Clinical trial NCT03954041
Conditions: Brain Contusion
Sponsor: Remedy Pharmaceuticals, Inc.
Start date: 2019-10-06; Completion date: 2023-06-27
Enrollment: 92 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to determine if BIIB093 reduces brain contusion expansion by Hour 96 when compared to placebo.

The secondary objectives are to evaluate the effects of BIIB093 on acute neurologic status, functional outcomes, and treatment requirements, to further differentiate the mechanism of action of BIIB093 on contusion expansion by examining differential effects on hematoma and edema expansion, and to determine if BIIB093 improves survival at Day 90 when compared to placebo.

Detailed description:

Arms: arm 1: Participants will be administered BIIB093 3 milligrams per day (mg/day) as a IV bolus followed by rapid and slow intravenous (IV) infusions for 96 hours. arm 2: Participants will be administered BIIB093 5 mg/day as a IV bolus followed by rapid and slow IV infusions for 96 hours. arm 3: Participants will be administered BIIB093 matching placebo as a IV bolus followed by rapid and slow IV infusions for 96 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: 
COVER PAGE 
Official Title: 
A Multicenter, Double-Blind, Multidose, Placebo-Controlled, 
Randomized, Parallel-Group, Phase 2 Study to Evaluate the Efficacy 
and Safety of Intravenous BIIB093 for Patients with Brain Contusion 
NCT Number: 
NCT03954041 
Document Date: 
Protocol Version 3.0: 14 Nov 2022 
 
 


 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
1 
 
 
 
 
 
 
Biogen MA Inc. 
225 Binney Street 
Cambridge, MA  02142 
United States 
 
PROTOCOL NUMBER: 
252BN201 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
 
PHASE OF DEVELOPMENT: 
2 
 
 
PROTOCOL TITLE:  A Multicenter, Double-Blind, Multidose, Placebo-Controlled, 
Randomized, Parallel-Group, Phase 2 Study to Evaluate the Efficacy and Safety of 
Intravenous BIIB093 for Patients with Brain Contusion 
 
 
EUDRA CT NUMBER: 
2018-003858-24 
 
 
DATE: 
14 November 2022 
Version 3 
FINAL 
 
Supersedes previous Version 2 dated 18 February 2020 
 
 
 


Protocol 252BN201 
Version 3 
Phase 2 Efficacy and Safety Study of BIIB093 in Brain Contusion 
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2 
SPONSOR SIGNATURE PAGE 
 
Protocol 252BN201 was approved by: 
 
 
__________________________________________ 
 
______________________ 
 MD 
Date 
  
 
Biogen 


Protocol 252BN201 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................9 
1. 
SYNOPSIS ....................................................................................................................10 
2. 
LIST OF ABBREVIATIONS .......................................................................................14 
3. 
SPONSOR INFORMATION ........................................................................................16 
4. 
INTRODUCTION ........................................................................................................17 
4.1. 
Brain Contusion Background ........................................................................................17 
4.2. 
Current Therapies for Brain Contusion .........................................................................17 
4.3. 
Profile of Previous Experience With BIIB093..............................................................18 
4.3.1. 
Nonclinical Experience .................................................................................................18 
4.3.2. 
Clinical Experience .......................................................................................................18 
4.3.3. 
Benefit/Risk ..................................................................................................................19 
4.4. 
Study Rationale .............................................................................................................20 
4.5. 
Dosing Rationale ...........................................................................................................21 
4.5.1. 
Dosing Regimen ............................................................................................................21 
4.5.1.1. 
Selection of 3 mg/day ...................................................................................................21 
4.5.1.2. 
Selection of 5 mg/day ...................................................................................................22 
4.5.1.3. 
IV Infusion Duration .....................................................................................................23 
5. 
SCHEDULE OF ACTIVITIES .....................................................................................24 
6. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................29 
7. 
STUDY DESIGN ..........................................................................................................32 
7.1. 
Study Overview .............................................................................................................32 
7.2. 
Study Duration for Participants .....................................................................................33 
7.3. 
Responsibilities of Site Staff .........................................................................................33 
7.4. 
Study Stopping Rules ....................................................................................................34 
7.5. 
End of Study ..................................................................................................................34 
8. 
SELECTION OF PARTICIPANTS ..............................................................................35 
8.1. 
Inclusion Criteria ...........................................................................................................35 
8.2. 
Exclusion Criteria..........................................................................................................36 


Protocol 252BN201 
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9. 
SCREENING AND RANDOMIZATION ....................................................................40 
9.1. 
Screening .......................................................................................................................40 
9.2. 
Randomization ..............................................................................................................40 
9.3. 
Blinding Procedures ......................................................................................................41 
10. 
DISCONTINUATION OF STUDY TREATMENT AND WITHDRAWAL 
OF PARTICIPANTS FROM THE STUDY .................................................................42 
10.1. 
Discontinuation of Study Treatment .............................................................................42 
10.2. 
Lost to Follow-Up .........................................................................................................43 
10.3. 
Withdrawal of Participants From Study ........................................................................43 
11. 
STUDY TREATMENT USE ........................................................................................45 
11.1. 
Regimen ........................................................................................................................45 
11.2. 
Modification of Dose and/or Treatment Schedule ........................................................46 
11.3. 
Precautions ....................................................................................................................46 
11.4. 
Concomitant Therapy and Procedures ..........................................................................46 
11.4.1. 
Concomitant Therapy ....................................................................................................46 
11.4.1.1. Allowed Concomitant Therapy .....................................................................................47 
11.4.1.2. Disallowed Concomitant Therapy ................................................................................50 
11.4.2. 
Concomitant Procedures ...............................................................................................50 
11.4.2.1. Neurosurgical Intervention ...........................................................................................50 
11.4.2.2. Intubation ......................................................................................................................50 
11.5. 
Continuation of Treatment ............................................................................................51 
12. 
STUDY TREATMENT MANAGEMENT ..................................................................52 
12.1. 
BIIB093 .........................................................................................................................52 
12.1.1. 
BIIB093 Preparation .....................................................................................................52 
12.1.2. 
BIIB093 Storage ...........................................................................................................53 
12.1.3. 
BIIB093 Handling and Disposal ...................................................................................53 
12.1.4. 
BIIB093 Accountability ................................................................................................53 
12.2. 
Placebo ..........................................................................................................................53 
13. 
EFFICACY, 
, 
PHARMACOGENETIC, AND GENETIC ASSESSMENTS .....................................54 
13.1. 
Clinical Efficacy Assessments ......................................................................................54 
 
 
 
 


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13.4. 
Pharmacogenetic and Genetic Assessments..................................................................55 
13.5. 
Other Assessments: Patient Outcome Measures ...........................................................56 
14. 
SAFETY ASSESSMENTS ...........................................................................................57 
14.1. 
Clinical Safety Assessments .........................................................................................57 
14.2. 
Laboratory Safety Assessments ....................................................................................57 
14.3. 
Product-Specific Safety Assessments ...........................................................................58 
15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES ....................................................................................................59 
15.1. 
Definitions .....................................................................................................................59 
15.1.1. 
Adverse Event ...............................................................................................................59 
15.1.2. 
Serious Adverse Event ..................................................................................................59 
15.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ..................60 
15.2. 
Safety Classifications ....................................................................................................60 
15.2.1. 
Investigator Assessment of Events................................................................................60 
15.2.2. 
Relationship of Events to Study Treatment ..................................................................60 
15.2.3. 
Severity of Events .........................................................................................................61 
15.2.4. 
Expectedness of Events .................................................................................................61 
15.3. 
Monitoring and Recording Events ................................................................................61 
15.3.1. 
Adverse Events .............................................................................................................61 
15.3.2. 
Adverse Events of Special Interest ...............................................................................62 
15.3.3. 
Serious Adverse Events.................................................................................................62 
15.3.4. 
Immediate Reporting of Serious Adverse Events .........................................................62 
15.3.4.1. Deaths ............................................................................................................................63 
15.3.5. 
Suspected Unexpected Serious Adverse Reactions ......................................................63 
15.4. 
Procedures for Handling Special Situations ..................................................................63 
15.4.1. 
Pregnancy ......................................................................................................................63 
15.4.2. 
Overdose .......................................................................................................................63 
15.4.3. 
Medical Emergency ......................................................................................................64 
15.4.3.1. Unblinding for Medical Emergency..............................................................................64 
15.5. 
Contraception Requirements .........................................................................................64 
15.6. 
Safety Responsibilities ..................................................................................................65 
15.6.1. 
The Investigator ............................................................................................................65 


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15.6.2. 
Biogen ...........................................................................................................................66 
16. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE .............67 
16.1. 
Demography and Baseline Disease Characteristics ......................................................67 
16.2. 
Efficacy .........................................................................................................................67 
16.2.1. 
Analysis Population ......................................................................................................67 
16.2.2. 
Methods of Analysis .....................................................................................................67 
16.2.2.1. General Considerations .................................................................................................67 
16.2.2.2. Analysis of the Primary Endpoint .................................................................................68 
16.2.2.3. Analysis of the Secondary Endpoints ...........................................................................68 
 
 
 
 
 
 
 
 
 
 
 
 
16.5. 
Pharmacogenetics ..........................................................................................................70 
16.6. 
Safety ............................................................................................................................70 
16.6.1. 
Analysis Population ......................................................................................................70 
16.6.2. 
Methods of Analysis .....................................................................................................70 
16.6.2.1. Adverse Events .............................................................................................................70 
16.6.2.2. Clinical Laboratory Results ..........................................................................................71 
16.6.2.3. ECG ...............................................................................................................................71 
16.6.2.4. Vital Signs .....................................................................................................................71 
16.7. 
Interim Analyses ...........................................................................................................72 
16.8. 
Sample Size Considerations ..........................................................................................72 
17. 
ETHICAL REQUIREMENTS ......................................................................................73 
17.1. 
Declaration of Helsinki .................................................................................................73 
17.2. 
Ethics Committee ..........................................................................................................73 
17.3. 
Participant Information and Consent ............................................................................74 
17.4. 
Participant Data Protection ...........................................................................................74 
17.5. 
Compensation for Injury ...............................................................................................75 
17.6. 
Conflict of Interest ........................................................................................................75 


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17.7. 
Registration of Study and Disclosure of Study Results ................................................75 
18. 
ADMINISTRATIVE PROCEDURES .........................................................................76 
18.1. 
Study Site Initiation ......................................................................................................76 
18.2. 
Quality Control and Quality Assurance ........................................................................76 
18.3. 
Monitoring of the Study ................................................................................................76 
18.4. 
Study Funding ...............................................................................................................77 
18.5. 
Publications ...................................................................................................................77 
19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ..........................78 
19.1. 
External Contract Organizations ...................................................................................78 
19.1.1. 
Contract Research Organization ...................................................................................78 
19.1.2. 
Interactive Response Technology .................................................................................78 
19.1.3. 
Electronic or Remote Data Capture ..............................................................................78 
19.1.4. 
Central Laboratories for 
 Pharmacogenetic (as applicable) 
Assessments ..................................................................................................................78 
19.1.5. 
Central Facility for Imaging Assessments ....................................................................78 
19.2. 
Study Committees .........................................................................................................79 
19.2.1. 
Advisory Committee .....................................................................................................79 
19.2.2. 
Independent Data Monitoring Committee ....................................................................79 
19.3. 
Changes to Final Study Protocol ...................................................................................79 
19.4. 
Ethics Committee Notification of Study Completion or Termination ..........................79 
19.5. 
Retention of Study Data ................................................................................................79 
19.6. 
Study Report Signatory .................................................................................................80 
20. 
REFERENCES ..............................................................................................................81 
APPENDIX 1. MEDICATIONS THAT MODULATE CYP2C9 AND CYP3A4 .....................84 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL ...........................................86 
 


Protocol 252BN201 
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LIST OF TABLES 
Table 1: 
BIIB093 Dosing Regimen ..........................................................................................21 
Table 2: 
Schedule of Activities .................................................................................................25 
Table 3: 
ECG, 
 Schedule of Activities .......................................................28 
Table 4: 
Dose Modification Schedule .......................................................................................46 
Table 5: 
Blood Glucose Monitoring and Management .............................................................48 
Table 6: 
Criteria to Determine Clinically Relevant Vital Signs Abnormalities .......................71 
 
 


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LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................33 
 


Protocol 252BN201 
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1. 
SYNOPSIS 
Protocol Title: 
A Multicenter, Double-Blind, Multidose, Placebo-Controlled, 
Randomized, Parallel-Group, Phase 2 Study to Evaluate the Efficacy 
and Safety of Intravenous BIIB093 for Patients with Brain Contusion. 
Protocol Number: 
252BN201 
Version Number: 
3 
Name of Study 
Treatment: 
BIIB093 
Study Phase: 
2 
Study Indication: 
Brain Contusion 
Study Rationale: 
Brain contusion is a devastating public health problem with no 
approved pharmacologic treatment to stop or slow the progression of 
the lesion following the initial trauma. Delayed progression of bleeding 
into the brain is known as the hemorrhagic progression of contusion 
(HPC). This expansion leads not only to an increase in hematoma 
volume, but also to the evolution of perihematomal edema surrounding 
the lesion itself. 
Sulfonylurea receptor 1-transient receptor potential melastatin 4 
(SUR1-TRPM4) is a cation channel, upregulated in human 
pericontusional endothelium and astrocytes that allows for harmful 
osmotic cell swelling under adenosine triphosphate-depleted 
conditions. Increased osmotic flux via the channel leads to the lysis of 
endothelial cells and the loss of capillary structural integrity. This 
results in the extravasation of blood, and the resultant expansion of the 
initial contusion. Moreover, loss of capillary structure permits the 
development of perihematomal vasogenic edema. Lastly, SUR1TRPM4 
also mediates cytotoxic edema, a further sequela worsening contusion 
progression. BIIB093 explicitly targets the SUR1-TRPM4 channel and 
mitigates HPC in animal models of brain and spinal cord contusion. 
BIIB093 has also repeatedly demonstrated anti-perihematomal edema 
effects in nonclinical models. 
The aim of this study is to provide evidence that BIIB093 reduces the 
progression of intracerebral hematoma and contusions in individuals 
who experience brain contusion, by antagonizing SUR1-TRPM4. 


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Study Objectives 
and Endpoints: 
The primary objective of the study is to determine if BIIB093 reduces 
brain contusion expansion by Hour 96 when compared to placebo. 
Measurements of contusion expansion are based on a comparison of the 
baseline images and the scans collected prior to and including the 
96-hour scan, or the scan obtained prior to decompressive craniectomy 
(DC), intraparenchymal hematoma (IPH) evacuation, or comfort 
measures only (CMO), if earlier.  
The primary endpoint as measured by brain imaging, is the 
change in total contusion volume (hematoma plus 
perihematomal edema) from baseline to 96 hours, or prior to 
DC, IPH evacuation, or CMO if these procedures occur before 
96 hours.  
Secondary objectives and endpoints for the study are as follows: 
• To evaluate the effects of BIIB093 on acute neurologic status, 
functional outcomes, and treatment requirements. 
o Glasgow Outcome Scale – Extended (GOS-E) at Day 180 
o Modified Rankin Scale (mRS) at Day 90 
o Proportion of participants requiring delayed intubation 
Note: delayed intubation is defined as participants requiring 
intubation (for neurologic deterioration only) at any time 
between 24 hours and 96 hours post injury. 
• To further differentiate the mechanism of action of BIIB093 
compared to placebo on contusion expansion by examining 
differential effects on hematoma and edema expansion. 
o Change in total contusion volume (hematoma plus 
perihematomal edema) as measured by brain imaging from 
baseline to 24 hours or prior to DC, IPH evacuation, or 
CMO if these procedures occur before 24 hours per the 
central review. 
o Change in absolute hematoma volume from baseline to 24 
hours 
o Change in absolute edema volume from baseline to 96 hours 
• To determine if BIIB093 improves survival at Day 90 when 
compared to placebo. 


Protocol 252BN201 
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o Time to all-cause death, including neurological death, 
through Day 90 
 
 
Study Design: 
This is a Phase 2, randomized, multicenter, double-blind, multidose, 
placebo-controlled study. 
Study Location: 
Approximately 60 sites in 7 countries globally are planned.  
Number of 
Planned 
Participants: 
Approximately 160 participants will be randomized. 
Study Population: 
This study will be conducted in participants aged 18 to 85 years old, 
inclusive, with a diagnosis of brain contusion, with lesions within the 
supratentorial brain parenchyma totaling > 3 mL in volume per 
Investigator assessment of baseline noncontrast computed tomography 
scan at Screening or site local radiologic assessment. Participants must 
have a score of 5 to 15 on the Glasgow Coma Scale (GCS) and have 
been functionally independent, in the opinion of the Investigator, prior 
to index head injury. 
Detailed criteria are described in Section 8. 
Treatment Groups: 
All participants must be dosed within 10 hours of time of trauma/last 
known normal (LKN) and within 6 hours of hospital arrival. Dosing 
should be initiated within 1 hour of randomization and continue for 96 
hours (4 days). Participants will receive study treatment (3 mg/day or 
5 mg/day) or matching placebo administered as a 3-stage continuous 
infusion: a bolus IV dose (given over 2 minutes), followed by 2 
different infusion rates (a rapid IV infusion for 6 hours followed by a 
slow IV infusion for the remaining 90 hours) for 96 hours total. 
Participants will be randomly assigned to 3 mg/day study treatment, 
5 mg/day study treatment, 3 mg/day matching placebo, or 5 mg/day 
matching placebo in a 1:1:1:1 ratio, stratified based on baseline 
contusion volume per Investigator assessment of noncontrast computed 
tomography scan or site local radiologic assessment (3 to 10 mL or 
> 10 mL), baseline GCS (5 to 8, 9 to 12, or 13 to 15), age (≤ 70 years 
old or > 70 years old), and region (North America [United States] or 
Rest of World). 


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Duration of 
Treatment and 
Follow-up: 
The study treatment or matching placebo will be administered for 
96 hours (4 days) in total. All participants will be followed up for 
functional outcome measures at Day 90 and Day 180. 


Protocol 252BN201 
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Phase 2 Efficacy and Safety Study of BIIB093 in Brain Contusion 
 
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2. 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BG 
blood glucose 
CI 
confidence interval 
CMO 
comfort measures only 
COVID-19 
Coronavirus disease 2019 
CRO 
contract research organization 
Css 
concentration at steady state 
CYP 
cytochrome P450 
DC 
decompressive craniectomy 
DHA 
Directions for Handling and Administration 
DWI 
diffusion-weighted imaging 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
early termination 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
GOS-E 
Glasgow Outcome Scale – Extended 
HPC 
hemorrhagic progression of contusion 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICL 
imaging core laboratory 
ICU 
intensive care unit 
IDMC 
independent data monitoring committee 
INR 
international normalized ratio 
IPH 
intraparenchymal hematoma 
IRT 
interactive response technology 
IV 
intravenous 
LAR 
legally authorized representative 
LHI 
large hemispheric infarction 
LKN 
last known normal 
MMP-9 
matrix metalloprotease-9 
MRI 
magnetic resonance imaging 
mRS 
modified Rankin Scale 
NCCT 
noncontrast computed tomography 
NOAC 
novel oral anticoagulants 
NSx 
neurosurgical intervention 
OATP 
organic anion transporting polypeptide 


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PD 
pharmacodynamics 
 
 
POC 
point-of-care 
PTT 
partial thromboplastin time 
PVC 
polymerizing vinyl chloride 
QTc 
QT interval corrected for heart rate 
rtPA 
recombinant tissue plasminogen activator 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
standard of care 
SUR1-TRPM4 
sulfonylurea receptor 1-transient receptor potential melastatin 4 
channel 
SUSAR 
suspected unexpected serious adverse reaction 
TBI 
traumatic brain injury 
ULN 
upper limit of normal 


Protocol 252BN201 
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Phase 2 Efficacy and Safety Study of BIIB093 in Brain Contusion 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
16 
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 study Medical Director 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. 


Protocol 252BN201 
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4. 
INTRODUCTION  
4.1. 
Brain Contusion Background 
Hemorrhagic lesions following trauma to the brain, which are referred to as contusions, may 
cause significant long-term morbidity and mortality. Bleeding into the brain parenchyma is 
problematic, due not only to the mass effect of a hematoma on intracranial pressure and 
associated brain herniation with compression of vital neurologic centers, but also to the 
neurotoxicity of hemoglobin [Kurland 2012]. 
In addition to the initial bleed following trauma, contusions often progress in size during the 
acute hospitalization period, significantly worsening prognosis. The delayed progression of 
bleeding into the brain is known as the hemorrhagic progression of contusion (HPC), or 
“blossoming” [Kurland 2012]. This expansion leads not only to an increase in hematoma 
volume, but also to the evolution of perihematomal edema surrounding the lesion itself. Both 
sequelae cause significant secondary brain injury. The prognosis for patients with traumatic brain 
injury (TBI) is often poor, with case fatality of up to 56%, and is worse for patients with HPC 
[OʼNeil-Pirozzi 2018; Song 2016]. 
Progression of contusions are largely a function of the initial contusion volume, although other 
factors also contribute. Use of traditional and novel anticoagulants, antiplatelet agents, 
coagulopathy, age, and uncontrolled hypertension are all thought to contribute to some degree 
and are routinely controlled as part of clinical practice. Other processes that contribute to the 
progression of a contusion are analogous to the dysfunction of the cerebral microvasculature. 
Microvascular impairment, caused primarily by endothelial cell swelling and fragmentation, 
worsens hematoma expansion via the ongoing extravasation of blood into the brain parenchyma. 
In addition to ongoing bleeding, endothelial cell breakdown also permits the formation of 
perihematomal edema by extravasation of endovascular fluids into the brain’s interstitium. 
[Kurland 2012; Park 2008]. 
4.2. 
Current Therapies for Brain Contusion 
Brain contusion is a devastating public health problem with no approved pharmacologic 
treatment to stop or slow the progression of lesions following the initial trauma. The standard of 
care remains primarily supportive, with the maintenance of hemostasis to limit ongoing bleeding, 
and with surgical evacuation or other means to reduce intracranial pressure (i.e., insertion of 
ventricular drains, osmotherapy, or decompressive craniectomy [DC]) [Carney 2016; Haddad 
and Arabi 2012]. Despite these interventions, brain contusions may continue to progress, 
particularly during the first 12 hours following a TBI. There is no standard of care to limit HPC, 
leaving an urgent unmet medical need. Studies of hemostatic agents, including recombinant 
factor 7 and tranexamic acid, have yielded mixed results and are not routinely used in clinical 
practice. 


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4.3. 
Profile of Previous Experience With BIIB093 
As a treatment for cytotoxic and vasogenic edema, glibenclamide administered as an intravenous 
(IV) formulation is currently being studied in a global Phase 3 randomized clinical study for 
large hemispheric infarction (LHI), a development program complementary to the protocol 
proposed here. IV glibenclamide is known as BIIB093 and was formerly known as CIRARA or 
RP 1127 when it was under development by Remedy Pharmaceuticals. 
See the BIIB093 Investigator’s Brochure for detailed information on relevant nonclinical and 
clinical studies. 
4.3.1. 
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 0440RR31.001, 
Remedy Study RPI-TOX1), an in vitro hemolytic potential assay (Study 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 reproductive toxicity as well as the 
pharmacology of the substance published since the early 1970s. 
4.3.2. 
Clinical Experience 
BIIB093 has been assessed in the following completed clinical studies: 1 Phase 1 study in 
healthy volunteers (Study 101), 2 Phase 2 studies in participants with LHI (Study 201 and 
Study 203), and 1 Phase 2 study in participants with TBI (Study 202). It is also being assessed in 
the ongoing Phase 3 study in participants with LHI (Study 301). 
In Study 201 (GAMES-PILOT), 10 participants 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 study treatment 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 participants 
with LHI with BIIB093, whether or not they were treated with IV recombinant tissue 
plasminogen activator (rtPA). Participants who received intra-arterial reperfusion therapy, 
prophylactic DC, or were on sulfonylurea treatment at presentation were excluded. Nine out of 
10 enrolled participants received rtPA within 4.5 hours from onset of stroke. Baseline National 
Institute of Health Stroke Scale 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, participants did not require osmotherapy, intubation, or DC. Results from this study 
indicated that it was feasible to enroll, evaluate, and treat participants with severe stroke 
according to the protocol. The regimen was well tolerated, and there were no reported cases of 
hypoglycemia. 


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Study 203 (GAMES-RP) was a randomized, double-blind, placebo-controlled, multicenter study 
of BIIB093 in participants with LHI. The study enrolled participants 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. Participants 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 participants 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 
participants who achieved a modified Rankin Scale (mRS) score of 0 to 4 at Day 90 without 
undergoing DC. At Day 90, 17 participants (41%) who received BIIB093 and 14 (39%) in the 
placebo group achieved the primary endpoint (adjusted odds ratio 0.87, 95% confidence interval 
[CI] 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]. 
Study 202 was a randomized, double-blind, placebo-controlled, multi-institutional study of 
BIIB093 in participants with moderate or severe TBI. The study enrolled participants aged 18 to 
75 years with documented closed head TBI, Glasgow Coma Scale (GCS) of 4 to 14, and time of 
injury to study treatment infusion of ≤ 10 hours. The dosing regimen was identical to that used in 
the LHI studies. The primary safety objective of the study was to assess the safety and 
tolerability of BIIB093 compared with placebo in participants with severe, moderate, or 
complicated mild TBI. No deaths were reported in Study 202 in participants with TBI. Seven 
serious adverse events (SAEs) were reported in 5 participants (3 participants in the BIIB093 
group and 2 participants in the placebo group). These included catheter site infection, 
pneumonia, septic shock, and hypoglycemia in the BIIB093 group, and vascular 
pseudoaneurysm, carotid artery thrombosis, and convulsion in the placebo group. Except for the 
SAE of hypoglycemia reported in 1 participant in the BIIB093 group, all other events were 
considered unrelated to study treatment. The incidence of adverse events (AEs) was comparable 
between the 2 treatment groups; a total of 170 events were reported in 27 participants 
(13 participants in the BIIB093 group and 14 participants in the placebo group). 
4.3.3. 
Benefit/Risk 
BIIB093 has been shown to potentially reduce mortality associated with LHI, reducing brain 
edema, and improving functional outcomes. 
BIIB093 given intravenously in a 3-stage dosing regimen over 72 hours was generally well 
tolerated in the population of participants with LHI and TBI. The only adverse drug reaction 
identified was hypoglycemia, which can be mitigated by frequent blood glucose (BG) 
measurement and dose adjustment. The safety profile of BIIB093 observed in completed studies 
in participant with LHI and TBI is detailed in the Investigator’s Brochure. Based on the safety 
profile and observed benefit in Phase 2 studies of BIIB093 for treatment of LHI and TBI, Biogen 


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20 
considers that the benefit/risk profile of BIIB093 remains positive and supports the continued 
development of BIIB093 for the treatment of patients with LHI and brain contusion. 
4.4. 
Study Rationale 
By understanding the biology of endothelial cells and capillary fragmentation, the expansion of 
cerebral contusions may be mitigated using pharmacologic means, in addition to control of 
coagulopathy, thrombocytopenia, and hemodynamics. Loss of microvascular integrity is thought 
to be due to the shearing forces of a brain trauma, as well as the upregulation of the sulfonylurea 
receptor 1-transient receptor potential melastatin 4 channel (known as SUR1-TRPM4) in 
endothelial cells. SUR1-TRPM4 is a cation channel that allows for harmful osmotic cell swelling 
under adenosine triphosphate-depleted conditions, which in turn leads to the lysis of endothelial 
cells and the loss of capillary structural integrity. This results in the extravasation of blood, and 
the resultant expansion of the initial contusion. Notably, deletion of ABCC8, the gene that 
encodes sulfonylurea receptor 1 (SUR1) reduces HPC and provides neuroprotection in animal 
models [Kurland 2012; Simard 2009b]. A recent review highlights the potential of BIIB093 to 
provide clinical benefit for brain contusion based on the totality of preclinical and preliminary 
clinical evidence [Jha 2020]. 
BIIB093 is being developed by Biogen for the treatment of patients with LHI and brain 
contusion. BIIB093 explicitly targets the SUR1-TRPM4 channel and mitigates HPC in animal 
models of brain and spinal cord contusion. Glibenclamide has also repeatedly demonstrated anti-
perihematomal edema effects in nonclinical models. Specifically, glibenclamide reduces lesion 
volume and promotes recovery in experimental models of LHI, TBI, spinal cord injury, and 
subarachnoid hemorrhage [Ortega 2012; Simard 2006; Simard 2012a; Simard 2009a; Simard 
2009b; Simard 2013; Simard 2010; Simard 2007; Simard 2012b; Simard 2008; Simard 2012c; 
Wali 2012; Zweckberger 2014]. Additionally, a multitude of clinical data obtained from biopsy 
samples from pericontusional tissue demonstrates upregulation of the SUR1-TRPM4 complex in 
astrocytes, as well as peri-contusional endothelium [Gerzanich 2018]. Lastly, upregulation of 
SUR1 in the cerebrospinal fluid of patients with TBI was recently demonstrated, with value as a 
biomarker of the evolution of cerebral edema [Jha 2017]. 
The proof of concept for BIIB093 was established in a Phase 2 study of LHI (Study 203, 
Section 4.3.2), a clinical entity with distinct pathophysiology (i.e., characterized by cytotoxic 
edema) from brain contusion, but similarly involving the SUR1-TRPM4 complex. As discussed, 
this study demonstrated a significant effect of BIIB093 on midline shift of the brain, a 
radiographic endpoint indicative of marked cerebral edema and increased intracranial pressure. 
The study provided evidence not only of proof of biology, but also confirmed the strong safety 
profile of BIIB093. Notably, these results were the impetus for the ongoing pivotal Phase 3 
study, Study 301 (CHARM), investigating BIIB093 as a therapy for malignant cerebral edema in 
LHI [Sheth 2016]. 


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4.5. 
Dosing Rationale 
4.5.1. 
Dosing Regimen 
Dosing must be started within 10 hours of trauma/last known normal (LKN) and within 6 
hours of arrival to the hospital. Dosing should be initiated within 1 hour of randomization, 
and continue for 96 hours (4 days). The dosing duration of 96 hours (4 days), spans the period 
during which patients are thought to be at highest risk for contusion expansion. Two BIIB093 
dose levels will be administered (Table 1). 
Table 1: 
BIIB093 Dosing Regimen 
 
IV bolus (slow IV push via syringe) 
Infusion 1 
Infusion 2 
3 mg/day 
0.13 mg 
(over approximately 2 minutes) 
0.99 mg 
(0.1644 mg/h for 6 h) 
10.21 mg 
(0.1134 mg/h for 90 h) 
Total dose: Day 1 (3.16 mg), Day 2 (2.72 mg), Day 3 (2.72 mg), Day 4 (2.72 mg) = 11.3 mg 
5 mg/day 
0.21 mg 
(over approximately 2 minutes) 
1.63 mg 
(0.2722 mg/h for 6 h) 
16.84 mg 
(0.1871 mg/h for 90 h) 
Total dose: Day 1 (5.21 mg), Day 2 (4.49 mg), Day 3 (4.49 mg), Day 4 (4.49 mg) = 18.7 mg 
h = hour(s); IV = intravenous. 
Note: 3 mg/day and 5 mg/day are approximate total daily doses. 
Refer to the Directions for Handling and Administration (DHA) for corresponding mL/h rates and further 
information on windows for infusion timings. 
The 2 BIIB093 dose levels (3 mg/day and 5 mg/day) selected for this study were determined 
based on clinical safety and pharmacokinetic (PK) data and preliminary exposure-response 
(efficacy/safety) analyses from the Phase 1 healthy volunteer studies (Study 101 and Study 102) 
and the Phase 2 LHI studies (Study 201 and Study 203). 
4.5.1.1. 
Selection of 3 mg/day 
The dosing recommendation for the investigation of brain contusion is guided by the clinical 
experience of BIIB093 in healthy volunteers and patients with LHI. Briefly, the IV infusion 
regimen for LHI in Phase 3 was refined based on dose escalation results from the Phase 1 study 
(Study 101: first-in-human study in healthy volunteers) and PK modeling, encompassing a 
3stage IV infusion regimen (IV bolus followed by 2 infusion periods). The 3 mg/day dose was 
the highest dose tested in Study 101 in which severe hypoglycemia was not observed, and it had 
an acceptable safety profile and was well tolerated in the LHI Phase 2 studies. Additionally, this 
dosing regimen is selected to rapidly achieve and maintain the desired systemic steady-state 
concentration (approximately 25 ng/mL) of BIIB093 previously shown to be efficacious in 
patients with LHI. Efficacy of BIIB093 at 3 mg/day in brain contusion is also anticipated based 
on the similar pathophysiology between LHI and brain contusion. This is also supported by 
preclinical evidence (rat models of brain contusion), which demonstrated that glibenclamide 
significantly reduced progressive secondary hemorrhage with a dosing regimen identical to that 
used in LHI animal models [Simard 2010]. 


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4.5.1.2. 
Selection of 5 mg/day 
In addition to 3 mg/day, this study will also evaluate a higher dose at 5 mg/day, on the basis of 
retrospective and exploratory exposure-response analyses, conducted by both Biogen and 
independent investigators, demonstrating increased efficacy of BIIB093 with higher exposures, 
as detailed below. 
A retrospective analysis of Study 201, a pilot study of BIIB093 in LHI, dichotomized 
participants into low and high exposure cohorts. Analysis of efficacy data by exposure 
demonstrated improved mitigation of vasogenic edema (measured by T2 Flair MRI) with higher 
BIIB093 exposures (average concentration of 32 ng/mL) versus lower plasma levels (average 
concentration 16 ng/mL) [Kimberly 2014]. Notably, 25 ng/mL is the target concentration for 
3 mg/day. Additionally, an exploratory analysis using data from Study 203 (pivotal Phase 2 LHI 
study) showed a consistent trend of higher BIIB093 exposure correlating with improved efficacy 
outcome (reduction of midline shift). A relationship between increasing BIIB093 exposure and 
decreasing matrix metalloprotease-9 (MMP-9) concentration was also observed, suggesting 
improved blood-brain- barrier integrity in the presence of higher BIIB093 drug exposure. 
Therefore, greater efficacy is anticipated for brain contusion at the higher dose of BIIB093. 
The specific dose level at 5 mg/day was selected based on a totality of clinical safety (severe 
hypoglycemia) and pharmacodynamics (PD) data (blood glucose). Up to 10 mg/day has been 
previously evaluated in the first-in-human study in healthy participants (Study 101). 
Symptomatic severe hypoglycemia, or BG < 55 mg/dL (~3.1 mmol/L), was observed in 
6 mg/day and 10 mg/day cohorts, and 3 mg/day was the highest dose studied that did not result 
in severe hypoglycemia. Doses between 3 and 6 mg/day have not been evaluated clinically. No 
apparent exposure-response relationship between BIIB093 plasma concentration and BG level 
was observed. As such, safety results from Study 101 were used to inform the clinical 
concentration threshold for severe hypoglycemia, which was 75 ng/mL. PK simulations of the 
anticipated exposures at 5 mg/day (mean plasma concentration at steady state: 40 ng/mL, 95% 
CI: 13.4, 61.8) showed the maximum predicted BIIB093 plasma concentration would remain 
below the threshold where severe hypoglycemia was observed. 
Furthermore, the exposures of 5 mg/day dose level are covered within the safety margin 
established in BIIB093 preclinical studies. A 14-day toxicity study in adult rats was conducted to 
assess safety and tolerability of BIIB093. During the 14-day continuous infusion period, no 
BIIB093-related clinical observations were noted, but clinical chemistry results showed 
pharmacologic hypoglycemia in female rats. A sex difference was noted in rats as exposure to 
BIIB093 was generally higher in female rats compared with male rats; however, combined male 
and female rat exposure is used to generate exposure margins because a sex difference is not 
observed in humans. The no observed adverse effects level was considered to be 18.2 mg/kg, 
which provides exposure margins of 3-fold and 6-fold based on the maximum observed 
concentration and concentration at steady state (Css), respectively, at 5 mg/day. The exposure 
data at 5 mg/day are the result of simulations. A dose range of 3 mg/day to 5 mg/day has a 
limited dynamic range but, based on preclinical data, appears to balance safety and the 
opportunity to maximize efficacy. 


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4.5.1.3. 
IV Infusion Duration 
For the brain contusion program, the BIIB093 treatment period will be extended to 96 hours, as 
opposed to the 72-hour infusion period implemented in participants with LHI. An extended 
treatment period is believed to be of additional benefit to patients with brain contusion because 
intracranial pressure monitoring in the intensive care unit (ICU) is typically carried out for 4 to 
5 days in these patients, and HPC and edema can occur as late as 3 to 4 days after head injury 
[Kurland 2012; Staykov 2011]. Dosing out to 96 hours will ensure that BIIB093 continues to 
affect the evolution of the hematoma and its surrounding edema, which tends to occur later in 
patients with brain contusion than in patients with a malignant infarction. 
During the additional 24-hour infusion period, the same plasma Css, will be maintained for 
BIIB093. While the overall drug exposure is increased, it is still within the safety margin 
established for BIIB093. It is also important to note that with the daily dose of 5 mg, the 
systemic exposure of BIIB093 acute treatment is significantly lower than that of the approved 
therapeutic oral glibenclamide (maximum dose of 20 mg/day approved for Micronase® or 
12 mg/day approved for Glynase®) taken chronically by patients with diabetes. 
Risk mitigation strategies will be applied for the occurrence of hypoglycemia (administration of 
IV dextrose or discontinuation/dose reduction/interruption of BIIB093, at the discretion of the 
Investigator) [see Section 11.4.1.1.1]. Based on the evidence available, the plasma Css is not 
expected to change; therefore, AEs are expected to be consistent with clinical studies to date, 
with hypoglycemia being the principal risk. Specific risk mitigation strategies are advised and for 
unmanageable hypoglycemia, discontinuation criteria are in place (see Section 10.1). 


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5. 
SCHEDULE OF ACTIVITIES 
 


Protocol 252BN201 
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Table 2: 
Schedule of Activities 
 
Screening/ 
Enrollment 
Hours 
0-121 
Hour 24 
(±6 h) 
Hour 48 
(±12 h) 
Hour 72 
(±12 h) 
Hour 96 
(±12 h)2 
Day 7 
(±24 h)3 
Hospital 
Discharge 
(±24 h)4 
Day 30 
(±7 d)4 
Day 90 
(±14 d)4 
Day 180 
(±14 d)4 
NSx/Comfort 
Measures 
(if applicable) 
ET 
Visit 
Inclusion/ 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical 
history, physical 
examination (including 
weight and height) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TT/LKN 
X 
 
 
 
 
 
 
 
 
 
 
 
 
NCCT5 
X6 
 
X 
 
 
X7 
 
 
 
 
 
X 
 
GCS 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
Pregnancy test (urine or 
serum) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood alcohol level 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for 
coagulation panel (INR, 
PTT, fibrinogen) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for 
hematology and blood 
chemistry 
X 
 
 
 
 
 
X 
 
 
 
 
 
X8 
Blood sampling for LFTs 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
Other assessments (ECG, 
) 
(see Table 3 for ECG, 
 schedule of activities) 
Blood sampling for 
pharmacogenetics 
(optional)10 
 
X 
 
 
 
 
 
Enrollment/randomizatio
n (TT/LKN < 10 h) 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Screening/ 
Enrollment 
Hours 
0-121 
Hour 24 
(±6 h) 
Hour 48 
(±12 h) 
Hour 72 
(±12 h) 
Hour 96 
(±12 h)2 
Day 7 
(±24 h)3 
Hospital 
Discharge 
(±24 h)4 
Day 30 
(±7 d)4 
Day 90 
(±14 d)4 
Day 180 
(±14 d)4 
NSx/Comfort 
Measures 
(if applicable) 
ET 
Visit 
Study treatment  
(TT/LKN < 10 h) 
 
96-hour infusion 
(see Section 4.5.1 for further details) 
 
 
 
 
 
 
 
Delayed intubation 
eCRF11 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
BG measurement12 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
procedures13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Craniectomy/comfort 
care/ 
cranioplasty assessment 
form(s) 
 
 
 
 
 
 
 
 
 
 
 
X 
 
MRI14, 5 
 
 
 
 
 
X15 
 
 
 
 
 
X 
X16 
GOS-E 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
mRS 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Review safety data and 
record AEs/SAEs17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Brief suicide 
ideation/behavior 
assessment18 
X 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
AE = adverse event; BG = blood glucose; CMO = comfort measures only; d = days; DC = decompressive craniectomy; ECG = electrocardiogram; 
eCRF = electronic case report form; ET = early termination; 
; GCS = Glasgow Coma Scale; GOS-E = Glasgow Coma 
Scale-Extended; h = hours; INR = international normalized ratio; IPH = intraparenchymal hematoma; LFT = liver function test; LKN = last known normal; 
MRI = magnetic resonance imaging; mRS = modified Rankin Scale; NCCT = noncontrast computed tomography; NSx = neurosurgical intervention; 
 PTT = partial thromboplastin time; 
; 
SAE = serious adverse event; SOC = standard of care; TT = time of trauma. 
  


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1 Hour 0 is defined as the start of study treatment infusion. 
2 In the event a participant is discharged from the hospital prior to Hour 96, every effort should be made to obtain neuroimaging (NCCT or MRI) prior to 
discharge. 
3 If a participant is due to be discharged from hospital prior to Day 7, every effort should be made to perform the Day 7 assessments at the time of discharge or 
just prior. 
4 All visits after hospital discharge can be conducted by telephone; however, the Day 90 and Day 180 Visits should be in person whenever possible. Should the 
follow-up visits at Day 90 and Day 180 be conducted remotely, 
. 
5 Scans (NCCT or MRI) obtained within 12 hours of IPH evacuation, DC, or CMO meet the requirement. Scans are not expected for other NSx interventions. If 
IPH evacuation, DC, or CMO are indicated prior to 96 hours, an NCCT or MRI scan in the 12 hours proceeding the procedure should be collected, and no 
further post procedural images are required beyond SOC. 
6 NCCT as SOC at Screening (prior to enrollment). If not eligible per SOC scan, a single, repeat, study-specific NCCT may be obtained to reassess contusion 
volume if feasible within the protocol-specified time window. 
7 Optional Hour 96 NCCT should be obtained in addition to the MRI whenever possible, after study treatment infusion is complete, within 18 hours of the Hour 
96 timepoint. 
8 Only performed if participant has not yet been discharged from hospital. 
9 Vital signs include temperature, pulse rate, systolic and diastolic blood pressure, respiratory rate, and oxygen saturation. Measurements taken nearest to the 
assessment timepoint should be recorded. 
10 The optional blood sample for pharmacogenetic analysis requires a separate informed consent form to be administered between the start of study and hospital 
discharge. The pharmacogenetic sample should be collected as close to the consenting procedure as possible and preferably within 24 hours of the start of study 
treatment. The date and time of collection should be recorded. 
11 A delayed intubation eCRF must be completed if a participant is intubated for deteriorating neurologic status. 
12 Hourly (±30 minutes) for Hour 0 to Hour 24, every 2 hours (±30 minutes) for Hour 25 to Hour 48, and every 4 hours (±60 minutes) for Hour 49 to Hour 96. If 
treatment for low BG (< 70 mg/dL [~3.9 mmol/L]) is initiated, then BG monitoring is required every 15 minutes (±10 minutes) until BG is ≥ 80 mg/dL (~4.4 
mmol/L) for 3 consecutive readings without exogenous bolus glucose supplementation. See Section 11.4.1.1.1  for details on BG monitoring and management. 
13
 A CMO eCRF must be completed for participants for whom care is withdrawn. 
14 An NCCT scan is sufficient for participants who cannot get an MRI. 
15 The 96 hour scan should be performed after study treatment infusion is complete, within 18 hours of the Hour 96 time point. 
16 Only required if ET occurs before the Hour 96 scan has been performed. 
17 Includes all AEs from the beginning of study treatment administration and all SAEs from the time of consent. AEs of special interest (hypoglycemia [BG < 55 
mg/dL {~3.1 mmol/L}]) will be upgraded to an SAE. See Section 15.3 for further details on monitoring and recording AEs. 
18 A short suicidal ideation/behavior questionnaire will be conducted on participants who are alert and capable of providing answers at Screening (prior to 
dosing). For these participants, this questionnaire should be repeated at Days 30, 90, 180, and ET Visit. The questionnaire conducted at Screening will record 
“Life Time” events and subsequent visits (at Days 30, 90, 180, and ET Visit) will record “Since the Last Visit” events. 
 
 


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Table 3: 
ECG, 
 Schedule of Activities 
 
12-lead ECG1 
Predose 
SOC ECG taken at Screening 
Minute 5 
±5 minutes 
Hour 6 
±5 minutes 
Hour 24 
±5 minutes 
Hour 48 
±5 minutes 
Hour 72 
±5 minutes 
Hour 96 
±5 minutes 
BG = blood glucose; ECG = electrocardiogram; 
; SAE = serious adverse events; 
SOC = standard of care. 
1 After the start of study treatment infusion, ECG must be collected before blood sampling for 
 
 
 
 
 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
Primary Objective 
Primary Endpoint 
To determine if BIIB093 reduces brain 
contusion expansion by Hour 96 when 
compared to placebo. Measurements of 
contusion expansion are based on a 
comparison of the baseline images and the 
scans collected prior to and including 96-hour 
scan, or the scan obtained prior to DC, 
intraparenchymal hematoma (IPH) 
evacuation, or comfort measures only (CMO), 
if earlier.  
Change in total contusion volume (hematoma 
plus perihematomal edema) as measured by 
brain imaging from baseline to 96 hours or 
prior to DC, IPH evacuation, or CMO if these 
procedures occur before 96 hours per the 
central review. 
Secondary Objectives 
Secondary Endpoints 
To evaluate the effects of BIIB093 on acute 
neurologic status, functional outcomes, and 
treatment requirements. 
• Glasgow Outcome Scale – Extended 
(GOS-E) at Day 180 
• Modified Rankin Scale at Day 90 
• Proportion of participants requiring 
delayed intubation 
Note: delayed intubation is defined as 
participants requiring intubation (for 
neurologic deterioration only) at any time 
between 24 hours and 96 hours postinjury. 
To further differentiate the mechanism of 
action of BIIB093 compared to placebo on 
contusion expansion by examining 
differential effects on hematoma and edema 
expansion. 
• Change in total contusion volume 
(hematoma plus perihematomal 
edema) as measured by brain imaging 
from baseline to 24 hours or prior to 
DC, IPH evacuation, or CMO if these 
procedures occur before 24 hours per 
the central review. 
• Change in absolute hematoma volume 
from baseline to 24 hours 
• Change in absolute edema volume 
from baseline to 96 hours 


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To determine if BIIB093 improves survival at 
Day 90 when compared to placebo. 
Time to all-cause death, including 
neurological death, through Day 90. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This is a Phase 2, randomized, multicenter, double-blind, multidose, placebo-controlled study to 
assess the efficacy and safety of BIIB093 in inhibiting the progression of traumatic intracerebral 
contusions in participants aged 18 to 85 years. 
Approximately 60 sites in 7 countries globally are planned. The study will randomize 
160 participants. 
Participants must be treated with BIIB093 within 10 hours of time of trauma/LKN and within 6 
hours of hospital arrival. Dosing should be initiated within 1 hour of randomization and continue 
for 96 hours (4 days). For participants in the 3 mg/day dose arm, treatment will be initiated 
similarly to the regimen in an ongoing Phase 3 study targeting edema associated with LHI. 
Participants will receive a bolus IV dose of 0.13 mg (given over approximately 2 minutes), 
followed by 2 different infusion rates (a rapid IV infusion of 0.1644 mg/h for 6 hours followed 
by a slow IV infusion of 0.1134 mg/h for the remaining 90 hours). In the 5 mg/day dose arm, 
participants will receive a bolus IV dose of 0.21 mg (given over approximately 2 minutes), 
followed by 2 different infusion rates (a rapid IV infusion of 0.2722 mg/h for 6 hours followed 
by a slow IV infusion of 0.1871 mg/h for the remaining 90 hours). These treatment rates should 
be administered within the limitation of the device at the site. The treatment duration will be for 
96 hours for both treatment groups. 
The primary endpoint of this study will be the change in total contusion volume (hematoma plus 
perihematomal edema) as measured by brain imaging from baseline to 96 hours, or prior to DC, 
IPH evacuation, or CMO, if these procedures occur before 96 hours.  
Participants will also have the functional assessments (i.e., GOS-E, 
 
, and mRS) performed at both Day 90 and Day 180 post trauma. 
After the last participant completes their Day 4 (Hour 96) Visit, data for the primary endpoint 
and available data for the secondary endpoints will be locked for analysis. The final database 
lock will occur after the last participant completes their Day 180 Follow-up Visit, marking the 
end of the study. 
See Figure 1 for a schematic of the study design. 


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Figure 1: 
Study Design 
 
h = hours; MRI = magnetic resonance imaging; NCCT = noncontrast computed tomography; SOC = standard of 
care; TT/LKN = time of trauma/last known normal.  
Dosing must be started within 10 hours from time of trauma/last known normal and within 6 hours of hospital 
arrival. Dosing should be initiated within 1 hour of randomization and continue for 96 hours (4 days). 
 
7.2. 
Study Duration for Participants 
The total duration of study participation for each participant will be approximately 180 days; this 
consists of a concurrent screening and enrollment period, a treatment period of 96 hours, and a 
follow-up period up to Day 180. 
The primary endpoint for the study is at Hour 96. All randomized participants will be followed 
for 180 days unless consent is withdrawn. 
The end of study for a participant is considered the final study assessment at Day 180 or the 
Early Termination (ET) Visit. 
7.3. 
Responsibilities of Site Staff 
The attending clinician has ultimate responsibility and discretion for treating participants. The 
clinician will use his/her best judgment in treating participants based upon the specific clinical 
situation and in accordance with Good Clinical Practice (GCP). 


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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 external 
independent 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. Details of the IDMC responsibilities will be provided in the 
IDMC charter. 
7.5. 
End of Study 
The end of the study is when the last participant completes the Day 180 Follow-up Visit or 
ET Visit. 


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8. 
SELECTION OF PARTICIPANTS 
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 regulations allow, and/or provision of informed consent by the 
participant’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. Aged 18 to 85 years old, inclusive, at the time of informed consent. 
Note: age 18 years at the time of informed consent or participant meets the minimum age 
of consent in accordance with national regulations (whichever is higher). 
Note: for countries where the minimum age of consent is over 18 years, participants may 
be enrolled provided a LAR is available, and if capable, the participant assents to 
treatment. The LAR must consider the participant’s involvement in the study and provide 
informed consent for the participant. 
3. A score of 5 to 15 on the GCS. Assessment should be made prior to medical intervention, 
where possible. 
Note: an enrollment cap on participants presenting with GCS 15 will be placed at 10% of 
total number of participants. 
4. A clinical diagnosis of brain contusion with lesions within the supratentorial brain 
parenchyma totaling > 3 mL in volume on noncontrast computed tomography (NCCT) 
scan (allowing for multiple contusions) at Screening. 
Notes: 
a. Participants with multifocal contusions totaling > 3 mL in volume will be included. 
The sum total of contusion volumes should be calculated based on the baseline 
imaging. 
b. Contusion volume for a single contusion (hyperintense hematoma and hypointense 
edema on NCCT) must be determined and documented by the Investigator or his/her 
designee using study-specific methods detailed in the Imaging Manual. 
c. If more than 1 NCCT scan is performed prior to randomization, eligibility should be 
based on the most recent NCCT scan. 


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d. In participants meeting all inclusion/exclusion criteria except for contusion volume 
totaling > 3 mL, a single repeat study-specific NCCT scan may be obtained to 
reassess contusion volume, if feasible, within the protocol-specified time window. 
5. Mechanism of injury is defined. 
Note: emergency medical technicians, emergency physicians, or members of the study 
team can identify a likely or possible mechanism of head injury based on the clinical 
history and/or patient presentation. 
6. Study drug (BIIB093) must be infused no more than 10 hours post trauma if known, or 
LKN (if time of trauma is unknown), and within 6 hours of hospital arrival. Dosing 
should be initiated within 1 hour of randomization and continue for 96 hours (4 days). 
7. Functionally independent, in the opinion of the Investigator, prior to index head injury. 
8. All women of childbearing potential and all men must practice highly effective 
contraception during the study and for 3 months after their last day of completing study 
treatment infusion. 
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, patient is likely to have supportive care withdrawn 
within 24 hours. 
2. Indication for immediate evacuation of IPH or DC. 
3. Clinical signs of brainstem herniation, in the opinion of the Investigator. 
4. NCCT or MRI evidence of penetrating brain injury impacting the brain parenchyma. 
Cerebrospinal fluid leak in isolation is not exclusionary unless evidence of parenchymal 
penetration by an external force (e.g., blunt object, bullet, or depressed skull fracture). 
5. Any presence of midbrain or posterior fossa injury as assessed by imaging and clinical 
examination. 
6. Symptoms and imaging suggestive of diffuse axonal injury as the predominant injury, in 
the opinion of the Investigator. 
7. Intracranial hemorrhage due to causes other than TBI (e.g., spontaneous intracerebral 
hemorrhage, saccular/fusiform/infective aneurysm rupture), based on medical history of 
no trauma and location of the bleed. 


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8. Coagulopathy (international normalized ratio [INR] > 1.5, activated partial 
thromboplastin time [PTT] > 60 s, or fibrinogen < 1.0 g/L), severe anemia (hemoglobin 
< 85 g/L), or thrombocytopenia (platelets < 75,000 cells/mm3) at Screening. 
9. Symptoms, in the opinion of the Investigator, or electrocardiogram (ECG)-based signs 
(QT interval corrected for heartrate [QTc] > 520 ms) of myocardial ischemia or unstable 
angina at Screening, based on local assessment. 
10. ECG evidence of second- or third-degree heart block or cardiac arrhythmia associated 
with hemodynamic instability. 
11. Presence of concomitant spinal cord injury as assessed by imaging and clinical 
examination. 
12.  Injury to ascending aorta, carotid, or vertebral arteries. 
13. Severe or unstable concomitant condition or disease (e.g., known significant neurologic 
deficit, cancer, sepsis, hematologic or coronary disease) that in the opinion of the 
Investigator may increase the risk of study participation or uninterpretable results, if 
known. 
14. Patients with, in the opinion of the Investigator, life expectancy < 3 months not related to 
current brain contusion, or those unlikely to be compliant with follow-up. 
15. Patients in whom a peripheral IV line cannot be placed. 
16. Mentally incompetent (prior to trauma) patients and wards of the state, if known. 
Medical History 
17. Known allergy to BIIB093 or another sulfonylurea drug or any of the components of the 
formulated BIIB093 or matching placebo. 
18. Participants who are known to have taken oral glibenclamide within the past 10 hours. 
19. A clinically significant severe form of renal or hepatic disorder in the Investigator’s 
opinion from the patient’s history (e.g., dialysis), if known. 
20. Known history of G6PD deficiency. 
21. Clinically significant hypoglycemia in the Investigator's opinion based on known medical 
history or screening laboratory assessments (i.e., screening BG < 70 mg/dL 
[~3.9 mmol/L]). 
22. Patients who have or have ever had diabetic ketoacidosis or diabetic coma/precoma, if 
known. 


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23. Uncontrolled hypertension (defined as systolic blood pressure > 200 mmHg continuously 
for over 60 minutes). 
24. Hemodynamic instability (use of inotrope or vasopressor therapy or resuscitation 
requiring > 6 L crystalloid or colloid). 
Note: transient vasopressor used to support blood pressure during specific procedures 
(e.g., intubation or hypotension associated with sedation/analgesics) is permitted. 
25. Diabetes controlled with sulfonylurea medication, if known. 
26. Life-threatening or nonsurvivable polytrauma, per Investigator’s judgment. 
27. Cardiopulmonary resuscitation required at any point after injury or suspected anoxic 
brain injury based on clinical judgment. 
28. History, within the past 6 months, of decompensated congestive heart failure (New York 
Heart Association heart failure Class III or IV – Class III: marked limitation in activity due to 
symptoms, even during less-than-ordinary activity, e.g., walking short distances [20 to 
100 m]; class IV: severe limitations, experiences symptoms even while at rest. Mostly 
bedbound patients), if known. 
29. Acute Coronary Syndrome within 3 months, if known. 
30. Likely to be moved to CMO in the next 24 to 96 hours, in the opinion of the Investigator. 
Medications 
Every effort should be made to determine if patient was taking any of the following 
medications prior to randomization: 
31. Use of potent organic anion transporting polypeptide (OATP) inhibitors (e.g., IV 
rifampin, cyclosporine) within 5 half-lives of the drug prior to enrollment, if known. 
32. Use of novel oral anticoagulants [NOAC] (including direct thrombin inhibitors such as 
dabigatran, or Factor Xa inhibitors such as rivaroxaban or apixaban), in preceding 3 days 
prior to the injury, if known. 
Note: Patients in whom NOAC anticoagulation can be adequately reversed with 
Andexanet alfa may be enrolled after the Andexanet alfa infusion has been completed. 
This applies to the NOACs apixaban or rivaroxaban. 
33. Use of antiplatelet therapy other than acetylsalicylic acid in the preceding 7 days prior to 
the injury, if known. 
34. Use of vitamin K antagonists within 5 days prior to the injury, if known. 


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Note: patients on vitamin K antagonists who are subtherapeutic with INR < 1.5 may be 
included. If a patient can be adequately reversed from vitamin K antagonism to a 
subtherapeutic INR in time for randomization, this is acceptable, and the patient should 
be screened for enrollment. 
Other 
35. Females who are pregnant or women of childbearing potential with a positive urine or 
serum pregnancy test at the time of admission. 
36. Nursing women who are unable to stop breastfeeding during study treatment infusion and 
for 7 days following the end of study treatment infusion. 
37. Known current participation or known history of participation in any other investigational 
study that involved treatment with an investigational drug or device within 30 days prior to 
enrollment and for the duration of the current study participation. 
38. Inability to comply with study requirements. 
39. Other unspecified reasons that, in the opinion of the Investigator, make the participant 
unsuitable for enrollment. 


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9. 
SCREENING AND RANDOMIZATION 
9.1. 
Screening 
Participants, their 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 participants arriving at the recruiting site with potential for dosing within the 10-hour 
window, and having a brain contusion due to a non-penetrating head injury should be considered 
for inclusion in this study. 
A screen failure log will be maintained at each study site. Participants are eligible for rescreening 
(i.e., an additional study-specific imaging scan), provided they meet the protocol-specified time 
window and all inclusion/exclusion criteria. Screen failures are defined as participants who have 
been diagnosed with brain contusion, signed the informed consent form (ICF), but are not 
subsequently randomized. If a participant is considered a screen failure, the reasons for exclusion 
must be documented in the participant’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.  
SAEs occurring during the screening period will be recorded on an SAE form; however, SAEs 
do not need to be recorded or followed once a participant is confirmed as a screen failure. 
Because pertinent participant information will already be collected as part of SOC, and to reduce 
additional study-specific procedures, baseline information may be taken from the participant’s 
medical records prior to obtaining informed consent. However, informed consent will be 
obtained prior to performing any study-specific procedures. 
A short suicidal ideation/behavior questionnaire will be conducted on participants who are alert 
and capable of providing answers at Screening (prior to dosing). For these participants, this 
questionnaire should be repeated at Days 30, 90, 180, and ET Visit. 
9.2. 
Randomization 
Enrollment and randomization will be concurrent. Participants will be randomized/enrolled after 
all screening assessments have been completed and after the Investigator has verified that the 
participants are eligible per criteria in Section 8. Participants will be assigned a unique 
identification number that will be used on study-related documents pertaining to the participant. 


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Any participant identification numbers that are assigned will not be reused even if the participant 
does not receive treatment or does not continue in the study. 
Randomization will be performed using interactive response technology (IRT). Participants will 
be randomly assigned to 3 mg/day study treatment, 5 mg/day study treatment, 3 mg/day 
matching placebo, or 5 mg/day matching placebo in a 1:1:1:1 ratio, stratified by baseline 
contusion volume per Investigator assessment of NCCT scan or site local radiologic assessment 
(3 to 10 mL or > 10 mL), baseline GCS (5 to 8, 9 to 12, or 13 to 15 [an enrollment cap on 
participants presenting with GCS 15 will be placed at 10% of total number of participants]), age 
(≤ 70 or > 70 years), and region (North America [United States] or Rest of World). 
Refer to the Study Reference Guide for details on randomization/enrollment. 
9.3. 
Blinding Procedures 
The Investigators, study site staff, participants, and caregivers will be blinded to the participant 
treatment assignments for the duration of the study. To maintain the study blind, it is imperative 
that subject treatment assignments are not shared with the subjects, their families, or any member 
of the blinded study team, both at the site and at Biogen. 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 (evaluators should not have participated in the treatment during the acute 
hospitalization phase of the study nor review the participant’s hospital records from the acute 
hospitalization study period including BG levels, BG management, or carbohydrate intake [e.g., 
intravenous glucose or parenteral nutrition]). 
The study Sponsor and CRO study management team will be fully blinded for the study. Interim 
analysis will be performed by an independent unblinded Sponsor team whose members are not 
part of the study management team for the continued data collection and study management. Full 
treatment assignment will only be available to this independent unblinded Sponsor team.  
After the last participant completes their Day 4 Visit, data for the primary endpoint and available 
data for the secondary endpoints will be locked for analysis. An independent unblinded Sponsor 
team whose members are not part of the study management team for the continued data 
collection and study management will perform the primary and secondary efficacy analyses. The 
Sponsor and CRO study management team responsible for all site interactions and data entry will 
remain blinded to individual treatment assignments until the final database lock. The final 
database lock will occur after the last participant completes their Day 180 Follow-up Visit. 
At the end of the study (i.e., once the clinical study report is finalized), if unblinding will not 
jeopardize the results of ongoing related studies, Biogen will provide the randomization codes to 
Investigators, who then can inform their participants about the treatment received. 


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10. 
DISCONTINUATION OF STUDY TREATMENT AND 
WITHDRAWAL OF PARTICIPANTS FROM THE STUDY 
10.1. 
Discontinuation of Study Treatment 
A participant must permanently discontinue study treatment for any of the following reasons: 
•  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 participant, and 
the infusion rate has already been reduced to 0.0795 mg/h (refer to the Directions for 
Handling and Administration [DHA] for corresponding mL/h rate) for > 30 minutes. 
• QT/QTc (formula not specified) of > 550 ms from local assessment, if the 
measurement is obtained and confirmed with a second ECG reading within 
15 minutes. 
• 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 participant has a positive pregnancy test during the 96-hour time window of 
treatment. 
• The participant experiences an AE that necessitates permanent discontinuation of 
study treatment. 
• The participant experiences a medical emergency that necessitates unblinding of the 
participant’s treatment assignment. 
• The participant experiences a hypersensitivity or suspected allergic reaction to study 
treatment, based on the Investigator's assessment. 
• Informed consent withdrawal. 
• At the discretion of the Investigator for medical reasons. 
If the study treatment infusion is stopped as a result of low BG, please refer to the guidance in 
Section 11.4.1.1.1, Table 5. Investigators must also use their own medical judgment in 
conjunction with referencing the guidance. The primary reason for discontinuation of study 
treatment must be recorded in the participant’s electronic case report form (eCRF). All 
participants who discontinue treatment, except for those who withdraw consent, will be followed 
to the end of study. 
If a site learns, while a participant is receiving study treatment, that the participant had taken 
sulfonylureas within 24 hours prior to or during the hospital stay, this will not be a cause for 
discontinuation of study treatment or of withdrawal from the study. 


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Participants who discontinue treatment should be encouraged to remain in the study and 
continue protocol-required tests and assessments. 
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 Measures 
If a decision is made to move the participant to comfort care measures during the study, the 
Investigator should complete the comfort care eCRF and determine the GOS-E, when possible. If 
a brain imaging study has not been performed within the prior 12 hours to the decision, it should 
be obtained whenever possible. 
10.2. 
Lost to Follow-Up 
Potential sources of follow-up information will include participant medical records, the 
participant, 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. Participants will be considered lost to 
follow-up if all attempts to collect the follow-up assessments are unsuccessful. The participant 
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 the participant with no response received 
within 30 days of sending the letter. 
The following actions must be taken if a participant fails to appear for or respond to a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study. 
• In cases in which the participant is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the participant. These contact attempts 
should be documented in the participant's medical record. 
• Should the participant continue to be unreachable, that participant will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
10.3. 
Withdrawal of Participants From Study 
Participants must be withdrawn from the study if the participant or LAR withdraws consent for 
any reason. 


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The primary reason for the participant’s withdrawal from the study must be recorded in the 
participant’s eCRF. If a participant is withdrawn due to pregnancy, ET study procedures will be 
performed. Participants must undergo ET assessments (see Section 5) unless withdrawal is due to 
death or withdrawal of consent. Participants 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 for detailed information. 
For participants in the 3 mg/day dose arm, study treatment administration will initiate with 
0.13 mg administered as a bolus over approximately 2 minutes, followed by 0.1644 mg/h for 
6 hours, followed by 0.1134 mg/h for the remaining 90 hours (or 0 mg in all cases for placebo) 
[refer to the DHA for corresponding mL/h rate]. 
For participants in the 5 mg/day dose arm, study treatment administration will initiate with 
0.21 mg administered as a bolus over approximately 2 minutes, followed by 0.2722 mg/h for 
6 hours, followed by 0.1871 mg/h for the remaining 90 hours (or 0 mg in all cases for placebo) 
[refer to the DHA for corresponding mL/h rate]. 
These treatment rates should be administered within the limitation of the device at the site. See 
the DHA for a summary of the study dosing. 
The bolus will be administered by withdrawing the study treatment from the bag and injecting it 
by syringe through peripheral IV over an approximately 2-minute period. 
BIIB093 cannot be administered with polymerizing vinyl chloride (PVC) bags and lines due to 
adsorption issues. Additionally, the drug adsorbs to inline filters. Refer to the DHA for additional 
information. The use of any IV components other than those specified per the DHA is strictly 
prohibited, unless permission to do so is provided by the Sponsor in writing (email). 
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 AS 
THESE CONTAIN PVC AND MAY ABSORB THE DRUG. 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. 
Note: Study treatment administration does not need to occur in the ICU, provided that the 
appropriate BG monitoring can occur in the floor/unit where the participant is under care. 


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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]). In the event of hypoglycemia, the study treatment infusion rate must be reduced 
as presented in Table 4.  
Table 4: 
Dose Modification Schedule 
If hypoglycemia occurs within the first 6 hours of infusion: 
For participants on high infusion rate 
(0.2722 mg/h) 
The infusion rate must be reduced to 0.1644 mg/h. If 
hypoglycemia cannot be rectified or reoccurs, the infusion rate 
must be further reduced to 0.0795 mg/h and must not be 
uptitrated. 
For participants on low infusion rate 
(0.1644 mg/h) 
The infusion rate must be reduced to 0.0795 mg/h and must not 
be uptitrated. 
If hypoglycemia occurs after the first 6 hours of infusion: 
For all study participants 
The infusion rate must be reduced to 0.0795 mg/h. The infusion 
rate can be uptitrated to 0.1134 mg/h when blood glucose is 
> 80 mg/dL (~4.4 mmol/L) for 3 consecutive readings. 
If, at the reduced rate (0.0795 mg/h), 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 
participant, treatment should be discontinued (see Table 5 for further details). 
If the study treatment needs to be temporarily stopped due to SOC ICU activities (e.g., transport 
of patient, IV-line changes or interstitial extravasation, etc.), the study treatment should be 
restarted as soon as possible per instructions in the DHA. 
The infusion period will not be extended to account for any stoppages or reduction. 
 
 
For mitigation strategies for hypoglycemia associated with dosing, please see Table 5. 
11.3. 
Precautions 
BIIB093 cannot be administered with PVC bags and lines due to adsorption issues. Additionally, 
the drug adsorbs to inline filters. Refer to the DHA for additional information. 
11.4. 
Concomitant Therapy and Procedures 
11.4.1. 
Concomitant Therapy 
A concomitant therapy is any medication administered between enrollment through Day 180 or 
early discontinuation (whichever is earlier). All concomitant therapy, including but not limited to 


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dextrose solutions, osmotherapy, paralytics, sedatives, and vasoactive drugs will be recorded in 
appropriate eCRF. 
11.4.1.1. Allowed Concomitant Therapy 
11.4.1.1.1. 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 studies involving glucose-lowering drugs [International 
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; however, Investigators must use their own medical judgment in 
conjunction with referencing the guidance (Table 5). 
Insulin 
Insulin and other BG-lowering agents are not permitted during study treatment administration 
when BG < 140 mg/dL (~7.8 mmol/L). 
Nutrition 
Enteral nutrition is encouraged to be initiated within 24 hours of admission if consistent with 
SOC. Participants may need postpyloric administration of nutritional support. 
Maintenance Dextrose-Containing IV Solution 
During the study treatment infusion period, BG monitoring is required as follows: 
• Hour 0 to Hour 24, monitor hourly (±30 minutes)  
• Hour 25 to Hour 48, monitor every 2 hours (±30 minutes)  
•  Hour 49 to Hour 96, monitor every 4 hours (±60 minutes)  
See Section 5 for further details on timings of BG measurements. If treatment for hypoglycemia 
is initiated (for BG < 70 mg/dL [~3.9 mmol/L], then BG monitoring is required every 15 minutes 
(±10 minutes) until BG is ≥ 80 mg/dL (~4.4 mmol/L) for 3 consecutive readings without 
exogenous bolus glucose supplementation. BG monitoring may be performed more often at the 
discretion of the Investigator. Table 5 shows how BG should be monitored and managed 
according to inpatient BG levels. 
Total fluid volume, inclusive of study treatment volume, infusion rate, infusion duration, sodium 
content, and percent of dextrose, should be guided by the clinical status of the subject and 
medical judgment. 


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It is recommended that maintenance dextrose-containing IV solution be initiated when BG is < 
120 mg/dL (~6.7 mmol/L) and maintained for the duration of the study treatment administration 
(up to 96 hours) with the new glycemic BG target in the range of 140 to < 180 mg/dL (~7.8-10 
mmol/L). 
Table 5: 
Blood Glucose Monitoring and Management 
Inpatient BG Level 
BG Monitoring and Management1 
Initiation of dextrose-containing IV solution 
< 120 mg/dL (~6.7 mmol/L)  
• 
It is recommended that D10NS at 35 to 50 mL/h be initiated as 
first-line management. Consider D5NS at a rate of 70 to 
100 mL/h or other percent dextrose solutions as alternatives.  
Maintenance of dextrose-containing IV solution after initiation 
≥ 180 mg/dL (~10 mmol/L) 
• It is recommended that dextrose-containing IV solution be 
titrated downward or stopped temporarily until BG is ≥ 140 to 
< 180 mg/dL (~7.8 to ~10 mmol/L). 
< 180 mg/dL (~10 mmol/L) but 
≥140 mg/dL (~7.8 mmol/L) 
• It is recommended that dextrose-containing IV solution be 
maintained or titrated to keep BG as ≥ 140 mg/dL 
(~7.8 mmol/L) but < 180 mg/dL (~10 mmol/L). 
< 140 mg/dL (~7.8 mmol/L) but 
≥80 mg/dL (~4.4 mmol/L) 
• Insulin and other BG-lowering agents are not permitted during 
study treatment administration when BG is < 140 mg/dL 
(~7.8 mmol/L). 
• It is recommended that dextrose- containing IV solution be 
maintained when BG is < 140 mg/dL (~7.8 mmol/L). Titrate 
up the IV infusion rate to keep BG ≥ 140 mg/dL (~7.8 
mmol/L) but < 180 mg/dL (~10 mmol/L) 
< 80 mg/dL (~4.4 mmol/L)  
• 
It is recommended that the infusion rate of the dextrose-
containing IV solution be increased to keep BG ≥ 140 mg/dL 
(~7.8 mmol/L) but < 180 mg/dL (~10 mmol/L). 
< 70 mg/dL (~3.9 mmol/L) 
• 
Test must be repeated to confirm level. 
• 
Must be treated with 50 mL of dextrose 50% in water or 
equivalent. 
• 
It is recommended that the infusion rate of the dextrose-
containing IV solution be increased after the dextrose bolus. 


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Inpatient BG Level 
BG Monitoring and Management1 
• 
It is recommended that the infusion rate of the dextrose-
containing IV solution be titrated up to keep BG ≥ 140 mg/dL 
(~7.8 mmol/L) to < 180 mg/dL (~10 mmol/L). 
< 55 mg/dL (~3.0 mmol/L) 
• 
Study treatment infusion rate must be reduced as follows: 
• 
If hypoglycemia occurs within the first 6 hours of infusion: 
− For participants on high infusion rate (0.2722 mg/h), the 
infusion rate must be reduced to 0.1644 mg/h. If 
hypoglycemia cannot be rectified or reoccurs, the infusion 
rate must be further reduced to 0.0795 mg/h and must not 
be uptitrated. 
− For participants on low infusion rate (0.1644 mg/h), the 
infusion rate must be reduced to 0.0795 mg/h and must 
not be uptitrated. 
• 
If hypoglycemia occurs after the first 6 hours of infusion, the 
infusion rate must be reduced to 0.0795 mg/h. The infusion 
rate can be uptitrated to 0.1134 mg/h when BG is > 80 mg/dL 
(~4.4 mmol/L) for 3 consecutive readings. 
• 
Study treatment should be discontinued if hypoglycemia 
cannot be rectified and is determined by the Investigator to be 
harmful to the participant 
BG = blood glucose; D10NS = 10% dextrose in normal saline (or fluid containing 10% dextrose); D5NS = 5% 
dextrose in normal saline (or fluid containing 5% dextrose); IV = intravenous. 
1 Total fluid volume, inclusive of study treatment volume, should be consistent with site practice and guided by 
clinical status of the participant and medical judgment. 
11.4.1.1.2. 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 participants 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 participant safety. 
Participants 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. 


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11.4.1.2. Disallowed Concomitant Therapy 
Insulin and other BG-lowering agents are not permitted during study treatment administration 
when BG < 140 mg/dL (~7.8 mmol/L). 
No other sulfonylurea agents may be administered during the hospital stay. 
No other investigational drugs may be administered during the 180-day follow-up period. 
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 participant is enrolled in the study and Day 180. The use of unapproved therapies 
and/or procedures is not permitted. 
Concomitant procedures will be recorded through Day 180 or early discontinuation, whichever is 
earlier. 
11.4.2.1. Neurosurgical Intervention 
NSx procedures or interventions may be performed according to local SOC. Study treatment 
should not be stopped if the participant undergoes NSx. Participants should undergo follow-up 
assessments as per normal study procedures, where possible. 
Information on the timing, type (craniotomy or DC), and reason for NSx (e.g., 1, radiographic 
changes; 2, change in symptoms and/or signs; 3, both radiographic changes and change in 
symptoms and/or signs; or 4, neither [i.e., prophylactic]) will be recorded in the eCRF. The 
evacuation of extra-axial hemorrhages and the placement of external ventricular drains using 
burr holes will also be collected in the eCRF. GCS should be recorded either at the time of 
decision to perform NSx or between such time and the intervention. 
IPH evacuations and DC requires additional imaging. If a brain imaging scan was not performed 
in the prior 12 hours as part of the assessment to perform IPH evacuation or DC, a follow-up 
brain imaging study should be performed prior to these procedures (IPH evacuation, DC, and 
CMO) when possible. 
Sites should be vigilant about intracranial pressure management and perform DC when it is 
clinically indicated as part of local SOC. The reasons for the DC should be recorded in the 
eCRF. 
11.4.2.2. Intubation 
Intubation may be performed according to local SOC. Timing of, and reasons for intubation, 
including whether the intubation was due to 1) change in level of alertness/consciousness, 2) 
respiratory distress 3) other (e.g., preparation for operative intervention) will be recorded in the 
eCRF. GCS should be recorded at the time of decision to intubate. 


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The intubation eCRF should only be completed if the intubation occurs between 24 and 96 hours 
after the injury. Intubations performed in the emergency room, trauma bay, or upon immediate 
admission to the ICU need not be recorded. Participants should undergo follow-up assessments 
as per normal study procedures, where possible. 
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. 
Site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment. The DHA should align 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 participants enrolled in this study. Once study treatment is 
prepared for a participant, it can be administered only to that participant. Study treatment are for 
one-time use only; any study treatment remaining in the vial should not be used for another 
participant. 
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 will 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% 
sodium chloride. 
The study treatment in normal saline is stable at room temperature for 30 hours. A new vial is 
used for dosing on each day of the 4-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 adsorbs 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. 


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Please refer to the DHA for detailed instructions regarding reconstitution of the study treatment. 
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) 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. For additional information, please refer to the DHA. 
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 (participant-by-participant 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. Please refer to the DHA for additional information. 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. 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, 
 
PHARMACOGENETIC, AND GENETIC ASSESSMENTS 
See Section 5 for the timing of all assessments. 
13.1. 
Clinical Efficacy Assessments 
NOTE: the 90- and 180-Day efficacy outcomes will be performed by personnel who are blinded 
to on-treatment BG levels, BG-related AEs, and carbohydrate administration (e.g., intravenous 
glucose or parenteral nutrition). Such persons will not have access to the participant’s medical 
record from the acute hospitalization study period but will instead be provided with 
participant/family/LAR contact details (if they are required to schedule the follow-up), the 
source documents for the assessments to be performed, and the list of unresolved AEs for the 30-
, 90-, and 180-day follow ups. 
The following clinical and imaging assessments will be performed to evaluate the efficacy of 
BIIB093: 
• NCCT/MRI Assessments 
− Total contusion volume will be assessed by the central imaging core laboratory on 
baseline NCCT, 24-hour NCCT, and the 96-hour scan (MRI and/ or NCCT) and 
the scans obtained prior to DC, IPH evacuation, or CMO. 
− Absolute hematoma volume from baseline to 24 hours (the NCCT scan closest to 
the 24-hour timepoint will be used) unless DC, IPH evacuation, or CMO occurred 
prior to 24 hours, the scan acquired just prior to these procedures will be used. 
− Absolute edema volume from baseline to 96 hours (the MRI and/or NCCT scan 
closest to the 96-hour timepoint will be used) unless DC, IPH evacuation, or 
CMO occurred prior to 96 hours, in which case the scan acquired just prior to 
these procedures will be used. 
 
 
 
 
− NCCT and MRI will be acquired per specifications outlined in the Imaging 
Manual. 
− All imaging reads for efficacy will be performed by trained and certified central 
readers blinded to treatment assignment per procedures detailed in the Imaging 
Manual. 
• Functional/Neurological Outcomes Assessments 


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− GCS and GOS-E 
− mRS: 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 and Day 180 should be conducted in person where 
possible, and otherwise by telemedicine or telephone call, in order of preference. 
The same mRS rater should follow a participant for the duration of the study 
whenever possible. The Day 90 and Day 180 mRS assessments may be reviewed 
centrally and if so, queries will be issued in the event of discrepancies or 
inconsistencies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.4. 
Pharmacogenetic and Genetic Assessments 
Where allowed by local, regional, and national regulatory authorities and ethics committees, 
participants will be offered the option to participate in genetic research related to brain contusion 
and metabolism of BIIB093. This is a 1-time optional blood draw. Participants, or the 
participant’s LAR, will be required to sign a separate ICF between the start of study and hospital 
discharge. The pharmacogenetic sample should be collected as close to obtaining consent as 
possible and preferably within 24 hours of the start of study treatment to minimize the influence 
of participant outcomes on obtaining consent. 
Genetic polymorphisms in genes associated with brain contusion or drug absorption, distribution, 
metabolism, and elimination (including but not limited to ABCC8, CYP2C9, OATP1B1, and 
G6PD) could influence the observed safety and efficacy of BIIB093. Genes of downstream 
pathways may also be explored. Despite continuing advances in genetic research and the 


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understanding of brain contusion, not all genetic factors relevant to BIIB093 have been 
identified. 
The DNA samples will be coded with the participant’s identification number and stored for 
15 years or a duration dictated by local, national, or regional laws or regulations. No genotyping 
or genetic data will be provided to the participant. Details on genetic sample collection will be 
provided in a separate laboratory manual. 
Other genetic tests for additional safety measures may be conducted where applicable (see 
Section 14.2). 
13.5. 
Other Assessments: 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 participant 
whenever possible for the duration of the study. 
 


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14. 
SAFETY ASSESSMENTS 
See 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 weight and height (may be estimated)  
• Vital sign measurements: temperature, pulse 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 180 are to be recorded 
in the eCRF. Concomitant procedures will be recorded through Day 180. 
 
 
 
• AE and SAE recording 
• Assessment of suicidal ideation/behavior at Screening and follow-up in patients 
whose level of consciousness is compatible with completion of the abbreviated 
suicidal ideation/behavior questionnaire. Investigators should use their best judgment 
to identify patients suitable for this assessment. 
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 and platelet count, and absolute neutrophil count 
• Blood chemistry: albumin, creatinine, blood urea nitrogen, glucose, calcium, 
phosphorus, bicarbonate (if available), chloride (if available), sodium, and potassium 


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• Liver function test: bilirubin (total and indirect), alkaline phosphatase, ALT, AST, 
and gamma-glutamyl transferase 
• Coagulation panel (INR, PTT, fibrinogen) 
• Note that in any case of confirmed hemolytic anemia after randomization, the 
required local standard tests should be performed to confirm etiology of disease, 
including a G6PD genetic or enzymatic test (in accordance with local practice). 
14.3. 
Product-Specific Safety Assessments 
BG will be also measured to determine the safety of BIIB093. See Section 11.4.1.1.1 for full 
details of BG monitoring and management. 
BG concentrations are to be measured by point-of-care (POC) testing of capillary blood (e.g., 
Accu-Chek). Alternatively, blood from an arterial or venous 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 versus arterial versus venous line) 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 participant. If necessary, 
appropriate medical intervention should be provided. 
At the signing of the ICF, each participant or his/her LAR and/or main caregiver must be given 
the names and telephone numbers of 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 participant 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
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 participant 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 participant 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 
• Results in a congenital anomaly/birth defect 


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• Is a medically important event 
A medically important event is an AE that, in the opinion of the Investigator, may jeopardize the 
participant 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 participant 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 
participant’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 participant’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 participant 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 participant or does not make participant uncomfortable; 
does not influence performance or functioning; prescription drug not ordinarily needed 
for relief of symptoms but may be given because of personality of participant. 
Moderate 
Symptoms of a sufficient severity to make participant uncomfortable; performance of 
daily activity is influenced; participant is able to continue in study; treatment for 
symptoms may be needed. 
Severe 
Symptoms cause severe discomfort; symptoms cause incapacitation or significant 
impact on participant’s daily life; severity may cause cessation of treatment with study 
treatment; treatment for symptoms may be given and/or participant 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 
Any AE experienced by the participant between the time of first dose of study treatment and the 
participant’s final clinic visit (including follow-up visit) is to be recorded on the eCRF, 
regardless of the severity of the event or its relationship to study treatment. At each study visit, 
the Investigator will assess the participant for AEs and will record any new AEs or updates to 
previously reported AEs on the eCRF. AEs that are ongoing when the participant completes or 
discontinues the study will be followed by the Investigator until the event has resolved, 
stabilized, or returned to baseline status. AEs ongoing at the time of the participant’s study 


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completion outcome will be recorded as ongoing on the eCRF. Serious AEs will be followed via 
ongoing Safety Report updates. 
15.3.2. 
Adverse Events of Special Interest 
An AE of special interest is an AE of scientific and medical concern specific to this study, for 
which ongoing monitoring and reporting are required.  
Hypoglycemia defined as confirmed BG < 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 participant between the time of the signing of the ICF and the last 
follow-up visit 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. 
Participants will be followed for all SAEs until the final study visit. 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 participant 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 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 participant has undergone study-related procedures 
• Whether or not the participant 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. 


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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 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 
Participants should not become pregnant or impregnate their partners during the study 
treatment and for 3 months after their last day of completing study treatment infusion. If a 
female participant becomes pregnant, study treatment must be discontinued immediately. 
The Investigator must report a pregnancy occurring in a female participant 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 participants should 
be reported as SAEs if conception occurred during the study or within 3 months after their last 
day of completing study treatment infusion. 
15.4.2. 
Overdose 
An overdose is any dose of study treatment administered to a participant or taken by a participant 
that exceeds the dose assigned to the participant 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. 


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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 
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 participant’s treatment assignment may 
influence the participant’s clinical care, the Investigator may access the participant’s treatment 
assignment by IRT. The Investigator must document the reasons for unblinding in the 
participant’s source documents. The Investigator is strongly advised not to divulge the 
participant’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 the study and for 3 months after their last day of completing study treatment 
infusion. In addition, participants 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. 


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• 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. 
• 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 participant, 
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 study. 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. 


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• Ensure all AE and SAE reports are supported by documentation in the participants’ 
medical records. 
• 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 participants, the Clinical Monitor is responsible for 
reviewing with 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 primary endpoint of the study will be the change in total contusion volume (hematoma plus 
perihematomal edema), as measured by brain imaging from baseline to 96 hours, or prior to DC, 
IPH evacuation, or CMO, if these procedures occur before 96 hours, per the central review. The 
analysis of the primary endpoint and available data of the secondary endpoints will be performed 
after the last participant completes the Day 4 (Hour 96) Visit. The final analysis will be 
performed after the last participant complete the Day 180 Follow-up Visit. 
A summary of demography, baseline disease characteristics, primary and secondary efficacy 
endpoints, 
 is provided in this section. Analyses of other supportive 
endpoints, including analyses of exposure-response relationships for clinical, imaging, and safety 
outcome measures, will be described in the Statistical Analysis Plan (SAP) prior to the database 
lock, 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, quartiles, and range) or with frequency distributions. 
16.2. 
Efficacy 
16.2.1. 
Analysis Population 
The primary efficacy analyses will be conducted in the modified intent-to-treat population, 
which is defined as participants who are randomized and treated and have at least 1 centralized 
read of contusion volume from an NCCT or MRI scan acquired between 12 hours after the 
initiation of study treatment and by the Hour 96 Visit or prior to DC, IPH evacuation, or CMO, if 
performed before the Hour 96 visit. 
16.2.2. 
Methods of Analysis 
16.2.2.1. General Considerations 
Summary statistics will be presented by treatment group. By-treatment-group analysis will be 
displayed as placebo, BIIB093 3 mg/day, BIIB093 5 mg/day, BIIB093 combined, and total (if 
applicable). For continuous endpoints, summary statistics will generally include the number of 
participants with data, mean, SD, median, quartiles, and range. For categorical endpoints, 
frequency and percentage of participants in each category will be presented. Statistical testing for 
efficacy endpoints will be performed between the BIIB093 (3 mg/day or 5 mg/day) and placebo 
groups. All tests will be 2-sided with a significance level equal to 0.05 (unless otherwise 
specified). 


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Multiplicity will not be adjusted for the tests of the primary and secondary endpoints. 
16.2.2.2. Analysis of the Primary Endpoint 
Primary analysis of the primary endpoint will compare BIIB093 (3 mg/day or 5 mg/day) and 
placebo groups using an ANCOVA (analysis of covariance) model, adjusting for covariates 
including all the stratification factors at randomization, 96 hours imaging modality (MRI vs 
NCCT) and baseline contusion volume per the central read. Multiple imputation will be used to 
account for the missing values for Hour 96. 
Sensitivity analyses for the assumptions will be performed to evaluate the impact of analysis 
sets, the impact of missing data, and the intercurrent event handling. Details will be specified in 
the SAP. 
16.2.2.3. Analysis of the Secondary Endpoints 
GOS-E at Day 180 
GOS-E at Day180 will be analyzed as a 7-category ordinal scale (1/2, 3, 4, 5, 6, 7, and 8) using 
ordinal logistic regression, adjusting for covariates including all the stratification factors at 
randomization and baseline contusion volume per the central review and baseline GCS. Multiple 
imputation will be used to account for missing GOS-E at Day 180. 
mRS at Day 90 
mRS at Day 90 will be analyzed as a 5-category ordinal scale (0/1, 2, 3, 4, and 5/6) using ordinal 
logistic regression, adjusting for covariates including all the stratification factors at 
randomization, baseline contusion volume per the central review, and baseline GCS. 
Proportion of participants requiring delayed intubation 
The proportion of participants requiring delayed intubation at any time between 24 hours and 
96 hours post injury or LKN will be analyzed at Day 4. The analysis will compare BIIB093 
(3 mg/day or 5 mg/day) and placebo groups using a binary logistic regression, adjusting for 
covariates including all the stratification factors at randomization and baseline contusion volume 
per the central review and baseline GCS. 
Change in total contusion volume (hematoma plus perihematomal edema) from baseline to 
24 hours 
An ANCOVA model will be used to compare BIIB093 (3 mg/day or 5 mg/day) and placebo 
groups, adjusting for covariates including all the stratification factors at randomization, and 
baseline contusion volume per the central read. This endpoint will be evaluated for all 
participants having a scan acquired between 12 hours after the initiation of study treatment and 
the end of the Hour 24 Visit. Summary statistics, including by-visit number of participants with 
data, mean, SD, median, quartiles, and range will be provided. 


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Change in absolute hematoma volume from baseline to 24 hours 
Analysis of covariance (ANCOVA) will be performed to compare the mean change from 
baseline between BIIB093 (3 mg/day or 5 mg/day combined) and placebo groups. This endpoint 
will be evaluated for all participants having a scan acquired between 12 hours after the initiation 
of study treatment and the end of the Hour 24 Visit. Summary statistics, including by-visit 
number of participants with data, mean, SD, median, quartiles, and range will be provided. 
Change in absolute edema volume from baseline to 96 hours 
ANCOVA will be performed to compare the mean change from baseline between BIIB093 
(3 mg/day or 5 mg/day) and placebo groups. This endpoint will be evaluated for all participants 
having a scan acquired between 12 hours after the initiation of study treatment and the 
Hour 96 Visit. Multiple imputation will be used to account for missing values for the Hour 96. 
Summary statistics, including by-visit number of participants with data, mean, SD, median, 
quartiles, and range will be provided. 
Time to all-cause death, including neurological death, through Day 90 
Survival time will be analyzed for all randomized participants. Cox proportional hazards 
regression models will be used to assess the treatment effects on overall survival at Day 90 after 
adjusting for covariates including the stratification factors at randomization, baseline contusion 
volume per the central review, and baseline GCS. Kaplan-Meier curves will be presented for 
BIIB093 (3 mg/day or 5 mg/day) and placebo groups. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.5. 
Pharmacogenetics 
The exploration of pharmacogenetic markers will depend on the number of consenting 
participants, the observed degree of PK variability, and the progression of the study. Results 
from any genetic or pharmacogenetic research will be reported separately. 
16.6. 
Safety 
16.6.1. 
Analysis Population 
The safety population is defined as all enrolled participants who receive any portion of the study 
treatment. 
16.6.2. 
Methods of Analysis 
All AEs, laboratory data, ECG, physical examination results, and vital signs will be evaluated for 
safety. 
16.6.2.1. Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities. 
AEs will be analyzed based on the principle of treatment emergence. A treatment-emergent event 
is defined as follows: 
• had onset any time after the start of study treatment, and/or 
• worsened since the event was previously reported (this includes worsening of signs, 
symptoms, laboratory values, or diagnoses that were present prior to the first dose of 
study treatment but then worsened any time after the start of study treatment). 
The incidence of treatment-emergent AEs will be summarized for each treatment group overall, 
by severity, and by relationship to study treatment. SAEs will be presented by treatment group 
and by relationship to study treatment. The summary tables will include incidence estimates for 


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overall system organ classes, as well as for individual events within each system organ class. If a 
participant 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 participant 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 and blood chemistry, including BG. 
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 participants with shifts to categorical values (abnormal but not an 
AE, or abnormal AE) will be summarized by treatment group. 
16.6.2.4. Vital Signs 
Vital signs measures include oxygen saturation, pulse rate, 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 
participants evaluated and the number and percentage of participants with clinically relevant 
postbaseline 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 rate, 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 predosing of at least 
1°C 
Pulse Rate 
> 120 beats per minute and an increase from 
predosing of > 20 beats per minute, or < 50 beats 
per minute and a decrease from predosing of 
> 20 beats per minute 
Systolic Blood Pressure 
> 180 mmHg and an increase from predosing of 
> 40 mmHg, or < 90 mmHg and a decrease from 
predosing of 30 mmHg 
Diastolic Blood Pressure 
> 105 mmHg and an increase from predosing of 
> 30 mmHg, or < 50 mmHg and a decrease from 
predosing of > 20 mmHg 


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16.7. 
Interim Analyses 
An interim analysis may be performed by an internal, independent, unblinded team when 
approximately 90 subjects are dosed for administrative purposes. The interim analysis may 
include, but not be limited to the efficacy, safety, 
 analysis by 
treatment group. A clear process will be specified and implemented to ensure that the treatment 
blinding will be strictly maintained for investigators, subjects, and study personnel from the 
Sponsor and CRO throughout the study. The interim analysis will not inform the continued 
blinded data collection in the study. There is no Type I error adjustment for the proposed interim 
analysis. The interim analysis, if being conducted, will lead to one of the following actions: 
1. Continue to complete the blinded study 
2. Continue to complete the blinded study while accelerating Phase 3 study preparation after 
the interim analysis 
The analysis of the primary and available data for the secondary endpoints will be performed 
after the last participant completes the Day 4 (Hour 96) Visit. 
16.8. 
Sample Size Considerations 
The study is planned to randomize approximately 160 participants. The primary endpoint for the 
study is the change in total contusion volume (hematoma plus perihematomal edema) as 
measured by brain imaging from baseline to 96 hours, or prior to DC, IPH evacuation, or CMO, 
if these procedures occur before 96 hours. Assuming the common standard deviation of 29 mL in 
contusion volume change from baseline, a sample size of 160 participants (40 each in the 
3 mg/day dose or matching placebo arms and 40 each in the 5 mg/day dose or matching placebo 
arms) will have approximately 90% power to detect assumed average difference of 15 mL 
between the pooled active treatment groups (n=80) and pooled placebo groups (n=80) using 2 
group t-test at a 2-sided significance level of 5%. 


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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 f or 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 study site must submit a close-out letter to the 
ethics committee and Biogen. 
 


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17.3. 
Participant 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 
participant, the participant’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 participant, must be explained to the participant (or 
the participant’s LAR). The participant must be given sufficient time to consider whether to 
participate in the study. 
Participants will be informed that their race and ethnicity will be collected (unless not permitted 
by local law or not approved by the governing ethics committee) and will be used during analysis 
of study results. 
In addition, participants who have the capacity should provide their assent to participate in the 
study. The level of information provided to participants 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 participant or the participant’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 participant’s 
medical record. 
17.4. 
Participant 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, participants’ 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 
 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 participant 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 participant’s personal medical 
data confidential. 


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17.5. 
Compensation for Injury 
Biogen maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws. 
17.6. 
Conflict of Interest 
The Investigators should address any potential conflicts of interest (e.g., financial interest in 
Biogen) with the participant before the participant makes a decision to participate in the study. 
17.7. 
Registration of Study and Disclosure of Study Results 
Biogen will register the study and poststudy 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 participants 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 eCRF 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 participants’ 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 locations 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, or may perform monitoring activities remotely (where 
permitted by local regulations) only during the COVID-19 pandemic where onsite monitoring is 
not allowed per local/regional restrictions. A clinical site monitoring plan will detail who 
performs the monitoring, how often, and the extent of review. It also will provide the monitoring 
strategy, with emphasis on participant safety, data integrity, and 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 participant 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. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
19.1. 
External Contract Organizations 
19.1.1. 
Contract Research Organization 
A CRO will be responsible for administrative aspects of the study including but not limited to 
study initiation, monitoring, and management of SAE reports and data management. Before 
participants are screened at each study site, the CRO will review study responsibilities with the 
Investigators and other site staff, as appropriate. 
19.1.2. 
Interactive Response Technology 
IRT will be used in this study. Before participants are screened or enrolled, the IRT vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system. 
19.1.3. 
Electronic or Remote Data Capture 
Participant data will be captured and managed by study sites on a Web-based electronic data 
capture tool (eCRF) configured by the CRO and hosted by the electronic data capture vendor. 
19.1.4. 
Central Laboratories for 
 Pharmacogenetic (as applicable) 
Assessments 
A central laboratory has been selected by Biogen to collect and store laboratory samples (
 
 genetic samples). Analyses will be performed at the central laboratory or by 
specialty laboratories based on assay availability. 
19.1.5. 
Central Facility for Imaging Assessments 
An independent imaging core laboratory (ICL) will collect, review, and analyze medical images 
acquired during this study. A study-specific Imaging Manual, developed by the Sponsor and the 
ICL, details the personnel, processes, and methods involved in managing and evaluating imaging 
data including the process for evaluating contusion volume by MRI and NCCT. The Imaging 
Manual provides standardized settings for imaging data acquisition and interpretation. 
All imaging data, including screening scans from participants consented prior to screen failure 
and those scans acquired as part of SOC for enrolled participants, will be transferred to the ICL. 
The ICL will perform a quality review of the per-protocol imaging data. 
The ICL will also evaluate the follow-up NCCT and MRI scans 
 
 to aid in interpretation of the study results. The ICL will 
remain blinded to treatment assignment throughout the 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. The IDMC may recommend 
the Sponsor to change or terminate the study based on safety data. 
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 participant 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 participant. 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 participant 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 
Carney N, Totten AM, O'Reilly C, et al. Guidelines for the Management of Severe Traumatic 
Brain Injury. 4th: Brain Trauma Foundation; 2016. 
Gerzanich V, Stokum JA, Ivanova S, et al. SUR1, TRPM4 and KIR6.2 – role in hemorrhagic 
progression of contusion. Journal of neurotrauma. 2018. 
Haddad SH, Arabi YM. Critical care management of severe traumatic brain injury in adults. 
Scand J Trauma Resusc Emerg Med. 2012;20:12. Epub 2012/02/03. 
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. 
Jha RM, Bell J, Citerio G, et al. Role of Sulfonylurea Receptor 1 and Glibenclamide in 
Traumatic Brain Injury: A Review of the Evidence. Int J Mol Sci. 2020;21(2) Epub 2020/01/09. 
Jha RM, Puccio AM, Chou SH, et al. Sulfonylurea Receptor-1: A Novel Biomarker for Cerebral 
Edema in Severe Traumatic Brain Injury. Crit Care Med. 2017;45(3):e255-e264. 
Kimberly WT, Battey TW, Pham L, et al. Glyburide is associated with attenuated vasogenic 
edema in stroke patients. Neurocrit Care. 2014;20(2):193-201. 
Kurland D, Hong C, Aarabi B, et al. Hemorrhagic progression of a contusion after traumatic 
brain injury: a review. Journal of neurotrauma. 2012;29(1):19-31. Epub 2011/12/05. 
OʼNeil-Pirozzi TM, Ketchum JM, Hammond FM, et al. Physical, Cognitive, and Psychosocial 
Characteristics Associated With Mortality in Chronic TBI Survivors: A National Institute on 
Disability, Independent Living, and Rehabilitation Research Traumatic Brain Injury Model 
Systems Study. J Head Trauma Rehabil. 2018;33(4):237-245. 
Ortega FJ, Gimeno-Bayon J, Espinosa-Parrilla JF, et al. ATP-dependent potassium channel 
blockade strengthens microglial neuroprotection after hypoxia-ischemia in rats. Exp Neurol. 
2012;235(1):282-96. Epub 2012/02/24. 
Park E, Bell JD, Baker AJ. Traumatic brain injury: can the consequences be stopped? CMAJ. 
2008;178(9):1163-70. 
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. 


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82 
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, Geng Z, Woo SK, et al. Glibenclamide reduces inflammation, vasogenic edema, and 
caspase-3 activation after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 
2009a;29(2):317-30. Epub 2008/10/15. 
Simard JM, Kilbourne M, Tsymbalyuk O, et al. Key role of sulfonylurea receptor 1 in 
progressive secondary hemorrhage after brain contusion. Journal of neurotrauma. 
2009b;26(12):2257-67. 
Simard JM, Popovich PG, Tsymbalyuk O, et al. MRI evidence that glibenclamide reduces acute 
lesion expansion in a rat model of spinal cord injury. Spinal Cord. 2013;51(11):823-7. Epub 
2013/09/17. 
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, Ivanov A, et al. Endothelial sulfonylurea receptor 1-regulated NC 
Ca-ATP channels mediate progressive hemorrhagic necrosis following spinal cord injury. J Clin 
Invest. 2007;117(8):2105-13. 
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. 
Simard JM, Woo SK, Bhatta S, et al. Drugs acting on SUR1 to treat CNS ischemia and trauma. 
Curr Opin Pharmacol. 2008;8(1):42-9. Epub 2007/11/26. 
Simard JM, Woo SK, Tsymbalyuk N, et al. Glibenclamide-10-h Treatment Window in a 
Clinically Relevant Model of Stroke. Transl Stroke Res. 2012c;3(2):286-95. Epub 2012/03/07. 
Song SY, Lee SK, Eom KS, et al. Analysis of Mortality and Epidemiology in 2617 Cases of 
Traumatic Brain Injury : Korean Neuro-Trauma Data Bank System 2010-2014. J Korean 
Neurosurg Soc. 2016;59(5):485-91. Epub 2016/09/08. 
Staykov D, Wagner I, Volbers B, et al. Natural course of perihemorrhagic edema after 
intracerebral hemorrhage. Stroke. 2011;42(9):2625-9. Epub 2011/07/07. 
Wali B, Ishrat T, Atif F, et al. Glibenclamide Administration Attenuates Infarct Volume, 
Hemispheric Swelling, and Functional Impairments following Permanent Focal Cerebral 
Ischemia in Rats. Stroke Res Treat. 2012;2012:460909. Epub 2012/09/04. 
Wilkes S, McCormack E, Kenney K, et al. Evolution of Traumatic Parenchymal Intracranial 
Hematomas (ICHs): Comparison of Hematoma and Edema Components. Front Neurol. 
2018;9:527. Epub 2018/07/04. 


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Zweckberger K, Hackenberg K, Jung CS, et al. Glibenclamide reduces secondary brain damage 
after experimental traumatic brain injury. Neuroscience. 2014;272:199-206. Epub 2014/04/30. 
 


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APPENDIX 1. MEDICATIONS THAT MODULATE CYP2C9 AND 
CYP3A4 
CYP2C9 
Substrates 
Inhibitors 
Inducers 
celecoxib 
Moderate 
Moderate 
Glimepiride 
amiodarone 
rifampin 
phenytoin 
felbamate 
enzalutamide 
tolbutamide 
fluconazole 
aprepitan 
warfarin 
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. 
 
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 
 


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buspirone 
conivaptan 
 
conivaptan 
danoprevir 
 
darifenacin 
elvitegravir 
 
darunavir 
lopinavir 
 
ebastine 
paritaprevir 
 
everolimus 
posaconazole 
 
ibrutinib 
telaprevir 
 
lomitapide 
tipranavir 
 
lovastatin 
Moderate 
Moderate 
dronedarone 
verapamil 
bosentan 
eletriptan 
tofisopam 
efavirenz 
eplerenone 
aprepitant 
etravirine 
felodipine 
erythromycin 
modafinil 
indinavir 
fluconazole 
 
lurasidone 
cimetidine 
 
maraviroc 
ciprofloxacin 
 
quetiapine 
clotrimazole 
 
sildenafil 
crizotinib 
 
ticagrelor 
cyclosporine 
 
tolvaptan 
dronedarone 
 
alprazolam 
imatinib 
 
aprepitant 
fluvoxamine 
 
atorvastatin 
Weak 
Weak 
colchicine 
ticagrelor 
armodafinil 
eliglustat 
chlorzoxazone 
rufinamide 
pimozide 
cilostazol 
 
rilpivirine 
fosaprepitant 
 
rivaroxaban 
istradefylline 
 
tadalafil 
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, “A Multicenter, Double-Blind, Multidose, 
Placebo-Controlled, Randomized, Parallel-Group, Phase 2 Study to Evaluate the Efficacy and 
Safety of Intravenous BIIB093 for Patients with Brain Contusion,” 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 Signature 
 
 
 
Date (DD MMM YYYY) 
 
 
____________________________________________________ 
Investigator’s Name (Print) 
 
 
 
____________________________________________________ 
Study Site (Print) 
 
 


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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 
 
 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Protocol 252BN201 
A Multicenter, Double-Blind, Multidose, Placebo-Controlled, Randomized, Parallel-Group, 
Phase 2 Study to Evaluate the Efficacy and Safety of Intravenous BIIB093 for Patients with 
Brain Contusion 
Version 3 
Date: 14 November 2022 
EUDRA CT Number: 2018-003858-24 
Version 3 of the protocol has been prepared for this amendment, which supersedes Version 2. 
 


Amendment Summary for Protocol 252BN201, Version 3.0 
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PRIMARY REASON FOR AMENDMENT 
The primary reasons for this amendment to Protocol 252BN201 is to expand the patient 
population to reflect the more common clinical presentation of TBI patients with contusion, 
update the primary endpoint analysis to consider contusion volume as a continuous variable, and 
include an interim analysis to facilitate an early opportunity to begin Phase 3 planning. The study 
population will be expanded to include those indicated for surgery and those with survivable 
polytrauma which will also be facilitated by the removal of midline shift and injury severity 
score thresholds. The dosing time window will be extended to 10 hours to allow for additional 
patients to be treated including inter-hospital transfers. An interim analysis, conducted by a 
separate unblinded team, will facilitate an earlier start to Phase 3 planning while continuing the 
Phase 2 as a blinded study. 
New text is shown in bold type; deleted text is shown with a strikethrough. 
Section 8.1, Inclusion Criteria 
Now reads: 
6. Randomization Study drug (BIIB093) must be infused must occur within 6 no more than 
10 hours post trauma, if known, or LKN last known normal (if time of trauma is unknown), 
and within 6 hours of hospital arrival. Dosing should be initiated within 1 hour of 
randomization and continue for 96 hours (4 days).  
Rationale: Inclusion criterion 6 was updated to expand the treatment time window, which would 
allow for inclusion of late presenters and to ensure that dosing of early patients is not delayed. 
This update would address the highest rate of recruitment failures, thereby accelerating 
recruitment in the process. The impact of dosing time on treatment effect will be explored. 
This change also affects Sections 1, Synopsis; 4.5.1, Dosing Regimen; 5, Schedule of Activities 
(Table 2); 7.1, Study Overview, including Figure 1, Study Design; and 9.1, Screening. 
Section 8.1, Inclusion Criteria 
Now reads: 
8. Absence of immediate indication for intracranial surgery to decompress or evacuate 
hematoma. 
Note: presence of other injuries within the cranial vault will be allowed provided they do not 
require immediate operative intervention (including rim subdural, epidural, subarachnoid, or 
intraventricular hemorrhage). Previous or planned insertion of external ventricular drains or 
drilling of burr holes are permitted. 


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Rationale: Inclusion criterion 8 was removed to allow operative intervention for extra-axial 
injuries and new exclusion 8.2. 
Section 8.2, Exclusion Criteria 
Now reads: 
2. Indication for immediate evacuation of IPH or DC.  
Rationale: Exclusion criterion 2 was updated to allow operative intervention for extra-axial 
injuries. 
This change also affects Section 5, Schedule of Activities, Table 2 (renumbered footnote 7). 
Section 8.2, Exclusion Criteria 
Now reads: 
8. Midline Shift >5 mm on baseline NCCT or MRI 
Rationale: Exclusion criterion 8 was removed because midline shift at baseline is often a 
function of extra-axial injuries, and the study now allows for operative management that could 
affect such injuries.  
Section 8.2, Exclusion Criteria 
Now reads: 
26. Life-threatening or nonsurvivable pPolytrauma per Investigator’s judgement.(intra-
abdominal or orthopedic trauma) requiring operative surgical management, if known. Minor 
fractures requiring splinting or reduction of dislocations are permitted, as are non-operative 
intra-abdominal injuries or placement of noninvasive external fixation devices. 
Note: as per the Investigator’s discretion, radiology procedures for embolization are allowed, 
provided they are minor and not associated with large-volume bleeding. 
Rationale: Exclusion criterion 26 was reworded to specify life-threatening or nonsurvivable 
polytrauma, based on site feedback that many patients with contusions have polytrauma. Patients 
with non-life threatening/survivable polytrauma may benefit from the drug, and enrollment of 
these patients would increase generalizability of results. Polytrauma that is normally survivable 
will have minimal impact to the primary endpoint of change in total contusion volume 
(hematoma plus perihematomal edema) for the following reasons: 
a. Polytraumas that lead to significant hematologic derangements will be excluded 
through laboratory exclusion criteria. Hematologic derangements would likely affect 
hematoma expansion. 


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b. Polytraumas that are likely nonsurvivable would likely lead to significant volume of 
fluid to resuscitate the patient which would likely lead to some effect on our primary 
outcome. 
c. Current TBI outcome predictors (IMPACT, CRASH) do not utilize the degree of 
polytrauma in their functional outcomes.  
Section 16.7, Interim Analysis 
Change: An interim analysis was added to the protocol. 
Now reads:  
No formal interim analysis was planned for the study. An interim analysis may be performed 
by an internal, independent, unblinded team, when approximately 90 subjects are dosed 
for administrative purposes. The interim analysis may include, but not be limited to the 
efficacy, safety, 
 analysis by treatment group. A clear 
process will be specified and implemented to ensure that the treatment blinding will be 
strictly maintained for investigators, subjects, and study personnel from the Sponsor and 
CRO throughout the study. The interim analysis will not inform the continued blinded 
data collection in the study. There is no Type I error adjustment for the proposed interim 
analysis. The interim analysis, if being conducted, will lead to one of the following actions: 
2. Continue to complete the blinded study. 
3. Continue to complete the blinded study while accelerating Phase 3 study 
preparation after the interim analysis. 
Rationale: The Sponsor plans to conduct an interim analysis in order to support internal decision 
making to enable pivotal study planning. Introduction of an interim analysis at N=90 would 
allow for an early signal to facilitate an earlier Phase 3 start. The final decision to start the Phase 
3 study will also depend on feedback from regulatory agencies and the continued data collection 
in the Phase 2 study. 


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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL 
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough. 
Section 1, Synopsis 
The synopsis was revised to reflect changes made throughout the protocol. 
Section 4.5.1.2, Selection of 5 mg/day 
Change: Clarified that exposure data from the 5 mg/day dose was the result of simulations. 
Now Reads: 
The no observed adverse effects level was considered to be 18.2 mg/kg, which provides exposure 
margins of 3-fold and 6-fold based on the maximum observed concentration and concentration at 
steady state (Css), respectively, at 5 mg/day. The exposure data at 5 mg/day are the result of 
simulations. 
Rationale: This change was made to ensure accurate reporting, and to meet a regulatory 
commitment to the French Regulatory Agency. 
Section 5, Schedule of Activities, Table 2 
Change: A new footnote pertaining to scans in relation to IPH evacuation, DC, or CMO was 
added to the NCCT and MRI row in Table 2. 
Now reads: 
5Scans (NCCT or MRI) obtained within 12 hours of IPH evacuation, DC, or CMO meet the 
requirement. Scans are not expected for other NSx interventions. If IPH evacuation, DC, or 
CMO are indicated prior to 96 hours, an NCCT or MRI scan in the 12 hours proceeding 
the procedure should be collected, and no further post-procedural images are required 
beyond SOC. 
This change also affects Section 6, Study Objectives and Endpoints (Primary Objectives and 
Endpoints, 
), and Section 13.1, Clinical Efficacy 
Assessments. 
Rationale: These changes were made to ensure that all scans are acquired as part of SOC and to 
allow use of them in cases of CMO or surgery involving IPH evacuation or DC.  It also clarifies 
that subsequent scans after IPH evacuation, DC, or CMO are not required.  
 


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Section 5, Schedule of Activities, Table 2 
Change: A new footnote pertaining to optional NCCT scans was added. 
Now Reads: 
7Optional Hour 96 NCCT should be obtained in addition to the MRI whenever possible, 
after study treatment infusion is complete, within 18 hours of the Hour 96 timepoint. 
Rationale: Measurement of contusion volume changes based on 96-hour MRI, and baseline 
NCCT may be influenced by the difference in sensitivity of the 2 imaging modalities. An 
optional 96-hour NCCT is being added to the assessment schedule to collect evidence on both 
NCCT and MRI in a subset of patients to allow for comparison of contusion volume between 
modalities. This additional NCCT is per investigator judgment and not expected to replace the 
existing MRI in cases where MRI is feasible. 
This change also affects Section 13.1, Clinical Efficacy Assessments. 
Section 5, Schedule of Activities, Table 2 
Change: Changed assessment language regarding MRI/NCCT, and this change was also 
reflected in the footnote.  
Now reads: MRI (if not possible NCCT is acceptable)MRI5, 14 
14 If An NCCT scan is sufficient for participants who cannot get an MRI. A participant 
cannot get an MRI due to the participant’s clinical condition, contraindication to MRI, or MRI 
technician/MRI unavailability, the participant is to get an NCCT scan. 
Rationale: This change was made to support the flexibility to use NCCT instead of MRI if MRI 
is contraindicated. 
Section 6, Study Objectives and Endpoints 
Change: The primary endpoint was amended to increase statistical power to detect a meaningful 
treatment effect while recognizing any reduction in contusion volume is desirable to detect. The 
GOS-E at Day 180 was 
 added as one of the secondary 
endpoints.
 
 Change in total contusion volume (hematoma plus perihematomal edema) 
from baseline to 24 hours was added as one of the secondary endpoints. 
Now reads: 
Primary Endpoint: 


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Change in total contusion volume (hematoma plus perihematomal edema) as measured by 
brain imaging from baseline to 96 hours or prior to DC, IPH evacuation, or CMO if these 
procedures occur before 96 hours per the central review. 
Proportion of participants with contusion (hematoma plus perihematomal edema) expansion by 
Hour 96 (or prior to NSx or CMO). 
Note: to meet criteria for expansion of total contusion volume per the central review, a 
participant must have the following: 
• ≥ 50% increase from baseline contusion volume, and 
• ≥ 4.0 mL absolute increase from baseline 
OR 
• ≥ 10.0 mL total expansion from baseline 
Secondary Endpoint: 
• Glasgow Outcome Scale-Extended (GOS-E) at Day 
 180. 
• Change in total contusion volume (hematoma plus perihematomal edema) as 
measured by brain imaging from baseline to 24 hours or prior to DC, IPH 
evacuation, or CMO if these procedures occur before 24 hours per the central 
review. 
• Change in absolute hematoma volume from baseline to 24 hours 
• Change in absolute edema volume from baseline to 96 hours 
Rationale: According to the current protocol definition of expansion, the pooled blinded 
proportion of patients meeting the contusion expansion criteria appeared to be very high, 
particularly for participants with MRI scans at 96 hours. This high proportion was significantly 
greater than the assumed 50% proportion in the placebo arm used to justify sample size. The 
revised primary endpoint analysis will treat contusion volume as a continuous variable and 
assess the change in volume from baseline as a continuous variable; adjusted by imaging 
modality. Change in contusion volume at 24 hours was added as a secondary endpoint which will 
involve NCCT to NCCT comparison. The Day 180 GOS-E assessment will be favored over its 
Day 
 measurement as it is the registrational endpoint in TBI studies. 
This change also affects Section 7.1, Study Overview; Section 11.4.2.1, Neurosurgical 
Intervention; Section 13.1, Clinical Efficacy Assessments; Section 16, Statistical Methods and 
Determination of Sample Size; Section 16.2.1, Analysis Population; Section 16.2.2.2, Analysis 
of the Primary Endpoint; Section 16.2.2.3, Analysis of the Secondary Endpoints; and 
Section 16.8, Sample Size Considerations. 


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Section 6, Study Objectives and Endpoints 
Change: 
 
 
 
GOS-E at Day 
 replaced GOS-E at Day 180. 
Now reads: 
 
 
 
 
 
 
Rationale: 
 
  
Section 7.1, Study Overview 
Change: The database-lock language was changed to remove the Day 90 lock 
Now reads: 
The study database will first be locked after the last participant finishes their Day 4 Visit and the 
primary and imaging based endpoints will be analyzed. A final study database-lock will occur 
when the last participant completes their Day 90 Follow-up Visit to analyze key functional 
outcomes. The long term follow-up database will be locked for evaluation of long term safety 
and efficacy after the last participant completes the Day 180 Follow-up Visit. The end of the 
study is when the last participant completes their Day 180 assessments. 
After the last participant completes their Day 4 (Hour 96) Visit, data for the primary 
endpoint and available data for the secondary endpoints will be locked for analysis. The 
final database lock will occur after the last participant completes their Day 180 Follow-up 
Visit, marking the end of the study. 
Rationale: The 90 Day database lock did not add significant value to accelerate study 
interpretation. This change is consistent with the greater importance of the Day 180 GOS-E over 
Day 
 GOS-E.  


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This change also affects Section 9.3, Blinding Procedures, and Section 16, Statistical Methods 
and Determination of Sample Size. 
Section 8.2, Exclusion Criteria 
Change: Exclusion criterion 14 was removed. 
Now reads:  
14. Injury Severity Score (not including head or face) >12. 
Rationale: This criterion was removed to be consistent with allowance of polytrauma patients.   
Section 11.4.1.1.1, Interventions Related to Blood Glucose 
Change: More detailed guidance for managing BG while on treatment was added. 
Now Reads: 
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 studies involving glucose-lowering drugs [International 
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; however, Investigators must use their own medical judgment in 
conjunction with referencing the guidance (Table 5). 
Insulin 
Insulin and other BG-lowering agents are not permitted during study treatment administration 
when BG is < 120 140 mg/dL (~6.7 7.8 mmol/L). 
Maintenance Fluids Dextrose-Containing IV Solution 
During the study treatment infusion period, BG monitoring is required as follows:  
• Hour 0 to Hour 24, monitor hourly (±30 minutes) for 
• Hour 0 25 to Hour 24 48, monitor every 2 hours (±30 minutes) for 
•  Hour 25 49 to Hour 48 96, and monitor every 4 hours (±60 minutes) for Hour 49 to 
Hour 96 
(s See Section 5 for further details on timings of BG measurements). If treatment for 
hypoglycemia is initiated (for BG <70mg/dL [~3.9 mmol/L]), then BG monitoring is required 
every 15 minutes (±10 minutes) until BG is ≥ 80 mg/dL (~4.4 mmol/L) for 3 consecutive 


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readings without exogenous bolus glucose supplementation. BG monitoring may be performed 
more often at the discretion of the Investigator. Table 5 shows how BG should be monitored and 
managed according to inpatient BG levels. 
Total fluid volume, inclusive of study treatment volume, infusion rate, infusion duration, 
sodium content, and percent of dextrose, should be guided by the clinical status of the 
subject and medical judgment. 
It is recommended that maintenance dextrose-containing IV solution be initiated when BG 
is < 120 mg/dL (~6.7 mmol/L) and maintained for the duration of the study treatment 
administration (up to 96 hours) with the new glycemic BG target in the range of  140 to 
< 180 mg/dL (~7.8-10 mmol/L). 


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Table 5: 
Blood Glucose Monitoring and Management 
Inpatient BG Level 
BG Monitoring and Management1 
>120 mg/dL (~6.7 mmol/L)2 
It is recommended that neither D5NS nor D10NS are administered. 
Initiation of dextrose-containing IV solution 
< 120 mg/dL (~6.7 mmol/L)2  
• 
It is recommended that D5NS D10NS at 35 to 50 mL/h be 
initiated as first-line management. Consider D5NS at a rate 
of 70 to 100 mL/h or other percent dextrose solutions as 
alternatives. is administered. 
• 
Insulin and other BG lower agents are not permitted during 
study treatment administration when BG < 120 mg/dL (~6.7 
mmol/L). 
Maintenance of dextrose-containing IV solution after initiation 
≥180 mg/dL (~10 mmol/L) 
• 
It is recommended that dextrose-containing IV solution be 
titrated downward or stopped temporarily until BG is ≥ 140 
to < 180 mg/dL (~7.8 to ~10 mmol/L). 
<180 mg/dL (~10 mmol/L) but 
≥140 mg/dL (~7.8 mmol/L) 
• 
It is recommended that dextrose containing IV solution be 
maintained or titrated to keep BG as ≥140 mg/dL (~7.8 
mmol/L) but < 180 mg/dL (~10 mmol/L). 
<140 mg/dL (~7.8 mmol/L) but 
≥ 80 mg/dL (~4.4 mmol/L) 
• 
Insulin and other BG lowering agents are not permitted 
during study treatment administration when BG is 
< 140 mg/dL (~7.8 mmol/L). 
• 
It is recommended that dextrose-containing IV solution be 
maintained when BG is < 140 mg/dL (~7.8 mmol/L). Titrate 
up the IV infusion rate to keep BG ≥ 140 mg/dL 
(~7.8 mmol/L) but < 180 mg/dL (~10 mmol/L). 
< 100 mg/dL (~5.6 mmol/L)2 
• 
It is recommended that D5NS is started at 70 to 100 mL/hr. 
• 
It is recommended that the IV fluid rate is titrated up or down 
to maintain BG > 80 mg/dL (~4.4 mmol/L). 
< 80 mg/dL (~4.4 mmol/L)2 
• 
D5NS must be started or, if D5NS is already being 
administered , the participants must be switched to D10NS. 
• 
It is recommended that the infusion rate of the dextrose-
containing IV solution be increased to keep BG 
≥ 140 mg/dL (~7.8 mmol/L) but < 180 mg/dL (~10 mmol/L). 
< 70 mg/dL (~3.9 mmol/L) 
 
 
 
 
 
• 
It is recommended that the infusion rate of the dextrose-
containing IV solution be increased after the dextrose 
bolus. 
• 
It is recommended that the infusion rate of the dextrose-
containing IV solution be titrated up to keep BG 
≥ 140 mg/dL (~7.8 mmol/L) but < 180 mg/dL (~10 mmol/L) 


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BG = blood glucose; D10NS = 10% dextrose in normal saline (or fluid containing 10% dextrose); D5NS = 5% 
dextrose in normal saline (or fluid containing 5% dextrose); IV = intravenous. 
1 Total fluid volume, inclusive of study treatment volume, should be consistent with site practice and guided by 
clinical status of the participant and medical judgment. 
2 Participants with a BG level greater than 70 mg/dL (~3.9 mmol/L) are not required to receive dextrose if they have 
cardiac or renal issues necessitating reduced fluid intake. 
Rationale: Protocol guidelines are updated to optimize blood- and dextrose-containing 
maintenance IV solution management to prevent or reduce the occurrence of hypoglycemia and 
to minimize fluid or sodium overload.  
This change also affects Section 10.1, Discontinuation of Study Treatment, and Section 11.4.1.2, 
Disallowed Concomitant Therapy. 
 
 
 
 
 
Inpatient BG Level 
BG Monitoring and Management1 
< 55 mg/dL (~3.0 mmol/L) 
• 
Study treatment infusion rate must be reduced as follows: 
o If hypoglycemia occurs within the first 6 hours of 
infusion: 
 
For participants on high infusion rate 
(0.2722 mg/h), the infusion rate must be 
reduced to 0.1644 mg/h. If hypoglycemia 
cannot be rectified or reoccurs, the infusion 
rate must be further reduced to 0.0795 mg/h 
and must not be uptitrated. 
 
For participants on low infusion rate 
(0.1644 mg/h), the infusion rate must be 
reduced to 0.0795 mg/h and must not be 
uptitrated. 
o If hypoglycemia occurs after the first 6 hours of 
infusion, the infusion rate must be reduced to 
0.0795 mg/h. The infusion rate can be uptitrated to 
0.1134 mg/h when BG is > 80 mg/dL (~4.4 mmol/L) 
for 3 consecutive readings. 
• 
Study treatment should be discontinued if hypoglycemia cannot 
be rectified and is determined by the Investigator to be harmful 
to the participant. 


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Section 18.3, Monitoring of the Study 
Change: Language added regarding the remote monitoring of study sites. 
Now Reads: 
The Clinical Monitor will visit the study site at regular intervals during the study and after the 
study has completed, as appropriate, or may perform monitoring activities remotely (where 
permitted by local regulations) only during the COVID-19 pandemic where on-site 
monitoring is not allowed per local/regional restrictions. 
Rationale: Accommodate remote clinical study site visits in the context of possible disruptions 
related to COVID-19.  


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SUMMARY OF MINOR CHANGES TO THE PROTOCOL 
The following minor changes were made to the protocol, as appropriate: 
• The version number and date were updated throughout the protocol. 
• Heart rate was replaced with pulse rate when referencing vital signs for 
harmonization with the CDISC CDASH industry standards. 
• The Sponsor Signatory name and credentials were updated. 
• It was specified that analysis of the primary and available data for the secondary 
endpoints will be performed after the last participant completes the Day 4 (Hour 96) 
Visit. 
• Section 2, List of Abbreviations, was updated. 
• In Section 4.5.1, Dosing Regimen, language was rephrased to start with the strictest 
dosing requirements, and in Table 1 (BIIB093 Dosing Regimen), the bolus infusion 
volume of study treatment was removed for the 3- and 5-mg dose due to anticipated 
changes in saline bag volume and concentration. The bolus infusion volume was also 
removed in Section 11.1, Regimen. 
• In Section 5, Schedule of Activities, Table 2, the following updates were made: 
− “Craniectomy” was removed from the column header and replaced with “NSx.” 
− “Comfort Care” was replaced with “Comfort Measures” in the column header for 
consistency. 
− Weight and height were specified as part of the physical examination. 
− Footnote 4 was updated to specify that if follow-up visits at Day 90 and 180 were 
conducted remotely, 
. (This was 
also reflected in Section 13.1, Clinical Efficacy Assessments.)  
− Footnotes were renumbered due to the addition of footnotes 5 and 7.  
− Footnote 13 was updated to say that 
 eCRFs, not a DC eCRF, should be 
completed for participants who receive 
.  
• In Section 6, Study Objective and Endpoints, It was clarified in the Primary Objective 
that scans be obtained prior to DC, IPH evacuation, or CMO if these procedures occur 
before Hour 96.  


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• In Section 8.2, Exclusion Criteria, criterion 32 was updated to allow enrollment of 
patients for whom anticoagulation from NOACs can be adequately reversed with 
Andexanet alfa. 
• In Section 9.3, Blinding Procedures, a paragraph describing how the interim analysis 
will be performed by an independent unblinded team was added. 
• In Section 10.1, Discontinuation of Study Treatment, the phrase “study treatment 
must be discontinued” was removed from the first bullet to avoid repetition. 
• In Section 11.4.1, Concomitant Therapy, it was clarified that all concomitant therapy 
will be recorded in the appropriate eCRF. 
• In Section 11.4.2, Concomitant Procedures, a sentence was added stating that the use 
of unapproved therapies and/or procedures is not permitted. 
• In Section 11.4.2.2, Intubation, the first sentence in the second paragraph was 
reworded from “after the start of infusion” to “after the injury.” 
• In Section 12, Study Treatment Management, language was changed to state that the 
DHA should align with all other reference documents instead of superseding all other 
documents. This revision is in response to a minor finding from an MHRA 
inspection. In addition, references to Pharmacy Manual were changed to DHA. 
• In Section 15.3.1, Adverse Events, clarifying language was added with regard to 
recording of ongoing AEs in the eCRF after study completion. 
• In Section 16.2.2.2, Analysis of the Primary Endpoint, and Section 16.2.2.3, Analysis 
of the Secondary Endpoint, it was stated that multiple imputation would be used to 
account for missing values at Hour 96. 
 


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LIST OF ABBREVIATIONS 
BG 
blood glucose 
CDISC 
Clinical Data Interchange Standards Consortium 
CDASH 
Clinical Data Acquisition Standards Harmonization 
CMO 
comfort measures only 
COVID-19 
Coronavirus disease 2019 
DC 
decompressive craniectomy 
DHA 
Directions for Handling and Administration 
eCRF 
electronic case report form 
GOS-E 
Glasgow Outcome Scale – Extended 
IPH 
intraparenchymal hematoma 
IV 
intravenous 
LKN 
last known normal 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRI 
magnetic resonance imaging 
NCCT 
noncontrast computed tomography 
NOAC 
novel oral anticoagulants 
NSx 
neurosurgical intervention 
SOC 
standard of care 
 


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Biogen Idec Research Limited
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______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 252BN201
A Multicenter, Double-Blind, Multidose, Placebo-Controlled, Randomized, Parallel-Group, 
Phase 2 Study to Evaluate the Efficacy and Safety of Intravenous BIIB093 for Patients with Brain 
Contusion
Version 2
Date: 18 February 2020
EUDRA CT Number: 2018-003858-24
Version 2.0 of the protocol has been prepared for this amendment, which supersedes Version 1.


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PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 252BN201 is to expand the population base 
for treatment with BIIB093. The age range for study inclusion was increased from up to 80 years 
old to up to 85 years old. In addition, the Glasgow Coma Scale (GCS) score range for study 
inclusion was increased from up to 14 to up to 15.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 8.1, Inclusion Criteria
Now reads:
2.
Aged 18 to 8085 years old, inclusive, at the time of informed consent.
Note: age 18 years at the time of informed consent or participant meets the minimum age 
of consent in accordance with national regulations (whichever is higher).
Note: for countries where the minimum age of consent is over 18 years, participants 
may be enrolled provided a LAR is available, and if capable, the participant assents 
to treatment. The LAR must consider the participant’s involvement in the study and 
provide informed consent for the participant.
3.
A score of 5 to 1415 on the GCS. Assessment should be made prior to medical 
intervention, where possible.
Note: an enrollment cap of participants presenting with GCS 15 will be placed at 
10% of total number of participants.
Rationale: This development program is intended to benefit as many participants as is feasible 
as well as scientifically-justified. The liberalization of enrollment criteria is intended to achieve a 
wider range of participants who might benefit from potential treatment with BIIB093. The first 
change related to age was based on review of prescreening data. Age range was increased based 
on data demonstrating participants > 80 but < 85 years of age are presenting with contusions and 
undergoing active medical care with good prognosis based on presenting GCS scores.
Secondly, many participants with contusions > 3 cc are presenting with unaltered neurologic 
status (GCS 15) and given the propensity for contusions to expand and clinical deterioration to 
occur as a result, these participants may benefit from treatment with BIIB093. With the inclusion 
of participants with GCS 15, an enrollment cap at 10% was placed to ensure that the study 
population is well-balanced amongst presenting GCS participants and to prevent excessive 
enrollment of participants with mild complicated traumatic brain injury. This change also affects 
Section 1, Synopsis; Section 7.1, Study Overview; and Section 9.2, Randomization.


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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 1, Synopsis
The synopsis was revised to reflect changes made throughout the protocol.
Section 5, Schedule of Activities, Table 2
Change: Footnote 2 was updated to clarify that if a participant is discharged from the hospital 
prior to Hour 96, sites should still obtain neuroimaging prior to the participant departing the 
hospital.
Footnote 11 was updated to clarify the definition of low blood glucose (BG).
Footnote 13 was updated to clarify that participants can get a noncontrast computed tomography 
(NCCT) scan if a magnetic resonance imaging (MRI) is not possible due to the participant’s 
clinical condition, contraindication to MRI, or MRI technician/MRI unavailability.
Footnote 14 was updated to clarify that Hour 96 MRI scan should be performed within 18 hours
of the Hour 96 time point.
Now reads:
2
In the event that a participant rapidly improves and is discharged from the intensive care 
unit before hospital prior to Hour 96 hours, every effort should be made to obtain 
theneuroimaging (NCCT/ or MRI scans) prior to discharge.
11
Hourly (±30 minutes) for Hour 0 to Hour 24, every 2 hours (±30 minutes) for Hour 25 to 
Hour 48, and every 4 hours (±60 minutes) for Hour 49 to Hour 96. If treatment for hypoglycemia
low BG (< 70 mg/dL [~3.9 mmol/L]) is initiated, then BG monitoring is required every 
15 minutes (±10 minutes) until BG is ≥80 mg/dL (~4.4 mmol/L) for 3 consecutive readings 
without exogenous bolus glucose supplementation. See Section 11.4.1.1.1 for details on BG 
monitoring and management.
13
If a participant cannot get an MRI for any reason (e.g., due to the participant’s clinical 
condition, contraindication to MRI, or equipment unavailable),MRI technician/MRI 
unavailability, the participant is to get an NCCT scan.
14
The 96-hour scan should be performed after study treatment infusion is complete, within 
18 hours of the Hour 96 time point.


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Rationale: Footnote 2 was updated to clarify that neuroimaging needs to be obtained prior to 
participant discharge in the event the participant is due to be discharged from hospital prior to 
Hour 96 due to clinical improvement.
Footnote 11 was updated to clarify that frequent BG monitoring every 15 minutes is required 
when BG < 70 mg/dL and not when BG < 55 mg/dL (per protocol definition of hypoglycemia).
Footnote 13 was updated to clarify that NCCT scan should still be obtained in the event an MRI 
is untenable due to participant’s clinical deterioration, contraindication to MRI, or 
equipment/technician unavailability.
Footnote 14 was updated to extend the time window for Hour 96 MRI and be consistent with the 
MRI to be acquired post treatment infusion. The extended time window reflects feedback from 
sites on the availability of MRI and need for extra time to conduct this assessment, given the 
possibility of participant presentation during off-hours (11 pm to 6 am).
Section 6, Study Objectives and Endpoints
Change:
Objectives related to evaluation of BIIB093 was updated.
Now reads:
To evaluate the 
 of BIIB093 up to Day 7/Discharge.4 (Hour 96).
Rationale: The infusion is discontinued at Day 4, the timing of the primary endpoint. Exposure 
to BIIB093 will rapidly decline from this point onward.
Section 7.1, Study Overview
Change: Schedule of study database lock and timing of endpoint analyses were clarified.
Now reads:
The study database will first be locked after the last participant finishes their Day 90 follow-up
visit4 Visit and the primary and secondaryimaging-based endpoints will be analyzed in the 
primary and secondary efficacy analyses. A final study database lock will occur when the last 
participant completes their Day 180 follow90 Follow-up visitVisit to analyze key functional 
outcomes. The long-term follow-up database will be locked for evaluation of long-term 
safety and efficacy after the last participant completes the remaining endpoints.Day 180 
Follow-up Visit. The end of the study is when the last participant completes their Day 180 
assessments.
Rationale: The schedule of the first study database lock was updated from after Day 90 to after 
Day 4. This change is consistent with the analysis of the primary endpoint which will be 
performed on Day 4 (Hour 96). Further clarification was added to specify that the final study 
database will be locked at Day 90 and the long-term follow-up database will be locked at 


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Day 180. These changes are also consistent with the analyses of key functional outcomes on 
Day 90 and long-term safety and efficacy endpoints on Day 180.
This change also affects Section 9.3, Blinding Procedures, and Section 16, Statistical Methods 
and Determination of Sample Size.
Section 8.1, Inclusion Criteria
Change: The mechanism of injury for study inclusion was clarified.
A note was added to inclusion criterion 8.
Now reads:
5.
Mechanism of injury is well defined.
First-responders/Note: emergency medical staff report identifiestechnicians, emergency 
physicians, or members of the study team can identify a clearlikely or possible
mechanism of head injury, i.e., motor vehicle accidents, assault, pedestrian struck, fall, or 
sports injuries, etc based on the clinical history and/or patient presentation.
a.
Presence of other injuries within the cranial vault will be allowed provided they 
do not require operative intervention (including rim subdural, epidural, subarachnoid, or 
intraventricular hemorrhage).
8.
Absence of immediate indication for intracranial surgery to decompress or 
evacuate hematoma.
Note: presence of other injuries within the cranial vault will be allowed provided 
they do not require immediate operative intervention (including rim subdural, 
epidural, subarachnoid, or intraventricular hemorrhage). Previous or planned 
insertion of external ventricular drains or drilling of burr holes are permitted.
Rationale: The change in inclusion criterion 5 was based on site feedback in which an exact 
mechanism of trauma was unknown. Liberalization of this wording is to allow for enrollment of 
participants whose injury-circumstances are not entirely clear but who may benefit from 
treatment nonetheless, so long as they remain within the treatment window.
The change in inclusion criterion 8 was made to clarify the meaning of “intracranial surgery” and 
that burr hole placement or external ventricular drain insertion are not exclusionary.


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Section 8.2, Exclusion Criteria
Change: The exclusion criterion for NCCT or MRI was clarified.
The use of transient vasopressor was clarified.
The use of interventional radiology procedures for embolization was clarified.
The use of vitamin K antagonists in the study was clarified.
Now reads:
3.
NCCT or MRI evidence of penetrating brain injury. impacting the brain 
parenchyma. Cerebrospinal fluid leak in isolation is not exclusionary unless 
evidence of parenchymal penetration by an external force (e.g., blunt object, bullet, 
or depressed skull fracture).
25.
Hemodynamic instability (use of inotrope or vasopressor therapy or resuscitation 
requiring > 6 L crystalloid or colloid).
Note: transient vasopressor used to support blood pressure during specific 
procedures (e.g., intubation or hypotension associated with sedation/analgesics) is 
permitted.
27.
Polytrauma (intra-abdominal or orthopedic trauma) requiring operative/surgical 
management, if known. Minor fractures requiring splinting or reduction of dislocations 
isare permitted, as are nonoperative intra-abdominal injuries or placement of 
noninvasive external fixation devices.
Note: as per the Investigator’s discretion, interventional radiology procedures for 
embolization are allowed, provided they are minor and not associated with 
large-volume bleeding.
35.
Use of vitamin K antagonists within 5 days prior to the injury, if known.
Note: patients on vitamin K antagonists who are subtherapeutic with INR < 1.5 may be 
included. If a patient can be adequately reversed from vitamin K antagonism to a 
subtherapeutic INR in time for randomization, this is acceptable, and the patient 
should be screened for enrollment.
Rationale: The change in exclusion criterion 3 was made to clarify that cerebrospinal fluid leaks 
are not exclusionary and provide further clarity on the meaning of “penetrating brain injury”.
The change in exclusion criterion 25 was based on the Investigator’s feedback at the 
Investigator’s meeting, vasopressors are often transiently used for blood pressure support during 


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procedures. This is to clarify that this does not reflect a hemodynamically unstable participant
and that these participants are eligible for enrollment.
The change in exclusion criterion 27 was based on the Investigator’s feedback at the 
Investigator’s meeting, trauma participants may undergo noninvasive endovascular repair of 
small-volume bleeding unlikely to affect volume status or the primary endpoint. These 
participants should be included.
The change in exclusion criterion 35 was made to provide additional clarity that reversal of 
vitamin K antagonists is acceptable.
Section 9.1, Screening
Change: Suicidal ideation assessment was added to the schedule of activities at Baseline and 
follow-up.
Now reads:
Because pertinent participant information will already be collected as part of SOC, and to reduce 
additional study-specific procedures, baseline information may be taken from the participant’s 
medical records prior to obtaining informed consent. However, informed consent will be 
obtained prior to performing any study-specific procedures.
A short suicidal ideation/behavior questionnaire will be conducted on participants who are 
alert and capable of providing answers at Screening (prior to dosing). For these 
participants, this questionnaire should be repeated at Days 30, 90, 180, and ET Visit.
Rationale: This change was made to comply with regulatory draft guidance stipulating that 
prospective suicidal ideation and behavior assessments should be carried out in all clinical trials 
involving any drug being developed for CNS activity. This assessment will only be carried out in 
participants deemed capable of understanding and appreciating the content of the questionnaire. 
In addition, this change was made to understand any possible association between BIIB093 and 
suicidal ideation in participants with brain contusion.
This change also affects Section 5, Schedule of Activities (Table 2) and Section 14.1, Clinical 
Safety Assessments.
Section 9.3, Blinding Procedures
Change: The blinding procedure was clarified.
Now reads:
The study Sponsor and CRO study management team will be fully blinded for the study. 
WhenAfter the last participant completes their Day 904 visitVisit, the clinical study database 
will be locked and designated personnel at the Sponsor will be unblinded for the purposes of 
evaluating the primary and secondary efficacy analyses. The final database lock will occur 


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whenafter the last participant completes their Day 90 Visit and the long-term follow-up 
database will be locked after the last participant completes the Day 180 Follow-up Visit. 
The Sponsor and CRO study management teams responsible for all site interactions and data 
entry will remain blinded through Day 180 to individual treatment assignments during the study.
Rationale: This change was made to clarify that blinding will be maintained until the End of 
Study for data integrity of long-term functional outcomes.
Change:
 
Now reads:
 
 
 
 
 
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.
Sites should be vigilant about intracranial pressure management and perform DC when it 
is clinically indicated as part of local SOC. The reasons for the DC should be recorded in 
the eCRF.
Rationale: This change was made to clarify the acceptability of minimally invasive procedures 
such as burr hole placement and external ventricular drain insertion, and that these procedures are 
not exclusionary for enrollment since these procedures have minimal impact on the primary 


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endpoint. Clarification was also added to ensure standard of care (SOC) is followed by all sites 
regarding the need for surgical decompression.
Section 12.1.2, BIIB093 Storage
Change: Storage requirement of BIIB093 was clarified.
Now reads:
All vials of BIIB093 are to be stored at room temperature (≤1°C to ≤25°C or (34°F to ≤77°F),)
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.
Rationale: This change was made to clarify specifications with more detail surrounding light 
sensitivity of BIIB093 and parameters for storage.
This change also affects Section 12.2, Placebo.
Section 14.2, Laboratory Safety Assessments
Change: laboratory tests for safety assessments were clarified.
Now reads:
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 with differential and platelet count, and absolute 
neutrophil count

Blood chemistry: total protein, albumin, creatinine, blood urea nitrogen, uric acid,
glucose, calcium, phosphorus, bicarbonate (if available), chloride (if available), 
sodium, and potassium

Liver function test: bilirubin (total and directindirect), alkaline phosphatase, ALT, 
AST, and gamma-glutamyl transferase, glucose, calcium, phosphorus, bicarbonate, 
chloride, sodium, and potassium

Coagulation panel (INR, PTT, fibrinogen)

Note that in any case of confirmed hemolytic anemia, after randomization, the 
required local standard tests should be performed to confirm etiology of disease, 
including a G6PD genetic or enzymatic test should be performed (in accordance with 
local practice).


Amendment Summary for Protocol 252BN201, Version 2
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
10
Rationale: Laboratory assessments in this study will be conducted at local laboratories and per 
the sites SOC. Required investigational parameters are adjusted to adopt sites SOC without 
compromising participants’ safety assessments and follow-up.
Section 16.2.2.2, Analysis of the Primary Endpoint
Change: The images that will be used to determine the primary endpoint and the timing of scans 
for contusion volume were clarified.
Now reads:
The primary endpoint of, the proportion of participants with contusion expansion, will be 
determined by final centralized readings of contusion volume from baseline and all on-protocol
images collected at baseline and 96 between 12 hours after the initiation of study treatment 
up to the Hour 96 visit or the time of NSx or CMO (if earlier). Primary analysis of the 
primary endpoint will compare BIIB093 (3 mg/day or 5 mg/day) and placebo groups using a 
binary logistic regression, adjusting for covariates including all the stratification factors at 
randomization and baseline contusion volume per the central read and baseline GCS.
Sensitivity analyses for the assumptions will be performed to evaluate the impact of analysis 
sets, the impact of missing data, and the missing dataintercurrent event handling. Details will 
be specified in the SAP.
Rationale: It is necessary to delineate the admissible images which will be used to determine 
contusion expansion. This change was made to clarify that the postbaseline images used for 
defining contusion expansion should be collected after 12 hours and before the time of NSx or 
CMO if that happens before Hour 96. This change also makes the definition of contusion 
expansion consistent with that of the modified intend-to-treat population. Furthermore, changes 
to sensitivity analyses were made to clarify the scope of the analyses.
This change also affects Section 16.2.1, Analysis Population.
Section 16.2.2.3, Analysis of the Secondary Endpoints
Change: The timing for the analysis of participants requiring delayed intubation was clarified.
The analysis population for survival time (all randomized participants) was clarified.
Now reads:
Proportion of participants requiring delayed intubation
The proportion of participants requiring delayed intubation at any time between 24 hours and 
96 hours postinjury or last known normal will be analyzed at Day 4. The analysis will 
compare BIIB093 (3 mg/day or 5 mg/day) and placebo groups using a binary logistic regression, 


Amendment Summary for Protocol 252BN201, Version 2
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
11
adjusting for covariates including all the stratification factors at randomization and baseline 
contusion volume per the central review and baseline GCS.
Time to all-cause death, including neurological death, through Day 90
Survival time will be analyzed for all randomized participants. Cox proportional hazards 
regression models will be used to assess the treatment effects on overall survival at Day 90 after 
adjusting for covariates including the stratification factors at randomization, baseline contusion 
volume per the central review, and baseline GCS. Kaplan Meier curves will be presented for 
BIIB093 (3 mg/day or 5 mg/day) and placebo groups.
Rationale: The change in the timing for the analysis of delayed intubation was made to clarify 
the definition of delayed intubation in relation to the note found in Section 6, Secondary 
Endpoints.
The change related to analysis population for survival time was made to clarify the analysis 
population for time-to-event endpoint since it is different from the rest of the endpoint analyses, 
where the modified intend-to-treat set is used. All randomized participants are used to capture as 
much survival information as possible regardless of whether the participants have admissible 
images collected after randomization.


Amendment Summary for Protocol 252BN201, Version 2
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
12
SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and date were updated throughout the protocol.

The number of countries participating in the study was changed from 5 to 7. Study 
sites in Canada were also removed from the study.

The equivalent unit of BG in mmol/L was added throughout the protocol.

New text and citation were added in Section 4.4, Study Rationale.

New text in the footnote was added in Section 4.5.1, Dosing Regimen, Table 1.

A new row for other assessments (ECG, 
) and additional 
information on timing/dosing windows for infusion were added in Section 5, 
Schedule of Activities, Table 2.

The statement related to database lock was removed in Section 7.5, End of Study.

In Section 8.2, Exclusion Criteria, other reasons for study exclusion was clarified to 
specify that the final decision on the exclusion of a participant from the study must be 
made by the Investigator without interference by the Sponsor.

In Section 11.1, Regimen, the delivery method of study treatment through central line 
or peripherally inserted central catheter line was further clarified. A note was also 
added to clarify that study treatment administration does not need to occur in the ICU.

Dose modification during the study was clarified in Section 11.2 by revising the text
and adding Table 4. The other succeeding tables were renumbered due to the addition 
of Table 4.

In Section 11.4, Concomitant Therapy and Procedures, the description of treatment 
guidelines provided in the Study Reference Guide was removed.

Table 5 in Section 11.4.1.1.2, Interventions Related to Blood Glucose was updated to 
reflect the information presented in Table 4.

Normal saline was changed to sodium chloride in Section 12.1, BIIB093.

Clarification was added in Section 14.3, Product-Specific Safety Assessments to note 
that venous line can also be used as a source of blood for BG measurement.


Amendment Summary for Protocol 252BN201, Version 2
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
13

The definition of hypoglycemia was revised in Section 15.3.2, Adverse Events of 
Special Interest.

The presentation of data by treatment group was clarified in Section 16.2.2, Methods 
of Analysis. By-treatment-group analysis will be displayed as placebo, BIIB093 
3 mg/day, BIIB093 5 mg/day, BIIB093 combined, and total (if applicable). 
Continuous endpoints will also be presented in quartiles.

Typographical errors and formatting were corrected.

SAP_001.pdf: 
C O V E R P A G E  
Offi ci al Titl e:  
A M ulti c e nt er, D o u bl e -Bli n d, M ulti d o s e, Pl a c e b o -C o ntr oll e d,  
R a n d o mi z e d, P ar all el -Gr o u p, P h a s e 2 St u d y t o E v al u at e t h e Effi c a c y  
a n d S af et y of I ntr a v e n o u s BII B 0 9 3 f or P ati e nt s wit h Br ai n C o nt u si o n  
N C T N u m b er:  
N C T 0 3 9 5 4 0 4 1  
D o c u m e nt  D at e : 
S A P  Ver si o n 3. 0: 1 7  J uly 2 0 2 3  


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 1
S T A TI S TI C A L A N A L Y SI S P L A N
Versi o n N o. : Fi nal 3. 0 
D ate : 1 4J ul y 2 0 2 3
 A ut h or:
St u d y Title : A M ultic e nt er, D o u bl e- Bli n d, M ulti d os e, Pl ac e b o- C o ntr oll e d, R a n d o miz e d, P ar all el- Gr o u p, 
P h as e 2 St u d y t o E v al u at e t h e Effic ac y a n d S af et y of I ntr a v e n o us BII B 0 9 3 f or P ati e nts wit h Br ai n 
C o nt usi o n  
N a me of St u d y Tre at me nt : BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)  
Pr ot oc ol N o .: 2 5 2 B N 2 0 1
St u d y P h ase : 2
C o nfi de nti al I nf or m ati o n
T he i nf or m ati o n c o nt ai ne d i n t his St atistic al A n alysis Pl a n ( S A P) is c o nfi de nti al a n d m ay n ot be 
re pr o d uce d or ot her wise disse mi n ate d wit h o ut t he a p pr ov al of Bi o ge n, I nc.  


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 2
A P P R O V A L
T his d oc u me nt h as bee n re vie we d a n d a p pr o ve d b y:
S M T Statisticia n 
Si g nat ure
Date
C D T Statisticia n 
Si g nat ure
Date
S M T Me dical Direct or 
Si g nat ure
Date


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 3
V E R SI O N HI S T O R Y
S A P Versi o n
D ate
Pri m ar y Re as o ns f or 
A me n d me nt
1. 0 
0 3- M A R- 2 0 2 3 
N ot a p plica ble
2. 0
1 2-J U L- 2 0 2 3
T o c orrect t he deri vati o n of 
t he act ual treat me nt f or t he 
5 m g/ da y gr o u p


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 4
T A B L E O F C O N T E N T S
S T A TI S TI C A L A N A L Y SI S P L A N .......................................................................................................... 1
A P P R O V A L ................................................................................................................................................ 2
V E R SI O N HI S T O R Y ................................................................................................................................. 3
T A B L E O F C O N T E N T S ........................................................................................................................... 4
LI S T O F A B B R E VI A TI O N S .................................................................................................................... 7
1. 
I ntr o d ucti o n ........................................................................................................................................ 9
2. 
St u d y O ver vie w ................................................................................................................................... 9
2. 1. 
St u d y O bjecti ves a n d E n d p oi nts ............................................................................................ 9
2. 2. 
St u d y Desi g n .......................................................................................................................... 1 1
2. 3. 
S a m ple Size C o nsi der ati o ns ................................................................................................. 1 2
3.  
Defi niti o ns ......................................................................................................................................... 1 3
3. 1.  
D ates a n d P oi nts of Refere nce ............................................................................................. 1 3
3. 2. 
St u d y Tre at me nt ................................................................................................................... 1 5
3. 2. 1 R a n d o miz e d Tr e at m e nt Gr o u p.................................................................................................. 1 6
3. 2. 2 Act u al Tr e at m e nt Gr o u p............................................................................................................ 1 6
3. 3. 
St u d y Peri o ds ........................................................................................................................ 1 6
Pr etr e at m e nt P eri o d........................................................................................................................... 1 6
O n- Tr e at m e nt P eri o d.......................................................................................................................... 1 7
F oll o w- U p P eri o d................................................................................................................................ 1 7
3. 4.  
Ke y Deri ve d V ari a bles .......................................................................................................... 1 7
3. 4. 1.  
C h a n ge i n T ot al C o nt usi o n V ol u me ( he m at o m a pl us peri he m at o m al e de m a) fr o m 
B aseli ne t o 9 6 H o urs ......................................................................................................................... 1 7
3. 4. 2.  
C h a n ge i n T ot al C o nt usi o n V ol u me ( he m at o m a pl us peri he m at o m al e de m a) fr o m 
B aseli ne t o 2 4 H o urs ......................................................................................................................... 1 8
3. 4. 3.  
C h a n ge i n A bs ol ute He m at o m a V ol u me fr o m B aseli ne t o 2 4 H o urs ............................ 1 8
3. 4. 4.  
C h a n ge i n A bs ol ute E de m a V ol u me fr o m B aseli ne t o 9 6 H o urs ................................... 1 8
3. 5. 
Str atific ati o n F act ors a n d S u b gr o u p V ari a bles ................................................................. 1 8
3. 5. 1. 
Str atific ati o n F act ors ........................................................................................................ 1 8


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 5
3. 5. 2. 
S u b gr o u p V ari a bles .......................................................................................................... 1 9
3. 6.  
A n al ysis Sets .......................................................................................................................... 1 9
3. 6. 1. 
F ull A n al ysis Set ................................................................................................................ 1 9
3. 6. 2. 
Per- Pr ot oc ol A n al ysis Set ................................................................................................. 1 9
3. 6. 3. 
S afet y A n al ysis Set ............................................................................................................ 2 0
4. 
List of Pl a n ne d St u d y A n al yses ....................................................................................................... 2 0
4. 1. 
I nteri m A n al ysis .................................................................................................................... 2 0
4. 2. 
Pri m ar y A n al ysis .................................................................................................................. 2 1
4. 3. 
Fi n al A n al ysis ........................................................................................................................ 2 1
4. 4. 
I n de pe n de nt D at a M o nit ori n g C o m mittee .......................................................................... 2 1
5. 
St atistic al Met h o ds f or Pl a n ne d A n al yses ....................................................................................... 2 2
5. 1.  
Ge ner al Pri nci ples ................................................................................................................ 2 2
5. 1. 1.  
H a n dli n g of Missi n g D ate/ti me i n C o nc o mit a nt Me dic ati o ns ....................................... 2 2
5. 1. 2.  
H a n dli n g of Missi n g D ate/ Ti me i n A d verse E ve nts ....................................................... 2 3
5. 1. 3.  
H a n dli n g of P arti al D ate/ Ti me i n C o nc o mit a nt Me dic ati o ns a n d A d verse E ve nts ..... 2 3
5. 1. 4.  
Missi n g V al ues f or G O S- E ............................................................................................... 2 4
5. 1. 5.  
Missi n g V al ues f or m R S ................................................................................................... 2 4
5. 2. 
P artici p a nt Acc o u nt a bilit y ................................................................................................... 2 5
5. 3.  
De m o gr a p hic a n d B aseli ne C h ar acteristics ........................................................................ 2 5
5. 3. 1.  
De m o gr a p hics per C R Fs .................................................................................................. 2 5
5. 3. 2. 
B aseli ne Dise ase C h ar acteristics per C R Fs .................................................................... 2 6
5. 3. 3. 
Str atific ati o n F act ors per I R T ......................................................................................... 2 6
5. 3. 4. 
P h ysic al Me as ure me nts at B aseli ne ................................................................................. 2 6
5. 3. 5.  
Me dic al Hist or y ................................................................................................................. 2 7
5. 4. 
Pr ot oc ol De vi ati o ns ............................................................................................................... 2 7
5. 5. 
St u d y Tre at me nt E x p os ure a n d C o nc o mit a nt Me dic ati o ns .............................................. 2 7
5. 5. 1. 
St u d y Tre at me nt E x p os ure .............................................................................................. 2 7
5. 5. 2.  
C o nc o mit a nt Me dic ati o ns ................................................................................................ 2 7
5. 5. 3.  
N o n- dr u g T her a pies .......................................................................................................... 2 8
5. 6. 
Effic ac y E n d p oi nts ................................................................................................................ 2 8


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 6
5. 6. 1.  
Ge ner al A n al ysis Met h o ds f or Effic ac y E n d p oi nts ........................................................ 2 8
5. 6. 2. 
Pri m ar y Effic ac y E n d p oi nt .............................................................................................. 3 1
5. 6. 3. 
Sec o n d ar y Effic ac y E n d p oi nts ......................................................................................... 3 1
5. 7. 
S afet y 
................................................................................................................... 3 7
5. 7. 1  
A d verse E ve nts .................................................................................................................. 3 7
5. 7. 2  
A d verse E ve nts of S peci al I nterest ( A E SI) ..................................................................... 3 8
5. 7. 3  
De at h .................................................................................................................................. 3 8
5. 7. 4  
Cli nic al L a b or at or y Res ults ............................................................................................. 3 9
A n al ysis of Li v er F u ncti o n T ests.......................................................................................................... 4 1
5. 7. 5 
Electr oc ar di o gr a m ( E C G) ................................................................................................ 4 2
5. 7. 6  
Vit al Si g ns .......................................................................................................................... 4 2
5. 1 0. 
< A d diti o n al > P atie nt Re p orte d O utc o mes ( P R Os) ............................................................ 4 3
5. 1 1. 
<e. g., A nti ge nicit y/I m m u n o ge nicit y > E n d p oi nts ................................................................ 4 3
5. 1 2. 
< Ot her A n al yses > ................................................................................................................. 4 3
5. 1 3. 
St atistic al C o nsi der ati o ns f or I nteri m A n al ysis ................................................................. 4 4
6.  
C h a n ges fr o m Pr ot oc ol- S pecifie d A n al yses .................................................................................... 4 4
7. 
S u m m ar y of C h a n ges fr o m t he Pre vi o us Versi o n of t he S A P ....................................................... 4 4
8.  
Refere nces ......................................................................................................................................... 4 4
A P P E N DI C E S ........................................................................................................................................... 4 5
A p p e n dix 1. 
I m a gi n g D at a p er t h e C e ntr al R e vi e w................................................................................. 4 6
A p p e n dix 2. 
Sc h e d ul e of Acti viti es.......................................................................................................... 4 7


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 7
LI S T O F A B B R E VI A TI O N S
A b bre vi ati o n
Defi niti o n
A E
a d verse e ve nt
A L T
a mi n otra nsferase
A N C O V A
a nal ysis of c o varia nce
A S T
as partate a mi n otra nsferase
B G
bl o o d gl uc ose
CI
c o nfi de nce i nter val
C M O
c o mf ort meas ures o nl y
C O VI D- 1 9
C or o na vir us disease 2 0 1 9
C R O
c o ntract researc h or ga nizati o n
C ss
c o nce ntrati o n at stea d y state
C Y P
c yt oc hr o me P 4 5 0
D C
dec o m pressi ve cra niect o m y
D H A
Directi o ns f or Ha n dli n g a n d A d mi nistrati o n
D WI
diff usi o n- wei g hte d i ma gi n g
E C G
electr ocar di o gra m
e C R F
electr o nic case re p ort f or m
E T
earl y ter mi nati o n
G C P
G o o d Cli nical Practice
G C S
Glas g o w C o ma Scale
G O S- E
Glas g o w O utc o me Scale – E xte n de d
H P C
he m orr ha gic pr o gressi o n of c o nt usi o n
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I C L
i ma gi n g c ore la b orat or y
I D M C
i n de pe n de nt data m o nit ori n g c o m mittee
I N R
i nter nati o nal n or malize d rati o
I P H
i ntra pare nc h y mal he mat o ma
I R T
i nteracti ve res p o nse tec h n ol o g y
I V
i ntra ve n o us
L A R
le gall y a ut h orize d re prese ntati ve
L HI
lar ge he mis p heric i nfarcti o n
L K N
last k n o w n n or mal
M RI
ma g netic res o na nce i ma gi n g
m R S
m o difie d Ra n ki n Scale


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 8
N C C T
n o nc o ntrast c o m p ute d t o m o gra p h y
N O A C
n o vel oral a ntic oa g ula nts
N S x
ne ur os ur gical i nter ve nti o n
O A T P
or ga nic a ni o n tra ns p orti n g p ol y pe pti de
P O C
p oi nt- of-care
P T T
partial t hr o m b o plasti n ti me
P V C
p ol y merizi n g vi n yl c hl ori de
Q Tc
Q T i nter val c orrecte d f or heart rate
rt P A
rec o m bi na nt tiss ue plas mi n o ge n acti vat or
S A E
seri o us a d verse e ve nt
S A P
Statistical A nal ysis Pla n
S D
sta n dar d de viati o n
S O C
sta n dar d of care
S U R 1- T R P M 4
s ulf o n yl urea rece pt or 1-tra nsie nt rece pt or 
p ote ntial melastati n 4 c ha n nel
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
T BI
tra u matic brai n i nj ur y
U L N
u p per li mit of n or mal


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 9
1.
I ntr o d ucti o n
T his statistical a nal ysis pla n ( S A P) pr o vi des details of all pre- pla n ne d statistical a nal yses f or 
St u d y 2 5 2 B N 2 0 1 ( pr ot oc ol versi o n 3. 0). A n y de viati o n t o t his S A P will be descri be d i n t he 
Cli nical St u d y Re p ort ( C S R). 
2.
St u d y O ver vie w
2. 1. St u d y O bjecti ves a n d E n d p oi nts
Pri m ar y O bjecti ve
Pri m ar y E n d p oi nt
T o deter mi ne if BII B 0 9 3 re d uces brai n 
c o nt usi o n e x pa nsi o n b y H o ur 9 6 w he n 
c o m pare d t o place b o. Meas ure me nts of 
c o nt usi o n e x pa nsi o n are base d o n a 
c o m paris o n of t he baseli ne i ma ges a n d 
t he sca ns c ollecte d 
pri or t o a n d 
i ncl u di n g 9 6- h o ur sca n, or t he sca n 
o btai ne d pri or t o D C, i ntra pare nc h y mal 
he mat o ma 
(I P H) 
e vac uati o n, 
or 
c o mf ort 
meas ures o nl y ( C M O), if 
earlier. 
C ha n ge i n t otal c o nt usi o n v ol u me 
( he mat o ma  
pl us  
peri he mat o mal 
e de ma) as meas ure d b y brai n i ma gi n g 
fr o m baseli ne t o 9 6 h o urs or pri or t o 
D C, I P H e vac uati o n, or C M O if t hese 
pr oce d ures occ ur bef ore 9 6 h o urs per 
t he ce ntral re vie w.
Sec o n d ar y O bjecti ves
Sec o n d ar y E n d p oi nts
T o e val uate t he effects of BII B 0 9 3 o n 
ac ute 
ne ur ol o gic stat us, f u ncti o nal 
o utc o mes, a n d treat me nt re q uire me nts.
•
Glas g o w O utc o me Scale – E xte n de d 
( G O S- E) at Da y 1 8 0
•
M o difie d Ra n ki n Scale at Da y 9 0
•
Pr o p orti o n of partici pa nts re q uiri n g 
dela ye d i nt u bati o n
N ote: dela ye d i nt u bati o n is defi ne d as 
partici pa nts re q uiri n g i nt u bati o n (f or 
ne ur ol o gic deteri orati o n o nl y) at a n y 
ti me bet wee n 2 4 h o urs a n d 9 6 h o urs 
p osti nj ur y.
T o f urt her differe ntiate t he mec ha nis m 
of acti o n of BII B 0 9 3 c o m pare d t o 
place b o o n c o nt usi o n e x pa nsi o n b y 
e xa mi ni n g 
differe ntial 
effects 
o n 
he mat o ma a n d e de ma e x pa nsi o n.
•
C ha n ge i n t otal c o nt usi o n v ol u me 
( he mat o ma pl us peri he mat o mal 
e de ma) as meas ure d b y brai n i ma gi n g 
fr o m baseli ne t o 2 4 h o urs or pri or t o 
D C, I P H e vac uati o n, or C M O if t hese 






Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 1 2
T he e n d of t he st u d y is w he n t he last partici pa nt c o m pletes t he Da y 1 8 0 F oll o w- u p Visit or 
E T Visit
Fi g ur e 1: 
St u d y D esi g n
h = h o urs; M RI = ma g netic res o na nce i ma gi n g; N C C T = n o nc o ntrast c o m p ute d t o m o gra p h y; S O C = sta n dar d of 
care; T T/ L K N = ti me of tra u ma/last k n o w n n or mal. 
D osi n g m ust be starte d wit hi n 1 0 h o urs fr o m ti me of tra u ma/last k n o w n n or mal a n d wit hi n 6 h o urs of h os pital 
arri val. D osi n g s h o ul d be i nitiate d wit hi n 1 h o ur of ra n d o mizati o n a n d c o nti n ue f or 9 6 h o urs ( 4 da ys).
2. 3. S a m ple Size C o nsi der ati o ns  
T he st u d y is pla n ne d t o ra n d o mize a p pr o xi matel y 1 6 0 partici pa nts. T he pri mar y e n d p oi nt f or t he 
st u d y is t he c ha n ge i n t otal c o nt usi o n v ol u me ( he mat o ma pl us peri he mat o mal e de ma) as meas ure d 
b y brai n i ma gi n g fr o m baseli ne t o 9 6 h o urs, or pri or t o D C, I P H e vac uati o n, or C M O, if t hese 
pr oce d ures occ ur bef ore 9 6 h o urs. Ass u mi n g t he c o m m o n sta n dar d de viati o n of 2 9 m L i n 
c o nt usi o n v ol u me c ha n ge fr o m baseli ne, a sa m ple size of 1 6 0 partici pa nts ( 4 0 eac h i n t he 3 m g/ da y 
d ose or matc hi n g place b o ar ms a n d 4 0 eac h i n t he 5 m g/ da y d ose or matc hi n g place b o ar ms) will 
ha ve a p pr o xi matel y 9 0 % p o wer t o detect ass u me d a vera ge differe nce of 1 5 m L bet wee n t he p o ole d 
acti ve treat me nt gr o u ps ( n = 8 0) a n d p o ole d place b o gr o u ps ( n = 8 0) usi n g 2 gr o u p t-test at a 2-si de d 
si g nifica nce le vel of 5 %.


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 1 3
3.
Defi niti o ns
3. 1. D ates a n d P oi nts of Refere nce
T he first date of starti n g st u d y dr u g i nf usi o n ( BII B 0 9 3 3 m g/ da y, 5 m g/ da y or t he matc hi n g 
place b o) is referre d t o as st u d y Da y 1. F or all t he dates i n t he st u d y
•
If a date is o n or after st u d y Da y 1
St u d y Da y = ( date of i nterest) – (st u d y Da y 1) + 1
•
If a date is bef ore st u d y Da y 1
St u d y Da y = ( date of i nterest) – (st u d y Da y 1)
St u d y H o ur 0 is defi ne d as t he start ti me of t he st u d y dr u g i nf usi o n. F or all t he ti mes i n t he st u d y 
bef ore a n d d uri n g t he st u d y dr u g i nf usi o n 
•
St u d y H o ur = ( h o ur of i nterest) – (st u d y H o ur 0)
F or efficac y data t hat are s u m marize d or a nal yze d b y visit, data c ollecte d o n all sc he d ule d visits 
a n d all u nsc he d ule d visits will be ma p pe d t o a n a p pr o priate a nal ysis visit usi n g t he wi n d o wi n g 
sc he me s h o w n i n Ta ble 1 . If t here are 2 or m ore assess me nts a vaila ble i n t he sa me a nal ysis wi n d o w 
f or a s u bject, u nless ot her wise s pecifie d, t he assess me nt t hat is cl osest t o t he tar get visit da y/ti me 
will be use d f or a nal ysis. If t here are 2 or m ore assess me nts i n t he sa me a nal ysis wi n d o w wit h t he 
sa me dista nce fr o m t he tar get visit da y, t he later assess me nt will be use d.
T a ble 1. Visit Wi n d o ws f or Effic ac y E n d p oi nts
V ol u me D at a
A n al ysis visit
T ar get ti me p oi nt i n 
hr
A n al ysis visit wi n d o w
Scree ni n g
0
M ost rece nt n o n- missi n g pre- d ose 
val ue
H o ur 2 4
2 4
[ 1 0, 3 8]
H o ur 9 6
9 6
[ 7 6, 1 1 6]
G O S- E
A n al ysis visit
T ar get visit d a y
A n al ysis visit wi n d o w
H os pital disc har ge
7
( 0, 2 3)
Da y 3 0
3 0
[ 2 3, 6 0]
Da y 9 0
9 0
( 6 0, 1 3 5)




Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 1 5
T a ble 2. St u d y peri o ds, a n al ysis visits a n d c orres p o n di n g a n al ysis visit wi n d o ws.
T a ble 2 : 
St u d y 
Peri o d
St u d y Visit
Visit N u m ber
T ar get Ti me
Visit Wi n d o w
Pre-treat me nt
Pre- Treat me nt 
1
0 h
< 0 h
O n-treat me nt
H o ur 0- 1 2
2
1 2 h
0 - 1 2 h 
H o ur 2 4
3
2 4 h
1 2 - 3 6 h
H o ur 4 8
4
4 8 h
3 6 - 6 0 h
H o ur 7 2
5
7 2 h
6 0 - 8 4 h
H o ur 9 6
6
9 6 h
8 4 - 1 2 0 h
H o ur 9 6 E xt
7
1 2 0 h
1 2 0 h – 7 2 h *
F oll o w- u p
Da y 3 0
8
3 0 d
> 7 2 h * – 6 0 d
Da y 9 0
9
9 0 d
6 0 – 1 5 0 d
Da y 1 8 0
1 0
1 8 0 d
1 5 0 – 2 1 0 d
Da y 1 8 0 E xt
1 1
2 7 0 d
> 2 1 0 d
h = h o urs, d = d a ys. d * = d a ys fr o m t h e e n d of st u d y dr u g i nf usi o n. T h e H o ur 9 6 Ext visit wi n d o w of e ac h p artici p a nt 
will e n d 7 2 h o urs aft er t h e e n d of st u d y dr u g i nf usi o n, p ossi bl y i ncl u di n g D a y 7 or Disc h ar g e o p er ati o n visits as 
d efi n e d i n T a bl e 2 of t h e pr ot oc ol. T h e a n al ysis visit wi n d o w of D a y 3 0 st arts > 7 2 h o urs aft er t h e e n d of st u d y dr u g 
i nf usi o n.
3. 2. St u d y Tre at me nt
All partici pa nts m ust be d ose d wit hi n 1 0 h o urs of ti me of tra u ma/last k n o w n n or mal ( L K N) a n d 
wit hi n 6 h o urs of h os pital arri val. D osi n g s h o ul d be i nitiate d wit hi n 1 h o ur of ra n d o mizati o n a n d 
c o nti n ue f or 9 6 h o urs ( 4 da ys). Partici pa nts will recei ve st u d y treat me nt ( 3 m g/ da y or 5 m g/ da y) 
or matc hi n g place b o a d mi nistere d as a 3-sta ge c o nti n u o us i nf usi o n: a b ol us I V d ose ( gi ve n o ver 
2 mi n utes), f oll o we d b y 2 differe nt i nf usi o n rates (a ra pi d I V i nf usi o n f or 6 h o urs f oll o we d b y a 
sl o w I V i nf usi o n f or t he re mai ni n g 9 0 h o urs) f or 9 6 h o urs t otal. Partici pa nts will be ra n d o ml y 
assi g ne d t o 3 m g/ da y st u d y treat me nt, 5 m g/ da y st u d y treat me nt, 3 m g/ da y matc hi n g place b o, or 
5 m g/ da y matc hi n g place b o i n a 1: 1: 1: 1 rati o, stratifie d base d o n baseli ne c o nt usi o n v ol u me per 
I n vesti gat or assess me nt of n o nc o ntrast c o m p ute d t o m o gra p h y sca n or site l ocal ra di ol o gic 
assess me nt ( 3 t o 1 0 m L or > 1 0 m L), baseli ne G C S ( 5 t o 8, 9 t o 1 2, or 1 3 t o 1 5), a ge ( ≤ 7 0 years 
ol d or > 7 0 years ol d), a n d re gi o n ( N ort h A merica [ U nite d States] or Rest of W orl d).
B y-treat me nt- gr o u p a nal ysis will be dis pla ye d as: 
•
Place b o 
•
BII B 0 9 3 3 m g/ da y 


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 1 6
•
BII B 0 9 3 5 m g/ da y 
•
BII B 0 9 3 c o m bi ne d 
•
T otal, if a p plica ble
T he treat me nt gr o u ps are defi ne d as f oll o ws.
3. 2. 1 R a n d o mize d Tre at me nt Gr o u p
Ra n d o mize d treat me nt refers t o t he treat me nt assi g ne d t o a partici pa nt at t he i nitial 
ra n d o mizati o n. 
Accr ual, st u d y c o n d uct, partici pa nt dis p ositi o n, de m o gra p hics, baseli ne disease c haracteristics, 
p h ysical meas ure me nts, c o nc o mita nt me dicati o ns a n d n o n- dr u g t hera pies, efficac y a n d o utc o me 
researc h res ults will be a nal yze d a n d prese nte d b y ra n d o mize d treat me nt gr o u p, u nless ot her wise 
s pecifie d. 
3. 2. 2 Act u al Tre at me nt Gr o u p
Act ual treat me nt refers t o t he act ual st u d y dr u g recei ve d b y a partici pa nt. 
•
Ra n d o mize d partici pa nts w h o are d ose d b ut ne ver recei ve a n y BII B 0 9 3 d uri n g st u d y 
treat me nt a d mi nistrati o n will be assi g ne d t o place b o gr o u p. 
•
Ra n d o mize d partici pa nts w h o recei ve a n y BII B 0 9 3 will be assi g ne d t o BII B 0 9 3 3 m g/ da y 
gr o u p, if t he I V d ose d uri n g b ol us < 0. 1 7 m g a n d t he f oll o wi n g I V i nf usi o n recei ve d b y 
t he partici pa nt < 1 1. 3 1 m g f or I nf usi o n 1 a n d < 1 3. 5 2 5 m g f or I nf usi o n 2; refer t o Ta ble 1 
of t he pr ot oc ol. 
•
Ra n d o mize d partici pa nts w h o recei ve a n y BII B 0 9 3 will be assi g ne d t o BII B 0 9 3 5 m g/ da y 
gr o u p, if t he I V d ose d uri n g b ol us > = 0. 1 7 m g or t he f oll o wi n g I V i nf usi o n recei ve d b y 
t he partici pa nt > = 1 1. 3 1 m g f or I nf usi o n 1 or > = 1 3. 5 2 5 m g f or I nf usi o n 2. 
•
Ra n d o mize d partici pa nts w h o ne ver recei ve a n y st u d y dr u g ( neit her BII B 0 9 3 n or t he 
matc hi n g place b o) will ha ve missi n g act ual treat me nt gr o u p a n d will be e xcl u de d i n t he 
a nal ysis b y act ual treat me nt gr o u p. 
St u d y res ults f or safet y (a d verse e ve nts, seri o us a d verse e ve nts, la b orat or y, vital si g ns, li ver 
f u ncti o n test, electr ocar di o gra m [ E C G]), e xte nt of e x p os ure, 
 
 will be a nal yze d a n d prese nte d b y act ual treat me nt gr o u p.
3. 3. St u d y Peri o ds 
Pretre at me nt Peri o d
T he pretreat me nt peri o d be gi ns at t he a d missi o n t o h os pital at t he scree ni n g visit u ntil start ti me 
of st u d y dr u g i nf usi o n ( H o ur 0).  
Meas ure me nts ta ke n bef ore t he ti me of st u d y dr u g i nf usi o n at H o ur 0 are c o nsi dere d 
pretreat me nt f or all data d o mai ns. If t he ti me of meas ure me nt is missi n g, meas ure me nts ta ke n o n 


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 1 7
Da y 1 are c o nsi dere d pretreat me nt f or t he f oll o wi n g data d o mai ns: de m o gra p h y, disease hist or y, 
E C G, h u ma n ge n ot y pi n g, la b orat or y test res ults, me dical hist or y, p h ysical e xa mi nati o ns, 
partici pa nt stat us, a n d vital si g ns. 
Baseli ne val ue is defi ne d as t he last n o n- missi n g val ue bef ore t he ti me of st u d y dr u g i nf usi o n 
( H o ur 0) or pri or t o or o n Da y 1 if t he ti me of st u d y dr u g i nf usi o n is missi n g.
O n- Tre at me nt Peri o d
T he o n-treat me nt peri o d be gi ns at t he ti me of st u d y dr u g i nf usi o n ( H o ur 0) o n Da y 1 a n d e n ds 7 2 
h o urs after t he e n d of st u d y dr u g i nf usi o n. T he wi n d o w of 7 2 h o urs is base d o n t he half-life of 
st u d y dr u g a n d all o ws t he re mai ni n g st u d y dr u g t o clear fr o m t he partici pa nt’s s yste m. 
Meas ure me nts ta ke n after t he ti me of t he i nitiati o n of st u d y dr u g i nf usi o n ( H o ur 0) o n Da y 1 
t hr o u g h t he e n d of st u d y dr u g i nf usi o n pl us 7 2 h o urs are c o nsi dere d o n treat me nt f or all data 
d o mai ns. I n a d diti o n, if t he ti me of meas ure me nt is missi n g, meas ure me nts ta ke n o n Da y 1 are 
c o nsi dere d o n-treat me nt f or t he f oll o wi n g data d o mai ns: A Es, dr u g dis pe nsati o n, e x p os ure, n o n-
st u d y me dicati o ns.
F oll o w- U p Peri o d
T he f oll o w- u p peri o d be gi ns at t he e n d of st u d y dr u g i nf usi o n pl us > 7 2 h o urs a n d e n ds at t he 
Da y 1 8 0 visit or at t he earl y ter mi nati o n ( E T) visit, w here ver a p plica ble.  
Meas ure me nts ta ke n after t he e n d of st u d y dr u g i nf usi o n pl us > 7 2 h o urs till t he e n d of st u d y f or 
a partici pa nt are c o nsi dere d f oll o w- u p peri o d f or all data d o mai ns.
3. 4. Ke y Deri ve d V ari a bles
I ma gi n g data base d o n o n- pr ot oc ol i ma ges per t he ce ntral re vie w is descri be d i n A p pe n di x 1 . 
I ma gi n g- base d varia bles will be deri ve d fr o m t he fi nal rea d per i ma ge a m o n g o n- pr ot oc ol i ma ges 
(i.e., pri or t o N S x or C M O or earl y ter mi nati o n of st u d y dr u g i nf usi o n) fr o m t he ce ntral re vie w as 
f oll o ws f or pla n ne d statistical a nal yses:
3. 4. 1.
C h a n ge i n T ot al C o nt usi o n V ol u me ( he m at o m a pl us peri he m at o m al e de m a) 
fr o m B aseli ne t o 9 6 H o urs
T otal c o nt usi o n v ol u me will be assesse d b y t he ce ntral i ma gi n g c ore la b orat or y o n baseli ne N C C T, 
2 4- h o ur N C C T, a n d t he 9 6- h o ur sca n ( M RI a n d / or N C C T) a n d t he sca ns o btai ne d pri or t o D C, 
I P H e vac uati o n or C M O. C ha n ge i n t otal c o nt usi o n v ol u me ( he mat o ma pl us peri he mat o mal 
e de ma) as meas ure d b y brai n i ma gi n g fr o m baseli ne t o 9 6 h o urs or pri or t o D C, I P H e vac uati o n, 
or C M O if t hese pr oce d ures occ ur bef ore 9 6 h o urs per ce ntral re vie w, will be deri ve d fr o m 
a vaila ble ce ntral rea ds, at baseli ne ( bef ore H o ur 0) a n d cl osest t o H o ur 9 6. If m ulti ple ti me p oi nts 




Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 1 9
o
Rest of W orl d ( R o W)
3. 5. 2.
S u b gr o u p V ari a bles
S u b gr o u p varia bles will i ncl u de stratificati o n fact ors per I R T as descri be d i n Secti o n 3. 5. 1  a n d 
f oll o wi n g s u b gr o u p varia bles per Case Re p ort F or ms ( C R Fs):
•
A ge cate g or y at scree ni n g ( ≤ 7 0; > 7 0 years) 
•
Se x ( Fe male; Male) 
•
Race cate g or y ( W hite; N o n- W hite)
•
Et h nicit y ( His pa nic/ Lati n o; N ot His pa nic/ Lati n o)
•
Baseli ne brai n c o nt usi o n v ol u me per i n vesti gat or ( ≤ 1 0; > 1 0 m L)
•
Baseli ne brai n c o nt usi o n v ol u me per t he ce ntral re vie w ( ≤ 1 0; > 1 0 m L)
•
Baseli ne he mat o ma v ol u me per ce ntral re vie w ( ≤ me dia n; > me dia n)
•
Baseli ne e de ma v ol u me per ce ntral re vie w ( ≤ me dia n; > me dia n)
•
Baseli ne Glas g o w C o ma Scale ( G C S: 5 t o 8; 9 t o 1 2; 1 3 t o 1 5)
•
Baseli ne bl o o d gl uc ose ( ≤ me dia n; > me dia n)
•
Baseli ne alc o h ol le vel ( ≤ me dia n; > me dia n)
•
Baseli ne s o di u m ( ≤ me dia n; > me dia n)
B y me dia n i n t he a b o ve s u b gr o u p defi niti o ns is referre d t o t he me dia n of a vaila ble meas ures of 
t he varia ble i n all treat me nt gr o u ps c o m bi ne d. 
3. 6. A n al ysis Sets
T he a nal ysis sets i ncl u de t he f ull a nal ysis set (t he m o difie d i nte nti o n-t o-treat partici pa nts), per-
pr ot oc ol a nal ysis set, a n d t he safet y a nal ysis set. All partici pa nts w h o ha ve si g ne d t he i nf or me d 
c o nse nt f or m will be use d f or t he e nr oll me nt s u m mar y. All ra n d o mize d partici pa nts f oll o wi n g t he 
i nte nti o n-t o-treat pri nci ple will be use d f or ti me-t o-e ve nt a nal ysis (i ncl u di n g t he partici pa nts w h o 
are ra n d o mize d b ut d o n ot recei ve a n y st u d y dr u g).
3. 6. 1.
F ull A n al ysis Set
T he f ull a nal ysis set, i.e., t he m o difie d i nte nti o n-t o-treat ( mI T T) partici pa nts, will i ncl u de all t he 
partici pa nts w h o are ra n d o mize d, recei ve a n y st u d y dr u g ( BII B 0 9 3 3 m g/ da y, BII B 0 9 3 5 m g/ da y 
or t he matc hi n g place b o), a n d ha ve at least o ne fi nal rea d per ce ntral re vie w of c o nt usi o n v ol u me 
fr o m a n N C C T or M RI sca n ac q uire d bet wee n 1 0 h o urs after t he i nitiati o n of st u d y dr u g i nf usi o n 
a n d t he H o ur 9 6 visit or N S x or C M O (if earlier). I n efficac y a nal yses perf or me d o n t he f ull 
a nal ysis set ( mI T T partici pa nts), partici pa nts will be a nal yze d acc or di n g t o t he ra n d o mize d 
treat me nt gr o u p (see Secti o n 3. 2. 1  f or t he defi niti o n).
3. 6. 2.
Per- Pr ot oc ol A n al ysis Set
T he per- pr ot oc ol a nal ysis set will i ncl u de mI T T partici pa nts w h o ha ve n o pr ot oc ol vi olati o ns 
descri be d bel o w. I n a nal yses perf or me d o n t he per- pr ot oc ol a nal ysis set, partici pa nts will be 
a nal yze d acc or di n g t o act ual treat me nt gr o u p (see Secti o n 3. 2. 2  f or t he defi niti o n). T he detaile d 


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 2 0
defi niti o ns of pr ot oc ol de viati o ns, liste d bel o w, will be deter mi ne d a n d d oc u me nte d pri or t o t he 
Da y 4 a d mi nistrati ve data base l oc k.
•
Vi olati o n of eli gi bilit y criteria 
o
Ti me t o i nf usi o n p ost i nj ur y/last k n o w n n or mal ( L K N) is m ore t ha n 1 0 h o urs
o
Baseli ne c o nt usi o n v ol u me per i n vesti gat or is ≤ 3 m L or missi n g
o
Baseli ne G C S is o utsi de t he ra n ge of 5- 1 5
•
Earl y disc o nti n uati o n of treat me nt
o
I nf usi o n is disc o nti n ue d wit hi n 1 2 h o urs fr o m t he i nitiati o n of st u d y dr u g i nf usi o n
3. 6. 3.
S afet y A n al ysis Set
T he safet y a nal ysis of treate d partici pa nts will i ncl u de all ra n d o mize d partici pa nts w h o recei ve d 
a n y i nf usi o n of st u d y dr u g ( BII B 0 9 3 3 m g/ da y, BII B 0 9 3 5 m g/ da y or t he matc hi n g place b o). I n 
a nal yses perf or me d o n t he safet y a nal ysis set, partici pa nts will be a nal yze d acc or di n g t o t heir 
act ual treat me nt gr o u ps (see Secti o n 3. 2. 2 f or the defi niti o n), u nless ot her wise s pecifie d. 
 
 
 
 
 
 
 
 
 
 
4.
List of Pl a n ne d St u d y A n al yses
4. 1. I nteri m A n al ysis
A n i nteri m a nal ysis will be perf or me d b y a n i nter nal, i n de pe n de nt, u n bli n de d tea m w he n 
a p pr o xi matel y 9 0 s u bjects are d ose d a n d c o m plete d H o ur 9 6 visit or ter mi nate d earl y, f or 
a d mi nistrati o n p ur p oses. T he i nteri m a nal ysis will i ncl u de all s u bjects w h o are i n t he mI T T or 
safet y p o p ulati o n as descri be d i n t he S A P. T he i nteri m a nal ysis will i ncl u de t he f oll o wi n g 
a nal yses:
•
De m o gra p hic a n d baseli ne
•
E x p os ure


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 2 1
•
Efficac y – t o i ncl u de:
o
C ha n ge i n t otal c o nt usi o n v ol u me at h o urs 2 4 a n d 9 6
o
G O S- E at h os pital disc har ge, Da y 3 0, Da y 9 0 a n d Da y 1 8 0
o
C ha n ge i n he mat o ma v ol u me at h o urs 2 4 
o
C ha n ge i n e de ma v ol u me at h o urs 9 6
o
C ha n ge i n t otal c o nt usi o n v ol u me b y G O S- E b y visit
•
Safet y – t o i ncl u de:
o
A Es/ S A Es
o
H y p o gl yce mia 
o
La b orat or y
o
E C G
4. 2. Pri m ar y A n al ysis
T he pri mar y a nal ysis will be perf or me d after t he Da y 4 ( H o ur 9 6) a d mi nistrati ve data base l oc k 
w he n t he last partici pa nt c o m pletes t heir st u d y dr u g i nf usi o n at t he H o ur 9 6 visit. T he pri mar y 
a nal ysis is use d t o f or mall y e val uate t he treat me nt effect of BII B 0 9 3 o n i ma gi n g- base d e n d p oi nts 
as well as t he o n-treat me nt safet y c o m pare d wit h t he matc hi n g place b o. It will i ncl u de t he 
a nal yses of pri mar y e n d p oi nt (c ha n ge i n t otal c o nt usi o n v ol u me as defi ne d i n Secti o n 3. 4. 1 ) an d 
ot her i ma gi n g- base d e n d p oi nts, a n d o n-treat me nt safet y data s u m maries. T he pri mar y efficac y 
a n d safet y a nal yses will be perf or me d o n t he f ull a nal ysis set a n d t he safet y a nal ysis set, 
res pecti vel y, as defi ne d i n Secti o n 3. 6,  u nless ot her wise s pecifie d i n Secti o n 5.
4. 3. Fi n al A n al ysis 
T he fi nal a nal ysis will be perf or me d after t he Da y 1 8 0 fi nal data base l oc k. T he fi nal a nal ysis is 
t o f or mall y e val uate t he treat me nt effect of BII B 0 9 3 o n f u ncti o nal a n d s ur vi val e n d p oi nts 
c o m pare d wit h t he matc hi n g place b o. It will i ncl u de all t he sec o n dar y 
 e n d p oi nts 
n ot a nal yze d i n t he pri mar y a nal ysis, i ncl u di n g f u ncti o nal, patie nt s ur vi val, ne ur oc o g niti ve, a n d 
patie nt-re p orte d 
, as well as treat me nt re q uire me nt a n d 
 
 T he efficac y a n d safet y a nal yses will be perf or me d o n t he f ull a nal ysis set a n d t he safet y 
a nal ysis set, res pecti vel y, u nless ot her wise s pecifie d.
4. 4. I n de pe n de nt D at a M o nit ori n g C o m mittee
A n i n de pe n de nt data m o nit ori n g c o m mittee (I D M C) is esta blis he d t o assess t he o verall safet y 
pr ofile of BII B 0 9 3 d uri n g t he st u d y.  T he I D M C c harter g ui des t he o verall g o ver na nce pla n f or 
t he I D M C. I D M C ma y rec o m me n d t he S p o ns or t o ter mi nate t he st u d y base d o n safet y data. T he 
I D M C will re vie w t he data e ver y 3- 5 m o nt hs.


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 2 2
5.
St atistic al Met h o ds f or Pl a n ne d A n al yses
5. 1.  Ge ner al Pri nci ples 
Descri pti ve statistics will be pr o vi de d f or all efficac y e n d p oi nts. F or c o nti n u o us or n u merical 
e n d p oi nts (c ha n ge i n v ol u me, 
, G O S- E, etc.), n u m ber of partici pa nts wit h 
n o n- missi n g meas ures, mea n, sta n dar d de viati o n ( S D), me dia n, q uartiles (t he 2 5 t h perce ntile or 
Q 1, a n d t he 7 5 t h perce ntile or Q 3), a n d ra n ge ( mi n, ma x) will be s u m marize d. F or cate g orical 
( n o mi nal a n d or di nal) e n d p oi nts ( G O S- E, m R S, etc.), n u m ber of partici pa nts wit h n o n- missi n g 
meas ures, n u m ber a n d perce nta ge ( %) of partici pa nts i n eac h cate g or y of t he e n d p oi nts will be 
s u m marize d. 
Treat me nt c o m paris o ns f or t he pri mar y a n d sec o n dar y efficac y e n d p oi nts will be e val uate d usi n g 
2-si de d tests at t he 0. 0 5 le vel of si g nifica nce.  P oi nt esti mates of t he treat me nt effect a n d 9 5 % 2-
si de d c o nfi de nce i nter vals ( CIs) will be prese nte d. T he calc ulati o n of t y pe I err or will n ot a dj ust 
f or m ulti ple c o m paris o ns u nless ot her wise s pecifie d. 
If m ore t ha n 1 0 % of data is missi n g f or a n y baseli ne c o variate, t hat c o variate will n ot be use d i n 
t he m o deli n g descri be d bel o w.
All i ma gi n g efficac y e n d p oi nts i ncl u di n g t he pri mar y e n d p oi nt will be e val uate d b y ra n d o mize d 
treat me nt gr o u p usi n g t he f ull a nal ysis set (t he mI T T partici pa nts; see Secti o n 3. 6 ), u nless 
ot her wise s pecifie d. T he a nal yses perf or me d o n t he f ull a nal ysis set will be c o nsi dere d as t he 
mai n a nal yses [ I C H E 9 ( R 1) A d de n d u m, 2 0 2 0]. 
T he pri mar y a n d sec o n dar y efficac y e n d p oi nts will als o be a nal yze d base d o n t he per- pr ot oc ol 
a nal ysis set as s u p ple me ntar y a nal yses.
T he fi nal m o del f or eac h mai n a nal ysis f or t he f ull a nal ysis set will be 
use d f or t he c orres p o n di n g per- pr ot oc ol a nal ysis. 
S u b gr o u p a nal ysis will be perf or me d f or pri mar y a n d sec o n dar y efficac y e n d p oi nts a n d will 
prese nt a p oi nt esti mate of t he treat me nt effect a n d 9 5 % 2-si de d CIs fr o m u na dj uste d a nal yses, 
i.e., wit h o ut i ncl u di n g stratificati o n fact ors or ot her c o variates i n t he m o del ot her t ha n t he 
treat me nt gr o u p.  T hese a nal yses will be perf or me d o n t he f ull a nal ysis set o nl y. If t he n u m ber of 
partici pa nts i n a s u b gr o u p is t o o s mall (e. g. < 1 0 % of mI T T partici pa nts), t he a nal ysis i n t hat 
s u b gr o u p ma y n ot be perf or me d.
T he s oft ware use d f or t his a nal ysis pla n is S A S St u di o.
5. 1. 1.
H a n dli n g of Missi n g D ate/ti me i n C o nc o mit a nt Me dic ati o ns
Missi n g start a n d/ or st o p date/ti me will be ha n dle d as f oll o ws f or defi ni n g c o nc o mita nt use of 
t hera pies. If st u d y treat me nt start date/ti me is n ot a vaila ble, t he date/ti me of ra n d o mizati o n will 
be use d.
•
If b ot h start a n d st o p date/ti me of a t hera p y are missi n g, t hat t hera p y is c o nsi dere d 
c o nc o mita nt.


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 2 3
•
If t he start date/ti me of a t hera p y is missi n g a n d t he st o p date/ti me of t hat t hera p y falls o n 
or after t he date/ti me of t he st u d y treat me nt start date/ti me, t hat t hera p y is c o nsi dere d 
c o nc o mita nt.
•
If t he start date/ti me of a t hera p y is pri or t o t he date/ti me of t he st u d y treat me nt start 
date/ti me a n d t he st o p date/ti me of t hat t hera p y is missi n g a n d t he t hera p y is liste d as 
c o nti n ui n g, t hat t hera p y is c o nsi dere d c o nc o mita nt.
•
If t he start date/ti me of a t hera p y is pri or t o t he date/ti me of t he st u d y treat me nt start 
date/ti me a n d t he st o p date/ti me of t hat t hera p y is missi n g a n d t he t hera p y is liste d as n ot 
c o nti n ui n g, t hat t hera p y is c o nsi dere d n ot c o nc o mita nt.
5. 1. 2.
H a n dli n g of Missi n g D ate/ Ti me i n A d verse E ve nts
Missi n g start/st o p date/ti me will be ha n dle d as f oll o ws f or defi ni n g treat me nt-e mer ge nt e ve nts. If 
st u d y treat me nt start date/ti me is n ot a vaila ble, t he date/ti me of ra n d o mizati o n will be use d.
•
If b ot h t he start a n d st o p dates/ti me f or a n e ve nt are missi n g, t he n t hat e ve nt is c o nsi dere d 
treat me nt-e mer ge nt.
•
If t he start date/ti me f or a n e ve nt is missi n g a n d t he st o p date/ti me fall after t he start 
date/ti me of t he st u d y treat me nt, t he n t hat e ve nt is c o nsi dere d treat me nt-e mer ge nt.
•
If t he start date was t he sa me as t he start date of t he st u d y treat me nt a n d t he start ti me 
was missi n g, a n d t he st o p date/ti me is after t he date/ti me of t he st u d y treat me nt or ca n n ot 
be c o m pare d wit h t he date/ti me of st u d y treat me nt, t he n t hat e ve nt is c o nsi dere d 
treat me nt-e mer ge nt.
5. 1. 3.
H a n dli n g of P arti al D ate/ Ti me i n C o nc o mit a nt Me dic ati o ns a n d A d verse 
E ve nts
F or a t hera p y or a n a d verse e ve nt wit h a partial start a n d/ or e n d date/ti me, t he year/ m o nt h/ da y of 
t he t hera p y start a n d/ or e n d will be c o m pare d t o t h ose of t he first d osi n g date/ti me of t he st u d y 
treat me nt t o deter mi ne t he i m p utati o n r ules. If a partici pa nt is n ot d ose d, t he date/ti me of 
ra n d o mizati o n will be use d. 
T he last date/ti me o n st u d y will be ta ke n as t he last visit/e val uati o n date/ti me fr o m all a vaila ble 
data f or t he partici pa nt. If a partici pa nt die d d uri n g t he st u d y, t he last date/ti me o n st u d y will be 
t he date/ti me of deat h.
•
F or t he start date/ti me of A Es or c o nc o mita nt me dicati o ns,
o
If o nl y ti me is missi n g, a n d t hat t he A E/c o nc o mita nt me dicati o n starts o n t he 
sa me da y as t he treat me nt ( or ra n d o mizati o n if t he partici pa nt is n ot d ose d), t he n 
i m p ute missi n g ti me usi n g t he treat me nt start ti me (st u d y H o ur 0); ot her wise use 
t he first ( 0 1) h o ur of t hat da y as t he h o ur.
o
If o nl y da y is missi n g, a n d t hat t he A E/c o nc o mita nt me dicati o n starts i n t he sa me 
m o nt h as t he treat me nt ( or ra n d o mizati o n if t he partici pa nt is n ot d ose d), t he n 
i m p ute missi n g da y usi n g t he treat me nt start date (st u d y Da y 1); ot her wise use t he 
first ( 0 1) da y of t hat m o nt h as t he da y.


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 2 4
o
If b ot h da y a n d m o nt h are missi n g, a n d t hat t he A E/c o nc o mita nt me diati o n starts 
i n t he sa me year as t he treat me nt ( or ra n d o mizati o n), t he n i m p ute missi n g da y a n d 
m o nt h usi n g t he treat me nt start date ( St u d y Da y 1); ot her wise, use Ja n uar y 0 1 
( 0 1J A N) as t he da y a n d m o nt h.
o
If t he date/ti me f or A E/c o nc o mita nt me dicati o n is c o m pletel y missi n g ( n o da y, 
m o nt h or year), t he start date/ti me of t he st u d y treat me nt will be use d.
•
F or t he st o p date/ti me of A Es or c o nc o mita nt me dicati o ns,
o
If o nl y ti me is missi n g, a n d t hat t he A E/c o nc o mita nt me dicati o n st o ps o n t he sa me 
da y as t he treat me nt, t he n i m p ute missi n g ti me usi n g t he treat me nt e n d ti me; 
ot her wise use t he last ( 2 3) h o ur of t hat da y as t he h o ur.
o
If o nl y da y is missi n g, a n d t hat t he A E/ c o nc o mita nt me dicati o n st o ps i n t he sa me 
m o nt h as t he treat me nt, t he n i m p ute missi n g da y usi n g t he treat me nt e n d date; 
ot her wise use t he last da y of t hat m o nt h as t he da y.
o
If b ot h da y a n d m o nt h are missi n g, a n d t hat t he A E/c o nc o mita nt me diati o n st o ps 
i n t he sa me year as t he treat me nt, t he n i m p ute missi n g da y a n d m o nt h usi n g t he 
treat me nt e n d date; ot her wise, use Dece m ber 3 1 ( 3 1 D E C) as t he da y a n d m o nt h.
o
If t he st o p date is c o m pletel y missi n g ( n o da y, m o nt h or year), t he st u d y e n d 
date/ti me will be use d.
5. 1. 4.
Missi n g V al ues f or G O S- E 
G O S- E at  
 1 8 0 will be a nal yze d as a 7-cate g or y or di nal scale ( 1/ 2, 3, 4, 5, 6, 7, 8). 
M ulti ple i m p utati o n will be use d t o acc o u nt f or missi n g val ues f or G O S- E.  Deat h a n d ve getati ve 
state are sc ore d as 1 a n d 2 i n G O S- E a n d t heref ore n o missi n g G O S- E val ues are e x pecte d d ue t o 
deat h or ve getati ve state.  Missi n g G O S- E val ues d ue t o reas o ns ot her t ha n deat h or ve getati ve 
state will be i m p ute d base d o n a li near m o del perf or me d o n t he G O S- E sc ores le vera gi n g t he 
i nf or mati o n of t he patie nt at ot her ti me p oi nts as well as t he ti me patter ns of all ot her 
partici pa nts. T he m o del will i ncl u de treat me nt as a classificati o n varia ble a n d ot her c o variates: 
G O S- E sc ore at t he pre vi o us ti me p oi nt, re gi o n ( N ort h A merica a n d R o W), a ge ( ≤ 7 0, > 7 0 
years), baseli ne G C S ( 5- 8, 9- 1 2, 1 3- 1 5), baseli ne c o nt usi o n v ol u me per i n vesti gat or ( > 3 t o 1 0 
m L vs > 1 0 m L). I m p ute d val ues will be r o u n de d t o t he cl osest vali d G O S- E sc ore, 1 0 0 
i m p utati o ns will be c o n d ucte d wit h ra n d o m see d pre-s pecifie d, a n d eac h i m p utati o n will res ult i n 
a c o m plete dataset f or all mI T T partici pa nts.  
T he missi n g data patter n will be e val uate d i ncl u di n g reas o ns f or missi n g ness, missi n g data b y 
ra n d o mize d treat me nt gr o u p a n d visit, a n d p ote ntial c o variates ass ociate d wit h missi n g ness. 
Se nsiti vit y a nal yses will be pla n ne d t o e val uate t he r o b ust ness of t he res ults fr o m t he mai n 
a nal ysis of G O S- E.
5. 1. 5.
Missi n g V al ues f or m R S
T he m R S 
 at Da y 1 8 0 will be a nal yze d as a 5-cate g or y or di nal scale ( 0/ 1, 2, 3, 4, 
5/ 6). N o m ulti ple i m p utati o n will be use d t o acc o u nt f or missi n g val ues f or m R S. 


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 2 5
5. 2.  P artici p a nt Acc o u nt a bilit y 
T he s u m maries i n t he e n d of treat me nt stat us secti o n will be base d o n all ra n d o mize d 
partici pa nts. Partici pa nt e n d- of-treat me nt stat us will be s u m marize d i n t otal a n d b y ra n d o mize d 
treat me nt gr o u p. T he s u m mar y statistics i ncl u de: 
•
N u m ber ( %) of partici pa nts ra n d o mize d a n d d ose d. 
•
N u m ber ( %) of partici pa nts w h o c o m plete t he treat me nt.
•
N u m ber ( %) of partici pa nts w h o disc o nti n ue t he treat me nt, a n d reas o n(s) f or n ot 
c o m pleti n g t he treat me nt will be s u m marize d.
A partici pa nt listi n g of reas o ns f or treat me nt disc o nti n uati o n will be pr o vi de d f or all e nr olle d 
partici pa nts.
T he s u m maries i n t he e n d of st u d y stat us secti o n will be base d o n t he f oll o w- u p set. Partici pa nts 
e n d- of-st u d y stat us will be s u m marize d i n t otal a n d b y ra n d o mize d treat me nt gr o u p. T he 
s u m mar y statistics i ncl u de:
•
N u m ber ( %) of partici pa nts w h o e nter 9 0- da y ( 1 8 0- da y) f oll o w- u p a n d ha ve at least o ne 
assess me nt after t he Da y 9 0 visit.
•
N u m ber ( %) of partici pa nts w h o c o m plete t he st u d y.
•
N u m ber ( %) of partici pa nts w h o wit h dra w fr o m t he st u d y, a n d reas o n(s) f or n ot 
c o m pleti n g t he st u d y.
A partici pa nt listi n g of reas o ns f or st u d y wit h dra wal will be pr o vi de d f or all e nr olle d 
partici pa nts.
5. 3.  De m o gr a p hic a n d B aseli ne C h ar acteristics
De m o gra p hic a n d baseli ne c haracteristics will be s u m marize d b y ra n d o mize d treat me nt gr o u p 
f or mI T T a n d all ra n d o mize d partici pa nts, res pecti vel y, u nless s pecifie d ot her wise. F or 
c o nti n u o us or n u merical varia bles, t he s u m mar y statistics will i ncl u de n u m ber ( %) of 
partici pa nts wit h n o n- missi n g meas ure me nts, mea n, sta n dar d de viati o n ( S D), me dia n, q uartiles 
( Q 1, Q 3), a n d ra n ge ( mi n, ma x). F or cate g orical ( n o mi nal or or di nal) varia bles, s u m mar y 
statistics i ncl u de n u m ber ( %) of partici pa nts i n c orres p o n di n g a nal ysis p o p ulati o n a n d n u m ber 
( %) of partici pa nts i n eac h le vel of t he cate g orical varia ble. T he n u m ber ( %) of partici pa nts wit h 
missi n g meas ure me nts will be pr o vi de d f or b ot h c o nti n u o us a n d cate g orical varia bles, if 
a p plica ble. 
5. 3. 1.
De m o gr a p hics per C R Fs
•
A ge ( years) at scree ni n g 
•
A ge cate g or y at scree ni n g ( ≤ 6 0, 6 0 t o 7 0, > 7 0 years) 
•
Se x (fe male, male, ot her)
•
Race ( W hite, Africa n- A merica n, Asia n, Ot her)


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 2 6
•
Et h nicit y ( His pa nic, N o n- His pa nic)
•
Ge o gra p hic re gi o n ( N ort h A merica, R o W)
5. 3. 2.
B aseli ne Dise ase C h ar acteristics per C R Fs
•
Ti me ( h o urs) t o ra n d o mizati o n p ost i nj ur y or L K N
•
Ti me ( h o urs) t o i nitiati o n of st u d y dr u g i nf usi o n p ost i nj ur y or L K N
•
Ti me ( h o urs) t o N C C T f or eli gi bilit y p ost i nj ur y or L K N
•
Ti me ( h o urs) t o i nitiati o n of st u d y dr u g i nf usi o n fr o m N C C T f or eli gi bilit y
•
I nj ur y t y pes
•
Baseli ne G C S bef ore ra n d o mizati o n 
•
T otal i nj ur y se verit y sc ori n g (I S S) sc ore e xcl u di n g hea d or face
•
Baseli ne brai n c o nt usi o n v ol u me ( m L) per i n vesti gat or 
•
Baseli ne brai n c o nt usi o n v ol u me ( m L) per t he ce ntral re vie w
•
Baseli ne he mat o ma v ol u me ( m L) per t he ce ntral re vie w
•
Baseli ne e de ma v ol u me ( m L) per t he ce ntral re vie w
•
Baseli ne bl o o d gl uc ose
•
Baseli ne alc o h ol le vel
•
Baseli ne s o di u m
5. 3. 3.
Str atific ati o n F act ors per I R T 
•
Baseli ne c o nt usi o n v ol u me per i n vesti gat or 
o
> 3 t o 1 0 m L 
o
> 1 0 m L 
•
Baseli ne Glas g o w C o ma Scale ( G C S) 
o
5 t o 8
o
9 t o 1 2 
o
1 3 t o 1 5
•
Baseli ne a ge 
o
≤ 7 0 years ol d
o
> 7 0 years ol d
•
Re gi o n
o
N ort h A merica ( U nite d States a n d Ca na da)
o
Rest of W orl d ( R o W)
•
C o nc or da nce rate of stratificati o n fact ors per I R T a n d per C R Fs b y strata a n d o verall
5. 3. 4.
P h ysic al Me as ure me nts at B aseli ne
T he p h ysical meas ure me nts will be ca pt ure d f or t he partici pa nts d uri n g h os pitalizati o n.
•
Hei g ht (c m)
•
Wei g ht ( k g) 
•
B o d y mass i n de x ( B MI; k g/ m 2)


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 2 7
5. 3. 5.
Me dic al Hist or y
Me dical hist or y ( me dical c o n diti o n or s ur gical pr oce d ure) will be c o de d usi n g t he Me dical 
Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A), if a p plica ble.
•
T he n u m ber ( %) of partici pa nts wit h me dical hist or y (i ncl u di n g o n g oi n g a n d st o p pe d 
c o n diti o ns) will be s u m marize d.
•
A partici pa nt listi n g of me dical hist or y will be pr o vi de d.
5. 4.  Pr ot oc ol De vi ati o ns
Pr ot oc ol de viati o ns i de ntifie d d uri n g site m o nit ori n g will be ca pt ure d i n t he Pr ot oc ol De viati o n 
L o g a n d cate g orize d as maj or or mi n or de viati o ns. 
•
N u m ber ( %) of partici pa nts wit h a n y maj or pr ot oc ol de viati o ns will be s u m marize d b y 
ra n d o mize d treat me nt gr o u p f or mI T T partici pa nts.
•
A listi n g of maj or a n d mi n or pr ot oc ol de viati o ns f or all ra n d o mize d partici pa nts will be 
pr o vi de d.
5. 5. St u d y Tre at me nt E x p os ure a n d C o nc o mit a nt Me dic ati o ns
5. 5. 1.
St u d y Tre at me nt E x p os ure
T he e xte nt of st u d y treat me nt e x p os ure will be s u m marize d b y act ual treat me nt gr o u p f or t he 
safet y a nal ysis set i n t he Da y 4 data base. T he t otal a m o u nt ( m g) of st u d y dr u g recei ve d via 
i nf usi o n is calc ulate d fr o m t he i nf usi o n rate wit h start a n d st o p date/ti me a n d v ol u me 
a d mi nistere d ( b ol us a n d re- b ol us o nl y). T he d urati o n of st u d y dr u g a d mi nistrati o n ( h o urs) is 
calc ulate d fr o m t he first b ol us date/ti me t o t he last i nf usi o n date/ti me. T he d urati o n of st u d y dr u g 
i nf usi o n ( h o urs) is calc ulate d fr o m start/st o p date/ti me of eac h b ol us or i nf usi o n (t he d urati o n of 
st u d y dr u g a d mi nistrati o n mi n us t he d ose i nterr u pti o n i nter vals). 
•
T otal a m o u nt of st u d y dr u g will be s u m marize d b y treat me nt gr o u p.
•
D urati o n of st u d y dr u g a d mi nistrati o n will be s u m marize d b y treat me nt gr o u p.
•
D urati o n of st u d y dr u g i nf usi o n will be s u m marize d b y treat me nt gr o u p. 
•
N u m ber ( %) of partici pa nts wit h a n y i nf usi o n i nterr u pti o ns a n d reas o n f or t he first 
i nterr u pti o n f or a partici pa nt will be s u m marize d b y treat me nt gr o u p.
•
N u m ber ( %) of partici pa nts wit h a n y rate c ha n ges a n d reas o n f or t he first c ha n ge f or a 
partici pa nt will be s u m marize d b y treat me nt gr o u p.
•
Listi n g of reas o ns f or i nterr u pti o n, rate c ha n ge a n d d ose re d ucti o n will be pr o vi de d.
•
Listi n g of kit n u m bers will be pr o vi de d.
5. 5. 2.
C o nc o mit a nt Me dic ati o ns 
All c o nc o mita nt me dicati o ns will be c o de d usi n g t he W orl d Healt h Or ga nizati o n ( W H O) 
me dicati o n dicti o nar y. 


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 2 8
•
N u m ber ( %) of partici pa nts ta ki n g a n y c o nc o mita nt me dicati o ns will be s u m marize d b y 
ra n d o mize d treat me nt gr o u p a n d t otal a n d b y i n dicati o n f or mI T T partici pa nts. 
•
A listi n g of c o nc o mita nt me dicati o ns f or ra n d o mize d partici pa nts will be prese nte d.
5. 5. 3.
N o n- dr u g T her a pies
A c o nc o mita nt t hera p y (i ncl u di n g me dicati o n or n o n- dr u g t hera p y) is defi ne d as a n y t hera p y t hat 
is ta ke n o n or after t he start date/ti me of st u d y dr u g i nf usi o n. T his i ncl u des t hera pies t hat are 
starte d pri or t o start of st u d y dr u g i nf usi o n if t heir use c o nti n ues after st u d y dr u g i nf usi o n.  If a 
partici pa nt ne ver recei ves st u d y dr u g, date of ra n d o mizati o n will be use d, if a p plica ble. Ha n dli n g 
of partial or missi n g start/st o p date/ti me is descri be d i n Secti o n 5. 1 . Co nc o mita nt n o n- dr u g 
t hera pies will be c o de d usi n g Me d D R A.
T he f oll o wi n g n o n- dr u g t hera pies will be s u m marize d b y ra n d o mize d treat me nt gr o u p a n d t otal 
a n d b y i n dicati o n f or mI T T partici pa nts:
•
N u m ber ( %) of partici pa nts ta ki n g a n y n o n- dr u g t hera pies. 
•
N u m ber ( %) of partici pa nts re q uiri n g N S x i ncl u di n g cra ni ot o m y a n d D C, ti me a n d t he 
reas o ns of D C.
•
N u m ber ( %) of partici pa nts wit h decisi o n of C M O, ti me a n d reas o ns of C M O. 
•
N u m ber ( %) of partici pa nts re q uiri n g dela ye d i nt u bati o n, ti me a n d reas o ns of dela ye d 
i nt u bati o n. 
A listi n g of n o n- dr u g t hera pies f or ra n d o mize d partici pa nts will be pr o vi de d.
5. 6. Effic ac y E n d p oi nts
All efficac y e n d p oi nts will be a nal yze d b y ra n d o mize d treat me nt gr o u p f or all mI T T partici pa nts 
i n t he f ull a nal ysis set, u nless ot her wise s pecifie d.
5. 6. 1.
Ge ner al A n al ysis Met h o ds f or Effic ac y E n d p oi nts
All e n d p oi nt m o dels ( bi nar y l o gistic re gressi o n, or di nal l o gistic re gressi o n, C o x m o del, a n d 
a nal ysis of c o varia nce) bel o w will re gress t he o utc o me o n t he ra n d o mize d treat me nt gr o u p, 
c o m pari n g t he BII B 0 9 3 c o m bi ne d wit h place b o gr o u ps, a dj usti n g f or all t he I R T stratificati o n 
fact ors at ra n d o mizati o n (see Secti o n 3. 5. 1 ), baseli ne c o nt usi o n v ol u me per t he ce ntral re vie w 
a n d baseli ne G C S.
A nal ysis of c o varia nce ( A N C O V A) will be perf or me d t o c o m pare t he c ha n ge i n t otal c o nt usi o n 
v ol u me ( pri mar y a nal ysis), c ha n ge i n a bs ol ute he mat o ma v ol u me, t he c ha n ge i n a bs ol ute e de ma 
v ol u me, 
 fr o m baseli ne i n t he mai n a nal ysis c o m pari n g 
t he BII B 0 9 3 c o m bi ne d wit h place b o gr o u ps. T he least s q uare ( L S) mea n differe nce wit h t he 
c orres p o n di n g 2-si de d 9 5 % CI a n d p- val ues f or t he treat me nt gr o u p will be pr o vi de d.


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 2 9
Bi nar y l o gistic re gressi o n will be use d f or bi nar y o utc o mes c o m pari n g t he BII B 0 9 3 c o m bi ne d 
wit h place b o gr o u ps. O d ds rati o, t he c orres p o n di n g 2-si de d 9 5 % c o nfi de nce i nter val ( CI) a n d p-
val ue will be re p orte d f or t he treat me nt gr o u p. 
Or di nal l o gistic re gressi o n ( pr o p orti o nal o d ds m o del) will be use d f or G O S- E as a 7-cate g or y 
or di nal scale ( 1/ 2, 3, 4, 5, 6, 7, 8) a n d f or m R S as a 5-cate g or y or di nal scale ( 0/ 1, 2, 3, 4, 5/ 6) at 
Da y 9 0 a n d 1 8 0. O d ds rati o, t he c orres p o n di n g 2-si de d 9 5 % CI a n d p- val ue f or t he treat me nt 
gr o u p will be re p orte d. 
T he pr o p orti o nal o d ds rati o ass u m pti o n will be teste d usi n g li keli h o o d rati o test base d o n 
o bser ve d data. I n t he case t he ass u m pti o n d oes n ot h ol d ( p- val ue < 0. 0 5) or n o n-c o n ver ge nce, t he 
Ma n n- W hit ne y test will be use d as t he pri mar y i nfere nce a n d t he s o urce of n o n- pr o p orti o nalit y 
or n o n-c o n ver ge nce will be i n vesti gate d. F oll o wi n g t he Ma n n- W hit ne y test, dic h ot o mize d 
a nal ysis will be c o n d ucte d t o assess t he treat me nt effects.
T he C o x pr o p orti o nal hazar d m o del will be use d t o assess t he treat me nt effect o n o verall s ur vi val 
at Da y 9 0 f or all ra n d o mize d partici pa nts. Hazar d rati o, 2-si de d 9 5 % CI as well as t he p- val ue f or 
t he treat me nt gr o u p will be re p orte d. Ka pla n- Meier c ur ves will be prese nte d b y ra n d o mize d 
treat me nt gr o u p, a n d Gree n w o o d’s f or m ula will be use d t o calc ulate t he sta n dar d err or of t he 
Ka pla n- Meier esti mates.
M ulti plicit y will be n ot be a dj uste d f or t he tests of t he pri mar y a n d sec o n dar y e n d p oi nts, si nce 
t he c urre nt st u d y sa m ple size is n ot p o were d f or a m o derate treat me nt effect o n G O S- E. 
T o e x pl ore t he e x p os ure-res p o nse relati o n of differe nt BII B 0 9 3 d oses, si milar efficac y e n d p oi nt 
m o dels will be use d f or a nal yzi n g t he t w o acti ve d ose ar ms se paratel y ( BII B 0 9 3 3 m g/ da y vs. 
BII B 0 9 3 5 m g/ da y vs. place b o). T he res ults of t he e x p os ure-res p o nse a nal ysis will re p ort p oi nt 
esti mate of t he treat me nt effect ( o d ds rati o, hazar d rati o, or least-s q uare mea n differe nce) a n d t he 
c orres p o n di n g 2-si de d 9 5 % CIs. N o p- val ues f or t he e x p os ure-res p o nse a nal ysis will be re p orte d.
Ta ble 3: Mai n A nal yses f or Efficac y E n d p oi nts
E n d p oi nts
A n al ysis met h o d
A n al ysis 
P o p ul ati o n
S A P Secti o n
Pri m ar y e n d p oi nt
C ha n ge i n t otal c o nt usi o n v ol u me as 
meas ure d b y brai n i ma gi n g fr o m 
baseli ne t o 9 6 h o urs or pri or t o D C, 
I P H e vac uati o n or C M O if t hese 
pr oce d ures occ ur bef ore 9 6 h o urs per 
t he ce ntral re vie w
A nal ysis  
of  
Varia nce 
( A N C O V A) 
mI T T
per-
pr ot oc ol
5. 6. 2


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 3 0
Sec o n d ar y e n d p oi nts
G O S- E at Da y 1 8 0
Or di nal l o gistic re gressi o n 
wit h m ulti ple i m p utati o n 
mI T T
per-
pr ot oc ol
5. 6. 3
m R S as 5-cate g or y or di nal scale 
( 0/ 1, 2, 3, 4, 5/ 6) at Da y 9 0
Or di nal l o gistic re gressi o n
mI T T
per-
pr ot oc ol
5. 6. 3
m R S as 2-cate g or y or di nal scal ( 0- 2 
vs 3- 6) at Da y 9 0
Bi nar y l o gistic re gressi o n
mI T T
per-
pr ot oc ol
5. 6. 3
Pr o p orti o n of partici pa nts re q uiri n g 
dela ye d i nt u bati o n
Bi nar y l o gistic re gressi o n
mI T T
per-
pr ot oc ol
5. 6. 3
C ha n ge i n t otal c o nt usi o n v ol u me 
fr o m baseli ne t o 2 4 h o urs or pri or t o 
D C, I P H e vac uati o n or C M O if t hese 
pr oce d ures occ ur bef ore 2 4 h o urs per 
t he ce ntral re vie w
A nal ysis  
of  
Varia nce 
( A N C O V A) 
mI T T
per-
pr ot oc ol
5. 6. 3
C ha n ge 
i n 
a bs ol ute 
he mat o ma 
v ol u me fr o m baseli ne t o 2 4 h o urs
A nal ysis  
of  
Varia nce 
( A N C O V A) 
mI T T
per-
pr ot oc ol
5. 6. 3
C ha n ge i n a bs ol ute e de ma v ol u me 
fr o m baseli ne t o 9 6 h o urs
A nal ysis  
of  
Varia nce 
( A N C O V A) 
mI T T
per-
pr ot oc ol
5. 6. 3
Ti me t o all-ca use deat h t hr o u g h da y 
9 0
C o x pr o p orti o nal hazar ds 
re gressi o n m o del
mI T T
per-
pr ot oc ol
5. 6. 3


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 3 1
5. 6. 2.
Pri m ar y Effic ac y E n d p oi nt 
Pri mar y e n d p oi nt is t he c ha n ge i n t otal c o nt usi o n v ol u me ( he mat o ma pl us peri he mat o mal e de ma) 
as meas ure b y brai n i ma gi n g fr o m baseli ne t o 9 6 h o urs or pri or t o D C, I P H e vac uati o n or C M O 
if t hese pr oce d ures occ ur bef ore 9 6 h o urs  per t he ce ntral re vie w. T he defi niti o n of mai n 
esti ma n d f oll o ws a w hite- o n-treat me nt strate g y [ I C H E 9 ( R 1) A d de n d u m, 2 0 2 0], i.e., all t he 
ce ntral rea ds bet wee n 1 2 h o urs after t he i nitiati o n of st u d y dr u g i nf usi o n a n d H o ur 9 6 or pri or t o 
D C, I P H e vac uati o n or C M O if t hese pr oce d ures occ ur bef ore 9 6 h o urs will be use d; see details 
i n Secti o n 3. 4. 1. 
M ai n A n al ysis
T he a nal ysis of t he pri mar y e n d p oi nt will c o nsist i n testi n g t he n ull h y p ot hesis H 0: p 1 = p 2 
vers us t he alter nati ve h y p ot hesis H 1: p 1 ≠ p 2, w here p 1 is t he c ha n ge fr o m baseli ne of t otal 
c o nt usi o n v ol u me i n t he place b o gr o u p a n d p 2 t hat i n t he BII B 0 9 3 c o m bi ne d gr o u p acc or di n g t o 
t he ra n d o mize d treat me nt gr o u p f or t he f ull a nal ysis set. 
•
T he h y p ot hesis will be teste d usi n g A N C O V A, a dj uste d f or c o variates s pecifie d i n 
Secti o n 5. 6. 1 , at a 2-si ded si g nifica nce le vel of 0. 0 5 wit h t he Da y 4 data base. 
•
T he esti mate d of least s q uare d mea n differe nce f or treat me nt gr o u p, t he c orres p o n di n g 
9 5 % c o nfi de nce i nter val a n d t he p- val ue will be re p orte d. 
•
I n case t hat t he A N C O V A d oes n ot c o n ver ge n u mericall y d ue t o perfect se parati o n of t he 
res p o nses b y s o me stratificati o n fact or, t he stratificati o n fact or t hat ca uses it will be 
e xcl u de d fr o m t he m o del.
Se nsiti vit y A n al ysis a n d S u p ple me nt ar y A n al ysis 
•
A s u p ple me ntar y a nal ysis o n t he pri mar y e n d p oi nt will be perf or me d o n t he mI T T 
p o p ulati o n a n d e xcl u di n g all D C, I P H e vac uati o n or C M O.
•
A se nsiti vit y a nal ysis o n t he pri mar y e n d p oi nt will be perf or me d o n t he P P p o p ulati o n.
•
A se nsiti vit y a nal ysis o n t he pri mar y e n d p oi nt will be perf or me d o n t he mI T T p o p ulati o n 
usi n g t he e C R F data as c o variates rat her t ha n I R T stratificati o n data.
5. 6. 3.
Sec o n d ar y Effic ac y E n d p oi nts 
G O S- E at D a y 1 8 0 
G O S- E will be assesse d as a 7-cate g or y or di nal scale ( 1/ 2, 3, 4, 5, 6, 7, 8) at disc har ge, Da y 3 0, 
Da y 9 0, a n d Da y 1 8 0.
•
G O S- E at Da y 1 8 0 will be a nal yze d b y ra n d o mize d treat me nt base d o n o bser ve d data f or 
t he f ull a nal ysis set usi n g or di nal l o gistic re gressi o n a dj usti n g f or c o variates s pecifie d i n 
Secti o n 5. 6. 1 .


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 3 2
•
Dic h ot o mize d G O S- E ( 0- 4 vers us 5- 8) at Da y 1 8 0 will be a nal yze d usi n g bi nar y l o gistic 
re gressi o n a dj usti n g f or c o variates s pecifie d i n Secti o n 5. 6. 1 .
•
M ulti ple i m p utati o n f or missi n g G O S- E val ues at Da y 1 8 0 will be c o n d ucte d as s pecifie d 
i n Secti o n 5. 1 . T he a nal ysis res ults fr o m i m p ute d datasets will be c o m bi ne d f or i nfere nce 
usi n g R u bi n’s r ule.
•
Descri pti ve statistics f or G O S- E sc ores will be s u m marize d b y visit (see Secti o n 5. 1 ).
m R S at D a y 9 0 
m R S will be assesse d at Da y 9 0 a n d Da y 1 8 0 as a 5-cate g or y or di nal scale ( 0/ 1, 2, 3, 4, 5/ 6). 
•
m R S at Da y 9 0 will be a nal yze d i n t he fi nal data base f or t he f ull a nal ysis set usi n g 
or di nal l o gistic re gressi o n base d o n o bser ve d data a dj usti n g f or c o variates s pecifie d i n 
Secti o n 5. 6. 1 .
•
Dic h ot o mize d m R S ( 0- 2 vers us 3- 6) at Da y 9 0 will be a nal yze d usi n g bi nar y l o gistic 
re gressi o n a dj usti n g f or c o variates s pecifie d i n Secti o n 5. 6. 1 .
Pr o p orti o n of P artici p a nts Re q uiri n g Del a ye d I nt u b ati o n 
Pr o p orti o n of partici pa nts w h o re q uire d dela ye d i nt u bati o n f or ne ur ol o gic deteri orati o n at a n y 
ti me bet wee n 2 4 h o urs a n d 9 6 h o urs p osti nj ur y or L K N will be a nal yze d f or t he f ull a nal ysis set 
i n t he Da y 4 data base. 
•
T he pr o p orti o n of partici pa nts re q uiri n g dela ye d i nt u bati o n will be a nal yze d usi n g bi nar y 
l o gistic re gressi o n a dj usti n g f or c o variates s pecifie d i n Secti o n 5. 6. 1 .
C h a n ge i n T ot al C o nt usi o n V ol u me fr o m B aseli ne t o 2 4 H o urs 
C ha n ge i n t otal c o nt usi o n v ol u me fr o m baseli ne t o 2 4 h o urs or pri or t o D C, I P H e vac uati o n or 
C M O if t hese pr oce d ures occ ur bef ore 2 4 h o urs per ce ntral re vie w will be a nal yze d i n t he Da y 4 
data base f or t he f ull a nal ysis set.
•
A N C O V A will be perf or me d t o c o m pare t he mea n c ha n ge bet wee n BII B 0 9 3 c o m bi ne d 
a n d place b o gr o u ps base d o n t he o bser ve d data.
•
B y- visit mea n a n d c ha n ge i n t otal c o nt usi o n v ol u me fr o m baseli ne will be s u m marize d.
C h a n ge i n A bs ol ute He m at o m a V ol u me fr o m B aseli ne t o 2 4 H o urs 
C ha n ge i n a bs ol ute he mat o ma v ol u me fr o m baseli ne t o 2 4 h o urs will be a nal yze d i n t he Da y 4 
data base f or t he f ull a nal ysis set.
•
A N C O V A will be perf or me d t o c o m pare t he mea n c ha n ge bet wee n BII B 0 9 3 c o m bi ne d 
a n d place b o gr o u ps base d o n t he o bser ve d data.
•
B y- visit mea n a n d c ha n ge i n a bs ol ute he mat o ma v ol u me fr o m baseli ne will be 
s u m marize d.


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 3 3
C h a n ge i n A bs ol ute E de m a V ol u me fr o m B aseli ne t o 9 6 H o urs 
C ha n ge i n a bs ol ute e de ma v ol u me fr o m baseli ne t o 9 6 h o urs will be a nal yze d i n t he Da y 4 
data base.
•
A N C O V A will be perf or me d t o c o m pare t he mea n c ha n ge bet wee n BII B 0 9 3 c o m bi ne d 
a n d place b o gr o u ps base d o n t he o bser ve d data.
•
B y- visit mea n a n d c ha n ge i n a bs ol ute e de ma v ol u me fr o m baseli ne will be s u m marize d.
Ti me t o All-c a use De at h, I ncl u di n g Ne ur ol o gic al De at h, t hr o u g h D a y 9 0 
S ur vi val ti me i n da ys t hr o u g h Da y 9 0 is defi ne d as t he ti me fr o m ra n d o mizati o n t o deat h, 
i ncl u di n g all-ca use deat h a n d ne ur ol o gical deat h.  F or a partici pa nt w h o disc o nti n ues a n d is n ot 
k n o w n t o ha ve die d d uri n g t he st u d y, s ur vi val ti me will be ce ns ore d at t he ti me w he n t he 
partici pa nt is last k n o w n t o be ali ve of t he st u d y. S ur vi val ti me will be a nal yze d i n t he Da y 9 0 
data base f or all ra n d o mize d partici pa nts.
•
S ur vi val ti me will be a nal yze d usi n g C o x pr o p orti o nal hazar ds re gressi o n m o dels of 
o verall s ur vi val after a dj usti n g f or c o variates s pecifie d i n Secti o n 5. 6. 1 .
•
Ka pla n Meier c ur ves of s ur vi val will be prese nte d f or BII B 0 9 3 3 m g/ da y, BII B 0 9 3 5 
m g/ da y, BII B 0 9 3 c o m bi ne d a n d place b o gr o u ps.
 
 
 
 
 
 
 
 
 
 


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 3 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 3 5
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 3 6
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 3 7
5. 7. S afet y 
A d verse e ve nts ( A Es) will be c ollecte d t hr o u g h o ut t he st u d y a n d c o de d usi n g t he Me dical 
Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A). A d verse e ve nts will be s u m marize d base d o n 
t he pri nci ple of treat me nt e mer ge nce. 
A treat me nt-e mer ge nt a d verse e ve nt is defi ne d as 1) a n y a d verse e ve nt t hat has o nset o n or after 
start of st u d y dr u g i nf usi o n, or 2) a n y pre-e xisti n g c o n diti o n t hat has w orse ne d after start of st u d y 
dr u g i nf usi o n. O n-treat me nt e ve nts are treat me nt-e mer ge nt e ve nts t hat occ urre d wit hi n 3 da ys 
after e n d of st u d y dr u g i nf usi o n. Si milarl y, o n-treat me nt la b orat or y data are t h ose fr o m t he 
sa m ples ta ke n fr o m start of st u d y dr u g i nf usi o n t o 3 da ys after t he e n d of st u d y dr u g i nf usi o n. 
Ha n dli n g of missi n g or partial date/ti me f or a d verse e ve nts a n d la b orat or y data is descri be d i n 
Secti o n 5. 1 .
5. 7. 1
A d verse E ve nts
T he i nci de nce of treat me nt-e mer ge nt a d verse e ve nts will be s u m marize d b y act ual treat me nt 
gr o u p a n d f or t he safet y a nal ysis set o verall, b y se verit y, a n d b y relati o ns hi p t o st u d y treat me nt. 
F or t he a nal ysis of A E i nci de nce b y se verit y, t he occ urre nce of t he A E wit h t he greatest se verit y 
will be use d, a n d a partici pa nt will be c o u nte d o nl y o nce a n d o nl y i n t he cate g or y of t he greatest 
se verit y f or eac h e ve nt. 
F or t he a nal ysis of A E i nci de nce b y relati o ns hi p t o st u d y treat me nt, t he occ urre nce of t he A E 
wit h t he str o n gest relati o ns hi p t o st u d y treat me nt will be use d a n d a partici pa nt is c o u nte d o nl y 
o nce a n d o nl y i n t he cate g or y of t he str o n gest relati o ns hi p t o st u d y treat me nt f or eac h e ve nt.
A Es d uri n g o n-treat me nt peri o d will be pr o vi de d f or t he safet y a nal ysis set of t he Da y 4 data base 
a n d s u m marize d f or C S R i n t he Da y 1 8 0 data base.
•
A Es d uri n g o n-treat me nt peri o d will be s u m marize d b y act ual treat me nt gr o u p a n d
o
b y s yste m or ga n class ( S O C) a n d preferre d ter m ( P T).
o
wit h ≥ 5 % hi g her i n i nci de nce f or BII B 0 9 3 c o m bi ne d c o m pare d t o place b o b y 
S O C a n d P T.
o
wit h ≥ 5 % hi g her i n i nci de nce f or BII B 0 9 3 c o m bi ne d or place b o b y S O C a n d P T.
o
wit h ≥ 5 % i n i nci de nce f or BII B 0 9 3 c o m bi ne d or place b o b y P T.
•
Relate d A Es (see Secti o n 1 5. 2. 2 of t he pr ot oc ol) d uri n g o n-treat me nt peri o d b y S O C a n d 
P T will be s u m marize d b y treat me nt gr o u p.
•
A Es a n d relate d a d verse e ve nt d uri n g o n-treat me nt peri o d b y ma xi m u m se verit y, S O C 
a n d P T will be s u m marize d b y act ual treat me nt gr o u p, res pecti vel y.
•
Seri o us a d verse e ve nts ( S A Es) a n d relate d S A Es d uri n g o n-treat me nt peri o d b y S O C a n d 
P T will be s u m marize d b y act ual treat me nt gr o u p, res pecti vel y.
•
A Es lea di n g t o t he f oll o wi n g e ve nts b y ma xi m u m se verit y, S O C a n d P T will be 
s u m marize d b y act ual treat me nt gr o u p, res pecti vel y.
o
A Es lea di n g t o earl y ter mi nati o n of st u d y dr u g i nf usi o n.
o
A Es lea di n g t o i nf usi o n i nterr u pti o n.


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 3 8
o
A Es lea di n g t o i nf usi o n rate c ha n ge.
o
A Es lea di n g t o i nf usi o n d ose re d ucti o n.
A Es d uri n g t he st u d y will be s u m marize d f or t he safet y a nal ysis set w he n a p plica ble:
•
A Es a n d relate d A Es d uri n g t he st u d y b y S O C a n d P T will be s u m marize d b y act ual 
treat me nt gr o u p, res pecti vel y.
•
A Es a n d relate d A Es d uri n g t he st u d y b y ma xi m u m se verit y, S O C a n d P T will be 
s u m marize d b y act ual treat me nt gr o u p, res pecti vel y.
•
S A Es a n d relate d S A Es d uri n g t he st u d y S O C a n d P T will be s u m marize d b y act ual 
treat me nt gr o u p, res pecti vel y.
•
A Es lea di n g t o wit h dra wal fr o m st u d y b y ma xi m u m se verit y, S O C a n d P T will be 
s u m marize d b y act ual treat me nt gr o u p, res pecti vel y.
T he f oll o wi n g listi n gs will be pr o vi de d, w he n a p plica ble: 
•
Listi n g of A Es d uri n g t he st u d y.
•
Listi n g of S A Es d uri n g t he st u d y.
•
Listi n g of A Es lea di n g t o earl y ter mi nati o n of st u d y dr u g i nf usi o n.
•
Listi n g of A Es lea di n g t o i nf usi o n i nterr u pti o n.
•
Listi n g of A Es lea di n g t o rate c ha n ge a n d d ose re d ucti o n.
•
Listi n g of A Es lea di n g t o wit h dra wal fr o m st u d y.
5. 7. 2
A d verse E ve nts of S peci al I nterest ( A E SI)
T he a d verse e ve nt of s pecial i nterest ( A E SI) cate g ories ma y i ncl u de b ut are n ot li mite d t o 
h y p o gl yce mia ( B G < 5 5 m g/ dl).  
•
A E SI d uri n g o n-treat me nt a n d d uri n g t he st u d y will be s u m marize d b y act ual treat me nt 
gr o u p f or t he safet y a nal ysis set, res pecti vel y. 
I n a d diti o n, t he f oll o wi n g listi n gs will be pr o vi de d: 
•
Listi n g of a d verse e ve nts of s pecial i nterest d uri n g t he st u d y.
•
Listi n g of h y p o gl yce mia e ve nts d uri n g t he st u d y.
•
Listi n g of a d verse e ve nts f or partici pa nts wit h a n y h y p o gl yce mia e ve nts.
5. 7. 3
De at h
All-ca use deat hs a n d deat hs b y t he ne ur ol o gical criteria will be s u m marize d f or all ra n d o mize d 
partici pa nts.
•
N u m ber ( %) of deat hs d uri n g o n-treat me nt will be s u m marize d b y act ual treat me nt 
gr o u p.
•
N u m ber ( %) of deat hs bef ore Disc har ge, Da y 3 0, Da y 9 0 a n d Da y 1 8 0 will be 
s u m marize d b y act ual treat me nt gr o u p.


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 3 9
•
Listi n g of deat hs d uri n g t he st u d y will be pr o vi de d, i ncl u di n g ti mi n g of t he deat h relati ve 
t o st u d y treat me nt a n d t he i n vesti gat or assess me nt of t he ca use of deat h.
5. 7. 4
Cli nic al L a b or at or y Res ults
Cli nical la b orat or y e val uati o ns i ncl u de he mat ol o g y a n d bl o o d c he mistr y will be s u m marize d b y 
act ual treat me nt gr o u p f or t he safet y a nal ysis set.
He mat ol o g y, i ncl u di n g b ut n ot li mite d t o t he f oll o wi n g para meters: 
•
W hite bl o o d cells (le u k oc ytes)
•
A bs ol ute ne utr o p hil c o u nts
•
Re d bl o o d cells 
•
He m o gl o bi n 
•
He mat ocrit 
•
Platelet c o u nt
Bl o o d c he mistr y, i ncl u di n g b ut n ot li mite d t o t he f oll o wi n g para meters:
•
Li ver: ala ni ne a mi n otra nsferase ( A L T), as partate a mi n otra nsferase ( A S T), al kali ne 
p h os p hatase ( A L P), t otal bilir u bi n, a n d direct bilir u bi n 
•
Re nal: bl o o d urea nitr o ge n ( B U N) a n d creati ni ne
•
Electr ol ytes: s o di u m, p otassi u m, a n d bicar b o nate
•
Ot her: gl uc ose, calci u m, p h os p h or us a n d al b u mi n 
S hift A n al yses 
La b orat or y a b n or malities will be s u m marize d wit h s hift ta bles. Ta bles will prese nt c ha n ges 
relati ve t o eac h para meter’s n or mal ra n ges. Eac h partici pa nt’s he mat ol o g y a n d bl o o d c he mistr y 
val ues will be fla g ge d as “l o w”, “ n or mal”, or “ hi g h” relati ve t o t he n or mal ra n ges of t he l ocal 
la b orat or y or as “ u n k n o w n” if n o res ult is a vaila ble. 
S hifts fr o m baseli ne t o hi g h/l o w stat us f or he mat ol o g y a n d bl o o d c he mistr y para meters will be 
prese nte d. I n eac h s u m mar y, t he de n o mi nat or f or t he perce nta ge is t he n u m ber of partici pa nts at 
ris k f or t he s hift. T he n u m ber at ris k f or s hift t o l o w is t he n u m ber of partici pa nts w h ose baseli ne 
val ue was n ot l o w a n d w h o ha d at least o ne p ost- baseli ne val ue. T he n u m ber at ris k f or s hift t o 
hi g h is t he n u m ber of partici pa nts w h ose baseli ne val ue was n ot hi g h a n d w h o ha d at least o ne 
p ost- baseli ne val ue. Partici pa nts will be c o u nte d o nl y o nce f or eac h para meter a n d eac h t y pe of 
s hift re gar dless of h o w ma n y p ost- d osi n g assess me nts ha d t hat t y pe of s hift. Partici pa nts wit h 
s hift t o l o w or hi g h will be liste d b y la b orat or y para meter a n d s hift t y pe.
P ote nti all y Cli nic all y Si g nific a nt L a b or at or y A b n or m alities A n al yses
F or he mat ol o g y a n d bl o o d c he mistr y, t he n u m ber of partici pa nts wit h p ote ntiall y cli nicall y 
si g nifica nt la b orat or y a b n or malities p ost- baseli ne will be s u m marize d f or t he para meters 
pr o vi de d i n Ta ble  4 . Partici pa nts nee d t o ha ve at least o ne p ost- baseli ne e val uati o n a n d a baseli ne 


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 4 0
val ue n ot p ote ntiall y cli nicall y si g nifica nt (i ncl u di n g missi n g) i n or der t o be i ncl u de d i n t he 
a nal ysis. 
T a ble 4. Criteri a t o P ote nti all y Cli nic all y Si g nific a nt ( P C S) L a b or at or y A b n or m alities
Cli nic al L a b or at or y O utlier Criteri a
P ar a meter n a me 
P C S L o w
P C S Hi g h
H E M A T O L O G Y 
W hite bl o o d cells 
< 3. 0 × 1 0 9/ L 
> 1 6 × 1 0 9/ L 
Ne utr o p hils 
< 1. 5 × 1 0 9/ L 
> 1 3. 5 × 1 0 9/ L 
Re d bl o o d cells 
≤ 3. 5 × 1 0 1 2/ L
≥ 6. 4 × 1 0 1 2/ L
He m o gl o bi n - Fe males 
≤ 9 5 g/ L 
≥ 1 7 5 g/ L 
He m o gl o bi n - Males 
≤ 1 1 5 g/ L 
≥ 1 9 0 g/ L 
He mat ocrit - Fe males 
≤ 3 2 % 
≥ 5 4 % 
He mat ocrit - Males 
≤ 3 7 % 
≥ 6 0 % 
Platelet c o u nt 
≤ 7 5 × 1 0 9/ L
≥ 7 0 0 × 1 0 9/ L
B L O O D C H E MI S T R Y 
Ala ni ne a mi n otra nsferase 
( A L T) 
N/ A 
> 3 × U L N 
As partate a mi n otra nsferase 
( A S T) 
N/ A 
> 3 × U L N 
Al kali ne p h os p hatase ( A L P)
N/ A 
> 3 × U L N 
T otal bilir u bi n 
N/ A 
> 1. 5 × U L N 
Bl o o d urea nitr o ge n ( B U N) 
N/ A 
≥ 1 0. 7 m m ol/ L 
Creati ni ne 
N/ A 
≥ 1 7 6. 8 μ m ol/ L 
S o di u m 
≤ 1 2 6 m m ol/ L 
≥ 1 5 6 m m ol/ L 
P otassi u m 
≤ 3 m m ol/ L 
≥ 6 m m ol/ L 
Bicar b o nate 
≤ 1 6 m m ol/ L 
≥ 3 5 m m ol/ L 
Gl uc ose 
≤ 2. 2 m m ol/ L 
≥ 9. 7 m m ol/ L 


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 4 1
Cli nic al L a b or at or y O utlier Criteri a
P ar a mete r n a me 
P C S L o w
P C S Hi g h
Calci u m 
≤ 2 m m ol/ L 
≥ 3 m m ol/ L 
P h os p h or us 
≤ 0. 6 m m ol/ L 
≥ 1. 7 m m ol/ L 
Al b u mi n 
≤ 2 5 g/ L 
≥ 6 2 5 g/ L
U L N = u p per li mit of n or mal 
B y- visit S u m m aries
•
F or n u merical la b orat or y para meters, act ual val ues, c ha n ge fr o m baseli ne a n d perce nt 
c ha n ge fr o m baseli ne will be s u m marize d b y visit. 
•
N u m ber of e val ua ble partici pa nts, mea n, sta n dar d de viati o n, q uartiles, mi n a n d ma x 
val ues will be prese nte d at eac h visit.
•
Pl ots of mea n val ues ( wit h sta n dar d err or) f or n u meric la b orat or y para meters at eac h visit 
will be pr o vi de d. 
•
Listi n gs of i n di vi d ual la b orat or y meas ure me nts f or all t he para meters will be pr o vi de d.
A n al ysis of Bl o o d Gl uc ose 
T he bl o o d gl uc ose fr o m l ocal la b orat or y are c ollecte d at scree ni n g, H o urs 0- 1 2, H o ur 2 4, H o ur 
4 8, H o ur 7 2, H o ur 9 6 a n d Da y 7 wit h t he n or mal ra n ges. A d diti o nall y, t he P oi nt- of- Care ( P O C) 
bl o o d gl uc ose is c ollecte d pre- d ose, h o url y u p t o H o ur 9 6 wit h o ut n or mal ra n ges. T he n or mal 
ra n ge f or P O C bl o o d gl uc ose data are assi g ne d as bet wee n 7 0 m g/ d L a n d 1 3 9 m g/ d L, acc or di n g 
t o t he refere nce ra n ge rec o m me n de d b y t he A merica n Dia betes Ass ociati o n f or ra n d o m bl o o d 
gl uc ose meas ure me nts. F or all a nal yses, t he t w o s o urces of data (l ocal la b orat or y a n d P O C) will 
be c o m bi ne d a n d a nal yze d t o get her.
S u m mar y of l o west p ost- baseli ne val ue of bl o o d gl uc ose will be pr o vi de d. T he n u m ber ( %) of 
partici pa nts wit h p ost- baseli ne bl o o d gl uc ose a b n or malities ( < 5 5 m g/ d L, < 8 0 m g/ d L, < 1 2 0 
m g/ d L) will be s u m marize d b y act ual treat me nt gr o u p. Bl o o d gl uc ose val ues f or partici pa nts 
wit h p ost- baseli ne bl o o d gl uc ose < 5 5 m g/ d L will be liste d. 
A n al ysis of Li ver F u ncti o n Tests
P ote ntial seri o us he pat ot o xicit y is defi ne d as ala ni ne a mi n otra nsferase ( A L T) or as partate 
a mi n otra nsferase ( A S T) > = 3 × u p per li mit of n or mal ( U L N) a n d t otal bilir u bi n > 2 × U L N at 
a n y ti me p ost- baseli ne, n ot necessaril y c o nc urre nt (i.e., o n t he sa me da y). 
A scatter pl ot of t he ma xi m u m p ost- baseli ne A L T or A S T val ue relati ve t o U L N a n d ma xi m u m 
p ost- baseli ne t otal bilir u bi n val ue relati ve t o U L N ( n ot necessaril y c o nc urre nt) f or eac h 


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 4 2
partici pa nt will be pr o vi de d. A li ne pl ot of A L T, A S T, al kali ne p h os p hatase ( A L P) a n d t otal 
bilir u bi n val ues o ver ti me f or partici pa nts wit h p ote ntial seri o us he pat ot o xicit y will be pr o vi de d. 
I n a d diti o n, t he n u m ber ( %) of partici pa nts meeti n g t he la b orat or y a b n or malit y criteria liste d 
bel o w will be s u m marize d, res pecti vel y: 
•
A L T > 3 × U L N
•
A L T > 5 × U L N
•
A S T > 3 × U L N
•
A S T > 5 × U L N
•
A S T or A L T > 3 × U L N
•
A S T or A L T > 5 × U L N
•
T otal Bilir u bi n > 2 × U L N
•
A L P > 1. 5 × U L N
•
A S T or A L T > 3 × U L N a n d T otal Bilir u bi n > 2 × U L N
C o nc urre nt is defi ne d as o n t he sa me da y. A listi n g of partici pa nts wit h p ote ntial seri o us 
he pat ot o xicit y will be pr o vi de d.
5. 7. 5
Electr oc ar di o gr a m ( E C G)
T he n u m ber ( %) of partici pa nts wit h s hifts t o cate g orical val ues (a b n or mal n ot A E, or a b n or mal 
A E) will be s u m marize d b y act ual treat me nt gr o u p. E C G para meters i ncl u de heart rate, P R 
I nter val, R R I nter val, Q R S D urati o n, Q T I nter val, Q Tc F, a n d Q Tc B, w here Q Tc B is calc ulate d 
as Q T/( R R/ 1 0 0 0) 1/ 2. T he act ual val ues a n d c ha n ge fr o m baseli ne f or eac h of t he E C G para meters 
will be s u m marize d b y act ual treat me nt gr o u p a n d b y visit s u m mar y. If t here are m ulti ple rec or ds 
fall i nt o t he sa me visit wi n d o ws, t he w orst rec or d will be prese nte d i n t he s u m mar y.  
5. 7. 6
Vit al Si g ns
Vital si g ns meas ures i ncl u de o x y ge n sat urati o n, heart rate ( p ulse), res pirat or y rate, te m perat ure, 
a n d s yst olic a n d diast olic bl o o d press ure. T he a nal ysis of vital si g ns will f oc us o n t he i nci de nce 
of cli nicall y rele va nt a b n or malities f or partici pa nts i n safet y a nal ysis set. T he a b n or malities f or 
te m perat ure, heart rate, s yst olic bl o o d press ure, a n d diast olic bl o o d press ure are pr o vi de d i n 
Ta ble 6 of t he pr ot oc ol.
•
T he n u m ber of partici pa nts e val uate d a n d t he n u m ber ( %) of partici pa nts wit h cli nicall y 
rele va nt p ost- baseli ne a b n or malities will be prese nte d b y act ual treat me nt gr o u p.
•
S u m mar y statistics f or act ual val ues a n d c ha n ge fr o m baseli ne will als o be prese nte d b y 
act ual treat me nt gr o u p.
•
Partici pa nt listi n g of vital si g ns will be pr o vi de d.




Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 4 4
5. 1 3. 
St atistic al C o nsi der ati o ns f or I nteri m A n al ysis
T he i nteri m a nal ysis will n ot i nf or m t he c o nti n ue d bli n de d data c ollecti o n i n t he st u d y. T here is 
n o T y pe I err or a dj ust me nt f or t he i nteri m a nal ysis. T he a nal ysis of t he pri mar y a n d a vaila ble 
data f or t he sec o n dar y e n d p oi nts will be perf or me d after t he last partici pa nt c o m pletes t he Da y 4 
( H o ur 9 6) Visit.
6.
C h a n ges fr o m Pr ot oc ol- S pecifie d A n al yses
N ot a p plica ble f or t his versi o n.
7.
S u m m ar y of C h a n ges fr o m t he Pre vi o us Versi o n of t he S A P
N ot a p plica ble f or t his versi o n.
8.
Refere nces
Mac ha mer, J., Te m ki n, N. R., Ma nle y, G. T., & Di k me n, S. ( 2 0 1 8). F u ncti o nal Stat us 
E xa mi nati o n i n patie nts wit h m o derate-t o-se vere tra u matic brai n i nj uries. J o ur n al of 
Ne ur otr a u m a , 1 1 3 2- 1 1 3 7.
Wil kes, S., Mc C or mac k, E., & Ke n ne y, K. ( 2 0 1 8). E v ol uti o n of Tra u matic Pare nc h y mal 
I ntracra nial He mat o mas (I C Hs): C o m paris o n of He mat o ma a n d E de ma C o m p o ne nts. 
Fr o nt Ne ur ol, 9 , 5 2 7.


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 4 5
A P P E N DI C E S


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 4 6
A P P E N DI X 1.
I M A GI N G D A T A P E R T H E C E N T R A L R E VI E W
O n- Pr ot oc ol I m a g es f or t h e C e ntr al R evi e w
M R a n d N C C T i ma ges will be use d t o assess c ha n ges i n brai n c o nt usi o n, he m orr ha ge a n d e de ma 
v ol u me, 
. Eli gi ble partici pa nts will u n der g o N C C T 
at baseli ne a n d H o ur 2 4 a n d M RI/ N C C T at H o ur 9 6.  
•
Scree ni n g N C C T will be t he o ne cl osest t o t he ra n d o mizati o n, w hic h is assesse d f or 
eli gi bilit y wit h a brai n c o nt usi o n v ol u me of > 3 m L per i n vesti gat or re vie w a n d use d f or 
stratificati o n at ra n d o mizati o n
•
All N C C T/ M RI brai n i ma ges c ollecte d b y t he i ma gi n g C R O u p t o t he H o ur 9 6 visit ( or 
N S x or C M O, if earlier) will be c o nsi dere d o n- pr ot oc ol i ma ges a n d will be s u b mitte d f or 
ce ntral re vie w
I m a gi n g D at a p er t h e C e ntr al R evi e w
Ke y rea di n g pr ocess a n d i ma gi n g data per t he ce ntral re vie w will be pr o vi de d as f oll o ws:
•
I ma ge q ualit y c o ntr ol ( Q C) pers o n nel will re vie w all recei ve d i ma gi n g data t o e ns ure 
acc urac y of la beli n g a n d a p pr o priate ness f or rea ds of all o n- pr ot oc ol i ma gi n g
•
T w o i n de pe n de nt ne ur ora di ol o gist rea ders trai ne d o n t he st u d y will rea d eac h partici pa nt 
case o nce all o n- pr ot oc ol i ma ges are a vaila ble. I nitial rea ds (i.e., 2 rec or ds per i ma ge) 
will be l oc ke d a n d pr o vi de d f or all a vaila ble ti me p oi nts
•
F oll o wi n g c o m pleti o n of i nitial rea di n g, a si n gle fi nal rea d per partici pa nt-ti me p oi nt is 
deter mi ne d t hr o u g h a vera gi n g of t he t w o i n de pe n de nt rea ds or b y rea der c o nse ns us per 
pr oce d ure o utli ne d i n t he brai n M RI/ N C C T w or ks heet ( B M C W) C o m pleti o n G ui deli nes 
versi o n 2. 0
 


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 4 7
A P P E N DI X 2.
S C H E D U L E O F A C TI VI TI E S
T h e sc h e d ul e of acti viti es is d escri b e d i n S ecti o n 5 of t h e pr ot oc ol.
T a bl e 3: 
Sc h e d ul e of Acti viti es
Scree ni n g/
E nr oll me nt
H o urs 
0- 1 2 1
H o ur 2 4
( ± 6 h)
H o ur 4 8
( ± 1 2 h)
H o ur 7 2
( ± 1 2 h)
H o ur 9 6
( ± 1 2 h)2
D a y 7
( ± 2 4 h)3
H os pit al 
Disc h ar ge
( ± 2 4 h)4
D a y 3 0
( ± 7 d)4
D a y 9 0
( ± 1 4 d)4
D a y 1 8 0
( ± 1 4 d)4
N S x/ C o mf ort 
Me as ures
(if a p plic a ble)
E T 
Visit
I ncl usi o n/
e xcl usi o n criteria
X
I nf or me d c o nse nt
X
De m o gra p hics, me dical 
hist or y, p h ysical 
e xa mi nati o n (i ncl u di n g 
wei g ht a n d hei g ht)
X
T T/ L K N
X
N C C T 5
X 6
X
X 7
X
G C S
X
X
X
X
Pre g na nc y test ( uri ne or 
ser u m)
X
Bl o o d alc o h ol le vel
X
Bl o o d sa m pli n g f or 
c oa g ulati o n pa nel (I N R, 
P T T, fi bri n o ge n)
X
Bl o o d sa m pli n g f or 
he mat ol o g y a n d bl o o d 
c he mistr y
X
X
X 8
Bl o o d sa m pli n g f or L F Ts
X
X
X
X
X
X
Vital si g ns 9
X
X
X
X
X
X
X
X


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 4 8
Scree ni n g/
E nr oll me nt
H o urs 
0- 1 2 1
H o ur 2 4
( ± 6 h)
H o ur 4 8
( ± 1 2 h)
H o ur 7 2
( ± 1 2 h)
H o ur 9 6
( ± 1 2 h)2
D a y 7
( ± 2 4 h)3
H os pit al 
Disc h ar ge
( ± 2 4 h)4
D a y 3 0
( ± 7 d)4
D a y 9 0
( ± 1 4 d)4
D a y 1 8 0
( ± 1 4 d)4
N S x/ C o mf ort 
Me as ures
(if a p plic a ble)
E T 
Visit
Ot her assess me nts ( E C G, 
)
(see Pr ot oc ol Ta ble 3 f or E C G, 
 sc he d ule of acti vities)
Bl o o d sa m pli n g f or 
p har mac o ge netics 
( o pti o nal)1 0
X
E nr oll me nt/ra n d o mizati o
n ( T T/ L K N < 1 0 h)
X
St u d y treat me nt 
( T T/ L K N < 1 0 h)
9 6- h o ur i nf usi o n
(see Pr ot oc ol Secti o n 4. 5. 1 f or f urt her details)
Dela ye d i nt u bati o n 
e C R F 1 1
X
X
X
X
B G  meas ure me nt1 2
X
X
X
X
X
X
X
C o nc o mita nt t hera p y
X
X
X
X
X
X
X
X
X
X
X
X
X
C o nc o mita nt 
pr oce d ures 1 3
X
X
X
X
X
X
X
X
X
X
X
X
X
Cra niect o m y/c o mf ort 
care/
cra ni o plast y assess me nt 
f or m(s)
X
M RI
1 4 , 5
X 1 5
X
X 1 6
G O S- E
X
X
X
X
X
m R S
X
X
X
Re vie w safet y data a n d 
rec or d A Es/ S A Es1 7
X
X
X
X
X
X
X
X
X
X
X
X


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 4 9
Scree ni n g/
E nr oll me nt
H o urs 
0- 1 2 1
H o ur 2 4
( ± 6 h)
H o ur 4 8
( ± 1 2 h)
H o ur 7 2
( ± 1 2 h)
H o ur 9 6
( ± 1 2 h)2
D a y 7
( ± 2 4 h)3
H os pit al 
Disc h ar ge
( ± 2 4 h)4
D a y 3 0
( ± 7 d)4
D a y 9 0
( ± 1 4 d)4
D a y 1 8 0
( ± 1 4 d)4
N S x/ C o mf ort 
Me as ures
(if a p plic a ble)
E T 
Visit
Brief s uici de 
i deati o n/ be ha vi or 
assess me nt 1 8
X
X
X
X
X
A E = a d verse e ve nt; B G = bl o o d gl uc ose; C M O = c o mf ort meas ures o nl y; d = da ys; D C = dec o m pressi ve cra niect o m y; E C G = electr ocar di o gra m; 
e C R F = electr o nic case re p ort f or m; E T = earl y ter mi nati o n; 
; G C S = Glas g o w C o ma Scale; G O S- E = Glas g o w C o ma 
Scale- E xte n de d; h = h o urs; I N R = i nter nati o nal n or malize d rati o; I P H = i ntra pare nc h y mal he mat o ma; L F T = li ver f u ncti o n test; L K N = last k n o w n n or mal; 
M RI = ma g netic res o na nce i ma gi n g; m R S = m o difie d Ra n ki n Scale; N C C T = n o nc o ntrast c o m p ute d t o m o gra p h y; N S x = ne ur os ur gical i nter ve nti o n; 
; P T T = partial t hr o m b o plasti n ti me; 
; 
S A E = seri o us a d verse e ve nt; S O C = sta n dar d of care; T T = ti me of tra u ma.
 
1 H o ur 0 is defi ne d as t he start of st u d y treat me nt i nf usi o n.
2 I n t he e ve nt a partici pa nt is disc har ge d fr o m t he h os pital pri or t o H o ur 9 6, e ver y eff ort s h o ul d be ma de t o o btai n ne ur oi ma gi n g ( N C C T or M RI) pri or t o 
disc har ge.
3 If a partici pa nt is d ue t o be disc har ge d fr o m h os pital pri or t o Da y 7, e ver y eff ort s h o ul d be ma de t o perf or m t he Da y 7 assess me nts at t he ti me of disc har ge or 
j ust pri or.
4 All visits after h os pital disc har ge ca n be c o n d ucte d b y tele p h o ne; h o we ver, t he Da y 9 0 a n d Da y 1 8 0 Visits s h o ul d be i n pers o n w he ne ver p ossi ble . S h o ul d t he 
f oll o w- u p visits at Da y 9 0 a n d Da y 1 8 0 be c o n d ucte d re m otel y, 
.
5 Sca ns ( N C C T or M RI) o btai ne d wit hi n 1 2 h o urs of I P H e vac uati o n, D C, or C M O meet t he re q uire me nt. Sca ns are n ot e x pecte d f or ot her N S x i nter ve nti o ns. If 
I P H e vac uati o n, D C, or C M O are i n dicate d pri or t o 9 6 h o urs, a n N C C T or M RI sca n i n t he 1 2 h o urs pr ocee di n g t he pr oce d ure s h o ul d be c ollecte d, a n d n o 
f urt her p ost pr oce d ural i ma ges are re q uire d be y o n d S O C.
6 N C C T as S O C at Scree ni n g ( pri or t o e nr oll me nt). If n ot eli gi ble per S O C sca n, a si n gle, re peat, st u d y-s pecific N C C T ma y be o btai ne d t o reassess c o nt usi o n 
v ol u me if feasi ble wit hi n t he pr ot oc ol-s pecifie d ti me wi n d o w.
7 O pti o nal H o ur 9 6 N C C T s h o ul d be o btai ne d i n a d diti o n t o t he M RI w he ne ver p ossi ble, after st u d y treat me nt i nf usi o n is c o m plete, wit hi n 1 8 h o urs of t he H o ur 
9 6 ti me p oi nt.
8 O nl y perf or me d if partici pa nt has n ot yet bee n disc har ge d fr o m h os pital.
9 Vital si g ns i ncl u de te m perat ure, p ulse rate, s yst olic a n d diast olic bl o o d press ure, res pirat or y rate, a n d o x y ge n sat urati o n. Meas ure me nts ta ke n nearest t o t he 
assess me nt ti me p oi nt s h o ul d be rec or de d.
1 0 T he o pti o nal bl o o d sa m ple f or p har mac o ge netic a nal ysis re q uires a se parate i nf or me d c o nse nt f or m t o be a d mi nistere d bet wee n t he start of st u d y a n d h os pital 
disc har ge. T he p har mac o ge netic sa m ple s h o ul d be c ollecte d as cl ose t o t he c o nse nti n g pr oce d ure as p ossi ble a n d prefera bl y wit hi n 2 4 h o urs of t he start of st u d y 
treat me nt. T he date a n d ti me of c ollecti o n s h o ul d be rec or de d.
1 1 A dela ye d i nt u bati o n e C R F m ust be c o m plete d if a partici pa nt is i nt u bate d f or deteri orati n g ne ur ol o gic stat us.


Pr o d uct: BII B 0 9 3 (i ntr a v e n o us gli b e ncl a mi d e)
St u d y: 2 5 2 B N 2 0 1
St atistic al A n al ysis Pl a n 
Versi o n: Fi n al 3. 0
Pa ge 5 0
1 2 H o url y ( ± 3 0 mi n utes) f or H o ur 0 t o H o ur 2 4, e ver y 2 h o urs ( ± 3 0 mi n utes) f or H o ur 2 5 t o H o ur 4 8, a n d e ver y 4 h o urs ( ± 6 0 mi n utes) f or H o ur 4 9 t o H o ur 9 6. If 
treat me nt f or l o w B G ( < 7 0 m g/ d L [ ~ 3. 9 m m ol/ L]) is i nitiate d, t he n B G m o nit ori n g is re q uire d e ver y 1 5 mi n utes ( ± 1 0 mi n utes) u ntil B G is ≥ 8 0 m g/ d L ( ~ 4. 4 
m m ol/ L) f or 3 c o nsec uti ve rea di n gs wit h o ut e x o ge n o us b ol us gl uc ose s u p ple me ntati o n. See Pr ot oc ol Secti o n 1 1. 4. 1. 1. 1 f or details o n B G m o nit ori n g a n d 
ma na ge me nt.
1 3
 A C M O e C R F m ust be c o m plete d f or partici pa nts f or w h o m care is wit h dra w n.
1 4 A n N C C T sca n is s ufficie nt f or partici pa nts w h o ca n n ot get a n M RI.
1 5 T he 9 6 h o ur sca n s h o ul d be perf or me d after st u d y treat me nt i nf usi o n is c o m plete, wit hi n 1 8 h o urs of t he H o ur 9 6 ti me p oi nt.
1 6 O nl y re q uire d if E T occ urs bef ore t he H o ur 9 6 sca n has bee n perf or me d.
1 7 I ncl u des all A Es fr o m t he be gi n ni n g of st u d y treat me nt a d mi nistrati o n a n d all S A Es fr o m t he ti me of c o nse nt. A Es of s pecial i nterest ( h y p o gl yce mia [ B G < 5 5 
m g/ d L { ~ 3. 1 m m ol/ L }]) will be u p gra de d t o a n S A E. See Pr ot oc ol Secti o n 1 5. 3 f or f urt her details o n m o nit ori n g a n d rec or di n g A Es.
1 8 A s h ort s uici dal i deati o n/ be ha vi or q uesti o n naire will be c o n d ucte d o n partici pa nts w h o are alert a n d ca pa ble of pr o vi di n g a ns wers at Scree ni n g ( pri or t o 
d osi n g). F or t hese partici pa nts, t his q uesti o n naire s h o ul d be re peate d at Da ys 3 0, 9 0, 1 8 0, a n d E T Visit. T he q uesti o n naire c o n d ucte d at Scree ni n g will rec or d 
“ Life Ti me” e ve nts a n d s u bse q ue nt visits (at Da ys 3 0, 9 0, 1 8 0, a n d E T Visit) will rec or d “ Si nce t he Last Visit” e ve nts.
T a bl e 4: 
E C G,
 Sc h e d ul e of Acti viti es
1 2-le a d E C G 1
Pre d ose
S O C E C G ta ke n at Scree ni n g
Mi n ute 5
± 5 mi n utes
H o ur 6
± 5 mi n utes
H o ur 2 4
± 5 mi n utes
H o ur 4 8
± 5 mi n utes
H o ur 7 2
± 5 mi n utes
H o ur 9 6
± 5 mi n utes
B G = bl o o d gl uc ose; E C G = electr ocar di o gra m; 
; S A E = seri o us a d verse e ve nts; S O C = sta n dar d of care.
1 After t he start of st u d y treat me nt i nf usi o n, E C G m ust be c ollecte d bef ore bl o o d sa m pli n g f or 
.


Si g n at ur e P a g e
D o c u m e nt N a m e: 2 5 2 B N 2 0 1 St ati sti c al A n al y si s Pl a n v 3. 0
D o c u m e nt Titl e:
Si g n e d b y
R ol e
D at e / Ti m e ( U T C)
Si g ni n g a s A ut h or
1 4- J ul- 2 0 2 3 1 4: 0 9: 2 3
Si g ni n g a s A p pr o v er
1 4- J ul- 2 0 2 3 1 5: 1 1: 5 1
Si g ni n g a s R e vi e w er
1 7- J ul- 2 0 2 3 1 2: 2 7: 2 2