hours. See 
DHA for a summary of the study dosing. The bolus may be administered either by programming 
the infusion pump appropriately per instructions in the DHA, or by withdrawing the study 
treatment from the bag and injecting it by syringe through peripheral IV over an approximately 
2-minute period, depending on site standards.
BIIB093 cannot be administered with PVC bags and lines due to adsorption issues.  
Additionally, the drug adsorbs to inline filters.  Refer to DHA for additional information.  The 
use of any bags, administration or extension sets, or any configuration of the components other 
than those specified per DHA is strictly prohibited, unless permission to do so is provided by the 
Sponsor in writing (e-mail).
The infusion of study treatment should only be through a dedicated peripheral IV line.  A 
calibrated infusion pump with a dedicated infusion line will be used to ensure infusion at the 
specified rates.  The study treatment may not be delivered through a central line or peripherally 
inserted central catheter line.  No other medication may be administered in the same line as the 
study treatment, nor should the line be used for blood withdrawal.
The date and time of the start and end of the infusion of each bag will be recorded in the eCRF.  
At the end of the infusion of each bag, tubing, bags, and IV catheters must be visually inspected 
to confirm that the fluid path is composed of only the allowed components.  If any components 
other than allowed components are found, these must be removed, and the incident documented 
and described in the eCRF.  The length of, and reason for, any stoppage of the infusion that lasts 
>15 minutes must be recorded.
11.2.
Modification of Dose and/or Treatment Schedule
The dosage should not be modified unless due to hypoglycemia (sustained BG <55 mg/dL 
[~3.1 mmol/L]). If hypoglycemia cannot be rectified by the treating team and the severity and 
length of hypoglycemia is determined by the Investigator to be harmful to the subject, then the 
study drug flow rate must be reduced to 0.0795 mg/h. Note that if the dose reduction occurs 
within the first 6 hours of treatment, the flow rate must be reduced to 0.0795 mg/h and must not 


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be increased at the end of the 6-hour period (refer to DHA for corresponding mL/h rate). If dose 
reduction occurs, maintenance fluids must be continued until BG ≥ 80 mg/dL (~4.4 mmol/L) for 
3 consecutive measures.
In the event administration of study treatment is halted due, for example, to IV infiltration, 
study treatment should be restarted per restart instructions provided in the DHA.
The infusion period will not be extended to account for any stoppages or reduction.
Study treatment should not be stopped if the subject undergoes DC; however, frequent BG 
monitoring should continue.  An effort should be made to obtain imaging prior to DC whenever 
possible.
11.3.
Precautions
BIIB093 cannot be administered with PVC bags and lines due to adsorption issues.  
Additionally, the drug has adsorption to inline filters.  Refer to DHA for additional information.
11.4.
Concomitant Therapy and Procedures
Specific treatment guidelines are provided in the Study Reference Guide.  These guidelines are a 
template for the care of subjects participating in the study and should be followed whenever 
clinically feasible.  
11.4.1.
Concomitant Therapy
A concomitant therapy is any medication administered between enrollment through Day 90 or 
early discontinuation (whichever is earlier).  All concomitant therapy including but not limited to 
dextrose solutions, osmotherapy, paralytics, sedatives, and vasoactive drugs will be recorded in 
the eCRF.
11.4.1.1.
Allowed Concomitant Therapy
11.4.1.1.1. IV thrombolysis (rtPA)
In general, IV thrombolysis, when indicated, should be administered to treat the index 
stroke prior to subject randomization as described in exclusion criteria #8.  However, if a 
decision was made to randomize the subject into the study and it was later determined that IV 
thrombolysis should be administered to the subject as part of standard of care, then this 
is allowed per the protocol.   
11.4.1.1.2. Interventions Related to Blood Glucose
In a joint statement from the American Diabetes Association and the European Association for 
the Study of Diabetes, the International Hypoglycemia Study Group concluded that a BG level of 
<54 mg/dL (~3.0 mmol/L) alone, without symptoms, is clinically important and should be 
included in reports of clinical trials involving glucose-lowering drugs [International 


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Hypoglycaemia Study Group 2017].  The statement further recommends an “alert” level of 70 
mg/dL (~3.9 mmol/L) for BG.  The following interventions are designed in accordance with 
those recommendations.
Insulin
Insulin and other BG-lowering agents are not permitted during study treatment administration 
when BG <120 mg/dL (~6.7 mmol/L).
Nutrition
Enteral nutrition is encouraged to be initiated within 24 hours of admission if consistent with 
SOC.  Subjects may need post-pyloric administration of nutritional support.
Maintenance Fluids 

If the BG at baseline is <120 mg/dL (~6.7 mmol/L), the initial maintenance fluid should 
be 5% dextrose in normal saline (D5NS, or fluid containing 5% dextrose) at a rate of 70 
to 100 cc/h. 

When BG falls below 100 mg/dL (~5.6 mmol/L), 5% dextrose in normal saline (D5NS, 
or fluid containing 5% dextrose) should be started at 70 to 100 cc/hr.  Titration of the 
IV fluid rate up or down can be used to maintain BG ≥ 80 mg/dL (~4.4 mmol/L).

If BG < 80 mg/dL (~4.4 mmol/L), 5% dextrose in normal saline (D5NS, or fluid 
containing 5% dextrose) must be started or, if D5NS is already being administered, then 
the subject should be switched to 10% dextrose in normal saline (D10NS, or fluid 
containing 10% dextrose).

If there is a rapid or continuous downward trend in BG, 5% dextrose in normal saline 
(D5NS, or fluid containing 5% dextrose) should be started or, if D5NS is already being 
administered, then the subject should be switched to 10% dextrose in normal saline 
(D10NS, or fluid containing 10% dextrose).

In the event of BG > 140 mg/dL (~7.8 mmol/L), neither 5% nor 10% dextrose in normal 
saline (D5NS, or fluid containing 5% dextrose; D10NS, or fluid containing 10% 
dextrose) should be administered.

Total fluid volume, inclusive of study treatment volume, should be consistent with site 
practice and the clinical status of the subject.


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Low Blood Glucose Treatment
Any confirmed BG of < 70 mg/dL (~3.9 mmol/L) must be treated with 40-50 mL of dextrose 
50% in water (D50W). If D50W is not available, another concentration of dextrose fluid may be 
used at a sufficient volume to achieve an equivalent amount of dextrose.
11.4.1.1.3. CYP2C9/CYP3A4 and Bosentan
BIIB093 is metabolized by cytochrome P450 (CYP) 2C9 and CYP3A4.  Medications that are 
strong inhibitors or inducers of the CYP enzymes may elicit significant PK-mediated drug 
interactions with BIIB093 (see Appendix 1).  Oral glibenclamide products do not contraindicate 
nor require dosage adjustment for concomitant use of inhibitors or inducer of CYP2C9 and 
CYP3A4.  Therefore, for subjects who require these medications during BIIB093 treatment, the 
use of these agents will be permitted in the study with additional monitoring per the 
Investigator’s judgment (e.g., BG levels) to ensure subject safety.  
Subjects receiving treatment with bosentan during Screening can be included in the study, and 
liver function tests should be collected more frequently if necessary at the discretion of the 
Investigator.
11.4.1.2.
Disallowed Concomitant Therapy

Insulin and other BG-lowering agents are not permitted during study treatment 
administration when BG <120 mg/dL (~6.7 mmol/L).

No other sulfonylurea agents may be administered during the hospital stay.

No other investigational drugs may be administered during the 90-day follow-up period.

The use of sphenopalatine ganglion stimulation (SPG-Stim) is not allowed. 
11.4.2.
Concomitant Procedures
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is enrolled in the study and Day 90. The use of unapproved therapies and/or 
procedures is not permitted.
Concomitant procedures will be recorded through Day 90 or early discontinuation, whichever is 
earlier.
11.4.2.1.
Thrombectomy
In general, thrombectomy, when indicated, should be performed to treat the index stroke prior to 
subject randomization as described in exclusion criteria #8.  However, if a decision was made to 
randomize the subject into the study and it was later determined that thrombectomy should be 
administered to the subject as part of standard of care, then this procedure is allowed per the 


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protocol.  In the event that a thrombectomy is performed after subject randomization, standard of 
care imaging should be performed following the procedure. 
11.4.2.2.
Decompressive Craniectomy
DC may be performed according to local SOC.  Timing of, and reasons for DC, including 
whether the DC was due to 1) radiographic changes, 2) change in level of alertness, 3) both [1] 
and [2] radiographic changes and change in level of alertness, or 4) neither (i.e., prophylactic) 
will be recorded in the eCRF.  Record NIHSS either at the time of decision to perform DC or 
between such time and the DC.  If a brain imaging scan was not performed in the prior 12 hours 
as part of the assessment to perform a hemicraniectomy, a follow-up brain imaging study should 
be performed when possible but prior to DC.  Study treatment should not be stopped if the 
subject undergoes DC.
Adherence to the Study Reference Guide (supplied separately) with regard to DC is particularly 
important in order to ensure uniformity of practice across the study.  Data collected that pertain 
to the decision to do a DC will be reviewed by a clinical committee on a study-wide, 
geographical, and site level to assess uniformity of practice.  The Sponsor may make certain 
results of this review available to all study investigators during the study in an ongoing effort to 
encourage uniformity.  The Sponsor may pause or end recruitment at specific sites where the 
Study Reference Guide is not followed sufficiently closely or DC rates are substantially higher 
than at other sites.  
11.5.
Continuation of Treatment 
There is no provision to provide study treatment after the study.


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12.
STUDY TREATMENT MANAGEMENT
Study treatment will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice.
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.  The DHA aligns with all other references 
(including the protocol).
Study treatment must be dispensed only by a pharmacist or appropriately qualified staff.  Study 
treatment is to be dispensed only to subjects enrolled in this study.  Once study treatment is 
prepared for a subject, it can be administered only to that subject.  Study treatment is for 
one-time use only; do not use any study treatment remaining in the vial for another subject.
Each study treatment kit will contain 1 vial. Any additional components provided will be 
described in the DHA. Study treatment vials (i.e., BIIB093 or placebo) contain a white to off-
white lyophilized powder for IV administration after reconstitution; vials of BIIB093 and 
placebo look identical.
12.1.
BIIB093
The contents of the BIIB093 label will be in accordance with all applicable regulatory 
requirements.  The expiry or use-by date is stored in the IRT system, and printable assignment 
reports are available to site personnel.  Study treatment should not be used after the expiration, 
expiry, or use-by date.  
Each vial of BIIB093 contains glibenclamide 6.0 mg, mannitol 180 mg, and sodium hydroxide to 
adjust the pH during manufacture.  Once reconstituted, study treatment is administered in 0.9% 
normal saline.
Stability at room temperature of study treatment in normal saline is 30 hours.  A new vial is used 
for dosing on each day of the 3-day infusion. 
12.1.1.
BIIB093 Preparation
Study treatment will be prepared at the site by a properly qualified blinded individual according 
to institutional standards.  The individual preparing BIIB093 should carefully review the 
instructions provided in the DHA.  As noted previously, BIIB093 cannot be administered with 
PVC bags and lines due to adsorption issues.  Additionally, the drug has adsorption to inline 
filters.  Refer to DHA for additional information.
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the vials or study treatment, do not use the study treatment.  The vial in question should be saved 
at the study site, and the problem immediately reported to Biogen.
Please refer to the DHA for detailed instructions regarding reconstitution of the Study Drug.


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12.1.2.
BIIB093 Storage
Study treatment must be stored in a secure location.  
All vials of BIIB093 are to be stored at 1°C to ≤25°C (34°F to ≤77°F) and protected from light in 
a locked location with limited access until used, in accordance with labeled storage requirements. 
Storage temperature must be monitored and recorded per the instructions provided in the DHA.
12.1.3.
BIIB093 Handling and Disposal
The Investigator must return all used and unused vials of BIIB093 as instructed by Biogen unless 
approved for onsite destruction.
If any BIIB093 supplies are to be destroyed at the study site, the institution or appropriate site 
personnel must obtain prior approval from Biogen, by providing, in writing, the destruction 
policy or details of the method of destruction.  After such destruction, Biogen must be notified, 
in writing, of the details of the study treatment destroyed (e.g., kit numbers, quantities), the date 
of destruction, and proof of destruction.
The Investigator must notify the Sponsor of any damaged or unusable study supplies that were 
supplied to the site.
12.1.4.
BIIB093 Accountability
Accountability for study treatment is the responsibility of the Investigator.  The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (subject-by-subject accounting), and accounts of any study treatment accidentally or 
deliberately destroyed or lost.  
Unless otherwise notified, all vials, both used and unused, must be saved for study treatment 
accountability.  By the end of the study, reconciliation must be made between the amount of 
BIIB093 supplied, dispensed, and subsequently destroyed, lost, or returned to Biogen.  A written 
explanation must be provided for any discrepancies.
12.2.
Placebo 
Placebo vials are to be stored at 1°C to ≤25°C (34°F to ≤77°F) and protected from light in a 
secured location with limited access until used, in accordance with labeled storage requirements.  
Each vial of matching placebo contains mannitol 180 mg, as well as sufficient sodium hydroxide 
to adjust pH during manufacture.  The pH of the infusion is approximately 6 to 8.


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13.
EFFICACY ASSESSMENTS
See Section 5 for the timing of all assessments.
13.1.
Clinical Efficacy Assessments
NOTE:  The 90-Day efficacy outcomes will be performed by personnel who are blinded to on-
treatment BG levels, BG-related AEs, and carbohydrate administration.  Such persons will not 
have access to the subject’s medical record from the acute hospitalization study period but will 
instead be provided with subject/family/LAR contact details (if they are required to schedule the 
follow up); the source documents for the assessments to be performed; and for 30- and 90-day 
follow ups, the list of unresolved AEs.
13.1.1.
Functional Outcome (mRS) 
The subject’s functional outcome will be measured by mRS as an ordinal scale.  
The mRS will be performed by independent personnel who have mRS training and certification.  
Biogen will provide an mRS source document that outlines the procedures and key questions to 
ask to assess mRS (see also blinding Section 9.3).  Details will be provided in the Study 
Reference Guide.
mRS assessments at Day 90 should be conducted in person where possible and otherwise by 
telemedicine or phone call, in order of preference.  The mRS raters should be available to travel 
to the subject at Day 90 when possible if the subject is unable to attend the clinic visit.  mRS 
assessments at other timepoints can be conducted by telemedicine visit or phone call.  The same 
mRS rater should follow a subject for the duration of the trial whenever possible.  The Day 90 
mRS assessments may be reviewed centrally and if so, queries will be issued in the event of 
discrepancies or inconsistencies. 
13.1.2.
Subject Disposition 
Subject status will be categorized as alive or dead, location (e.g., hospice, nursing home, 
rehabilitation facility, home), and level of rehabilitation.
If a subject death occurs during the study, the primary cause of death and date and time of death 
will be determined and recorded.  Brain death and death associated with withdrawal of care must 
be documented.
For subjects who are lost to follow-up, publicly available death records will be sought.
13.1.3.
Midline Shift
Midline shift will be assessed by NCCT or MRI performed at 72 hours [or prior to DC or CMO, 
if earlier].  Only images acquired prior to DC can facilitate an accurate measure of midline shift.  
Images will be acquired per specifications outlined in the Imaging Manual.  Reading of the 
midline shift, the perpendicular distance between the septum pellucidum and the line drawn 


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between the anterior and posterior attachments of the falx to the inner table of the skull, will be 
performed by trained and certified central readers blinded to treatment assignment. 
13.1.4.
Patient Outcome Measures
Complete instructions for outcomes measure assessments will be provided separately.  Raters 
must be trained and qualified to perform any assessment and meet the guidelines outlined in the 
Study Reference Guide.  To eliminate inter-rater bias, the same rater should follow a subject 
whenever possible for the duration of the study.
13.1.4.1.
European Quality of Life Assessment (EQ-5D-5L)
EQ-5D-5L is a standardized instrument developed by the EuroQol Group for measuring generic 
health status.  The health status measured with EQ-5D-5L is used for estimating preference 
weight for that health status.  The measure of quality-adjusted life-years gained is used as an 
outcome in cost-utility analysis, which is a type of economic evaluation that compares the 
benefit and cost of health care programs or interventions.
13.1.4.2.
Zarit Burden Interview
The Zarit Burden Interview was originally developed to measure subjective burden among 
caregivers of adults with dementia.  Items were generated based on clinical experience with 
caregivers and prior studies resulting in a 22-item self-report inventory that examines burden 
associated with functional/behavioral impairments and the home care situation.  The items are 
worded subjectively, focusing on the affective response of the caregiver.
13.1.4.3.
Barthel Index 
This index measures the extent to which somebody can function independently and has mobility 
in their activities of daily living (i.e., feeding, bathing, grooming, dressing, bowel 
control, bladder control, toileting, chair transfer, ambulation, and stair climbing).  The index also 
indicates the need for assistance in care.  The BI is a widely used measure of 
functional disability.  The index was developed for use in rehabilitation patients with stroke and 
other neuromuscular or musculoskeletal disorders but may also be used for oncology patients.
13.1.4.4.
Stroke Impact Scale 16
The SIS-16 was developed to assess physical function in patients with stroke at approximately 1 
to 3 months poststroke using items from the composite physical domain of the SIS version 3.0; 
and compare the SIS-16 and a commonly used disability measure, the BI, in terms of their ability 
to discriminate disability.
13.1.4.5.
HealthCare Resource Utilization Questionnaire
Healthcare Resource Utilization Questionnaires are developed to address the need for valid 
costing estimates of a particular disease state.  They are critical components when building 
economic models for submission to health technology assessment agencies and pharmacy & 




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14.
SAFETY ASSESSMENTS
Refer to Section 5 for the timing of all safety assessments.
14.1.
Clinical Safety Assessments
The following clinical assessments will be performed to evaluate the safety profile of BIIB093:

Medical history

Physical examinations, including height and weight (may be estimated)

Vital sign measurements:  temperature, heart rate, systolic and diastolic blood 
pressure, respiratory rate, and oxygen saturation

12-lead ECGs

Concomitant therapy and procedure recording
All medications including but not limited to dextrose solutions, osmotherapy, 
paralytics, sedatives, and vasoactive drugs used through Day 90 be recorded in the 
eCRF.  Concomitant procedures will be recorded through Day 7 or hospital discharge, 
whichever is earlier.
Timing of, and reasons for DC, including whether the DC was due to radiographic 
changes, change in level of alertness, both radiographic changes and change in level 
of alertness, or neither (i.e., prophylactic) will be recorded in the eCRF.

AE and SAE recording
14.2.
Laboratory Safety Assessments
Samples will be analyzed using Good Laboratory Practice-validated assays.
The following laboratory assessments, in accordance with the schedule of activities, will be 
performed to evaluate the safety profile of BIIB093. All assessments will be performed at a local 
laboratory where possible.

Hematology: complete blood count, platelet count, and absolute neutrophil count 

Blood chemistry: albumin, creatinine, blood urea nitrogen, bilirubin (total and direct), 
alkaline phosphatase, ALT, AST, glucose, calcium bicarbonate (when available), 
chloride (when available), sodium, and potassium

Note that in any case of confirmed hemolytic anemia, a G6PD genetic or enzymatic 
test should be performed in accordance with local practice.


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14.3.
Product-Specific Safety Assessments
The following additional laboratory safety assessment will be performed to determine the safety 
of BIIB093:

Blood glucose
BG concentrations are to be measured by point-of-care (POC) testing of capillary blood 
(e.g., Accu-Chek).  Venous blood is also acceptable for monitoring BG concentrations. 
Alternatively, blood from an arterial line may be used if one is in place, with POC or 
laboratory testing performed.  If blood from an arterial line is used, the line must be back-
flushed with sufficient discard volume of arterial blood (at least 5 ml) to avoid falsely 
low BG readings from dilution with the arterial line carrier (i.e., heparinized saline).  
If BG measures <70 mg/dL (~3.9 mmol/L), it must be verified by repeat test to confirm.  
The source of the blood (capillary vs. arterial line vs. venous) and whether the analysis 
was performed by POC or laboratory must be recorded in the eCRF.


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15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided.
At the signing of the ICF, each subject or his/her legally authorized representative and/or main 
caregiver must be given the names and telephone numbers of study site staff for reporting AEs 
and medical emergencies.
15.1.
Definitions
15.1.1.
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
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.
Determination of whether an abnormal laboratory value, vital sign result, and/or ECG result 
meets the definition of an AE will be made by the Investigator.  Abnormal results are not 
considered AEs unless one or more of the following criteria are met:

The result meets the criteria for an SAE

The result requires the subject to receive specific corrective therapy

The result is considered by the Investigator to be clinically significant
15.1.2.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:

Results in death

In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions


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
Results in a congenital anomaly/birth defect

Is a medically important event
A medically important event is an AE that, in the opinion of the Investigator, may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the definition 
above.  (Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization.)
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized.  The study site must document all of the following:

The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the subject’s 
consent to participate in the study.

The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject’s consent to participate in the study and the time of 
the procedure or treatment.

The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission.
o
If a subject is hospitalized due to local requirements for administration of the 
study treatment, the hospitalization should not be considered an SAE unless 
one of the requirements in Section 15.1.2 is met.
15.2.
Safety Classifications
15.2.1.
Investigator Assessment of Events
All events must be assessed to determine the following:

If the event meets the criteria for an SAE as defined in Section 15.1.2.

The relationship of the event to study treatment as defined in Section 15.2.2. 

The severity of the event as defined in Section 15.2.3.
15.2.2.
Relationship of Events to Study Treatment
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment.


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Relationship of Event to Study Treatment
Not related
An AE will be considered “not related” to the use of the investigational product if there 
is not a reasonable possibility that the event has been caused by the product under 
investigation.  Factors pointing toward this assessment include but are not limited to the 
lack of reasonable temporal relationship between administration of the investigational 
product and the AE, the presence of a biologically implausible relationship between the 
product and the AE, or the presence of a more likely alternative explanation for the AE.
Related
An AE will be considered “related” to the use of the investigational product if there is a 
reasonable possibility that the event may have been caused by the product under 
investigation.  Factors that point toward this assessment include but are not limited to a 
positive rechallenge, a reasonable temporal sequence between administration of the 
investigational product and the AE, a known response pattern of the suspected product, 
improvement following discontinuation or dose reduction, a biologically plausible 
relationship between the product and the AE, or a lack of an alternative explanation for 
the AE.
15.2.3.
Severity of Events
The following definitions should be considered when evaluating the severity of AEs and SAEs.
Severity of Event
Mild
Symptoms barely noticeable to subject or does not make subject uncomfortable; does 
not influence performance or functioning; prescription drug not ordinarily needed for 
relief of symptoms but may be given because of personality of subject.
Moderate
Symptoms of sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptoms may 
be needed.
Severe
Symptoms cause severe discomfort; symptoms cause incapacitation or significant 
impact on subject’s daily life; severity may cause cessation of treatment with study 
treatment; treatment for symptoms may be given and/or subject hospitalized. 
15.2.4.
Expectedness of Events
Expectedness of all AEs will be determined by Biogen according to the Investigator’s Brochure.  
15.3.
Monitoring and Recording Events
15.3.1.
Adverse Events
In Part 1 of the study, any AE experienced by the subject between the time of first dose of study 
treatment and through Day 90 is to be recorded on the eCRF, regardless of the severity of the 
event or its relationship to study treatment.  At each study visit in Part 1, the Investigator will 
assess the subject for AEs and will record any new AEs or updates to previously reported AEs on 
the eCRF.  


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15.3.2.
Adverse Events of Special Interest
Hypoglycemia, defined as confirmed glucose <55 mg/dL (~3.1 mmol/L), is considered an AE of 
special interest and will be upgraded to an SAE.  Occurrences of these events should be 
submitted on an SAE form per the guidelines in Section 15.3.3.
15.3.3.
Serious Adverse Events
Any SAE experienced by the subject between the time of the signing of the ICF and the last 
follow-up visit in Part 2 of the study is to be recorded on an SAE form, regardless of the severity 
of the event or its relationship to study treatment.  SAEs must be reported to Biogen within 24 
hours as described in Section 15.3.4.  Follow-up information regarding an SAE also must be 
reported within 24 hours.  
Subjects will be followed for all SAEs until the final study visit in Part 2. Thereafter, the event 
should be reported to Biogen only if the Investigator considers the SAE to be related to study 
treatment.
Any SAE that is ongoing when the subject completes or discontinues the study will be followed 
by the Investigator until the event has resolved, stabilized, or returned to baseline status.
15.3.4.
Immediate Reporting of Serious Adverse Events
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify Biogen within 24 hours of the study site staff becoming aware of the SAE.  It is 
the Investigator’s responsibility to ensure that the SAE reporting information and procedures are 
used and followed appropriately.
Reporting Information for SAEs
A report must be submitted to Biogen regardless of the following:

Whether or not the subject has undergone study-related procedures

Whether or not the subject has received study treatment

The severity of the event

The relationship of the event to study treatment
To report initial or follow-up information on an SAE, fax or email a completed SAE form; 
refer to the Study Reference Guide for complete contact information. 
15.3.4.1.
Deaths
Death is an outcome of an event.  The event that resulted in death should be recorded on the 
appropriate eCRF.  All causes of death must be reported as SAEs within 24 hours of the site 
becoming aware of the event.  The Investigator should make every effort to obtain and send 


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death certificates and autopsy reports to Biogen.  The term death should be reported as an SAE 
only if the cause of death is not known and cannot be determined.
15.3.5.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or Biogen to be related to the study treatment administered.
Appropriate personnel at Biogen will unblind SUSARs for the purpose of regulatory reporting.  
Biogen will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies according 
to local law.  Biogen will submit SUSARs to Investigators in a blinded fashion.
15.4.
Procedures for Handling Special Situations
15.4.1.
Pregnancy
Subjects should not become pregnant or impregnate their partners during the study 
treatment and for 3 months after their last day of study treatment.  If a female subject 
becomes pregnant, study treatment must be discontinued immediately.
The Investigator must report a pregnancy occurring in a female subject by faxing or emailing the 
appropriate form to Biogen within 24 hours of the study site staff becoming aware of the 
pregnancy.  Refer to the Study Reference Guide’s Official Study Contact List for complete 
contact information.  The Investigator or study site staff must report the outcome of the 
pregnancy to Biogen.  A pregnancy is not considered an AE and should not be recorded on the 
AE eCRF.
Congenital abnormalities and birth defects in the offspring of male or female subjects should be 
reported as SAEs if conception occurred during the first 3-months of the study.
15.4.2.
Overdose
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol.  Overdoses are not considered 
AEs and should not be recorded as an AE on the eCRF; however, all overdoses must be recorded 
on an Overdose form and faxed or emailed to Biogen within 24 hours of the study site staff 
becoming aware of the overdose.  An overdose must be reported to Biogen even if the overdose 
does not result in an AE.  If an overdose results in an AE, the AE must be recorded.  If an 
overdose results in an SAE, both the SAE and Overdose forms must be completed and faxed or 
emailed to Biogen.  All study treatment-related dosing information must be recorded on the 
dosing eCRF.
15.4.3.
Medical Emergency
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current SOC.  The Investigator should contact the study’s 


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Medical Monitor.  Refer to the Study Reference Guide’s Official Study Contact List for 
complete contact information.  
15.4.3.1.
Unblinding for Medical Emergency
In a medical emergency when knowledge of the subject’s treatment assignment may influence 
the subject’s clinical care, the Investigator may access the subject’s treatment assignment by 
IRT.  The Investigator must document the reasons for unblinding in the subject’s source 
documents.  The Investigator is strongly advised not to divulge the subject’s treatment 
assignment to any individual not directly involved in managing the medical emergency, or to 
personnel involved with the analysis and conduct of the study.  The Investigator can contact 
Biogen to discuss such situations.
15.5.
Contraception Requirements
All women of childbearing potential and all men must ensure that highly effective contraception 
is used during Part 1 of the study and for 3 months after their last day of completing study 
treatment infusion.  In addition, subjects should not donate sperm or eggs for the duration of the 
study and for 3 months after their last day of completing study treatment infusion.
For the purposes of this study, women who do not meet one of the following criteria are 
considered to be physiologically capable of becoming pregnant and are, therefore, defined as 
women of childbearing potential:

Postmenopausal
o
12 continuous months of natural (spontaneous) amenorrhea without an alternative 
medical cause and a serum follicle-stimulating hormone level >40 mIU/mL 
o
6 weeks after surgical bilateral oophorectomy with or without hysterectomy

Posthysterectomy
For the purposes of the study, highly effective contraception is defined as contraception that 
achieves a failure rate of less than 1% when used consistently and correctly.  
For females:

Established use of oral, intravaginal, or transdermal combined (estrogen and progestogen 
containing) hormonal methods of contraception associated with the inhibition of 
ovulation.

Established use of oral, injected, or implanted hormonal methods of contraception 
associated with the inhibition of ovulation. 

Placement of an intrauterine device or intrauterine hormone-releasing system.


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
Sex with a male who has undergone surgical sterilization (with the appropriate 
postvasectomy documentation of the absence of sperm in the ejaculate).

Female surgical sterilization (e.g., bilateral tubal ligation) 
For males:

Vasectomy with negative semen analysis at follow-up.

Sex with a woman who uses the methods described for females if she is of childbearing 
potential.
True abstinence, when this is consistent with the preferred and usual lifestyle of the subject, can 
be considered an acceptable method of contraception based on the evaluation of the Investigator 
who should also take into consideration the duration of the clinical trial.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not 
considered acceptable methods of contraception. 
Pregnancy reporting is described in Section 15.4.1.
15.6.
Safety Responsibilities
15.6.1.
The Investigator
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, on the eCRF regardless of the severity 
or relationship to study treatment.

Determine the seriousness, relationship, and severity of each event.

Determine the onset and resolution dates of each event.

Monitor and record all pregnancies and follow up on the outcome of all pregnancies.

Complete an SAE form for each SAE and fax or email it to Biogen within 24 hours of 
the study site staff becoming aware of the event.

Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to Biogen within 24 hours of the study site staff becoming aware of 
new information.

Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records.


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
Pursue AE follow-up information, if possible, until the event has resolved or become 
stable.  Record AE follow-up information, including resolution, on the eCRF, as 
applicable.

Report SAEs to local ethics committees, as required by local law.
15.6.2.
Biogen 
Biogen’s responsibilities include the following:

Before a site can enroll any subjects, the Clinical Monitor is responsible for reviewing 
with study site staff the definitions of AE and SAE, as well as the instructions for 
monitoring, recording, and reporting AEs and SAEs.

Biogen is to notify all appropriate regulatory authorities, central ethics committees, 
and Investigators of SAEs, as required by local law, within required time frames.


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16.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
The objectives of the study and the endpoints to be analyzed are listed in Section 6.  The study 
database will be locked after the last subject completes the Day 90 visit, and the endpoints for 
Part 1 of the study will be analyzed.  A second database lock will occur after the last subject 
completes the Month 12 visit to analyze the Part 2 endpoints.  A detailed SAP will be prepared 
prior to the corresponding database lock.  
A summary of Part 1 demography, baseline disease characteristics, primary and secondary 
efficacy endpoints, pharmacokinetics, and safety endpoints is provided in this section, but 
information on the analysis of 
 from Part 1 and data from all of 
Part 2 will be detailed in the SAP, which will contain the final details on the statistical methods 
used in this study.
16.1.
Demography and Baseline Disease Characteristics
Demographics and baseline data will be summarized by treatment group with summary statistics 
(mean, standard deviation [SD], median, and range) or with frequency distributions.
16.2.
Efficacy
16.2.1.
Analysis Population
The efficacy analysis will be conducted in the mITT population, which is defined as those 
subjects aged 18 to 70 years (inclusive) who are randomized, receive study treatment, and who 
have at least 1 post-baseline mRS before or at the Day 90 visit.
Analyses for subjects aged >70 to 85 years will be descriptive.  Details of the analyses will be 
specified in the SAP.
16.2.2.
Methods of Analysis
16.2.2.1.
General Considerations
Summary statistics will be presented.  For continuous endpoints, summary statistics will 
generally include:  number of subjects with data, mean, SD, median, and range.  For categorical 
endpoints, frequency and percentage of subjects in each category will be presented.  Statistical 
testing for efficacy endpoints will be performed between the BIIB093 treatment group and 
placebo.  All tests will be 2-sided with a significance level equal to 0.05 (unless otherwise 
specified).  To control for a type 1 error, a sequential closed testing procedure will be used for 
the secondary endpoints such that if statistical significance is not achieved from an endpoint for a 
comparison, all endpoints of a lower rank for that comparison will not be considered statistically 
significant.






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a subject experiences an event more than once with varying severity during the study, he/she will 
be counted only once with the maximum severity within each system organ class/preferred term.  
For incidence of relationship to study treatment, a subject will be counted only once and only in 
the category of the strongest relationship to study treatment within each system organ 
class/preferred term.
16.6.2.2.
Clinical Laboratory Results
Clinical laboratory evaluations include hematology, blood chemistry including blood glucose.  
Laboratory abnormalities will be summarized with shift tables.  Tables will present changes 
relative to each parameter’s normal ranges. Laboratory values and the corresponding changes 
from baseline may be summarized over time.
16.6.2.3.
ECG
The number and percentage of subjects with shifts to categorical values (abnormal not AE, or 
abnormal AE) will be summarized by treatment group.
16.6.2.4.
Vital Signs
Vital signs measures include oxygen saturation, heart rate (pulse), respiratory rate, temperature, 
and systolic and diastolic blood pressure.  The analysis of vital signs will focus on the incidence 
of clinically relevant abnormalities, which will be defined in more detail in the SAP.  The 
number of subjects evaluated and the number and percentage of subjects with clinically relevant 
post-baseline abnormalities will be presented by treatment group.  Summary statistics for actual 
values and change from baseline will also be presented.  The definitions of these abnormalities 
for temperature, pulse, and blood pressure values are provided in Table 4.
Table 4:
Criteria to Determine Clinically Relevant Vital Signs Abnormalities
Vital Sign
Criteria for Abnormalities
Temperature
38C and an increase from pre-dosing of at least 1C
Pulse
120 beats per minute and an increase from pre-dosing 
of >20 beats per minute, or 50 beats per minute and a 
decrease from pre-dosing of >20 beats per minute
Systolic Blood Pressure
180 mmHg and an increase from pre-dosing of >40 
mmHg, or 90 mmHg and a decrease from pre-dosing 
of >30 mmHg
Diastolic Blood Pressure
105 mmHg and an increase from pre-dosing of >30 
mmHg, or 50 mmHg and a decrease from pre-dosing 
of >20 mmHg
16.7.
Interim Analyses
An interim futility analysis may be performed based on the primary endpoint when 
approximately 30% of planned mITT subjects complete Day 90.  At the same interim analysis, 
an unblinded sample size re-estimation may be performed. The sample size re-estimation 


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employs an approach in which the sample size will be increased when the interim results are in 
the promising zone [Mehta and Pocock 2011]. Criteria for futility and sample size increase and 
details for the interim analysis will be prespecified in the SAP and included in the DMC 
charter.  The interim analysis will be conducted by an external independent team and be 
reviewed by the IDMC.  The IDMC may recommend stopping for futility based on prespecified 
criteria.  If the interim sample size re-estimation is performed, then the IDMC may recommend a 
single-step sample size increase to approximately 1044 subjects based on prespecified 
criteria.  To control the type I error after the sample size adaptation, if it occurs, the final 
hypothesis testing for the primary endpoint will be conducted using the Cui-Hung-Wang (CHW) 
method [Cui 1999; Mehta and Pocock 2011] at the significance level of α=0.05 two sided. The 
decision whether or not to conduct the sample size re-estimation at the interim analysis will be 
documented by an official communication from the study Sponsor to the IDMC that will occur 
within 30 days after randomization of approximately 30% of the planned enrollment has been 
achieved.  A clear process will be specified and implemented to ensure that the blind will be 
strictly maintained for investigators, subjects, and Sponsor’s study personnel.
The final CHW test statistic is defined as follows: 
𝑍∗2,𝑐ℎ𝑤=
𝑛1
𝑛2
𝑍1 +
𝑛2
𝑛2
𝑍∗2
where 𝑛1 is the sample size at interim, 𝑛2 is the total planned sample size for the study, 𝑛2 = 𝑛2
― 𝑛1 is the sample size after interim, Z1 is the Wald test statistic from the proportional odds 
model calculated from the interim data, and 𝑍∗2 is the incremental Wald test statistic based on the 
data observed after the interim analysis. 
16.8.
Sample Size Considerations
The study will randomize approximately 768 subjects aged 18 to 85 years.  Based on the 
observed Day 90 5-category mRS distributions of the BIIB093 group and the placebo group in 
the mITT population aged 18 to 70 years from the GAMES-RP Phase 2 trial, a sample size of 
327 subjects aged 18 to 70 years per arm (total of 654 subjects) will have approximately 90% 
power using ordinal logistic regression to detect, with 5% significance, an odds ratio of 1.595 in 
shifting the distributions of the 5-category mRS in the direction of lower disability.  Assuming 
up to 5% of the sample will not be evaluable for the primary analysis, it is planned to randomize 
up to approximately 688 subjects to the population aged 18 to 70 years, inclusive.  In addition, 
approximately 80 subjects aged >70 and up to 85 years (inclusive) will also be randomized for 
safety 
 evaluations.  Final sample size may be determined by the 
potential interim sample size re-estimation (Section 16.7).


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17.
ETHICAL REQUIREMENTS
Biogen, the CRO, and the Investigator must comply with all instructions, regulations, and 
agreements in this protocol and applicable International Council for Harmonisation (ICH) and 
GCP guidelines and conduct the study according to local regulations.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated.  The Investigator 
is responsible for supervising those individuals and for implementing procedures to ensure the 
integrity of the tasks performed and any data generated.
17.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
17.2.
 Ethics Committee
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the ethics committee.  A copy of the approved ICF must be provided to 
Biogen.  After approval, the ICF must not be altered without the agreement of the relevant ethics 
committee and Biogen.
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations.
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  Protocol 
amendments will be subject to the same requirements as the original protocol.
A progress report must be submitted to the ethics committee at required intervals and not less 
than annually.
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and Biogen.
17.3.
Subject Information and Consent
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject, 


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the subject’s LAR (e.g., spouse, parent, or legal guardian), or physician, as applicable, in 
accordance with local practice and regulations.
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 
subject’s LAR).  The subject must be given sufficient time to consider whether to participate in 
the study.
Subjects will be informed that their race and ethnicity will be collected (unless not permitted by 
local law or not approved by the governing ethics committees) and will be used during analysis 
of study results.   
In addition, subjects who have the capacity should provide their assent to participate in the study.  
The level of information provided to subjects should match their level of understanding as 
determined by the Investigator and in accordance with applicable regulations and guidelines.
A copy of the signed and dated ICF or assent must be given to the subject or the subject’s LAR.  
The original signed and dated ICF will be retained with the study records.  Local regulations 
must be complied with in respect to the final disposition of the original (wet signature) and 
copies of the signed and dated ICFs.
Confirmation of informed consent or assent must also be documented in the subject’s medical 
record.
17.4.
Subject Data Protection
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., Protected Health Information 
authorization in North America).
During the study, subjects’ race and ethnicity will be collected (unless not permitted by local law 
or not approved by the governing ethics committee).  These data will be used in the analysis of 
the safety and/or PK profile of the study treatment.  It is unknown whether the effects of the 
study treatment are influenced by race or ethnicity.
Study reports will be used for research purposes only.  The subject will not be identified by name 
in eCRFs, study-related forms, study reports, or any related publications.  Biogen, its partners 
and designees, ethics committees, and various government health agencies may inspect the 
records of this study.  Every effort will be made to keep the subject’s personal medical data 
confidential.
17.5.
Compensation for Injury
Biogen maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws.


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17.6. Conflict of Interest
The Investigators should address any potential conflicts of interest (e.g., financial interest in 
Biogen) with the subject before the subject makes a decision to participate in the study.
17.7.
Registration of Study and Disclosure of Study Results
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.


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18.
ADMINISTRATIVE PROCEDURES
18.1. Study Site Initiation
The Investigator must not screen any subjects prior to completion of a study initiation visit, 
conducted by the CRO.  This initiation visit will include a detailed review of the protocol and 
study procedures.
18.2. Quality Control and Quality Assurance
Quality control procedures will be implemented at each stage of data handling to ensure that all 
data are reliable and have been processed correctly.  Data anomalies will be communicated to the 
sites for clarification and resolution, as appropriate.  The Investigator is responsible for 
endorsing all CRF data prior to any database lock.
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will be 
expected to cooperate with any audit or inspection and to provide assistance and documentation 
(including source data) as requested.
18.3.
Monitoring of the Study
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories.  Source data must be attributable, legible, 
contemporaneous, original, accurate, and complete.  Changes to source data must be traceable, 
not obscure the original entry, and be explained if necessary (e.g., with an audit trail).  The 
Investigator should maintain a record of the location(s) of essential documents.
The Clinical Monitor will visit the study site at regular intervals during the study and after the 
study has completed, as appropriate.  A clinical site monitoring plan will detail who performs the 
monitoring, how often, and the extent of the review.  It also will provide the monitoring strategy, 
with emphasis on subject safety, data integrity, critical data, and processes.
During monitoring visits, the eCRF, supporting documentation, and essential documentation 
related to the study will be reviewed and any discrepancies or omissions will be queried until 
fully resolved.  Documentation of results will be provided to Biogen in a timely fashion to allow 
follow-up and verification of compliance with the monitoring plan.  Remote evaluation of data 
(centralized monitoring) may also be conducted and reported as defined in the monitoring plan.
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure the protection of subject rights and well-being, protocol adherence, quality of data 
(accurate, complete, and verifiable), study treatment accountability, compliance with regulatory 
requirements, and continued adequacy of the investigational site and its facilities.


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18.4. Study Funding
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contracts between the institution, Investigator, and Biogen.  
18.5.
Publications
Details are included in the clinical trial agreement for this study.




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19.2.
Study Committees
19.2.1.
Advisory Committee
An advisory committee will be formed to provide scientific and medical direction for the study 
and to oversee the administrative progress of the study.  Further details will be available in the 
Advisory Committee charter.  The advisory committee will be blinded to treatment assignment.
19.2.2.
Independent Data Monitoring Committee 
An IDMC will be established to assess the overall safety profile of BIIB093 during the study.  
An IDMC charter will guide the overall governance plan for the IDMC. IDMC may recommend 
the Sponsor to terminate the study based on safety data or following the interim futility analysis. 
If the interim sample size re-estimation is performed, then the IDMC may recommend a sample 
size increase based on prespecified criteria in the SAP and IDMC charter.
19.3.
Changes to Final Study Protocol
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law.  Protocol modifications that affect subject safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study.  If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation.
However, Biogen may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a subject.  In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification.
In the event of a protocol modification, the ICF may require similar modifications (see 
Section 17).
19.4.
Ethics Committee Notification of Study Completion or Termination
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines.
19.5.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local, national, or regional laws or 
regulations.  Prior to proceeding with destruction of records, the Investigator must notify Biogen 
in writing and receive written authorization from Biogen to destroy study records.  In addition, 
the Investigator must notify Biogen of any changes in the archival arrangements including but 
not limited to archival at an offsite facility or transfer of ownership if the Investigator leaves the 
site.


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19.6.
Study Report Signatory
Biogen will designate one or more of the participating Investigators as a signatory for the study 
report.  This determination will be made by several factors, including but not limited to, the 
Investigator's experience and reputation in the studied indication; the Investigator's contribution 
to the study in terms of design, management, and/or subject enrollment; or by other factors 
determined to be relevant by Biogen.
Biogen will follow all applicable local regulations pertaining to study report signatories.


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20.
REFERENCES
Arac A, Blanchard V, Lee M, et al. Assessment of outcome following decompressive 
craniectomy for malignant middle cerebral artery infarction in patients older than 60 years of 
age. Neurosurg Focus. 2009;26(6):E3.
Bereczki D, Fekete I, Prado GF, et al. Mannitol for acute stroke. Cochrane Database Syst Rev. 
2007(3):CD001153. Epub 2007/07/18.
Berrouschot J, Sterker M, Bettin S, et al. Mortality of space-occupying ('malignant') middle 
cerebral artery infarction under conservative intensive care. Intensive Care Med. 1998;24(6):620-
3.
Chen M, Dong Y, Simard JM. Functional coupling between sulfonylurea receptor type 1 and a 
nonselective cation channel in reactive astrocytes from adult rat brain. J Neurosci. 
2003;23(24):8568-77.
Chen M, Simard JM. Cell swelling and a nonselective cation channel regulated by internal Ca2+ 
and ATP in native reactive astrocytes from adult rat brain. J Neurosci. 2001;21(17):6512-21.
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics. 1999;55(3):853-7.
Hacke W, Schwab S, Horn M, et al. 'Malignant' middle cerebral artery territory infarction: 
clinical course and prognostic signs. Arch Neurol. 1996;53(4):309-15.
Hallenbeck JM, Dutka AJ. Background review and current concepts of reperfusion injury. Arch 
Neurol. 1990;47(11):1245-54.
International Hypoglycaemia Study Group. Glucose Concentrations of Less Than 3.0 mmol/L 
(54 mg/dL) Should Be Reported in Clinical Trials: A Joint Position Statement of the American 
Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 
2017;40(1):155-157. Epub 2016/11/21.
Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with 
acute ischemic stroke: a guideline for healthcare professionals from the American Heart 
Association/American Stroke Association. Stroke. 2013;44(3):870-947.
Koudstaal PJ, Stibbe J, Vermeulen M. Fatal ischaemic brain oedema after early thrombolysis 
with tissue plasminogen activator in acute stroke. BMJ. 1988;297(6663):1571-4.
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a 
practical guide with examples. Statistics in medicine. 2011;30(28):3267-84. Epub 2010/11/30.
Nielsen TH, Ståhl N, Schalén W, et al. Recirculation usually precedes malignant edema in 
middle cerebral artery infarcts. Acta neurologica Scandinavica. 2012;126(6):404-10. Epub 
2012/04/12.


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Qizilbash N, Lewington SL, Lopez-Arrieta JM. Corticosteroids for acute ischaemic stroke. 
Cochrane Database Syst Rev. 2002(2):CD000064.
Rudolf J, Grond M, Stenzel C, et al. Incidence of space-occupying brain edema following 
systemic thrombolysis of acute supratentorial ischemia. Cerebrovasc Dis. 1998;8(3):166-71.
Sheth KN, Elm JJ, Molyneaux BJ, et al. Safety and efficacy of intravenous glyburide on brain 
swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-
controlled phase 2 trial. Lancet Neurol. 2016;15(11):1160-9. Epub 2016/08/23.
Simard JM, Chen M, Tarasov KV, et al. Newly expressed SUR1-regulated NC(Ca-ATP) channel 
mediates cerebral edema after ischemic stroke. Nat Med. 2006;12(4):433-40. Epub 2006/03/19.
Simard JM, Geng Z, Silver FL, et al. Does inhibiting Sur1 complement rt-PA in cerebral 
ischemia? Annals of the New York Academy of Sciences. 2012a;1268:95-107.
Simard JM, Kent TA, Chen M, et al. Brain oedema in focal ischaemia: molecular 
pathophysiology and theoretical implications. Lancet Neurol. 2007;6(3):258-68.
Simard JM, Tsymbalyuk N, Tsymbalyuk O, et al. Glibenclamide is superior to decompressive 
craniectomy in a rat model of malignant stroke. Stroke. 2010;41(3):531-7. Epub 2010/01/21.
Simard JM, Tsymbalyuk O, Keledjian K, et al. Comparative effects of glibenclamide and 
riluzole in a rat model of severe cervical spinal cord injury. Exp Neurol. 2012b;233(1):566-74. 
Epub 2011/12/08.
Torbey MT, Bösel J, Rhoney DH, et al. Evidence-based guidelines for the management of large 
hemispheric infarction : a statement for health care professionals from the Neurocritical Care 
Society and the German Society for Neuro-intensive Care and Emergency Medicine. Neurocrit 
Care. 2015;22(1):146-64.
Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignant infarction of 
the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet 
Neurol. 2007;6(3):215-22.
Wijdicks EF, Sheth KN, Carter BS, et al. Recommendations for the management of cerebral and 
cerebellar infarction with swelling: a statement for healthcare professionals from the American 
Heart Association/American Stroke Association. Stroke. 2014;45(4):1222-38. Epub 2014/01/30.


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APPENDIX 1.
MEDICATIONS THAT MODULATE CYP2C9 AND CYP3A4
CYP2C9
SUBSTRATES
INHIBITORS
INDUCERS
celecoxib
Strong
Glimepiride
-
phenytoin
Moderate
Moderate
tolbutamide
amiodarone
rifampin
warfarin
felbamate
enzalutamide
fluconazole
aprepitan
miconazole
carbamazepine
piperine
ritonavir
Weak
diosmin
disulfiram
fluvastatin
fluvoxamine
voriconazole
  Source: FDA 9/26/2016 Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers


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CYP3A4
SUBSTRATES
INHIBITORS
INDUCERS
midazolam
Strong
Strong
tacrolimus
ritonavir
phenytoin
sirolimus
indinavir
carbamazepine
naloxegol
nelfinavir
rifampin
nisoldipine
saquinavir
saquinavir
clarithromycin
simvastatin
troleandomycin
tipranavir
voriconazole
triazolam
ketoconazole
vardenafil
itraconazole
budesonide
nefazodone
dasatinib
grapefruit juice (bergamottin)
alfentanil
boceprevir
avanafil
cobicistat
buspirone
conivaptan
conivaptan
danoprevir
darifenacin
elvitegravir
darunavir
lopinavir
ebastine
paritaprevir
everolimus
posaconazole
ibrutinib
telaprevir
lomitapide
tipranavir
lovastatin
dronedarone
Moderate
Moderate
eletriptan
verapamil
bosentan
eplerenone
tofisopam
efavirenz
felodipine
aprepitant
etravirine
indinavir
erythromycin
modafinil
lurasidone
fluconazole
maraviroc
cimetidine
quetiapine
ciprofloxacin
sildenafil
clotrimazole
ticagrelor
crizotinib
tolvaptan
cyclosporine
alprazolam
dronedarone
aprepitant
imatinib
atorvastatin
fluvoxamine


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colchicine
eliglustat
Weak
Weak
pimozide
ticagrelor
armodafinil
rilpivirine
chlorzoxazone
rufinamide
rivaroxaban
cilostazol
tadalafil
fosaprepitant
istradefylline
ivacaftor
lomitapide
ranitidine
ranolazine
tacrolimus
  Source: FDA 9/26/2016 Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers


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21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group, Multicenter, Phase 3 Study to Evaluate the Efficacy and Safety of Intravenous BIIB093 
(Glibenclamide) for Severe Cerebral Edema following Large Hemispheric Infarction” and agree 
to conduct the study according to the protocol and the applicable ICH guidelines and GCP 
regulations, and to inform all who assist me in the conduct of this study of their responsibilities 
and obligations.
_____________________________
Investigator’s SignatureDate
______________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)

SAP_001.pdf: 
 
Oﬃcial Title: 
Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
MulƟcenter, Phase 3 Study to Evaluate the Eﬃcacy and Safety of 
Intravenous BIIB093 (Glibenclamide) for Severe Cerebral Edema Following 
Large Hemispheric InfarcƟon 
NCT Number: 
NCT02864953 
Document Date: 
SAP Version 3.0: 11 Jul 2023 
COVER PAGE 


STATISTICAL ANALYSIS PLAN
CLINICAL PROTOCOL NUMBER: 252LH301
Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Phase 3 
Study to Evaluate the Efficacy and Safety of Intravenous BIIB093 (Glibenclamide) for 
Severe Cerebral Edema Following Large Hemispheric Infarction
Protocol Version: 3.0, 3.1, and other country specific versions 
Date of Protocol: February 11, 2022 and May 5, 2022 
Date of Statistical Analysis Plan: June 21, 2023, Final Version 3.0
Sponsor: Biogen
Approved By:
, SMT Statistician, 
Date
, 
Date
 
Date


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2
Table of Contents
1
INTRODUCTION .................................................................................................................6
2
STUDY SYNOPSIS ...............................................................................................................6
3
STUDY OBJECTIVES AND ENDPOINTS .......................................................................7
3.1
PART 1 Objectives and Endpoints ...........................................................................................7
3.2
PART 2 Objectives and Endpoints ...........................................................................................8
4
ANALYSIS POPULATIONS ...............................................................................................8
4.1
Intent-to-Treat Population ........................................................................................................9
4.2
Modified Intent-to-Treat Population – Primary Population for Efficacy Assessments.......9
4.3
Per-protocol Population.............................................................................................................9
4.4
Age Over 70 Population.............................................................................................................9
4.5
Safety Populations ......................................................................................................................9
9
9
5
DESIGN CONSIDERATIONS.............................................................................................9
5.1
Sample Size Determination......................................................................................................10
5.2
Randomization..........................................................................................................................10
5.3
Blinding .....................................................................................................................................10
5.4
Independent Data Monitoring Committee.............................................................................11
6
STATISTICAL ANALYSES FOR PART 1 DATA .........................................................11
6.1
Study Subjects...........................................................................................................................11
6.1.1
Accounting of Subjects.........................................................................................................11
6.1.2
Demographics and Baseline Characteristics.........................................................................12
6.1.3
Concomitant Medications and Non-drug Therapies.............................................................12
6.1.4
Protocol Deviations...............................................................................................................13
6.1.5
Study Drug Exposure............................................................................................................13
6.2
Efficacy......................................................................................................................................14
6.2.1
General Methods of Analysis................................................................................................14
6.2.2
Primary Efficacy Endpoint ...................................................................................................16
6.2.3
Secondary Efficacy Endpoints..............................................................................................17
6.2.3.1 Time to All-cause Death Over the 90-day Period...................................................................18
6.2.3.2 Proportion of Subjects Who Achieved mRS 0-4 at Day 90....................................................18
6.2.3.3 Midline Shift at 72 Hours (or at Time of DC or CMO, if Earlier)..........................................18
6.2.4
Supportive Efficacy Analyses...............................................................................................18
6.2.4.1 Per-protocol Analysis............................................................................................................18
6.2.4.2 Subgroup Analyses for the Primary Endpoint ......................................................................18
6.2.4.3 Sensitivity/Supplementary Analyses for the Primary Endpoint ...........................................19
19
19
20
20
20
21
21
21
6 2 6
Efficacy Analysis for the Age Over 70 Population
21
21


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22
6.5
Safety Analyses .........................................................................................................................22
6.5.1
Adverse Events .....................................................................................................................22
6.5.2
Adverse Events of Special Interest .......................................................................................24
6.5.3
Clinical Laboratory Results ..................................................................................................24
6.5.4
ECG.......................................................................................................................................28
6.5.5
Vital Signs.............................................................................................................................29
6.6
Interim Analysis .......................................................................................................................29
6.6.1
Interim Analysis for Non-Binding Futility ...........................................................................30
6.6.2
Interim Analysis for Sample Size Re-Estimation .................................................................30
7
STATISTICAL ANALYSES FOR LONG-TERM DATA ..............................................31
7.1
Study Subjects...........................................................................................................................31
7.1.1
Accounting of Subjects.........................................................................................................31
7.1.2
Protocol Deviations...............................................................................................................31
7.2
Efficacy Analyses......................................................................................................................31
7.2.1
General Methods of Analysis................................................................................................31
7.2.2
Modified Rankin Scale .........................................................................................................32
7.2.3
Time to All-cause Death Over the 1-year Period..................................................................33
7.2.4
Barthel Index.........................................................................................................................33
7.2.5
Health-related Quality of Life...............................................................................................33
7.2.6
SIS-16 ...................................................................................................................................33
7.2.7
HCRUQ and Subject’s Current Location .............................................................................33
7.2.8
Zarit Burden Interview..........................................................................................................33
7.3
Safety Analyses .........................................................................................................................34
7.3.1
Serious Adverse Events ........................................................................................................34
8
Changes from the Protocol Defined Analyses...................................................................34
9
References.............................................................................................................................34
10
Appendix...............................................................................................................................34
10.1
Schedule of Activities ...............................................................................................................35
10.2
Sample SAS Code .....................................................................................................................39
10.2.1
Primary Endpoint – 5-Category mRS at Day 90: .................................................................39
10.2.2
Secondary Endpoint – Time to all-cause death over the 90-day period ...............................40
10.2.3
Secondary Endpoint – Proportion of subjects who achieved mRS 0-4 at Day 90................41
10.2.4
Secondary Endpoint – Midline Shift at 72 hours (or at time of DC or CMO, if earlier)......41
10.2.5
Multiple Imputation for Primary Endpoint – 5-Category mRS at Day 90: ..........................41
List of Tables
Table 1. Main Analyses for Efficacy Endpoints in Part 1 .............................................................14
Table 2. Visit Windows for Efficacy Endpoints in Part 1 .............................................................15
Table 3. Criteria to Determine Potentially Clinically Significant (PCS) Laboratory Abnormalities
.......................................................................................................................................................25
Table 4. Visit Windows for Local Lab by Timepoint Summaries ................................................26
Table 5. Visit Windows for ECG by Timepoint Summaries.........................................................29
Table 6. Criteria to Determine Clinically Relevant Vital Signs Abnormalities ............................29
Table 7. Analysis for Efficacy Endpoints in Part 2 .......................................................................31
Table 8. Schedule of Activities – Part 1 (Screening through Day 90) ..........................................35


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Table 9. Schedule of Activities – Part 2 (Day 91 through Month 12)...........................................38
Table 10. Supportive Analyses for Efficacy Endpoints in Part 1..................................................42
ABBREVIATIONS
Term
Definition
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ASPECTS
Alberta Stroke Program Early CT Score
AST
aspartate aminotransferase
BI
Barthel Index
BG
blood glucose
BUN
blood urea nitrogen
CMO
comfort measures only
CRO
contract research organization
DC
Decompressive Craniectomy 
ECG
electrocardiogram
eCRF
electronic case report form
EQ-5D-5L
EuroQol 5-level assessment of health outcomes
GCP
Good Clinical Practice
HCRUQ 
HealthCare Resource Utilization Questionnaire
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
IP
investigational product
IRB
Institutional Review Board
IV
intravenous
LHI
large hemispheric infarction
mITT
modified intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model repeated measures
MRI
magnetic resonance imaging
mTICI
modified treatment in cerebral ischemia
NIHSS
National Institutes of Health Stroke Scale
PD
pharmacodynamic(s)
PE
physical examination
POC
Point-of-Care
rtPA
recombinant tissue plasminogen activator or thrombolysis
SAE
serious adverse event


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SIS-16
Stroke Impact Scale 16 Questions
SOC
standard of care
TOAST
Trial of Org 10172 in Acute Stroke Treatment
ULN
upper limit of normal
US
United States
Zarit
Zarit Burden Interview


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1
INTRODUCTION
This document provides details of the statistical analyses planned for 252LH301. This document 
defines all pre-planned analyses. 
2
STUDY SYNOPSIS
This is a Phase 3 randomized, multicenter, placebo-controlled, double-blind study of subjects 
aged 18 to 85 with a large hemispheric infarction (LHI) and time from symptom onset to start of 
study drug infusion of ≤ 10 hours.  The study allows standard of care (SOC) therapy including 
IV recombinant tissue plasminogen activator (rtPA), thrombectomy, mannitol, hypertonic saline, 
decompressive craniotomy (DC), and other treatments for LHI per local guidelines as determined 
by the Investigator.  Following a 3-stage 72-hour continuous infusion of BIIB093 or matching 
placebo, subjects will receive efficacy and safety evaluations for 90 days.  The primary efficacy 
assessment will be the mRS at Day 90. The study will be conducted as a single study in two 
parts. Part 1 of the study consists of the baseline visit, study drug infusion and efficacy and 
safety period through Study Day 90 (primary endpoint).  Part 2 will be a LHI follow-up period 
from Day 91 to Month 12. Approximately 200 to 250 sites in 20 to 25 countries globally are 
planned.
The study is designed to determine whether BIIB093 improves functional outcomes measured by 
the modified Rankin scale (mRS) at Day 90 in the modified Intent-to-Treat Population (“mITT” 
Population; see Section 4), which is defined as those subjects aged 18 to 70 years (inclusive) 
who are randomized, receive study treatment, and who have at least 1 post-baseline mRS before 
or at the Day 90 visit.  The study seeks to enroll approximately 688 subjects age 18 to 70 and 
approximately 80 subjects above 70 to 85, for a total of approximately 768 subjects. Since there 
is limited experience with thrombectomy in LHI patients, the number of subjects with 
thrombectomy performed prior to randomization is targeted at approximately 20% in the ≤70 
year age group but may vary from this to reflect the evolving standard of care and stroke 
treatment guidelines. The number of subjects with thrombectomy performed prior to 
randomization is targeted at approximately 8% in the >70 year age group.   
Subjects will be randomized to receive either BIIB093 or placebo in a 1:1 ratio. As part of 
randomization, for each age group (18 to 70 vs. >70 to 85), a minimization method will be used 
to achieve balance over the following baseline covariates: country, rtPA administration (yes, no), 
thrombectomy (yes, no), use of ASPECTS for screening (yes, no), and baseline NIHSS (≤20 vs. 
>20).  A buffered commercial formulation that provides greater control over drug product pH 
during administration and is therefore fully compatible with PVC and non-PVC infusion 
materials is planned to be introduced into this study. To investigate the safety of a commercial 
formulation, at least 90 subjects of the approximately 688 planned subjects aged 18 to 70 years 
will be dosed with the commercial formulation or matching placebo. The 1:1 randomization ratio 
between BIIB093 (clinical formulation or commercial formulation) and placebo remains 
unchanged. Therefore, approximately 45 or more subjects are expected to be dosed with 
BIIB093 commercial formulation. The overall sample size (n=768), dose and dosing regimen, 
schedule of assessments, and efficacy analysis will remain unchanged. Additional safety 
analyses by formulation will be performed. The PK, efficacy, and safety are not expected to be 
altered as the administered dose and infusion amount per unit time does not change.


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3
STUDY OBJECTIVES AND ENDPOINTS
3.1
PART 1 Objectives and Endpoints
Primary Objective
Primary Endpoint
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.  
Day 90 mRS score as a 5-category ordinal scale 
(the 5-category mRS combines mRS categories 0 
and 1 and mRS categories 5 and 6).
Secondary Objectives
Secondary Endpoints
To determine if BIIB093 improves overall 
survival at Day 90 when compared with placebo 
in the modified intent-to-treat (mITT) population.
Time to all-cause death over the 90-day period. 
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.
Proportion of subjects who achieved mRS 0-4 at 
Day 90.
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.
Midline shift at 72 hours (or at time prior to DC or 
CMO, if earlier).
To evaluate the safety and tolerability of BIIB093 
in subjects with LHI.
Incidence of adverse events (AEs), serious 
adverse events (SAEs), and clinically significant 
abnormal vital signs, 12-lead electrocardiogram 
(ECG) findings, and laboratory results (including 
those associated with blood glucose (BG) levels). 


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3.2
PART 2 Objectives and Endpoints
Objectives
Endpoints
To evaluate long-term disability following LHI. 
mRS score at Month 6 and Month 12 as a 5-
category ordinal scale (the 5-category mRS 
combines mRS categories 0 and 1 and mRS 
categories 5 and 6)
To evaluate long-term outcome measures of 
clinical function, quality of life, and healthcare 
utilization
•
EQ-5D-5L at Months 6 and 12
•
BI score at Months 6 and 12
•
SIS-16 at Months 6 and 12
•
Zarit Burden Interview at Month12
•
HealthCare Resource Utilization 
Questionnaire at Month 12
To assess the safety of BIIB093 in subjects with 
LHI during the follow-up period.
Incidence of SAEs 
4
ANALYSIS POPULATIONS
All data from sites in ROW and China will be included in all analysis populations. The analysis 
populations include: Intent-to-Treat (ITT), mITT, Per-protocol, Age over 70,  Safety,  Safety age 
≤70, and Safety age>70, 
.




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5.1
Sample Size Determination
The study will randomize approximately 768 subjects aged 18 to 85 years. Based on the 
observed Day 90 5-category mRS distributions of the BIIB093 group and the placebo group in 
the mITT population aged 18 to 70 years from the GAMES-RP Phase 2 trial, a sample size of 
327 subjects aged 18 to 70 years per arm (total of 654 subjects) will have approximately 90% 
power using ordinal logistic regression to detect, with 5% significance (2-sided), an odds ratio of 
1.595 in shifting the distributions of the 5-category mRS in the direction of lower disability. 
Assuming up to 5% of the sample will not be evaluable for the primary analysis, it is planned to 
randomize up to approximately 688 subjects to the population aged 18 to 70 years, inclusive. In 
addition, approximately 80 subjects aged >70 and up to 85 years (inclusive) will also be 
randomized for safety and 
 efficacy evaluations. Final sample size may be impacted 
by the potential interim sample size re-estimation (Section 6.6). 
Of approximately 688 planned subjects aged 18 to 70 years, a target of at least 90 subjects will 
be dosed with the commercial formulation or matching placebo. The 1:1 randomization ratio 
between BIIB093 (clinical formulation or commercial formulation) and placebo remains 
unchanged. Therefore, approximately 45 or more subjects are expected to be dosed with 
BIIB093 commercial formulation. The sample size of 45 subjects dosed with commercial 
formulation will allow for a ≥90% chance to observe any AEs with an expected incidence of 5% 
or greater. The 95% confidence interval estimate of AE incidence of 5% is 0 to 11.4% (margin of 
error = 6.4%) and the 95% confidence interval estimate of AE incidence of 10% is 1.2% to 
18.8% (margin of error = 8.8%).
5.2
Randomization
Randomization will be performed using interactive response technology (IRT). Subjects will be 
randomized to receive BIIB093 or placebo in a 1:1 ratio. As part of randomization, for each age 
group (18 to 70 vs. >70 to 85), a minimization method will be used to achieve balance over the 
following baseline covariates: country, rtPA (yes, no), thrombectomy (yes, no), use of ASPECTS 
for screening (yes, no), and baseline NIHSS (≤20 vs. >20). The number of subjects with 
thrombectomy performed prior to randomization is targeted at approximately 20% in the ≤70 
year age group but may vary from this to reflect the evolving standard of care and stroke 
treatment guidelines. The number of subjects with thrombectomy performed prior to 
randomization is targeted at approximately 8% in the >70 year age group.  To avoid any 
selection bias, the system will randomly assign a patient with 15% probability to the non-optimal 
treatment group. The detailed algorithm is documented in the randomization specification.
5.3
Blinding
The investigators, study site staff, subjects, and caregivers will be blinded to the subject 
treatment assignments for the duration of the trial (Parts 1 and 2).  To ensure that efficacy and 
outcome assessors are blinded to study treatment, evaluators performing all efficacy and 
outcome evaluations will be blinded to knowledge of AEs and SAEs during the acute 
hospitalization phase of the study (should not have participated in the treatment during the acute 
hospitalization phase of the study nor review the subject’s hospital records from this period 
including blood glucose (BG) levels, BG management, or carbohydrate intake).  


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The Sponsor and contract research organization (CRO) study management team will be fully 
blinded for Part 1 of the study.  After Part 1 is completed and the clinical study database is 
locked, designated personnel at the Sponsor will be unblinded to the Part 1 data for the purposes 
of evaluating the Day 90 data.  The Sponsor and CRO study management team responsible for 
all site interactions and data entry will remain blinded to individual treatment assignments during 
Part 2 of the study. 
5.4
Independent Data Monitoring Committee
An independent data monitoring committee (IDMC) is established to assess the overall safety 
profile of BIIB093 during the study.  The IDMC charter guides the overall governance plan for 
the IDMC. IDMC may recommend the Sponsor to terminate the study based on safety data or 
following the interim futility analysis if conducted. If the interim sample size re-estimation is 
performed, then the IDMC may recommend a sample size increase based on pre-set criteria in 
Section 6.6 and IDMC charter.
6
STATISTICAL ANALYSES FOR PART 1 DATA
The objectives of the study and the endpoints to be analyzed are listed in Section 3. The study 
database will be locked after the last subject completes the Day 90 visit and the endpoints for 
Part 1 of the study will be analyzed.  A second database lock will be used to analyze the Part 2 
endpoints after the last subject completes the month 12 visit or withdraws from the study (see 
Section 7).  
6.1
Study Subjects
6.1.1
Accounting of Subjects
The summaries in this subsection will be based on the ITT population. Disposition of subjects 
will be summarized, and the summary data will include number (%) of subjects randomized and 
dosed, number (%) of subjects who completed the treatment/study Part 1, and number (%) of 
subjects who discontinued treatment and/or withdrew from study Part 1. For subjects who 
discontinued treatment and/or withdrew from study, the reasons for discontinuation and/or 
withdrawal, and days on treatment and days on study will be summarized and listed. Number of 
subjects in each analysis population will be summarized. In addition, number of subjects dosed 
and number of subjects who completed the treatment/study will be summarized by region and 
country. Number of subjects who completed the treatment/study will be presented only by 
treatment group.
The categorization of region is based not only on consideration of geography but also on type of 
health care system and access to health care in each country. The categories for regions will be:
•
Region 1: United States (US);
•
Region 2: Western European countries (including Belgium, Denmark, Finland, France, 
Germany, Italy, Portugal, Spain, Switzerland, and United Kingdom), plus Australia, 
Canada, and Israel;


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•
Region 3: Eastern European countries (including Czech Rep, Hungary, Russia, Croatia 
and Lithuania), plus Brazil, and Asian countries (including Japan, South Korea and 
Taiwan, China).
6.1.2
Demographics and Baseline Characteristics
The summaries in this subsection will be based on the ITT population, unless otherwise 
specified. 
Unless otherwise specified, baseline data is defined as the most recent non-missing measurement 
collected prior to and/or on the date/time of the first infusion. 
The demographic data include age, gender, ethnicity, race, height, weight, and body mass index 
(BMI). Baseline characteristics include baseline disease characteristics, eligibility imaging 
parameters, and time to procedures. Demographic and baseline characteristics will be presented 
for the modified intent-to-treat (mITT, defined in Section 4), intent-to-treat (ITT, defined in 
Section 4), and per-protocol (PP, defined in Section 4) populations. Demographic variables and 
baseline characteristics of the two study arms will be tabulated as well as for all subjects 
combined.  For continuous endpoints, the summary statistics will generally include number of 
subjects with data, mean, standard deviation, median, 25% percentile, 75% percentile, and 
minimum and maximum. For categorical endpoints, the summary statistics will generally include 
number of subjects in corresponding analysis population, and number and percentage of subjects 
in each category. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number (%) of subjects with history (including both ongoing and not ongoing 
medical conditions) will be summarized by system organ class and preferred term, and by 
preferred term only. A listing of medical history will be generated.
TOAST classification for the stroke will be summarized. The number (%) of subjects receiving 
IV thrombolytic/tPA will be summarized.
The number (%) of subjects who received thrombectomy and time of the thrombectomy will be 
summarized. For subjects who received thrombectomy, the pre-procedure rating of modified 
treatment in cerebral infarction (mTICI) score and final rating of vessel patency and perfusion 
will be summarized.
The number and percentage of subjects with intracerebral hemorrhage at baseline 
(intraventricular hemorrhage, subarachnoid hemorrhage, remote intraparenchymal hemorrhage, 
subdural hematoma, epidural hematoma, HI-1 small petechia, HI-2 confluent petechiae, and PH-
1, PH-2) will be summarized by treatment.
6.1.3
Concomitant Medications and Non-drug Therapies
The summaries in this subsection will be based on the ITT population. All concomitant 
medications will be coded using the World Health Organization (WHO) medication dictionary. 
All concomitant non-drug therapies will be coded using the MedDRA dictionary.  A concomitant 
medication/therapy will be defined as any therapy that was taken on or after the day of the first 


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infusion of study drug. This includes therapies that start prior to the initiation of the first infusion 
if their use continues on or after the date of first infusion. To define concomitant use for 
therapies with missing start or stop dates, the following additional criteria will be used:
•
if both the start and stop dates of a therapy are missing, that therapy will be 
considered concomitant.
•
if the start date of a therapy is missing and the stop date of that therapy falls on or 
after the date of the first infusion, that therapy will be considered concomitant. 
•
if the start date of a therapy is prior to the date of the first infusion and the stop date 
of that therapy is missing and the therapy is listed as continuing, that therapy will be 
considered concomitant, or
•
if the start date of a therapy is prior to the date of the first infusion and the stop date 
of that therapy is missing and the therapy is not listed as continuing, that therapy will 
be considered non-concomitant.
For a therapy with a partial start date, the year/month of the therapy date will be compared to that 
of the first infusion date to determine whether the therapy is concomitant.
The number (%) of subjects taking concomitant medication and non-drug therapies will be 
summarized. Non-drug therapies will be presented only by treatment group. Listings of 
concomitant medications and non-drug therapies will be presented.
The number (%) of subjects receiving maintenance fluid will be summarized. The number (%) of 
subjects received DC, time and the reasons of DC will be summarized.
Number (%) of subjects with decision of comfort measures only (CMO), time and reasons of 
CMO will be summarized.
6.1.4
Protocol Deviations
The summaries in this subsection will be based on the ITT population. Protocol deviations 
identified during site monitoring will be captured in a Protocol Deviation log and categorized as 
major or minor deviations. The major protocol deviations will be summarized and listed. The 
minor protocol deviations will also be listed. All summaries for protocol deviations will be 
presented by treatment group.
6.1.5
Study Drug Exposure
The summaries in this subsection will be based on dosed subjects in the ITT, mITT and PP 
populations. The total amount of BIIB093 received in mg via infusion will be calculated based 
on the infusion rate, infusion time period, and concentration, and will be summarized as a 
continuous variable. The number of hours on study drug (BIIB093 or placebo), calculated as 
hours between the end date and time of the last infusion and the start date and time of the first 
infusion subtracting the interruption period time, will be summarized as a continuous variable. 
This table will be presented by treatment group.


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6.2
Efficacy
6.2.1
General Methods of Analysis
The efficacy assessments will be primarily based on the mITT population.  Primary and 
secondary efficacy endpoints will also be analyzed based on the per-protocol population. The   
analysis method for each endpoint in the mITT population will also be used for the Per-Protocol 
analysis and any pre-defined subgroup analyses. Subjects will be analyzed in the group to which 
they are randomized for the mITT analysis and based on actual treatment received in the Per-
Protocol analysis. 
The primary and secondary endpoints and main analyses on them are listed in the protocol, and 
details are presented in the following sections.
Summary statistics will be presented.  For continuous endpoints, the summary statistics may 
include number of subjects with data, mean, standard deviation, median, 25% percentile, 75% 
percentile, and minimum and maximum. For categorical endpoints, the summary statistics may 
include number of subjects in corresponding analysis population, number, and percentage of 
subjects in each category. Statistical testing for efficacy endpoints will be performed between the 
BIIB093 treatment group and placebo. All tests will be 2-sided with significance level equals to 
0.05 (unless otherwise specified). 
Table 1. Main Analyses for Efficacy Endpoints in Part 1
Endpoints
Analysis method
Analysis 
Population
SAP 
Section
Primary endpoint
mRS as 5-category ordinal scale (0/1, 2, 3, 4, 
5/6) at Day 90
Ordinal logistic regression with 
multiple imputation
mITT
per-protocol
6.2.2
Secondary endpoints
Time to all-cause death over the 90-day 
period
Cox proportional hazards 
regression model
mITT
per-protocol
6.2.3 1
Proportion of subjects who achieved mRS 0-4 
at Day 90
Logistic regression
mITT
per-protocol
6.2.3 2
Midline shift at 72 hours (or at time of DC or 
CMO, if earlier)
Analysis of Variance 
(ANOVA) with multiple 
imputation
mITT
per-protocol
6.2.3 3
Supportive efficacy analyses




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Subject’s current location
Analysis visit
Target visit day
Analysis visit window
Day 7
7
[1 (post infusion only), 18]
Day 30
30
(18, 60]
Day 90
90
>60 up to last day in Part 1
6.2.2
Primary Efficacy Endpoint
The primary estimand [ICH E9 (R1) Addendum 2014, 2017] employs the treatment-policy 
strategy to evaluate the treatment effect of BIIB093 compared to placebo regardless of DC or 
other co-therapy as determined by the following 4 attributes:
•
Population: Intended post-approval population for BIIB093 defined through the study 
inclusion/exclusion criteria. All subjects in the mITT population (in Section 4.2) will be 
used in analyzing this estimand.
•
Variable: Day 90 mRS as a 5-category ordinal scale
•
Handling intercurrent events: regardless of whether use of any SOC therapy or procedure 
had occurred. The intercurrent events for the primary endpoint are use of standard of care 
therapies or procedures after the starting of infusion and before Day 90 assessment 
including DC, rtPA, and thrombectomy.
•
Population-level summary: odds of achieving a lower disability 
All observed data, including data collected after intercurrent events, i.e., standard of care 
including decompressive craniectomy and other concomitant SOC therapy, will be included. 
Missing data will be imputed using multiple imputation. Death is scored as 6 in mRS and thus 
there will be no missing mRS values due to death.   
The primary estimand is then the shift in Day 90 mRS as a 5-category ordinal scale [ICH E9 
(R1) Addendum 2014, 2017] regardless of whether use of any SOC therapy or procedure had 
occurred. 


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The primary endpoint of mRS as 5-category ordinal scale (0/1, 2, 3, 4, 5/6) at Day 90 will be 
analyzed using ordinal logistic regression (proportional odds model), adjusting for baseline 
covariates including region, rtPA (yes, no), thrombectomy (yes, no), use of ASPECTS for 
screening (yes, no), and baseline NIHSS (≤20 vs. >20).  Odds ratio, the 95% confidence interval 
as well as the p-value will be reported. If the interim sample size re-estimation is conducted and 
the sample size is increased, the final hypothesis testing for the primary endpoint will be 
conducted using the Cui-Hung-Wang (CHW) method (Cui et al 1999; Mehta and Pocock 2011; 
see Section 6.6.2).
The proportional odds ratio assumption will be tested using likelihood ratio test based on 
observed data. In the case the assumption does not hold (p-value < 0.05) or non-convergence, the 
Mann-Whitney test will be used as the primary inference and the source of non-proportionality 
or non-convergence will be investigated (see Section 9 for the sample SAS code). Following the 
Mann-Whitney test, dichotomized analysis will be conducted to assess the treatment effects. If 
sample size is increased but proportional odds assumption does not hold, the CHW method with 
combination of Mann-Whitney test statistics will be used.
Multiple imputation will be used to account for missing values for the 90-day mRS. Assessment 
of mRS is made on Day 30 and Day 90 or early termination visit.  Death is scored as 6 in mRS 
and thus there will be no missing mRS values due to death. Missing mRS values due to reasons 
other than death will be imputed based on a linear model performed on the 7-category mRS 
scores leveraging the information of the patient at other time points in part 1. The model will also 
include treatment as a classification variable and the covariates described above. Multiple 
imputations will be performed using PROC MI in SAS. Fully conditional specification method 
will be used in this SAS procedure. Imputed values based on the original 7-category will be 
rounded to the closest valid mRS score and then combined as 5-category. A total of 100 
imputations will be conducted with random seed pre-specified: each result in a complete dataset 
for all subjects. The point and interval estimate of the odds ratio as well as p-value from the 
primary analysis models will be obtained using PROC MIANALYZE. 
The missing data pattern will be evaluated including reasons for missingness, missing data by 
treatment arms and visit, and potential covariates associated with missingness. Supplementary 
analyses will be planned to evaluate the robustness of the primary analysis results (Section 
6.2.4.3).
6.2.3
Secondary Efficacy Endpoints
If the null hypothesis for the primary endpoint is rejected, the secondary efficacy endpoints will 
be tested in the following order in a hierarchical manner at the significance level of 0.05. To 
control the type 1 error rate among the secondary endpoints, a sequential closed testing 
procedure will be used such that if statistical significance is not achieved from an endpoint for a 
comparison, all endpoint(s) of a lower rank for that comparison will not be considered as 
statistically significant.
1. Time to all-cause death over the 90-day period
2. Proportion of subjects who achieved mRS 0-4 at Day 90
3. Midline shift at 72 hours (or at time of DC or CMO, if earlier)


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 6.2.3.1 Time to All-cause Death Over the 90-day Period
Time to all-cause death is defined as the time period from randomization to the time of death. 
For a subject who does not die in Part 1 of the study, time to all-cause death is censored at the 
time when the subject is last known to be alive while in Part 1 of the study. A Cox proportional 
hazards regression model will be used to assess the treatment effect on overall survival at Day 90 
after adjusting for baseline covariates including region, rtPA (yes, no), thrombectomy (yes, no), 
use of ASPECTS for screening (yes, no), and baseline NIHSS (≤20 vs. >20) as covariates. 
Hazard ratio and its 95% confidence interval as well as the p-value will be reported. Kaplan-
Meier curves and estimates will be presented for both treatment groups. Greenwood’s formula 
will be used to calculate the standard error on the Kaplan-Meier estimates (see Section 9 for the 
sample SAS code).
 6.2.3.2 Proportion of Subjects Who Achieved mRS 0-4 at Day 90
A logistic regression model will be used to estimate an odds ratio (and 95% CI) of improvement 
on the mRS dichotomized as 0-4 vs. 5-6 at Day 90.  The model will include region, rtPA (yes, 
no), thrombectomy (yes, no), use of ASPECTS for screening (yes, no), and baseline NIHSS (≤20 
vs. >20) as baseline covariates. Odds ratio, the 95% confidence interval as well as the p-value 
will be reported (see Section 9 for the sample SAS code). Subjects with missing values will be 
assigned with the worst-case value, that is 5-6. 
 6.2.3.3 Midline Shift at 72 Hours (or at Time of DC or CMO, if Earlier)
Analysis of Variance (ANOVA) will be used to compare the two study arms to assess the 
treatment effects on midline shift. The ANOVA will adjust for baseline covariates including 
region, rtPA (yes, no), thrombectomy (yes, no), use of ASPECTS for screening (yes, no) and 
baseline NIHSS (≤20 vs. >20) (see Section 9 for the sample SAS code). Multiple Imputation 
method will be used for missing data imputation, where the imputation model for the missing 
observations in the treatment group and the control group is constructed from the observed data 
in the corresponding group. Only data collected in the [24, 102] hours will be considered for the 
primary analysis. Sensitivity analysis without the time interval constraint will be conducted.
The relationship between midline shift at 72 hours (or DC/CMO if earlier) and mRS at Day 90 
may be explored.
6.2.4
Supportive Efficacy Analyses
6.2.4.1
Per-protocol Analysis
Primary and secondary efficacy endpoints will be analyzed for the per-protocol population with 
the same model for the mITT population. Subjects will be analyzed based on actual treatment 
received in the Per-Protocol analysis. Multiple imputation including only subjects in PP 
population similar as in Section 6.2.2 will be used to account for missing values for the Day 90 
mRS. Multiple imputation including only subjects in PP population similar as in Section 6.2.3.3 
will be used to account for the missing values for the midline shift data.
6.2.4.2
Subgroup Analyses for the Primary Endpoint
Shift in Day 90 mRS will be assessed within different subgroups in the mITT population using 
the ordinal logistic regression. Multiple imputation as in Section 6.2.2 will be used to account for 










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The following AE incidence tables will be provided for the safety population, the safety 
population age ≤70, and safety population age>70 respectively:
1. AEs by system organ class and preferred term sorted by decreasing frequency* 
2. AEs by system organ class and preferred term sorted by alphabetical order  
3. AEs by system organ class, high level group term and preferred term 
4. AEs by system organ class
5. AEs with at least 2% higher in incidence for BIIB093 compared to placebo by system 
organ class and preferred term* 
6. AEs by preferred term 
7. AEs with an incidence of 5% or more in any treatment group by preferred term* 
8. Severe AEs by system organ class and preferred term* 
9. Severe AEs by preferred term 
10. AEs by maximum severity by system organ class and preferred term (System organ class 
will be presented alphabetically. Preferred terms will be presented in decreasing 
frequency order. Maximum severity will be presented within each preferred term in the 
order of mild, moderate, severe, very severe, unknown and total. A subject will be 
counted only once at the maximum severity within each system organ class and preferred 
term.) 
11. AEs by maximum severity by preferred term (Preferred terms will be presented in 
decreasing frequency order. Maximum severity will be presented within each preferred 
term in the order of mild, moderate, severe, very severe, unknown and total. A subject 
will be counted only once at the maximum severity within each preferred term.)
12. Related AEs by system organ class and preferred term* 
13. SAEs by system organ class and preferred term* 
14. SAEs by preferred term 
15. Related SAEs by system organ class and preferred term* 
16. AEs that led to discontinuation of study treatment by system organ class and preferred 
term*
17. AEs that led to withdrawal from study by system organ class and preferred term*
18. SAEs with fatal outcome by system organ class and preferred term*
*Additional descriptive safety summaries will be provided for the BIIB093-dosed subjects by 
BIIB093 formulation respectively.  
The following listings will be provided. 
1. Listing of AEs


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2. Listing of SAEs (including pre-dosing SAEs)
3. Listing of AEs that led to discontinuation of study treatment
4. Listing of AEs that led to withdrawal from study 
5. Listing of deaths
The incidence of treatment-emergent AEs will be summarized by system organ class and 
preferred term for each treatment group by time interval defined as [Day 1, Day 7] and [Day 8, 
end of Part 1].
The number (%) of subjects with recurrent stroke checked by investigators will be summarized 
by treatment group.
6.5.2
Adverse Events of Special Interest
The incidence of adverse events of special interest will also be presented for the safety 
population, the safety population age ≤70, and safety population age>70 respectively. These 
adverse event of special interest categories are defined mainly based on Standardized MedDRA 
Queries (SMQs), SOCs, and/or PTs. The AEs of special interest categories may include but are 
not limited to hypoglycaemia events. Hypoglycaemia events are defined as follows:
•
SMQ of hypoglycaemia (narrow search terms).
Hypoglycaemia events will also be separately summarized by formulation for subjects dosed 
with BIIB093. Hypoglycaemia events will be listed by actual treatment received and BIIB093 
formulation.
6.5.3
Clinical Laboratory Results
Clinical laboratory evaluations include hematology and blood chemistry, which are performed at 
a local laboratory.
o
Hematology:  
•
White blood cells (leukocytes), absolute neutrophil count
•
Red blood cells
•
Hemoglobin
•
Hematocrit
•
Platelet count
o
Blood chemistry: 
•
Liver: alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), total bilirubin, direct bilirubin


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•
Renal: blood urea nitrogen (BUN), creatinine
•
Electrolytes: sodium, potassium, bicarbonate 
•
Other: glucose, calcium, phosphorus, albumin  
Shift analyses
Laboratory abnormalities will be summarized with shift tables. Tables will present changes 
relative to each parameter’s normal ranges. Each subject’s hematology and blood chemistry 
values will be flagged as “low”, “normal”, or “high” relative to the normal ranges of the local 
laboratory or as “unknown” if no result is available. 
Shifts from baseline to high/low status for hematology and blood chemistry parameters will be 
presented. In each summary, the denominator for the percentage is the number of patients at risk 
for the shift. The number at risk for shift to low is the number of subjects whose baseline value 
was not low and who had at least one post-baseline value. The number at risk for shift to high is 
the number of subjects whose baseline value was not high and who had at least one post-baseline 
value. Subjects will be counted only once for each parameter and each type of shift regardless of 
how many post-dosing assessments had that type of shift. Subjects with shift to low or high will 
be listed by laboratory parameter and shift type.
Potentially Clinically Significant laboratory abnormalities analyses
For hematology and blood chemistry, the number of subjects with potentially clinically 
significant laboratory abnormalities post-baseline will be summarized for the parameters 
provided in Table 3. Subjects need to have at least one post-baseline evaluation and a baseline 
value not potentially clinically significant (including missing) to be included in the analysis. 
Table 3. Criteria to Determine Potentially Clinically Significant (PCS) Laboratory 
Abnormalities
Clinical Laboratory Outlier Criteria
Parameter name 
PCS Low
PCS High
HEMATOLOGY 
White blood cells 
<3.0 x 109/L 
>16 x 109/L 
Neutrophils 
<1.5 x 109/L 
>13.5 x 109/L 
Red blood cells 
≤3.5 x 1012/L
≥6.4 x 1012/L
Hemoglobin - Females 
≤95 g/L 
≥175 g/L 
Hemoglobin - Males 
≤115 g/L 
≥190 g/L 
Hematocrit - Females 
≤32% 
≥54% 
Hematocrit - Males 
≤37% 
≥60% 
Platelet count 
≤75 x 109/L
≥700 x 109/L
BLOOD CHEMISTRY 
Alanine aminotransferase (ALT) 
N/A 
>3 x ULN 
Aspartate aminotransferase (AST) 
N/A 
>3 x ULN 
Alkaline phosphatase (ALP)
N/A 
>3 x ULN 


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Clinical Laboratory Outlier Criteria
Parameter name 
PCS Low
PCS High
Total bilirubin 
N/A 
>1.5 x ULN 
Blood urea nitrogen (BUN) 
N/A 
≥10.7 mmol/L 
Creatinine 
N/A 
≥176.8 umol/L 
Sodium 
≤126 mmol/L 
≥156 mmol/L 
Potassium 
≤3 mmol/L 
≥6 mmol/L 
Bicarbonate 
≤16 mmol/L 
≥35 mmol/L 
Glucose 
≤2.2 mmol/L 
≥9.7 mmol/L 
Calcium 
≤2 mmol/L 
≥3 mmol/L 
Phosphorus 
≤0.6 mmol/L 
≥1.7 mmol/L 
Albumin 
≤25 g/L 
≥625 g/L
ULN = upper limit of normal 
By visit summaries
For numeric laboratory parameters, actual values, change from baseline and percent change from 
baseline will be summarized by visit. Number of evaluable subjects, mean, standard deviation, 
25% and 75% quartiles, min and max values will be presented at each visit. 
Plots of mean values (with standard error) for numeric laboratory parameters at each visit will be 
provided. 
Listings of individual laboratory measurements by patients for all the parameters will be 
provided.  
For laboratory by visit summaries, the analysis visit should be defined using visit windows (see 
Table 4 below).  If there is more than 1 value in the same analysis visit window (>1 value for the 
same analysis visit) for a certain parameter for a subject, then the closest record to the target visit 
day will be used for the by visit analysis.  If there are 2 values in the same analysis visit window 
with the same distance from the target visit day for a certain parameter for a subject, then the 
record with the later date will be used for the by visit analysis.  If there are 2 values on the same 
day for a certain parameter for a subject, then the record with the later time will be used for the 
by visit analysis.
Table 4. Visit Windows for Local Lab by Timepoint Summaries
Analysis visit
Target timepoint in hour
Analysis visit window
Baseline
0
Most recent non-missing pre-dose value
Hr 24
24
(0, 36]
Hr 48
48
(36, 60]
Hr 72
72
(60, 96]


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Day 7
168
>96
Analysis visit for blood 
glucose
Target timepoint in hour
Analysis visit window
Baseline
0
Most recent non-missing pre-dose value
Hr 1
1
(0, 1.5]
Hr 2
2
(1.5, 2.5]
…
Hr 23
23
(22.5, 23.5]
Hr 24
23
(23.5, 25]
Hr 26
26
(25, 27]
Hr 28
28
(27, 29]
…
Hr 46
46
(45,47]
Hr 48
48
(47, 50]
Hr 52
52
(50, 54]
Hr 56
56
(54, 58]
Hr 60
60
(58, 62]
Hr 64
64
(62, 66]
Hr 68
68
(66, 70]
Hr 72
72
(70, 96]
Day 7
168
>96
Analysis of blood glucose 
The blood glucose from local laboratory is collected at screening, day 1, day 2, day 3 and day 7 
with the normal ranges. Additionally, the Point-of-Care (POC) blood glucose is collected pre-
dose, hourly for the first 24 hours, every 2 hours for Hour 25-48, and every 4 hours for Hour 49 
to 72 without normal ranges. The normal ranges for POC blood glucose data are assigned with 
70 mg/dl and 139 mg/dl, which are the reference range recommended by the American Diabetes 
Association for random blood glucose measurements. For all the analyses, the two sources of 
data (local laboratory and POC) will be combined and analyzed together.
Summary of lowest post-baseline value of blood glucose will be provided for the safety 
population, the safety population age ≤70, and safety population age>70 respectively. The 


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number (%) of subjects with post-baseline blood glucose abnormalities (<55 mg/dL, <80 mg/dL) 
will be summarized by treatment group for the safety population, the safety population age ≤70, 
and safety population age>70 respectively. Blood glucose values for subjects with post-baseline 
blood glucose <55 mg/d and <70 mg/dL will be listed respectively by actual treatment received 
and BIIB093 formulation.
Analysis of Liver Function Tests
Potential serious hepatotoxicity is defined as ALT or AST > 3× ULN and total bilirubin > 2× 
ULN at any time post-baseline, not necessarily concurrent. A scatterplot of the maximum post-
baseline ALT or AST value relative to ULN and maximum post-baseline total bilirubin value 
relative to ULN (not necessarily concurrent) for each subject will be provided. A line plot of 
ALT, AST, ALP and total bilirubin values over time for subjects with potential serious 
hepatotoxicity will be provided. In addition, a summary of the number and percentages of 
subjects meeting the laboratory abnormality criteria listed below will be provided:
•
ALT > 3×ULN
•
ALT > 5×ULN
•
AST > 3×ULN
•
AST > 5×ULN
•
AST or ALT > 3×ULN
•
AST or ALT > 5×ULN
•
Total Bilirubin > 2×ULN
•
ALP >1.5×ULN
•
AST or ALT ≥3× ULN and Total Bilirubin > 2× ULN
Concurrent is defined as on the same day. A listing of subjects with potential serious 
hepatotoxicity will be provided.
6.5.4
ECG
The number and percentage of subjects with shifts from unknown or normal baseline to 
categorical values (abnormal not AE, or abnormal AE) will be summarized by treatment group 
for the safety population, the safety population age ≤70, and safety population age>70 
respectively. ECG parameters include Heart Rate, PR Interval, RR Interval, QRS Duration, QT 
Interval, QTcF, and QTcB, where QTcB is calculated as QT/(RR/1000)1/2. The actual values and 
change from baseline for each of the ECG parameters will be summarized by treatment group 
and by visit summary. If there are multiple records fall into the same visit windows, the worst 
record will be presented in the summary.


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Table 5. Visit Windows for ECG by Timepoint Summaries
Analysis visit
Target timepoint in hour
Analysis visit window
Baseline
0
Most recent non-missing pre-dose value
Hr 4-6
5
(0, 14.5]
Hr 24
24
(14.5, 36]
Hr 48
48
(36, 60]
Hr 72
72
(60, 96]
Day 7
168
>96
6.5.5
Vital Signs
Vital signs measures include oxygen saturation, heart rate (pulse), respiratory rate, temperature, 
and systolic and diastolic blood pressure. The analysis of vital signs will focus on the incidence 
of clinically relevant abnormalities.  The number of subjects evaluated and the number and 
percentage of subjects with clinically relevant post-baseline abnormalities will be presented by 
treatment group.  Summary statistics for actual values and change from baseline will also be 
presented.  The definitions of these abnormalities for temperature, pulse, and blood pressure 
values are provided in Table 6.
Table 6. Criteria to Determine Clinically Relevant Vital Signs Abnormalities
Vital Sign
Criteria for Abnormalities
Temperature
38C and an increase from pre-dosing of at least 1C
Pulse
120 beats per minute and an increase from pre-dosing 
of more than 20 beats per minute, or 50 beats per 
minute and a decrease from pre-dosing of more than 20 
beats per minute
Systolic Blood Pressure
180 mmHg and an increase from pre-dosing of more 
than 40 mmHg, or 90 mmHg and a decrease from pre-
dosing of more than 30 mmHg
Diastolic Blood Pressure
105 mmHg and an increase from pre-dosing of more 
than 30 mmHg, or 50 mmHg and a decrease from pre-
dosing of more than 20 mmHg
6.6
Interim Analysis
An interim futility analysis may be performed based on the primary endpoint when 
approximately 30% of planned mITT subjects complete Day 90. At the same interim analysis an 
unblinded sample size re-estimation may be performed. The decision whether or not to conduct 
the sample size re-estimation at the interim analysis will be documented by an official 
communication from the study Sponsor to the Independent Data Monitoring Committee (IDMC) 
that will occur within 30 days after randomization of 30% of the planned enrollment has been 


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achieved. The sample size re-estimation employs an approach in which the sample size will be 
increased when the interim results are in the promising zone (Mehta & Pocock 2011). To control 
Type I error after the sample size adaptation, if it occurs, the final hypothesis testing for the 
primary endpoint will be conducted using the CHW method (Cui et al 1999; Mehta and Pocock 
2011) at the significance level of α=0.05 (two-sided). 
Both the futility criteria and the decision rules for the potential sample size re-estimation will be 
based on the calculation of conditional power using the primary endpoint (5-category mRS at 
Day 90). The conditional power based on the treatment effect observed from the interim data is 
calculated using: 
𝐶𝑃= 1 ― Ф
𝑧𝛼
2
𝑛2 ― 𝑧1 𝑛1
𝑛2
― 𝑧1 𝑛2
𝑛1
,     (1)
where 𝑛1 is the sample size at interim (number of subjects in the mITT population included in 
the interim analysis), 𝑛2=654 is the total initially planned sample size for the study, 𝑛2 = 𝑛2 ―
𝑛1 is the sample size after interim and 𝑧1 is the test statistic observed at interim. 
6.6.1
Interim Analysis for Non-Binding Futility
The study may be stopped for futility if the conditional power is too low , 𝐶𝑃< 0.05 based on 
the primary endpoint (5-category mRS at Day 90). This conditional power cut-off is chosen such 
that the chance to stop for futility and the power loss are low under the presumed treatment 
effect, and the chance to stop study early for futility is reasonably high if there is truly no 
treatment effect. The proposed rule for futility is non-binding. In addition to the primary efficacy 
result, the totality of data will be considered, including but not limited to secondary efficacy 
endpoints and consistency of efficacy data over time and across key subgroups. 
6.6.2
Interim Analysis for Sample Size Re-Estimation
The promising zone definition and decision rules for the unblinded sample size re-estimation are 
pre-specified as follows for this study:
•
If the study does not stop for futility (i.e., if CP ≥ 0.05) and CP < 0.43, there will be no 
sample size change, i.e., the trial continues to recruit the original planned sample size 768.
•
If 0.43 <= CP < 0.90, there will be a one-step sample size increase to approximately 1044 
subjects (Age ≤70 population increases to 964 from 688; >70-85 population remains 
approximately 80).
•
If CP ≥ 0.90, there will be no sample size change, i.e., the trial continues to recruit the 
original planned sample size 768.
The upper bound of the promising zone is defined as CP<0.90 to align with the targeted power 
(90%) of the initial sample size 𝑛2. The lower bound of the promising zone 𝐶𝑃𝑚𝑖𝑛 is derived 
using the method described in Mehta & Pocock 2011. 


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To adjust for the sample size adaptation if that occurs, the primary analysis of 5-category mRS at 
Day 90 will use the CHW method (Cui et al 1999; Mehta & Pocock 2011) to preserve the type I 
error. The final CHW test statistic is defined as follows:
𝑍∗
2,𝑐ℎ𝑤=
𝑛1
𝑛2
𝑍1 +
𝑛2
𝑛2
𝑍∗
2
where 𝑛1, 𝑛2, 𝑛2, and Z1 are defined as for equation (1), and 𝑍∗
2 is the incremental Wald test 
statistic based on the independent subjects’ data either observed after or not being used at the 
interim analysis. If sample size is increased but proportional odds assumption does not hold, the 
CHW method with combination of Mann-Whitney test statistics will be used.
An interim analysis will be conducted by a completely independent team and be reviewed by the 
IDMC. IDMC may recommend stopping for futility based on the pre-specified criteria. If the 
interim sample size re-estimation is performed, then the IDMC may recommend a one-step 
sample size increase to approximately 1044 subjects only when the interim results are within the 
promising zone. The hypothesis testing for the primary endpoint will be two-sided at the 
significance level of 0.05 whether the sample size is increased or not. A clear process will 
be specified and implemented to ensure that the blind will be strictly maintained for 
investigators, patients, and sponsor’s study personnel until database lock. Additional details on 
the interim analysis are listed in the Appendix 9.3.
7
STATISTICAL ANALYSES FOR LONG-TERM DATA
7.1
Study Subjects
7.1.1
Accounting of Subjects
Disposition of subjects will be summarized for the ITT population and the summary data will 
include number (%) of subjects randomized and dosed, number (%) of subjects who completed 
the study Part 2, and number (%) of subjects who withdrew from study Part 2.
7.1.2
Protocol Deviations
The major protocol deviations during Part 2 will be summarized and listed for the ITT 
population. The minor protocol deviations will also be listed. All summaries for protocol 
deviations will be presented only by treatment group.
7.2
Efficacy Analyses
7.2.1
General Methods of Analysis


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Table 7. Analysis for Efficacy Endpoints in Part 2
Endpoints
Analysis Method
Analysis Population
SAP Section
mRS at Months 6 and 12
(Ordinal) logistic 
regression/Descriptive 
summary
mITT/
Age Over 70 Population
7.2.2
Time to all-cause death 
over the 1-year period
Cox proportional 
hazards regression 
model/Descriptive 
summary
mITT/
Age Over 70 Population
7.2.3
Barthel index at Months 
6 and 12
Descriptive summary
mITT
Age Over 70 Population
7.2.4
EQ-5D-5L at Months 6 
and 12
Descriptive summary
mITT
Age Over 70 Population
7.2.5
SIS-16 at Months 6 and 
12
Descriptive summary
mITT
Age Over 70 Population
7.2.6
HCRUQ at Month 12
Descriptive summary
mITT
Age Over 70 Population
7.2.7
Zarit Burden Interview 
at Month 12
Descriptive summary
mITT
Age Over 70 Population
7.2.8
7.2.2
Modified Rankin Scale
The mRS at Months 6 and 12 will be analyzed in the mITT population in the same way as Day 
90 mRS using the ordinal logistic regression combining mRS 0/1 and 5/6.  The proportional odds 
ratio assumption will be tested using likelihood ratio test. In the case the assumption does not 
hold, the Mann-Whitney test will be used. The mRS 0-4 versus 5- 6 dichotomizations will also 
be examined using logistic regression. All regression analyses will control for region, rtPA (yes, 
no), thrombectomy (yes, no), use of ASPECTS for screening (yes, no) and baseline NIHSS (≤20 
vs. >20) as baseline covariates.  Odds ratio and the 95% confidence interval will be reported. 
The same model in the mITT population will be used in the Age over 70 population. If the model 
is not applicable, descriptive statistics of observed mRS at Months 6 and 12 in the Age over 70 
population will be provided by time points and by treatment group.


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7.2.3
Time to All-cause Death Over the 1-year Period
Time to all-cause death is defined as the time period from randomization to the time of death. 
For a subject who discontinues and does not die in Part 1 of the study, time to all-cause death is 
censored at the time when the subject is last known to be alive while in Part 1 of the study. For a 
subject who continues and does not die in Part 2 of the study, time to all-cause death is censored 
at the time when the subject is last known to be alive while in Part 2 of the study. A Cox 
proportional hazards regression model will be used to assess the treatment effect on overall 
survival at 1-year in the mITT population after adjusting for region, rtPA (yes, no), 
thrombectomy (yes, no), use of ASPECTS for screening (yes, no), and baseline NIHSS (≤20 vs. 
>20) as baseline covariates. Hazard ratio, 95% confidence interval as well as the p-value will be 
reported. Kaplan-Meier curves and estimates will be presented for both treatment groups. 
Greenwood’s formula will be used to calculate the standard error on the Kaplan-Meier estimates 
(see Section 9 for the sample SAS code).
Kaplan-Meier estimates will be provided for the Age over 70 population.
7.2.4
Barthel Index
Descriptive statistics (mean, median, SD, 25% percentile, 75% percentile, minimum and 
maximum) of observed BI at Months 6 and 12 in the mITT population and in the Age over 70 
population will be provided by time point and by treatment group, respectively. 
7.2.5
Health-related Quality of Life
Summary statistics for the EQ-5D and EQ VAS at Months 6 and 12 will be presented for 
observed data in the mITT population and in the Age over 70 population. 
7.2.6
SIS-16
Descriptive statistics (mean, median, SD, 25% percentile, 75% percentile, minimum and 
maximum) of observed SIS-16 subdomain scores at Months 6 and 12 in the mITT population 
and in the Age over 70 population will be provided by time point and by treatment group, 
respectively.  
 
7.2.7
HCRUQ and Subject’s Current Location
Descriptive summary statistics for observed HCRUQ at Month 12 in the mITT population and in 
the Age over 70 population will be presented by treatment group, respectively.
Subject’s current location (e.g., hospice, nursing home, rehabilitation facility, home) will be 
summarized at each visit (month 6 and month 12).
7.2.8
Zarit Burden Interview
Descriptive summary statistics for observed Zarit Burden Interview total score at Month 12 in 
the mITT population and in the Age over 70 population will be presented by treatment group, 
respectively.


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7.3
Safety Analyses
7.3.1
Serious Adverse Events
All treatment-emergent SAEs during part 1 and part 2 will be evaluated for safety on the safety 
population and on the safety population age ≤70, respectively. The incidence of treatment-
emergent SAEs will be summarized for each treatment group overall, by severity, and by 
relationship to study drug. The summary tables will include incidence estimates for overall 
system organ classes, as well as for individual events within each system organ class.
Additionally, selected analyses will be provided for the safety population age >70.
Listing of SAEs and deaths during part 2 will be provided.
8
Changes from the Protocol Defined Analyses 
The company decided to terminate the study. The analysis populations will now include data 
from China (Protocol V3.5) along with ROW (Protocol V3.0). Data from China will be included 
in Region 3.
9
References
Cui L, Hung HM, Wang SJ. 1999. Modification of sample size in group sequential clinical trials. 
Biometrics; 55:853--857. 
Mehta CR, Pocock SJ. 2011. Adaptive increase in sample size when interim results are 
promising: A practical guide with examples. Statistics in Medicine. 30: 3267-3284.
10 Appendix


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10.1 Schedule of Activities
Table 8. Schedule of Activities – Part 1 (Screening through Day 90) 
Screening
/
Enroll-
ment
Hrs 
>0-12
Hr 24
(±12h)
Hr 48
(±12h)
Hr 72
(±12h)
Day 7
(±24h)/
Hospital
Discharge
Day 30
(±7 d)
Telephone/
Telemedicine
Visit
Day 90
(±14 d)1
In-person
Visit
Preferred
Craniectomy
/Comfort 
Care (if
Applicable)
Early
Term.
Visit2
Inclusion/exclusion 
criteria
X
-
-
-
-
-
-
-
-
-
Informed consent
X
-
-
-
-
-
-
-
-
-
Demographics, medical 
history, physical 
examination (including 
height and weight), 
rtPA/thrombectomy 
status3
X
-
-
-
-
-
-
-
-
-
Time of symptoms onset 
or if unknown, last 
known normal
X
-
-
-
-
-
-
-
-
-
Imaging 
(MRI/CTP/NCCT) for 
lesion size or ASPECTS 
estimation4
X
-
-
-
-
-
-
-
-
-
Pregnancy test
X
-
-
-
-
-
-
-
-
-
NIHSS5
X
Clinical laboratory 
samples (hematology, 
blood chemistry)6,7
X
-
X
X
X
X
-
-
-
X8
Vital signs9
X
-
X
X
X
X
-
-
-
X8
12-lead ECG7,10
X
Hr 4-6
X
X
X
X
-
-
-
X8
Enrollment/
Randomization11
X
-
-
-
-
-
-
-
-
-
Craniectomy/comfort 
care/cranioplasty 
assessment form(s)
-
-
-
-
-
-
-
-
X
-
Pharmacogenetic sample 
(optional)
-
after infusion start but before hosp. discharge
-
-
-
-
Study Treatment
Administration
-
……72-hr infusion……
-
-
-
-
-
Blood glucose
measurement12
X
X
X
X
X
X
-
-
-
-






252LH301 Statistical Analysis Plan 
Table 9. Schedule of Activities – Part 2 (Day 91 through Month 12)
Month 6 (± 30 days)
Telephone/Telemedicine Visit1
Month 12 (± 30 days)
Telephone/Telemedicine Visit1
mRS
X
X
Subject disposition2
X
 X
EQ-5D-5L, BI, SIS-16
X
X
HCRUQ, Zarit
-
X
SAEs
X
X
BI = Barthel Index; EQ-5D-5L = EuroQol 5-level assessment of health outcome; HCRUQ = HealthCare Resource Utilization Questionnaire; mRS = modified Rankin Scale; 
SIS-16 = Stroke Impact Scale 16 Questions, Zarit = Zarit Burden Interview.
1 In-person clinic visits may be conducted at the study subject’s/representative’s request.
2 Subject disposition: location (e.g., hospice, nursing home, rehabilitation facility, home), level of rehabilitation, and if death occurred, the primary cause of 
death and date and time of death will be recorded. Brain death and death associated with withdrawal of care must be documented. 


252LH301 Statistical Analysis Plan 
10.2  Sample SAS Code 
The following SAS code (sas version 13.2 and later) illustrated the key SAS procedures to be 
used for the primary and secondary analyses. This section is not meant to provide the 
comprehensive list all SAS codes to be used under the definition of this SAP. The data set and 
variable names are examples for illustration purposes and do not represent the actual submission-
ready data formats.
Note: TRT01P = “Placebo” or “BIIB093”; Region, rtPA, thrombectomy, ASPECTS, NIHSS are 
categorical variables defined per SAP.
10.2.1 Primary Endpoint – 5-Category mRS at Day 90: 
The primary endpoint of mRS as 5-category ordinal scale (0/1, 2, 3, 4, 5/6) at Day 90 will be 
analyzed using the following ordinal logistic regression (proportional odds model), adjusting for 
baseline covariates including region, rtPA (yes, no), thrombectomy (yes, no), use of ASPECTS 
for screening (yes, no), and baseline NIHSS (≤20 vs. >20).  Odds ratio, the 95% confidence 
interval as well as the p-value will be reported.
proc logistic data=ADMRS; *Ordinal Logistic Regression
class TRT01P (ref="Placebo") region rtPA thrombectomy ASPECTS NIHSS/ 
param=ref order=data; * data that is ordered as the last/highest mRS 
class value will be the reference level. The odds ratio is then the 
odds for being lower (than reference) mRS compared to placebo.;
model aval=TRT01P region rtPA thrombectomy ASPECTS NIHSS/ clodds=wald;
where avisit="Day 90" and mITT="Y";
run;
The proportional odds ratio assumption will be tested using the following likelihood ratio test 
between the proportional odds model and the logistic regression model with nonproportional 
odds for treatment group effect.
 %macro LRTest(data=dsname,model1=,model2=,class=,freq=,print=1);                  
/*--------------------------------------------------------------------
  Computes the likelihood ratio test between the two models.  Small p-
values mean the extra parameters in the larger model significantly 
describe some variation in the data.  Called by the %LRTestCycle 
macro.
  data=   name of the input data set. 
  model1= the MODEL statement for the first model without the word 
'MODEL'. 
  model2= the MODEL statement for the 2nd model. 
  class=  the CLASS statement without the word 'CLASS'. 
  freq=   name of the FREQ variable, if there is one 
  print=  1=print the test results
  ------------------------------------------------------------------*/ 
proc logistic data=&data; *Will use proportional odds model;
   %if (%length(&class)>0) %then class &class;;                                   
   model &model1; 


252LH301 Statistical Analysis Plan
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    %if (%length(&freq)>0) %then freq &freq;;                                     
   ods select globaltests;  
   ods output globaltests=temp1; 
proc logistic data=&data; *Will use nonproportional odds for treatment 
group;
   %if (%length(&class)>0) %then class &class;;                                   
   model &model2; 
    %if (%length(&freq)>0) %then freq &freq;;                                     
   ods select globaltests; 
   ods output globaltests=temp2; 
data temp2; 
   set temp2; 
   ChiSq2=ChiSq; 
   DF2=DF; 
data temp; 
   merge temp2 temp1; 
   where Test='Likelihood Ratio'; 
   keep Chisq DF P; 
   ChiSq=abs(ChiSq2-ChiSq); 
   DF= abs(DF2-DF); 
   if (DF^=0) then P=1-probchi(ChiSq,DF);  
   else P=.; 
run; 
%if %eval(&print eq 1) %then %do; 
proc print data=temp noobs; 
   var DF ChiSq P; 
run; 
%end; 
%mend; 
   
%LRTest(data=ADMRS,model1=aval=TRT01P region rtPA thrombectomy ASPECTS 
NIHSS/ clodds=wald,model2=aval=TRT01P region rtPA thrombectomy ASPECTS 
NIHSS/ clodds=wald unequalslopes=TRT01P,class=TRT01P (ref="Placebo") 
region rtPA thrombectomy ASPECTS NIHSS/ param=ref order=data,print=1);
Mann-Whitney test
proc NPAR1WAY data=ADMRS wilcoxon; 
class TRT01P;
var AVAL;
exact wilcoxon;
where avisit="Day 90" and mITTFL="Y";
run;
10.2.2 Secondary Endpoint – Time to all-cause death over the 90-day period
Cox proportional hazards regression model will be used to assess the treatment effect on overall 
survival at Day 90 after adjusting for region, rtPA (yes, no), thrombectomy (yes, no), use of 
ASPECTS for screening (yes, no), and baseline NIHSS (≤20 vs. >20) as baseline covariates. 
Hazard ratio, 95% confidence interval as well as the p-value will be reported.


252LH301 Statistical Analysis Plan
Confidential. Biogen
proc phreg data=Death90;
class TRT01P (ref = 'Placebo') region rtPA thrombectomy ASPECTS NIHSS;
model aval*ddfl(0)=TRT01P region rtPA thrombectomy ASPECTS 
NIHSS/alpha=0.05 rl=both;
where mITTFL="Y";
title "Cox model on mortality by Day 90";
run;
Note: aval represents time at death; ddfl = 0 indicates censoring;
10.2.3 Secondary Endpoint – Proportion of subjects who achieved mRS 0-4 at Day 90
A logistic regression model will be used to estimate an odds ratio (and 95% CI) of improvement 
on the mRS dichotomized as 0-4 vs. 5-6 at Day 90.  The model will include region, rtPA (yes, 
no), thrombectomy (yes, no), use of ASPECTS for screening (yes, no), and baseline NIHSS (≤20 
vs. >20) as baseline covariates. Odds ratio, the 95% confidence interval as well as the p-value 
will be reported.
proc logistic data=ADMRS04; *Logistic Regression
class TRT01P (ref="Placebo") region rtPA thrombectomy ASPECTS NIHSS/ 
param=ref order=data; * data that is ordered as the last/highest mRS 
class value will be the reference level. The odds ratio is then the 
odds for being lower (than reference) mRS compared to placebo.;
model aval=TRT01P region rtPA thrombectomy ASPECTS NIHSS/ clodds=wald;
 where avisit="Day 90" and mITT="Y";
run;
10.2.4 Secondary Endpoint – Midline Shift at 72 hours (or at time of DC or CMO, if earlier)
Analysis of Variance (ANOVA) will be used to compare the two study arms to assess the 
treatment effects on midline shift. The ANOVA will adjust for baseline covariates including 
region, rtPA (yes, no), thrombectomy (yes, no), use of ASPECTS for screening (yes, no) and 
baseline NIHSS (≤20 vs. >20)
proc glm data=ADMLS outstat=contrasts (where=(_type_='CONTRAST')) 
;*noprint;
class TRT01P region rtPA thrombectomy ASPECTS NIHSS;
model AVAL = TRT01P region rtPA thrombectomy ASPECTS NIHSS;
run;
10.2.5 Multiple Imputation for Primary Endpoint – 5-Category mRS at Day 90: 
The primary endpoint of mRS as 5-category ordinal scale (0/1, 2, 3, 4, 5/6) at Day 90 will be 
analyzed using ordinal logistic regression (proportional odds model), adjusting for covariates 
including region, rtPA (yes, no), thrombectomy (yes, no), use of ASPECTS for screening (yes, 
no), and baseline NIHSS (≤20 vs. >20).
Multiple imputation will be used to handle missing data. The missing mRS values will be 
imputed by a regression model with independent variables including Day 30 mRS, region, rtPA 
(yes, no), thrombectomy (yes, no), use of ASPECTS for screening (yes, no), and baseline NIHSS 


252LH301 Statistical Analysis Plan
Confidential. Biogen
(≤20 vs. >20). The predicted values will be rounded to the closest valid mRS score. 100 
completed datasets will be created and saved in a dataset named outmi. The proportional odds 
model (described above) will be run for each dataset. The parameter estimates and standard 
errors from 100 datasets will be combined (PROC MIANALYZE).
proc mi data=ADMRS noprint out=outmi nimpute=100 seed=201912; 
class TRT01P region rtPA thrombectomy ASPECTS NIHSS; 
fcs reg (mRS90=mRS30 TRT01P region rtPA thrombectomy ASPECTS NIHSS ); 
var mRS30 mRS90 TRT01P region rtPA thrombectomy ASPECTS NIHSS; /*mRS30 
and mRS90 are the mRS scores at Day30 and Day90*/
run;
data outmit;
set outmit;
mRS90=round(mRS90,1);
run;
proc sort data=outmi; by impnum;run;
proc logistic data=outmi; 
class TRT01P (ref="Placebo") region rtPA thrombectomy ASPECTS NIHSS/ 
param=ref order=data; 
model aval=TRT01P region rtPA thrombectomy ASPECTS NIHSS/ clodds=wald;
ods output ParameterEstimates=est;
where avisit="Day 90" and mITT="Y";
by impnum;
run;
proc mianalyze data=est;
ods output PARAMETERESTIMATES=stat;
modeleffects Estimate;
stderr  stderr;
run;


252LH301 Statistical Analysis Plan
Confidential. Biogen


Signature Page
Document Name: 252LH301 Statistical Analysis Plan v3.0
Document Title:
Signed by
Role
Date / Time (UTC)
Signing as Author
11-Jul-2023 07:44:35
Signing as Approver
11-Jul-2023 11:54:31
Signing as Reviewer
11-Jul-2023 12:57:49