Clinical trial NCT03352557
Conditions: Alzheimer's Disease
Keywords: Mild cognitive impairment Alzheimer's disease
Sponsor: Biogen
Start date: 2018-05-03; Completion date: 2021-08-30
Enrollment: 654 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the placebo-controlled period is to evaluate the safety and tolerability of BIIB092 in participants with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or with mild AD. The secondary objectives of the placebo-controlled period are 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, and to evaluate the immunogenicity of BIIB092 after multiple doses in participants with MCI due to AD or with mild AD.

The primary objective of the long-term extension period is to evaluate the long-term safety and tolerability of BIIB092 in participants with MCI due to AD or with mild AD.

Detailed description:

Arms: arm 1: Intravenous (IV) infusion once every 4 weeks OR once every 12 weeks and placebo at the other 4-week dosing visits to maintain the treatment blind. arm 2: Intravenous (IV) infusion once every 4 weeks. arm 3: Intravenous (IV) infusion once every 4 weeks. arm 4: Intravenous (IV) infusion once every 4 weeks.
Interventions: intervention 1: BIIB092 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered as specified in treatment arm. intervention 2: Administered as specified in treatment arm.

Protocol documents:
SAP_002.pdf: 
Statistical Analysis Plan 
Placebo-Controlled Period
Version 2.0 
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Tango 
251AD201/NCT03352557
Statistical Analysis Plan 
Placebo-Controlled Period 
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Statistical Analysis Plan 
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Table of Contents 
LIST OF ABBREVIATIONS .............................................................................................................................. 6 
1 
INTRODUCTION ....................................................................................................................................... 8 
2 
STUDY OVERVIEW ................................................................................................................................. 8 
2.1 
PRIMARY OBJECTIVE AND ENDPOINT ........................................................................................................ 8 
2.2 
SECONDARY OBJECTIVES AND ENDPOINTS ............................................................................................... 8 
2.3 
EXPLORATORY OBJECTIVES AND ENDPOINTS ............................................................................................ 8 
2.4 
STUDY DESIGN .......................................................................................................................................... 9 
2.5 
STUDY SCHEMATIC ................................................................................................................................. 12 
2.6 
SAMPLE SIZE JUSTIFICATION ................................................................................................................... 13 
3 
DEFINITIONS .......................................................................................................................................... 14 
3.1 
DATES AND POINTS OF REFERENCE......................................................................................................... 14 
3.2 
STUDY TREATMENT ................................................................................................................................ 15 
3.3 
KEY DERIVED VARIABLES ...................................................................................................................... 15 
3.4 
STRATIFICATION FACTORS AND SUBGROUP VARIABLES ......................................................................... 19 
3.5 
ANALYSIS SETS ....................................................................................................................................... 20 
4 
LIST OF PLANNED STUDY ANALYSES ............................................................................................ 22 
4.1 
INTERIM ANALYSIS ................................................................................................................................. 22 
4.2 
FINAL ANALYSIS ..................................................................................................................................... 22 
5 
STATISTICAL ANALYSIS METHODS ............................................................................................... 22 
5.1 
GENERAL CONSIDERATIONS ................................................................................................................... 22 
5.2 
STUDY SUBJECTS .................................................................................................................................... 22 
5.2.1 
Accounting of Subjects .................................................................................................................. 22 
5.2.2 
Demographics and Baseline Characteristics ................................................................................ 23 
5.2.3 
Concomitant Medications and Non-drug Therapies ..................................................................... 24 
5.2.4 
Protocol Deviations ...................................................................................................................... 25 
5.2.5 
Study Drug Exposure and Study Drug Compliance ...................................................................... 25 
5.2.6 
COVID-19 Related Analysis ......................................................................................................... 25 
 
Accounting of subjects who discontinued due to Covid-19 ..................................................................... 25 
 
Concomitant Non-Drug Treatment for Covid-19 ..................................................................................... 26 
 
Covid-19 Effect on Drug Compliance ...................................................................................................... 26 
 
Covid-19 Protocol Deviation.................................................................................................................... 26 
 
Protocol Alternation Due to Covid-19...................................................................................................... 26 
5.3 
EFFICACY ANALYSIS ............................................................................................................................... 26 
5.3.1 
General Considerations ................................................................................................................ 26 
 
Covid-19 consideration ............................................................................................................................ 27 
5.3.2 
Considerations for base MMRM model for change from baseline analyses................................. 28 
5.3.3 
Primary Efficacy Endpoint ........................................................................................................... 28 
 
Primary analysis ....................................................................................................................................... 28 
 
Sensitivity analysis ................................................................................................................................... 29 
 
Per-protocol analysis ................................................................................................................................ 31 
5.3.4 
Exploratory Efficacy Endpoints .................................................................................................... 32 
5.3.5 
Subgroup Analysis ........................................................................................................................ 32 
5.3.6 
Additional Analysis ....................................................................................................................... 32 
 
CDR Subscores, CDR Global Score, ADCS-bADL, ADCS-iADL and individual scores for CDR, 
ADCS-ADL and ADAS-Cog 13 .............................................................................................................................. 32 
 
Slope analysis ........................................................................................................................................... 33 
 
Summary of CDR-SB, ADAS-Cog 13 total score, and MMSE by tau PET reduction at Week 78 .......... 33 
 
Responder analysis of CDR-SB ............................................................................................................... 34 
5.4 
SAFETY ANALYSIS .................................................................................................................................. 34 
5.4.1 
General Considerations ................................................................................................................ 34 
 
Analysis Set.............................................................................................................................................. 34 
 
Safety treatment groups ............................................................................................................................ 34 
 
Incidence, incidence proportion and incidence rate .................................................................................. 35 
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5.4.2 
Clinical Adverse Events ................................................................................................................ 35 
 
Treatment-emergent AEs (TEAEs) .......................................................................................................... 35 
 
Summary and incidence analysis.............................................................................................................. 36 
 
Incidence rate analysis ............................................................................................................................. 37 
 
Infusion reactions ..................................................................................................................................... 38 
 
Adverse event of special interest .............................................................................................................. 38 
5.4.3 
Clinical Laboratory Data ............................................................................................................. 38 
 
Quantitative analyses ............................................................................................................................... 39 
 
Qualitative analyses ................................................................................................................................. 39 
5.4.4 
C-SSRS Data ................................................................................................................................. 41 
5.4.5 
ECG Data ..................................................................................................................................... 41 
5.4.6 
Vital Sign Data ............................................................................................................................. 42 
5.4.7 
Physical Examination ................................................................................................................... 43 
5.4.8 
Neurological Examination ............................................................................................................ 43 
5.4.9 
Safety MRI Data ........................................................................................................................... 43 
5.4.10 
COVID-19 Related Safety analysis .......................................................................................... 44 
5.5 
PHARMACOKINETICS ANALYSIS .............................................................................................................. 44 
5.5.1 
Serum and CSF PK Concentration Data ...................................................................................... 45 
5.5.2 
Serum PK Parameters .................................................................................................................. 45 
5.6 
BIOMARKER ............................................................................................................................................ 46 
5.6.1 
Pharmacodynamics Analysis ........................................................................................................ 46 
5.6.2 
Structural MRI Analysis ................................................................................................................ 47 
 
By visit summary and MMRM model ...................................................................................................... 47 
 
Pearson and Spearman correlation ........................................................................................................... 47 
5.6.3 
Tau PET Analysis ......................................................................................................................... 47 
 
Tau PET substudy .................................................................................................................................... 47 
 
Tau PET target and reference regions ...................................................................................................... 48 
 
Tau PET primary analysis ........................................................................................................................ 48 
 
Correlation between Tau PET vs. Cognitive results and other assessments ............................................. 49 
 
Subgroup analysis .................................................................................................................................... 50 
5.7 
ANTI-DRUG ANTIBODY ANALYSIS .......................................................................................................... 50 
5.7.1 
Analysis Methods for Anti-drug antibody Data ............................................................................ 50 
5.8 
HEALTH OUTCOMES ................................................................................................................................ 51 
5.8.1 
QoL-AD and ZBI ........................................................................................................................... 51 
5.8.2 
RUD-Lite ...................................................................................................................................... 51 
6 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ............................................................... 53 
6.1 
MMRM MODEL ...................................................................................................................................... 54 
6.2 
MCP-MOD MODEL ................................................................................................................................. 54 
7 
APPENDIX I: VISIT WINDOW MAPPING ......................................................................................... 55 
8 
APPENDIX II: DESCRIPTION OF MCP-MOD METHOD ............................................................... 59 
9 
APPENDIX III: QUESTIONNAIRE ...................................................................................................... 60 
9.1 
CLINICAL DEMENTIA RATING SCALE (CDR) .......................................................................................... 60 
9.2 
MINI-MENTAL STATE EXAMINATION (MMSE) ...................................................................................... 60 
9.3 
INTERNATIONAL SHOPPING LIST TEST IMMEDIATE RECALL (ISLT) ....................................................... 60 
9.4 
DELIS-KAPLAN EXECUTIVE FUNCTION SYSTEM (DKEFS) ..................................................................... 61 
9.5 
DIGIT SYMBOL SUBSTITUTION TEST (DSST) .......................................................................................... 61 
9.6 
TRAIL MAKING TEST, PART A (TRAIL A) ............................................................................................... 62 
9.7 
EVERYDAY COGNITION (ECOG) .............................................................................................................. 62 
9.8 
ALZHEIMER’S DISEASE COOPERATIVE STUDY – ACTIVITIES OF DAILY LIVING (ADCS-ADL) ............... 63 
9.9 
FUNCTIONAL ACTIVITIES QUESTIONNAIRE (FAQ) .................................................................................. 63 
9.10 ALZHEIMER’S DISEASE ASSESSMENT SCALE –COGNITIVE (13 ITEM) (ADAS-COG 13) ........................... 63 
9.11 NEUROPSYCHIATRIC INVENTORY – 10 (NPI-10) ..................................................................................... 63 
9.12 ZARIT BURDEN INTERVIEW (ZBI) ........................................................................................................... 64 
9.13 QUALITY OF LIFE FOR ALZHEIMER’S DISEASE (QOL-AD) ....................................................................... 64 
9.14 RESOURCE UTILIZATION IN DEMENTIA-LITE VERSION (RUD-LITE) ....................................................... 64 
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10 
APPENDIX IV: ADVERSE EVENT OF SPECIAL INTEREST CUSTOM SEARCH CRITERIA 66 
11 
APPENDIX V: INFUSION REACTIONS CUSTOM SEARCH .......................................................... 67 
12 
REFERENCES .......................................................................................................................................... 68 
 
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List of Abbreviations  
AD 
Alzheimer’s Disease 
ADA 
Anti-Drug Antibody 
ADAS-Cog 13 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale (13 Items) 
ADCOMS 
Ad Composite Score 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study - Activities Of Daily Living 
Inventory  
ADCS-iADL 
ADCS-ADL Instrumental Total Score 
ADCS-bADL 
ADCS-ADL Basic Total Score 
ADNI 
Alzheimer’s Disease Neuroimaging Initiative 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ApoE 
Apolipoprotein E 
APTT 
Activated Partial Thromboplastin Tim 
AST 
Aspartate Aminotransferase 
BLQ 
Below the Limit of Quantification 
BMI 
Body Mass Index 
bpm 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
CDR 
Clinical Dementia Rating  
CDR-SB 
Clinical Dementia Rating-Sum of Boxes 
CI 
Confidence Interval 
CIR 
Copy Increment from Reference 
Cmax 
Observed Maximum Serum BIIB092 Concentration 
Cmin 
Observed Minimum Serum BIIB092 Concentration 
CSF 
Cerebrospinal Fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale  
CV 
Coefficient of Variation 
DKEFS 
Delis-Kaplan Executive Function System 
DSST 
Digit Symbol Substitution Test 
ECG 
Electrocardiogram 
EMACC 
Early Ad/ MCI Alzheimer’s Cognitive Composite 
Emax 
Maximum Response 
EOS 
End of Study 
EOT 
End of Treatment 
ET 
Early Termination 
FAQ 
Functional Activities Questionnaire 
FAS 
Full Analysis Set 
eCOG 
Everyday Cognition 
eCRF 
Electronic Case Report Form 
ICE 
Intercurrent Event 
ICH 
International Conference on Harmonisation 
INR 
Prothrombin Intl. Normalized Ratio 
IRT 
Interactive Response Technology 
LS 
Lease Square Mean 
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iADRS 
The Integrated Alzheimer’s Disease Rating Scale  
ISLR 
International Shopping List Test Delayed Recall 
ISLT 
International Shopping List Test Immediate Recall 
LLOQ 
Lower Limit of Quantification 
LTE 
Long-Term Extension 
LP 
Lumbar Puncture 
MA 
Macrohemorrhage 
MCI 
Mild Cognitive Impairment 
MCMC 
Markov Chain Monte Carlo 
MCP-MOD 
Multiple Comparison Procedure - Modelling 
MedDRA 
Medical Dictionary for Regulatory Activities 
mH 
Microhemorrhages 
MMRM 
Mixed-Model Repeated Measures 
MMSE 
Mini-Mental State Examination 
MRI 
Magnetic Resonance Imaging 
NIA-AA 
National Institute on Aging-Alzheimer’s Association 
NPI-10 
Neuropsychiatric Inventory-10 
PCS 
Potentially Clinically Significant 
PD 
Pharmacodynamics(S) 
PET 
Positron Emission Tomography 
pH 
Potential of Hydrogen 
PLS 
Partial Least Squares 
PMM 
Pattern Mixture Model  
PK 
Pharmacokinetic(S) 
PPS 
Per-Protocol Analysis Set  
PT 
Preferred Term 
PT 
Prothrombin Time 
Qol-AD 
Quality of Life for Alzheimer’s Disease 
QTcF 
Corrected QT Interval by Fredericia 
RCmin 
Accumulation Ratio Using Cmin 
RCmax 
Accumulation Ratio Using Cmax 
ROI 
Region of Interest 
RUD-Lite 
Resource Utilization In Dementia – Lite Version 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SS 
Superficial Siderosis 
SUVR 
Standard Uptake Value Ratio 
TEAE 
Treatment-Emergent Adverse Event 
TIV 
Total Intracranial Volume 
Trails A 
Trail Making Test, Part A 
ULN 
Upper Limit of Normal 
VE 
Vasogenic Edema 
WHO 
World Health Organization 
ZBI 
Zarit Burden Interview 
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1 Introduction 
This statistical analysis plan (SAP) only covers the analyses for the primary, secondary and 
exploratory objectives for the placebo-controlled period of 251AD201. Hereafter, the placebo-
controlled period of the study will be referred to as “the study” in the rest of this SAP (e.g., 
completion of the study means completion of the placebo-controlled portion). A separate SAP 
will be prepared for the analyses of the LTE period and integrated analyses across both portions 
of the study.  
Unless stated otherwise, all statistical tests will be 2-sided with statistical significance level of 
0.05.  
The statistical software, SAS® will be used for all summaries and analyses. 
  
2 Study Overview  
2.1 
Primary Objective and Endpoint 
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 placebo-controlled period. 
2.2 
Secondary Objectives and Endpoints 
 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. 
2.3 
Exploratory objectives and endpoints 
 To assess the effect of BIIB092 on the clinical progression of AD as measured by 
changes from Baseline over time up to Week78 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-Cog13 [13item]), and 
Neuropsychiatric Inventory-10 (NPI-10).  
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 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 visits indicated in the Schedule of Activities in participants with MCI 
due to AD or with mild AD. 
 To assess BIIB092 PK in CSF from the samples collected at the visits indicated in the 
Schedule of Activities in participants with MCI due to AD or with mild AD who 
consent to participate in the CSF sampling substudy.  
 To assess the effect of BIIB092 on tau protein concentrations in CSF (in subjects 
consenting to participate in the CSF sampling substudy) as measured by changes from 
Baseline over time up to Week 76 in CSF N-terminal eTau concentration. 
 To assess the effect of BIIB092 on biomarkers in blood as measured by changes from 
Baseline over time up to Week76 on blood levels of disease-related biomarkers, 
including but not limited to, tau and other markers of neurodegenerative disease.  
 To assess the effect of BIIB092 on disease-related biomarkers in CSF (only for 
participants who consent to participate in the CSF sampling substudy) as measured by 
changes from Baseline over time up to Week76 in disease-related CSF biomarkers, 
including but not limited to, phosphor-tau, neurogranin, and neurofilament 
(neurofilament light and phospho-neurofilament heavy). 
 To assess the effect of BIIB092 on cerebral tau changes (in participants consenting to 
participate in the tau positron emission tomography [PET] substudy) as measured by 
changes from Baseline over time up to Week 78 on 18F-MK6240 PET binding signal in 
certain brain regions. 
 To assess the effect of BIIB092 on brain structure as measured by changes from 
Baseline over time up to Week 78 on magnetic resonance imaging (MRI) morphometric 
measures, including volume of certain brain areas. 
 
2.4 
Study Design 
Study 251AD201 (TANGO) is a Phase 2, randomized, double-blind, placebo-controlled study 
of BIIB092 in subjects aged 50 to 80 years inclusive, with MCI due to AD or mild AD 
according to National Institute on Aging-Alzheimer’s Association criteria (NIA-AA).  Subjects 
must have Aβ positivity confirmed at Screening by either CSF sampling or an amyloid PET 
scan. Subjects must also perform at 1 standard deviation (SD) below the age-adjusted 
normative mean on either the ISLT or the International Shopping List Test Delayed Recall 
(ISLR) and have a Clinical CDR global score of 0.5 for MCI due to AD or 0.5 or 1 for mild 
AD, an MMSE score of 22 to 30 (inclusive), and a CDR Memory Box score of ≥0.5. 
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The study is conducted in a parallel-group design, with 3 BIIB092 dose groups (including 4 
BIIB092 doses) and a placebo group. Approximately 528 subjects was planned to be 
randomized across approximately 90 study sites globally.  Subjects were stratified by tau 
PET/CSF sampling substudy enrollment (see substudy description below), region, baseline 
disease stage (MCI or mild AD), and baseline AD symptomatic medication use.  Subjects who 
enroll in both substudies will be considered as enrolled in the tau PET substudy for 
randomization purposes.   
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 
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 Screening 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. 
Randomized participants will receive 1 of the following study treatments by IV infusion, 
starting on Study Day 1 during the placebo-controlled period: 
 low-dose BIIB092 -125mg once every 4 weeks or 375mg once every 12 weeks and 
placebo at the other 4-week dosing visits to maintain the treatment blind (88 subjects 
in total, 44 per regimen) 
 medium-dose BIIB092 -600mg once every 4 weeks (88 subjects) 
 high-dose BIIB092 -2000mg once every 4 weeks (176 subjects) 
 placebo (176 subjects) 
Overall, participants will have a 2:1 chance of being randomized to BIIB092 or to placebo 
during the placebo-controlled period. 
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 LTE period may be changed based on emerging data from the BIIB092 
clinical development program. 
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 monitoring 
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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. 
Investigators, study staff (except for a designated Pharmacist/Technician), and study subjects 
and their families, caregivers, legal representatives will be blinded to the subjects’ randomized 
treatment assignments. 
This study includes 2 substudies to address exploratory study objectives: a tau PET substudy 
and a CSF sampling substudy.  The tau PET substudy is mandatory at study sites that have 
access to the 18F-MK6240 PET radioligand and have the capability to perform 18F-MK6240 
PET scans.  During the placebo-controlled period, the CSF sampling substudy is mandatory 
at all study sites that do not have access to the 18F-MK6240 PET radioligand.  Participants 
will provide consent during Screening to participate in at least 1 of these substudies during 
the placebo-controlled period.  Participants enrolled in the LTE period and who are 
participating in the tau PET substudy are required to continue participation in the tau PET 
substudy.  Participation in the CSF sampling substudy during the LTE will be optional for all 
study participants, although participation will be encouraged. Participants may withdraw 
consent to participate in the substudies at any time. 
 
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2.5 
Study Schematic 
Figure 1. 
Study Design with Planned Sample Size 
 
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. 
 
 
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2.6 
Sample Size Justification 
There was no formal sample size calculation for the primary endpoint of safety.  
The planned sample size is 528 subjects, randomized in a 1:1:2:2 ratio, with 88 subjects 
assigned to the BIIB092 low-dose group (44 assigned to 125mg once every 4weeks and 44 
assigned to 375mg once every 12 weeks), 88 subjects assigned to the medium-dose group 
(600mg once every 4weeks), 176 subjects assigned to the high-dose group (2000mg once every 
4 weeks), and 176 subjects assigned to the placebo group.  This sample size provides 
approximately 80% power to detect a dose-response relationship in the change from baseline 
in CDR-SB (primary efficacy endpoint) at 18 months (Week 78), assuming a mean change of 
1.99 from baseline in CDR-SB at 18 months in the placebo group and a common SD of 2.38, 
a maximal 40% reduction for the highest BIIB092 dose group compared with the placebo 
group, and an estimated 20% dropout rate at 18 months (Week 78) in this study.  Six different 
dose-response relationships will be tested at the 2-sided 5% significance level, using the MCP-
MOD method to control for multiplicity.  Optimal contrasts will be constructed to detect 
potential dose-response trends under common dose-response curves (e.g., Emax, exponential, 
logistic, linear in log dose, and quadratic model) which are illustrated with the parameters 
shown in Figure2.   
The mean and SD of the change from baseline in CDR-SB at 18 months for the placebo group 
is based on available Alzheimer’s Disease Neuroimaging Initiative (ADNI) data from ADNI1, 
ADNI2, and ADNI GO (amyloid positive from amyloid PET or CSF, MMSE ≥22, CDR global 
score of 0.5 for late MCI and 0.5 or 1 for mild AD).   
Based on mean changes in tau PET from Baseline to 9 months and 18 months in the 
Longitudinal Flortaucipir A05 study, it is assumed, by linear extrapolation, that the mean (SD) 
change from Baseline to 12 months (Week 52) for the placebo group in this study is assumed 
to be 0.034(0.033).  Following the same MCP-MOD method under the same dose-response 
curves and parameters, the planned sample size for the tau PET substudy is 330 subjects, in a 
1:1:2:2 randomization ratio, with 55 subjects assigned to the BIIB092 low-dose group (27 
assigned to 125mg once every 4weeks and 28 assigned to the 375 mg once every 12weeks), 55 
subjects assigned to the medium-dose group (600 mg once every 4weeks), 110 subjects 
assigned to the high-dose group (2000 mg once every 4weeks), and 110 subjects assigned to 
the placebo group to provide approximately 80% power to detect a maximal 40% reduction 
(mean change of 0.0136) and a common SD (0.033) for the highest BIIB092 dose group 
compared with the placebo group, with an estimated 15% dropout rate at 12 months (Week 
52).  Similarly, 6 different dose-response relationships will be tested at the 2-sided 5% 
significance level using the MCP-MOD method to control for multiplicity.  
There was no formal sample size calculation for the CSF sampling substudy.  
Sample size re-estimation was not done. However, blinded power was re-evaluated based on 
final randomized number of subjects after enrollment completed. Detailed information was 
documented in Note to File (251ad201 NTF_power re-estimation in CMF). 
 
 
 
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3.2 
Study Treatment 
For efficacy, health outcome, statistical modeling of fluid PD and imaging biomarker analyses, 
the following treatment groups of BIIB092 (per randomization) will be evaluated and 
compared with placebo: 
 Placebo 
 low-dose BIIB092 -125mg once every 4weeks or 375mg once every 12weeks  
 medium-dose BIIB092 - 600mg once every 4 weeks  
 high-dose BIIB092 - 2000mg once every 4 weeks 
The following treatment groups of BIIB092 will be evaluated for other analyses, such as study 
subject accounting, safety, fluid PD biomarkers and PK analyses, low dose group will be split 
out for different frequencies. If determined necessary, statistical modeling of fluid PD 
biomarkers may be conducted using the following treatment groups, as well.  
 Placebo 
 low-dose BIIB092 -125mg once every 4weeks 
 low-dose BIIB092 - 375mg once every 12weeks  
 medium-dose BIIB092 - 600mg once every 4 weeks  
 high-dose BIIB092 - 2000mg once every 4 weeks 
3.3 
Key Derived Variables 
 Handling of missing items for scales  
If any of the individual items for the primary efficacy endpoint and exploratory efficacy 
endpoints is missing, the total score of the corresponding endpoint will be imputed by 
prorating the observed scores [van Ginkel 2010]. 
 
o For ADAS-Cog13, if 3 or fewer of 13 items (<25%) are missing, the total score 
will be imputed by the following algorithm: Total score = total score from the 
completed items * [maximum total score (=85) / maximum total score for the 
completed items]. The imputed number will be rounded up to the nearest 
integer. If more than 3 items are missing, the total score of ADAS-Cog 13 at 
that visit will be considered missing. 
o For ADCS-ADL, if 8 or fewer of 32 items (<25%) are missing, the total score 
will be imputed by a similar algorithm as that for ADAS-Cog 13. The imputed 
number will be rounded down to the nearest integer. If more than 8 items are 
missing, the total score for ADCS-ADL at that visit will be considered missing. 
Following the similar idea, for ADCS-iADL, if 6 or fewer out of 26 items are 
missing, the score will be imputed. For ADCS-bADL, if only 1 out of 6 items 
is missing, the total score will be imputed. 
o The same imputation algorithm will be applied to CDR-SB and MMSE, if only 
1 box (of 6) of CDR is missing or if only 2 or fewer items (out of 11) are missing 
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for MMSE. The imputed CDR-SB will be rounded up to the nearest half integer, 
and the imputed MMSE will be rounded down to the nearest integer. If the score 
from more than 1 box of CDR or more than 2 items of MMSE is not available, 
the CDR-SB or MMSE at that visit will be considered missing.  
o The total score of the exploratory endpoint NPI-10 and FAQ will be imputed 
using the same prorating principle and round up to the nearest integer if only 1 
item (out of 10) is missing.   
 
 iADRS derivation 
The iADRS is a composite score based on ADAS-Cog and ADCS-iADL (instrumental 
ADCS-ADL) [Wessels et al. 2015, Wessels et al. 2018]. The iADRS is calculated as a 
linear combination of total scores of the two individual components, the ADAS-Cog13 
(score range 0 to 85) and the ADCS-iADL (score range 0 to 56). Because higher score 
on the ADAS-Cog13 reflect worse performance, whereas higher scores on the iADCS-
ADL reflect better performance, the ADAS-Cog score is multiplied by (-1) in the 
calculation of the integrated scale. To anchor the ADAS-Cog at 0, a constant (85) is 
added. The iADRS score is then computed as the sum of the transformed ADAS-Cog13 
and the ADCS-ADL, as shown in the formula below:  
  
iADRS score = [ (-1) (ADAS-Cog13) + 85] + ADCS-iADL 
The iADRS score ranges from 0 to 141 with lower scores indicating worse 
performance.  If either ADAS-Cog13 or ADCS-iADL is missing, the iADRS score will 
be considered missing. 
 
 EMACC derivation 
The EMACC is a new and sensitive composite of well-known and validated 
neuropsychological tests that is suitable for examining the effect of disease modifying 
compounds on cognitive decline in the early Alzheimer Disease or MCI stage of 
Alzheimer’s disease [Jaeger et al. 2018].  
Cognitive variables (ISLT, DKEFS Category Fluency total correct score, DKEFS Letter 
Fluency total correct score, DSST total score, Trails A total time to complete) will be z-
score transformed using the baseline score’s mean and SD. For Trails A total time to 
complete, negative one (-1) will be multiplied when calculate the z-score. The EMACC 
score will be computed by taking the average of the z-scores across the five tests. Since 
the direction of Trails A total time to complete will be reversed, the higher EMACC score 
means cognitive improvement. If Trails A is missing, EMACC will be computed by 
taking the average of the z-scores across the remaining four tests. For the rest 4 
component scores, if any of them is missing then the composite score will be missing.  
 
 ADCOMS derivation 
ADCOMS is a novel instrument developed to improve the sensitivity of currently 
available cognitive and functional measures for subjects in the prodromal stage of AD 
and mild AD dementia. It consists of 4 Alzheimer’s Disease Assessment Scale–
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cognitive subscale items, 2 Mini-Mental State Examination items, and all 6 Clinical 
Dementia Rating—Sum of Boxes items (Table 1). The composite score is a weighted 
linear combination of the individual scale’s items using the corresponding PLS 
coefficients as weighting factors as listed in Table 1 [Wang et al. 2016]. The lower 
ADCOMS score shows clinical improvement. If any of the individual item is missing, 
then the composite score will be missing.  The range of ADCOMS is between 0 and 
1.97.  
The formula for ADCOMS composite score is as below: 
ADCOMS = ADCDRL * 0.008 + ADCOR * 0.017 + ADCRG * 0.004 + ADCDIF * 
0.016 + (5 – MMS101) * 0.042 + (1 – MMS111) *0.038 + CDR0106 * 
0.054 + CDR0104 * 0.109 + CDR0105 * 0.089 + CDR0103 * 0.069 + 
CDR0101 * 0.059 + CDR0102 * 0.078 
 
Table 1. 
Items included in ADCOMS and their corresponding PLS coefficients 
Scale 
Item ID 
Item name 
PLS coefficients 
ADAS-cog 
ADCDRL 
Delayed word recall 
0.008 
ADCOR 
Orientation 
0.017 
ADCRG 
Word recognition 
0.004 
ADCDIF 
Word finding difficulty 
0.016 
MMSE 
MMS101 
Orientation time 
0.042 
MMS111 
Drawing 
0.038 
CDR-SB 
CDR0106 
Personal care 
0.054 
CDR0104 
Community affairs 
0.109 
CDR0105 
Home and hobbies 
0.089 
CDR0103 
Judgement and problem 
solving 
0.069 
CDR0101 
Memory 
0.059 
CDR0102 
Orientation 
0.078 
ADAS-cog, Alzheimer’s Disease Assessment Scale–cognitive subscale; CDR-SB, 
Clinical Dementia Rating, sum of boxes; MMSE, Mini-Mental State Exam; PLS, partial 
least squares. 
 
 
 Adjusted structural MRI volume (% of TIV) 
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The adjusted structural MRI volume is defined as the percentage of ROI volume to 
the total intracranial volume (TIV). For example, the adjusted lateral ventricles 
volume at week 78 = (lateral ventricles volume at week 78/TIV) * 100%. The TIV 
(total intracranial volume) is measured at baseline and kept the same for all post-
baseline visit.  
 
 
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3.4 
Stratification Factors and Subgroup Variables 
Stratification factors are: 
 Tau PET/CSF substudy enrollment (If subjects enrolled in both substudies, subjects 
will be counted as tau PET substudy) 
 Region [US, Australia, Japan, EU (EU countries include France, Germany, Italy, 
Spain, and Sweden), and Poland] 
 Baseline disease stage (MCI or mild AD) 
 Baseline AD symptomatic medication use (Yes or No) 
Subgroup variables for the subgroup analysis in efficacy (Section 5.3.5)  
 Baseline clinical stage (MCI due to AD or mild AD) per the Investigator’s assessment 
based on the National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria 
 Tau level at baseline measuring by tau PET (e.g. SUVR in primary target regions with 
primary reference region), CSF p-tau, or blood p-tau 
 TIV adjusted hippocampal volume at baseline (quartiles of total hippocampal volume 
expressed as a % of TIV)   
 Laboratory ApoE ε4 status (carrier/non-carrier)  
 Use of AD symptomatic medication at baseline (yes or no) 
 Age category (e.g. < 65, 65-<70, 70-<75, >=75) 
 Gender (female or male) 
 MMSE at baseline (e.g. > median MMSE score at baseline vs. < median MMSE score 
at baseline)  
 CDR global score at baseline (0.5 vs 1) 
 Health Care Regions (US vs. other countries): 
- 
US 
- 
Non-US (Australia, Japan, France, Germany, Italy, Spain, Sweden, and Poland) 
* may analyze a country or countries separately if their data is not consistent 
comparing to other countries within the same category 
Additional subgroup variables for subgroup analysis in efficacy: 
 Magnitude of change on tau PET measures for the primary targets and reference 
regions at Week 78:  
- 
Change from baseline less than (mean - one standard deviation) of the placebo 
group at Week 78 vs. 
- 
Change from baseline greater than or equal (mean - one standard deviation) of the 
placebo group at Week 78 
 
Subgroup variables for the subgroup analysis in Tau PET (Section 5.6.3.5) for primary target 
regions [Braak 1 and 2, Braak 3 and 4, Braak 5 and 6] with primary reference region 
(Cerebellum [superior section eroded]). Other target regions and reference regions may be 
explored.  
 
 Baseline clinical stage (MCI due to AD and mild)  
 Tau PET level at baseline (e.g. quartiles),  
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 Baseline amyloid PET level (where available), for Amyloid Composite ROI SUVR 
measure as the target region with Cerebellum as the reference region using florbetapir 
tracer only [e.g. quartiles] (subjects who provided baseline amyloid level) 
 Use of AD symptomatic medication at baseline (yes or no) 
 Age category (e.g. < 65, 65-<70, 70-<75, >=75) 
 Gender (female or male) 
 MMSE at baseline (e.g. > median MMSE score at baseline vs. < median MMSE score 
at baseline)  
  
 
 In addition, the following subgroup analysis may be explored for analysis: 
 AD symptomatic concomitant medication change during the study duration (Yes vs. 
No) 
 Subjects who received >=10 infusions vs subjects who received <10 infusions 
 Baseline ISLT score 
 Time since AD diagnosis 
 Time since AD symptom onset 
 
3.5 
Analysis Sets 
 Enrolled subjects: all subjects who signed informed consent and were assigned a subject 
identification number. 
 
 Randomized subjects: enrolled subjects who received a randomization treatment 
assignment from the Interactive Response Technology (BIIB092 or placebo). 
 
 Full Analysis Set (FAS): The Full Analysis Set (FAS) includes all randomized subjects 
who received study treatment (BIIB092 or placebo). In analyses performed on the FAS, 
participants will be analyzed, based on the intention-to-treat principle, according to their 
randomized treatment assignment regardless of treatment received. 
 
 Per-Protocol Analysis Set:  
The Per-Protocol Analysis Set is defined as all subjects in the FAS and  
o had no violations of the following inclusion criteria: 
 Must have evidence of cerebral Aβ accumulation, as determined by an amyloid 
PET scan or by CSF testing 
 Must have the following at baseline: 
 CDR global score of 0.5 or 1  
 MMSE score of 22 to 30 (inclusive) 
 CDR Memory Box score of ≥0.5 
o had at least 14 infusions 
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o did not miss ≥4 infusions consecutively  
o did not make any change to concomitant AD symptomatic medications during the 
study 
 
 Safety Analysis Set:  
The Safety Analysis Set includes all randomized subjects who received at least one dose 
of study treatment (BIIB092 or placebo), essentially the same set of participants included 
in the FAS. 
 
 Safety MRI Evaluable Set: 
The Safety MRI Evaluable Set is defined as subjects in the FAS who had at least one post-
baseline safety MRI scan. 
 
 Serum PK Evaluable Set:  
The serum PK evaluable set is defined as subjects in the FAS who had at least one 
measurable post-baseline BIIB092 concentration in serum before the End of Study of PCP. 
 
 CSF PK Evaluable Set:  
The CSF PK evaluable set is defined as subjects in the FAS who had at least one measurable 
post-baseline BIIB092 concentration in CSF.  
 
 Blood PD Evaluable Set:  
The blood PD Evaluable Set is defined as subjects in the FAS who had baseline and at least 
one post baseline assessment of the specific parameter being analyzed in blood before the 
End of Study of PCP. 
 
 CSF PD Evaluable Set:  
The CSF PD Evaluable Set is defined as subjects in the FAS who had lumbar puncture 
(LP), which will be used in analyses, such as subject accounting and summary of AE related 
to LP. The CSF PD Modified Evaluable Set is defined as subjects in the FAS who have 
baseline and at least one post baseline assessment of the specific parameter being analyzed 
in CSF. 
 
 Tau PET Evaluable Set: 
The tau PET Evaluable Set is defined as subjects in the FAS who had tau PET, which will 
be used in analyses, such as subject accounting and summary of AE related to tau PET. The 
tau PET Modified Evaluable Set is defined as subjects in the FAS who had a valid baseline 
and a post-baseline tau PET SUVR measure using the 18F-MK6240 tracer. 
 
 Structural MRI Evaluable Set:  
The Structural MRI Evaluable Set is defined as subjects in the FAS who have an evaluable 
baseline and a post-baseline structural MRI scan.  
 
 Anti-drug antibody (ADA) Evaluable Set: 
The ADA Evaluable Set is defined as subjects in the FAS who have an evaluable post-
baseline ADA sample. 
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4 List of Planned Study Analyses 
4.1 
Interim Analysis 
The protocol of 251AD201 covers PC and LTE periods. Therefore, end of PC period analysis 
will be considered as an interim analysis for this protocol. All planned analyses in this SAP 
will be finalized.  
 
At the time of PC database lock, an interim analysis of LTE period will be conducted. A 
separate SAP will be prepared for the analyses of the LTE period and integrated analyses 
across both portions of the study. 
 
4.2 
Final analysis 
At the end of the long-term extension after which the study will be finally locked and 
analyzed.  
5 Statistical Analysis Methods 
5.1 
General Considerations 
Summary tables will be presented using descriptive summary statistics. For continuous 
variables, summary statistics will generally include: number of subjects with data, mean, 
standard deviation, median, 25% percentile, 75% percentile, minimum and maximum. For 
categorical variables, this will generally include: number of subjects randomized or dosed, 
number with data, and the percent of those with data in each category.  
5.2 
Study Subjects 
The summaries in this section will be based on the FAS. Unless otherwise specified, summary 
tables will be presented by treatment group: placebo, BIIB092 125 mg/4wk, BIIB092 375 
mg/12wk, BIIB092 600 mg/4wk, BIIB092 2000 mg/4wk, and total. All of the listings will be 
presented by treatment group, unless otherwise specified. 
5.2.1 Accounting of Subjects 
Disposition of subjects will be summarized and the summary data will include number (%) of 
subjects randomized and dosed, number (%) of subjects in each analysis set, number (%) of 
subjects who completed the treatment/study, number (%) of subjects who are active in the 
treatment period, number (%) of subjects who discontinued treatment and/or withdrew from 
study, and number (%) of subjects who discontinued treatment yet completed the placebo-
controlled period. For subjects who discontinued treatment and/or withdrew from study, the 
reasons for discontinuation and/or withdrawal will be summarized and listed. Subjects 
excluded from the per-protocol analysis set will also be listed.  
In addition, the following will be summarized for country, substudies (CSF and Tau PET), and 
baseline clinical stage (MCI and Mild): 
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 Number of subjects dosed  
 Number of subjects who completed treatment  
 Number of subjects who completed the study  
 
5.2.2 Demographics and Baseline Characteristics 
The demographic data including age, gender, ethnicity, race, height, weight, body mass index 
(BMI), years of formal education, substudy enrollment, and region will be summarized. Age 
will also be categorized and presented using the following grouping: < 65, 65-<70, 70-<75, 
>=75. In addition, Asian group will also be summarized for the following subclassification: 
Chinese, Indian, Japanese, Korean, and other. 
Summary of the baseline characteristics of AD includes baseline clinical stage (MCI due to 
AD or mild AD), years since first AD symptom(s), years since diagnosis of AD, laboratory 
ApoE status (carrier, non-carrier, and undetermined), baseline AD symptomatic medication 
use (yes or no; see Section 4.2.3 for definition of AD symptomatic medication use at baseline), 
ISLT raw score, ISLT z-score, ISLR raw score, ISLR z-score, CDR global score, CDR memory 
box score, CDR sum of boxes score, CDR cognitive subscore, CDR functional subscore, 
MMSE, ADAS-Cog 13, ADCS-ADL, ADCS-iADL, ADCS-bADL, EMACC, ADCOMS and 
iADRS. ApoE carrier will be further classified as homozygote and heterozygote. MMSE will 
also be categorized by the following subgroups: <22, 22-24, 25-27, and 28-30. Baseline 
Amyloid PET level will be summarized for Amyloid Composite ROI SUVR measure as the 
target region with Cerebellum as the reference region, using florbetapir tracer only. 
Subject listings will be generated for demographics and baseline characteristics. 
The same summary will be also conducted for MCI subjects, Mild subjects, tau PET evaluable 
set (including subjects enrolled in both tau PET and CSF substudies) and CSF PD evaluable 
set.  
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA 23.1). The number (%) of subjects with history (including both ongoing and not 
ongoing medical conditions) will be summarized by system organ class and preferred term. A 
listing of medical history will be generated. 
Previous treatment of AD stopped prior to the date of first infusion, duration of previous 
therapies and reason for stopping treatment will be summarized by treatment group. Listing of 
previous AD treatment will also be generated.  
Note that ApoE status is defined as below: 
 ApoE carrier: E2/E4, E3/E4, E4/E4 
o Heterozygote: E2/E4, E3/E4 
o Homozygote: E4/E4 
 ApoE non-carrier: E2/E2, E2/E3, E3/E3 
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5.2.3 Concomitant Medications and Non-drug Therapies 
All concomitant medications will be coded using the World Health Organization (WHO) 
medication dictionary (version: WHODrug Globa B3 MAR20). All concomitant non-drug 
therapies will be coded using the MedDRA dictionary.  A concomitant medication/therapy will 
be defined as any therapy that was taken on or after the day of the first dose of study drug. This 
includes therapies that start prior to the initiation of the first dose if their use continues on or 
after the date of first dose. To define concomitant use for therapies with missing start or stop 
dates, the following additional criteria will be used: 
 If both the start and stop dates of a therapy are missing, that therapy will be considered 
concomitant. 
 If the start date of a therapy is missing and the stop date of that therapy fall on or after 
the date of the first dose, that therapy will be considered concomitant.  
 If the start date of a therapy is prior to the date of the first dose and the stop date of that 
therapy is missing and the therapy is listed as continuing, that therapy will be considered 
concomitant, or 
 If the start date of a therapy is prior to the date of the first dose and the stop date of that 
therapy is missing and the therapy is not listed as continuing, that therapy will be 
considered non-concomitant. 
For a therapy with a partial start and/or stop date, the following imputation method will be used 
to determine if the event is concomitant: 
 If the start day is missing, then impute the first day of the month (01) as the day 
 If the start day and month are missing then impute the first day of the year (01January) 
as the start day 
 If the stop day is missing then impute the last day of the month as the day 
 If the stop day and month are missing then impute the last day (31December) of the 
year as the stop day 
The number (%) of subjects taking concomitant medication and non-drug therapies will be 
summarized by treatment group. Listings of concomitant medications and non-drug therapies 
will be presented. 
AD symptomatic medications taken concomitantly at baseline are defined as AD symptomatic 
medications that were being taken at the time of the first dose, i.e., started prior to the first dose 
and continued until after the first dose. The number (%) of subjects taking AD symptomatic 
medications concomitantly at baseline will be summarized. Subjects who have any new or 
change in AD symptomatic medications after the initiation of study treatment will be 
summarized by the timing of change, i.e., the number of subjects first changing between Day 
1 and Week 24, the number of subjects changing between Week 24 and Week 52, etc., subjects 
who have changes in multiple intervals may be counted in each interval. The start and stop 
date/time of AD symptomatic medication will be listed for these subjects. 
AD symptomatic medications including the following terms will be considered: 
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Anticholinesterases, Donepezil, Donepezil hydrochloride, Galantamine, Galantamine 
hydrobromide, Huperzine A, Mimopezil, Nivabex, Rivastigmine, Rivastigmine tartrate, 
Robinulneostigmine, Tacrine, Tacrine hydrochloride, Mortha, Energix, Memantine, 
Memantine hydrochloride, Donamem, and Gemcitabine Hydrochloride. 
5.2.4 Protocol Deviations 
Protocol deviations identified during site monitoring will be captured in a Protocol Deviation 
log and categorized as major or minor deviations based on Protocol Deviation Classification. 
The major protocol deviations will be summarized and listed. The minor protocol deviations 
will also be listed. Subjects who had incorrect dose assigned by interactive response technology 
(IRT) will be summarized and listed. This data will be provided by the unblinded monitors 
after database lock.  
5.2.5 Study Drug Exposure and Study Drug Compliance 
Number of infusions (BIIB092 or placebo) received will be summarized as a categorical 
variable (categories as integers from 1 to 20, and 1-5, 6-10, 11-15, and 15-20) as well as a 
continuous variable. Number of consecutively missed infusions will be summarized as a 
categorical variable (categories as consecutively missed 2, 3, 4, >=5). Number of weeks on 
study treatment (BIIB092 or placebo), calculated as (date of last dose – date of first dose +1)/7, 
will be summarized as a categorical variable (every 8 weeks from 0 to >= 72 weeks) as well as 
a continuous variable. Percentage of study treatment taken up to the last dose, calculated as 
(the actual number of infusions / by the number of infusions a subject is expected to take until 
the date of last infusion)*100, will be summarized as a continuous variable. This table will be 
presented by treatment group.  
A listing of study drug administration records, including dose level at each infusion, cumulative 
number of infusions and cumulative dose will be provided. 
A listing of study drug administration records for placebo subjects who received any doses of 
active treatment will be provided.  
 
5.2.6 COVID-19 Related Analysis 
 
  Accounting of subjects who discontinued due to Covid-19 
Disposition of subjects will be summarized for subjects who discontinued due to Covid-19. 
The summary data will include number (%) of subjects who died due to Covid-19, AE due to 
Covid-19 and all the other reasons which led to discontinue treatment and/or study because of 
Covid-19. 
For subjects who discontinued treatment and/or withdrew from study due to covid-19, the 
reasons for discontinuation and/or withdrawal will be listed with days on treatment and days 
on study. 
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 Concomitant Non-Drug Treatment for Covid-19 
The number (%) of subjects using concomitant Non-Drug Treatment for Covid-19 will be 
summarized by treatment group.  
Date imputation will be done as per Section 5.2.3 
 
 
 Covid-19 Effect on Drug Compliance  
Effect of Covid-19 on Drug compliance may be assessed by a summary table. Total number 
of expected infusions, Number of Missed doses due to covid-19, Average missed dose per 
subject with its SD, Number of infusions delayed, Average delay in dosing per subject with 
its SD, and Number of alternate methods of infusion due to covid-19, Average alternate 
dosing per subject with its SD may be presented.  
 
 Covid-19 Protocol Deviation  
Covid-19 protocol deviation will be summarized. Number of subjects with any protocol 
deviation, list of Major protocol deviation including Non-Data protocol deviation, Not done, 
Out of window, Performed at alternate location, Performed by caregiver, Performed 
remotely, Self-administered, Rater change and Other will be presented.  
PD due to covid-19 will be listed including all major and minor deviations by treatment 
group and subject. Type of PD, PD category, PD text and deviation day will be presented in 
the listing. 
 
 Protocol Alternation Due to Covid-19  
Protocol alternation due to covid-19 will be listed by treatment group and subject. Type of 
protocol alternation, Protocol alternation category, Protocol alternation text and Alternation 
day will be presented in the listing. 
 
5.3 
Efficacy Analysis  
5.3.1 General Considerations 
The efficacy analysis will be presented by treatment group (per randomization). The change 
from baseline scores of primary efficacy and exploratory efficacy endpoints will be 
summarized by treatment group at each post-baseline visit for FAS. 
The primary, sensitivity, supplementary and additional analyses for the primary efficacy and 
exploratory efficacy secondary endpoints are listed in Table 2. 
 
Table 2. 
Analysis for Primary efficacy and exploratory efficacy Endpoints  
Endpoint 
Analysis 
Analysis Set 
CDR-SB 
Primary: Analysis of change from baseline at Week 78 
(MMRM) 
FAS 
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Primary: Dose-response (MCP-MOD) 
FAS 
Sensitivity: Censoring after intercurrent events (MMRM), 
Pattern mixture model; copy increment from reference (CIR) 
method 
FAS 
 
Per-protocol analysis (MMRM) 
Per-Protocol 
 
Additional: Responder analysis (Logistic regression) 
FAS 
 
Subgroup analysis 
FAS 
 
Slope analysis 
FAS 
MMSE, ADAS-Cog13, 
ADCS-ADL, ISLT, 
eCog, FAQ    
Primary: Analysis of change from baseline at Week 78 
(MMRM) 
Primary: Dose-response (MCP-MOD) (1) 
FAS 
 
FAS 
Subgroup analysis (2) 
FAS 
 
Slope analysis 
FAS 
EMACC, ADCOMS, 
iADRS 
Primary: Analysis of change from baseline at Week 78 
(MMRM) 
FAS 
Subgroup analysis 
FAS 
CDR individual 
domain score, CDR 
Cognitive score, CDR 
functional score, 
ADCS-ADL 
individual item score, 
ADCS-bADL, ADCS-
iADL, ADAS-Cog 13 
individual item score, 
NPI-10, ISLT, 
DKERS, DSST and 
Trails A 
Analysis of change from baseline at Week 78 (MMRM) 
FAS 
(1) MCP-MOD may be conducted for eCog, FAQ, and other endpoints as exploratory analysis. 
(2) Subgroup analysis will only be conducted for MMSE, ADAS-Cog13, ADCS-ADL. 
 
 Covid-19 consideration 
If a participant and his/her study partner is unable to attend a scheduled study visit, 
selected prioritized clinical assessments (e.g. CDR, ADCS-ADL, ISLT, DKEFS CFT 
and LFT, CSSRS) may be able to be performed via telephone. These assessments 
will be included in efficacy analysis.   
 
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5.3.2 Considerations for base MMRM model for change from baseline analyses 
A mixed model with repeated measures (MMRM) will be used to analyze changes from 
baseline in a parameter of interest using fixed effects of treatment, time, treatment-by-time 
interaction, baseline of the parameter of interest, baseline of the parameter of interest-by-time 
interaction, baseline MMSE, region (Japan and Australia will be combined), disease stage 
(MCI versus mild AD), and baseline AD symptomatic medication use.  The correlation 
between repeated measures of the outcomes will be taken into consideration.  An unstructured 
covariance matrix will be used to model the within-subject variance-covariance errors. If the 
unstructured covariance structure matrix results in a lack of convergence, the heterogeneous 
first-order autoregressive covariance structure followed by the heterogeneous Toeplitz 
covariance structure will be used. The least-squares (LS) means, the differences in LS means 
between each treatment group versus placebo at post-baseline visits, 95% confidence intervals 
(CIs), and p-values will be presented. In the primary analysis of each endpoint, missing data 
are assumed to be missing at random [Rubin 1976].  
 
5.3.3 Primary Efficacy Endpoint 
 
Primary analysis 
Estimand 1: The difference in change from baseline CDR-SB scores at Week 78 in subjects 
assigned to BIIB92, comparing to placebo group, regardless of what actual treatment is 
received, acknowledging a participant may miss >4 infusions, consecutively), change AD 
symptomatic medication and/or discontinue treatment early. 
 Analysis set: all subjects in the FAS 
 Variable: The change from baseline CDR-SB scores at Week 78 regardless of 
intercurrent events (ICEs) 
 Analysis set level summary: Least square (LS) mean difference from MMRM model 
in change from baseline between BIIB092 and placebo 
 ICEs and Strategies for Addressing ICEs:  
ICEs include 
o AD symptomatic medication change (treatment policy strategy) 
o Treatment discontinuation (treatment policy strategy) 
o Missing ≥ 4 infusions consecutively (treatment policy strategy) 
Since a treatment policy strategy will be used for all ICEs in this estimand, all observed data 
will be included regardless of miss more than or equal to four infusions consecutively, 
treatment discontinuation or AD symptomatic medication change. The primary analysis is the 
mean difference of the change from baseline CDR-SB scores at Week 78 between treatment 
groups in the FAS who have a baseline and at least one post-baseline CDR-SB score [ICH E9 
(R1) Addendum 2014, 2017]. All observed data will be included in the primary analysis, 
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including data collected after intercurrent events [ICH E9 (R1) Addendum 2017], i.e., 
treatment discontinuation or a change in concomitant use of AD symptomatic medication. 
A mixed model with repeated measures (MMRM) will be used to analyze changes from 
Baseline in CDR-SB as described in Section 5.3.2. A line plot of adjusted mean change from 
baseline over time will be provided.  
The multiple comparison procedure modelling (MCP-MOD) method (Appendix II) 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 
protocol 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. A line plot of final dose-response relationship may be provided. 
If model assumption for MMRM does not hold, nonparametric analysis will be conducted. 
 
Sensitivity analysis 
The following sensitivity analyses may be performed to assess the robustness of the primary 
analysis to deviation from the missing-at-random assumption. All the sensitivity analyses will 
be conducted for the FAS. 
Pattern mixture model 
The pattern mixture model (PMM) represents a general and flexible framework to model the 
predictive distribution of missing data conditional on the observed data [Little 1993, 1994]. It 
allows formulating assumptions regarding missing data in a transparent and clinically 
interpretable manner.  
In the PMM framework, subjects are grouped into missing patterns so that subjects in the 
same pattern share similar missingness characteristics. In this analysis, missing patterns will 
be defined according to the reasons for early withdrawal from study as reported on the 
electronic case report form (eCRF). The following two patterns will be considered: 
 Subjects who withdraw due to reasons that may be related to efficacy, including:  
o withdrawal by subject - desire for change in treatment (unrelated to safety) 
o withdrawal by subject – other 
o withdrawal by caregiver - desire for change in treatment (unrelated to safety) 
o withdrawal by caregiver - unable to continue to enable participation due to 
illness/hospitalization/death 
o withdrawal by caregiver - other 
o physician decision - unrelated to safety 
o death 
o non-compliance with study drug treatment 
o disease progression 
o other 
 Subjects who withdraw due to reasons that are unlikely related to efficacy, including:  
o adverse event  
o randomized by mistake 
o lost to follow-up  
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o pregnancy  
o withdrawal by subject - planning for pregnancy 
o withdrawal by subject - study visit burden/scheduling conflicts 
o withdrawal by subject - concern about study procedures/perceived risks 
o withdrawal by subject - relocation (moving or has moved) 
o withdrawal by caregiver - study visit burden/scheduling conflicts 
o withdrawal by caregiver - concern about study procedures/perceived risks 
o withdrawal by caregiver -relocation (moving or has moved) 
o protocol deviation 
o site terminated by sponsor 
o study terminated by sponsor 
o technical problems 
The pattern (time and rate) of study withdrawal will be displayed by Kaplan-Meier plot for 
each missing pattern within each treatment group. Subjects who withdraw due to reasons that 
may be related to efficacy will be penalized and their missing data will be imputed using the 
copy increment from reference (CIR) method [Carpenter et al. 2013]. Subjects who withdraw 
due to reasons that are unlikely related to efficacy will be handled using the missing-at-
random assumption and their missing data will be imputed using the standard multiple 
imputation method [Rubin 1987]. Subjects that do not have change from baseline CDR-SB at 
Week 78 due to reasons other than early withdrawal (such as item missing, out of window, 
etc.) will be handled using the missing-at-random assumption. For both imputation methods, 
the following covariates will be included in the imputation model: treatment, baseline of the 
parameter of interest, baseline MMSE, region, disease stage (MCI versus mild AD), and 
baseline AD symptomatic medication use.  
The imputed datasets will be analyzed by an analysis of covariance (ANCOVA) model 
adjusting fixed effects of treatment, baseline of the parameter of interest, region, disease stage 
(MCI versus mild AD), baseline MMSE, and baseline AD symptomatic medication use. The 
analyzed results from the imputed datasets will be combined based on Rubin’s rules [Rubin 
1987] assuming that the statistics estimated from each imputed dataset are normally 
distributed. 
If intermediate missing values are encountered (such as data missing at Week 26 but are 
available at subsequent visits), a Markov chain Monte Carlo (MCMC) method that assumes 
multivariate normality will be used to impute the intermediate missing values and produce a 
monotone missing pattern (data with only terminal missing and no intermediate missing) [Li 
1988; Schafer 1997]. 
Copy increment from reference method 
The copy increment from reference (CIR) method may be applied to impute the post-
withdrawal data for any BIIB92 treated subject who withdraws from study early based on 
data from the placebo group rather than the subject’s own randomized treatment group 
[Carpenter et al. 2013]. Specifically, for a subject on BIIB92 who withdraws early, his or her 
mean trajectory after early withdrawal is assumed to be parallel to the mean trajectory of the 
placebo group, and the difference between the two means is the same as the difference at the 
time of withdrawal. This method assumes that any benefit gained from previous treatment 
will be retained, but subjects progress as if they were on placebo after withdrawal from study. 
For any subject on placebo who withdraws early, his or her post-withdrawal profile will be 
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imputed following the missing-at-random principle. After all missing data have been 
imputed, an ANCOVA model adjusting treatment group, baseline of the parameter of 
interest, baseline MMSE, region, disease stage (MCI versus mild AD), and baseline AD 
symptomatic medication use will be applied to analyze the change from baseline of CDR-SB. 
 
Censoring after intercurrent events  
Estimand 2: The treatment effects of BIIB92 had all participants never missed >4 infusions 
consecutively, change AD symptomatic medication and/or discontinue treatment early 
 Analysis set: all subjects in the FAS 
 Variable: The change from baseline CDR-SB scores at Week 78 with data after ICEs 
are set to missing 
 Analysis set level summary: Least square (LS) mean difference from MMRM model 
in change from baseline between BIIB92 and placebo 
 ICEs and Strategies for Addressing ICEs:  
ICEs include 
o AD symptomatic medication change (hypothetical strategy) 
o Treatment discontinuation (hypothetical strategy) 
o Missing more > 4 infusions consecutively (hypothetical strategy) 
 
The estimand of this analysis reflects the treatment effect of BIIB092 if the drug is taken as 
directed. The primary analysis for Estimand 1 will be repeated with the data censored after any 
of the following intercurrent events (if multiple events occur to the same subject, data after the 
earliest event will be censored): 
o premature discontinuation of the study treatment 
o any change to concomitant AD symptomatic medications after the initiation of study 
treatment 
o missing more than or equal to four infusions consecutively 
 
 
 
Per-protocol analysis 
Estimand 3: The treatment effect of BIIB92 in subjects included in PPS regardless if subjects 
discontinue treatment early 
 Analysis set: all subjects in the PPS 
 Variable: The change from baseline CDR-SB scores at Week 78 regardless of 
intercurrent events (ICEs) 
 Analysis set level summary: Least square (LS) mean difference from MMRM model 
in change from baseline between BIIB92 and placebo 
 ICEs and Strategies for Addressing ICEs:  
ICEs include 
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o Treatment discontinuation (treatment policy strategy) 
Since a treatment policy strategy will be used for all ICEs in this estimand, all observed data 
will be included regardless of treatment discontinuation early.  
The per-protocol analysis will be done using the same model as the primary analysis (Section 
4.3.2.1) and applying in the Per-Protocol Analysis Set (Section 3.5).  
 
5.3.4 Exploratory Efficacy Endpoints 
The clinical endpoints assessing AD progression from Baseline include the results of the 
MMSE, ADAS-Cog13, ADCS-ADL, ISLT, DKEFS Category Fluency, DKEFS Letter 
Fluency, DSST, Trails A, eCog, FAQ, NPI-10, iADRS, EMACC and ADCOMS.  
A mixed model with repeated measures (MMRM) may be used to analyze changes from 
Baseline as described in Section 5.3.2. A line plot of adjusted mean change from baseline over 
time will be provided. 
For MMSE, ADAS-Cog13, ADCS-ADL, ISLT, eCog, FAQ, and other exploratory efficacy 
endpoints multiple comparison procedure modelling (MCP-MOD) method (Appendix II) may 
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 Section16.10) while controlling for multiplicity.  The dose-response parameter of 
interest for MCP-MOD will be the LS means at Week78 for each dose group from the mixed-
effects model.  Pairwise comparisons of each BIIB092 dose group versus placebo will also be 
conducted. A line plot of final dose-response relationship will be provided. 
5.3.5 Subgroup Analysis 
Subgroup analyses will be performed for the primary endpoint (CDR-SB) and exploratory 
endpoints (e.g. MMSE, ADAS-Cog13, ADCS-ADL, iADRS, EMACC, and ADCOMS). The 
subgroups to be considered are in Section 3.4.  
Subjects in each subgroup category will be analyzed separately using the same mixed model 
with repeated measures (MMRM) used to analyze changes from Baseline as described in 
Section 5.3.2.  A forest plots of adjusted mean change from baseline at Week 78 will be 
provided. 
 
5.3.6 Additional Analysis 
 
CDR Subscores, CDR Global Score, ADCS-bADL, ADCS-iADL and 
individual scores for CDR, ADCS-ADL and ADAS-Cog 13 
The CDR is comprised of 6 domains: Memory, Orientation, Judgment and Problem Solving, 
Community Affairs, Home and Hobbies, and Personal Care. CDR-SB is the sum of the scores 
for these 6 domains. In addition, two CDR subscores have been proposed [Tractenberg 2005]: 
a “cognitive” subscore equaling the sum of the Memory, Orientation, and Judgment and 
Problem Solving box scores, and a “functional” subscore equaling the sum of Community 
Affairs, Home and Hobbies and Personal Care box scores. For each of the 6 domains, and the 
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CDR cognitive subscore and CDR functional subscore, the actual value and the change from 
baseline at each visit will be summarized by treatment group. The same MMRM model as the 
primary analysis will also be applied to the CDR individual domains, cognitive subscore and 
CDR functional subscore. 
The CDR global score is a composite score obtained by combining the 6 sub-domain scores 
using a scoring algorithm that weights memory as the primary domain and all other domains 
as secondary [Morris 1993]. The actual and change from baseline in CDR global score will be 
summarized (as a categorical variable) by treatment group at each visit. In addition, subjects 
with ≥ 0.5 worsening in CDR global score may be summarized by treatment group at each 
post-baseline visit. 
ADCS-ADL basic total score (ADCS-bADL) and ADSL-ADL instrumental total score 
(ADCS-iADL) will also be calculated in addition of ADCS-ADL total score. ADCS-bADL, 
which contains 6 out of 23 ADCS-ADL items, is measuring the basic self-care tasks which are 
generally recognizable in all cultures such as feeding, mobility, toileting, bathing, grooming 
and dressing. The measure and conceptualization of ADCS-iADL, which contains 17 out of 23 
ADCS-ADL items, is more complex due to the influence of cultural norms and gender roles 
that may impact which tasks are even attempted by a patient. As such, scales that measure 
iADLs tend to include a broad range of activities. The same MMRM model as the primary 
analysis will also be applied for ADCS-ADL, ADCS-ADL individual items, ADCS-bADL and 
ADCS-iADL.  
Similarly, the same MMRM model used for ADAS-Cog 13, will be applied for ADAS-Cog 13 
individual items. 
 
Slope analysis 
Slope analysis will be conducted to assess the difference between each BIIB092 treatment 
group and placebo in the slope of clinical measures from baseline up to Week 78. A reduction 
in the slope of clinical worsening in the BIIB092 treatment group compared with placebo 
would indicate a slower rate of disease progression, thus reflecting a disease modifying effect 
of BIIB092. This analysis will be conducted for the CDR-SB, MMSE, ISLT, eCog, ADCS-
ADL, FAQ, ADAS-Cog 13, NPI-10, and may be conducted for other exploratory endpoints. A 
linear mixed model will be used, with change from baseline as dependent variable at each visit 
and with fixed effects of treatment, time (as a continuous variable), treatment-by-time 
interaction, baseline of the parameter of interest, baseline of the parameter of interest-by-time 
interaction, baseline MMSE, region, disease stage (MCI versus mild AD), and baseline AD 
symptomatic medication use.  Random intercept and slope will also be included in the model 
to characterize subject-specific progression. In addition, a quadratic linear mixed model may 
also be fitted to address potential non-linearity associated with natural disease progression 
and/or non-constant treatment effect over the treatment course. 
 
 
Summary of CDR-SB, ADAS-Cog 13 total score, and MMSE by tau PET 
reduction at Week 78 
Subjects may be separated into 2 subgroups based on the magnitude of change on tau PET 
measures for the primary target and reference regions at Week 78: (1) change from baseline 
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less than (mean - one standard deviation) of the placebo group at Week 78; (2) change from 
baseline greater than or equal (mean - one standard deviation) of the placebo group at Week 
78.  MMRM model or by visit summaries for CDR-SB, ADAS-Cog 13 total score, and 
MMSE may be conducted on these 2 subgroups by treatment groups.  
 
 
Responder analysis of CDR-SB  
To further assess whether subjects on BIIB092 progress differently from those on placebo, 
responder analysis may be conducted. The responders will be determined by a threshold of 
the primary endpoint, i.e., subjects whose change from baseline CDR-SB at Week 78 is 
smaller than the threshold will be classified as responders and otherwise will be classified as 
non-responders. All subjects with missing data at Week 78 will be classified as non-
responders. 
The continuous responder curve that displays the percentage of responders under a wide 
range of threshold values will be presented by treatment group.  The responder analysis may 
be conducted for threshold value 0.5 or 1.5, i.e., subjects whose change from baseline CDR-
SB at Week 78 ≤ 0.5 may be classified as responders. The number of responders and the 
response rate may be summarized by treatment group. In addition, the dichotomized 
response, responder vs. non-responder, may be modeled using a logistic regression with the 
covariates: fixed effects of treatment, baseline of CDR-SB, baseline of MMSE, region, 
disease stage (MCI versus mild AD), and baseline AD symptomatic medication use (Y/N). 
Since all missing data will be considered as non-response, which is a special form of missing-
not-at-random, this analysis can provide additional insights for the robustness of the primary 
analysis results. 
5.4 
Safety Analysis  
5.4.1 General Considerations 
For subjects who enrolled in LTE period, AEs and SAEs started after Week 78 will be 
entered and reported in LTE period.  
 
 Analysis Set 
The Safety Analysis Set will be used for safety analyses of AEs, SAEs, clinical laboratory data, 
Columbia Suicide Severity Rating Scale (C-SSRS) data, ECG data and vital sign data.  The 
safety MRI evaluable set will be used for the analysis of safety MRI data. 
 
 Safety treatment groups  
Different from the randomization treatment groups, if a subject who was randomized to placebo 
group accidentally received one or more doses of the active treatment during the study, he/she 
will be classified as either low (BIIB092 125 mg/4wk or BIIB092 375 mg/12wk), medium or 
high dose group according to the majority of active treatment dose he/she received, for all the 
safety analyses (Section 3.5). If a subject randomized to BIIB092 treatment groups but received 
all placebo throughout the study, this subject will be counted in placebo group. A listing of 
such subjects will be provided, as described in Section 5.2.5.  Safety treatment groups will be 
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the same as the randomization treatment groups for other subjects (subjects randomized to 
active treatment groups, and subjects randomized to placebo without any accidental active 
dose).  
 
 Incidence, incidence proportion and incidence rate 
 Incidence and incidence proportion will be provided in incidence tables. Incidence is 
defined as the number of subjects who experienced an event. Incidence proportion is 
defined as the number of subjects who experienced an event divided by total number of 
subjects in the analysis set, i.e., percentage. Each subject will be counted only once within 
each category. 
 Incidence and incidence rate will be provided in incidence rate tables. Incidence rate of an 
event based on the entire follow-up time – defined as the number of subjects who 
experienced an event divided by the total of entire follow-up time among the subjects in 
the analysis set (e.g., incidence rate per 100 subject-years). The entire follow-up time for a 
subject (subject-years) is defined as the sum of all subjects’ follow-up time, where a 
subject’s follow-up time is calculated as the number of days (inclusive) from first dose of 
study drug until the last day on study, divided by 365.25. Each subject will be counted only 
once within each category.  
5.4.2  Clinical Adverse Events 
 
 Treatment-emergent AEs (TEAEs) 
All AEs will be analyzed based on the principle of treatment emergence.  A treatment-emergent 
AE is defined as an AE that started or worsened after the start of first infusion of study 
treatment.  
To define treatment emergence for AEs with missing start or stop date or time the following 
additional criteria will be used: 
 if both the start and stop dates for a particular AE are missing, then that AE is considered 
treatment emergent 
 if the start date for a particular AE is missing and the stop date/time falls after the first dose 
date/time, then that AE is considered treatment emergent 
 if the start date for a particular AE was the same as the first dose date, and the start time 
was missing, then that event is considered treatment emergent 
For AEs with a partial start date, the following imputation method will be used to determine if 
the event is treatment emergent: 
 When only the day is missing, and the year/month is equal to the year/month of first dose 
date, and the AE stop date is missing or on/after the first dose date, then use the first dose 
date as AE start date. Otherwise impute the AE start date as the first day (1) of the AE start 
month 
 When the AE start month is missing, and the year equals to the year of first dose date, and 
the AE stop date is missing or on/after the first dose date, then use the first dose date as AE 
start date. Otherwise impute the AE start date as the first day (01January) of the AE start 
year 
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For AEs with a partial end date, the following imputation method will be used: 
 When only the day is missing, and the year/month equal to the year/month of the last date 
on study, then use the last date on study as AE stop date. Otherwise impute the AE stop 
date as the last day of the AE stop month 
 When the AE stop month is missing, and the year equals to the year of last date on study, 
then use the last date on study as AE stop date. Otherwise impute the AE stop date as the 
last day (31December) of the AE stop year 
Only TEAEs will be included in the tables, unless otherwise specified. All SAEs (including 
pre-dosing SAEs) and AEs (including pre-dosing AEs related to tau PET) will be included in 
the listing, with an indicator of pre-dosing or treatment emergent. 
 
Summary and incidence analysis 
Overall summary of AE table will summarize the number of subjects with any AE, with any 
AE by maximum severity, the number of subjects with any related AE (related to study drug 
as assessed by investigator), the number of subjects with SAE, the number of subjects with 
related SAE, the number of subjects with AE leading to drug withdrawal, the number of 
subjects with AE leading to of subjects with a fatal event. This table will be done by treatment 
group. 
The sorting order for AE incidence tables, unless otherwise specified, will be by decreasing 
frequency order of “BIIB092 total” column within each category in the tables presented by 
treatment group. A subject is counted only once within each category in each table. For 
example, for the table of AEs by system organ class and preferred terms sorted by decreasing 
frequency presented by treatment group, system organ class will be presented in decreasing 
frequency order of BIIB092 total column, and within each system organ class, preferred terms 
will be presented in decreasing frequency order of BIIB092 total column. A subject is counted 
only once within each system organ class and preferred term.  
The following AE incidence tables will be provided (presented by treatment group, unless 
otherwise specified): 
1. AEs by system organ class and preferred term sorted by decreasing frequency  
2. AEs by system organ class and preferred term sorted by alphabetical order  
3. AEs by system organ class 
4. AEs at least 2% higher in incidence by system organ class and preferred term for 
BIIB092 2000 mg/4wk compared to placebo 
5. AEs by preferred term 
6. Adverse events with an incidence of 5% or more in any treatment group by preferred  
term  
7. AEs by maximum severity by system organ class and preferred term by decreasing 
frequency (System organ class will be presented alphabetically. Preferred terms will be 
presented in decreasing frequency order. Maximum severity will be presented within 
each preferred term in the order of mild, moderate, severe, unknown and total. A subject 
will be counted only once at the maximum severity within each system organ class and 
preferred term.)  
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8. AEs by maximum severity by preferred term 
9. Severe AEs by system organ class and preferred term by decreasing frequency 
10. Severe AEs by preferred term 
11. Related AEs by system organ class and preferred term by decreasing frequency 
12. AEs related to tau PET ligand by system organ class and preferred term by decreasing 
frequency (Subjects in tau PET evaluable set) 
13. SAEs by system organ class and preferred term by decreasing frequency 
14. SAEs by preferred term 
15. Related SAEs by system organ class and preferred term by decreasing frequency 
16. SAEs with fatal outcome by system organ class and preferred term by decreasing 
frequency 
17. AEs that led to drug interrupted by system organ class and preferred term by decreasing 
frequency 
18. AEs that led to discontinuation of study treatment by system organ class and preferred 
term by decreasing frequency 
19. AEs that led to withdrawal from study by system organ class and preferred term by 
decreasing frequency 
20. AEs related to lumbar puncture (LP) by system organ class and preferred term (Subjects 
in CSF PD evaluable set)  
 
The following listings will be provided.  
1. Listing of AEs 
2. Listing of SAEs (including pre-dosing SAEs) 
3. Listing of AEs that led to infusion interruption 
4. Listing of AEs that led to discontinuation of study drug 
5. Listing of AEs that led to withdrawal from study 
6. Listing of AEs related to tau PET ligands 
7. Listing of SAEs with fatal outcome 
8. Listing of AEs related to lumbar puncture (LP)  
9. Listing of death 
 
Incidence rate analysis 
Follow-up adjusted incidence rate of AEs for the placebo-controlled period may be 
summarized by SOC and PT as below 
 Incidence rate of an event based on the entire follow-up time – defined as the number 
of subjects who experienced an event divided by the total of entire follow-up time 
among the subjects in the analysis population. The entire follow-up time for a subject 
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is defined as the time from the first dose until the last day on study. Each subject will 
be counted only once within each category. 
 
 
Infusion reactions  
Infusion reactions will be identified through 1) temporal association, defined as those adverse 
events which occur on the day of an infusion or the subsequent two calendar days after an 
infusion; and 2) through a custom MedDRA search of preferred terms. A serious infusion 
reaction is a serious adverse event which is identified by one or both methods. An overall 
summary of infusion reactions will be provided with the number of subjects (n, %) with any 
infusion reaction; with any infusion reaction identified by temporal association only; with any 
infusion reaction identified through the custom search (Appendix V) only; and any infusion 
reaction identified through both methods. A listing of infusion reactions will be provided. 
Additionally, the following incidence proportion tables will be provided: 
 
1. Infusion reactions that occurred in temporal association to an infusion by SOC and PT  
2. Serious infusion reactions that occurred in temporal association to an infusion by SOC 
and PT  
3. Infusion reactions identified through custom search criteria by PT 
4. Serious infusion reactions identified through custom search criteria by PT 
5. Infusion reactions (temporal association or custom search) by 12-week intervals by PT 
 
Adverse event of special interest 
Anti-drug antibody is an AESI in the BIIB092 clinical development program. Adverse events 
representing potential immune/hypersensitivity reactions will be identified using customized 
MedDRA search criteria, including: Anaphylactic reaction SMQ narrow, Allergic conditions 
NEC HLT, and miscellaneous PTs. Further details are given in (Appendix IV)10  
  
An incidence proportion table for potential immune/hypersensitivity reactions by PT, and 
similarly for potential immune/hypersensitivity reactions for subjects with and without 
treatment emergent positive anti-drug antibody (ADA) results (as defined in Section 5.7) by 
PT may be presented. A listing of potential immune/hypersensitivity reactions will be 
provided.  
 
The following analyses (incidence proportion only) may be performed to explore the 
relationship between ADAs and the safety of BIIB092: 
 AEs for subjects with and without positive treatment emergent ADAs 
 SAEs for subjects with and without positive treatment emergent ADAs 
5.4.3 Clinical Laboratory Data 
The following clinical laboratory parameters are assessed in the protocol: 
 Hematology: red blood cell count, platelet count, hemoglobin level, hematocrit, mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
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concentration, and total white blood cell count with absolute counts and percentages of 
neutrophils, monocytes, lymphocytes, eosinophils, and basophils 
 Blood chemistry: total protein, albumin, creatinine, BUN, uric acid, bilirubin (total and 
direct), alkaline phosphatase, ALT, AST, lactate dehydrogenase, gamma-glutamyl 
transferase, glucose, calcium, phosphorus, bicarbonate, chloride, sodium, and potassium 
 Urinalysis: color, specific gravity, pH, protein, glucose, leukocyte esterase, blood, and 
ketones (and microscopic examination, if abnormal) 
 Coagulation: Activated Partial Thromboplastin Time (APTT), Prothrombin Intl. 
Normalized Ratio (INR), Prothrombin Time (PT) 
All the laboratory tables and listings, unless otherwise specified, will be presented by treatment 
group. 
 
 
Quantitative analyses  
For numeric laboratory parameters, actual values, change from baseline and percent change 
from baseline will be summarized by visit. number of evaluable subjects, mean, standard 
deviation, 25% and 75% quartiles, min and max values will be presented at each visit. 
For coagulation, only actual value summaries will be presented.  
Plots of actual values and change from baseline for numeric laboratory parameters at each visit 
will be provided.  
Listings of individual laboratory measurements by patients for all the parameters will be 
provided.  
 
Visit Windows for by visit summaries 
For Laboratory data that are summarized by visit, assessment from all scheduled visits, EOT 
visit, EOS visit and unscheduled visits will be mapped to an appropriate analysis visit using a 
windowing scheme (Appendix I). 
 
 
Qualitative analyses 
For all qualitative analyses, all values will be included (not just the “analyzed record” within 
each visit window in the quantitative analyses). 
Shift analyses 
Laboratory data will be summarized using shift tables where appropriate.  Each subject’s 
hematology, blood chemistry and urinalysis values will be flagged as “low”, “normal”, or 
“high” relative to the normal ranges of the central laboratory or as “unknown” if no result is 
available.   
For each parameter, the analysis will be based on subjects with at least one post-baseline value.  
Shifts from baseline to high/low status will be presented for hematology, blood chemistry 
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coagulation, serology, and urinalysis.  Shift to low includes normal to low, high to low, and 
unknown to low; Shift to high includes normal to high, low to high, and unknown to high. 
Subjects need to have at least one post-baseline evaluation and a baseline value not low or high 
(including missing) in order to be included in the analysis for corresponding categories in the 
analyses. 
Potentially Clinically Significant laboratory abnormalities analyses 
For hematology, blood chemistry and urinalysis, the number of subjects with potentially 
clinically significant laboratory abnormalities post-baseline will be summarized for the 
parameters provided in Table 3.  Subjects need to have at least one post-baseline evaluation 
and a baseline value not potentially clinically significant (including missing) in order to be 
included in the analysis.  
Table 3. 
Criteria to Determine Potentially Clinically Significant (PCS) Laboratory 
Abnormalities 
Clinical Laboratory Outlier Criteria 
Parameter name  
PCS Low 
PCS High 
 
HEMATOLOGY  
White blood cells  
<3.0 x 109/L  
>16 x 109/L  
Lymphocytes  
<0.8 x 109/L  
>12 x 109/L  
Neutrophils  
<1.5 x 109/L  
>13.5 x 109/L  
Monocytes  
N/A  
>2.5 x 109/L  
Eosinophils  
N/A  
>1.6 x 109/L  
Basophils  
N/A  
>1.6 x 109/L  
Red blood cells  
≤3.5 x 1012/L 
≥6.4 x 1012/L 
Hemoglobin - Females  
≤95 g/L  
≥175 g/L  
Hemoglobin - Males  
≤115 g/L  
≥190 g/L  
Hematocrit - Females  
≤32%  
≥54%  
Hematocrit - Males  
≤37%  
≥60%  
Platelet count  
≤75 x 109/L 
≥700 x 109/L 
BLOOD CHEMISTRY  
Alanine aminotransferase (ALT)  
N/A  
>3 x ULN  
Aspartate aminotransferase (AST)  
N/A  
>3 x ULN  
Alkaline phosphatase (ALP) 
N/A  
>3 x ULN  
Total bilirubin  
N/A  
>1.5 x ULN  
Blood urea nitrogen (BUN)  
N/A  
≥10.7 mmol/L  
Creatinine  
N/A  
≥176.8 umol/L  
Sodium  
≤126 mmol/L  
≥156 mmol/L  
Potassium  
≤3 mmol/L  
≥6 mmol/L  
Chloride  
≤90 mmol/L  
≥118 mmol/L  
Bicarbonate  
≤16 mmol/L  
≥35 mmol/L  
Glucose  
≤2.2 mmol/L  
≥9.7 mmol/L  
Calcium  
≤2 mmol/L  
≥3 mmol/L  
Phosphorus  
≤0.6 mmol/L  
≥1.7 mmol/L  
Albumin  
≤25 g/L  
≥625 g/L 
Total protein  
≤45 g/L  
≥100 g/L  
URINALYSIS  
Glucose  
N/A  
≥ ++++  
Ketones  
N/A  
≥ ++++  
Protein  
N/A  
≥ ++ 
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Clinical Laboratory Outlier Criteria 
Parameter name  
PCS Low 
PCS High 
 
ULN = upper limit of normal  
 
Potential serious hepatotoxicity 
Potential serious hepatotoxicity is defined as ALT or AST > 3x ULN and total bilirubin > 2x 
ULN at any time post-baseline, not necessarily concurrent. A scatterplot of the maximum post-
baseline ALT or AST value relative to ULN and maximum post-baseline total bilirubin value 
relative to ULN (not necessarily concurrent) for each subject will be provided. A line plot of 
ALT, AST, ALP and total bilirubin values over time for subjects with potential serious 
hepatotoxicity will be provided. In addition, a summary of subjects with ALT > 1x ULN, >3x 
ULN, >5x ULN, >10x ULN or >20x ULN, subjects with AST > 1x ULN, >3x ULN, >5x ULN, 
>10x ULN or >20x ULN, subjects with total bilirubin >1x ULN or >2x ULN, subjects with 
ALP >1x ULN or >1.5x ULN, and subjects with AST or ALT > 3x ULN post-baseline 
accompanied by concurrently elevated total bilirubin >1.5x ULN or > 2x ULN will be 
presented. A listing of subjects with potential serious hepatotoxicity will be provided with the 
concurrent records labeled. Concurrent is defined as on the same day. 
5.4.4 C-SSRS Data 
Suicide-related events based on the Columbia Suicide Severity Rating Scale (CSSRS) at post-
baseline visits will be summarized by treatment group. Suicidal ideation events include: (1) 
Wish To Be Dead, (2) Non-Specific Active Thoughts, (3) Active Thoughts Without Intent To 
Act, (4) Active Thoughts With Some Intent—No Plan, (5) Active Thoughts with Plan and 
Intent. Suicidal behavior events include: (6) Preparatory acts or behavior, (7) Aborted Attempt, 
(8) Interrupted Attempt, (9) Actual Attempt, (10) Suicidal behavior, (11) Completed Suicide. 
Another “Yes/No” question of whether the subject has engaged in non-suicidal self-injurious 
behavior is also collected. The analysis will be based on the Safety Analysis Set.   
Number of subjects in each ideation category at any post-baseline visit, number of subjects in 
each suicidal ideation and suicidal behavior category at any post-baseline visit, number of 
subjects with at least one suicidal ideation or behavior event at any post-baseline visit, and 
subjects who have engaged in non-suicidal self-injurious behavior at any post-baseline visit 
will be summarized. A listing of subjects with suicide-related events will be provided.  
5.4.5 ECG Data 
Actual and change from baseline values of numeric ECG parameters will be summarized by 
visit. number of evaluable subjects, mean, standard deviation, 25% and 75% quartiles, min and 
max values will be presented at each visit. 
Summary of ECGs (number of normal, <abnormal, not adverse event>, or <abnormal, adverse 
event>) at scheduled visits will be presented by treatment group.   
Shift table from normal or unknown ECG at baseline to abnormal post-baseline ECG 
(<abnormal, not adverse event>, or <abnormal, adverse event>) will be summarized.  
Denominator will be number of subjects who have a baseline value not abnormal (including 
unknown) and at least one post-baseline value.  
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In addition, PR and QTcF values will be summarized for below categories: 
o QTcF interval (msec) at post-baseline in below categories:  
 >450  
 >480  
 >500 
o QTcF increase from baseline (msec) in below categories: 
 >30  
 >60 
o PR interval (msec) at post-baseline in below categories: 
 ≤ 200  
 > 200  
 
 
Visit Windows for By Visit Summaries 
For ECG data that are summarized by visit, assessment from all scheduled visits, EOT visit, 
EOS visit and unscheduled visits will be mapped to an appropriate analysis visit using a 
windowing scheme (Appendix I).   
5.4.6 Vital Sign Data 
Vital sign parameters include temperature, diastolic blood pressure, systolic blood pressure, 
heart rate, and respiration rate. The descriptive statistics for actual values and change from 
baseline will be summarized over time for each treatment group. Plot of mean vital sign values 
at each visit will be provided. Vital signs will be measured with the subject supine and after 
the subject has been resting for at least 10 minutes. A by-patient listing will also be presented. 
The analysis of vital signs will also focus on the incidence of clinically relevant outliers based 
on the following criteria (Table 4 – study specific and Table 5 – required by STAN V2). The 
number of clinically relevant outliers determined by each criterion will be summarized by 
treatment group. 
 
Table 4. 
Criteria Used to Assess Potential Clinically Relevant Outliers in Vital Signs 
Variable 
Low 
High 
Systolic Blood Pressure 
<90 mm Hg post-BL or ≥20 mm Hg 
decrease from Baseline (BL) 
>180 mm Hg post-BL or ≥20 mm 
Hg increase from BL 
Diastolic Blood Pressure 
<50 mm Hg post-BL or ≥15 mm Hg 
decrease from BL 
>105 mg Hg post-BL or ≥15 mm 
Hg increase from BL 
Heart Rate 
<50 bpm post-BL or ≥15 bpm 
decrease from BL 
>120 bpm post-BL or ≥15 bpm 
increase from BL 
Temperature 
>2 degree C decrease from BL 
>38 .5 ̊C or >2 ̊C increase from BL 
Respiration Rate 
< 10 breaths per minute or > 50% 
decrease from BL 
>25 breaths per minute or >50% 
increase from BL 
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BL= baseline; bpm = beats per minute 
 
 
Table 5. 
Criteria for post-baseline vital sign abnormalities 
Variable 
Criteria 
Temperature 
<36 degrees C 
>38 degrees C 
Heart rate 
<60bpm 
>100bpm 
Systolic blood pressure 
<90 mmHg 
>140 mmHg 
>160 mmHg 
Diastolic blood pressure 
<50 mmHg 
>90 mmHg 
>100 mmHg 
Weight 
7% or more increase from BL 
7% or more decrease from BL 
Respiratory rate 
<12 breaths/min 
>20 breaths/min 
BL= baseline; bpm = beats per minute 
 
The number of subjects evaluated and the number and percentage of subjects with clinically 
relevant outliers will be presented by treatment group.   
Visit Windows for By Visit summaries 
For vital sign data that are summarized by visit, assessment from all scheduled visits, EOT 
visit, EOS visit and unscheduled visits will be mapped to an appropriate analysis visit using a 
windowing scheme (Appendix I).   
5.4.7 Physical Examination 
Since clinically significant findings during physical examinations will be recorded as AEs, a 
listing of physical examination data will be presented.  
5.4.8 Neurological Examination 
Since clinically significant findings during neurological examinations will be recorded as AEs, 
a listing of neurological examination data will be presented.  
5.4.9 Safety MRI Data 
The following MRI data will be summarized by treatment group using safety MRI evaluable 
set: 
 Number of subjects with new or worsening of vasogenic edema (VE) at post-baseline 
o New VE or questionable VE is considered as subjects who has a VE which is 
worsening as post-baseline or for the following: 
- 
The subject has answered “Not-Applicable” at any post-baseline visit for 
question: VE on this MRI as compared to previous MRI 
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- 
The subject has answered “VE present and increased in size” at any post-
baseline visit for question: VE on this MRI as compared to previous MRI 
o Worsening of VE from baseline is defined as any severity increase compared to 
baseline. The following sequence indicates the increase of the severity: 
No VEVE present < Questionable presence of VE (VE (Mild Severity) < 
Questionable presence of VE (Moderate Severity) < Questionable presence of VE 
(VE (Severe Severity) < VE present ((Mild Severity) < VE present ((Moderate 
Severity) < VE present (Severe Severity) 
 Number of subjects with new microhemorrhages (mH) findings at post-baseline 
o New mH is define as subjects who has mH increased in number and/or size at any 
post-baseline comparing to the baseline. If a subject has no mHs at baseline, then 
new mH is defined as any initial identification at any post-baseline visit. 
 Number of subjects with macrohemorrhages (MA) (>1cm) at post-baseline 
 Number of subjects with superficial siderosis (SS) (>1cm3) at post-baseline 
 Number of subjects with SS (≤1cm3) at post-baseline 
5.4.10 COVID-19 Related Safety analysis 
Overall summary of COVID-19 adverse events will be presented. Number of subjects with 
Covid-19 AE, severity, related events, serious events, related serious events, events leading to 
drug withdrawal, events leading to study discontinuation and AE with Fatal outcomes may be 
included in the summary.  
AEs by system organ class and preferred term sorted by decreasing frequency will also be 
presented. 
5.5 
Pharmacokinetics Analysis  
The Serum PK evaluable set as defined in Section 3.5, will be used for the description of the 
serum concentration data, and for the estimation of serum PK parameters. The CSF PK 
evaluable set as defined in Section 3.5, will be used for the description of CSF concentration 
data. PK analysis will be conducted with serum and CSF concentrations of BIIB092 by visit 
and dose group. Subjects who receive BIIB092 125mg once every 4 weeks will be analyzed 
separately from those who receive 375mg once every 12 weeks. For subjects whose serum and 
CSF sample collected after LTE first infusion will be excluded. 
Atypical drug concentrations (e.g., very low or very high) will be excluded from the analysis, 
if no apparent explanation exists.  Concentration observations will also be removed from the 
data set if 
i) 
corresponding dosing or sampling times are missing or cannot be reconstructed,  
ii) 
large deviations between actual administered dose and nominal dose exists,  
iii) 
large deviations between scheduled and actual sampling days or times exists, 
iv) 
large deviations between actual and nominal dose administration time exists.   
All deletions of data points will be appropriately documented.  
Population PK analysis may be conducted to estimate BIIB092 population PK parameters and 
to identify potential covariates (e.g., demographics, body weight, and anti-BIIB092 antibodies) 
on the variability of BIIB092 PK.  Results will be presented in a separate report. 
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In addition, an exposure-response (E-R) analysis will be conducted by Pharmacometrics 
group to detect any E-R relationship trend and potential covariate using any primary or 
secondary endpoint and BIIB092 exposure metrics as deemed appropriate.  Other tables and 
figures based on the population PK and E-R analyses will be generated by Clinical 
Pharmacology and Pharmacometrics (CPP) team and will be included in a separate report from 
CPP.  This analysis may not be included in the CSR. 
5.5.1 Serum and CSF PK Concentration Data 
Individual serum and CSF concentrations will be listed for BIIB092. Concentrations below the 
lower limit of quantification (LLOQ) will be indicated by “BLQ”. Differences between 
scheduled and actual sampling times may be listed for these subjects, along with the percentage 
differences between nominal and actual dose amount. Additional listings may be generated as 
deemed necessary. 
Descriptive statistics (N, arithmetic mean, standard deviation, geometric mean, CV, median, 
minimum, and maximum), will also be used to summarize serum PK and CSF concentrations 
of BIIB092 by visit/scheduled time points and dose group. For the purpose of calculating 
typical descriptive statistics (n, mean, SD, %CV, geometric mean, geometric %CV, median, 
minimum, and maximum) for serum PK, BLQ value on pre-day 1 of study treatment will be 
set to 0, and all post first dose of study treatment BLQ values will be set to half the LLOQ 
value. In linear and semi-logarithmic plots, all BLQ values will be treated as LLOQ/2. Mean 
CSF concentrations that are BLQ will be presented as BLQ, and the SD and %CV will be 
reported as not applicable.  When summarizing concentrations or PK parameters in serum and 
CSF, a minimum of 2 values are required to show the arithmetic mean and geometric mean, 
and at least 3 values are required to show the standard deviation and coefficient of variation 
(CV).    
Serum and CSF concentrations of BIIB092 will be plotted versus time by dose group on both 
a linear and a logarithmic scale.  Additional plots may be included as deemed necessary.  
CSF to serum concentration ratio will be computed using pre-infusion concentrations at week 
12, 48, and 76. Individual ratios along with descriptive statistics (N, arithmetic mean, standard 
deviation, geometric mean, CV, median, minimum, and maximum) at 12, 48, and 76 weeks, 
by dose will be listed. Any BLQ value will be excluded from CSF to serum ratio calculation, 
and exclusions will be appropriately documented. Individual CSF vs. serum concentrations 
above LLOQ (for both serum and CSF) will be plotted (scatter plot) by week, color coded by 
dose.  
5.5.2 Serum PK Parameters 
The following PK parameters will be listed per visit, as data permits, from serum concentration 
data: 
Parameter  
Definition/Calculation  
Units  
Cmax  
Observed maximum serum BIIB092 concentration collected at end 
of infusion 
ug/mL  
Ctrough 
Observed troughtrough serum BIIB092 concentration collected at 
end of dosing interval (before next infusion starts) 
ug/mL  
Individual PK parameter data will be listed. Descriptive statistics (N, mean, standard deviation, 
CV, median, minimum, and maximum) will be used to summarize the PK parameters by visit 
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and dose. Geometric means (by visit and dose) will also be presented. Box plots and plots of 
individual Cmax and Ctrough over time will be provided.  
 
5.6 
Biomarker 
5.6.1 Pharmacodynamics Analysis  
The CSF PD evaluable set or CSF PD modified evaluable set as defined in Section 3.5, will be 
used for the statistical modeling of CSF PD data. 
The actual, change from baseline, and percentage change from baseline of CSF N-terminal tau 
and CSF p-tau, and possibly CSF markers of synaptic change or neurofilament will be 
summarized to evaluate pharmacodynamics effect after multiple IV infusions of BIIB092. For 
descriptive statistics, BLQ is imputed as LLOQ/2. For individual subject listings, BLQs are 
listed as BLQ. For CSF to serum ratio calculation, BLQ are excluded, as a ratio using the 
imputed values will lead to unreasonable estimates.  Summary statistics will be generated 
showing N, mean, median, standard deviation, Q1, Q3, minimum and maximum results over 
time by treatment group for CSF N-terminal tau.  
Pearson and Spearman correlations between PD parameters (CSF n-terminal tau, CSF p-tau 
and possibly CSF synaptic or neurofilament marker change from baseline values) and CDR-
SB, ADAS-Cog-13 total score, ADCS-ADL total score and MMSE scores change from 
baseline values may be evaluated using Pearson and Spearman correlation at Week 52 and 
Week 78, respectively. Pearson and Spearman partial correlations adjusting for age, 
corresponding baseline PD parameters and baseline clinical assessment may also be explored.  
For subjects who had both CSF and tau PET assessments. Their data may be used to evaluate 
the correlation between CSF PD parameters and key tau PET parameters at Baseline, 1 year 
(Week 48 for CSF and Week 52 for tau PET) and 18 months (Week 76 for CSF and Week 78 
for tau PET). Pearson and Spearman correlations and partial correlations adjusting for age and 
corresponding baseline values may be evaluated.  
In addition, MMRM model specified in Section 5.3.2 without region as one of the covariates 
will be done for p-tau. Age may be considered as one of the covariates. In addition, these 
analyses might be considered for total tau, N-terminal tau and other fluid biomarkers. For PD 
biomarker by visit summaries and MMRM models, the analysis visit should be defined using 
visit windows (Table 16 in Appendix I). Week 12 data will not be used in the MMRM due to 
small sample size.  
Adjusted mean (± standard error) plots of change from baseline of CSF N-terminal tau and p-
tau over time by treatment group and mean % change of CSF N-terminal tau and p-tau over 
time by treatment group may be presented. The exposure response relationships may be 
explored graphically as appropriate. 
 
Other Fluid Biomarker Analysis  
Other PD parameters analyzed may include, but not limited to, other measures of phospho-tau, 
biomarkers of synaptic change and neurofilament in CSF and in some cases blood if available. 
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Data for these exploratory potential biomarker candidates related to BIIB092 biological activity 
or disease progression may be summarized using descriptive statistics and will be presented by 
treatment group. 
 
5.6.2 Structural MRI Analysis 
Structural magnetic resonance imaging (MRI) results analyzed may include, but will not be 
limited to, volume measures of hippocampus, whole brain, whole cortex and lateral ventricles. 
The analyses will be based on Structural MRI evaluable set as defined in Section 3.5. 
Structural MRI is performed on all randomized subjects at screening visit, Week 28, Week 52, 
Week 78 and early termination visits. Structural MRI readings with QC failure or major scanner 
upgrade will not be included in the analysis. 
 
By visit summary and MMRM model   
The actual values and change from baseline values will be summarized by treatment groups 
(placebo, low dose, medium dose and high dose) and by visit for each of the ROI measurements 
up to Week 78 for Structural MRI evaluable set.   
In addition, some of the parameters measuring volumetric MRI ROIs will be analyzed as a 
percentage of total intracranial volume at baseline (i.e. “% of TIV”). The selected ROIs (e.g., 
lateral ventricles) volumes (% of TIV) will also by summarized by treatment for each visit for 
Structural MRI evaluable set.   
A mixed model with repeated measures (MMRM) will be used to analyze changes from 
baseline as described in Section 5.3.2, including age as covariate. The MMRM analyses will 
be performed on both the raw volume (all ROIs) and the adjusted volume (% of TIV, for 
selected ROIs only, e.g. lateral ventricles).    
 
Pearson and Spearman correlation 
Pearson and Spearman correlations between change from baseline volume MRI at Week 78 
and change from baseline CDR-SB at Week 78 will be conducted by treatment groups. 
Pearson and Spearman partial correlation adjusting for age, corresponding baseline volume 
MRI measure, baseline TIV and baseline CDR-SB will also be conducted by treatment 
groups at Week 78. The estimated correlation coefficients, p-values and the 95% confidence 
intervals will be provided. Given that reductions in volume MRI may precede clinical effects 
(e.g., slowing of clinical decline), Pearson and Spearman correlations and partial correlations 
between change from baseline volume MRI at Week 52 and change from baseline CDR-SB 
at Week 78 might also be conducted. Similar models may be conducted for MMSE, ADAS-
Cog-13 total score, and ADCS-ADL total score. 
5.6.3 Tau PET Analysis 
 
Tau PET substudy  
The tau PET substudy (using 18F-MK6240 tracer only) will include a subset of subjects in USA 
and Australia. Subjects enrolled into the tau PET substudy will receive serial 18F-MK6240 Tau 
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PET scans at Screening, Week 52 and Week 78/Early Termination to investigate the effect of 
BIIB092 on cerebral tau pathology. The analyses for Tau PET will be based on Tau PET 
evaluable set or Tau PET modified evaluable set as defined in Section 3.5. 
 
Tau PET target and reference regions 
Tau PET standardized uptake value ratio (SUVR) is a quantitative measure of cerebral tau 
level.  The SUVR was calculated as the ratio of tracer binding in target brain region (brain 
regions expected to harbor tau pathology) to reference region (brain region devoid of tau 
pathology).   
 
For the SUVR measures the following target and reference regions may be analyzed.  
 
 The primary target regions include: Braak 1 and 2, Braak 3 and 4, and Braak 5 and 6.  
 Secondary target regions may include: Posterior composite, Temporal composite, 
Amyloid composite, Frontal cortex, Parietal cortex, Occipital cortex, Anterior 
cingulate cortex, Posterior cingulate cortex, Lateral temporal cortex, Inferior temporal 
cortex, Medial temporal lobe, Lateral temporal lobe.   
 The primary reference region is Cerebellum (superior section eroded).  
 Other exploratory reference regions may include: cortex (superior section eroded) and 
Cerebellum (superior and inferior section eroded).    
In addition to SUVR measures, Tau PET extent measures may also be analyzed. The extent 
measure is an exploratory approach of quantifying the spatial extent of tau pathology in brain 
regions of interest. The Tau PET extent measures for Braak 1 and 2, Braak 3 and 4, Braak 5 
and 6, Whole cortex using Cerebellum (superior section eroded) as reference region may be 
analyzed.  
 
SUVR and extent measures derived from additional target and reference region combinations 
may be explored. 
 
 
Tau PET primary analysis  
The actual and change from baseline tau PET measures will be summarized by treatment 
groups and by visit for each target region and the primary reference region.  
For tau PET by visit summaries and MMRM models, the analysis visit should be defined using 
visit windows (see 0 in Appendix I). The rationale is to use consistent analysis visit windows 
as for the efficacy endpoints for Week 52 and Week 78. If there is more than 1 value in the 
same analysis visit window (>1 value for the same analysis visit) for a certain parameter for a 
subject, then select the closest record to the target visit day for the by visit analysis.  If they are 
with the same distance from the target visit day, then select the later one for the by visit analysis.   
MMRM model 
A mixed model with repeated measures (MMRM) will be used to analyze changes from 
Baseline in tau PET measures as described in Section 5.3.2 without geographic region as one 
of the covariates for all tau PET primary target regions and primary reference regionregion. 
Age is adjusted in the model as a continuous covariate.  A line plot of adjusted mean change 
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from baseline over time will be provided.  A supplementary MMRM analysis may also be 
performed using the primary target regions and primary reference region on the Tau PET 
population excluding subjects with change in smoking status during the study duration. 
A forest plot of adjusted mean change from baseline at Week 78 may be provided for other 
secondary target regions (using primary reference region) and the primary target regions (using 
other exploratory reference regions).  
MCP-MOD model 
The multiple comparison procedure modelling (MCP-MOD) method (Appendix II) 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 
Section16.10) while controlling for multiplicity for the primary regions (Braak 1 and 2, Braak 
3 and 4, Braak 5 and 6) using the primary reference region (Cerebellum, superior section 
eroded).)  The dose-response parameter of interest for MCP-MOD will be the LS means at 
Week78 for each dose group from the mixed-effects model.  Pairwise comparisons of each 
BIIB092 dose group versus placebo will also be conducted. A line plot of final dose-response 
relationship will be provided. 
 
Correlation between Tau PET vs. Cognitive results and other 
assessments 
Pearson and Spearman correlation 
Pearson and Spearman correlations between change from baseline tau PET primary summary 
measures at Week 78 and change from baseline CDR-SB at Week 78 may be conducted by 
treatment groups in subjects participating in tau PET substudy. Pearson and Spearman partial 
correlation adjusting for age, corresponding baseline tau PET measure and baseline CDR-SB 
will also be conducted by treatment groups at Week 78. The estimated correlation 
coefficients, p-values and the 95% confidence intervals will be provided. Same analyses will 
be used to analyze the correlations between change from baseline of tau PET at Week 52 and 
change from baseline of CDR-SB at Week 52. Given that reductions in tau burden may 
precede clinical effects (e.g., slowing of clinical decline), Pearson and Spearman correlations 
and partial correlations between change from baseline tau PET composite ROI at Week 52 
and change from baseline CDR-SB at Week 78 will also be conducted. Similar models 
maybe conducted for MMSE, ADAS-Cog-13 total score, and ADCS-ADL total score. 
 
ANCOVA model 
 
An Analysis of Covariance (ANCOVA) approach might be used to explore the treatment 
effect with respect to change from baseline of tau PET at week 78 and change from baseline 
of CDR-SB at week 78. If a significant treatment benefit on CDR-SB is detected at week 78, 
three ANCOVA models will be included: Model 1 for change from baseline of tau PET at 
week 78, with factors of treatment, corresponding tau PET baseline value, age, baseline 
disease stage (MCI vs. mild AD), and baseline AD symptomatic medication use; Model 2 for 
change from baseline of CDR-SB at week 78, with factors of treatment, baseline CDR-SB, 
baseline tau PET value, age, baseline disease stage (MCI vs. mild AD), and baseline AD 
symptomatic medication use; Model 3 for change from baseline of CDR-SB at week 78, with 
factors in model 2, plus change from baseline of tau PET at week 78. The estimated treatment 
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effect, the associated 95% CI and p-value of the coefficient will be presented to show how 
much of the treatment effect with respect to CDR-SB can be explained by the treatment effect 
with respect to tau PET.  
 
The same analyses might be explored for other clinical assessments: ADAS-Cog 13 total 
score, MMSE score and ADCS-ADL score. The same ANCOVA model might be used to 
analyze the treatment effect with respect to clinical endpoint and tau PET at different 
timepoint (both at week 52, or change from baseline of tau PET at week 52 with change from 
baseline of clinical assessment at week 78). 
 
Correlation between tau PET and structural MRI 
 
Pearson and Spearman correlations between change from baseline tau PET primary summary 
measures at Week 78 and change from baseline structural MRI at Week 78 may be conducted 
by treatment groups for key tau PET and structural MRI parameters. Pearson and Spearman 
partial correlation adjusting for age, corresponding baseline tau PET measure and baseline 
structural MRI measures may also be conducted by treatment groups at Week 78. 
 
Subgroup analysis 
Subgroup analysis may be conducted using the same MMRM model for the subgroup defined 
Section 3.4. Categorical covariates will be moved out of the model if they are used as a 
subgroup factor; for example, AD stage at baseline and AD symptomatic medication use at 
baseline.   
5.7 
Anti-drug Antibody Analysis  
5.7.1 Analysis Methods for Anti-drug antibody Data 
Anti-drug antibody (ADA) evaluable set will be used to analyze ADA data. For ADA 
endpoints, the following treatment groups will be presented in both tables and listings: placebo, 
BIIB092 125 mg/4wk, BIIB092 375 mg/12wk, BIIB092 600 mg/4wk, BIIB092 2000 mg/4wk, 
and BIIB092 total.  Associations of ADA measures with PK and/or select AEs may be explored 
as needed. 
The baseline value is defined as the last available value prior to first dose of placebo or 
BIIB092. For subjects with missing baseline assessment, the most conservative approach will 
be taken, and they will be considered negative for ADA at baseline. 
 
Treatment emergent positive: Anti-BIIB092 antibody responses in antibody-positive subjects 
are defined as treatment emergent if a patient is: 
 ADA-negative at baseline and ADA-positive post-baseline, or  
 ADA-positive at baseline and had a greater than or equal to 4-fold increase in antibody 
titer post-baseline. If the titer value is not available for a positive baseline result, then 
the baseline titer value will be imputed as the minimum required dilution (MRD); or 
 A positive post-baseline result where no titer is available, regardless of baseline value 
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Persistently positive: Anti-BIIB092 antibody responses in antibody-positive subjects are 
defined as persistent, if more than one positive evaluation occurs ≥16 weeks apart, regardless 
of the number of negative results between positive results, or if a positive evaluation occurs at 
the last time point with no further samples available.  
Transiently positive: Anti-BIIB092 antibody responses in antibody-positive subjects are 
defined as transient, if a subject is treatment emergent positive at a single timepoint not 
including the last sampling timepoint, or treatment emergent with multiple positive anti- 
BIIB092 results <16 weeks apart, with the final timepoint being ADA negative.  
Summary table with the number and percentage of all anti-BIIB092 positive antibody events 
by treatment group and visit will be displayed.  In addition, a summary table of patients with 
treatment-emergent, persistent, and transient responses will be presented by treatment group. 
A listing of anti- BIIB092 antibody results will also be provided. 
Visit windows for by visit summaries 
For ADA data that are summarized by visit, assessment from all scheduled visits, EOT visit, 
and unscheduled visits will be mapped to an appropriate analysis visit using a windowing 
scheme (Appendix I). 
5.8 
Health Outcomes  
The FAS will be used for the analysis of health outcomes data. 
5.8.1 QoL-AD and ZBI 
The actual and changes from baseline scores for health outcome measures in the ZBI total 
score, QoL-AD total score up to Week 68, will be summarized by treatment group.  
A mixed model with repeated measures (MMRM) will be used to analyze changes from 
Baseline in ZBI and QoL-AD measures as described in Section 4.3.2 for ZBI and QOL-AD.  
5.8.2 RUD-Lite 
RUD-Lite is a brief measure of resource utilization developed for use in clinical trials for 
Alzheimer’s disease. The RUD-Lite is completed by the caregiver and allows for cost 
calculation of caregiver burden. Components of the RUD-Lite include informal caregiver 
time, living accommodations and long-term care, use of respite, home nursing, and day care. 
Outpatient, hospital, and social services visits, as well as formal and informal caregiver time, 
are also captured. There are two different forms of the RUD-Lite: one for use at baseline and 
one for use at subsequent visits. 
RUD-Lite consists of continuous and categorical items (see Table 5).  
Table 6. 
RUD-Lite Items 
Item 
Parameter (Units) 
Type 
Caregiver Items in Last 30 Days 
1 
Time per day or night spent asleep (hours) 
Continuous 
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Item 
Parameter (Units) 
Type 
2A 
Time spent per day assisting subject with tasks (toilet 
visit, eating, etc.) (hours) 
Continuous 
2B 
Days spent assisting subject with tasks (toilet visit, 
eating, etc.) (days) 
Continuous 
3A 
Time spent per day assisting subject with tasks 
(shopping, food preparation, etc.) (hours) 
Continuous 
3B 
Days spent assisting subject with tasks (shopping, 
food preparation, etc.) (days) 
Continuous 
4A 
Time spent per day supervising subject (hours) 
Continuous 
4B 
Days spent supervising subject (days) 
Continuous 
Caregiver Work Status in Last 30 Days 
 
2A 
Missed any whole days of work 
Continuous 
2B 
Missed any part of days of work 
Continuous 
Patient Current Living Accommodation 
1 
Any permanent changes since last visit 
Categorical (yes, no), post-
baseline only  
1a, 2 
Current living accommodation 
Categorical (own home, ..., 
other) 
2a 
With whom subject lives 
Categorical 
(alone, 
..., 
not 
applicable) 
3a, 4 
Temporary living accommodation 
Categorical (own home, ..., 
other) 
Patient Health Care Resource Utilization in Last 30 Days (Baseline) or Since Last Visit (Post-
Baseline) 
1 
How many times admitted to hospital 
Continuous 
2 
Ward type, if admitted to hospital 
Categorical (geriatric, ..., other) 
3 
How many times received care in hospital 
emergency room 
Continuous 
4 
Visited health care professional (doctor, 
physiotherapist, etc.) 
Categorical (yes, no) 
4 
Type of care, if visited health care professional 
Categorical 
(general 
practitioner, ..., other) 
5 
Received nursing service 
Categorical (yes, no) 
5 
Type of care, if received nursing service 
Categorical (district nurse, ..., 
other) 
a Baseline 
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For Caregiver Items in Last 30 Days, Items 1, 2A, 3A, and 4A, the total time spent (hours) in 
the last 30 days will be calculated as time per day (or night) x 30 days. The actual score for all 
the items in this section will be summarized by visit.  
For caregiver work status, the percentage of caregivers working for pay will be summarized by 
treatment group at each time point. In addition, among those caregivers working for pay, the 
following summary will be provided by treatment group at each time point: 
 The number of entire work days missed 
 The percentage of caregivers of those who are working, who missed at least 1 entire 
day of work 
 The number of partial work days missed 
 The percentage of caregivers of those are working, who missed at least part of a day of 
work 
For subject current living accommodation, the proportion of subjects who have a change in 
permanent living accommodation will be summarized by treatment group at each time point. 
Number of nights spent in the temporary living accommodation for subjects with a temporary 
change will also be summarized. 
For subject health care resource utilization, the following summary will be provided by 
treatment group at each time point.  
 Percentage of subjects admitted to hospital; number of times and nights admitted to 
hospital for subjects admitted to hospital 
 Percentage of subjects received care in hospital emergency room; number of times of 
emergency room care for subjects received care in hospital emergency room 
 Percentage of subjects visited health care professional (doctor, physiotherapist, etc.); 
number of times visited for subjects visited health care professional 
Percentage of subjects received nursing care; number of visits and hours of nursing care for 
subjects received nursing care. 
6 Changes from Protocol-Specified Analyses 
In order to follow Biogen standard, the below population names have been changed. 
However, the definition remains the same. 
Protocol specified name 
SAP name 
Intent-to-treat population 
Full Analysis Set 
Per-protocol population 
Per-Protocol Analysis Set 
Safety population 
Safety Analysis Set 
Safety MRI population 
Safety MRI Evaluable Set 
Serum PK analysis population 
Serum PK Evaluable Set 
CSF PK analysis population 
CSF PK Evaluable Set 
Serum PD population 
Serum PD Evaluable Set 
CSF PD population 
CSF PD Evaluable Set 
Tau PET population 
Tau PET Evaluable Set 
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Structural MRI population  
Structural MRI Evaluable Set 
Anti-drug antibody population 
Anti-Drug Antibody Evaluable Set 
 
6.1 
MMRM model  
The MMRM model specified in SAP section includes “baseline MMSE” as one more fixed 
effect than protocol section 16.4.2.1 and 16.4.2.2.  
 
6.2 
MCP-MOD model 
Besides six planed dose-response relationships as illustrated in Figure2, linear dose-response 
relationship was added for both models to detect the change from baseline in CDR-SB and tau 
PET. The approximately power remains at 80%. 
 
 
 
 
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7 Appendix I: Visit Window Mapping 
For data that are summarized by visit and longitudinal analysis, assessment from all scheduled 
visits including EOT visit and EOS visit, and all unscheduled visits will be mapped to an 
appropriate analysis visit using a windowing scheme. Analysis visit windows are defined in 
[Table 7 - Table 15] for different endpoints. To define analysis visit window, the target visit 
day is calculated as (week number*7+1). The lower bound of visit window is calculated as 
target day−(target day−target day of previous visit)/2+1, except for the first post-baseline visit 
window whose lower bound is set as Day 2; the upper bound of visit window is calculated as 
target day+(target day of next visit−target day)/2. 
If there are 2 or more assessments from visits, including EOT and EOS visits, mapped to the 
same analysis visit for a subject, the assessment that is closest to the target visit day will be 
used for analysis.  If there are 2 or more assessments from visits, including EOT and EOS 
visits, mapped to the same analysis visit with the same distance from the target visit day, then 
select the later one(s) for the analysis.  If there are 2 or more assessments from visits, including 
EOT and EOS visits, mapped to the same analysis visit and on the same day, use the average 
value for quantitative parameters and the worst value for qualitative parameters for analysis. 
 
Table 7. 
Visit Windows for Efficacy Endpoints 
Efficacy 
Endpoint 
Analysis visit 
Target 
visit 
day  
Analysis visit window 
CDR, 
NPI-
10, ADAS-
Cog13, 
FAQ, 
and 
ADCS-ADL 
Baseline 
1 
Most recent non-missing pre-dose 
value 
Week 24 
169 
[2, 267] 
Week 52 
365 
[268, 456] 
Week 78 
547 
[457, *] 
ISLT, 
DKEFS, 
DSST, Trails 
A,  
Baseline 
1 
Most recent non-missing pre-dose 
value 
Week 12 
85 
[2, 141] 
Week 28 
197 
[142, 239] 
Week 40 
281 
[240, 337] 
Week 56 
393 
[338, 435] 
Week 68 
477 
[436, 512] 
Week 78 
547 
[513, *] 
eCog 
Baseline 
1 
Most recent non-missing pre-dose 
value 
Week 28 
197 
[2, 295] 
Week 56 
393 
[296, 470] 
Week 78 
547 
[471, *] 
MMSE 
Baseline 
1 
Most recent non-missing pre-dose 
value 
Week 12 
85 
[2, 127] 
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Efficacy 
Endpoint 
Analysis visit 
Target 
visit 
day  
Analysis visit window 
Week 24 
169 
[128, 225] 
Week 40 
281 
[226, 323] 
Week 52 
365 
[324, 421] 
Week 68 
477 
[422, 512] 
Week 78 
547 
[513, *] 
 
* Up to the end day of the placebo-controlled period. 
 
 
Table 8. 
Visit Windows for Laboratory by Visit Summaries 
Analysis visit  
Target visit day  
Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value 
Week 12 
85 
[2, 127] 
Week 24 
169 
[128, 253] 
Week 48 
337 
[254, 421] 
Week 72 
505 
[422, 526] 
Week 78 
547 
[527, 589] 
If subjects who enter LTE, visit window is: [527, 
the end day of the placebo-controlled period] 
Week 90 
631 
[590, the end day of the placebo-controlled 
period] 
 
 
Table 9. 
Visit Windows for ECG by Visit Summaries 
Analysis visit 
Target visit day  
Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value 
D1 Post dose 
1 
Any day 1 post dose infusion 
Week 12 
85 
[2, 127] 
Week 24 
169 
[128, 253] 
Week 48 
337 
[254, 421] 
Week 72 
505 
[422, 526] 
Week 78 
547 
[527, 589] 
If subjects who enter LTE, visit window is: 
[527, the end day of the placebo-controlled 
period] 
Week 90 
631 
[590, the end day of the placebo-controlled 
period] 
Table 10. 
Visit Windows for Vital Sign by Visit Summaries 
Analysis visit 
Target visit day  
Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value 
D1 Post dose 
1 
Day 1 post dose infusion (if more than one 
Day 1 post dose results available, the 
average of the available results will be used) 
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Analysis visit 
Target visit day  
Analysis visit window 
Week 4 – Pre dose 
29  
[2, 43] (Pre-dose assessment) 
Week 4 – Post dose  29 
[2, 43] (Post dose infusion) 
Week 8 – Pre dose 
57 
[44, 71] (Pre-dose assessment) 
Week 8 – Post dose 57 
[44, 71] (Post dose infusion) 
Week 12 – Pre dose 85 
[72, 99] (Pre-dose assessment) 
Week12 – Post 
dose 
85 
[72, 99] (Post dose infusion) 
Week 16 
113 
[100, 127] 
Week 20 
141 
[128, 155] 
Week 24 
169 
[156, 183] 
Week 28 
197 
[184, 211] 
Week 32 
225 
[212, 239] 
Week 36 
253 
[240, 267] 
Week 40 
281 
[268, 295] 
Week 44 
309 
[296, 323] 
Week 48 
337 
[324, 351] 
Week 52 
365 
[352, 379] 
Week 56 
393 
[380, 407] 
Week 60 
421 
[408, 435] 
Week 64 
449 
[436, 463] 
Week 68 
477 
[464, 491] 
Week 72 
505 
[492, 519] 
Week 76 
533 
[520, 540] 
Week 78 
547 
[541, 589] 
If subjects who enter LTE, visit window is: 
[541, the end day of the placebo-controlled 
period] 
Week 90 
631 
[590, the end day of the placebo-controlled 
period] 
 
 
Table 11. 
Visit Windows for ADA by Visit Summarized 
Analysis visit 
Target visit day 
Analysis visit window 
Baseline 
1 
See baseline definition in Section 5.7 
Week 4 
29 
[2, 99] 
Week 24 
169 
[100, 253]  
Week 48 
337 
[254, 435] 
Week 76 
533 
[436, 582] 
If subjects who enter LTE, visit window is: 
[436, the end day of the placebo-controlled 
period] 
Week 90 
631 
[583, the end day of the placebo-controlled 
period] 
 
 
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Table 12. 
Visit Windows for tau PET data 
Analysis visit  
Target visit day  
Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value 
Week 52 
365 
[120, 456] 
Week 78 
547 
[457, *] 
* The upper bound of Week 78, for subjects not enrolled into LTE, is the last day in 
study for PC period; for subjects enrolled into LTE, their Week 78 upper bound is less 
than the day of third infusion in LTE (Due to Covid-19, subjects could complete Week 
78 tau PET after week 78 but before third infusion in LTE.) 
 
Table 13. 
Visit Windows for structural MRI data 
Analysis visit  
Target visit day  
Analysis visit window  
Baseline  
1  
Most recent non-missing pre-dose value  
Week 28  
197  
[90, 281]  
Week 52  
365  
[282, 456]  
Week 78  
547  
[457, the end day of the placebo-controlled 
period]  
 
 
Table 14. 
Visit Windows for C-SSRS data 
Analysis visit  
Target visit day  
Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value 
Week 24 
169 
[2, 267] 
Week 52 
365 
[268, 456] 
Week 78 
547 
[457, the end day of the placebo-controlled 
period] 
 
Table 15. 
Visit Windows for Health Outcome (RUD-Lite, ZBI, and Qol-AD) data 
Analysis visit  
Target visit day  
Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value 
Week 20 
141 
[2, 239] 
Week 48 
337 
[240, 407] 
Week 68 
477 
[408, the end day of the placebo-controlled 
period] 
 
Table 16. 
Visit Windows for CSF PD biomarker data 
Analysis visit  
Target visit day  
Analysis visit window  
Baseline  
1  
Most recent non-missing pre-dose value  
Week 12  
85 
[2, 211]  
Week 48  
337  
[212, 456]  
Week 76  
533  
[457, the end day of the placebo-controlled 
period]  
 
Table 17. 
Visit Windows for Serum PD biomarker data 
Analysis visit  
Target visit day  
Analysis visit window  
Baseline  
1  
Most recent non-missing pre-dose value  
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Analysis visit  
Target visit day  
Analysis visit window  
Week 16 
113 
[2, 225]  
Week 48 
337 
[226, 379] 
Week 60  
421 
[380, 477]  
Week 76  
533  
[478, the end day of the placebo-controlled 
period] 
 
 
8 Appendix II: Description of MCP-MOD method 
MCP-MOD method works in the following steps.  
Step 1: Set of candidate models 
Candidate models include linear, exponential (δ = 1200), quadratic (δ=-0.0003), Emax 
(ED50=110), linear in log dose (off = 72), exponential (δ=380) and logistic (ED50 = 600, 
δ=370). The response shapes are displayed in 0. 
Step 2: Optimal model contrast 
The LS means at Week 78 and the covariance matrix of the LS means will be estimated 
from the mixed model and used to determine the optimal contrasts. The coefficients of the 
contrasts are pre-specified during the design stage once the candidate models are selected 
in Step 1. 
Step 3: Testing for dose response signal 
A multiple contrast test will be used to test the overall dose response signal and to identify 
all contrasts that have adjusted p-values<0.1 for one sided. As a result, the significance of 
the dose response signal was established and all models with a significant contrast will be 
considered in the next step. 
Step 4: Model selection 
AIC criterion will be used to select the best model for Step 5. 
Step 5: Dose estimation 
The model selected in Step 4 will be used to fit the data. The fitted model and corresponding 
confidence interval will be displayed graphically. The minimum effective dose giving the 
40% reduction or the clinically relevant improvement 25% reduction over placebo will be 
estimated along with the 90% and 95% confidence interval. This step may be explored if 
there is a significant dose response. 
 
 
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9 Appendix III: Questionnaire 
9.1 
Clinical Dementia Rating Scale (CDR) 
The CDR is derived from a semi-structured interview with the patient and an appropriate 
informant and rates impairment in each of six cognitive categories (Memory, Orientation, 
Judgment and Problem Solving, Community Affairs, Home and Hobbies, and Personal Care) 
on a five-point scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2, and severe 
= 3. (Note: Personal Care has no questionable impairment level.) From the six individual 
category ratings, or “box scores”, the global CDR is established by clinical scoring rules where 
CDR 0 = no dementia and CDR 0.5, 1, 2, or 3 indicates questionable, mild, moderate, or severe 
dementia. The usefulness of the CDR may result from several factors: (1) it is clinically based 
(i.e., independent of psychometric test scores); (2) the six categories used for rating dementia 
severity are directly linked to validated clinical diagnostic criteria for AD; (3) it has high inter-
rater reliability for physicians and non-physicians; and (4) and expanded and more quantitative 
version of the scale can be achieved by summing the ratings in each of the six categories to 
provide the Sum of Bases. [Morris 1993] 
 
 
9.2 
Mini-Mental State Examination (MMSE) 
The Mini-Mental State Examination (MMSE) includes eleven questions, requires only 5-10 
min to administer. It is “mini” because it concentrates only on the cognitive aspects of mental 
functions, and excluded questions concerning mood, abnormal mental experiences and the 
form of thinking. But within the cognitive realm it is thorough.  
The MMS is divided into two sections, the first of which requires vocal responses only and 
covers orientation, memory, and attention; the maximum score is 21. The second part tests 
ability to name, follow verbal and written commands, write a sentence spontaneously, and copy 
a complex polygon similar to a Bender-Gestalt Figure; the maximum score is nine. Because of 
the reading and writing involved in Part II, patients with severely impaired vision may have 
some extra difficulty that can usually be eased by large writing and allowed for in the scoring. 
Maximum total score is 30. [Folstein MF 1975] 
9.3 
International Shopping List Test Immediate Recall (ISLT) 
The International Shopping List Test (ISLT) is a 12-word, 3-trial word learning test with 
established construct and criterion validity, and high reliability for the detection of memory 
impairment in AD 
The design of the ISLT allows it to be used for the assessment of memory in individuals from 
different languages, cultures or geographic regions without the necessity of the complex 
translations or cultural adaptions that must be applied to other verbal memory tests, such as the 
Free and Cued Selective Reminding Test (FCSRT) or Wechsler Memory Scale Logical 
Memory Test (LM), which were developed and validated in well-educated and middle-class 
settings 
The ISLT has been used extensively to measure the magnitude and nature of memory 
impairment in experimental and clinical studies; however, there is less information about the 
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utility of the ISLT to screen individuals’ memory for entry into clinical trials in prodromal AD 
[Paul Maruff 2017]. 
9.4 
Delis-Kaplan Executive Function System (DKEFS) 
The Delis-Kaplan Executive Function System (D-KEFS; Delis, Kaplan, & Kramer, 2001) 
provides a standardized assessment of higher-level cognitive functions, called executive 
functions, in children, adolescents, and adults between the ages of 8 and 89.  The D-KEFS is 
composed of the following nine stand-alone tests that can be individually or group 
administered: Trail Making Test; Verbal Fluency Test; Design Fluency Test; Color-Word 
Interference Test; Sorting Test; Twenty Questions Test; Word Context Test; Tower Test; and 
Proverb Test.  Most of these D-KEFS tests use a game-like format without employing 
right/wrong feedback procedures; this is intended to reduce unproductive discouragements and 
frustrations caused by repeated negative feedback during testing. 
The D-KEFS Verbal Fluency Test (VF) is comprised of three testing conditions: Letter 
Fluency, Category Fluency, and Category Switching. The VF measures multiple aspects of 
verbal behavioral productivity and cognitive flexibility. It evaluates effectiveness of novel and 
semantic search strategies and assesses flexibility in the implementation of semantic search 
strategies. The process approach enables further evaluation of self-monitoring of information 
search, as well as difficulties related to initiation and sustaining effort. There are three 
conditions in the VF in which the examinee must say as many words as they can by letter, 
category, and category switching prompts. 
1. Letter Fluency: The examinee says words beginning with a specified letter as quickly as 
possible; 
2. Category Fluency: The examinee is asked to say words belonging to a designated semantic 
category; and 
3. Category Switching: The examinee must alternate between saying words from two different; 
semantic categories. 
 
In this study, only Letter Fluency and Category Fluency tests are used, but NOT Category 
Switching. The Letter Fluency test measures the examinee’s ability to generate words fluently 
in an effortful, phonemic format. The Category Fluency test measures the examinee’s ability 
to generate words fluently from overlearned concepts. 
9.5 
Digit Symbol Substitution Test (DSST) 
The Digit Symbol Substitution Test (DSST) was initially developed as an experimental tool 
over a century ago by researchers seeking to understand human associative learning. The DSST 
is a paper-and-pencil cognitive test presented on a single sheet of paper that requires a subject 
to match symbols to numbers according to a key located on the top of the page. The subject 
copies the symbol into spaces below a row of numbers. The number of correct symbols within 
the allowed time, usually 90 to 120 seconds, constitutes the score.  
This study is using the most recent version of Wechsler Adult Intelligence Scale (WAIS), the 
fourth edition (WAIS IV). The duration of DSST in this version is 120 seconds. The DSST 
measures a range of cognitive operations. Good performance on the DSST requires intact motor 
speed, attention, and visuo perceptual functions, including scanning and the ability to write or 
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draw (ie, basic manual dexterity). That the DSST is sensitive to age effects is well known. The 
DSST has been a useful tool to demonstrate age differences in the effects of drugs on cognition, 
for example, owing to reduced clearance resulting in higher plasma concentrations in older 
than in younger subjects. [Judith Jaeger, 2018] 
 
9.6 
Trail Making Test, Part A (Trail A) 
Trail Making Test consist of 25 circles distributed over a sheet of paper. In Part A, the circles 
are numbered 1 – 25, and the patient should draw lines to connect the numbers in ascending 
order, and the participants were asked to connect the numbers in order as quickly as possible. 
The total completion time will be evaluated as final result. The maximal allowed time is <5mins 
in our study. Longitudinal studies have shown that the Trail Making Test is capable of 
forecasting clinical and functional changes in patients with Alzheimer’s disease (Chen et al., 
2001).  Moreover, in older adults, Trail Making Test performance has been related to physical 
decline and higher risk of mortality [Vazzana et al., 2010, Jordi Llinàs-Reglà, 2017]. 
9.7 
Everyday Cognition (eCog) 
The Everyday Cognition (eCog) scales were developed in response to some of the limitations 
of existing instruments. One goal in developing the eCog was to measure relatively mild 
functional changes that may predate loss of independence in major activities of daily living. A 
second aim in developing the eCog was to assess functional abilities that are clearly linked to 
specific cognitive abilities, in other words, the everyday correlates of specific 
neuropsychological impairments. 
The original version of the eCog is an informant-based measure of cognitively-relevant 
everyday abilities comprised of 39 items, covering six cognitively-relevant domains: Everyday 
Memory, Everyday Language, Everyday Visuospatial Abilities, and Everyday Planning, 
Everyday Organization, and Everyday Divided Attention. For each item, informants compare 
the participant’s current level of everyday functioning with how he or she functioned 10 years 
earlier. In this way, individuals serve as their own control. Ratings are made on a four-point 
scale: 1 = better or no change compared to 10 years earlier, 2 = questionable/occasionally 
worse, 3 = consistently a little worse, 4 = consistently much worse. The original eCog was 
developed through a rigorous process that included initial pilot testing of a larger potential pool 
of items. A goal of that initial pilot testing was to identify and discard items with obvious poor 
psychometric properties. For example, items were not retained if they were associated with a 
high percentage of “I don’t know” responses – indicating the item did not readily apply to many 
individuals or was not frequently observed by an informant. However, few functional abilities 
will universally apply to all individuals so an ‘I don’t know’ response option was retained. The 
original version has been shown to have excellent psychometric properties including good test-
retest reliability (r = 0.82, p<.001) as well as evidence of various aspects of validity including 
content, construction, convergent and divergent, and external validity [Sarah Tomaszewski 
Farias, 2011]. 
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9.8 
Alzheimer’s disease Cooperative Study – Activities of Daily Living 
(ADCS-ADL) 
The ADCS-ADL was designed to assess patients’ ability to complete activities relevant to 
elderly individuals. It is a subjective assessment, with the patient rated by an informant, based 
on their performance over the previous 4 weeks. 
The ADCS-ADL has 23-item which focuses on complex items, such as reading, pastime 
activities, and household chores, and is appropriate for the assessment of mild to moderate AD. 
Each item has descriptions of performance levels and corresponding scores; the informant is 
asked to choose the most accurate description of the patient’s performance during the past 4 
weeks. The ADCS-ADL23 Total score ranges from 0 (worst) to 78 (best). [Galasko et al. 1997; 
Robert et al. 2010]. ADCS-ADL basic (ADCS-bADL) total score includes questions 1 (eating), 
2 (walking), 3 (bowel and bladder function at the toilet), 4 (bathing), 5 (grooming), and 6b 
(getting dressed). ADCS-ADL instrumental (ADCS-iADL) total score includes 6a (selecting 
his/her first set of clothes), and the remaining questions from 7 -23 in ADCS-ADL. 
9.9 
Functional Activities Questionnaire (FAQ) 
The Functional Activities Questionnaire (FAQ) is not self-administered but is completed by a 
lay informant such as the spouse, a relative, or a close friend. There are 10 questions included. 
For each activity, four levels ranging from dependence (scored 3) to independence (scored 0) 
are specified. For activities not normally undertaken by the person, the informant must specify 
whether the person would be unable to undertake the task if required (scored 1) or could do so 
if required (0). The total score is the sum of individual item scores; higher scores reflect greater 
dependency. [Robert I. Pfeffer, 1982] 
9.10 Alzheimer’s disease Assessment Scale –Cognitive (13 item) (ADAS-
Cog 13) 
The modified ADAS-Cog 13-item scale (Mohs et al. 1997) includes all original ADAS-Cog 
items with the addition of a number cancellation task and a delayed free recall task, for a total 
of 85 points. As in the parent instrument, higher scores indicated greater severity. According 
to Mohs and colleagues, the purpose of these additional items was to increase the number of 
cognitive domains and range of symptom severity without a substantial increase in the time 
required for administration. [Jeannine Skinner, 2012] 
9.11 Neuropsychiatric Inventory – 10 (NPI-10) 
The Neuropsychiatric Inventory (NPI) was developed by Cummings et al. (1994) to assess 
dementia-related behavioral symptoms which they felt other measures did not sufficiently 
address. The NPI originally examined 10 sub-domains of behavioral functioning: delusions, 
hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, 
irritability/lability, and aberrant motor activity.  The NPI is administrated to caregivers of 
dementia patients. A screening question is asked about each sub-domain. If the responses to 
these questions indicate that the patient has problems with a particular sub-domain of behavior, 
the caregiver is only then asked all the questions about that domain, rating the frequency of the 
symptoms on a 4-point scale, their severity on a 3-point scale, and the distress the symptom 
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causes them on a 5-point scale. The score of each item is then calculated by multiplying severity 
by frequency, thus obtaining a score ranging between 0 and 12. The total NPI score is finally 
obtained by adding all the single item scores (thus, ranging from 0 to 120). Higher scores 
indicate greater psychopathology. 
9.12 Zarit Burden Interview (ZBI) 
The Zarit Burden Interview (ZBI), which provides a comprehensive assessment of both 
objective and subjective burden, is one of the most commonly used burden measures and has 
been validated in many culturally or ethnically different populations. 
The Zarit Burden Interview (ZBI) is a 22-item instrument for measuring the caregiver’s 
perceived burden of providing family care. The 22 items are assessed on a 5-point Likert scale, 
ranging from 0 = ‘never’ to 4 = ‘nearly always’. Item scores are added up to give a total score 
ranging from 0 to 88, with higher scores indicating greater burden. The questions focus on 
major areas such as caregiver’s health, psychological well-being, finances, social life and the 
relationship between the caregiver and the patient [Boon Kheng Seng, 2010]. 
9.13 Quality of Life for Alzheimer’s disease (Qol-AD) 
QOL is an important consideration in AD because of the devastating impact of this currently 
incurable disease on patients and caregivers. From the patient’s perspective, QOL measures 
may assist understanding of the magnitude of the impact of treatment intervention, whereas, 
from a payer perspective, QOL measures can provide a common metric of comparison across 
disease states. The QOL-AD has been shown to have excellent internal consistency reliability 
for both patient and caregiver reports (a 5 0.84 and 0.86, respectively) at all levels of cognitive 
functioning and good validity as indicated by correlations with measures of depression, day-
to-day functioning, and pleasant events frequency. Thorgrimsen and colleagues [2003] 
reported the QOL-AD to have good content validity, construct validity, interrater reliability (all 
Cohen’s kappa values .0.70), test-retest reliability, and internal consistency (Cronbach a 
coefficient of 0.82). QOL is measured using the 13-item QOL-AD scale (total score range 13–
52; higher scores indicate better QOL). The QOL-AD scale uses a scale of 1–4 (poor, fair, 
good, or excellent) to rate a variety of life domains, including the patient’s physical health, 
mood, relationships, activities, and ability to complete tasks [Kristin Kahle-Wrobleski, 2017]. 
9.14 Resource Utilization in Dementia-Lite Version (RUD-Lite) 
The RUD was designed for use in clinical trials to assess the level of resource usage among 
patients with dementia. As the full RUD tool is extensive, a shortened version was created – 
the RUD Lite. 
The RUD Lite consists of two sections: one about the caregiver (including questions about the 
caregiver him- or herself, and time spent caring for the patient), and one about the patient 
(including questions about the patient’s living arrangements and their healthcare resource 
usage). 
The RUD Lite is a questionnaire rather than an assessment scale, and, as such, it is not ‘scored’. 
Instead, individual questions of the patient component provide resource use information, such 
as the number of hospitalizations, and the number of nights spent in hospital. 
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Regarding the caregiver component, the number of hours per day that the caregiver cares for 
the patient is recorded, based on a typical care day during the past month. This is broken down 
into time spent assisting with personal ADLs (such as bathing and dressing), time spent 
assisting with instrumental ADLs (more complex activities such as shopping and 
housekeeping), and time spent supervising the patient. [Wimo & Winblad. Brain Aging 
2003;3(1):48–59] 
 
 
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10 Appendix IV: Adverse event of special interest custom search criteria 
Anti-drug antibody is an AESI in the BIIB092 clinical development program. Adverse events 
representing potential immune/hypersensitivity reactions will be identified using the following 
customized MedDRA (23.1) search criteria: 
 
Immunogenicity is an AESI in the BIIB092 clinical development program. Adverse events 
representing potential immune/hypersensitivity reactions will be identified using the following 
customized MedDRA (23.1) search criteria: 
 
 Anaphylactic reaction SMQ narrow and broad 
 Angioedema SMQ narrow and broad 
 Severe cutaneous adverse reactions SMQ narrow and broad 
 Eosinophilia (PT terms: Eosinophilia; Eosinophil count increased; Allergic eosinophilia; 
Pulmonary eosinophilia) 
 HLT Allergic conditions NEC  
 Miscellaneous terms 
 
Antibody test 
 
Antibody test abnormal 
 
Antibody test positive 
 
Cytokine release syndrome 
 
Documented hypersensitivity to administered 
product 
 
Drug specific antibody present 
 
Infusion related reaction 
 
Infusion site reaction 
 
Neutralising antibodies 
 
Neutralising antibodies positive 
 
Non-neutralising antibodies positive 
 
Respiratory dyskinesia 
 
Rheumatoid arthritis 
 
Systemic lupus erythematosus 
 
Vasculitis 
 
 
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11 Appendix V: Infusion reactions custom search 
 
 Infusion site reaction 
 Infusion site rash 
 Infusion site dermatitis 
 Infusion site hypersensitivity 
 Infusion site photosensitivity reaction 
 Infusion site urticaria 
 Infusion site eczema 
 Infusion site vasculitis 
 Infusion site recall reaction 
 Infusion related reaction 
 Administration site rash 
 Administration site dermatitis 
 Administration site eczema 
 Administration site hypersensitivity 
 Administration site urticaria 
 Administration site photosensitivity reaction 
 Administration site recall reaction 
 Administration site vasculitis 
 Administration related reaction 
 Injection site dermatitis 
 Injection site hypersensitivity 
 Injection site rash 
 Injection site urticaria 
 Injection site photosensitivity reaction 
 Injection site eczema 
 injection site recall reaction 
 Injection site vasculitis 
 Injection related reaction 
 Immediate post-injection reaction 
 allergic reaction to excipient 
 reaction to excipient 
 cytokine storm 
 cytokine release syndrome 
 immune-mediated adverse reaction 
 
 
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12 References  
Folstein MF, Folstein SE, McHugh PR: “Mini-mental state: A practical method for grading the 
cognitive state of patients for the clinician.” J Psychiatr Res 1975;12:189-198. 
 
Paul Maruff, PhD, Adrian Schembri. Utility of the International Shopping List Test for 
detection of memory impairment associated with prodromal and early Alzheimer’s disease in 
clinical trials 
 
Susan Homack , Donghyung Lee & Cynthia A. Riccio: Test Review: Delis-Kaplan Executive 
Function System 
 
Judith Jaeger, PhD, MPA: Digit Symbol Substitution Test the Case for Sensitivity Over 
Specificity in Neuropsychological Testing 
 
Caterina Rosano: Digit Symbol Substitution test and future clinical and subclinical disorders 
of cognition, mobility and mood in older adult 
 
Jordi Llinàs-Reglà: The Trail Making Test: Association With Other Neuropsychological 
Measures and Normative Values for Adults Aged 55 Years and Older From a Spanish-
Speaking Population-Based Sample 
 
Sarah Tomaszewski Farias: The Measurement of Everyday Cognition (ECog): Development 
and validation of a short form 
 
Ian McDowell, Measuring Health: A Guide to Rating Scales and Questionnaires, Third Edition. 
Oxford University Press 
 
Jeannine Skinner: The Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-
Plus): an expansion of the ADAS-Cog to improve responsiveness in MCI 
 
Richard C. MohsDeborah MarinCynthia R. GreenKenneth L. Davis: The Alzheimer’s Disease 
Assessment Scale: Modifications That Can Enhance its Use in Future Clinical Trials. Springer 
Link 
 
Boon Kheng Seng: Validity and Reliability of the Zarit Burden Interview in Assessing 
Caregiving Burden 
 
Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol deviation: 
a framework for relevant, accessible assumptions, and inference via multiple imputation. J 
Biopharm Stat. 2013;23(6):1352-71. 
 
Galasko D, Bennett D, Sano M, Ernesto C, R Thomas R, Grundman M, S Ferris S. An 
inventory to assess activities of daily living for clinical trials in Alzheimer's disease, The 
Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997; 11(Suppl 2): S33–
S39;  
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ICH E9 (R1): Addendum to statistical principles for clinical trials on choosing appropriate 
estimands and defining sensitivity analyses in clinical trials. Endorsed by the ICH Steering 
Committee. 2014. 
 
ICH E9 (R1): Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the 
Guideline on Statistical Principles for Clinical Trials. European Medicines Agency. 2017. 
 
Jinping Wang, Veronika Logovinsky, Suzanne B Hendrix. ADCOMS: a composite clinical 
outcome for prodromal Alzheimer’s disease trials. J Neurol Neurosurg Psychiatry 
2016;87:993–999 
 
Judith Jaeger, PhD, Clint Hagen, MS, Henrik Loft, PhD. Cognitive Endpoints for Early 
Alzheimer’s Disease Trials: Development of the Early AD/ MCI Alzheimer’s Cognitive 
Composite (EMACC). ISCTM  2018 
 
Li, K. H. (1988), "Imputation Using Markov Chains," Journal of Statistical Computation and 
Simulation, 30, 57–79. 
 
Little, R.J.A. (1993). Pattern‑mixture models for multivariate incomplete data. Journal of the 
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Robert P, Ferris S, Gauthier S, Ihl R, Winblad B, Tennigkeit F. Review of Alzheimer's disease 
scales: is there a need for a new multi-domain scale for therapy evaluation in medical practice? 
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Rubin, D. B. (1976) “Inference and missing data.” Biometrika, 63(3), 581-592. 
 
Rubin D.B. Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons. 1987. 
 
Schafer J.L. Analysis of Incomplete Multivariate Data. Chapman and Hall, New York. 1997. 
 
Tractenberg RE, Weiner MF, Cummings JL, Patterson MB, Thal LJ. Independence of changes 
in behavior from cognition and function in community-dwelling persons with Alzheimer’s 
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van Ginkel, J. R., Sijtsma, K., van der Ark, L. A., & Vermunt, J. K. (2010). Incidence of 
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Wessels, A.M., Andersen, S.W., Dowsett, S.A., and Siemers, E.R. (2018), “The integrated 
Alzheimer’s disease rating scale (iADRS) findings from the expedition3 trial”, Journal of 
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K., Stern Y., Rentz, D.M., Dubois, B., Jones, R.W., Cummings, J., and Aisen, P.S. (2015), “A 
combined measure of cognition and function for clinical trials: the integrated Alzhermer’s 
disease rating scale (iADRS)”, Journal of Prevention of Alzheimer’s Disease. 
 
 
 
 
 
 
 
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Statistical Analysis Plan 
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Table of Contents 
LIST OF ABBREVIATIONS .............................................................................................................................. 5 
1 
INTRODUCTION ....................................................................................................................................... 7 
2 
DESCRIPTION OF LONG-TERM EXTENSION (LTE) OBJECTIVES AND ENDPOINTS ........... 7 
2.1 
PRIMARY LTE OBJECTIVE AND ENDPOINT ................................................................................................ 7 
2.2 
EXPLORATORY LTE OBJECTIVES AND ENDPOINTS ................................................................................... 7 
2.3 
STUDY DESIGN .......................................................................................................................................... 8 
2.4 
STUDY SCHEMATIC ................................................................................................................................. 10 
3 
DEFINITIONS .......................................................................................................................................... 12 
3.1 
ANALYSIS SETS ....................................................................................................................................... 12 
3.2 
ANALYSES PERIOD .................................................................................................................................. 13 
3.3 
STUDY TREATMENT ................................................................................................................................ 13 
3.4 
DATES AND POINTS OF REFERENCE ........................................................................................................ 14 
3.5 
KEY DERIVED VARIABLES ...................................................................................................................... 15 
3.6 
STRATIFICATION FACTORS AND SUBGROUP VARIABLES ......................................................................... 18 
4 
LIST OF PLANNED STUDY ANALYSES ............................................................................................ 19 
4.1 
LTE INTERIM ANALYSES AT PC PERIOD DATABASE LOCK ....................................................................... 19 
4.2 
FINAL ANALYSIS ..................................................................................................................................... 19 
5 
STATISTICAL METHODS FOR PLANNED ANALYSES ................................................................. 20 
5.1 
GENERAL CONSIDERATIONS ................................................................................................................... 20 
5.2 
STUDY SUBJECTS .................................................................................................................................... 20 
5.2.1 
Accounting of Subject ................................................................................................................... 20 
5.2.2 
Demographics and Baseline Characteristics ................................................................................ 20 
 
Concomitant Medications and Non-drug Therapies ................................................................................. 20 
5.2.3 
Protocol Deviations ...................................................................................................................... 21 
5.2.4 
Study Drug Exposure and Study Drug Compliance ...................................................................... 21 
5.2.5 
COVID-19 Related Analysis ......................................................................................................... 21 
 
Accounting of subjects who discontinued due to COVID-19................................................................... 21 
 
Concomitant Non-Drug Treatment for COVID-19 .................................................................................. 22 
 
COVID-19 Effect on Drug Compliance ................................................................................................... 22 
 
COVID-19 Protocol Deviation ................................................................................................................. 22 
 
Protocol Alternation Due to COVID-19cx ............................................................................................... 22 
5.3 
EFFICACY ANALYSIS ............................................................................................................................... 22 
5.3.1 
General Considerations ................................................................................................................ 22 
5.3.2 
Method of Analysis ....................................................................................................................... 23 
 
Considerations for base MMRM model for change from baseline analyses ............................................ 23 
5.3.3 
Primary Efficacy Endpoint ........................................................................................................... 23 
5.3.4 
Exploratory Efficacy Endpoints .................................................................................................... 24 
5.4 
SAFETY ANALYSES ................................................................................................................................. 24 
5.4.1 
General Considerations ................................................................................................................ 24 
 
Analysis Population ................................................................................................................................. 24 
 
LTE Safety Treatment Groups ................................................................................................................. 24 
 
Incidence, Incidence Proportion and Incidence Rate ................................................................................ 25 
5.4.2 
Clinical Adverse Events ................................................................................................................ 25 
 
Summary and Incidence Analysis ............................................................................................................ 26 
 
Incidence Rate Analysis ........................................................................................................................... 28 
 
Infusion Reactions .................................................................................................................................... 28 
 
AE of Special Interest .............................................................................................................................. 28 
5.4.3 
Clinical Laboratory Data ............................................................................................................. 29 
 
Quantitative analyses ............................................................................................................................... 29 
 
Qualitative analyses ................................................................................................................................. 30 


 
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5.4.4 
C-SSRS Data ................................................................................................................................. 31 
5.4.5 
ECG Data ..................................................................................................................................... 31 
 
ECG analyses ........................................................................................................................................... 31 
5.4.6 
Vital Sign Data ............................................................................................................................. 32 
 
Vital Sign Data Analyses ......................................................................................................................... 32 
5.4.7 
Physical Examination ................................................................................................................... 33 
5.4.8 
Neurological Examination ............................................................................................................ 33 
5.4.9 
Safety MRI Data ........................................................................................................................... 33 
5.4.10 
COVID-19 Related Safety Analysis .......................................................................................... 33 
5.5 
PHARMACOKINETICS ANALYSIS  ............................................................................................................. 34 
5.5.1 
Serum and CSF PK Concentration Profile ................................................................................... 34 
5.5.1 
Serum PK Parameters .................................................................................................................. 35 
5.6 
BIOMARKER ............................................................................................................................................ 35 
5.6.1 
Pharmacodynamics Analysis ........................................................................................................ 35 
5.6.2 
Structural MRI Analysis ................................................................................................................ 35 
5.6.3 
Tau PET Analysis ......................................................................................................................... 35 
 
By visit summary ..................................................................................................................................... 36 
5.7 
ANTI-DRUG ANTIBODY ANALYSIS .......................................................................................................... 36 
5.7.1 
Analysis Methods for Anti-Drug Antibody Data ........................................................................... 36 
5.8 
ADDITIONAL EXPLORATORY ENDPOINTS ................................................................................................ 36 
5.8.1 
Health Outcomes .......................................................................................................................... 36 
6 
APPENDIX I: VISIT WINDOW MAPPING ......................................................................................... 37 
REFERENCE ..................................................................................................................................................... 47 
 
 


 
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List of Abbreviations  
AD 
Alzheimer’s disease
ADA 
Anti-drug Antibody
ADAS-Cog 13 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale (13 items)
ADCOMS 
AD Composite Score 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study - Activities of Daily Living 
Inventory  
ADCS-iADL  
ADCS-ADL Instrumental Total Score  
ADCS-bADL  
ADCS-ADL Basic Total Score  
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
APTT 
Activated Partial Thromboplastin Tim 
AST 
aspartate aminotransferase 
BLQ 
below the limit of quantification 
BMI 
body mass index 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CDR 
Clinical Dementia Rating  
CDR-SB 
Clinical Dementia Rating-Sum of Boxes
CI 
confidence interval
Ctrough 
Observed trough serum BIIB092 concentration collected at end of 
dosing interval (before next infusion starts) 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale  
CV 
coefficient of variation 
DKEFS 
Delis-Kaplan Executive Function System 
DSST 
Digit Symbol Substitution Test 
ECG 
electrocardiogram 
EMACC 
Early AD/ MCI Alzheimer’s Cognitive Composite 
Emax 
Maximum response 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
FAQ 
Functional Activities Questionnaire
FAS 
Full Analysis Set
eCOG 
Everyday Cognition
ICH 
International Conference on Harmonisation
INR 
Prothrombin Intl. Normalized Ratio
IRT 
interactive response technology
iADRS  
The Integrated Alzheimer’s Disease Rating Scale 
LS 
Lease Square Mean 
ISLR 
International Shopping List Test Delayed Recall
ISLT 
International Shopping List Test Immediate Recall
LLOQ 
lower limit of quantification
LTE 
long-term extension 
LP 
Lumbar puncture 
MA 
macrohemorrhages 
MCI 
mild cognitive impairment 


 
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MedDRA 
Medical Dictionary for Regulatory Activities 
mH 
microhemorrhages 
MMRM 
mixed-model repeated measures
MMSE 
Mini-Mental State Examination3 
 
MRI 
magnetic resonance imaging 
NPI-10 
Neuropsychiatric Inventory-10 
PC 
Placebo control 
PCP 
Placebo control period 
PCS 
potentially clinically significant 
PD 
Pharmacodynamics(s) 
PET 
positron emission tomography 
PLS 
Partial least squares 
PK 
pharmacokinetic(s) 
PT 
Preferred term 
PT 
Prothrombin Time 
Qol-AD 
Quality of Life for Alzheimer’s Desease 
QTcF 
Corrected QT interval by Fredericia
ROI 
region of interest
RUD-Lite 
Resource Utilization in Dementia – Lite Version
SAE 
serious adverse event
SAP 
statistical analysis plan
SD 
standard deviation
SOC 
System organ class
SS 
superficial siderosis
SUVR 
standard uptake value ratio
TEAE 
treatment-emergent adverse event
TIV  
Total Intracranial Volume  
Trails A 
Trail Making Test, Part A 
ULN 
upper limit of normal 
VE 
vasogenic edema 
WHO 
World Health Organization 
ZBI 
Zarit Burden Interview 


 
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1 Introduction 
This statistical analysis plan (SAP) covers the analyses of the LTE period and the analyses 
across both the placebo-controlled period and the LTE period of the study, 251AD201. A 
separate SAP has been prepared for the analyses of the placebo-controlled period.  
Unless stated otherwise, all statistical tests will be 2-sided with statistical significance level of 
0.05.  
The statistical software, SAS® will be used for all summaries and analyses. 
2 DESCRIPTION OF LONG-TERM EXTENSION (LTE) 
OBJECTIVES AND ENDPOINTS  
2.1 
Primary LTE Objective and Endpoint 
The primary objective for the long-term extension (LTE) period is to evaluate the long-term 
safety and tolerability of BIIB092 in participants with MCI due to AD or with mild AD. 
The primary safety endpoint that relates to this objective is the incidence of AEs and SAEs 
over the placebo-controlled period and LTE period of the study. 
2.2 
 Exploratory LTE Objectives and Endpoints 
 To further 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 238. 
 To further assess the effect of BIIB092 on disease progression as measured by fluid and 
radiological biomarkers, as well as additional clinical and health outcomes as measured 
by the following: 
 Changes over the placebo-controlled period and LTE period on the CDR-SB, 
MMSE, ISLT, Category Fluency and Letter Fluency tests from the DKEFS, 
DSST, Trails A, eCog, ADCS-ADL, FAQ, ADAS-Cog-13 (13-item), and NPI-
10 
 Changes over the placebo-controlled period and LTE period on the ZBI, QoL-
AD, and RUD-Lite 
 Changes over the placebo-controlled period and LTE period in CSF and blood 
biomarkers (for those who consent to participate in the optional CSF sampling 
substudy) 
 Changes over the placebo-controlled period and LTE period on 18F-MK6240 
PET and MRI brain morphometric measures (for those who consent to 
participate in the optional PET substudy) 
 To assess BIIB092 PK in serum (trough serum BIIB092 concentrations) and in CSF 
(for those who consent to participate in the optional CSF sampling substudy) from the 
samples collected at the visits indicated in the Schedule of Activities in participants 
with MCI due to AD or with mild AD. 


 
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2.3 
Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group study 
consisting of a double-blind, placebo-controlled period and an LTE period. 
The study includes 2 substudies to address exploratory study objectives: a tau PET substudy 
and a CSF sampling substudy. The tau PET substudy is mandatory at study sites that have 
access to the 18F-MK6240 PET radioligand and have the capability to perform 18F-MK6240 
PET scans. During the placebo-controlled period, the CSF sampling substudy is mandatory at 
all study sites that do not have access to the 18F-MK6240 PET radioligand. Participants will 
provide consent during Screening to participate in at least 1 of these substudies during the 
placebo-controlled period. Participants enrolled in the LTE period and who are participating in 
the tau PET substudy are required to continue participation in the tau PET substudy. 
Participation in the CSF sampling substudy during the LTE will be optional for all study 
participants, although participation is encouraged. 
This study will be conducted in participants aged 50 to 80 years, inclusive, with MCI due to 
AD or mild AD according to National Institute on Aging-Alzheimer’s Association criteria. 
Participants must have amyloid beta positivity confirmed at Screening by either CSF sampling 
or an amyloid PET scan. Participants must also perform at least 1 standard deviation below the 
age-adjusted normative mean on either the ISLT or the International Shopping List Test 
Delayed Recall and have a CDR global score of 0.5 for MCI due to AD or 0.5 or 1 for mild 
AD, an MMSE score of 22 to 30 (inclusive), and a CDR Memory Box score of ≥0.5. 
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. 
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. 
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. 
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. 


 
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 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 104, 128, 
152, 176, 200, 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. 
Certain visits during the study may be conducted as home visits as specified in the Schedule of 
Activities, if the Investigator is in agreement and appropriate services are available to perform 
the required study procedures and adequately monitor for potential safety events. 
 


 
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2.4 
Study Schematic 
Figure 1: Study Design 
 
Aβ = amyloid beta; AD = Alzheimer’s disease; EOS = End of Study; LTE = long-term extension; MCI = mild 
cognitive impairment; N = 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 


 
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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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3 Definitions 
3.1 
Analysis Sets 
 Full Analysis Set (FAS):  
The FAS includes all randomized subjects who received at least one dose of study treatment 
(BIIB092 or placebo). In analyses performed on the FAS, subjects will be analyzed, based on 
the intention-to-treat principle, according to their randomized treatment assignment regardless 
of treatment received.  
 
 
 Safety Analysis Set:  
The safety Analysis Set includes all randomized subjects who received at least one dose of 
study treatment (BIIB092 or placebo), essentially the same set of participants included in the 
FAS. In analyses performed on the Safety Analysis Set, subjects will be analyzed according 
to their actual treatment received. 
 
 Safety MRI Evaluable Set: 
The Safety MRI Evaluable Set is defined as subjects in the FAS who had at least one post-
baseline safety MRI scan. 
 
 Serum PK Evaluable Set:  
The serum PK evaluable set is defined as subjects in the FAS who had at least one measurable 
post-baseline BIIB092 concentration in serum before the End of Study of LTE. 
 
 CSF PK Evaluable Set:  
The CSF PK evaluable set is defined as subjects in the FAS who had at least one measurable 
post-baseline BIIB092 concentration in CSF. 
 
 CSF PD Evaluable Set:  
The CSF PD evaluable set is defined as subjects in the FAS who had lumbar puncture (LP), 
which will be used in analyses, such as subject accounting and summary of AE related to LP. 
The CSF PD Modified Evaluable Set is defined as subjects in the FAS who have baseline and 
at least one post baseline assessment of the specific parameter being analyzed in CSF. 
 
 Tau PET Evaluable Set 
The tau PET evaluable set is defined as subjects in the FAS who had tau PET, which will be 
used in analyses, such as subject accounting and summary of AE related to tau PET. The tau 
PET Modified Evaluable Set is defined as subjects in the FAS who had a valid baseline and a 
post-baseline tau PET SUVR measure using the 18F-MK6240 tracer. 
 


 
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 Anti-drug antibody (ADA) Evaluable Set: 
The evaluable set for anti-drug antibody is defined as subjects in the FAS who have an 
evaluable post-baseline ADA sample. 
 
3.2 
Analyses Period 
Depending on the purpose, different analyses will be conducted on the following study periods: 
1. LTE period. Only data in the LTE period will be included in these analyses. This LTE 
analysis period will be applied to all the AE analyses, and the analyses will include all 
subjects who were dosed in the LTE period. 
2. Placebo-controlled and LTE period. All the data in the placebo-controlled and LTE periods 
will be included in these analyses. This analysis period will be applied to analyses 
including, but not limited to all efficacy analyses and listings. The analyses will include all 
subjects who were dosed in the study including those who did not enroll into the LTE 
period. For example, line plot of CDR sum of box mean change from baseline over time. 
in the placebo-controlled and LTE period.  
3. Placebo-controlled and LTE active treatment period. Active treatment period is defined as 
the study period(s) that a subject received BIIB092. For early start subjects – subjects who 
received BIIB092 in both placebo-controlled and LTE period, all the data (placebo-
controlled and LTE periods) will be included in the analyses. For late start subjects – 
subjects who received placebo in the Placebo-controlled period and BIIB092 in the LTE 
period, only data in the LTE period will be included. This analysis period will be applied 
to majority of safety tables, and the analyses will include all subjects who were dosed in 
the study except for subjects who received only placebo in the placebo-controlled period 
and did not get dosed in the LTE period.  An example is the incidence rate of adverse events 
in the placebo-controlled and LTE active treatment period.     
Subjects to be included in a certain output is determined by both the analysis set and the analysis 
period. For example, the incidence table of adverse events in the LTE period will include subjects 
in the safety population for the LTE period, i.e., all randomized subjects who received at least one 
dose of study treatment in the LTE period. The incidence rate table of adverse events in the 
placebo-controlled and LTE active treatment period will include subjects in the safety population 
for the active treatment period, i.e., all randomized subjects who received at least one dose of study 
treatment in the active treatment period. In this SAP we do not separately define the analysis set 
in each analysis period. 
3.3 
Study Treatment 
For efficacy and health outcome analyses, the following LTE treatment groups of BIIB092 (per 
randomization) will be evaluated: 
 low-dose (BIIB092 -125mg once every 4weeks or 375mg once every 12weeks) 


 
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 medium-dose (BIIB092 - 600mg once every 4 weeks) 
 early start high-dose (BIIB092 - 2000mg once every 4 weeks) 
 late start high-dose (BIIB092 - 2000mg once every 4 weeks) 
For other analyses, such as safety, PK, PD, biomarker, and anti-drug antibody analyses, low dose 
group will be split out for different frequencies. The following LTE treatment groups of BIIB092 
will be evaluated:  
 low-dose 125mg once every 4weeks 
 low-dose 375mg once every 12weeks  
 medium-dose (BIIB092 - 600mg once every 4 weeks)  
 early start high-dose (BIIB092 - 2000mg once every 4 weeks) 
 late start high-dose (BIIB092 - 2000mg once every 4 weeks) 
 
Since subjects in low-dose group and medium-dose group are taking the same treatment from the 
start of placebo-controlled period to the end of LTE period, so the subjects in these treatment 
groups are all considered as early start subjects. Late start subjects refer to subjects who were on 
placebo during placebo-controlled period then switched to high-dose (BIIB092 - 2000mg once 
every 4 weeks). Throughout this SAP, these study treatment schemes will be referred as LTE 
treatment. 
3.4 
Dates and Points of Reference 
The study day and baseline are defined for each analyses period respectively  
 
1. LTE period 
 Study Day 1: the date of the first dose of study treatment in the LTE period 
 Study Day 
o For a date on or after Study Day 1 
Study Day = (Date of Interest) – (Study Day 1) + 1 
o For a date before Study Day 1 
Study Day = (Date of Interest) – (Study Day 1) 
 LTE baseline: the baseline value for the LTE period is defined as the most recent non-
missing measurement collected prior to the first dose in the LTE period. 
 Change from baseline will be defined as post-baseline value minus baseline value 
 
2. Placebo-controlled and LTE period  
 Study Day 1: the date of the first dose of study treatment in the PC period 


 
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 Study Day 
o For a date on or after Study Day 1 
Study Day = (Date of Interest) – (Study Day 1) + 1 
o For a date before Study Day 1 
Study Day = (Date of Interest) – (Study Day 1) 
 PC and LTE baseline: the baseline value for the Placebo-controlled and LTE period is 
defined as the most recent non-missing measurement collected prior to the first dose in 
the PC period. 
 Change from baseline will be defined as post-baseline value minus baseline value 
 
3. Placebo-controlled and LTE active treatment period 
 
 Study Day 1: the date of the first dose of BIIB092. For low-dose, medium-dose and 
early start high-dose subjects, this will be the date of first dose of BIIB092 in the 
placebo-controlled (PC) period; for late start high-dose subjects, this will be the date of 
first dose of BIIB092 in the LTE period.  
 Study Day 
o For a date on or after Study Day 1 
Study Day = (Date of Interest) – (Study Day 1) + 1 
o For a date before Study Day 1 
Study Day = (Date of Interest) – (Study Day 1) 
 Active treatment baseline: the baseline value for the active treatment period and is 
defined as the most recent non-missing measurement collected prior to study day 1. 
 Change from baseline will be defined as post-baseline value minus baseline value 
 
For data that are summarized by visit, assessment from all scheduled visits, EOS visit 
and unscheduled visits will be mapped to an appropriate analysis visit using a 
windowing scheme as describe in Appendix I 
3.5 
Key Derived Variables 
 Handling of missing items for scales  
o If any of the individual items for the primary efficacy endpoint and exploratory 
efficacy endpoints is missing, the total score of the corresponding endpoint will be 
imputed by prorating the observed scores [van Ginkel 2010]. 
o For ADAS-Cog13, if 3 or fewer of 13 items (<25%) are missing, the total score 
will be imputed by the following algorithm: Total score = total score from the 
completed items * [maximum total score (=85) / maximum total score for the 


 
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completed items]. The imputed number will be rounded up to the nearest integer. 
If more than 3 items are missing, the total score of ADAS-Cog 13 at that visit will 
be considered missing. 
o For ADCS-ADL, if 8 or fewer of 32 items (<25%) are missing, the total score will 
be imputed by a similar algorithm as that for ADAS-Cog 13. The imputed number 
will be rounded down to the nearest integer. If more than 8 items are missing, the 
total score for ADCS-ADL at that visit will be considered missing. 
o The same imputation algorithm will be applied to CDR-SB and MMSE, if only 1 
box (of 6) of CDR is missing or if only 2 or fewer items (out of 11) are missing for 
MMSE. The imputed CDR-SB will be rounded up to the nearest half integer, and 
the imputed MMSE will be rounded down to the nearest integer. If the score from 
more than 1 box of CDR or more than 2 items of MMSE is not available, the CDR-
SB or MMSE at that visit will be considered missing.  
o The total score of the tertiary endpoint NPI-10 and FAQ will be imputed using the 
same prorating principle and round up to the nearest integer if only 1 item (out of 
10) is missing.   
 
 
 iADRS derivation 
The iADRS is a composite score based on ADAS-Cog and ADCS-iADL (instrumental 
ADCS-ADL) [Wessels et al. 2015, Wessels et al. 2018]. The iADRS is calculated as a 
linear combination of total scores of the two individual components, the ADAS-Cog13 
(score range 0 to 85) and the ADCS-iADL (score range 0 to 59). Because higher score on 
the ADAS-Cog13 reflect worse performance, whereas higher scores on the ADCS-iADL 
reflect better performance, the ADAS-Cog score is multiplied by (-1) in the calculation of 
the integrated scale. To anchor the ADAS-Cog at 0, a constant (85) is added. The iADRS 
score is then computed as the sum of the transformed ADAS-Cog13 and the ADCS-ADL, 
as shown in the formula below:  
  
iADRS score = [ (-1) (ADAS-Cog13) + 85] + ADCS-iADL 
The iADRS score ranges from 0 to 144 with lower scores indicating worse performance.  
If either ADAS-Cog13 or ADCS-iADL is missing, the iADRS score will be considered 
missing. 
 
 EMACC derivation  
The EMACC is a new and sensitive composite of well-known and validated 
neuropsychological tests that is suitable for examining the effect of disease modifying 
compounds on cognitive decline in the early Alzheimer Disease or MCI stage of Alzheimer’s 
disease [Jaeger et al. 2018].  
Cognitive variables (ISLT, DKEFS Category Fluency total correct score, DKEFS Letter 
Fluency, DSST, Trails A total time to complete) will be z-score transformed using the 


 
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baseline score’s mean and SD. The EMACC will be computed by taking the average of the 
z-scores across the five tests. If Trails A is missing, EMACC will be computed by taking the 
average of the z-scores across the remaining four tests. For the rest 4 component scores, if 
any of them is missing then the composite score will be missing. 
 
 ADCOMS derivation 
ADCOMS is a novel instrument developed to improve the sensitivity of currently available 
cognitive and functional measures for subjects in the prodromal stage of AD and mild AD 
dementia. It consists of 4 Alzheimer’s Disease Assessment Scale–cognitive subscale items, 
2 Mini-Mental State Examination items, and all 6 Clinical Dementia Rating—Sum of Boxes 
items (Table 1). The composite score is a weighted linear combination of the individual 
scales items using the corresponding partial least squares (PLS) coefficients as weighting 
factors as listed in Table 1 [Wang et al. 2016]. If any of the individual item is missing, then 
the composite score will be missing. The range of ADCOMS is between 0 and 1.97. 
 
 
Table 1. 
Items included in ADCOMS and their corresponding PLS coefficients 
Scale 
Item name 
PLS coefficients 
ADAS-cog 
Delayed word recall 
Orientation 
Word recognition 
Word finding difficulty 
0.008 
0.017 
0.004 
0.016 
MMSE 
Orientation time 
Drawing 
0.042 
0.038 
CDR-SB 
Personal care 
Community affairs 
Home and hobbies 
Judgement and problem 
solving 
Memory 
Orientation 
0.054 
0.109 
0.089 
0.069 
0.059 
0.078 
ADAS-cog, Alzheimer’s Disease Assessment Scale–cognitive subscale; CDR-SB, 
Clinical Dementia Rating, sum of boxes; MMSE, Mini-Mental State Exam; PLS, partial 
least squares. 


 
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3.6 
Stratification Factors and Subgroup Variables 
Stratification factors are: 
 Tau PET/CSF sampling substudy enrollment (If subjects enrolled in both substudies, 
subjects will be counted as tau PET substudy) 
 Region (US, Australia, Japan, EU < EU countries include France, Germany, Italy, Spain, 
and Sweden >, Poland) 
 Baseline disease stage (MCI or mild AD) 
 Baseline AD symptomatic medication use (Yes/No) 
All stratification factors are based on subjects’ status at PC baseline. A comprehensive list of 
baseline AD symptomatic medication can be found in PC SAP.   
 
No subgroup analyses will be conducted.  
 
 
 


 
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4 List of Planned Study Analyses 
There are two milestone LTE analyses planned for this study: LTE analysis at PC period database 
lock and the final analysis. The final analysis, which is also known as End of LTE analysis, will 
only be performed when the LTE study is completed.  
 
4.1 
LTE interim analyses at PC period database lock 
 
The LTE interim analyses (IA) will be performed at the PC period database lock after the last 
patient out in the PC period. All the efficacy analyses described in Section 5.3 will be performed 
with available efficacy data up to week 104 at the PC period database lock. Given the timeline of 
scheduled data collection, only a few subjects will have tau PET, CSF biomarker and health 
outcomes data collected in LTE visits. No LTE analyses of tau PET, biomarker or health outcomes 
will be included at LTE IA at PC period database lock.  
 
4.2 
Final analysis 
The LTE analyses will be performed at the end of the LTE period database lock after the last 
patient out in the LTE period. All the analyses described in Section 5 will be performed with 
complete data of in the study.  
 
 
 


 
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5 Statistical Methods for Planned Analyses 
5.1 
General Considerations 
Summary tables will be presented using descriptive summary statistics. For continuous variables, 
summary statistics will generally include: number of subjects with data, mean, standard deviation, 
median, 25% percentile, 75% percentile, minimum and maximum. For categorical variables, this 
will generally include: number of subjects randomized or dosed, number with data, and the percent 
of those with data in each category. 
5.2 
Study Subjects 
The summaries in this section will be based on the FAS. Analysis period will be specified for each 
table or figure. Unless otherwise specified, summary tables will be presented by LTE treatment 
group. If not otherwise specified in later text in this SAP, listings will include all data in the 
placebo-controlled and LTE periods (all data in the study), with an indicator of the study period 
(pre-dosing, placebo-controlled, or LTE) for each record to indicate when the event occurred. 
Listings will be presented by LTE treatment group. 
5.2.1 Accounting of Subject 
Disposition in the LTE period will be summarized for subjects enrolled in LTE. The summary data 
will include number (%) of subjects randomized and dosed, number (%) of subjects who completed 
the treatment/study in LTE, and number (%) of subjects who discontinued treatment and/or 
withdrew from study in LTE. For subjects who discontinued treatment and/or withdrew from 
study, the reasons for discontinuation and/or withdrawal, days on treatment and days on study in 
LTE period will be summarized and listed.  
Number (%) of subjects who completed the placebo-controlled period but did not enter the LTE 
period, number (%) of subjects enrolled in LTE (who signed the LTE informed consent) and 
number (%) of subjects dosed in LTE period will be summarized by LTE treatment group.  
5.2.2 Demographics and Baseline Characteristics 
Demographics, baseline characteristics, medical history and AD treatment history at PC period 
baseline will be summarized for subjects enrolled in the LTE period. Please refer to the SAP for 
the placebo-controlled period. 
 Concomitant Medications and Non-drug Therapies 
The number (%) of subjects taking concomitant medication and non-drug therapies in the LTE 
period will be summarized. In addition, number of subjects in the FAS that have taken any 
concomitant medications in the placebo-controlled and LTE active treatment period will be 
summarized. Concomitant medications and non-drug therapies will be listed for placebo-
controlled and LTE period.  


 
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For subjects enrolled in the LTE period, the number (%) of subjects taking AD symptomatic 
medications concomitantly during the LTE period will be summarized. Please refer to the placebo-
controlled SAP for definitions of concomitant therapies and AD symptomatic medication use at 
baseline. 
Disallowed Therapies 
Per Section 11.4.1.2 of the Protocol, prohibited and/or restricted medications taken prior to study 
treatment administration and during the study will be monitored. Disallowed therapies will be 
reported as Protocol Deviations.  
5.2.3 Protocol Deviations 
Protocol deviations identified during site monitoring will be captured in a Protocol Deviation log 
and categorized as major or minor deviations based on Protocol Deviation Classification. The 
major protocol deviations occurred in the LTE period will be summarized for subjects enrolled in 
LTE. The major protocol deviations for all FAS subjects in the combined placebo-controlled and 
LTE periods will also be summarized.  Major and minor protocol deviations for all FAS subjects 
will be listed, respectively, across the placebo-controlled period and the LTE period. Subjects who 
had incorrect dose assigned by interactive response technology (IRT) in LTE will be summarized 
and listed. This data will be provided by the unblinded monitors. All summaries for protocol 
deviations will be presented only by LTE treatment group. 
5.2.4 Study Drug Exposure and Study Drug Compliance 
A summary table of study drug exposure and compliance in the placebo-controlled and LTE active 
treatment period will be provided. Number of infusions (BIIB092) received will be summarized 
as a categorical variable (categories as integers from 1 to 20, and 1-5, 6-10, 11-15, 15-20, 21-26) 
as well as a continuous variable. Number of weeks on study treatment (BIIB092), calculated as 
(date of last dose – date of first dose +1)/7, will be summarized as a categorical variable (every 8 
weeks from 0 to >= 96 weeks) as well as a continuous variable. Percentage of study treatment 
taken up to the last dose, calculated as (the actual number of infusions / by the number of infusions 
a subject is expected to take until the date of last infusion) *100, will be summarized as a 
continuous variable. This table will be presented only by LTE treatment group. Similar outputs 
will also be generated for LTE period.  
A listing of study drug administration records will be provided for the combined placebo-
controlled and LTE period. 
5.2.5 COVID-19 Related Analysis 
 Accounting of subjects who discontinued due to COVID-19 
The disposition table due to COVID-19 will be generated for LTE period. The listing of subjects 
who discontinued treatment and/or withdrew from study due to COVID-19 will be generated for 
PC and LTE period. Please refer to the placebo-controlled SAP for more details. 


 
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 Concomitant Non-Drug Treatment for COVID-19 
The summary table for the number of subjects using concomitant Non-Drug Treatment for 
COVID-19 will be summarized for both LTE period and PC and LTE active treatment period. 
Please refer to the placebo-controlled SAP for more details. 
 COVID-19 Effect on Drug Compliance 
Effect of COVID-19 on drug compliance may be assessed for LTE period. Please refer to the 
placebo-controlled SAP for more details. 
 COVID-19 Protocol Deviation 
The table of protocol deviations due to COVID-19 and the summary of impact and reason for 
major protocol deviations due to COVID-19 will be generated for LTE period. Please refer to the 
placebo-controlled SAP for more details. 
 Protocol Alternation Due to COVID-19cx 
Protocol alternation due to COVID-19 will be listed for PC and LTE period. Please refer to the 
placebo-controlled SAP for more details. 
5.3 
Efficacy Analysis 
5.3.1 General Considerations 
The analysis population for efficacy analysis is the same as the FAS and data from both the 
placebo-controlled and LTE periods will be include. All efficacy analyses will be presented by 
study treatment groups as defined in Section 3.3. The early start high-dose subjects are the subjects 
who were randomized to high-dose BIIB092 group in the PC period, and the late start high-dose 
subjects are the subjects who were randomized to Placebo in the PC period, regardless of 
enrollment of the LTE period or not.  
The following comparison will be evaluated for the long-term efficacy of BIIB092: 
 The early start high dose compared with the late start high dose. 
The comparisons between low-dose and late start high dose, and middle-dose and late start high 
dose might be conducted. There will be no multiple comparison adjustments. 
Visit windows for mapping efficacy endpoint 
For efficacy data that are summarized by visit, assessment from all scheduled visits, EOS visit and 
unscheduled visits will be mapped to an appropriate analysis visit using a windowing scheme 
(Appendix I). 


 
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5.3.2 Method of Analysis 
 Considerations for base MMRM model for change from baseline analyses 
A mixed model with repeated measures (MMRM) will be used to analyze changes from baseline 
in a parameter of interest using fixed effects of LTE treatment group, visit (categorical), LTE 
treatment group-by-visit interaction, baseline of the parameter of interest, baseline of the parameter 
of interest-by-visit interaction, region (Japan and Australia will be combined), baseline MMSE, 
baseline disease stage, and baseline AD symptomatic medication use.  The correlation between 
repeated measures of the outcomes will be taken into consideration.  An unstructured covariance 
matrix will be used to model the within-subject variance-covariance errors. If the unstructured 
covariance structure matrix results in a lack of convergence, the heterogeneous first-order 
autoregressive covariance structure followed by the heterogeneous Toeplitz covariance structure 
will be used. The least-squares (LS) means, the differences in LS means between each LTE 
treatment group versus placebo at each visit, 95% confidence intervals (CIs), and p-values will be 
presented. In the primary analysis of each endpoint, missing data are assumed to be missing at 
random [Rubin 1976]. 
 
For the LTE interim analysis at PC DBL, only records up to week 104 will be included in the 
MMRM model.  
  
5.3.3 Primary Efficacy Endpoint 
Estimand 1 (treatment policy strategy): The difference in change from baseline CDR-SB scores 
in subjects assigned to BIIB092 group in the PC period, comparing to late start BIIB092 group, 
regardless what actual treatment is received acknowledging a participant may miss more than four 
infusions, consecutively, change AD symptomatic medication and/or discontinue treatment early 
 Analysis set: all subjects in the FAS 
 Variable: The change from baseline CDR-SB scores at the week of interest regardless of 
intercurrent events (ICEs) 
 Analysis set level summary: Least square (LS) mean difference from MMRM model in 
change from baseline between BIIB092 and placebo 
 ICEs and Strategies for Addressing ICEs:  
ICEs include 
o AD symptomatic medication change (treatment policy strategy) 
o Treatment discontinuation (treatment policy strategy) 
o Missing more than or equal to four infusions consecutively (treatment policy 
strategy) 
Since a treatment policy strategy will be used for all ICEs in this estimand, all observed data will 
be included regardless of miss more than or equal to four infusions consecutively, treatment 
discontinuation or AD symptomatic medication change. At LTE interim analysis, the primary 


 
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analysis is the mean difference of the change from baseline CDR-SB scores at Week 104 between 
treatment groups in the FAS who have a baseline and at least one post-baseline CDR-SB score 
[ICH E9 (R1) Addendum 2014, 2017]. At final analysis, the primary analysis is the mean 
difference of the change from baseline CDR-SB scores at the week of interest between treatment 
groups in the FAS who have a baseline and at least one post-baseline CDR-SB score. All observed 
data will be included in the primary analysis, including data collected after intercurrent events 
[ICH E9 (R1) Addendum 2017], i.e., treatment discontinuation or a change in concomitant use of 
AD symptomatic medication 
The baseline and change from baseline CDR-SB scores at each post-baseline visit will be 
summarized by LTE treatment group. A mixed model with repeated measures (MMRM) will be 
used to analyze changes from Baseline in CDR-SB as described in Section 5.3.2.1.A line plot of 
adjusted mean change from baseline over time will be provided.  
5.3.4 Exploratory Efficacy Endpoints 
The clinical endpoints assessing AD progression from Baseline include the results of the MMSE, 
ADAS-Cog13, ADCS-ADL, ISLT, eCog, FAQ, NPI-10, EMACC (composite score of ISLT, 
DKEFS, DSST, and Trails A), ADCOMS (composite score of selected items from CDR, MMSE, 
and ADAS-Cog 13) and iADRS.  
 
The by visit summary and MMRM analysis will be performed for MMSE, ISLT, eCog, ADCS-
ADL, FAQ, ADAS-Cog-13 (13-item), NPI-10, EMACC, ADCOMS, and iADRS as described in 
Section 5.3.2.1. For LTE interim analysis at PC DBL, all available records up to week 104 will be 
analyzed in MMRM table. The baseline and change from baseline scores at each post-baseline 
visit will be summarized by LTE treatment group at final analysis. 
 
5.4 
Safety Analyses 
5.4.1 General Considerations 
 Analysis Population 
The safety analysis set will be used for safety analyses of AEs, SAEs, clinical laboratory data, 
Columbia Suicide Severity Rating Scale (C-SSRS) data, ECG data and vital sign data.  The safety 
MRI evaluable set will be used for the analysis of safety MRI data. 
 
 LTE Safety Treatment Groups 
Since all the subjects are supposed to receive active treatment in LTE, the LTE safety treatment 
groups which are the same as the LTE treatment groups will be used for all the safety analyses. 


 
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 Incidence, Incidence Proportion and Incidence Rate 
 Incidence and incidence proportion will be provided in incidence proportion tables. Incidence 
is defined as the number of subjects who experienced an event. Incidence proportion is defined 
as the number of subjects who experienced an event divided by total number of subjects in the 
analysis population, i.e., percentage. Each subject will be counted only once within each 
category. 
  
 Incidence and incidence rate will be provided in incidence rate tables. Incidence rate of an 
event based on the entire follow-up time – defined as the number of subjects who experienced 
an event divided by the total of entire follow-up time among the subjects in the analysis set 
(e.g., incidence rate per 100 subject-years). The entire follow-up time for a subject (subject-
years) is defined as the sum of all subjects’ follow-up time, where a subject’s follow-up time 
is calculated as the number of days (inclusive) from first dose of study drug until the last day 
on study, divided by 365.25. Each subject will be counted only once within each category.  
5.4.2 Clinical Adverse Events  
Treatment-emergent AEs (TEAE) 
A treatment-emergent AE is defined as AE that started or worsened after the start of first infusion 
of study treatment in LTE period. 
First dose for below definitions is the first dose in LTE period 
To define treatment emergence for AEs with missing start or stop date or time the following 
additional criteria will be used: 
 if both the start and stop dates for a particular AE are missing, then that AE is considered 
treatment emergent; 
 if the start date for a particular AE is missing and the stop date/time falls after the first dose 
date/time, then that AE is considered treatment emergent; 
 if the start date for a particular AE was the same as the first dose date, and the start time was 
missing and stop time is after the first dose or missing, then that event is considered treatment 
emergent. 
For AEs with a partial start date, the following imputation method will be used to determine if the 
event is treatment emergent: 
 When only the day is missing, and the year/month is equal to the year/month of first dose date, 
and the AE stop date is missing or on/after the first dose date, then use the first dose date as 
AE start date. Otherwise impute the AE start date as the first day (1) of the AE start month 
 When the AE start month is missing, and the year equals to the year of first dose date, and the 
AE stop date is missing or on/after the first dose date, then use the first dose date as AE start 
date. Otherwise impute the AE start date as the first day (01January) of the AE start year 


 
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For AEs with a partial end date, the following imputation method will be used: 
 When only the day is missing, and the year/month equal to the year/month of the last date on 
study, then use the last date on study as AE stop date. Otherwise impute the AE stop date as 
the last day of the AE stop month 
 When the AE stop month is missing, and the year equals to the year of last date on study, then 
use the last date on study as AE stop date. Otherwise impute the AE stop date as the last day 
(31December) of the AE stop year 
Only TEAEs will be included in the tables, unless otherwise specified. All SAEs (including pre-
dosing SAEs) will be included in the listing of SAEs, with an indicator of pre-dosing or treatment-
emergent. Only TEAEs will be included in other AE listings, if not otherwise specified. A listing 
of AE will be provided for the combined placebo-controlled and LTE period. 
Pre-treatment AE: AE starting before LTE first dose are considered pre-treatment AE for LTE 
period if it does not qualify for above TEAE definition i.e., no worsening. 
 
Analysis period and analysis displays 
Analysis period will be specified for each output. However, for either analysis period in this SAP 
(LTE period or placebo-controlled and LTE active treatment period), AE data will be summarized 
by LTE treatment group (5 LTE treatment groups as low-dose BIIB092 125mg/4weeks, low-dose 
BIIB092 375mg/12weeks, medium-dose, early start high-dose, late start high-dose, and BIIB092 
total). Listings will include all data in placebo-controlled and LTE period (all data in the study), 
with an indicator of the study period (pre-dosing, placebo-controlled, or LTE) for each record 
when the event occurred.  
 Summary and Incidence Analysis 
Overall summary of AE table will be done for the LTE period and placebo-controlled and LTE 
active treatment period, presented by LTE treatment group. The following information will be 
summarized: the number of subjects with any AE, with any AE by maximum severity, the number 
of subjects with any related AE (related to study drug as assessed by investigator), the number of 
subjects with SAE, the number of subjects with related SAE, the number of subjects with AE 
leading to drug withdrawal, the number of subjects with AE leading to study withdrawal, and the 
number of subjects with a fatal event.  
The sorting order of AE incidence tables, unless otherwise specified, will be by decreasing 
frequency order of “BIIB092 total” column within each category in the tables presented by LTE 
treatment group. A subject is counted only once within each category in each table. For example, 
for the table of AEs by system organ class and preferred terms sorted by decreasing frequency 
presented by LTE treatment group, system organ class will be presented in decreasing frequency 
order of BIIB092 total column, and within each system organ class, preferred terms will be 
presented in decreasing frequency order of BIIB092 total column. A subject is counted only once 
within each system organ class and preferred term.  


 
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The following AE incidence tables will be provided for the LTE period. Selected tables (marked 
with *) will be presented for incidence rate of AEs for the placebo-controlled and LTE active 
treatment period: 
1. AEs by system organ class and preferred term sorted by decreasing frequency * 
2. AEs by system organ class and preferred term sorted by alphabetical order  
3. AEs by system organ class * 
4. AEs at least 2% higher in incidence by system organ class and preferred term for early start 
BIIB092 2000 mg/4wk compared to late start BIIB092 2000 mg/4wk presented only for 
LTE period 
5. AEs by preferred term * 
6. AEs by preferred term with an incidence of 5% or more 
7. AEs by maximum severity by system organ class and preferred term by decreasing 
frequency (System organ class will be presented alphabetically. Preferred terms will be 
presented in decreasing frequency order. Maximum severity will be presented within each 
preferred term in the order of mild, moderate, severe, unknown and total. A subject will be 
counted only once at the maximum severity within each system organ class and preferred 
term.)  
8. AEs by maximum severity by preferred term 
9. Severe AEs by system organ class and preferred term by decreasing frequency * 
10. Severed AEs by preferred term * 
11. Related AEs by system organ class and preferred term by decreasing frequency * 
12. AEs related to tau PET ligand by system organ class and preferred term by decreasing 
frequency (using tau PET population) 
13. SAEs by system organ class and preferred term by decreasing frequency * 
14. SAEs by preferred term * 
15. Related SAEs by system organ class and preferred term by decreasing frequency * 
16. SAEs with fatal outcome by system organ class and preferred term by decreasing frequency 
17. AEs that led to drug interrupted by system organ class and preferred term by decreasing 
frequency 
18. AEs that led to discontinuation of study treatment by system organ class and preferred term 
by decreasing frequency 
19. AEs that led to withdrawal from study by system organ class and preferred term by 
decreasing frequency 
20. AEs related to lumbar puncture (LP) by system organ class and preferred term (using CSF 
population)  


 
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The following listings will be provided.  
1. Listing of AEs 
2. Listing of SAEs (including pre-dosing SAEs) 
3. Listing of AEs that led to infusion interruption 
4. Listing of AEs that led to discontinuation of study drug 
5. Listing of AEs that led to withdrawal from study 
6. Listing of AEs related to tau PET ligands 
7. Listing of SAEs with fatal outcome 
8. Listing of AEs related to lumbar puncture (LP)  
9. Listing of death 
10. Listing of pre-treatment AEs 
  
 Incidence Rate Analysis  
Incidence rate of AEs based on the entire follow-up time for subjects with at least 1 AE in LTE 
period may be summarized by system organ class and preferred terms. The incidence rate tables 
will be presented by LTE treatment group. The entire follow-up time for LTE period is from the 
first dose in LTE period until the last day on study.  
Follow-up adjusted incidence rate of AEs may also be summarized for placebo-controlled and 
LTE active treatment period, ue to the different length of placebo-controlled and LTE active 
treatment period in early start versus late start high-dose BIIB002 subjects. The entire follow-up 
time is from the first dose in active treatment period (placebo-controlled period first dose of 
BIIB092 for early start subjects and LTE period first dose of BIIB092 for late start subjects) until 
the last day in the study.  
 Infusion Reactions 
Please refer to the placebo-controlled period SAP for infusion reaction definitions. The same 
infusion reaction tables as described in placebo-controlled period SAP will be summarized for 
LTE period by LTE treatment groups.  
 AE of Special Interest 
Please refer to the placebo-controlled period SAP for AEs of special interest. The same tables as 
described in placebo-controlled period SAP will be summarized for LTE by LTE treatment 
groups.  
 


 
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5.4.3 Clinical Laboratory Data 
The following clinical laboratory parameters are assessed in the protocol: 
 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 
neutrophils, monocytes, lymphocytes, eosinophils, and basophils 
 Blood chemistry: total protein, albumin, creatinine, BUN, uric acid, bilirubin (total and direct), 
alkaline phosphatase, ALT, AST, lactate dehydrogenase, gamma-glutamyl transferase, 
glucose, calcium, phosphorus, bicarbonate, chloride, sodium, and potassium 
 Urinalysis: color, specific gravity, pH, protein, glucose, leukocyte esterase, blood, and ketones 
(and microscopic examination, if abnormal) 
 Coagulation: Activated Partial Thromboplastin Time (APTT), Prothrombin Intl. Normalized 
Ratio (INR), Prothrombin Time (PT) 
Analysis period will be specified for each table or figure. Unless otherwise specified, all the 
laboratory tables will be summarized by LTE treatment group. Listings will include all data in the 
study, with an indicator of the study period (pre-dosing, placebo-controlled, or LTE) for each 
record when the assessment occurred. Listings will be presented by PC treatment group. 
 
Study day and analysis visit window for analyses using LTE baseline will be derived based on the 
first day of study drug in LTE. Details are specified in Appendix I.  
 Quantitative analyses  
For numeric laboratory parameters, actual values will be summarized by visit for all the visits in 
the placebo-controlled and LTE active treatment period. Number of evaluable subjects, mean, 
standard deviation, 25% and 75% quartiles, min and max values will be presented at each visit. 
Plots of mean actual values (with standard error) at each visit for all the visits in the placebo-
controlled and LTE active treatment period will be provided.  
Summary of change from baseline and percent change from baseline for numeric laboratory 
parameters will be done on the placebo-controlled and LTE active treatment period. LTE baseline 
will be used for late start high-dose group subjects, while placebo-controlled baseline will be used 
for the rest of the subjects (low-dose BIIB092 125mg/4weeks, low-dose BIIB092 375mg/12weeks, 
medium-dose, early start high-dose). Number of evaluable subjects, mean, standard deviation, 
25% and 75% quartiles, min and max values will be presented at each visit.  
Listings of individual laboratory measurements by patients for all the parameters will be provided.  
 
Visit windows for by visit summaries 


 
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For Laboratory data that are summarized by visit, assessment from all scheduled visits, EOT visit, 
EOS visit and unscheduled visits will be mapped to an appropriate analysis visit using a windowing 
scheme (Appendix I). 
 
 Qualitative analyses 
For qualitative analyses, all values will be included (not just the “analyzed record” within each 
visit window in the quantitative analyses). 
 
Shift analyses 
Laboratory data will be summarized using shift tables where appropriate for the placebo-controlled 
and LTE active treatment period. Each subject’s hematology, blood chemistry and urinalysis 
values will be flagged as “low”, “normal”, or “high” relative to the normal ranges of the central 
laboratory or as “unknown” if no result is available.   
For each parameter, the analysis will be based on subjects with at least one post-baseline value.  
Shifts from baseline to high/low status will be presented for hematology, blood chemistry 
coagulation, serology, and urinalysis.  Shift to low includes normal to low, high to low, and 
unknown to low; Shift to high includes normal to high, low to high, and unknown to high. Subjects 
need to have at least one post-baseline evaluation and a baseline value not low or high (including 
missing) in order to be included in the analysis for corresponding categories in the analyses. 
For early start subjects, the placebo-controlled baseline will be used and shifts that occurred in 
either placebo-controlled or LTE period will be included. For late start subjects, the LTE baseline 
will be used and shifts that occurred in the LTE period based on LTE baseline will be included. 
 
Potentially Clinically Significant laboratory abnormalities analyses 
Please refer to the placebo-controlled SAP for the parameters and criteria for potentially clinically 
significant laboratory abnormalities analyses.  
The number of subjects with potentially clinically significant laboratory abnormalities post-
baseline will be summarized for the placebo-controlled and LTE active treatment period.  
Subjects need to have at least one post-baseline evaluation in the active treatment period and a 
baseline value not potentially clinically significant (including missing) in order to be included in 
the analysis.  
Same as the shift analysis, for early start subjects, the placebo-controlled baseline will be used and 
abnormalities that occurred in either placebo-controlled or LTE period will be included. For late 
start subjects, the LTE baseline will be used and PCS abnormalities that occurred in the LTE period 
based on LTE baseline will be included. 
 


 
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Potential serious hepatotoxicity 
 
In this SAP, we define potential serious hepatotoxicity as ALT or AST > 3x ULN and total 
bilirubin > 2x ULN at any time post-baseline in the placebo-controlled and LTE active treatment 
period (not necessarily concurrent). A scatterplot of the maximum post-baseline ALT or AST 
value relative to ULN and maximum post-baseline total bilirubin value relative to ULN (not 
necessarily concurrent) for each subject will be provided. A line plot of ALT, AST, ALP and total 
bilirubin values over time in the active treatment period for subjects with potential serious 
hepatotoxicity will be provided. In addition, subjects with ALT > 1x ULN, >3x ULN, >5x ULN, 
>10x ULN or >20x ULN, subjects with AST > 1x ULN, >3x ULN, >5x ULN, >10x ULN or >20x 
ULN, subjects with total bilirubin >1x ULN or >2x ULN, subjects with ALP >1x ULN or >1.5x 
ULN, and subjects with AST or ALT > 3x ULN post-baseline accompanied by concurrently 
elevated total bilirubin >1.5x ULN or > 2x ULN in the active treatment period will be presented. 
A listing of subjects with potential serious hepatotoxicity will be provided with the concurrent 
records labeled. Concurrent is defined as on the same day. 
5.4.4 C-SSRS Data 
Suicidal ideation events include 11 categories: (1) Wish To Be Dead, (2) Non-Specific Active 
Thoughts, (3) Active Thoughts Without Intent To Act, (4) Active Thoughts With Some Intent—
No Plan, (5) Active Thoughts with Plan and Intent. Suicidal behavior events include: (6) 
Preparatory acts or behavior, (7) Aborted Attempt, (8) Interrupted Attempt, (9) Actual Attempt, 
(10) Suicidal behavior, (11) Completed Suicide. Another “Yes/No” question of whether the subject 
has engaged in non-suicidal self-injurious behavior is also collected.   
The analysis will be based on the safety population.  Number of subjects in each ideation category 
at any post-baseline visit, number of subjects in each suicidal behavior category at any post-
baseline visit, number of subjects with at least one suicidal ideation or behavior event at any post-
baseline visit, and subjects who have engaged in non-suicidal self-injurious behavior at any post-
baseline visit will be summarized in the placebo-controlled and LTE active treatment period.  A 
listing of C-SSRS data by subjects will be provided. 
5.4.5 ECG Data 
 ECG analyses 
Actual values of numeric ECG parameters will be summarized by visit. number of evaluable 
subjects, mean, standard deviation, 25% and 75% quartiles, min and max values will be presented 
at each visit for placebo-controlled and LTE period active treatment period. Similarly change from 
baseline values will be summarized in the same fashion for placebo-controlled and LTE active 
treatment period. 
Summary of ECGs (number of normal, <abnormal, not adverse event>, or <abnormal, adverse 
event>) at scheduled visits will be presented by the LTE treatment group through the placebo-
controlled and LTE active treatment period.   


 
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Shift table from normal or unknown ECG at baseline to ever abnormal ((<abnormal, not adverse 
event>, or <abnormal, adverse event>) post-baseline ECG will be summarized for the placebo-
controlled and LTE active treatment group. The worst post-baseline record of each subject is 
selected.   
For the above mentioned ECG analyses, for early start subjects, the placebo-controlled baseline 
will be used while for late start subjects, the LTE baseline will be used. 
In addition, PR and QTcF values will be summarized. Please see the detail in the SAP for placebo-
controlled period. 
 
Visit windows for by visit summaries 
For ECG data that are summarized by visit, assessment from all scheduled visits, EOT visit, EOS 
visit and unscheduled visits will be mapped to an appropriate analysis visit using a windowing 
scheme (Appendix I).   
5.4.6 Vital Sign Data 
 Vital Sign Data Analyses 
Vital sign parameters include temperature, diastolic blood pressure, systolic blood pressure, heart 
rate, and respiration rate. The descriptive statistics for actual values will be summarized by all the 
visits in the combined placebo-controlled and LTE active treatment period.  The lines of mean 
vital sign over time by LTE treatment group will be graphed in the combined placebo-controlled 
and LTE active treatment period. 
Summary of change from baseline including number of subjects, mean, standard deviation, 
median, minimum, and maximum values will be summarized in the placebo-controlled and LTE 
active treatment period.  Placebo-controlled baseline will be used for early start subjects and LTE 
baseline will be used for late start analysis.   
A by-patient listing for all vital sign parameters in the combined placebo-controlled and LTE 
period will also be presented. 
The analysis of vital signs will also focus on the incidence of clinically relevant outliers.  
For details of criteria to assess potential clinically relevant outliers in vital sign, refer to section 
5.4.6 in the SAP for the placebo-controlled period. The number of clinically relevant outliers 
determined by each criterion will be summarized across combined placebo-controlled and LTE 
active treatment period by treatment group.     
 
Visit windows for by visit summaries 
For vital sign data that are summarized by visit, assessment from all scheduled visits, EOT visit, 
EOS visit and unscheduled visits will be mapped to an appropriate analysis visit using a windowing 
scheme (Appendix I). 


 
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5.4.7 Physical Examination 
Clinically significant findings during physical examinations will be recorded as AEs. Abnormal 
findings from physical examination will be included in AE listing.. 
5.4.8 Neurological Examination 
Clinically significant findings during neurological examinations will be recorded as AEs. 
Abnormal findings from neurological examination will be included in AE listing.. 
5.4.9 Safety MRI Data 
The following MRI data will be summarized by LTE treatment group using safety MRI population 
for placebo-controlled and LTE active treatment period: 
 Number of subjects with new or worsening of vasogenic edema (VE) at post-baseline 
o New VE or questionable VE is considered as subjects who has a VE which is worsening 
as post-baseline or for the following: 
- 
The subject has answered “Not-Applicable” at any post-baseline visit for question: 
VE on this MRI as compared to previous MRI 
- 
The subject has answered “VE present and increased in size” at any post-baseline 
visit for question: VE on this MRI as compared to previous MRI 
o Worsening of VE from baseline is defined as any severity increase compared to 
baseline. The following sequence indicates the increase of the severity: 
No VE present < Questionable presence of VE (Mild Severity) < Questionable presence 
of VE (Moderate Severity) < Questionable presence of VE (Severe Severity) < VE 
present (Mild Severity) < VE present (Moderate Severity) < VE present (Severe 
Severity) 
 
 Number of subjects with new microhemorrhages (mH) findings at post-baseline 
o New mH is define as subjects who has mH increased in number and/or size at any post-
baseline comparing to the baseline. If a subject has no mHs at baseline, then new mH is 
defined as any initial identification at any post-baseline visit. 
 Number of subjects with macrohemorrhages (MA) (>1cm) at post-baseline 
 Number of subjects with new superficial siderosis (SS) (>1cm3) at post-baseline 
 Number of subjects with new SS (≤1cm3) at post-baseline 
5.4.10 COVID-19 Related Safety Analysis 
All AE tables due to COVID-19 will be summarized for LTE period and PC and LTE active 
treatment period. Please refer to the placebo-controlled SAP for more details. 


 
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5.5 
Pharmacokinetics Analysis  
The Serum PK evaluable set as defined in Section 3.1, will be used for the description of the serum 
concentration data, and for the estimation of serum PK parameters. The CSF PK evaluable set as 
defined in Section 3.1, will be used for the description of CSF concentration data. PK analysis will 
be conducted with serum and CSF concentrations of BIIB092 by visit and dose group. Subjects 
who receive BIIB092 125mg once every 4 weeks will be analyzed separately from those who 
receive 375mg once every 12 weeks. The summaries and listing will be done using the combined 
placebo-controlled and LTE active treatment period.  
Atypical drug concentrations (e.g., very low or very high) will be excluded from the analysis, if 
no apparent explanation exists.  Concentration observations will also be removed from the data set 
if  
i)  
corresponding dosing or sampling times are missing or cannot be reconstructed 
ii)  
large deviations between actual administered dose and nominal dose exists 
iii)  
large deviations between scheduled and actual sampling days or times exists 
iv)  
large deviations between actual and nominal dose administration time exists.   
All deletions of data points will be appropriately documented.  
5.5.1 Serum and CSF PK Concentration Profile 
Individual serum and CSF concentrations will be listed for BIIB092. Concentrations below the 
lower limit of quantification (LLOQ) will be indicated by “BLQ”. Differences between scheduled 
and actual sampling times will be listed for these subjects, along with the percentage differences 
between nominal and actual dose amount. Additional listings may be generated as deemed 
necessary. 
Descriptive statistics (N, arithmetic mean, standard deviation, geometric mean, CV, median, 
minimum, and maximum), will also be used to summarize serum PK and CSF concentrations of 
BIIB092 by visit/scheduled time points and dose group. For the purpose of calculating typical 
descriptive statistics (n, mean, SD, %CV, geometric mean, geometric %CV, median, minimum, 
and maximum) for serum PK, BLQ value on pre-day 1 of study treatment will be set to 0, and all 
post first dose of study treatment BLQ values will be set to half the LLOQ value. In linear and 
semi- plots, all BLQ values will be treated as LLOQ/2. Mean CSF concentrations that are BLQ 
will be presented as BLQ, and the SD and %CV will be reported as not applicable.  When 
summarizing concentrations or PK parameters in serum and CSF, a minimum of 2 values are 
required to show the arithmetic mean and geometric mean, and at least 3 values are required to 
show the standard deviation and coefficient of variation (CV).    
Serum and CSF concentrations of BIIB092 will be plotted versus time by dose group on both a 
linear and a logarithmic scale.  Additional plots may be included as deemed necessary.  
CSF to serum concentration ratio will be computed using pre-infusion concentrations at week 12, 
48, 76, 128, 176, and 224. Individual ratios along with descriptive statistics (N, arithmetic mean, 
standard deviation, geometric mean, CV, median, minimum, and maximum) at 12, 48, 76, 128, 


 
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176, and 224 weeks, by dose will be listed. Any BLQ value will be excluded from CSF to serum 
ratio calculation, and exclusions will be appropriately documented. Individual CSF vs. serum 
concentrations above LLOQ (for both serum and CSF) will be plotted (scatter plot) by week, color 
coded by dose. 
5.5.1 Serum PK Parameters 
The following PK parameters will be listed per visit, as data permits, from serum concentration 
data: 
Parameter  
Definition/Calculation
Units
Ctrough 
Observed trough serum BIIB092 concentration collected at end of 
dosing interval (before next infusion starts)
ug/mL  
Individual PK parameter data will be listed. Descriptive statistics (N, mean, standard deviation, 
CV, median, minimum, and maximum) will be used to summarize the PK parameters by visit and 
dose. Geometric means (by visit and dose) will also be presented. Box plots and plots of individual 
Ctrough over time will be provided.  
 
5.6 
Biomarker 
The CSF PD evaluable set or CSF PD modified evaluable set as defined in Section 3.1, will be 
used for the statistical modeling of CSF PD data. 
5.6.1 Pharmacodynamics Analysis  
The actual, change from baseline, and percentage change from baseline of CSF N-terminal tau will 
be summarized to evaluate pharmacodynamics effect after multiple IV infusions of BIIB092. For 
descriptive statistics, BLQ is imputed as LLOQ/2. For individual subject listings, BLQs are listed 
as BLQ. Summary statistics will be generated showing N, mean, median, standard deviation, Q1, 
Q3, minimum and maximum results over time by treatment group for CSF N-terminal tau for 
placebo-control and LTE period.  
Mean (± standard error) plots of change from baseline of CSF N-terminal over time by treatment 
group and mean (± standard error) % change of CSF N-terminal tau over time by treatment group 
may be presented.  
 
5.6.2 Structural MRI Analysis 
No subjects reached week 226, the primary analysis timepoint for structural MRI. Therefore, 
structural MRI is not reported or statistically analyzed for the LTE period.  
5.6.3 Tau PET Analysis  
 


 
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All tau PET analysis will be using tau PET evaluable set defined in Section 3.1 
 By visit summary 
The baseline, change and percent change from baseline tau PET SUVR scores will be 
summarized by LTE treatment groups by visit for placebo-controlled and LTE period for each 
primary (Braak 1&2, Braak 3&4, and Braak 5&6) and secondary (Posterior composite, Temporal 
composite, Amyloid composite, Frontal cortex, Parietal cortex, Occipital cortex, Anterior 
cingulate cortex, Posterior cingulate cortex, Lateral temporal cortex, Inferior temporal cortex, 
Medial temporal lobe, Lateral temporal lobe) target region and primary reference region 
(Cerebellum (superior section eroded)). Visit window is defined in Appendix I.  
5.7 
Anti-Drug Antibody Analysis 
5.7.1 Analysis Methods for Anti-Drug Antibody Data 
Anti-Drug Antibody (ADA) population will be used to analyze ADA data.  
The baseline value is defined as the last available value prior to first dose of placebo or BIIB092 
in placebo-controlled period. For subjects with missing baseline assessment, the most conservative 
approach will be taken and they will be considered negative for ADA at baseline. 
For the definitions of treatment emergent positive, persistently positive, and transiently positive, 
please refer to the placebo-controlled SAP. 
Summary table listing the number and percentage of all anti-BIIB092-positive and -negative 
antibody events by LTE treatment group and visits throughout the placebo-controlled and LTE 
active treatment period will be displayed.   
In addition, a summary table of patients with treatment-emergent, persistent, and transient 
responses will be presented by LTE treatment group during the placebo-controlled and LTE active 
treatment period. A listing of anti-BIIB092 antibody results will also be provided. 
Visit windows for by visit summaries 
For ADA data that are summarized by visit, assessment from all scheduled visits, EOT visit, and 
unscheduled visits will be mapped to an appropriate analysis visit using a windowing scheme 
(Appendix I). 
5.8 Additional Exploratory Endpoints 
5.8.1 Health Outcomes  
The FAS will be used for the analysis of health outcomes data for LTE period. The result will be 
listed by LTE treatment group for placebo-controlled and LTE period. 
 
 
 


 
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6 Appendix I: Visit Window Mapping 
For data that are summarized by visit and longitudinal analysis, assessment from all scheduled 
visits including EOT visit and EOS visit, and all unscheduled visits will be mapped to an 
appropriate analysis visit using a windowing scheme. Analysis visit windows are defined in [Table 
1 - Table 12] for different endpoints.  
If there are 2 or more assessments from visits other than EOT or EOS visits mapped to the same 
analysis visit for a subject, the assessment that is closest to the target visit day will be used for 
analysis.  If there are 2 or more assessments from visits other than EOT or EOS visits mapped to 
the same analysis visit with the same distance from the target visit day, then select the later one(s) 
for the analysis.  If there are 2 or more assessments from visits other than EOT or EOS visits 
mapped to the same analysis visit and on the same day, use the average value for quantitative 
parameters and the worst value for qualitative parameters for analysis. 
 
Table 1. 
Visit Windows for Efficacy Endpoints 
Efficacy 
Endpoint 
Analysis visit 
Target visit day  
Analysis visit window 
CDR, 
NPI-10, 
ADAS-Cog13, 
FAQ, 
and 
ADCS-ADL 
Baseline 
1 
Most recent non-missing pre-dose value 
Week 24 
169 
[2, 267] 
Week 52 
365 
[268, 456] 
Week 78 
547 
[457, the end day of the placebo-controlled period 
1]
Week 104 
729 
[one day after the start day of the LTE period2 , 
813]
Week 128 
897 
[814, 981] 
Week 152 
1065 
[982, 1149] 
Week 176 
1233 
[1150, 1317] 
Week 200 
1401 
[1318, 1492] 
Week 226 
1582 
≥1493 
ISLT, 
DKEFS, 
DSST, Trails A,  
Baseline800- 
1 
Most recent non-missing pre-dose value 
Week 12 
85 
[2, 141] 
Week 28 
197 
[142, 239] 
Week 40 
281 
[240, 337] 
Week 56 
393 
[338, 435] 
Week 68 
477 
[436, 512] 
Week 78 
547 
[513, the end day of the placebo-controlled period 
1]
Week 108 
757 
[one day after the start day of the LTE period2, 
841]


 
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Efficacy 
Endpoint 
Analysis visit 
Target visit day  
Analysis visit window 
Week 132 
925 
[842, 1009] 
Week 156 
1093 
[1010, 1261] 
Week 204 
1429 
[1262, 1506] 
Week 226 
1582 
≥1507 
eCog 
Baseline 
1 
Most recent non-missing pre-dose value 
Week 28 
197 
[2, 295] 
Week 56 
393 
[296, 470] 
Week 78 
547 
[471, the end day of the placebo-controlled period 
1]
Week 108 
757 
[one day after the start day of the LTE period2, 
841]
Week 132 
925 
[842, 1009] 
Week 156 
1093 
[1010, 1261] 
Week 204 
1429 
[1262, 1506] 
Week 226 
1582 
≥1507 
MMSE 
Baseline 
1 
Most recent non-missing pre-dose value 
Week 12 
85 
[2, 127] 
Week 24 
169 
[128, 225] 
Week 40 
281 
[226, 323] 
Week 52 
365 
[324, 421] 
Week 68 
477 
[422, 512] 
Week 78 
547 
[513, the end day of the placebo-controlled 
period1]
Week 104 
729 
[one day after the start day of the LTE period2, 
813]
Week 128 
897 
[814, 981] 
Week 152 
1065 
[982, 1149] 
Week 176 
1233 
[1150, 1317] 
Week 200 
1401 
[1318, 1492] 
Week 226 
1582 
≥1493 
 
1 The end day of the placebo-controlled period is the last day on or before the first infusion in 
LTE for subjects who enter LTE and is the last day in study for subjects who do not enter LTE. 
2 The start day of the LTE period is the day of the first infusion in the LTE period. 
 


 
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Table 2. 
Visit Windows for Laboratory by Visit Summaries using Placebo-
Controlled Baseline 
Analysis visit  
Target visit day  
Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value
Week 12 
85 
[2, 127]
Week 24 
169
[128, 253]
Week 48 
337
[254, 421]
Week 72 
505
[422, 526]
Week 78 
547
[527, 630* or the end day of the placebo-controlled period1]
Week 90* 
631
[631, the last day in the study]
Week 100 
701
[the start day of the LTE period2, 785]
Week 124 
869
[786, 953]
Week 148 
1037 
[954, 1121]
Week 172 
1205 
[1122, 1289]
Week 196 
1373 
[1290, 1457]
Week 220 
1541 
[1458, 1562]
Week 226 
1582 
[1563, 1625]
Week 238 
1667 
≥1626
* Applicable only for the subjects who do not go to LTE. They are expected to have week 90 follow-up assessment. 
1 The end day of the placebo-controlled period is the last day before the first infusion in LTE for subjects who enter 
LTE and is the last day in study for subjects who do not enter LTE. 
2 The start day of the LTE period is the day of the first infusion in the LTE period.
 
Table 3. 
Visit Windows for Laboratory by Visit Summaries using LTE Baseline 
 
 
Analysis visit  
Target visit day Analysis visit window 
Protocol visit 
Baseline 
1 
Most recent non-missing value 
prior to the first infusion in LTE
 
Week 24 
169
[2, 253]
Week 100 
Week 48 
337
[254, 421]
Week 124 
Week 72 
505
[422, 526]
Week 148 
Week 100 
701
[527, 785]
Week 172 
Week 124 
869
[786, 953]
Week 196 
Week 148 
1037 
[954, 1121]
Week 220 and Week 226
Week 172 
1205 
≥1122 
Week 238 
Note: Study day and analysis visit window are derived based on the first day of study drug in LTE. 
 
Table 4. 
Visit Window for Coagulation Panel by Visit Summaries using Placebo-
Controlled Baseline 
Analysis visit  
Target visit day  
Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value 
Week 8 
57 
[2,183]
Week 44 
309 
[184, 407]
Week 72 
505 
[408, the end day of the placebo-controlled period1] 
Week 124 
869 
[the start day of the LTE period2, 1037] 
Week 172 
1205 
[1038, 1373]
Week 220 
1541 
> 1373


 
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1 The end day of the placebo-controlled period is the last day before the first infusion in LTE for subjects who enter 
LTE and is the last day in study for subjects who do not enter LTE. 
2 The start day of the LTE period is the day of the first infusion in the LTE period.
 
Table 5. 
Visit Window for Coagulation Panel by Visit Summaries using LTE 
Baseline 
Analysis 
visit  
Target 
visit day  
Analysis visit window 
Protocol visit 
Baseline 
Most recent 
non-missing 
value  
Most recent non-missing value prior to 
the first infusion in LTE 
Week 72 
Week 44 
309 
[2, 477] 
Week 124
Week 72 
645 
[478, 813]
Week 172
Week 124 
981 
> 813 
Week 220
 
Table 6. 
Visit Windows for ECG by Visit Summaries for Placebo-Controlled and 
LTE Period using Placebo-Controlled Baseline 
Analysis visit 
Target visit day 
Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value 
D1 Post dose 
1 
Day1: 15 min post dose or 1 hour post dose 
Week 12 
85 
[2, 127]
Week 24 
169 
[128, 253]
Week 48 
337 
[254, 421]
Week 72 
505 
[422, 526]
Week 78 
547 
[527, 630* or the end day of the placebo-controlled period1]
Week 90* 
631 
[631, the last day in the study]
Week 104 
729 
[the start day of the LTE period2, 813] 
Week 128 
897 
[814, 981]
Week 152 
1065 
[982, 1149]
Week 176 
1233 
[1150, 1317]
Week 200 
1401 
[1318, 1492]
Week 226 
1582 
[1493, 1625]
Week 238 
1667 
[1626, the end day of the LTE period] 
* Applicable only for the subjects who do not go to LTE. They are expected to have week 90 follow-up assessment. 
1 The end day of the placebo-controlled period is the last day before the first infusion in LTE for subjects who enter 
LTE and is the last day in study for subjects who do not enter LTE. 
2 The start day of the LTE period is the day of the first infusion in the LTE period.
 
Table 7. 
Visit Windows for ECG by Visit Summaries using LTE Baseline 
 
Analysis visit 
Target 
visit 
day 
Analysis visit window 
Protocol visit 
Baseline 
Most recent non-
missing 
value 
prior to the first 
infusion in LTE 
Most recent non-missing value prior to the 
first infusion in LTE 
Week 78 


 
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Analysis visit 
Target 
visit 
day 
Analysis visit window 
Protocol visit 
Week 24 
169 
[the start day of the LTE period, 253]
Week 104 
Week 48 
337 
[254, 421]
Week 128 
Week 72 
505 
[422, 589]
Week 152 
Week 104 
673 
[590, 757]
Week 176 
Week 128 
841 
[758, 932]
Week 200 
Week 152 
1023 
[933, 1065]
Week 226 
Week 176 
1107 
>1065
Week 238 
Day 1 is the first infusion day in LTE period
 
Table 8. 
Visit Windows for Vital Sign by Visit Summaries using Placebo-Controlled 
Baseline 
Analysis visit 
Target visit day  
Analysis visit window 
Baseline 
1 
Most recent non-missing pre-dose value
D1 Post dose  
1 
Day 1 post dose infusion (if more than one Day 1 
post dose results available, the average of the 
available results will be used)  
Week 4– Pre dose  
 
29  
[2, 43] (Pre-dose assessment)  
Week 4- Post dose 
29  
[2, 43] (Post dose assessment) 
Week 8– Pre dose 
57 
[44, 71] (Pre-dose assessment) 
Week 8- Post dose 
57 
[44, 71] (Post dose assessment) 
Week 12– Pre dose 
85 
[72, 99] (Pre-dose assessment) 
Week 12- Post dose 
85 
[72, 99] (Post dose assessment) 
Week 16 
113 
[100, 127]
Week 20 
141 
[128, 155]
Week 24 
169 
[156, 183]
Week 28 
197 
[184, 211]
Week 32 
225 
[212, 239]
Week 36 
253 
[240, 267]
Week 40 
281 
[268, 295]
Week 44 
309 
[296, 323]
Week 48 
337 
[324, 351]
Week 52 
365 
[352, 379]
Week 56 
393 
[380, 407]
Week 60 
421 
[408, 435]
Week 64 
449 
[436, 463]
Week 68 
477 
[464, 491]
Week 72 
505 
[492, 519]
Week 76 
533 
[520, 540]
Week 78 
547 
[541, 589* or the end day of the placebo-
controlled period1]
Week 90* 
631 
[590, the last day in the study] 
Week 80 
561 
[the start day of the LTE period2, 575]
Week 84 
589 
[576, 603]
Week 88 
617 
[604, 631]
Week 92 
645 
[632, 659]
Week 96 
673 
[660, 687]


 
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Analysis visit 
Target visit day  
Analysis visit window 
Week 100 
701 
[688, 715]
Week 104 
729 
[716, 743]
Week 108 
757 
[744, 771]
Week 112 
785 
[772, 799]
Week 116 
813 
[800, 827]
Week 120 
841 
[828, 855]
Week 124 
869 
[856, 883]
Week 128 
897 
[884, 911]
Week 132 
925 
[912, 939]
Week 136 
953 
[940, 967]
Week 140 
981 
[968, 995]
Week 144 
1009 
[996, 1023]
Week 148 
1037 
[1024, 1051]
Week 152 
1065 
[1052, 1079]
Week 156 
1093 
[1080, 1107]
Week 160 
1121 
[1108, 1135]
Week 164 
1149 
[1136, 1163]
Week 168 
1177 
[1164, 1191]
Week 172 
1205 
[1192, 1219]
Week 176 
1233 
[1220, 1247]
Week 180 
1261 
[1248, 1275]
Week 184 
1289 
[1276, 1303]
Week 188 
1317 
[1304, 1331]
Week 192 
1345 
[1332, 1359]
Week 196 
1373 
[1360, 1387]
Week 200 
1401 
[1388, 1415]
Week 204 
1429 
[1416, 1443]
Week 208 
1457 
[1444, 1471]
Week 212 
1485 
[1472, 1499]
Week 216 
1513 
[1500, 1527]
Week 220 
1541 
[1528, 1555]
Week 224 
1569 
[1556, 1576]
Week 226 
1582 
[1577, 1625]
Week 238 
1667 
[1626, the end of the LTE period] 
* Applicable only for the subjects who do not go to LTE. They are expected to have week 90 follow-up assessment. 
1 The end day of the placebo-controlled period is the last day before the first infusion in LTE for subjects who enter 
LTE, and is the last day in study for subjects who do not enter LTE. 
2 The start day of the LTE period is the day of the first infusion in the LTE period.
 
Table 9. Visit Windows for Vital Sign by Visit Summaries using LTE baseline 


 
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Analysis visit 
Target 
visit 
day  
Analysis visit window 
Protocol visit 
LTE Baseline 
1 
Most recent non-missing value 
prior to the first infusion in LTE
Week 80 pre dose 
D1 Post dose  
1 
Day 1 post dose infusion (if more 
than one Day 1 post dose results 
available, the average of the 
available results will be used)
Week 80 post dose 
Week 4– Pre dose 
29 
[2, 43] (Pre-dose assessment)
Week 84 (Pre-dose assessment)
Week 4-- Post dose 
29 
[2, 43] (Post dose assessment)
Week 84 (Post dose assessment)
Week 8– Pre dose 
57 
[44, 71] (Pre-dose assessment)
Week 88 (Pre-dose assessment)
Week 8- Post dose 
57 
[44, 71] (Post dose assessment)
Week 88 (Post dose assessment)
Week 12– Pre dose 
85 
[72, 99] (Pre-dose assessment)
Week 92 (Pre-dose assessment)
Week 12- Post dose 
85 
[72, 99] (Post dose assessment)
Week 92 (Post dose assessment)
Week 16 
113 
[100, 127]
Week 96 
Week 20 
141 
[128, 155]
Week 100 
Week 24 
169 
[156, 183]
Week 104 
Week 28 
197 
[184, 211]
Week 108 
Week 32 
225 
[212, 239]
Week 112 
Week 36 
253 
[240, 267]
Week 116 
Week 40 
281 
[268, 295]
Week 120 
Week 44 
309 
[296, 323]
Week 124 
Week 48 
337 
[324, 351]
Week 128 
Week 52 
365 
[352, 379]
Week 132 
Week 56 
393 
[380, 407]
Week 136 
Week 60 
421 
[408, 435]
Week 140 
Week 64 
449 
[436, 463]
Week 144 
Week 68 
477 
[464, 491]
Week 148 
Week 72 
505 
[492, 519]
Week 152 
Week 76 
533 
[520, 547]
Week 156 
Week 80 
561 
[548, 575]
Week 160 
Week 84 
589 
[576, 603]
Week 164 
Week 88 
617 
[604, 631]
Week 168 
Week 92 
645 
[632, 659]
Week 172 
Week 96 
673 
[660, 687]
Week 176 
Week 100 
701 
[688, 715]
Week 180 
Week 104 
729 
[716, 743]
Week 184 
Week 108 
757 
[744, 771]
Week 188 
Week 112 
785 
[772, 799]
Week 192 
Week 116 
813 
[800, 827]
Week 196 
Week 120 
841 
[828, 855]
Week 200 
Week 124 
869 
[856, 883]
Week 204 
Week 128 
897 
[884, 911]
Week 208 
Week 132 
925 
[912, 939]
Week 212 
Week 136 
953 
[940, 967]
Week 216 
Week 140 
981 
[968, 995]
Week 220 
Week 144 
1009 
[996, 1023]
Week 224 
Week 148 
1037 
[1024, 1051]
Week 226 
Week 152 
1065 
[1052, the end day of the LTE 
period]
Week 238 
 


 
Statistical Analysis Plan 
Long-Term Extension Period 
V1.0 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
44 
 
Table 10. Visit Windows for ADA data using Placebo controlled baseline 
Analysis visit 
Target visit day 
Analysis visit window 
Baseline 
1 
See baseline definition in Section 3.7.1 
Week 4 
29 
[2, 99] 
Week 24 
169 
[100, 253]  
Week 48 
337 
[254, 435] 
Week 76 
 
533 
[436, the end day of the placebo-controlled period1] 
Week 80 
561 
[the start day of the LTE period2, 645] 
Week 104 
729 
[646, 771] 
Week 116 
813 
[772, 953] 
Week 156 
1093 
[954, 1163] 
Week 176 
1233 
[1164, 1303] 
Week 196 
1373 
[1304, 1471] 
Week 224 
1569 
[1472, 1618] 
Week 238 
1667 
≥1619 
1 The end day of the placebo-controlled period is the last day before the first infusion in LTE for subjects who enter 
LTE, and is the last day in study for subjects who do not enter LTE. 
2 The start day of the LTE period is the day of the first infusion in the LTE period. 
 
Table 11. 
Visit Windows for ADA data using LTE Baseline 
Analysis visit 
Target 
visit 
day 
Analysis visit window 
Protocol visit 
Baseline 
Most recent non-
missing 
value 
prior to the first 
infusion in LTE 
Most recent non-missing value prior to the 
first infusion in LTE 
Week 80 
Week 24 
169 
[2, 253]
Week 104 
Week 48 
337 
[254, 435]
Week 116 
Week 76 
533 
[436, 631]
Week 156 
Week 104 
729 
[632, 771]
Week 176 
Week 116 
813 
[772, 953]
Week 196 
Week 156 
1093 
[954, 1163]
Week 224 
Week 176 
1233 
>1163
Week 238 
Day 1 is the first infusion day in LTE period
 
Table 12. Visit Windows for tau PET data 
Analysis visit * 
Target visit day  
Analysis visit window 
Baseline 
1
Most recent non-missing pre-dose value 
Week 52 
364
[120, 456]
Week 78 
547
[457, 727*]
Week 152 
1065
[728, 1324]
Week 226 
1583
>1325
* 180 days after Week 78 target date. 
 
 




 
Statistical Analysis Plan 
Long-Term Extension Period 
V1.0 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
46 
 
 
Analysis visit   
Target visit day  
Analysis visit window
Protocol specified visit  
Baseline   
1   
Most recent non-missing pre-
dose value
Week 78   
Week 28  
169 
[2, 351]
Week 104 
Week 52 
533  
[352, 778]
Week 156 
Week 78 
1023  
>778
Week 226 
 
 
 
 
 


 
Statistical Analysis Plan 
Long-Term Extension Period 
V1.0 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
47 
 
Reference 
van Ginkel, J. R., Sijtsma, K., van der Ark, L. A., & Vermunt, J. K. (2010). Incidence of missing 
item scores in personality measurement, and simple item-score imputation. Methodology: 
European Journal of Research Methods for the Behavioral and Social Sciences, 6(1), 17-30. 
 
Wessels, A.M., Andersen, S.W., Dowsett, S.A., and Siemers, E.R. (2018), “The integrated 
Alzheimer’s disease rating scale (iADRS) findings from the expedition3 trial”, Journal of 
Prevention of Alzhermer’s Disease, 2018(5), 134-136.  
 
Wessels, A.M., Siemers, E.R., Yu, P., Andersen, S.W., Holdridge K.C., Sims, J.R., Sundell, K., 
Stern Y., Rentz, D.M., Dubois, B., Jones, R.W., Cummings, J., and Aisen, P.S. (2015), “A 
combined measure of cognition and function for clinical trials: the integrated Alzhermer’s disease 
rating scale (iADRS)”, Journal of Prevention of Alzheimer’s Disease. 
 
Judith Jaeger, PhD, Clint Hagen, MS, Henrik Loft, PhD. Cognitive Endpoints for Early 
Alzheimer’s Disease Trials: Development of the Early AD/ MCI Alzheimer’s Cognitive 
Composite (EMACC). ISCTM 2018 
 
Jinping Wang, Veronika Logovinsky, Suzanne B Hendrix. ADCOMS: a composite clinical 
outcome for prodromal Alzheimer’s disease trials. J Neurol Neurosurg Psychiatry 2016;87:993–
999 
 
Rubin, D. B. (1976) “Inference and missing data.” Biometrika, 63(3), 581-592. 
 

Prot_000.pdf: 




Protocol 251AD201
Version 4
Phase 2 Study of BIIB092 in Mild Cognitive Impairment due to Alzheimer’s Disease and Mild Alzheimer’s Disease
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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
Version 4
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
Version 4
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
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.
7
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
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
8
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
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
9
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
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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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
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.
14
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
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.
15
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
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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
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
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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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17
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
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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
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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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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
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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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20
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
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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
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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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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
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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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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
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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
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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
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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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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
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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
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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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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






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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42
 
14Participants’ tobacco use status will be assessed while collecting information on concomitant therapies.


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.
43
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


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.
44
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.












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.
50
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.






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.
53
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 


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.
54
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. 










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.
59
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).


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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60

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.


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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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.


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.
62
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.






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.
65
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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9
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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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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; 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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14
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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21
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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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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4
Figure 1:
Study SchematicDesign
Deleted Figure:


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5
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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6
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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7
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
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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
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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
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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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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
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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
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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