Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Safety, Tolerability, and Efficacy of BIIB092 in Subjects With Mild Cognitive Impairment Due to Alzheimer's Disease or With Mild Alzheimer's Disease
Phase: PHASE2
Conditions: Alzheimer's Disease
Sponsor: Biogen



Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
3
TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ....................................................................................................2
1.
SYNOPSIS ...................................................................................................................9
2.
LIST OF ABBREVIATIONS.....................................................................................17
3.
SPONSOR INFORMATION .....................................................................................19
4.
INTRODUCTION......................................................................................................20
4.1.
Overview of Alzheimer’s Disease..............................................................................20
4.2.
Current Therapies for Alzheimer’s Disease ...............................................................21
4.3.
Profile of Previous Experience With BIIB092 ...........................................................21
4.3.1.
Nonclinical Experience...............................................................................................21
4.3.2.
Clinical Experience.....................................................................................................21
4.4.
Study Rationale...........................................................................................................22
4.5.
Overall Benefits and Risks Assessment .....................................................................24
4.5.1.
Overall Benefit............................................................................................................24
4.5.2.
Potential Risks ............................................................................................................24
4.5.3.
Summary.....................................................................................................................25
5.
SCHEDULE OF ACTIVITIES ..................................................................................26
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................47
7.
STUDY DESIGN .......................................................................................................51
7.1.
Study Overview ..........................................................................................................51
7.2.
Study Duration for Participants ..................................................................................53
.........................................................................................................55
7.4.
Study Stopping Rules .................................................................................................56
7.5.
End of Study ...............................................................................................................56
8.
SELECTION OF PARTICIPANTS ...........................................................................57
8.1.
Inclusion Criteria ........................................................................................................57
8.2.
Exclusion Criteria.......................................................................................................58
8.3.
Inclusion Criteria for Long-Term Extension Period...................................................64
8.4.
Exclusion Criteria for Long-Term Extension Period..................................................65
9.
SCREENING AND RANDOMIZATION .................................................................67
9.1.
Screening ....................................................................................................................67
9.2.
Randomization............................................................................................................68

Protocol 251AD201
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Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
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9.3.
Blinding Procedures....................................................................................................69
10.
DISCONTINUATION OF STUDY TREATMENT AND WITHDRAWAL 
OF PARTICIPANTS FROM THE STUDY...............................................................71
10.1.
Discontinuation of Study Treatment...........................................................................71
10.2.
Lost to Follow-Up.......................................................................................................72
10.3.
Withdrawal of Participants From Study .....................................................................72
11.
STUDY TREATMENT USE .....................................................................................74
11.1.
Regimen......................................................................................................................74
11.1.1.
Placebo-Controlled Period..........................................................................................74
11.1.2.
Long-Term Extension Period .....................................................................................74
11.2.
Modification of Dose and/or Treatment Schedule......................................................74
11.2.1.
Dose Suspension.........................................................................................................75
11.2.2.
Infusion Interruption...................................................................................................75
11.3.
Compliance.................................................................................................................75
11.4.
Concomitant Therapy and Procedures........................................................................75
11.4.1.
Concomitant Therapy .................................................................................................75
11.4.1.1.
Allowed Concomitant Therapy...................................................................................76
11.4.1.2.
Disallowed Concomitant Therapy..............................................................................76
11.4.2.
Concomitant Procedures.............................................................................................78
11.4.3.
Tobacco Use ...............................................................................................................78
11.5.
Continuation of Treatment..........................................................................................78
12.
STUDY TREATMENT MANAGEMENT................................................................79
12.1.
BIIB092 ......................................................................................................................79
12.1.1.
BIIB092 Preparation...................................................................................................79
12.1.2.
BIIB092 Storage.........................................................................................................79
12.1.3.
BIIB092 Handling and Disposal.................................................................................80
12.1.4.
BIIB092 Accountability..............................................................................................80
12.2.
Placebo........................................................................................................................80
12.3.
Additional Protocol-Designated Products –
 
.................................................................................................80
13.
EFFICACY, PHARMACOKINETIC, PHARMACODYNAMIC, 
IMMUNOGENICITY, AND HEALTH OUTCOMES ASSESSMENTS.................82
13.1.
Clinical Efficacy Assessments....................................................................................82

Protocol 251AD201
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Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
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13.2.
Pharmacokinetic Assessments....................................................................................82
13.3.
Pharmacodynamic Assessments.................................................................................83
...............................................................83
....................................................................84
13.6.
Immunogenicity..........................................................................................................84
13.7.
Health Outcomes Assessments...................................................................................85
14.
SAFETY ASSESSMENTS ........................................................................................86
14.1.
Clinical Safety Assessments.......................................................................................86
14.2.
Laboratory Safety Assessments..................................................................................86
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................88
15.1.
Definitions ..................................................................................................................88
15.1.1.
Adverse Event.............................................................................................................88
15.1.2.
Serious Adverse Event................................................................................................88
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................89
15.2.
Safety Classifications..................................................................................................89
15.2.1.
Investigator Assessment of Events.............................................................................89
15.2.2.
Relationship of Events to Study Treatment
 
.................................................................................................................90
15.2.3.
Severity of Events.......................................................................................................91
15.2.4.
Expectedness of Events ..............................................................................................91
15.3.
Monitoring and Recording Events..............................................................................91
15.3.1.
Adverse Events ...........................................................................................................91
15.3.2.
Adverse Events of Special Interest.............................................................................92
15.3.3.
Serious Adverse Events..............................................................................................92
15.3.4.
Immediate Reporting of Serious Adverse Events.......................................................92
15.3.4.1.
Deaths .........................................................................................................................92
15.3.5.
Suspected Unexpected Serious Adverse Reactions....................................................93
15.4.
Procedures for Handling Special Situations ...............................................................93
15.4.1.
Pregnancy ...................................................................................................................93
15.4.2.
Overdose.....................................................................................................................93
15.4.3.
Medical Emergency....................................................................................................93
15.4.3.1.
Unblinding for Medical Emergency...........................................................................94

Protocol 251AD201
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Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
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15.5.
Contraception Requirements ......................................................................................94
15.6.
Safety Responsibilities................................................................................................95
15.6.1.
The Investigator..........................................................................................................95
15.6.2.
Biogen.........................................................................................................................96
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........97
16.1.
General Considerations...............................................................................................97
16.2.
Demography and Baseline Disease Characteristics....................................................97
16.3.
Safety..........................................................................................................................97
16.3.1.
Analysis Population....................................................................................................97
16.3.2.
Methods of Analysis...................................................................................................97
16.3.2.1.
Adverse Events ...........................................................................................................97
16.3.2.2.
Clinical Laboratory Results........................................................................................98
16.3.2.3.
Vital Signs ..................................................................................................................98
16.3.2.4.
Electrocardiograms.....................................................................................................98
16.3.2.5.
Physical and Neurological Examinations...................................................................98
16.3.2.6.
Columbia - Suicide Severity Rating Scale..................................................................98
16.4.
Efficacy.......................................................................................................................98
16.4.1.
Analysis Population....................................................................................................98
16.4.2.
Methods of Analysis...................................................................................................99
16.4.2.1.
Analysis of Primary Efficacy Endpoint (Clinical Dementia Rating Scale –
Sum of Boxes) ............................................................................................................99
16.4.2.2.
Analysis of Exploratory Clinical Endpoints...............................................................99
16.4.3.
Analysis for the Long-Term Extension Period.........................................................100
16.5.
Pharmacokinetics......................................................................................................100
16.5.1.
Analysis Population..................................................................................................100
16.5.2.
Methods of Analysis.................................................................................................100
16.6.
Pharmacodynamics...................................................................................................101
16.6.1.
Analysis Population..................................................................................................101
16.6.2.
Methods of Analysis for Tau Positron Emission Tomography Results ...................101
16.6.3.
Methods of Analysis for Other Pharmacodynamic Parameters................................101
16.7.
Health Outcomes ......................................................................................................102
16.7.1.
Analysis Population..................................................................................................102

Protocol 251AD201
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Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
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16.7.2.
Methods of Analysis.................................................................................................102
16.8.
Immunogenicity........................................................................................................102
16.8.1.
Analysis Population..................................................................................................102
16.8.2.
Methods of Analysis.................................................................................................102
16.9.
Interim Analyses.......................................................................................................102
16.10.
Sample Size Considerations .....................................................................................103
17.
ETHICAL REQUIREMENTS .................................................................................105
17.1.
Declaration of Helsinki.............................................................................................105
17.2.
Ethics Committee......................................................................................................105
17.3.
Participant Information and Consent........................................................................106
17.4.
Participant Data Protection.......................................................................................107
17.5.
Compensation for Injury...........................................................................................108
17.6.
Conflict of Interest....................................................................................................108
17.7.
Registration of Study and Disclosure of Study Results............................................108
18.
ADMINISTRATIVE PROCEDURES.....................................................................109
18.1.
Study Site Initiation..................................................................................................109
18.2.
Quality Control and Quality Assurance....................................................................109
18.3.
Monitoring of the Study............................................................................................109
18.4.
Study Funding...........................................................................................................110
18.5.
Publications...............................................................................................................110
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION......................111
19.1.
External Contract Organizations...............................................................................111
19.1.1.
Contract Research Organization...............................................................................111
19.1.2.
Interactive Response Technology.............................................................................111
19.1.3.
Electronic Data Capture............................................................................................111
19.1.4.
Central Laboratories for Laboratory Assessments ...................................................111
19.1.5.
Central Facility for Other Assessments ....................................................................111
19.1.6.
Neurocognitive Assessments....................................................................................112
19.2.
Study Committees.....................................................................................................112
19.3.
Changes to Final Study Protocol ..............................................................................112
19.4.
Ethics Committee Notification of Study Completion or Termination......................112
19.5.
Retention of Study Data............................................................................................113

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
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19.6.
Study Report Signatory.............................................................................................113
20.
REFERENCES .........................................................................................................114
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.......................................115
LIST OF TABLES
Table 1:
Schedule of Activities During the Placebo-Controlled Period and the LTE 
Screening Period.........................................................................................................27
Table 2:
Schedule of Activities for Week 80 Through Week 128 of the Long-Term 
Extension Period.........................................................................................................35
Table 3:
Schedule of Activities for Week 132 Through Week 176 of the Long-Term 
Extension Period.........................................................................................................39
Table 4:
Schedule of Activities for Week 180 Through Week 238 or Follow-Up Visit 
of the Long-Term Extension Period ...........................................................................43
LIST OF FIGURES
Figure 1:
Study Design...............................................................................................................53
Figure 2:
Dose-Response Shapes Based on Clinical Dementia Rating Scale – Sum of 
Boxes Mean Change from Baseline at Week 78 ......................................................104

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
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Biogen MA Inc.
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1.
SYNOPSIS
Protocol Title:
Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study 
to Assess the Safety, Tolerability, and Efficacy of BIIB092 in Subjects 
with Mild Cognitive Impairment due to Alzheimer’s Disease or with 
Mild Alzheimer’s Disease
Protocol Number:
251AD201
Version Number:
4
Name of Study 
Treatment:
BIIB092 (formerly known as BMS 986168, IPN007)
Study Phase:
2
Study Indication:
Mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) or 
mild AD
Study Rationale:
BIIB092 is a humanized immunoglobulin G4 monoclonal antibody that 
has been shown to bind tau at the amino terminus.  Although tau is 
primarily an intracellular protein, a portion of tau is secreted by 
neurons as N-terminal tau fragments.
BIIB092 has been shown to lower cerebrospinal fluid (CSF) 
concentrations of N-terminal tau in nonclinical studies, a 
single-ascending-dose study in healthy participants, and a 
multiple-ascending-dose study in participants with progressive 
supranuclear palsy.  Based upon the close links between tau pathology,
neurodegeneration, and clinical features consistent with AD, coupled 
with the evidence that tau pathology can spread via neuronal release 
and uptake of pathological tau species, examination of BIIB092 in the 
clinical AD setting is strongly supported as a potential 
disease-modifying therapy.  This study will assess the safety and 
efficacy of BIIB092 in participants with MCI due to AD or with mild 
AD and help to inform on dose selection in this patient population.
Study Objectives 
and Endpoints:
Placebo-Controlled Period
The primary objective of the study for the placebo-controlled period is 
to evaluate the safety and tolerability of BIIB092 in participants with 
MCI due to AD or with mild AD. 
The primary safety endpoints that relate to this objective are the 
incidence of adverse events (AEs) and serious AEs (SAEs) during the 

Protocol 251AD201
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Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
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placebo-controlled period.
Secondary objectives and endpoints are as follows:

To evaluate the efficacy of multiple doses of BIIB092 in 
slowing cognitive and functional impairment in participants 
with MCI due to AD or with mild AD as measured by the 
change from Baseline over time at Week 78 on the Clinical 
Dementia Rating Scale (CDR) - Sum of Boxes (CDR-SB).  
This is the primary efficacy objective, with the primary 
efficacy endpoint.

To evaluate the immunogenicity of BIIB092 after multiple 
doses in participants with MCI due to AD or with mild AD 
as measured by the incidence of anti-BIIB092 antibodies in 
serum over time up to Week 90.
Exploratory objectives and endpoints are as follows:

To assess the effect of BIIB092 on the clinical progression 
of AD as measured by changes from Baseline over time up 
to Week 78 on the Mini-Mental State Examination 
(MMSE), International Shopping List Test Immediate 
Recall (ISLT), Category Fluency and Letter Fluency tests 
from the Delis-Kaplan Executive Function System 
(DKEFS), Digit Symbol Substitution Test (DSST), Trail 
Making Test Part A (Trails A), Everyday Cognition (eCog), 
Alzheimer’s Disease Cooperative Study-Activities of Daily 
Living (ADCS-ADL), Functional Activities Questionnaire 
(FAQ), Alzheimer’s Disease Assessment Scale-Cognitive 
(ADAS-Cog 13 [13 item]), and Neuropsychiatric 
Inventory-10 (NPI-10).

To assess the effect of BIIB092 on changes in caregiver 
burden and participant quality of life as measured by 
changes from Baseline over time up to Week 68 on the Zarit 
Burden Interview (ZBI) and Quality of Life for Alzheimer’s 
Disease (QoL-AD).

To assess the effect of BIIB092 on resource utilization as 
measured by the Resource Utilization in Dementia-Lite 
(RUD-Lite) Version results over time up to Week 68.

To assess BIIB092 pharmacokinetics (PK) in serum (trough 
serum BIIB092 concentrations and end-of-infusion serum 
BIIB092 concentrations) from the samples collected at the 

Protocol 251AD201
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Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
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During the dose-blinded LTE period, participants will receive BIIB092 
by IV once every 4 weeks beginning at Week 80.  Participants who 
were randomized to receive BIIB092 during the placebo-controlled 
period will continue to receive BIIB092 at the dose they were randomly 
assigned.  Participants randomized to receive placebo during the 
placebo-controlled period will receive BIIB092 at the high dose 
(2000 mg) once every 4 weeks during the LTE period.
Duration of 
Treatment and 
Follow-up:
The total duration for participants who complete the placebo-controlled 
period and do not enter the LTE period will be approximately 
99 weeks. For participants who complete both the placebo-controlled 
period and the LTE period, the total study duration will be 
approximately 247 weeks.
Placebo-Controlled Period
Participation in the placebo-controlled period will be approximately 
99 weeks, which includes the Screening Period of approximately 
9 weeks, the 76-week Treatment Period, and the End-of-Study (EOS) 
Visit at Week 78, and for participants not entering the LTE period, a 
Follow-up Safety Visit at Week 90, or approximately 14 weeks after 
the last dose of study treatment. It is recommended that all the 
screening procedures be completed within 65 days; however, the 
overall Screening Period may be extended up to 90 days in consultation 
with the Medical Monitor in advance and provided that written 
documentation is received from the Sponsor or delegate 
 
.  Participants will have 
approximately 25 outpatient clinic visits:

Participant eligibility will be determined at up to 3 visits 
during the Screening Period (Screening Visits 1, 2, and 3).

On Study Day 1, eligible participants will be randomized, 
have scheduled assessments per the Schedule of Activities, 
and receive the first infusion of randomized study treatment.

Participants will return to the clinic at 4-week intervals 
during the Treatment Period for infusions of study treatment 
and study assessments (Weeks 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44, 48, 52, 56, 60, 64, 68, 72, and 76).  The last dose 
of study treatment will be administered at Week 76 
(End-of-Treatment Visit).  

For a participant who completes the Treatment Period at 
Week 76, there will be an EOS Visit at Week 78 for final 

Protocol 251AD201
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Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
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study assessments of the placebo-controlled period.  A 
Follow-up Safety Visit will occur at Week 90 (14 weeks 
after the last dose of study treatment is administered), unless 
the participant elects to enter an extension study following 
the Week 78 Visit.  

Participants who discontinue study treatment 
prematurely will be asked to remain in the study and 
continue all protocol-specified visits and procedures.  
These participants should be encouraged to attend at 
least the Week 24, Week 52, and Week 78 visits, 
depending on when treatment was discontinued, and 
undergo all the scheduled procedures.  At a minimum, 
these visits should include assessment of AEs/SAEs and 
concomitant medications and key clinical assessments, 
including at least the CDR, MMSE, ISLT, 
ADAS-Cog 13, ADCS-ADL, and FAQ.  Participants 
who discontinue study treatment prematurely will also 
be asked to return to the study site for a Follow-up 
Safety Visit 14 weeks after receiving the last dose of 
study treatment.

Participants who withdraw from the study prematurely 
are to return to the study site for an Early Termination 
(ET) Visit and assessments and for the Follow-up Safety 
Visit 14 weeks after administration of the final infusion 
of study treatment.
Long-Term Extension Period
Participants who meet the LTE inclusion and exclusion criteria will be 
eligible to enter the dose-blinded LTE period, which includes the LTE 
Screening Period of approximately 4 weeks starting at Week 76, the 
144-week Treatment Period starting at Week 80, the EOS Visit at 
Week 226, and the Follow-up Visit at Week 238. 
Participants will have approximately 39 outpatient clinic visits during 
the LTE period:

Participant eligibility will be determined at Week 76 or 
Week 78 of the placebo-controlled period and confirmed at 
Week 80 of the LTE period.

At the Week 80 Visit, eligible participants will have 
scheduled assessments per the Schedule of Activities and 
receive the first infusion of BIIB092 during the LTE period.  

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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All participants receiving placebo in the placebo-controlled 
period will receive BIIB092 at the high dose (2000 mg) 
once every 4 weeks during the LTE period.

Participants will return to the clinic at 4-week intervals 
during the Treatment Period for infusions of study treatment 
and study assessments.

The last dose of study treatment will be administered at 
Week 224 (End-of-Treatment Visit).  The EOS Visit will 
occur at Week 226 and the Follow-up Visit at Week 238.

Participants who discontinue study treatment 
prematurely will be asked to remain in the study and 
continue all protocol-specified visits and procedures.  
These participants should be encouraged to attend at 
least the Week 80, 104, 116, 128, 152, 156, 176, 196, 
200, 224, and 226 Visits, depending on when treatment 
was discontinued, and undergo all the scheduled 
procedures.  At a minimum, these visits should include 
assessment of AEs/SAEs and concomitant medications 
and key clinical assessments, including at least the CDR, 
MMSE, ISLT, ADAS-Cog 13, ADCS-ADL, and FAQ.  
Participants who discontinue study treatment 
prematurely will also be asked to return to the study site 
for a Follow-up Safety Visit 14 weeks after receiving the 
last dose of study treatment.

Participants who withdraw from the study prematurely 
are to return to the study site for an Early Termination 
Visit and assessments and for the Follow-up Safety Visit 
14 weeks after receiving the last dose of study treatment.

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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2.
LIST OF ABBREVIATIONS
Aβ 
amyloid beta
AD
Alzheimer’s disease
ADAS-Cog 13
Alzheimer’s Disease Assessment Scale – Cognitive (13 item)
ADCS-ADL
Alzheimer’s Disease Cooperative Study – Activities of Daily 
Living
ADNI
Alzheimer’s Disease Neuroimaging Initiative
AE
adverse event
ALT
alanine aminotransferase
anti-HBc
hepatitis B core antibody
anti-HBs
hepatitis B surface antibody
AST
aspartate aminotransferase
BUN
blood urea nitrogen
CBC
complete blood count
CDR
Clinical Dementia Rating Scale
CDR–SB
Clinical Dementia Rating Scale – Sum of Boxes
CI
confidence interval
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia – Suicide Severity Rating Scale
DBP
diastolic blood pressure
DHA
Directions for Handling and Administration
DKEFS
Delis-Kaplan Executive Function System
DMC
Data Monitoring Committee
DSST
Digit Symbol Substitution Test
ECG
electrocardiogram
eCog
Everyday Cognition
Emax
maximum response
EOS
end of study
ET
early termination
FAQ
Functional Activities Questionnaire
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation

Protocol 251AD201
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Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
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Biogen MA Inc.
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Ig
immunoglobulin
INR
international normalized ratio
IRT
interactive response technology
ISLR
International Shopping List Test Delayed Recall
ISLT
International Shopping List Test Immediate Recall
ITT
intent-to-treat
IV
intravenous
LS
least squares
LTE
long-term extension
MAD
multiple-ascending-dose
MAO
monoamine oxidase
MCI
mild cognitive impairment
MCP – MOD
multiple comparison procedure – modelling
MMRM
mixed model with repeated measures
MMSE
Mini-Mental State Examination
MRI
magnetic resonance imaging
NFT
neurofibrillary tangle
NIA-AA
National Institute on Aging – Alzheimer’s Association
NPI-10
Neuropsychiatric Inventory – 10
PD
pharmacodynamic(s)
PET
positron emission tomography
PK
pharmacokinetic(s)
PSP
progressive supranuclear palsy
QoL-AD
Quality of Life for Alzheimer’s Disease
RUD-Lite
Resource Utilization in Dementia-Lite Version
SAD
single-ascending-dose
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
SUSAR
suspected unexpected serious adverse reaction
Trails A
Trail Making Test, Part A
ULN
upper limit of normal
UTI
urinary tract infection
UV
unscheduled visit
ZBI
Zarit Burden Interview

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
19
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 see 
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 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
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4.
INTRODUCTION 
4.1.
Overview of Alzheimer’s Disease
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder clinically characterized by 
cognitive impairment, behavioral disturbances, psychiatric symptoms, and disability in activities 
of daily living.  These clinical manifestations constitute the syndrome dementia.  AD 
International estimates that the number of people living with dementia worldwide will increase 
from (the current estimate of) 46.8 million to 131.5 million by 2050 [Alzheimer's Disease 
International 2015].  As the most common cause of dementia, AD accounts for 60% to 80% of 
dementia cases [Alzheimer's Association 2015].
The main neuropathological hallmarks of AD are extracellular senile (neuritic) plaques 
containing aggregated β-amyloid (Aβ) peptides and intraneuronal neurofibrillary tangles (NFTs) 
composed of abnormal hyperphosphorylated tau protein.  
The amyloid hypothesis of AD etiology postulates that misfolded Aβ peptide is a causative 
factor, which is strongly supported by human genetics [Hardy and Selkoe 2002].  While the 
evidence for Aβ as the initiator of the pathophysiological cascade leading to AD dementia is 
strong, the link between Aβ pathology and neurodegeneration in AD and the subsequent clinical 
progression, both temporally and anatomically, is relatively weak [Musiek and Holtzman 2015; 
Serrano-Pozo 2011].  Amyloid plaques are present in patients with AD 10 to 15 years before 
onset of AD symptoms and overt neuronal loss, and they reach a plateau around clinical onset 
[Jack 2013].  
A much stronger correlation has been demonstrated between tau pathology (in the form of NFTs 
of the aggregated, misfolded microtubule-associated protein tau) and neuronal loss and cognitive
decline.  In AD, atrophy as seen on magnetic resonance imaging (MRI) and hypometabolism as 
seen with fluorodeoxyglucose (FDG) positron emission tomography (PET), correlate highly with 
postmortem histochemical analysis of synaptic and neuron loss and, importantly, tau burden 
[Jack 2013; Serrano-Pozo 2011].  Imaging data obtained using novel PET tau radioligands alone 
or in combination with functional and structural imaging methods (e.g., FDG PET or structural 
MRI) as well as cognitive testing demonstrated stronger correlations between tau PET signal and 
neurodegeneration, hypometabolism, and cognitive deficits, than for amyloid PET signal 
[Johnson 2016; Pontecorvo 2017].  While these are early findings, and a better understanding of 
the existing tau PET imaging agents as well as longitudinal studies are needed, the recent 
findings lend further support to the close link between tau pathology, neurodegeneration and AD 
symptoms.  
There are currently no approved therapies that modify the course of AD.  However, due to the 
central role of tau in neurodegeneration and its close correlation with cognitive decline in AD, 
modification of tau pathology has potential for the treatment of AD.  

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
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21
4.2.
Current Therapies for Alzheimer’s Disease
No new therapies for AD have been approved in more than a decade.  Currently approved 
therapies (and their approval dates) include the central cholinesterase inhibitors (donepezil 
[Aricept®; 2004], rivastigmine [Exelon®; 2000], and galantamine [Reminyl®; 2001]) and the 
N-methyl-D-aspartate antagonist memantine (Ebixa®; Namenda®; 2003).  These medications 
provide only symptomatic benefit and do not attenuate the course of the disease [Birks 2006; 
McShane 2006].  
4.3.
Profile of Previous Experience With BIIB092
Please see the BIIB092 Investigator’s Brochure for detailed information on relevant nonclinical 
and clinical studies.
4.3.1.
Nonclinical Experience
In nonclinical pharmacology studies, BIIB092 was shown to recognize a linear, 
nonphosphorylated, amino terminal epitope (including amino acid residues 15-24 of full-length 
human tau) of the microtubule-associated protein tau.  BIIB092 exhibited high affinity for human 
and cynomolgus monkey tau, with binding affinities of 7.10-10 M and 6.35-10 M, respectively.  
The primary site of action of BIIB092 is believed to be the interstitial space between neurons 
where it binds tau, thereby reducing eTau-mediated spread of tau pathology, and this proposed 
site of action is supported by nonclinical studies.
Pharmacokinetic (PK) and pharmacodynamic (PD) analysis of serum and cerebrospinal fluid 
(CSF) BIIB092 concentrations from 3 experiments in cynomolgus monkeys (intravenous [IV] 
injection/infusion doses of 0.5 to 60 mg/kg) showed that CSF N-terminal tau levels were reduced 
in a dose-dependent manner.  The duration of reduction of CSF N-terminal tau was also 
dose-dependent.  Higher doses were associated with longer reductions of N-terminal tau in CSF.  
For example, the reduction of N-terminal tau in CSF (25% to 50%) persisted for more than 
58 days at doses ≥20 mg/kg.  
The nonclinical toxicology studies conducted to date have demonstrated an acceptable safety 
profile for BIIB092 to support continued use in clinical studies.
4.3.2.
Clinical Experience
The present study is the first study of BIIB092 in AD.  Previous clinical studies have been 
conducted to support development of BIIB092 for the treatment of patients with progressive 
supranuclear palsy (PSP).  
BIIB092 has been evaluated in 4 completed or ongoing clinical studies (Studies CN002001, 
CN002003, 251PP201 [CN002004], and 251PP301 [CN002012]):

Study CN002001, the first-in-human study of BIIB092, was a Phase 1, randomized, 
double-blind, placebo-controlled, single-ascending-dose (SAD) study in healthy 
participants to characterize the safety, tolerability, PK, PD, and immunogenicity of 

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
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Biogen MA Inc.
22
single doses of BIIB092 ranging from 21 mg to 4200 mg.  Single doses of BIIB092 
were safe and well tolerated at all dose levels tested.  The extent and duration of 
suppression of CSF N-terminal tau increased with increasing dose.  Following single 
doses of BIIB092, the mean suppression of CSF N-terminal tau on Study Day 29 
ranged from 65% to 96% at doses ranging from 70 mg to 4200 mg.  Greater than 80% 
suppression of CSF N-terminal tau was achieved with single doses of BIIB092 ≥210 
mg.  The suppression of N-terminal tau following dosing with BIIB092 persisted over 
the course of the 12-week study.  

Study CN002003 was a Phase 1b, randomized, double-blind, placebo-controlled 
multiple-ascending-dose (MAD) study to characterize the safety, tolerability, PK, PD, 
and immunogenicity of BIIB092 doses of 150 mg, 700 mg, and 2100 mg 
administered every 4 weeks in participants with PSP.  All 3 doses were safe and well 
tolerated, based on results from the dose-escalation phase of the study.  Treatment 
with multiple monthly doses of BIIB092 decreased CSF N-terminal tau by mean 
values of approximately 90%, 93%, and 96% on Study Day 29 and 91%, 95%, and 
97% on Study Day 85 at doses of 150, 700, and 2100 mg, respectively.  

Study 251PP201 is an ongoing Phase 1b open-label extension study to evaluate the 
long-term safety and tolerability of multiple doses of BIIB092 in participants with 
PSP who participated in CN002003. 

Study 251PP301 is an ongoing Phase 2b randomized, double-blind, 
placebo-controlled, parallel-group study to evaluate the efficacy and safety of 
intravenously administered BIIB092 2000 mg versus placebo (2:1 randomization 
ratio) in participants with PSP.
4.4.
Study Rationale
BIIB092 is a humanized immunoglobulin (Ig) G4 monoclonal antibody that has been shown to 
bind tau at the amino terminus.  Although tau is primarily an intracellular protein, a portion of 
tau is secreted by neurons as N-terminal tau fragments.
BIIB092 has been shown to lower CSF concentrations of N-terminal tau in nonclinical studies, a 
SAD study in healthy participants (Study CN002001), and a MAD study in participants with PSP 
(Study CN002003).  AD is defined by 2 neuropathologic hallmarks:  extracellular neuritic 
plaques containing Aβ peptide and intraneuronal NFTs composed of hyperphosphorylated tau 
protein.  Based upon the close links between tau pathology, neurodegeneration, and clinical 
features consistent with AD, coupled with the evidence that tau pathology can spread via 
neuronal release and uptake of pathological tau species, examination of BIIB092 in the clinical 
AD setting is strongly supported as a potential disease-modifying therapy.  This study will assess 
the safety and efficacy of BIIB092 in participants with mild cognitive impairment (MCI) due to 
AD or with mild AD, selected by proof of brain amyloid burden.  This study will also help to 
inform on dose selection in this patient population.

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
24
4.5.
Overall Benefits and Risks Assessment
4.5.1.
Overall Benefit
BIIB092 has the potential to slow or stop the spread of tau pathology observed in 
neurodegenerative diseases such as PSP, AD, and other tauopathies. 
In participants with PSP, BIIB092 has been evaluated in 2 completed clinical studies 
(Studies CN002001 and CN002003) and is currently being evaluated in the ongoing 
Studies 251PP201 and 251PP301. The first-in-human study of BIIB092 (Study CN002001) was 
designed as a randomized, double-blind, placebo-controlled, SAD study in healthy participants to 
characterize the safety, tolerability, PK, PD, and immunogenicity of single doses of BIIB092, 
ranging from 21 to 4200 mg. Study CN002003, a Phase 1b study, was designed as a randomized, 
double-blind, placebo-controlled MAD study to characterize the safety, tolerability, PK, PD, and 
immunogenicity of multiple doses of BIIB092, ranging from 150 to 2100 mg, in participants 
with PSP. In both of these completed studies, BIIB092 was found to be well tolerated at the 
doses tested in both healthy participants and participants with PSP. The ongoing Phase 1b study, 
Study 251PP201, is designed as an open-label extension study to evaluate the long-term safety 
and tolerability of multiple doses of BIIB092 in participants with PSP who participated in Study 
CN002003. Several interim analyses of the data being collected in this study have been 
performed to date. Study 251PP301 is an ongoing Phase 2b study designed as a randomized, 
double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of 
IV-administered BIIB092 in participants with PSP.
In participants with AD, this study (Study 251AD201) will evaluate the safety and efficacy of 
BIIB092.
Based on the PK and PD data from Studies CN002001 and CN002003, the mean concentrations 
of BIIB092 in CSF increased in a generally dose-proportional manner. A robust and persistent 
lowering of unbound N-terminal tau was observed following administration of single and 
multiple doses of BIIB092 in healthy participants and in participants with PSP, consistent with 
the observations in cynomolgus monkeys.
4.5.2.
Potential Risks
The nonclinical studies conducted to date have demonstrated an acceptable safety profile for 
BIIB092 to support continued use in clinical studies.
As of 25 November 2018, an estimated 486 healthy participants or participants with PSP or AD 
have been exposed to BIIB092 in clinical studies. The following summary of the safety profile 
of BIIB092 is based on safety data from the completed Studies CN002001 and CN002003 and 
the ongoing Study 251PP201.  In the SAD study in healthy participants, there were no safety 
findings of note, and development continued in patients with PSP. In participants with PSP, to 
date, the most commonly reported AEs were fall, urinary tract infection (UTI), contusion, and 
headache. Most AEs have been reported as mild or moderate in intensity. Serious AEs (SAEs) 
have generally been consistent with disease (UTI, respiratory arrest, aspiration pneumonia, and 
progressive PSP) or are not unexpected in the patient population enrolled in the trials 

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
25
(cholecystitis, cancer, fractures, and anemia). There have been 3 deaths, all of which were likely 
related to underlying disease (respiratory arrest, aspiration pneumonia, and progressive disease). 
None of the SAEs or deaths were considered related to BIIB092 by Investigators. No safety 
concerns have been identified from laboratory, vital signs, or electrocardiogram (ECG) 
assessments. Nonserious infusion reactions have been observed and are an identified risk of 
BIIB092.
BIIB092 is a humanized IgG4 monoclonal antibody. While a low risk of immunogenicity is 
suggested by preclinical studies, the risk of immunogenicity in humans is unknown. 
Immunogenicity is an AE of special interest that is under monitoring in all ongoing studies. No 
safety data regarding this topic have emerged that would change the safety profile of BIIB092.
In general, BIIB092 has been well tolerated in the clinical study participants. There are no
important identified or potential risks in the program. The safety profile is acceptable to 
continue development.
4.5.3.
Summary
Currently available treatments for AD offer modest symptomatic relief, but none has the 
potential to modify the underlying disease pathology or course of the disease.  In addition, no 
medications have been approved for the treatment of PSP. Therefore, there is a significant 
unmet need for the development of effective disease-modifying therapies in both PSP and AD.
Based on the PK and PD data from Studies CN002001 and CN002003, the mean concentrations 
of BIIB092 in CSF increased in a generally dose-proportional manner. A robust and persistent 
lowering of unbound N-terminal tau was observed following administration of single and 
multiple doses of BIIB092 in healthy participants and in participants with PSP, consistent with 
the observations in cynomolgus monkeys.
Based on the safety data from the completed Studies CN002001 and CN002003 and the data 
from an interim analysis of the ongoing Study 251PP201, BIIB092 was generally well tolerated 
and demonstrated an acceptable safety profile for continued development.
The overall analysis of potential benefits (based on the robust and persistent lowering of 
unbound N-terminal tau in healthy participants and in participants with PSP, consistent with 
cynomolgus monkeys) and risks (available safety data indicating that BIIB092 is generally well 
tolerated) supports the continued development of BIIB092 in both PSP and AD.

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
26
5.
SCHEDULE OF ACTIVITIES
The schedule of study activities is presented in Table 1, Table 2, Table 3, and Table 4.

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
27
Table 1:
Schedule of Activities During the Placebo-Controlled Period and the LTE Screening Period
Baseline 
Screening 
Period1, 2 within 
65 days3 of Day 
1
Placebo-Controlled Period4
UV for 
Change in 
AD 
Medication
5
FUV6
Study Week
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76 
EOT
78/ 
EOS 
or
ET7
90
Study Day
S1
S2
S38
1
29 
±7
57 
±
7
85 
±7
11
3 
±7
14
1 
±7
169 
±7
19
7 
±7
22
5 
±7
25
3 
±7
28
1 
±7
30
9 
±7
337 
±7
36
5 
±7
39
3 
±7
42
1 
±7
44
9 
±7
47
7 
±7
50
5 
±7
533 
±7
547 
±7
631 
±7
Study day 
infusion4, 9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Initial screening 
consent 
(optional)10
X
Full informed 
consent11
X
X12
X12
Randomization
X
Eligibility 
criteria
X
X
X
X
X13
X13
NIA-AA 
criteria review
X
Medical history
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Pregnancy 
test14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Follicle-
stimulating 
hormone15
X
Alcohol/drug 
screen
X
HbA1c
X

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
28
Baseline 
Screening 
Period1, 2 within 
65 days3 of Day 
1
Placebo-Controlled Period4
UV for 
Change in 
AD 
Medication
5
FUV6
Study Week
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76 
EOT
78/ 
EOS 
or
ET7
90
Study Day
S1
S2
S38
1
29 
±7
57 
±
7
85 
±7
11
3 
±7
14
1 
±7
169 
±7
19
7 
±7
22
5 
±7
25
3 
±7
28
1 
±7
30
9 
±7
337 
±7
36
5 
±7
39
3 
±7
42
1 
±7
44
9 
±7
47
7 
±7
50
5 
±7
533 
±7
547 
±7
631 
±7
HIV16/hepatitis 
tests
X
Physical 
examination
X
X
X
X
X
X
X
X
Neurological 
examination
X
X
X
X
X
X
X
X
12-lead paper 
ECG18
X
X
X
X
X
X
X
X
Vital signs19
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology/ 
clinical 
chemistry/ 
urinalysis
X
X
X
X
X
X
X
X
Blood sample 
for anti-
BIIB092 Ab4
X
X
X
X
X
X
Blood sample 
for BIIB092 
concentration
X
X20
X
X20
X
X
X20
X
X20
X
X20
X

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
29
Baseline 
Screening 
Period1, 2 within 
65 days3 of Day 
1
Placebo-Controlled Period4
UV for 
Change in 
AD 
Medication
5
FUV6
Study Week
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76 
EOT
78/ 
EOS 
or
ET7
90
Study Day
S1
S2
S38
1
29 
±7
57 
±
7
85 
±7
11
3 
±7
14
1 
±7
169 
±7
19
7 
±7
22
5 
±7
25
3 
±7
28
1 
±7
30
9 
±7
337 
±7
36
5 
±7
39
3 
±7
42
1 
±7
44
9 
±7
47
7 
±7
50
5 
±7
533 
±7
547 
±7
631 
±7
Blood sample 
for plasma and 
serum 
biomarkers4
X
X
X
X
X
Brain MRI22
X
X
X
X23
CDR28
X
X
X
X
X
NPI-10
X
X
X
X
ISLR
X
ISLT
X
X
X
X
X
X
X
X
X
DKEFS 
Category 
Fluency and 
Letter Fluency 
tests
X
X
X
X
X
X
X
X
DSST
X
X
X
X
X
X
X
X

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
30
Baseline 
Screening 
Period1, 2 within 
65 days3 of Day 
1
Placebo-Controlled Period4
UV for 
Change in 
AD 
Medication
5
FUV6
Study Week
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76 
EOT
78/ 
EOS 
or
ET7
90
Study Day
S1
S2
S38
1
29 
±7
57 
±
7
85 
±7
11
3 
±7
14
1 
±7
169 
±7
19
7 
±7
22
5 
±7
25
3 
±7
28
1 
±7
30
9 
±7
337 
±7
36
5 
±7
39
3 
±7
42
1 
±7
44
9 
±7
47
7 
±7
50
5 
±7
533 
±7
547 
±7
631 
±7
Trails A
X
X
X
X
X
X
X
X
eCog (39-item 
version)
X
X
X
X
ADAS-Cog 
1329
X
X
X
X
X
X
FAQ
X
X
X
X
X
ADCS-ADL
X
X
X
X
X
C-SSRS29
X
X
X
X
X
MMSE
X
X
X
X
X
X
X
X
RUD-Lite
X
X
X
X
X if 
ET
ZBI
X
X
X
X
X if 
ET
QoL-AD
X
X
X
X
X if 
ET
AE reporting
Monitor and record continuously beginning on Study Day 1 at the start of dosing
SAE reporting
Monitor and record continuously throughout the study
Concomitant 
therapy and 
procedures 
reporting
Monitor and record continuously throughout the study

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
35
Table 2:
Schedule of Activities for Week 80 Through Week 128 of the Long-Term Extension Period
Long-Term Extension Period
UV for Change in 
AD Medication1
Study Week
80
84
88
92
96
100
104
108
112
116
120
124
128
Study Days (±7 days)
561
589
617
645
673
701
729
757
785
813
841
869
897
Study day infusion2, 3
X
X
X
X
X
X
X
X
X
X
X
X
X
Eligibility criteria
X
Pregnancy test4
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
Body weight
X
X
X
Neurological 
examination
X
X
X
12-lead paper ECG6
X
X
Vital signs7
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology/clinical 
chemistry/ urinalysis
X
X
Blood sample for anti-
BIIB092 Ab
X
X
X
Blood sample for 
BIIB092 concentration
X
X
X
Blood sample for plasma 
and serum biomarker
X
Brain MRI8
X
CDR12
X
X
X

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
36
Long-Term Extension Period
UV for Change in 
AD Medication1
Study Week
80
84
88
92
96
100
104
108
112
116
120
124
128
Study Days (±7 days)
561
589
617
645
673
701
729
757
785
813
841
869
897
NPI-10
X
X
ISLT
X
X
DKEFS Category 
Fluency and Letter 
Fluency tests
X
DSST
X
Trails A
X
eCog (39-item version)
X
ADAS-Cog 13
X
X
X
FAQ
X
X
X
ADCS-ADL
X
X
X
C-SSRS
X
X
MMSE
X
X
X
RUD-Lite
X
ZBI
X
QoL-AD
X
AE reporting  
Monitor and record continuously throughout the LTE period
SAE reporting
Monitor and record continuously throughout the LTE period
Concomitant therapy and 
procedures reporting
Monitor and record continuously throughout the LTE period
Tobacco use status14
Monitor and record continuously throughout the LTE period
Ab = antibodies; AD = Alzheimer’s disease; ADAS-Cog 13 = Alzheimer’s Disease Assessment Scale-Cognitive (13 item); ADCS-ADL = Alzheimer’s Disease 
Cooperative Study – Activities of Daily Living; AE = adverse event;  CDR = Clinical Dementia Rating Scale; 
; C-SSRS = 
Columbia-Suicide Severity Rating Scale; DBP = diastolic blood pressure; DKEFS = Delis-Kaplan Executive Function System; DSST = Digit Symbol 
Substitution Test; ECG = electrocardiogram; eCog = Everyday Cognition; EOS = end of study; EOT = end of treatment; ET = early termination; FAQ = 
Functional Activities Questionnaire; 
; ISLT = International Shopping List Test Immediate Recall; 
; 

Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
39
Table 3:
Schedule of Activities for Week 132 Through Week 176 of the Long-Term Extension Period
Long-Term Extension Period
UV for Change in 
AD Medication1
Study Week 
132
136
140
144
148
152
156
160
164
168
172
176
Study Days (±7 days)
925
953
981
1009
1037
1065
1093
1121
1149
1177
1205
1233
Study day infusion2, 3
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test4
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
Body weight
X
X
Neurological examination
X
X
12-lead paper ECG6
X
X
Vital signs7
X
X
X
X
X
X
X
X
X
X
X
X
Hematology/clinical 
chemistry/ urinalysis
X
X
Blood sample for anti-
BIIB092 Ab
X
X
Blood sample for 
BIIB092 concentration
X
X
Blood sample for plasma 
and serum biomarker
X
Brain MRI8
X
CDR12
X
X
X
NPI-10
X
ISLT
X
X
X
DKEFS Category 
X
X

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14Participants’ tobacco use status will be assessed while collecting information on concomitant therapies.

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Table 4:
Schedule of Activities for Week 180 Through Week 238 or Follow-Up Visit of the Long-Term Extension Period
Long-Term Extension Period
UV for Change 
in AD 
Medication1
Study Week
180
184
188
192
196
200
204
208
212
216
220
224/ 
EOT
226/ 
EOS 
or ET2
238/FUV (14 
weeks After 
Last Dose)3
Study Days (±7 days)
1261
1289
1317
1345
1373
1401
1429
1457
1485
1513
1541
1569
1583
1667
Study day infusion4, 5
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
Body weight
X
X
X
Neurological examination
X
X
X
12-lead paper ECG8
X
X
X
Vital signs9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology/clinical chemistry/ urinalysis
X
X
X
X
Blood sample for anti-BIIB092 Ab
X
X
X
Blood sample for BIIB092 concentration
X
X
X
Blood sample for plasma and serum 
biomarker
X
X
Brain MRI10
X
CDR14
X
X
X
NPI-10
X
X
ISLT
X
X
X
DKEFS Category Fluency and Letter 
Fluency tests
X
X

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Long-Term Extension Period
UV for Change 
in AD 
Medication1
Study Week
180
184
188
192
196
200
204
208
212
216
220
224/ 
EOT
226/ 
EOS 
or ET2
238/FUV (14 
weeks After 
Last Dose)3
Study Days (±7 days)
1261
1289
1317
1345
1373
1401
1429
1457
1485
1513
1541
1569
1583
1667
DSST
X
X
Trails A
X
X
eCog (39-item version)
X
X
ADAS-Cog 13
X
X
X
FAQ
X
X
X
ADCS-ADL
X
X
X
C-SSRS
X
X
MMSE
X
X
X
RUD-Lite
X
ZBI
X
QoL-AD
X
AE reporting  
Monitor and record continuously throughout the LTE period
SAE reporting
Monitor and record continuously throughout the LTE period
Concomitant therapy and procedures 
reporting
Monitor and record continuously throughout the LTE period
Tobacco use status16
Monitor and record continuously throughout the LTE period
Ab = antibodies; AD = Alzheimer’s disease; ADAS-Cog 13 = Alzheimer’s Disease Assessment Scale-Cognitive (13 item); ADCS-ADL = Alzheimer’s Disease 
Cooperative Study – Activities of Daily Living; AE = adverse event; CDR = Clinical Dementia Rating Scale; 
; 
C-SSRS = Columbia-Suicide Severity Rating Scale; DBP = diastolic blood pressure; DKEFS = Delis-Kaplan Executive Function System; DSST = Digit Symbol 
Substitution Test; ECG = electrocardiogram; eCog = Everyday Cognition; EOS = End of Study; EOT = End of Treatment; ET = early termination; 
FAQ = Functional Activities Questionnaire; FUV = Follow-up Visit; 
; ISLT = International Shopping List Test Immediate 
Recall; 
; LTE = long-term extension; MMSE = Mini-Mental State Examination; MRI = magnetic resonance imaging; 
NPI-10 = Neuropsychiatric Inventory 10; 
; PK = pharmacokinetic; 
 
; QoL-AD = Quality of Life in Alzheimer’s Disease; RUD-Lite = Resource Utilization in Dementia-Lite Version; SAE = serious adverse event; 
SBP = systolic blood pressure; Trails A = Trail Making Test Part A; UV = unscheduled visit; ZBI = Zarit Burden Interview.

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This clinical study will collect samples that, under separate optional consent, may be used for 
future scientific and genetic research.  Specific objectives related to this future research have not 
been determined.

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Figure 1:
Study Design
Aβ = amyloid beta; AD = Alzheimer’s disease; EOS = End of Study; LTE = long-term extension; MCI = mild 
cognitive impairment; N = planned number of participants; Q4W = once every 4 weeks; Q12W = once every 12 
weeks
Note: Overall, participants will have a 2:1 chance of being randomized to BIIB092 versus placebo during the 
placebo-controlled period, and all participants will receive BIIB092 during the dose-blinded LTE period.
Note:  The study comprises a double-blind, placebo-controlled period and an LTE period. The total duration for 
participants who complete the placebo-controlled period and do not enter the LTE period will be approximately 
99 weeks. The total study duration for participants who complete both the placebo-controlled period and the LTE 
period will be approximately 247 weeks. The double-blind placebo-controlled period comprises a Screening Period 
of approximately 9 weeks (65 days), a Treatment Period of 76 weeks, and for participants not entering the 
LTE period, an EOS Visit at Week 78 and a Follow-up Safety Visit at Week 90, or approximately 14 weeks after the 
last dose of study treatment.  The LTE period comprises an LTE Screening Period of approximately 4 weeks starting 
at Week 76, a 144-week Treatment Period starting at Week 80, an EOS Visit at Week 226, and a Follow-up Safety 
Visit at Week 238, or approximately 14 weeks after the last dose of study treatment.
7.2.
Study Duration for Participants
The study consists of a double-blind, placebo-controlled period and a dose-blinded LTE period. 
The total duration for participants who complete the placebo-controlled period and do not enter 
the LTE period will be approximately 99 weeks. The total study duration for participants who 

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complete both the placebo-controlled period and the LTE period will be approximately 
247 weeks.
Placebo-Controlled Period
Participation in the double-blind, placebo-controlled period will be approximately 99 weeks, 
which includes the Screening Period of approximately 9 weeks, the 76-week Treatment Period, 
the EOS Visit at Week 78, and for participants not entering the LTE period, a Follow-up Safety 
Visit at Week 90, or approximately 14 weeks after the last dose of study treatment (see Table 1).  
It is recommended that all the screening procedures be completed within 65 days; however, the 
overall Screening Period may be extended up to 90 days in consultation with the Medical 
Monitor in advance and provided that written documentation is received from the Sponsor or 
delegate (
).
Participants will have approximately 25 outpatient clinic visits:

Participant eligibility will be determined at up to 3 visits during the Screening Period 
(Screening Visits 1, 2, and 3).

On Study Day 1, eligible participants will be randomized, have scheduled 
assessments per the Schedule of Activities (Table 1), and receive the first infusion of 
randomized study treatment.

Participants will return to the clinic at 4-week intervals during the Treatment Period 
for infusions of study treatment and study assessments (Weeks 4, 8, 12, 16, 20, 24, 
28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, and 76).  The last dose of study 
treatment will be administered at Week 76 (End-of-Treatment Visit).

For a participant who completes the Treatment Period at Week 76, there will be an 
EOS Visit at Week 78 for final study assessments of the placebo-controlled period.  A 
Follow-up Safety Visit will occur at Week 90 (14 weeks after the last dose of study 
treatment is administered), unless the participant elects to enter an extension study 
following the Week 78 Visit.  Final visit scheduling and procedures are described in 
Section 10.1 for participants who discontinue study treatment prematurely but remain 
in the study and in Section 10.3 for participants who withdraw from the study.
All participants should be observed and monitored by study staff for a minimum of 1 hour after 
the end of an infusion. Participants who experience an AE or SAE related to BIIB092 infusion 
should remain at the site or be sent to an inpatient monitoring facility until the Investigator has 
determined that the event(s) has resolved or do not require further monitoring at the site or in an 
inpatient setting. 

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3. Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] 
and/or total hepatitis B core antibody [anti-HBc]). Participants with immunity to 
hepatitis B from previous natural infection (defined as negative HBsAg, positive 
anti-HBc, and positive hepatitis B surface antibody [anti-HBs]) or vaccination (defined as 
negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in 
the study.
4. Any medical or neurological/neurodegenerative condition (other than AD) that, in the 
opinion of the Investigator, might be a contributing cause to the participant’s cognitive 
impairment (e.g., current history of substance abuse, uncontrolled vitamin B12 deficiency 
or abnormal thyroid function, stroke or other cerebrovascular condition, Parkinson’s 
disease, Lewy body dementia, or frontotemporal dementia), or could lead to 
discontinuation, lack of compliance, interference with study assessments, or safety 
concerns.
5. History of seizures within 10 years prior to Screening Visit 1 or history of epileptic 
syndrome (except for history of febrile seizures in childhood).
6. History within 5 years prior to Screening Visit 1 of a serious infectious disease affecting 
the brain (including neurosyphilis, Lyme disease, meningitis, or encephalitis), or severe 
head trauma, including concussions, that may have resulted in a protracted loss of 
consciousness.
7. Presence of clinically significant and/or unstable psychiatric illness, in the Investigator’s 
opinion (e.g., bipolar affective disorder), within the 6 months prior to Screening Visit 1. 
8. Any documented prior history of chronic schizophrenia.
9. History of long-term major depression or bipolar affective disorder with an active episode 
in the past 5 years.
10. Transient ischemic attack or stroke or any unexplained loss of consciousness within 
1 year prior to Screening Visit 1.
11. Brain MRI performed at Screening Visit 2 (centrally read) that shows evidence of any of 
the following:

Acute or subacute hemorrhage.

Prior macrohemorrhage (defined as >1 cm in diameter on T2* sequence) unless it 
can be documented that the finding is not due to an underlying structural or 
vascular abnormality (i.e., finding does not suggest participant is at risk of 
recurrent hemorrhage).

More than 5 microhemorrhages (defined as ≤1 cm in diameter on T2* sequence).

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
Cortical infarct (including cerebellar infarct) [defined as >1.5 cm in diameter] or 
any infarct in the hippocampus.

>2 lacunar infarcts (defined as ≤1.5 cm in diameter).

Superficial siderosis in >1 zone.

Superficial siderosis >1 cm3 in any zone.

Diffuse white matter disease as defined by a score of 3 on the Age-Related White 
Matter Changes scale [Wahlund 2001].

Any finding that, in the opinion of the Investigator, might be a contributing cause 
of the participant’s dementia, might pose a risk to the participant, or might 
prevent a satisfactory MRI assessment.
12. History of bleeding disorder or predisposing conditions, blood clotting, or clinically 
significant abnormal results on coagulation profile at Screening, as determined by the 
Investigator.
13. Presence of diabetes mellitus that, in the judgment of the Investigator, is not controlled or 
adequately managed.
14. History of unstable angina, myocardial infarction, chronic heart failure (New York Heart 
Association Class III or IV), or clinically significant conduction abnormalities (e.g., 
unstable atrial fibrillation) within 1 year prior to Screening Visit 1.
15. Clinically significant 12-lead ECG abnormalities, as read by the central reading facility 
and determined by the Investigator.
16. History of severe allergic or anaphylactic reactions.
17. Known allergy to BIIB092 or a history of hypersensitivity to any of the inactive 
ingredients in the drug product (see the Investigator’s Brochure for information on the 
BIIB092 clinical formulation).
18. Any major surgery within 12 weeks of Screening Visit 1 or during the Screening Period.
19. Uncontrolled hypertension defined as: an average of 3 systolic blood pressure 
(SBP)/diastolic blood pressure (DBP) readings >165/100 mm Hg at Screening (blood 
pressure measurements exceeding these limits may be repeated as warranted by the 
Investigator, but values must be within the specified limits for the participant to be 
eligible for the study), or persistent SBP/DBP readings >180/100 mm Hg within 
12 weeks prior to randomization (Study Day 1) that, in the opinion of the Investigator, 
are indicative of chronic uncontrolled hypertension.

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20. History of premalignant or malignant disease. Exceptions to premalignant disease 
exclusions may be made after discussion with the Sponsor. The following exceptions 
may be made for malignant disease exclusions after discussion with the Sponsor:

Participants with cancers in remission ≥5 years prior to Screening Visit 1.

Participants with a history of excised or treated basal cell or squamous carcinoma 
of the skin.

Participants with localized prostate cancer with treatment cycles that completed at 
least 6 months prior to Screening Visit 1.
21. Indication of impaired liver function as shown by an abnormal liver function profile at 
Screening (e.g., repeated values of aspartate aminotransferase [AST] and alanine 
aminotransferase [ALT] ≥2 × the upper limit of normal [ULN]).
22. Indication of impaired renal function at Screening (e.g., repeated values of creatinine and 
blood urea nitrogen [BUN] ≥1.5 × ULN or estimated glomerular filtration rate 
<45 mL/minute/1.73 m2 and corroborating medical history and physical examination).
23. History or evidence of an autoimmune disorder considered clinically significant by the 
Investigator or requiring long-term use of systemic corticosteroids or other 
immunosuppressants.
24. History of any clinically significant cardiac, endocrinologic, hematologic, hepatic, 
immunological, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, 
and renal, or other major disease, as determined by the Investigator.
25. Recent history (within 1 year of Screening Visit 1) of alcohol or substance abuse as 
determined by the Investigator, a positive urine drug (due to nonprescription drug) or 
alcohol test at Screening, or use of cannabinoids (prescription or recreational).
26. Clinically significant systemic illness or serious infection (e.g., pneumonia, septicemia) 
within 30 days prior to or during the Screening Period.
Medications
27. Use of allowed medications for chronic conditions at doses that have not been stable for 
at least 4 weeks prior to Screening Visit 1and during the Screening Period up to Study 
Day 1. 
28. Use of AD medications (including but not limited to donepezil, rivastigmine, 
galantamine, tacrine, and memantine) at doses that have not been stable for at least 
8 weeks prior to Screening Visit 1 and during the Screening Period up to Study Day 1.

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29. Use of any medications that, in the opinion of the Investigator, may contribute to 
cognitive impairment, put the participant at higher risk for AEs, or impair the 
participant’s ability to perform cognitive testing or complete study procedures.  
30. Use of the following medications:

Long-acting benzodiazepines (e.g., valium), except for sedation prior to MRI 
scans for those participants requiring sedation and should not be administered 
within 24 hours prior to cognitive testing.

Short/medium-acting benzodiazepines (e.g., alprazolam, lorazepam, oxazepam, 
temazepam) except if used chronically for sleep and on a stable dose for 8 weeks 
prior to Screening Visit 1 and during the Screening Period up to Study Day 1, or 
used short term on an as-needed basis.  May not be taken within 12 hours prior to 
cognitive testing.

Sedating antihistamines if taken within 12 hours prior to cognitive testing.  
Nonsedating antihistamines (e.g., fexofenadine, cetirizine) are allowed.

Anticonvulsants that have significant effects on cognition per the Investigator’s 
opinion and/or anticonvulsants used for treatment of seizures.  Anticonvulsants 
with limited cognitive effects, such as lamotrigine, pregabalin, levetiracetam for 
treatment of pain, and other non-epilepsy indications are allowed if, in the opinion 
of the Investigator, they are not producing sedation or contributing to cognitive 
impairment.  The participant must have been on a stable dose for 8 weeks prior to 
Screening Visit 1 and during the Screening Period up to Study Day 1.

Antidepressants that may, in the Investigator’s opinion, affect the participant’s 
cognition (e.g., tricyclic antidepressants).  Mild depression or depressive mood 
arising in the context of AD are not criteria for exclusion.  Use of antidepressants 
is allowed if at stable doses for 8 weeks prior to Screening Visit 1 and during the 
Screening Period up to Study Day 1.

High-dose antipsychotics used on a regular basis.  Low doses of atypical and 
typical antipsychotics if used on an as-needed basis or if used at a stable dose for 
8 weeks prior to Screening Visit 1 and during the Screening Period up to Study 
Day 1.  The definition of “low dose” and “high dose” should be judged by the 
Investigator, and the Medical Monitor can be consulted if needed.

Anticholinergics such as benztropine.  Anticholinergics for bladder control with 
limited cognitive effects are permitted but should be avoided if possible.

Prior use of levodopa or anti-Parkinsonian medications including dopaminergic 
agents, amantadine, selegiline, benztropine, and monoamine oxidase (MAO) 
inhibitors prescribed for the treatment of Parkinsonism or Parkinson’s disease.

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2. Participant must have completed the placebo-controlled period of the study, including the 
Week 78 Visit. Participant must have taken at least 14 doses of study treatment and not 
have missed more than 4 consecutive doses of study treatment.  Participants who do not 
meet these criteria may enter the LTE period only with the Sponsor’s approval.
3. All women of childbearing potential and all men with female partners of childbearing 
potential must practice highly effective contraception during the study and for 6 months 
(24 weeks) after their last dose of study treatment.  For further details of contraceptive 
requirements for this study, see Section 15.5.  Female participants should not become 
pregnant during the study and for 6 months (24 weeks) after their last dose of study 
treatment.  It is recommended that male participants should not father children during 
their participation in the study and for 6 months (24 weeks) after their last dose of study 
treatment (same as above in Section 8.1).
4. Medically able to undergo the study procedures and to adhere to the visit schedule at the 
time of study entry into the LTE period, as determined by the Investigator.  Apart from a 
clinical diagnosis of MCI due to AD or mild AD, the participant must be in good health 
as determined by the Investigator, based on medical history.
5. Must have the ability to comply with procedures for protocol-related tests.
6. Must have 1 informant/study partner who, in the Investigator’s opinion, has frequent and 
sufficient contact with the participant (at least 10 hours/week) as to be able to provide 
accurate information about the participant’s cognitive and functional abilities.  The study 
partner must agree to accompany the participant to clinic visits and/or be available by 
phone at designated times to provide information to the Investigator and study staff about 
the participant (and to attend in-person clinic visits that require partner input for scale 
completion) and must agree to monitor the participant’s administration of any prescribed 
medications.  A study partner should be available for the duration of the study, and the 
participation of the same study partner for the duration of the study is encouraged. The 
study partner must be literate and give informed consent (same as above in Section 8.1).
8.4.
Exclusion Criteria for Long-Term Extension Period
Participants will be excluded from entering the LTE period if any of the following exclusion 
criteria exist at Week 76 or 78 and confirmed at Week 80:
1. Any medical or psychiatric contraindication or clinically significant abnormality that, in 
the opinion of the Investigator, will substantially increase the risk associated with the 
participant’s participation in and completion of the study.
2. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
participant unsuitable for the study (same as above in Section 8.2).

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For the LTE period, the dose information must remain restricted. The study staff, the individuals 
conducting the rating scale assessments, and the Investigator should remain blinded to dose 
assignment and only have access to the information necessary to carry out their responsibilities. 
To maintain the study blind, it is imperative that dose information is not shared with the 
participants, their families, or any member of the blinded study team, either at the study site or at 
Biogen or its representatives, except the unblinded pharmacist (or designee), the unblinded 
pharmacy monitor, and the unblinded CRO or Biogen safety staff.
Once the clinical study report has been 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:

The participant becomes pregnant.  Study treatment must be discontinued 
immediately, and the pregnancy must be reported according to the instructions in 
Section 15.4.1.

The participant withdraws consent to continue study treatment.  

The participant experiences a medical emergency that necessitates permanent 
discontinuation of study treatment or unblinding of the participant’s treatment 
assignment.

The participant experiences an AE or SAE that does not resolve or requires continued 
treatment that meets exclusionary criteria.

The participant experiences a severe infusion reaction

At the discretion of the Investigator for medical reasons.

At the discretion of the Investigator or the Sponsor for noncompliance with the terms 
of the protocol.
The primary reason for discontinuation of study treatment must be recorded in the participant’s 
case report form (CRF).
All participants who discontinue study treatment prematurely will be asked to remain in the 
study and continue all protocol-specified visits and procedures for the period in which they 
discontinued treatment (i.e., placebo-controlled or LTE).  Participants who discontinue treatment 
during the placebo-controlled period should be encouraged to attend at least the Week 24, 
Week 52, and Week 78/EOS Visits and who discontinue treatment during the LTE should be 
encouraged to attend at least the Week 80, 104, 116, 128, 152, 156, 176, 196, 200, 224, and 
226/EOS Visits, depending on when treatment was discontinued, and undergo all the scheduled 
procedures.  At a minimum, these visits should include assessment of AEs/SAEs and 
concomitant medications and key clinical assessments, including at least the CDR, MMSE, 
ISLT, ADAS-Cog 13, ADCS-ADL, and FAQ.  Participants who discontinue study treatment 
prematurely, regardless of the treatment period, will be asked to return to the study site for a 
Follow-up Safety Visit 14 weeks after receiving the last dose of study treatment.  See Table 1, 
Table 2, Table 3, and Table 4 for the Schedule of Activities.

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11.
STUDY TREATMENT USE
11.1.
Regimen
Follow the Directions for Handling and Administration (DHA).
11.1.1.
Placebo-Controlled Period
Randomized, blinded study treatment will be administered by IV infusion at the study site once 
every 4 weeks, beginning on Study Day 1 and continuing through Week 76, for a total of 
20 infusions (see Table 1).
Participants will receive 1 of the following treatment regimens:

low-dose BIIB092 - 125 mg once every 4 weeks or 375 mg once every 12 weeks and 
placebo at the other 4-week dosing visits to maintain the treatment blind

medium-dose BIIB092 - 600 mg once every 4 weeks

high-dose BIIB092 - 2000 mg once every 4 weeks

placebo
11.1.2.
Long-Term Extension Period
In the LTE period, participants will receive BIIB092 beginning at Week 80 and continuing 
through Week 224. Participants who were randomized to receive BIIB092 during the 
placebo-controlled period will continue to receive BIIB092 at the dose they were randomly 
assigned. Participants randomized to receive placebo during the placebo-controlled period will 
receive BIIB092 at the high dose (2000 mg) during the LTE period.
11.2.
Modification of Dose and/or Treatment Schedule
See Section 11.2.1 (Dose Suspension) and Section 11.2.2 (Infusion Interruption).  
Dosing visits are not to be skipped, but may be delayed within the time window specified in the 
Schedule of Activities (Table 1).  Doses should be administered at least 21 days apart, per the 
regimen of dosing once every 4 weeks.  If the dosing interval cannot be met, the dose 
administration schedule should be assessed by the study Medical Monitor.
Participants should be carefully monitored for infusion reactions during dose administration.  If 
an acute infusion reaction is observed, the participant should be managed per Section 11.2.2
(Infusion Interruption).

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11.2.1.
Dose Suspension
The independent DMC will review safety data on an ongoing basis to ensure safe and proper 
treatment of participants.  The DMC, based on the nature, frequency, and/or severity of an AE(s), 
may recommend dose suspension or dose termination.  See Section 19.2 for additional 
information about the independent DMC.
11.2.2.
Infusion Interruption
The IV administration infusion time for all treatment groups is 1 to 2 hours at approximately 
100 mL/hour.  No premedications should be used prior to the start of study treatment infusion 
unless discussed with the Medical Monitor in advance and written documentation is received 
from Biogen authorizing the use of the premedication.

If any mild or moderate infusion-related reaction occurs during an infusion, the 
infusion may be slowed or interrupted and appropriate treatment per local standards 
of care may be given, at the discretion of the Investigator (or designee).  Based on the 
clinical response, the Investigator or designee will determine if the infusion may be 
resumed/continued, in consultation with the Medical Monitor as needed.  If the 
infusion is resumed/continued, the infusion rate should not exceed the original 
infusion rate (see the DHA for infusion rate information).

If a severe infusion-related reaction occurs during an infusion, the participant should 
be permanently discontinued from treatment and appropriate supportive care must be 
initiated in accordance with local practice.
Criteria for determining the severity of events are described in Section 15.2.3.
Discussion with the Medical Monitor can occur as needed, and it should not delay management 
of the medical emergency.
See Section 15.3 for reporting of AEs and Section 10 for discontinuation of study treatment.
11.3.
Compliance
Compliance with treatment dosing is to be monitored and recorded by study site staff.
11.4.
Concomitant Therapy and Procedures
11.4.1.
Concomitant Therapy
A concomitant therapy is any drug or substance administered between Screening Visit 1 and the 
Follow-up Safety Visit.
The use of concomitant therapies or procedures as defined below must be recorded on the 
participant’s CRF, according to instructions for CRF completion.  AEs related to administration 
of these therapies or procedures must be documented on the appropriate CRF.

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The Medical Monitor should be contacted with any questions about allowed or disallowed 
concomitant therapies.
11.4.1.1.
Allowed Concomitant Therapy

Medications for chronic conditions are allowed during the study as long as the 
participant has been on a stable dose of the medication(s) for 4 weeks prior to 
Screening Visit 1 and during the Screening Period up to Study Day 1.

AD medications (including, but not limited to, donepezil, rivastigmine, galantamine, 
tacrine, and memantine) are allowed provided that participants are receiving a stable 
dose for at least 8 weeks prior to Screening Visit 1 and remains stable during the 
Screening Period up to Study Day 1 and during the study.

Vaccination with live or attenuated vaccine is allowed during the study.  
Administration of any vaccine or booster should not occur <10 days prior to any 
dosing visit and for 10 days after a dosing visit.
11.4.1.2.
Disallowed Concomitant Therapy
Any medications that, in the opinion of the Investigator, may contribute to cognitive impairment, 
put the participant at higher risk for AEs, or impair the participant’s ability to perform cognitive 
testing or complete study procedures are disallowed.
Use of the following medications is disallowed:

Long-acting benzodiazepines (e.g., valium), except for sedation prior to MRI scans 
for those participants requiring sedation and should not be administered within 
24 hours prior to cognitive testing.

Short/medium-acting benzodiazepines (e.g., alprazolam, lorazepam, oxazepam, 
temazepam) except if used chronically for sleep and on a stable dose for 8 weeks 
prior to Screening Visit 1 and during Screening or used short term on an as-needed 
basis.  May not be taken within 12 hours prior to cognitive testing.

Sedating antihistamines if taken within 12 hours prior to cognitive testing.  
Nonsedating antihistamines (e.g., fexofenadine, cetirizine) are allowed.

Anticonvulsants that have significant effects on cognition per the Investigator’s 
opinion and/or anticonvulsants used for treatment of seizures.  Anticonvulsants with 
limited cognitive effects, such as lamotrigine, pregabalin, levetiracetam for treatment 
of pain, and other non-epilepsy indications are allowed if, in the opinion of the 
Investigator, they are not producing sedation or contributing to cognitive impairment.  
The participant must have been on a stable dose for 8 weeks prior to Screening Visit 1 
and during the Screening Period up to Study Day 1.

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Participants should be instructed to continue the usual medications they were on at enrollment 
(see allowed concomitant therapy above) and to avoid starting any new medications or herbal 
preparations during the study period, as these may confound the results of the study.  However, 
medically indicated medication or treatment should not be withheld.  Participants should inform 
the Investigator of any change in medication.  The change should be reviewed by the Investigator 
and, if needed, the Medical Monitor to determine whether the participant’s study treatment 
should be suspended.  Medications used to treat AEs would not result in automatic withdrawal.  
Biogen may be consulted if required.
Participants should have an unscheduled visit (UV) prior to the initiation of, change in dose, or 
discontinuation of AD medication.  That visit should include assessment of AEs/SAEs and 
concomitant medications and key clinical assessments, including, at a minimum, the CDR, 
MMSE, ISLT, ADAS-Cog 13, ADCS-ADL, and FAQ.  During the UV, these clinical 
assessments need not be repeated if performed within the previous 30 days. If the visit for a 
change in AD medication occurs at the same time as another planned visit, all originally 
scheduled assessments must also take place as required and without repetition (see Table 1, 
Table 2, Table 3, and Table 4).
11.4.2.
Concomitant Procedures
Concomitant procedures are allowed only when deemed necessary by the participant’s healthcare 
provider.  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 until the participant’s final clinic 
visit (including the Follow-up Safety Visit), unless the participant is being followed for 
study-related toxicity.
11.4.3.
Tobacco Use
Participants’ tobacco use status will be monitored continuously throughout the study and should 
be assessed while collecting information on concomitant therapies.
11.5.
Continuation of Treatment
The participant may elect to enter the LTE following the Week 78 Visit.  No further provisions 
are made for access to the study treatment otherwise.

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12.
STUDY TREATMENT MANAGEMENT
Study treatment will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice.
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.  The DHA will also describe the masking of 
the IV bags of study treatment (both BIIB092 and placebo) to maintain the treatment blind.  The 
DHA supersedes all other references (e.g., protocol or Investigator’s Brochure).
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 vials 
are for one-time use only; do not use any study treatment remaining in the vial for another 
participant.
12.1.
BIIB092
BIIB092 is a humanized, hinge-stabilized IgG4 monoclonal antibody derived from a mouse IgG1 
monoclonal antibody (IPN002).  BIIB092 is produced from cell culture using a Chinese hamster 
ovary cell line.
BIIB092 is supplied as a liquid drug product in glass vials containing an extractable dose as per 
the DHA.
The contents of the BIIB092 label will be in accordance with all applicable regulatory 
requirements.  BIIB092 should not be used after the expiration date.
12.1.1.
BIIB092 Preparation
The individual preparing BIIB092 should carefully review the instructions provided in the DHA.
BIIB092 is to be administered by IV infusion following dilution with 0.9% sodium chloride 
solution.
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.
12.1.2.
BIIB092 Storage
Study treatment must be stored in a secure location.  
Vials of BIIB092 are to be stored at 2°C to 8°C (36°F to 46°F), in a locked storage container 
with limited access.  BIIB092 should be protected from light and freezing.

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13.
EFFICACY, PHARMACOKINETIC, PHARMACODYNAMIC, 
IMMUNOGENICITY, AND HEALTH OUTCOMES 
ASSESSMENTS
See Section 5 for the timing of all assessments.
13.1.
Clinical Efficacy Assessments
The following clinical assessments will be performed to evaluate the efficacy of BIIB092:

CDR (to derive the primary efficacy endpoint)

MMSE, ISLT, DKEFS Category Fluency and Letter Fluency tests, DSST, Trails A, 
eCog, ADCS-ADL, FAQ, ADAS-Cog 13, and NPI-10 (to derive exploratory efficacy 
endpoints)
Assessments administered to the participant include the CDR, MMSE, ISLT, ISLR (Screening 
Visit 1 only), DKEFS Category Fluency and Letter Fluency tests, DSST, Trails A, and 
ADAS-Cog 13.  Assessments that require caregiver/informant input include the CDR, eCog, 
ADCS-ADL, FAQ, and NPI-10.
The clinical assessments must be administered by a trained clinician or rater, preferably by a 
neuropsychologist, a psychometrician or another qualified person who is experienced in the 
assessment of participants with cognitive deficits.
It is recommended that postbaseline CDR assessments be conducted at the same time of day at 
which the baseline assessment was performed to avoid diurnal variation.  The rater who conducts 
the CDR for a participant/informant cannot complete any other rating scales for that same 
participant/informant or be the study site coordinator.
The rater must be certified before any assessments may be performed.  When possible, the same 
rater should administer a given test across all visits for a given participant.  See the Study 
Reference Guide for specific guidelines required for administration of each test and the order in 
which the tests should be performed.
13.2.
Pharmacokinetic Assessments
BIIB092 concentrations in serum 
 will be determined using validated assays.
Serum PK parameters of BIIB092 to be assessed may include, but will not be limited to, the 
following:

Trough concentration

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24, 48, 76, 80, 104, 116, 156, 176, 196, 224, and 238/FUV (see Section 5).  All samples will be 
collected predose.
13.7.
Health Outcomes Assessments
The following tests will be performed to assess the effects of BIIB092 on caregiver burden, 
participant quality of life, and resource utilization:

ZBI

QoL-AD

RUD-Lite
The ZBI, QoL-AD, and RUD-Lite are administered to the caregiver; the QoL-AD is also 
administered to the participant.  The recommended order of administration of these assessments 
is specified in the Study Reference Guide.
See Section 5 for the timing of assessments.

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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 BIIB092:

Physical examinations, including height and weight measurements.

Neurological examinations.

Vital sign measurements:  temperature, pulse rate, SBP, DBP, and respiratory rate.  
Measurements will be recorded after the participant has been resting in a supine 
position for 10 minutes.  At selected timepoints (see Table 1), blood pressure and 
pulse rate will also be recorded after the participant has been standing for 
≥2 minutes.

12-lead (paper) ECGs, to be performed in triplicate at each timepoint with 
approximately 1 minute between replicates.  Each ECG must be performed after the 
participant has been resting in a supine position for 10 minutes.  The ECGs will be 
read by a central reader; copies of all raw ECG data must be made available to 
Biogen.

Laboratory safety assessments (see Section 14.2).

Columbia - Suicide Severity Rating Scale (C-SSRS).

Concomitant therapy and procedure recording.

AE and SAE monitoring.
14.2.
Laboratory Safety Assessments
Samples will be analyzed using Good Laboratory Practice-validated assays.
The following laboratory assessments will be performed to evaluate the safety profile of 
BIIB092:

Hematology:  red blood cell count, platelet count, hemoglobin level, hematocrit, 
mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, and total white blood cell count with absolute counts and 
percentages of differential cells (neutrophils, monocytes, lymphocytes, eosinophils, 
and basophils).

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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 legally authorized representative, in 
countries where applicable laws allow, and/or main caregiver must be given the names and 
telephone numbers of study site staff for reporting AEs and medical emergencies.
15.1.
Definitions
15.1.1.
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation 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

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
Results in a congenital anomaly/birth defect

Is a medically important event
A medically important event is an AE that, in the opinion of the Investigator, may jeopardize the 
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.

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death certificates and autopsy reports to Biogen.  The term death should be reported as an SAE 
only if the cause of death is not known and cannot be determined.
15.3.5.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or Biogen to be related to the study treatment administered.
Appropriate personnel at Biogen will unblind SUSARs for the purpose of regulatory reporting.  
Biogen will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies according 
to local law.  Biogen will submit SUSARs to Investigators in a blinded fashion.
15.4.
Procedures for Handling Special Situations
15.4.1.
Pregnancy
Participants should not become pregnant during the study and for 6 months (24 weeks) 
after their last dose of study treatment.  If a female participant becomes pregnant, study 
treatment must be discontinued immediately.  It is recommended that male participants should 
not father children during their participation in the study and for 6 months (24 weeks) after their 
last dose of study treatment.
The Investigator must report a pregnancy occurring in a female participant by faxing the 
appropriate form to Biogen within 24 hours of the study site staff becoming aware of the 
pregnancy.  See 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 CRF.
Congenital abnormalities and birth defects in the offspring of male or female participants should 
be reported as an SAE if conception occurred during the study Treatment Period.
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 CRF; however, all overdoses must 
be recorded on an Overdose form and faxed to Biogen within 24 hours of the study site 
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 to 
Biogen.  All study treatment related dosing information must be recorded on the dosing CRF.
15.4.3.
Medical Emergency
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator (or designee) 

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should contact Biogen 24-hour emergency medical support: 1-973-659-6677.  See 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 or appropriate designee may access the 
participant’s treatment assignment in the IRT system by accessing the internet or using a 
phone-based interface.  Further information about the IRT unblinding function or 24-hour, 
7-day-a-week support contact information is available in the IRT manual for the study.
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 or its designee to discuss such situations, but such a 
discussion should not delay management of the medical emergency.  The Investigator should 
inform Biogen or its designee as soon as possible if unblinding occurs.
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 6 months (24 weeks) after their last dose of study treatment.  In 
addition, participants should not donate sperm or eggs for the duration of the study and for at 
least 5 times the half-life of BIIB092 or 6 months, whichever is longer, after their last dose of 
study treatment.
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:

12 continuous months of natural (spontaneous) amenorrhea without an alternative 
medical cause and a serum FSH level >40 mIU/mL at Screening Visit 1.

6 weeks after surgical bilateral oophorectomy with or without hysterectomy.

Posthysterectomy.

Female surgical sterilization (e.g., bilateral tubal ligation).
For the purposes of the study, highly effective contraception is defined as use of 2 of the 
following:

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For female participants:

Established use of oral, intravaginal, or transdermal combined (estrogen and 
progestogen containing) hormonal methods of contraception associated with the 
inhibition of ovulation.

Established use of oral, injected, or implanted hormonal methods of contraception.

Placement of an intrauterine device or intrauterine hormone-releasing system.

Barrier methods of contraception with use of a spermicide, including condom, 
nonprescription sponge, or occlusive cap (diaphragm or cervical vault cap) used with 
spermicidal foam, gel, film, or cream suppository.

Sex with a male who has undergone surgical sterilization (with the appropriate 
postvasectomy documentation of the absence of sperm in the ejaculate).
For male participants:

Vasectomy with negative semen analysis at follow-up.

Condoms with spermicide.

Sex with a woman who uses the methods described for females if she is of 
childbearing potential.
For all participants, 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 CRF regardless of the severity or 
relationship to study treatment, 
 
.

Determine the seriousness, relationship to study treatment, 
 
, and severity of each event.

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
Determine the onset and resolution dates of each event.

Monitor and record all pregnancies in female participants and follow up on the 
outcome of all pregnancies.

Complete an SAE form for each SAE and fax or email it to Biogen within 24 hours of 
the study site staff becoming aware of the event.

Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to Biogen within 24 hours of the study site staff becoming aware of 
new information.

Ensure all AE and SAE reports are supported by documentation in the 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 CRF, 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 study site can enroll any participants, the Clinical Monitor is responsible for 
reviewing with study site staff the definitions of AE and SAE, as well as the 
instructions for monitoring, recording, and reporting AEs and SAEs.

Biogen is to notify all appropriate regulatory authorities, central ethics committees, 
and Investigators of SAEs, as required by local law, within required time frames.

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16.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The objectives of the study and the endpoints to be analyzed are listed in Section 6.
16.1.
General Considerations
Data will be collected and analyzed separately for the placebo-controlled period and LTE period:
1. After the placebo-controlled period is completed, efficacy and safety analyses will be 
performed.
2. Analyses will be performed as needed during the LTE period. Descriptive statistics will 
be used to evaluate the long-term safety and efficacy data of BIIB092.
Summary statistics will be presented.  For continuous endpoints, summary statistics will 
generally include: number of participants with data, mean, SD, median, and range.  For 
categorical endpoints, this will generally include: number of participants randomized or dosed, 
number of participants with data, and the percentage of those with data in each category.  Data 
for participants who were randomized to BIIB092 low dose (125 mg once every 4 weeks or 
375 mg once every 12 weeks) will be pooled for statistical testing and modeling for efficacy, PD, 
and health outcome analyses, unless otherwise specified in the placebo-controlled period.  All 
statistical tests will be 2-sided.
Similar analyses will be applied to both the placebo-controlled and LTE periods, except for 
efficacy analyses, which will be detailed in the statistical analysis plan (SAP).
16.2.
Demography and Baseline Disease Characteristics
Demographics and baseline data will be summarized by treatment group with summary statistics 
or with frequency distributions.
16.3.
Safety
16.3.1.
Analysis Population
The population for safety analyses is defined as all participants who were randomized and who 
received at least 1 dose of study treatment.
16.3.2.
Methods of Analysis
16.3.2.1.
Adverse Events
All analyses of AEs will be based on the principle of treatment emergence.  An AE is considered 
to be treatment emergent if it has an onset date on or after the date of first dosing, or if it was 

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present prior to the first dose and subsequently worsened.  The incidence of all AEs will be 
presented by system organ class and preferred term by dose group and for the overall active 
treatment group.  In addition, the incidence of all AEs will be presented by severity, by 
relationship to study treatment, 
.
16.3.2.2.
Clinical Laboratory Results
Clinical laboratory evaluations include hematology, blood chemistry, and urinalysis evaluations.  
Analyses of clinically significant abnormalities, shifts from baseline to postbaseline relative to 
the normal range, as well as changes from baseline by visit, will be presented by dose group and 
for the overall active treatment group.
16.3.2.3.
Vital Signs
The analysis of vital signs will focus on clinically relevant abnormalities, which will be defined 
in more detail in the SAP.  The incidence of clinically relevant abnormalities in vital signs will 
be summarized by dose group and for the overall active treatment group.
16.3.2.4.
Electrocardiograms
The analysis of ECG data will focus on clinically relevant abnormalities, which will be defined 
in more detail in the SAP.  ECG changes from baseline may be summarized using descriptive 
statistics and presented by dose group, overall active treatment group, and visit.
16.3.2.5.
Physical and Neurological Examinations
Abnormal findings during physical and neurological examinations will be recorded as AEs and 
will be reflected in the summary of AEs.
16.3.2.6.
Columbia - Suicide Severity Rating Scale
C-SSRS data will be summarized using descriptive statistics and presented by dose group and for 
the overall active treatment group.
16.4.
Efficacy
16.4.1.
Analysis Population
Efficacy analyses will use the intent-to-treat (ITT) population, defined as all participants who 
were randomized and who received at least 1 dose of study treatment.  For each endpoint, 
additional conditions may apply to the definition of the population for the analysis.  Participants 
will be analyzed in the groups to which they were randomized.  Subgroup analysis may be done 
for selected endpoints (e.g., CDR-SB).

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16.4.2.
Methods of Analysis
16.4.2.1.
Analysis of Primary Efficacy Endpoint (Clinical Dementia Rating Scale – Sum of 
Boxes)
The CDR-SB is the primary efficacy endpoint.  The population for the analysis of CDR-SB will 
be participants in the ITT population who have a baseline and at least 1 postbaseline CDR-SB 
score.
A mixed model with repeated measures (MMRM) will be used to analyze changes from Baseline 
in CDR-SB using fixed effects of treatment, time, treatment-by-time interaction, baseline 
CDR-SB, baseline CDR-SB-by-time interaction, region, disease stage (MCI versus mild AD), 
and baseline AD medication use.  The correlation between repeated measures of the outcomes 
will be taken into consideration.  The least-squares (LS) means, the differences in LS means 
between each treatment group versus placebo at Weeks 24, 52, and 78, 95% confidence intervals 
(CIs), and p-values will be presented.  Changes from baseline in CDR subscores will be analyzed 
in a similar model.  Additional details will be provided in the SAP.
The multiple comparison procedure modelling (MCP-MOD) method will be used to assess and 
model dose-response relationships (potential candidate models will include linear, linear-log, 
quadratic, maximum response [Emax], and logistic models as specified in Section 16.10) while 
controlling for multiplicity.  The dose-response parameter of interest for MCP-MOD will be the 
LS means at Week 78 for each dose group from the mixed-effects model.  Pairwise comparisons 
of each BIIB092 dose group versus placebo will also be conducted.
16.4.2.2.
Analysis of Exploratory Clinical Endpoints
The clinical endpoints assessing AD progression from Baseline include the results of the MMSE, 
ISLT, DKEFS, DSST, Trails A, eCog, ADCS-ADL, FAQ, ADAS-Cog 13, and NPI-10.
These clinical endpoints will be analyzed using data from participants in the ITT population who 
have a baseline and at least 1 postbaseline score for the specific endpoint being analyzed.  As 
these are exploratory endpoints in this study, no additional multiplicity adjustment procedures 
will be applied to the analyses of these endpoints.
An MMRM approach will be used to analyze changes from baseline using fixed effects of 
treatment, time, treatment-by-time interaction, baseline score, baseline score-by-time interaction, 
region, disease stage (MCI versus mild AD), and baseline AD medication use.  The correlation 
between repeated measures of the outcomes will be taken into consideration.  The LS means, the 
differences in LS means between each treatment group versus placebo at Weeks 24, 52, and 78, 
and the 95% CIs and p-values will be presented.
Exploratory analysis may be performed to develop a composite cognitive score participants with 
MCI due to AD and/or participants with mild AD.

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In the LTE period, the actual sample size, 
, is dependent on the 
enrollment rate, and thus, sample size calculation is not needed.
Figure 2:
Dose-Response Shapes Based on Clinical Dementia Rating Scale – Sum of 
Boxes Mean Change from Baseline at Week 78
ED50 = median effective dose; Emax = maximum response
Note:  This figure was generated using ADDPLAN® DF Version 3.1.8, by Aptiv solutions.

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17.
ETHICAL REQUIREMENTS
Biogen, a CRO, and the Investigator must comply with all instructions, regulations, and 
agreements in this protocol and applicable International Council for Harmonisation (ICH) and 
Good Clinical Practice (GCP) guidelines and conduct the study according to local regulations.
The Investigator is responsible for endorsing all data on completed CRFs electronically, prior to 
any Interim lock or Database lock.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated.  The Investigator 
is responsible for supervising those individuals and for implementing procedures to ensure the 
integrity of the tasks performed and any data generated.
17.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
17.2.
Ethics Committee
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study.  Biogen will submit documents on behalf of the 
study sites worldwide in compliance with local regulations.
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 participant 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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17.5.
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 post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.

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18.
ADMINISTRATIVE PROCEDURES
18.1.
Study Site Initiation
The Investigator must not screen any participants prior to completion of a study initiation visit, 
conducted by Biogen.  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 
study sites for clarification and resolution, as appropriate.  The Investigator is responsible for 
endorsing all CRF data prior to any interim or final 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 location(s) of essential documents.
The Clinical Monitors will visit the study sites at regular intervals during the study and after the 
study has completed, as appropriate.  A clinical site monitoring plan will detail who performs the 
monitoring, how often, and the extent of review.  It also will provide the monitoring strategy, 
with emphasis on participant safety, data integrity, and critical data and processes.
During these visits, CRFs, supporting documentation, and essential documentation related to the 
study will be reviewed and any discrepancies or omissions will be resolved.
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 study 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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19.5.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
study 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 
study site.
19.6.
Study Report Signatory
Biogen will designate 1 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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21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “Randomized, Double-Blind, Placebo-Controlled,
Parallel-Group Study to Assess the Safety, Tolerability, and Efficacy of BIIB092 in Subjects 
with Mild Cognitive Impairment due to Alzheimer’s Disease or with Mild Alzheimer’s Disease,” 
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
____________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)

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Biogen MA Inc.
1
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 251AD201
Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Safety, 
Tolerability, and Efficacy of BIIB092 in Subjects with Mild Cognitive Impairment due to 
Alzheimer’s Disease or with Mild Alzheimer’s Disease
Version 2
Date:  07 September 2018
EUDRA CT Number:  2017-002901-37
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 251AD201 is to update the list of allowed 
concomitant medications for subjects enrolled in this study, washout period of Alzheimer’s 
disease (AD) medications, and to add the requirement for stable doses of key concomitant 
medications prior to and during Screening and for the duration of the study.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 8.2, Exclusion Criteria
Now reads:
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:
….
24.26 Use of allowed medications for chronic conditions at doses that have not been stable 
for at least 4 weeks prior to Screening Visit 1 and during the screening period up to 
Study Day 1.,
27. or useUse of AD medications (including but not limited to donepezil, rivastigmine, 
galantamine, tacrine, and memantine) at doses that have not been stable for at least 
8 weeks prior to Screening Visit 1 and during the screening period up to Study Day 1.
25.28. Use of any medications that, in the opinion of the Investigator, may contribute to 
cognitive impairment, put the subject at higher risk for AEs, or impair the subject’s 
ability to perform cognitive testing or complete study procedures.  Such medications 
include, but are not limited to, the following:
29. Use of the following medications:

Long-acting benzodiazepines (e.g., valium), except for sedation prior to MRI 
scans for those subjects requiring sedation and should not be administered 
within 24 hours prior to cognitive testing.

Short/medium-acting benzodiazepines (e.g., alprazolam, lorazepam, oxazepam, 
temazepam) except if used on an as needed basischronically for sleep and on a 
stable dose for 8 weeks prior to Screening Visit 1 and during the screening 
period up to Study Day 1, or used short term on an as-needed basis.  May not 
be taken within 12 hours prior to cognitive testing.

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
Short/medium acting benzodiazepines (e.g., alprazolam, lorazepam, oxazepam, 
temazepam) Sedating antihistamines if taken within 12 hours prior to cognitive 
testing.  Nonsedating antihistamines (e.g., fexofenadine, cetirizine) are 
allowed.
Sedating antihistamines if used on a regular basis or if taken more than 3 times 
per week or if taken within 24 hours prior to cognitive testing. Nonsedating 
antihistamines (e.g., fexofenadine, cetirizine) are allowed.

Anticonvulsants used for treatment of seizures and anticonvulsants that have 
significant effects on cognition per the Investigator’s opinion and/or 
anticonvulsants used for treatment of seizures.  Anticonvulsants with limited 
cognitive effects, such as lamotrigine, pregabalin, levetiracetam for treatment of 
pain, and other non-epilepsy indications are allowed if, in the opinion of the 
Investigator, they are not producing sedation or contributing to cognitive 
impairment.  The subject must have been on a stable dose for 8 weeks prior to 
Screening Visit 1 and during the screening period up to Study Day 1.

Sedating antidepressantsAntidepressants that may, in the Investigator’s 
opinion, affect the subject’s cognition (e.g., tricyclic antidepressants).  Mild 
depression or depressive mood arising in the context of AD are not criteria for 
exclusion.  Use ofnonsedating antidepressants is allowed if at stable doses for 
8 weeks prior to Screening Visit 1 and during the screening period up to Study 
Day 1.

Antipsychotics used on a regular basis.  Low, except for low doses of atypical 
antipsychotics (e.g., risperidone, aripiprazole, or quetiapine) are allowedif used on 
an as-needed basis or if used at a stable dose for 8 weeks prior to Screening 
Visit 1 and during the screening period up to Study Day 1.  The definition of 
“low doses” should be judged by the Investigator, and the Medical Monitor 
can be consulted if needed.  
…
27.31. Prior participation in any active or passive immunotherapy study targeting Aβ or tau, 
unless documentation of receipt of placebo is available.
32. Last administration of β-secretase inhibitors and γ-secretase inhibitors in a study 
within 3 months or 5 half-lives (whichever is longer) prior to Screening Visit 1unless 
documentation of receipt of placebo is available. 
33. Participation in any study involving an investigational treatment targeting tau, 
unless documentation of receipt of placebo is available. 

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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 3, Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 4.5, Overall Benefits and Risks Assessment
Change:  Text was added regarding the benefits and risks to subjects participating in this clinical 
study.
Now reads: 
4.5
Overall Benefits and Risks Assessment
Due to its eTau-lowering effects, BIIB092 has the therapeutic potential to prevent 
transmission of tau pathology in neurodegenerative disorders known as tauopathies, which 
include PSP and AD.  The proposed indications under the current program of research are 
for use in patients with PSP and AD.
To date, 2 clinical studies have been completed with BIIB092. These include the 
first-in-human study, CN002001 (SAD study in healthy adult subjects) and CN002003 
(MAD study in subjects with PSP).  In addition to this study, 2 studies are ongoing: Study 
251PP201 (formerly referred to as CN002004), an open-label extension study, and Study 
251PP301 (formerly referred to as CN002012), a Phase 2b randomized controlled efficacy 
and safety study in subjects with PSP.  Please refer to Section 4.3.2 for more information.
All available clinical benefit and risk information to date has been derived from studies in 
healthy volunteers or subjects with PSP.  PSP is a rare neurodegenerative disease that 
results in a rapidly progressing, fatal movement disorder that includes cognitive and 
behavioral abnormalities.  There are currently no approved or effective treatments for 
PSP.  Nonclinical models support the anti-eTau mechanism as potentially efficacious in the 
treatment of PSP. 
Binding to eTau, the murine antibody from which BIIB092 is derived, prevented tau 
transmission in nonclinical studies.  Furthermore, the murine antibody from which 
BIIB092 was derived prevented tau-dependent behavioral and pathologic changes in a 
mouse model of tauopathy.  Finally, BIIB092 reduced free eTau levels in the CSF of 
cynomolgus monkeys following a single IV administration.  For additional details, please 
refer to Section 4.3.1.  By binding eTau, it is expected that BIIB092 will prevent tau 

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transmission in diseases such as AD and PSP and thereby potentially provide therapeutic 
benefit.
The nonclinical toxicity profile of BIIB092 was used to determine the starting dose and 
eligibility criteria and to develop appropriate safety monitoring for BIIB092 studies.  
Clinical data from the completed first-in-human SAD study in healthy adult subjects 
(CN002001) demonstrated that single doses of BIIB092 up to 4200 mg in Caucasian 
subjects and up to 2100 mg in Japanese subjects were generally safe and well tolerated.  
The completed (MAD) study in subjects with PSP (CN002003) evaluated multiple doses of 
BIIB092 (150, 700, and 2100 mg) or placebo administered once every 4 weeks for 3 months. 
The available data suggest that multiple doses of BIIB092 up to 2100 mg are safe and well 
tolerated in subjects with PSP.  Correspondingly, the current ongoing open-label, 
long-term extension, safety and tolerability study (251PP201) also suggests that multiple 
doses of BIIB092 up to 2100 mg are safe and well tolerated in subjects with PSP. 
Frequent safety assessments will be utilized by the Sponsor/Medical Monitor and 
Investigators to determine whether dose modification, additional safety measures, or 
termination of the ongoing studies is required at any time.  Serum immunogenicity 
sampling will be performed to monitor for the emergence of anti-drug antibodies.  
Thorough evaluation of safety monitoring procedures and of AEs and serious adverse 
events (SAEs) will be reviewed on an ongoing basis by the Sponsor’s Medical Monitor and 
Global Pharmacovigilance representatives to monitor for any safety signals or trends.
In addition, an independent Data Monitoring Committee (DMC) will also be established 
for Studies 251PP201 and 251PP301 to monitor the benefit/risk profile of BIIB092.
For information on specific risk mitigation strategies, please refer to Section 10, 
Section 11.2.2, and Section 15.4.
A need exists for disease-modifying therapies for subjects with AD and those with PSP.  
The doses of BIIB092 currently being explored have the potential to benefit study subjects. 
Furthermore, the nonclinical efficacy profile and the evidence for anti-eTau activity, 
together with the benign safety profile, indicate that the balance of benefit to risk is likely 
to be favorable for study subjects.
Rationale:  The additions to text on the topic of the benefits and risks to subjects participating in 
this clinical study have been extracted from the Investigational Medicinal Product Dossiers 
(IMPD) and added to the protocol at the request of the Swedish Medical Products Agency and 
now been have added it to global protocol.

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Section 5, Schedule of Activities
Change:  
The screening period window was increased up to 90 days with Sponsor approval.
The list of assessments to be performed, in case the screening period was increased up to 
90 days, was modified.
The timing of clinical assessments at Visit S3 was updated.
The timing window for coagulation tests after randomization was updated.
The timing window for the electrocardiogram (ECG) performed after the end of infusion on 
Study Day 1 was updated.
The fasting requirement for subjects before blood samples for hematology, clinical chemistry and 
urinalysis laboratory assessments was removed.
The timing of the postbaseline Clinical Dementia Rating Scale (CDR) assessment was updated.
The timing of the Alzheimer’s Disease Assessment Scale-Cognitive (13 item) [ADAS-Cog 13] 
and Columbia - Suicide Severity Rating Scale (C-SSRS) assessments during the screening period 
was updated.
The reporting of serious AEs and concomitant medication was updated.

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Now reads:
Table 1:
Schedule of Activities
Study Week
Baseline Screening 
Period1,2
within 65 days3 of 
Day 1
Placebo-controlled Period4,5,6
FU7
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
EOT
78/
EOS 
or
ET8
90
Study Day
S1
S2
S39
1
29
±7
57
±7
85
±7
113
±7
141
±7
169
±7
197
±7
225
±7
253
±7
281
±7
309
±7
337
±7
365
±7
393
±7
421
±7
449
±7
477
±7
505
±7
533
±7
547
±7
631
±7
Study day infusion
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Initial screening consent
(optional) 10
X
Full informed consent11
X
Randomization
X
Eligibility criteria
X
X
X
X
NIA-AA criteria review
X
Medical history
X
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Pregnancy test12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Follicle-stimulating 
hormone13
X
Alcohol/drug screen
X
HbA1c
X
HIV14/
hepatitis tests
X
Physical examination
X
X
X
X
X
X
X
X
Neurological 
examination
X
X
X
X
X
X
X
X

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Study Week
Baseline Screening 
Period1,2
within 65 days3 of 
Day 1
Placebo-controlled Period4,5,6
FU7
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
EOT
78/
EOS 
or
ET8
90
Study Day
S1
S2
S39
1
29
±7
57
±7
85
±7
113
±7
141
±7
169
±7
197
±7
225
±7
253
±7
281
±7
309
±7
337
±7
365
±7
393
±7
421
±7
449
±7
477
±7
505
±7
533
±7
547
±7
631
±7
12-lead paper ECG16
X
X
X
X
X
X
X
X
Vital signs17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology/ clinical 
chemistry/ urinalysis 8
X
X
X
X
X
X
X
X
Blood sample for anti-
BIIB092 Ab4
X
X
X
X
X
X
Blood sample for 
BIIB092 concentration
X
X1918
X
X1918
X
X
X1918
X
X1918
X
X1918
X
Blood sample for 
plasma and serum 
biomarkers4
X
X
X
X
X
Brain MRI2120
X
X
X
X
CDR2625
X
X
X
X
NPI-10
X
X
X
X
ISLR
X
ISLT
X
X
X
X
X
X
X
X

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10
Study Week
Baseline Screening 
Period1,2
within 65 days3 of 
Day 1
Placebo-controlled Period4,5,6
FU7
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
64
68
72
76
EOT
78/
EOS 
or
ET8
90
Study Day
S1
S2
S39
1
29
±7
57
±7
85
±7
113
±7
141
±7
169
±7
197
±7
225
±7
253
±7
281
±7
309
±7
337
±7
365
±7
393
±7
421
±7
449
±7
477
±7
505
±7
533
±7
547
±7
631
±7
DKEFS Category 
Fluency and Letter 
Fluency tests
X
X
X
X
X
X
X
X
DSST
X
X
X
X
X
X
X
X
Trails A
X
X
X
X
X
X
X
X
eCog (39-item version)
X
X
X
X
ADAS-Cog 1326
X
X
X
X
X
FAQ
X
X
X
X
ADCS-ADL
X
X
X
X
C-SSRS26
X
X
X
X
X
MMSE
X
X
X
X
X
X
X
RUD-Lite
X
X
X
X
X if 
ET
ZBI
X
X
X
X
X if 
ET
QoL-AD
X
X
X
X
X if 
ET
AE reporting
Monitor and record continuously beginning on Day 1 at the start of dosing
SAE reporting
Monitor and record continuously throughout the study
Concomitant therapy 
and procedures 
reporting
Monitor and record continuously throughout the study
Ab = antibodies; AD = Alzheimer’s disease; ADAS-Cog 13 = Alzheimer’s Disease Assessment Scale-Cognitive (13 item); ADCS-ADL = Alzheimer’s Disease 
Cooperative Study – Activities of Daily Living; AE = adverse event; 
; CDR = Clinical Dementia Rating Scale; 
 

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11
; C-SSRS = Columbia - Suicide Severity Rating Scale; DBP = diastolic blood pressure; DKEFS = Delis-Kaplan Executive Function System; DSST = Digit 
Symbol Substitution Test; ECG = electrocardiogram; eCog = Everyday Cognition; EOS = end of study; EOT = end of treatment; ET = early termination; 
FAQ = Functional Activities Questionnaire; FU = follow up; HbA1c = glycosylated hemoglobin; HIV = human immunodeficiency virus; ICF = informed 
consent form;
; ISLR = International Shopping List Test Delayed Recall; ISLT = International Shopping List Test 
Immediate Recall; 
; MMSE = Mini-Mental State Examination; MRI = magnetic resonance imaging; NIA-AA = National Institute on 
Aging – Alzheimer’s Association; NPI-10 = Neuropsychiatric Inventory-10; 
 
; QoL-AD = Quality of Life in Alzheimer’s Disease; 
; RUD-Lite = Resource Utilization in Dementia-LightLite 
Version; SAE = serious adverse event; SBP = systolic blood pressure; Trails A = Trail Making Test Part A; ZBI = Zarit Burden Interview
1 The screening process will generally involve up to 3 visits, and most screening procedures will be performed within these designated visits (S1-S3).  However 
additional screening visits may be needed for some procedures, e.g., MRI 
.  In addition, it may sometimes be necessary for subjects to return for repeat 
assessments (e.g., if the MRI scan does not pass the quality control process).  Brain MRI (S2) will only be performed after the subject has met the eligibility 
criteria and has acceptable laboratory tests from Visit S1.  
 
 
  
2 The clinical assessments performed during Visit S1 are to be administered in the order specified: 1) MMSE; 2) neuropsychological tests in the following order: 
ISLT, DSST, Trails A, Category Fluency and Letter Fluency tests from the DKEFS, ISLR; 3) CDR.  Note that the Visit S1 results from CDR, ISLT/ISLR, and 
MMSE will be used to determine subject eligibility; Visit S3 ISLT assessments will provide baseline measures.  At Visit S3, the clinical assessments will be 
administered as follows:  1) neuropsychological tests in the following order: ISLT, DSST, Trails A, Category Fluency and Letter Fluency tests from the 
DKEFS; 2) ADAS-Cog 13; 3) QoL-AD.
3 The nominal It is recommended that all the screening procedures be completed within 65 day days; however, the overall screening period may be 
increased with the permission of extended up to 90 days in consultation with the Medical Monitor in advance and provided that written documentation is 
received from the Sponsor or delegate (
).The following screening assessments should be repeated if the 
screening period is >65 days: confirmation of eligibility criteria, abbreviated medical history, and physical examination, ECG, hematology, clinical chemistry, 
and serum pregnancy test (women of childbearing potential).  In addition, some cognitive and /or safety assessments may require repeating depending on the 
duration of the screening window extension, in discussion with the Medical Monitor.
4 All assessments and blood collection during dosing days will be performed prior to infusion, unless otherwise specified.  Doses should be administered at least 
21 days apart.
5 The visits at Weeks 32, 36, 44, and 64 may qualify for home visits, if appropriate; see Section 7.1 for details.
6 Prior to initiation of and/or a change in AD medication, a subject should have an unscheduled visit for assessment of AEs/serious SAEs and concomitant 
medications and key clinical assessments, including, at a minimum, the CDR, MMSE, ISLT, ADAS-Cog 13, ADCS-ADL, and FAQ.
7 Subjects who complete the Treatment Period and do not enter an extension study (separate protocol, to be initiated at the Sponsor’s discretion) are to return to 
the study site for a Follow-up Safety Visit at Week 90.  Subjects who discontinue study treatment and withdraw from the study early are to have a Follow-up 
Safety Visit 14 weeks after the final dose.  Subjects who discontinue study treatment prematurely are to return to the study site for a Follow-up Safety Visit 
14 weeks after receiving the last dose of study treatment.
8 All subjects who discontinue study treatment prematurely will be asked to remain in the study and continue all protocol-specified visits and procedures.  These 
subjects should be encouraged to attend at least the Week 24, Week 52, and Week 78 visits, depending on when treatment was discontinued, and undergo all the 
scheduled procedures.  At a minimum, these visits should include assessment of AEs/SAEs and concomitant medications and key clinical assessments, including 
at least the CDR, MMSE, ISLT, ADAS-Cog 13, ADCS-ADL, and FAQ.  Subjects who discontinue study treatment prematurely will also be asked to return to 

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Rationale:  
In footnote #3 and footnote #22 (now footnote #21), text was added to clarify that the screening 
period may be extended to 90 days, if needed, 
, pending 
the Sponsor’s approval. 
Footnote #3 was modified to clarify the assessments that are to be repeated if the screening 
period is increased to 90 days.
In footnote #9, the timing of clinical assessments at Screening Visit 3 was updated to provide 
flexibility to be performed at Study Day 1, in case of site’s and/or subject’s availability, 
 
.
In footnote #15, the timing window was increased to reduce burden on subjects and to allow 
appropriate time for review of the coagulation tests results.  Additional text was added to clarify 
that the repeats test may be performed locally.
Footnote #16 was updated to increase the timing window and facilitate performing the ECG after 
the end of infusion on Study Day 1, now timed with vital sign assessment.
Footnote #18 (Version 1) was deleted.  No safety concerns are expected with removal of the 
fasting requirement.  It would be difficult to confirm compliance with the requirement of fasting
across the study and the number of protocol deviations for blood sample collection.  
Furthermore, cognitive testing and, particularly, the primary efficacy endpoint, the CDR sum of 
boxes, are often performed on the same visit as the collection of blood samples for hematology 
and clinical chemistry laboratory assessments.  Requiring this elderly subject population to fast 
before performing cognitive assessment tests may increase the variability in the data collected at 
these visits.
In footnote #25, the timing of the postbaseline CDR assessments was updated to allow additional 
flexibility in the schedule of study visits and reduce burden on subjects.
The timing of ADAS-Cog-13 and C-SSRS assessments during the screening period was updated 
to allow some flexibility and therefore reduce burden on subjects (footnote # 26 was added).
Clarification was made to the serious AE and concomitant medication reporting in the Schedule 
of Activities table, that it will be collected throughout the study, including during the screening 
period and made consistent with Section 15.3.3, Serious Adverse Events.
This change also affects Section, 7.1, Study Overview; Section 7.2, Study Duration for Subjects;
Section 9.1, Screening; Section 13.1, Clinical Efficacy Assessments; Section 14.2, Laboratory 
Safety Assessments; and Section 15.3.1, Adverse Events.

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The Investigator must document the reasons for unblinding in the subject’s source documents.  
The Investigator is strongly advised not to divulge the subject’s treatment assignment to any 
individual not directly involved in managing the medical emergency, or to personnel involved 
with the analysis and conduct of the study.
The Investigator can contact Biogen or its designee to discuss such situations, but such a 
discussion should not delay management of the medical emergency.  The Investigator should 
inform Biogen or its designee as soon as possible if unblinding occurs.
Rationale:  This change was made to clarify how to access the IRT system in the case of 
unblinding for a medical emergency and that unblinding for a medical emergency can be 
completed at any time.  This change is provided at the request of the Swedish Medical Products 
Agency.  Because this change relates to clarification of the process of unblinding for a medical 
emergency, it is also made available to all the participating sites within the global protocol. 
Section 16.9, Interim Analyses
Change:  Text regarding review by an independent team of interim analysis data for the purpose 
of future study planning was added.
Text regarding the interim analyses was modified.
Now reads:
Interim analyses may be performed after 50% to 70% of, or all, 50% to 100% of subjects have 
completed the Week 52 visit (or discontinued) for the purpose of future study planning and/or
futility analyses.  In order to maintain the treatment blind, an independent group external to 
Biogen that will not be involved in the conduct of the study after unblinding will perform the 
interim analyses.  This independent group will present the unblinded interim analyses to the 
DMC for review.  After the DMC review, a small internal independent team (separate from 
the study team) may review the unblinded results for the purpose of future study planning 
under a study integrity charter.  No Type I error adjustment will be made.  No changes will be 
made to this study based on the interim analysis results.  
Rationale: The text was added to clarify how unblinded outputs from interim analysis that may 
support clinical study design of future studies will be evaluated.  A small internal team 
independent from the study team will be involved in this evaluation to avoid any influence of this 
assessment on study conduct.
The text regarding interim analyses was modified to clarify that one or more interim analyses 
may be performed when between 50% and 100% of subjects have completed the Week 52 visits 
(or discontinued). 

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
In Section 17 and Section 19, reference to Quintiles was updated to Contract Research 
Organization (CRO) to avoid a protocol amendment if there is a change in vendor. 

Typographical errors and formatting were corrected.

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1
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 251AD201
Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Safety, 
Tolerability, and Efficacy of BIIB092 in Subjects with Mild Cognitive Impairment due to 
Alzheimer’s Disease or with Mild Alzheimer’s Disease
Version 3
Date: 29 March 2019
EUDRA CT Number: 2017-002901-37
Version 3 of the protocol has been prepared for this amendment, which supersedes Version 2.

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2
PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 251AD201 is to add a dose-blinded
long-term extension (LTE) period of approximately 3 years. The primary purpose of the LTE is 
to obtain long-term safety and tolerability information on BIIB092 and further explore its effects 
on immunogenicity, disease progression, and additional clinical and health outcomes.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 7.1, Study Overview
Now reads:
…
The study consists of a double-blind, placebo-controlled period and a dose-blinded LTE 
period. The total duration for participants who complete the placebo-controlled period and 
do not enter the LTE period will be approximately 99 weeks. For participants who 
complete both the placebo-controlled period and the LTE period, the total study duration 
will be approximately 247 weeks. The placebo-controlled period comprises a Screening 
Period of up to approximately 9 weeks (65 days), a Treatment Period of 76 weeks, and for 
participants not entering the LTE period, an End-of-Study (EOS) Visit at Week 78 and a 
Follow-up Safety Visit at Week 90, or approximately 14 weeks after the last dose of study 
treatment. However, the overall sScreening Period for the placebo-controlled period may be 
extended up to 90 days in consultation with the Medical Monitor in advance and provided that 
written documentation is received from the Sponsor or delegate (e.g., for logistical issues such as 
PET radioligands). At the end of the placebo-controlled period, participants who meet the 
LTE entry criteria may enter the dose-blinded LTE period. The LTE period comprises an 
LTE Screening Period of approximately 4 weeks starting at Week 76, a 144-week 
Treatment Period, an EOS Visit at Week 226, and a Follow-up Safety Visit at Week 238, or 
approximately 14 weeks after the last dose of study treatment.
…
During the LTE period, participants who were randomized to receive BIIB092 during the 
placebo-controlled period will continue to receive BIIB092 at the dose they were randomly 
assigned. Participants receiving placebo during the placebo-controlled period will receive 
BIIB092 at the high dose (2000 mg) once every 4 weeks during the LTE period. The 
BIIB092 dose concentration (i.e. low, medium, or high) to which participants are assigned 
to receive during the LTE period may be changed based on emerging data from the 
BIIB092 clinical development program.
The visits at Weeks 84, 88, 96, 112, 116, 120, 136, 140, 144, 160, 164, 168, 184, 188, 192, 208, 
212, and 216 of the LTE period may be conducted as home visits, if the Investigator is in 

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Figure 1:
Study SchematicDesign
Deleted Figure:

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Inserted Figure:
Aβ = amyloid beta; AD = Alzheimer’s disease; EOS = End of Study; LTE = long-term extension; MCI = Mmild 
Ccognitive Iimpairment; N = number of subjectsparticipants; Q4W = once every 4 weeks; Q12W = once every 12 
weeks
Note: Overall, participating subjectsparticipants will have a 2:1 chance of being randomized to BIIB092 versus 
placebo during the placebo-controlled period, and all participants will receive BIIB092 during the 
dose-blinded LTE period.
Note: The study comprises a double-blind, placebo-controlled period and an LTE period.  The total duration 
for participants who complete the placebo-controlled period and do not enter the LTE period will be 
approximately 99 weeks. The total study duration for participants who complete both the placebo-controlled 
period and the LTE period will be approximately 247 weeks. The double-blind placebo-controlled period 
comprises a Screening Period of up to approximately 9 weeks (65 days), a Treatment Period of 76 weeks, and for 
participants not entering the LTE period, an End of Study EOS Visit at Week 78, and a Follow-up Safety Visit 
at Week 90, or approximately 14 weeks after the last dose of study treatment. The LTE period comprises an LTE 
Screening Period of approximately 4 weeks starting at Week 76, a 144-week Treatment Period starting at 
Week 80, an EOS Visit at Week 226, and a Follow-up Safety Visit at Week 238, or approximately 14 weeks 
after the last dose of study treatment. 

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Rationale: To date, BIIB092 has been generally well tolerated in the clinical study participants. 
There are no important identified or important potential risks in the program, including in the 
completed studies CN002001 and CN002003 and in the ongoing studies 251PP201, 251PP301,
and 251AD201. The current safety profile supports continued investigation of the proposed 
doses of 125 to 2000 mg. The LTE will provide additional long-term safety data.
Switching all participants who received placebo during the placebo-controlled period to 1 group 
(2000 mg every 4 weeks) in the LTE period allows delayed start analysis to be maximized for 
1 of the dose groups. 
This change also affects Section 5, Schedule of Activities (addition of 3 new tables for the LTE
period); Section 6, Study Objectives and Endpoints; Section 7.2, Study Duration for Participants; 
 addition of Section 8.3, Inclusion Criteria for Long-Term 
Extension Period and Section 8.4, Exclusion Criteria for Long-Term Extension Period; 
Section 9.1 Screening; Section 9.2, Randomization; Section 9.3, Blinding Procedures; 
Section 10.1, Discontinuation of Study Treatment; Section 11.1, Regimen; Section 11.5, 
Continuation of Treatment; Section 13.6, Immunogenicity; and Section 16, Statistical Methods 
and Determination of Sample Size.

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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, Overall Benefits and Risk Assessment
Change: Updated the benefits and risks assessment information.
Now reads:
Due to its eTau lowering effects, BIIB092 has the therapeutic potential to prevent transmission 
of tau pathology in neurodegenerative disorders known as tauopathies, which include PSP and 
AD.  The proposed indications under the current program of research are for use in patients with 
PSP and AD.
To date, 2 clinical studies have been completed with BIIB092.  These include the first in human 
study, CN002001 (SAD study in healthy adult subjects) and CN002003 (MAD study in subjects 
with PSP).  In addition to this study, 2 studies are ongoing: Study 251PP201 (formerly referred 
to as CN002004), an open label extension study, and Study 251PP301 (formerly referred to as 
CN002012), a Phase 2b randomized controlled efficacy and safety study in subjects with PSP.  
Please refer to Section 4.3.2 for more information.
All available clinical benefit and risk information to date has been derived from studies in 
healthy volunteers or subjects with PSP.  PSP is a rare neurodegenerative disease that results in a 
rapidly progressing, fatal movement disorder that includes cognitive and behavioral 
abnormalities.  There are currently no approved or effective treatments for PSP.  Nonclinical 
models support the anti eTau mechanism as potentially efficacious in the treatment of PSP. 
Binding to eTau, the murine antibody from which BIIB092 is derived, prevented tau 
transmission in nonclinical studies.  Furthermore, the murine antibody from which BIIB092 was 
derived prevented tau dependent behavioral and pathologic changes in a mouse model of 
tauopathy.  Finally, BIIB092 reduced free eTau levels in the CSF of cynomolgus monkeys 
following a single IV administration.  For additional details, please refer to Section 4.3.1.  By 
binding eTau, it is expected that BIIB092 will prevent tau transmission in diseases such as AD 
and PSP and thereby potentially provide therapeutic benefit.

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The nonclinical toxicity profile of BIIB092 was used to determine the starting dose and 
eligibility criteria and to develop appropriate safety monitoring for BIIB092 studies.  Clinical 
data from the completed first in human SAD study in healthy adult subjects (CN002001) 
demonstrated that single doses of BIIB092 up to 4200 mg in Caucasian subjects and up to 
2100 mg in Japanese subjects were generally safe and well tolerated.  The completed (MAD) 
study in subjects with PSP (CN002003) evaluated multiple doses of BIIB092 (150, 700, and 
2100 mg) or placebo administered once every 4 weeks for 3 months.  The available data suggest 
that multiple doses of BIIB092 up to 2100 mg are safe and well tolerated in subjects with PSP.  
Correspondingly, the current ongoing open label, long term extension, safety and tolerability 
study (251PP201) also suggests that multiple doses of BIIB092 up to 2100 mg are safe and well 
tolerated in subjects with PSP. 
Frequent safety assessments will be utilized by the Sponsor/Medical Monitor and Investigators to 
determine whether dose modification, additional safety measures, or termination of the ongoing 
studies is required at any time.  Serum immunogenicity sampling will be performed to monitor 
for the emergence of anti drug antibodies.  Thorough evaluation of safety monitoring procedures 
and of AEs and serious adverse events (SAEs) will be reviewed on an ongoing basis by the 
Sponsor’s Medical Monitor and Global Pharmacovigilance representatives to monitor for any 
safety signals or trends.
In addition, an independent Data Monitoring Committee (DMC) was established to monitor the 
benefit/risk profile of BIIB092.
For information on specific risk mitigation strategies, please refer to Section 10, Section 11.2.2, 
and Section 15.4.
A need exists for disease modifying therapies for participants with AD and those with PSP.  The 
doses of BIIB092 currently being explored have the potential to benefit study subjects.  
Furthermore, the nonclinical efficacy profile and the evidence for anti eTau activity, together 
with the benign safety profile, indicate that the balance of benefit to risk is likely to be favorable 
for study subjects.
4.5.1. Overall Benefit
BIIB092 has the potential to slow or stop the spread of tau pathology observed in 
neurodegenerative diseases such as PSP, AD, and other tauopathies. 
In participants with PSP, BIIB092 has been evaluated in 2 completed clinical studies 
(Studies CN002001 and CN002003) and is currently being evaluated in the ongoing Studies 
251PP201 and 251PP301. The first-in-human study of BIIB092 (Study CN002001) was 
designed as a randomized, double-blind, placebo-controlled, SAD study in healthy 
participants to characterize the safety, tolerability, PK, PD, and immunogenicity of single 
doses of BIIB092, ranging from 21 to 4200 mg. Study CN002003, a Phase 1b study, was 
designed as a randomized, double blind, placebo-controlled MAD study to characterize the 
safety, tolerability, PK, PD, and immunogenicity of multiple doses of BIIB092, ranging 
from 150 to 2100 mg, in participants with PSP. In both of these completed studies, BIIB092 

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was found to be well tolerated at the doses tested in both healthy participants and 
participants with PSP. The ongoing Phase 1b study, Study 251PP201, is designed as an 
open-label extension study to evaluate the long term safety and tolerability of multiple 
doses of BIIB092 in participants with PSP who participated in Study CN002003. Several 
interim analyses of the data being collected in this study have been performed to date. 
Study 251PP301 is an ongoing Phase 2b study designed as a randomized, double blind, 
placebo-controlled, parallel-group study to evaluate the efficacy and safety of IV 
administered BIIB092 in participants with PSP.
In participants with AD, this study (Study 251AD201) will evaluate the safety and efficacy 
of BIIB092.
Based on the PK and PD data from Studies CN002001 and CN002003, the mean 
concentrations of BIIB092 in CSF increased in a generally dose-proportional manner. A 
robust and persistent lowering of unbound N-terminal tau was observed following 
administration of single and multiple doses of BIIB092 in healthy participants and in 
participants with PSP, consistent with the observations in cynomolgus monkeys.
4.5.2. Potential Risks
The nonclinical studies conducted to date have demonstrated an acceptable safety profile 
for BIIB092 to support continued use in clinical studies.
As of 25 November 2018, an estimated 486 healthy participants or participants with PSP or 
AD have been exposed to BIIB092 in clinical studies. The following summary of the safety 
profile of BIIB092 is based on safety data from the completed Studies CN002001 and 
CN002003 and the ongoing Study 251PP201.  In the SAD study in healthy participants, 
there were no safety findings of note, and development continued in patients with PSP. In 
participants with PSP, to date, the most commonly reported AEs were fall, urinary tract 
infection (UTI), contusion, and headache. Most AEs have been reported as mild or 
moderate in intensity. Serious AEs (SAEs) have generally been consistent with disease 
(UTI, respiratory arrest, aspiration pneumonia, and progressive PSP) or are not 
unexpected in the patient population enrolled in the trials (cholecystitis, cancer, fractures, 
and anemia). There have been 3 deaths, all of which were likely related to underlying 
disease (respiratory arrest, aspiration pneumonia, and progressive disease). None of the 
SAEs or deaths were considered related to BIIB092 by Investigators. No safety concerns 
have been identified from laboratory, vital signs, or electrocardiogram (ECG) assessments. 
Nonserious infusion reactions have been observed and are an identified risk of BIIB092.
BIIB092 is a humanized IgG4 monoclonal antibody. While a low risk of immunogenicity is 
suggested by preclinical studies, the risk of immunogenicity in humans is unknown. 
Immunogenicity is an AE of special interest that is under monitoring in all ongoing studies. 
No safety data regarding this topic have emerged that would change the safety profile of 
BIIB092.

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In general, BIIB092 has been well tolerated in the clinical study participants. There are no 
important identified or potential risks in the program. The safety profile is acceptable to 
continue development.
4.5.3. Summary
Currently available treatments for AD offer modest symptomatic relief, but none has the 
potential to modify the underlying disease pathology or course of the disease.  In addition, 
no medications have been approved for the treatment of PSP. Therefore, there is a 
significant unmet need for the development of effective disease-modifying therapies in both 
PSP and AD.
Based on the PK and PD data from Studies CN002001 and CN002003, the mean 
concentrations of BIIB092 in CSF increased in a generally dose-proportional manner. A 
robust and persistent lowering of unbound N-terminal tau was observed following 
administration of single and multiple doses of BIIB092 in healthy participants and in 
participants with PSP, consistent with the observations in cynomolgus monkeys. 
Based on the safety data from the completed Studies CN002001 and CN002003 and the 
data from an interim analysis of the ongoing Study 251PP201, BIIB092 was generally well 
tolerated and demonstrated an acceptable safety profile for continued development.
The overall analysis of potential benefits (based on the robust and persistent lowering of 
unbound N terminal tau in healthy participants and in participants with PSP, consistent 
with cynomolgus monkeys) and risks (available safety data indicating that BIIB092 is 
generally well tolerated) supports the continued development of BIIB092 in both PSP and 
AD.
Rationale: Updated the benefit and risk assessment information for BIIB092 to align with the 
Investigational Medicinal Product Dossier. Note that the overall risk and benefit assessment 
remains unchanged as a result of this update.
Section 7.1, Study Overview
Change: Require that participants be observed for a minimum of 1 hour after the end of infusion 
on dosing visits. 
Now reads: 
…
Throughout the study, all participants should be observed and monitored by study staff for 
a minimum of 1 hour after the end of an infusion. Participants who experience an AE or 
SAE related to BIIB092 infusion should remain at the site or be sent to an inpatient 

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Now reads: 
Medical history
2. History of, or positive test result at Screening for, Current hepatitis C virus antibody or 
infection (defined as positive hepatitis C virus [HCV] antibody and detectable HCV 
ribonucleic acid [RNA]). Participants with positive HCV antibody and undetectable 
HCV RNA are eligible to participate in the study (United States Centers for Disease 
Control and Prevention).
3. Current hepatitis B virus infection (defined as positive for both hepatitis B surface 
antigen [HBsAg] and/or total hepatitis B core antibody [anti-HBc]) unless fully 
recovered with no active infection indicated by a serology panel.  Participants with 
immunity to hepatitis B from previous natural infection (defined as negative HBsAg, 
positive anti-HBc, and positive hepatitis B surface antibody [anti-HBs]) or 
vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti-HBs) 
are eligible to participate in the study.  
…..
10.11. Brain MRI performed at Screening Visit 2 (centrally read) that shows evidence of 
any of the following:
…..

Cortical infarct (including cerebellar infarct) [defined as >1.5 cm in diameter]
or any infarct in the hippocampus.
…..
19.20. History of premalignant or malignant disease.  Exceptions to premalignant 
disease exclusions may be made after discussion with the Sponsor. The following 
exceptions may be made for malignant disease exclusions after discussion with the 
Sponsor:

SubjectsParticipants with cancers in remission ≥5 years prior to Screening 
Visit 1.

SubjectsParticipants with a history of excised or treated basal cell or squamous 
carcinoma of the skin.

SubjectsParticipants with localized prostate cancer with treatment cycles that 
completed at least 6 months prior to Screening Visit 1.
…..

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Biogen MA Inc.
1
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 251AD201
Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Safety, 
Tolerability, and Efficacy of BIIB092 in Subjects with Mild Cognitive Impairment due to 
Alzheimer’s Disease or with Mild Alzheimer’s Disease
Version 4
Date: 13 January 2020
EUDRA CT Number: 2017-002901-37
Version 4 of the protocol has been prepared for this amendment, which supersedes Version 3.

Amendment Summary for Protocol 251AD201, Version 4
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
3
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
Change: The following changes were made to the timing of scheduled assessments:
Safety Procedures
The frequency of MRIs was adjusted by removing MRI from Week 176 and Week 128 and 
adding it to Week 156. MRI will now be performed at Week 104 (6 months after start of LTE), 
Week 156 (18 months after start of LTE), and Week 226 (36 months after start of LTE). A row 
for body weight was added to Tables 2 through 4. Body weight measurements were added to all 
clinical visits that include a physical examination. A row for tobacco use status was added to 
Tables 1 through 4 below concomitant therapy and procedures reporting.
Biomarker
The frequency of PK/biomarkers/anti-BIIB092 antibodies collection during the LTE was adjusted 
for multiple study visits. PK/biomarkers/anti-BIIB092 antibodies will now be assessed at 
Week 116, Week 156, Week 196, and Week 224.
Clinical Assessments
Removal of NPI-10 and FAQ at Week 176 and ISLT, DKEFS, DSST, Trails A, and eCog at 
Week 180.
Rationale: To reduce the burden to participants, the original 4 MRIs planned during the LTE at 
Weeks 104, 128, 176, and 226 (at 6, 12, 24, and 36 months after starting the LTE, respectively) 
were reduced to 3 MRIs at Weeks 104, 156, and 226 (at 6, 18, and 36 months after starting the
LTE, respectively). The Week 104 MRI represents a critical safety assessment for participants
switching from placebo to treatment during the LTE. The Week 226 MRI is key for PD 
evaluation and for safety assessment at the end of the study. The Week 128 and Week 176 MRIs 
were condensed into a single Week 156 MRI in order to minimize participant burden. Based on 

Amendment Summary for Protocol 251AD201, Version 4
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
4
current evaluations, this frequency of MRI monitoring is not expected to significantly affect the 
participants’ benefit-risk. In addition, ad hoc MRI visits are possible as needed.
The frequency of biomarker and clinical assessments was reduced to decrease the burden to 
participants, particularly towards the end of the study.
A row for body weight was added to Tables 2 through 4 to provide further clarification on the 
frequency of body weight measurements.
A row for tobacco use status was added to Tables 1 through 4 to provide clarification on 
frequency and timing of the assessment.
This change also affects Section 11.4.3, Tobacco Use.
Section 5, Schedule of Activities
Change: A footnote was added to Table 1 for the Week 78 MRI.
Now reads:
23Sites should schedule the Week 78 MRI within 10 days prior to the Week 78 visit where possible to allow for 
MRI results to be available before participants enter the LTE at Week 80.
Rationale: This change was made to improve the efficiency of eligibility assessments by 
allowing MRI results to be available before entering the LTE at Week 80.
Section 5, Schedule of Activities
Change: The footnote in Table 1 regarding blood samples for assessment of BIIB092 
concentration on days of infusion was revised.
Now reads:
20Two samples must be obtained: 1 sample taken before infusion and 1 sample taken at ≤1015 minutes after the end 
of infusion.
Rationale: This change was made to increase flexibility by providing a larger time window for 
sample collection with minimal impact on PK.

Amendment Summary for Protocol 251AD201, Version 4
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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Rationale: These changes were made for logistical reasons and are not expected to affect patient 
safety.
This change also affects Section 5, Schedule of Activities and Section 7.2, Study Duration for 
Participants.
Section 10.1, Discontinuation of Study Treatment
Change: Changes were made to recommended visits for participants who discontinue study 
treatment to reflect changes in the Schedule of Activities.
Now reads:
All participants who discontinue study treatment prematurely will be asked to remain in the study 
and continue all protocol-specified visits and procedures for the period in which they 
discontinued treatment (i.e., placebo-controlled or LTE).  Participants who discontinue treatment 
during the placebo-controlled period should be encouraged to attend at least the Week 24, 
Week 52, and Week 78/EOS Visits and who discontinue treatment during the LTE should be 
encouraged to attend at least the Week 80, 104, 116, 128, 152, 156, 176, 196, 200, 224, and 
226/EOS Visits, depending on when treatment was discontinued, and undergo all the scheduled 
procedures.  At a minimum, these visits should include assessment of AEs/SAEs and 
concomitant medications and key clinical assessments, including at least the CDR, MMSE, 
ISLT, ADAS-Cog 13, ADCS-ADL, and FAQ.  Participants who discontinue study treatment 
prematurely, regardless of the treatment period, will be asked to return to the study site for a 
Follow-up Safety Visit 14 weeks after receiving the last dose of study treatment.  See Table 1, 
Table 2, Table 3, and Table 4 for the Schedule of Activities.
Rationale: Revision made to account for updates to timing of significant assessments in Table 2, 
Table 3, and Table 4.
Section 11.4.1.2, Disallowed Concomitant Therapy
Change: Details were added regarding UVs for a change in AD medication.

Amendment Summary for Protocol 251AD201, Version 4
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The information contained herein may not be used, disclosed, or published without the written consent of 
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Now reads:
Participants should have an unscheduled visit (UV) prior to the initiation of, and/or a change in,
dose, or discontinuation of AD medication. That visit should include assessment of AEs/SAEs 
and concomitant medications and key clinical assessments, including, at a minimum, the CDR, 
MMSE, ISLT, ADAS-Cog 13, ADCS-ADL, and FAQ. During the UV, these clinical 
assessments need not be repeated if performed within the previous 30 days. If the visit for a 
change in AD medication occurs at the same time as another planned visit, all originally 
scheduled assessments must also take place as required and without repetition (see Table 1, 
Table 2, Table 3, and Table 4).
Rationale: Details were added to minimize participant burden and to optimize the assessments 
performed during a change in AD medication as well as provide clarification for study sites.
This change also affects Section 5, Schedule of Activities.

Amendment Summary for Protocol 251AD201, Version 4
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
8
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.

Section 2, List of Abbreviations, was updated.

Abbreviations were updated throughout the protocol where appropriate.

The abbreviation list in the Figure 1 footnotes was updated to clarify that N represents 
the planned number of participants.

All references to free eTau were changed to N-terminal tau or removed.

Section 16.5.2, Methods of Analysis, was revised to clarify that concentration values 
below the limit of quantification will be appropriately handled per the Statistical 
Analysis Plan.

Internal references were added as hyperlinks where appropriate.

Typographical errors and formatting were corrected.

Amendment Summary for Protocol 251AD201, Version 4
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
9
LIST OF ABBREVIATIONS
AD
Alzheimer’s disease
ADAS-Cog 13
Alzheimer’s Disease Assessment Scale – Cognitive (13 item)
ADCS-ADL
Alzheimer’s Disease Cooperative Study – Activities of Daily Living
AE
adverse event
CDR
Clinical Dementia Rating Scale
DKEFS
Delis-Kaplan Executive Function System
DSST
Digit Symbol Substitution Test
eCog
Everyday Cognition
EOS
end of study
FAQ
Functional Activities Questionnaire
ISLT
International Shopping List Test Immediate Recall
IV
intravenous
LTE
long-term extension
MCI
mild cognitive impairment
MMSE
Mini-Mental State Examination
MRI
magnetic resonance imaging
NPI-10
Neuropsychiatric Inventory – 10
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
SAE
serious adverse event
Trails A
Trail Making Test, Part A
UV
unscheduled visit