Conditions: Alzheimer's Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1027
Healthy volunteers: no

Brief summary:
The primary objective of this study is to verify the clinical benefit of monthly doses of aducanumab in slowing cognitive and functional impairment as measured by changes in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score as compared with placebo in participants with early Alzheimer's disease.

Detailed description:

Arms:
arm 1: Participants will receive aducanumab, up to 10 milligrams per kilogram (mg/kg), monthly (once every four weeks), administered as intravenous (IV) infusion. arm 2: Participants will receive placebo, monthly (once every four weeks), administered as IV infusion.

Interventions: intervention 1: Aducanumab intervention 2: Placebo
Intervention descriptions: intervention 1: Administered as specified in the treatment arm. intervention 2: Administered as specified in the treatment arm.

Protocol document:
Prot_000.pdf: 
COVER PAGE 
Official Title: A Phase 3b/4 Randomized, Double-Blind, Placebo-Controlled, 
Parallel- Group Study to Verify the Clinical Benefit of Aducanumab 
(BIIB037) in Participants with Alzheimer’s Disease  
NCT Number: NCT05310071  
Document Date: 15 April 2022 
 
 


CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
1 
Biogen MA Inc. 
225 Binney Street 
Cambridge, MA 02142 
United States 
PROTOCOL NUMBER: 
221AD305 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead, Berkshire 
SL6 4AY 
United Kingdom 
PHASE OF DEVELOPMENT: 
3b/4 
PROTOCOL TITLE: A Phase 3b/4 Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group Study to Verify the Clinical Benefit of Aducanumab (BIIB037) in Participants with 
Alzheimer’s Disease 
IND Number: 
106230 
DATE: 
15 April 2022 
Version 2.0 
FINAL 
Supersedes previous Version 1.0 dated 22 March 2022 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
2 
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 4  
2 Banfield Road 
Macquarie Park, NSW 
2113 
Australia 
 
For urgent medical issues in which the study Medical Director should be contacted, please refer 
to the Official Study Contact List in the Study Reference Manual for complete contact 
information.  
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization and other third parties; however, Biogen retains overall accountability for these 
activities. 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
 
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SPONSOR SIGNATURE PAGE 
 
Protocol 221AD305 was approved by: 
 
__________________________________________ 
 
______________ 
, PhD 
Date (DD MMM YYYY) 
  
Biogen 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
 
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TABLE OF CONTENTS 
SPONSOR INFORMATION...........................................................................................................2 
SPONSOR SIGNATURE PAGE ....................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
1. 
KEY STUDY ELEMENTS ........................................................................................10 
1.1. 
Synopsis ......................................................................................................................10 
1.2. 
Study Design Schematic .............................................................................................19 
1.3. 
Schedule of Activities .................................................................................................20 
2. 
LIST OF ABBREVIATIONS .....................................................................................33 
3. 
INTRODUCTION ......................................................................................................35 
3.1. 
Study Rationale ...........................................................................................................35 
3.1.1. 
Rationale for Study Population ...................................................................................35 
3.1.2. 
Rationale for Dosing Regimen ...................................................................................35 
3.2. 
Background .................................................................................................................36 
3.2.1. 
Overview of Alzheimer’s Disease ..............................................................................36 
3.2.2. 
Other Current Therapies for Alzheimer’s Disease .....................................................37 
3.2.3. 
Profile of Previous Experience With Aducanumab ....................................................37 
3.2.3.1. 
Nonclinical Experience ...............................................................................................37 
3.2.3.2. 
Clinical Experience .....................................................................................................38 
3.3. 
Benefit-Risk Assessment ............................................................................................39 
4. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................41 
5. 
STUDY DESIGN .......................................................................................................45 
5.1. 
Study Overview ..........................................................................................................45 
5.2. 
Study Duration for Participants ..................................................................................46 
5.3. 
Monitoring and Management of ARIA ......................................................................47 
5.3.1. 
Dose Suspension or Permanent Discontinuation for ARIA Events ............................47 
5.3.1.1. 
ARIA-E .......................................................................................................................48 
5.3.1.2. 
ARIA-H (Microhemorrhage) ......................................................................................49 
5.3.1.3. 
ARIA-H (Superficial Siderosis) .................................................................................51 
5.3.1.4. 
Cerebral Hemorrhage > 1 cm .....................................................................................52 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
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5.3.1.5. 
Coincident (Concurrent) ARIA-H and ARIA-E Cases ..............................................52 
5.3.1.6. 
Resumption of Study Treatment and MRI Monitoring After Suspension Due 
to ARIA ......................................................................................................................52 
5.3.1.7. 
Management After Recurrent ARIA ..........................................................................53 
5.3.2. 
Infusion Interruption ...................................................................................................53 
5.4. 
Study Termination ......................................................................................................54 
5.5. 
Unscheduled Visits .....................................................................................................54 
5.6. 
End of Study ...............................................................................................................54 
6. 
STUDY POPULATION .............................................................................................55 
6.1. 
Inclusion Criteria ........................................................................................................55 
6.2. 
Exclusion Criteria .......................................................................................................56 
6.3. 
Screening, Rescreening, and Screen Failures .............................................................61 
6.3.1. 
Screening Visits 1 to 3 ................................................................................................61 
6.3.2. 
Rescreening and Screen Failures ................................................................................61 
7. 
STUDY TREATMENT ..............................................................................................64 
7.1. 
Regimen ......................................................................................................................64 
7.1.1. 
Aducanumab ...............................................................................................................64 
7.1.2. 
Placebo ........................................................................................................................64 
7.2. 
Modification of Dose and/or Treatment Schedule ......................................................64 
7.3. 
Study Treatment Management ....................................................................................64 
7.3.1. 
Aducanumab ...............................................................................................................65 
7.3.1.1. 
Preparation ..................................................................................................................65 
7.3.1.2. 
Storage ........................................................................................................................66 
7.3.1.3. 
Handling and Disposal ................................................................................................66 
7.3.1.4. 
Accountability .............................................................................................................66 
7.3.2. 
Placebo ........................................................................................................................66 
7.4. 
Blinding Procedures ....................................................................................................66 
7.5. 
Precautions ..................................................................................................................67 
7.6. 
Compliance .................................................................................................................67 
7.7. 
Concomitant Therapy and Procedures ........................................................................67 
7.7.1. 
Concomitant Therapy .................................................................................................67 
7.7.1.1. 
Allowed Concomitant Therapy ...................................................................................68 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
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7.7.1.2. 
Disallowed Concomitant Therapy ..............................................................................68 
7.7.2. 
Concomitant Procedures .............................................................................................70 
7.8. 
Continuation of Treatment ..........................................................................................70 
8. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF PARTICIPANTS FROM THE STUDY ..................................71 
8.1. 
Discontinuation of Study Treatment ...........................................................................71 
8.2. 
Lost to Follow-Up .......................................................................................................72 
8.3. 
Withdrawal of Participants From Study .....................................................................72 
9. 
EFFICACY, PHARMACOKINETIC, AND PHARMACODYNAMIC 
ASSESSMENTS .........................................................................................................74 
9.1. 
Clinical Efficacy Assessments ....................................................................................74 
9.2. 
Laboratory Efficacy Assessments ...............................................................................76 
9.3. 
Pharmacokinetic Assessments ....................................................................................77 
9.4. 
Pharmacodynamic Assessments .................................................................................77 
 
78 
 
78 
 
78 
9.6. 
Future Scientific Research Assessments ....................................................................79 
9.7. 
Additional Assessments ..............................................................................................79 
10. 
SAFETY ASSESSMENTS ........................................................................................80 
10.1. 
Clinical Safety Assessments .......................................................................................80 
10.2. 
Laboratory Safety Assessments ..................................................................................80 
10.3. 
Immunogenicity Assessments ....................................................................................81 
11. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................82 
11.1. 
Definitions ..................................................................................................................82 
11.1.1. 
Adverse Event .............................................................................................................82 
11.1.2. 
Serious Adverse Event ................................................................................................82 
11.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................83 
11.2. 
Safety Classifications ..................................................................................................83 
11.2.1. 
Investigator Assessment of Events .............................................................................83 
11.2.2. 
Relationship of Events to Study Treatment ................................................................84 
11.2.3. 
Severity of Events .......................................................................................................84 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
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11.2.4. 
Expectedness of Events ..............................................................................................85 
11.3. 
Monitoring and Recording Events ..............................................................................85 
11.3.1. 
Adverse Events ...........................................................................................................85 
11.3.2. 
Adverse Events of Special Interest .............................................................................85 
11.3.3. 
Serious Adverse Events ..............................................................................................86 
11.3.4. 
Immediate Reporting of Serious Adverse Events .......................................................86 
11.3.4.1. 
Deaths .........................................................................................................................86 
11.3.5. 
Suspected Unexpected Serious Adverse Reactions ....................................................87 
11.4. 
Procedures for Handling Special Situations ...............................................................87 
11.4.1. 
Public Health Emergencies .........................................................................................87 
11.4.2. 
Pregnancy ...................................................................................................................88 
11.4.3. 
Overdose .....................................................................................................................88 
11.4.4. 
Medical Emergency ....................................................................................................88 
11.4.4.1. 
Unblinding for Medical Emergency ...........................................................................88 
11.5. 
Contraception Requirements ......................................................................................89 
11.6. 
Safety Responsibilities ................................................................................................90 
11.6.1. 
The Investigator ..........................................................................................................90 
11.6.2. 
The Sponsor ................................................................................................................91 
12. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........92 
12.1. 
Demography and Baseline Disease Characteristics ....................................................92 
12.2. 
Efficacy and Pharmacodynamics ................................................................................92 
12.2.1. 
Analysis Sets ...............................................................................................................92 
12.2.2. 
Methods of Analysis ...................................................................................................92 
12.2.2.1. 
General Considerations ...............................................................................................92 
12.2.2.2. 
General Considerations for Analyses of Week 78 Endpoints ....................................92 
12.2.2.3. 
Considerations for Multiple Comparison Adjustments ..............................................92 
12.2.2.4. 
Considerations for Efficacy Endpoint Analysis .........................................................93 
12.2.2.5. 
Analysis of the Primary Endpoint ...............................................................................93 
12.2.2.6. 
Key Secondary Endpoints ...........................................................................................94 
12.2.2.7. 
Secondary Endpoints ..................................................................................................94 
12.2.2.8. 
Tertiary 
 Endpoints ...........................................................................94 
12.3. 
Methods of Analysis for Pharmacokinetic Endpoints ................................................95 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
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12.3.1. 
Analysis Set ................................................................................................................95 
 
95 
 
95 
12.5. 
Analysis of Safety Endpoints ......................................................................................95 
12.5.1. 
Analysis Set ................................................................................................................95 
12.5.2. 
Methods of Analysis ...................................................................................................95 
12.5.3. 
Adverse Events ...........................................................................................................95 
12.5.4. 
Clinical Laboratory Results ........................................................................................96 
12.5.5. 
Vital Signs ..................................................................................................................96 
12.5.6. 
ECGs ...........................................................................................................................96 
12.5.7. 
C-SSRS .......................................................................................................................96 
12.6. 
Methods of Analysis for Immunogenicity Data .........................................................96 
12.6.1. 
Analysis Set ................................................................................................................96 
12.6.2. 
Methods of Analysis ...................................................................................................96 
12.7. 
Interim Analyses .........................................................................................................96 
12.8. 
Sample Size Considerations .......................................................................................97 
13. 
ETHICAL AND REGULATORY REQUIREMENTS ..............................................98 
13.1. 
Declaration of Helsinki ...............................................................................................98 
13.2. 
Ethics Committee ........................................................................................................98 
13.3. 
Changes to Final Protocol ...........................................................................................99 
13.4. 
Informed Consent .......................................................................................................99 
13.5. 
Participant Data Protection .......................................................................................100 
13.6. 
Compensation for Injury ...........................................................................................100 
13.7. 
Conflict of Interest ....................................................................................................101 
13.8. 
Study Report Signatory .............................................................................................101 
13.9. 
Registration of Study and Disclosure of Study Results ............................................101 
13.10. 
Retention of Study Data ............................................................................................101 
14. 
KEY ROLES AND STUDY GOVERNANCE COMMITTEES .............................102 
14.1. 
Site Staff ...................................................................................................................102 
14.2. 
Vendors .....................................................................................................................103 
14.2.1. 
Contract Research Organization ...............................................................................103 
14.2.2. 
Interactive Response Technology .............................................................................103 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
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14.2.3. 
Electronic or Remote Data Capture ..........................................................................103 
14.2.4. 
Central Laboratories for Laboratory Assessments ...................................................103 
14.2.5. 
Central Facility for Other Assessments ....................................................................104 
14.2.6. 
Central Review of Raters ..........................................................................................104 
14.2.7. 
Neurocognitive Assessments ....................................................................................104 
14.3. 
Study Committees .....................................................................................................104 
14.3.1. 
Advisory Committee .................................................................................................104 
14.3.2. 
Independent Data Monitoring Committee ................................................................104 
15. 
ADMINISTRATIVE PROCEDURES .....................................................................105 
15.1. 
Study Site Initiation ..................................................................................................105 
15.2. 
Quality Control and Quality Assurance ....................................................................105 
15.3. 
Monitoring of the Study ............................................................................................105 
15.4. 
Study Funding ...........................................................................................................106 
15.5. 
Publications ...............................................................................................................106 
16. 
REFERENCES .........................................................................................................107 
17. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .......................................110 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities From Screening Through Week 32 ........................................20 
Table 2: 
Schedule of Activities From Week 36 to End of Study ..............................................26 
Table 3: 
Abbreviated Schedule of Activities for Participants Who Discontinue Study 
Treatment but Remain in the Study ............................................................................30 
Table 4: 
Disposition of ARIA-E Cases .....................................................................................48 
Table 5: 
Disposition of ARIA-H (Microhemorrhage) Cases ....................................................49 
Table 6: 
Disposition of ARIA-H (Superficial Siderosis) Cases ...............................................51 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................19 
 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
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1. 
KEY STUDY ELEMENTS 
1.1. 
Synopsis 
Protocol Title: 
A Phase 3b/4 Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Verify the Clinical Benefit of Aducanumab 
in Participants with Alzheimer’s Disease 
Protocol Number: 
221AD305 
Version Number: 
2.0 
Name of Study 
Treatment: 
Research Name: 
BIIB037 
Generic Name: 
Aducanumab-avwa 
Trade Names:  
Aduhelm™ 
Study Phase: 
3b/4 
Study Indication: 
Alzheimer’s Disease 
Study Rationale: 
The purpose of this Phase 3b/4 confirmatory study is to verify the 
clinical benefit of aducanumab compared with placebo in participants 
with Alzheimer’s disease, including those with MCI due to 
Alzheimer’s disease or mild Alzheimer’s disease dementia.   
In clinical studies, aducanumab demonstrated a dose- and time-
dependent reduction in amyloid plaque, one of the pathological 
hallmarks of Alzheimer's disease. In a Phase 3 study (221AD302), 
the effect of aducanumab high dose on amyloid plaque was 
accompanied by statistically significant clinical efficacy as measured 
on the primary outcome (CDR-SB), all secondary outcomes (MMSE, 
ADAS-Cog13, ADCS-ADL-MCI), and the tertiary clinical efficacy 
outcome (NPI-10). The results of Study 221AD302 were supported 
by sensitivity analyses and analyses of prespecified subgroups as well 
as data indicating that the reductions in brain amyloid and in clinical 
decline were correlated. Another Phase 3 study (221AD301) did not 
confirm the clinical efficacy seen in Study 221AD302. However, the 
positive biomarker and clinical efficacy results in Study 221AD302 
were supported by a third, independently conducted Phase 1b study 
(221AD103). 
Aducanumab was approved by the US FDA as a treatment for 
Alzheimer’s disease under the accelerated approval pathway based 
on aducanumab's reduction in brain amyloid coupled with evidence 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
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that reduction in brain amyloid is reasonably likely to predict clinical 
benefit in Alzheimer’s disease. Consistent with the accelerated 
approval regulations, the present study is being conducted to fulfill a 
postmarketing requirement from the US FDA to verify the clinical 
benefit of aducanumab. 
Rationale for Dose 
and Schedule 
Selection: 
Participants will be assigned to 1 of 2 treatment groups in a 2:1 ratio 
of aducanumab or placebo administered IV Q4W, respectively.  
Treatment is initiated via titration, which has been demonstrated to 
result in a lower incidence of ARIA. Titration will start at 1 mg/kg 
and will escalate to 3, 6 and 10 mg/kg as detailed in Section 3.1.2.   
Primary Objective 
Primary Endpoint 
To verify the clinical benefit of monthly 
doses of aducanumab in slowing cognitive 
and functional impairment as measured by 
changes in the CDR-SB score as compared 
with placebo in participants with early 
Alzheimer’s disease. 
Change from baseline in CDR-SB score at 
Week 78 
Key Secondary Objectives 
Key Secondary Endpoints 
To assess the effect of monthly doses of 
aducanumab as compared with placebo on 
clinical decline as measured by the iADRS 
Change from baseline in iADRS score at 
Week 78 
To assess the effect of monthly doses of 
aducanumab as compared with placebo on 
clinical decline as measured by 
ADCS-ADL-MCI 
Change from baseline in ADCS-ADL-MCI 
score at Week 78 
To assess the effect of monthly doses of 
aducanumab as compared with placebo on 
clinical decline as measured by ADAS-
Cog13 
Change from baseline in ADAS-Cog13 score 
at Week 78 
To assess the effect of monthly doses of 
aducanumab as compared with placebo on 
clinical decline as measured by the MMSE 
Change from baseline in MMSE score at 
Week 78 
To assess the effect of monthly doses of 
aducanumab as compared with placebo on 
clinical decline as measured by NPI-10 
Change from baseline in NPI-10 score at 
Week 78  


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Secondary Objectives 
 
Secondary Endpoints 
To assess the effect of aducanumab on 
cerebral amyloid plaque level as measured 
by amyloid PET imaging (in a subset of 
sites and participants) 
Change from baseline in amyloid PET signal 
at Week 78 and Week 104 
To assess the effect of aducanumab on 
cerebral tau levels as measured by tau PET 
imaging (in a subset of sites and 
participants) 
Change from baseline in tau PET signal at 
Week 78 and Week 104 
To assess the effect of monthly doses of 
aducanumab as compared with placebo on 
clinical decline as measured by the 
CDR-SB score  
Change from baseline in CDR-SB score at 
Week 106 
To assess the effect of monthly doses of 
aducanumab as compared with placebo on 
clinical decline as measured by the iADRS 
Change from baseline in iADRS score at 
Week 106 
To assess the effect of monthly doses of 
aducanumab as compared with placebo on 
clinical decline as measured by 
ADCS-ADL-MCI 
Change from baseline in ADCS-ADL-MCI 
score at Week 106 
To assess the effect of monthly doses of 
aducanumab as compared with placebo on 
clinical decline as measured by 
ADAS-Cog13 
Change from baseline in ADAS-Cog13 score 
at Week 106 
To assess the effect of monthly doses of 
aducanumab as compared with placebo on 
clinical decline as measured by the MMSE 
Change from baseline in MMSE score at 
Week 106 
To assess the effect of monthly doses of 
aducanumab as compared with placebo on 
clinical decline as measured by NPI-10 
Change from baseline in NPI-10 score at 
Week 106 
To assess the effect of monthly doses of 
aducanumab as compared with placebo on 
clinical decline as measured by the GST 
composite z-score  
Change from baseline in GST composite z-
score (based on CDR-SB, ADAS-Cog13, and 
ADCS-ADL-MCI) at Week 78 and Week 106 
 


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Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
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Study Design: 
Study 221AD305 is a multicenter, randomized, double-blind, 
placebo-controlled, and parallel group study in participants with early 
Alzheimer’s disease, including those with MCI due to Alzheimer’s 
disease or mild Alzheimer’s disease dementia. Enrollment will be 
monitored, via the IRT system, so that the population of participants 
with mild Alzheimer’s disease represents approximately 50% of the 
total number of participants enrolled in the study. The study will 
include up to 24 months of treatment as well as screening and post-
treatment FU periods. Approximately 1512 participants will be 
enrolled across an estimated 220 centers globally.  
The primary study objective is to verify the clinical benefit of 
monthly doses of aducanumab on CDR-SB relative to placebo at 
Week 78. Key secondary objectives include assessment of the effect 
of monthly doses of aducanumab on clinical decline as compared to 
placebo at Week 78 as measured by a variety of cognitive and 
functional scales such as those implemented in the Phase 3 studies 
(i.e., ADCS-ADL-MCI, ADAS-Cog13, MMSE, and NPI-10), as well 
as the composite scale, iADRS, which is a linear combination of the 
ADAS-Cog13 and the ADCS-ADL-MCI. Secondary objectives 
include assessment of the effect of monthly doses of aducanumab on 
change in amyloid PET and tau PET signal at Week 78 and 104 as 
compared to placebo, as well as all clinical endpoints (i.e., CDR-SB, 
iADRS, ADCS-ADL-MCI, ADAS-Cog13, MMSE, and NPI-10) 
assessed at the Week 106 timepoint. Secondary objectives also 
include an assessment of the effect of monthly doses of aducanumab 
on the GST composite z-score, defined as the average of standardized 
z scores of the CDR-SB, ADCS-ADL-MCI, and ADAS-Cog13, at 
Weeks 78 and 106. Tertiary objectives include confirmation of the 
safety, tolerability, and associated immunogenicity of aducanumab 
and its PK characteristics, and HEOR and QoL metrics. 
 
 
 
 
 
 
 
 
 
Substudies 
Three optional longitudinal substudies will be completed within this 
study in subsets of consenting participants: 1) an amyloid PET 
substudy involving assessments of amyloid by PET scan at 


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Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
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Screening, and Weeks 78 and 104; 2) a tau PET substudy involving 
assessments of tau by PET scan at Screening, and Weeks 78 and 104 
and 
 
 
 
 
Study Location: 
Approximately 220 sites globally are planned. 
Study Population: 
This study will be conducted in participants who meet the following 
criteria:  
• Must be 60 to 85 years old, inclusive, at the time of informed 
consent. 
• Must meet all of the following clinical criteria for MCI due 
to Alzheimer’s disease or mild Alzheimer’s disease 
according to NIA-AA criteria [Albert 2011; McKhann 
2011]: 
o Have an MMSE score between 22 and 30 inclusive 
o Have a CDR memory score ≥ 0.5 
o Have a CDR-GS of 0.5 or 1.0 
o Have an RBANS score of 85 or lower indicative of 
objective cognitive impairment (based upon the DMI 
score) 
• Must consent to ApoE genotyping.  
• Must have confirmed amyloid beta pathology by either PET 
or CSF. (Note: For participants providing only a screening 
amyloid PET scan, a historical amyloid PET scan obtained 
within 18 months of Screening Visit 2 is permissible and 
must be submitted to the central imaging vendor to confirm 
that study inclusion criteria are met.) In the case of 
discordant results between CSF and PET, PET scans will be 
used to assess eligibility. 
Detailed criteria are described in Section 6.  
Number of Planned 
Participants: 
Approximately 1512 participants will be enrolled and randomized. 
Treatment Groups: 
Participants will receive IV infusions of aducanumab or placebo 
approximately Q4W for 104 weeks. Participants will be 
randomized to receive aducanumab:placebo in a 2:1 ratio. The 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
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randomization will be stratified by geographical region, baseline 
Alzheimer’s disease stage status, and ApoE ε4 status (carrier or 
noncarrier). Randomization will be performed using IRT. 
Aducanumab will be initiated with a 6-dose titration period prior 
to reaching the target dose of 10 mg/kg as detailed in 
Section 3.1.2.  
Sample Size 
Determination: 
The sample size is mainly based on results from the primary analysis 
of Study 221AD302. Results from the post-PV4 population (i.e., the 
221AD302 and 221AD301 protocol amendment in which the high 
dose of aducanumab was increased from 6 mg/kg to 10 mg/kg) in 
pooled Study 221AD302 and Study 221AD301 data were also 
considered. A total sample size of 1512 participants is planned to 
have approximately 90% power to detect a mean difference of 0.48 in 
change from baseline CDR-SB at Week 78 between the 2 treatment 
groups. This power calculation is based on a 2-sided t-test assuming 
equal variance with a final significance level of 0.05, an SD of 2.33, a 
dropout rate through Week 78 of 27%, and a randomization ratio of 
2:1. The assumed mean difference of 0.48 between the 2 treatment 
groups represents an approximately 24% reduction in the placebo 
mean change from baseline at Week 78 if the placebo mean change is 
estimated to be 2.  
A blinded assessment of the pooled SD for the primary efficacy 
endpoint may be performed approximately 3 months prior to the 
completion of enrollment and the sample size may be increased as a 
result. The sample size could also be increased using internal and 
external clinical study results that become available after the start of 
this study.  In addition, the sample size may be increased if the 
dropout rate through Week 78 is estimated to exceed 27%.  The 
sample size will not be reduced based on this assessment. 
Visit Schedule: 
Participants will have approximately 39 scheduled visits, 27 of 
which are dosing visits, as well as up to 8 telephone safety FU 
contacts, as follows: 
• Screening Visits 1 to 3 will occur no more than 60 days 
before the first dose of study treatment on Day 1. All 
screening procedures should be completed within 60 days; 
however, with Sponsor approval, the overall screening 
period may be extended up to 90 days in the event of 
logistical issues related to PET scans (and/or due to other 
major causes [i.e., institutional restrictions or participant 
disposition due to COVID-19 or other major 
disasters/disruptions]). These screening visits will include 
baseline brain MRI, clinical scales of cognition and function, 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
16 
biological fluid sampling (including CSF), amyloid and tau 
PET scans (where available), physical and neurological 
examinations, and all other safety and efficacy assessments.  
• Twenty-seven dosing visits (Day 1 and Weeks 4, 8, 12, 16, 
20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 
84, 88, 92, 96, 100, and 104). 
• Eight telephone safety FU contacts after each of the first 8 
doses. 
• Four visits separate from dosing for clinical functional and 
cognitive assessments (Weeks 26, 50, 78, and 106). 
• One FU safety visit at Week 122, 18 weeks after last dose at 
Week 104, or 18 weeks after administration of last dose for 
those participants who discontinue treatment early. 
• A minimum of 6 MRI visits, with 4 during treatment 
(Week 14 [before escalation to 6 mg/kg, before the fifth 
dose], Week 22 [before escalation to 10 mg/kg, before the 
seventh dose], Week 30 [before the third dose at 10 mg/kg], 
Week 42 [before the sixth dose at 10 mg/kg]. Two additional 
MRIs will be performed at Week 106, and at the Week 122 
safety FU 18 weeks after the final dose [EOS]) or 18 weeks 
after administration of the last dose for participants who 
discontinue treatment early.  
See the study schematic in Section 1.2.  
Duration of Study 
Participation: 
The total duration of the study for each participant will be 
approximately 130 weeks, including a series of screening visits 
within 8 weeks before administration of the first dose, and a 
104-week placebo-controlled treatment period. Participants will 
additionally undergo a safety FU Visit 18 weeks after the final dose 
of aducanumab. 
Benefit-Risk 
Analysis: 
Alzheimer’s disease is a major public health issue that imposes 
immense burden on patients and caregivers.  
The Phase 3 Study 221AD302 met its prespecified primary and 
secondary endpoints. The statistically significant effect of 
aducanumab on clinical endpoints was supported by statistically 
significant dose- and time-dependent reductions of markers of brain 
amyloid beta plaques, and dose-dependent reductions of relevant 
markers of downstream Alzheimer’s tau pathophysiology and 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
17 
neurodegeneration. Supportive efficacy data were provided from the 
Phase 1b Study 221AD103, a smaller randomized, placebo-
controlled, dose-finding study that demonstrated a dose-related 
numerical reduction in decline relative to placebo for CDR-SB and 
MMSE, as well as dose- and time-dependent reduction of markers of 
brain amyloid beta plaques. Although Study 221AD301 did not 
contribute to the evidence of effectiveness on clinical outcomes for 
aducanumab, the study did further demonstrate that aducanumab 
reduces amyloid beta plaques, since the PET subset demonstrated 
statistically significant time- and dose-dependent decreases in 
amyloid beta plaques. There is also extensive scientific evidence of 
the role of amyloid in Alzheimer’s disease. Collectively, the imaging, 
fluid biomarker results, the correlation analysis, and the exposure-
response modeling are all consistent with a direct effect of 
aducanumab on lowering brain amyloid beta pathology with a 
subsequent effect on reducing tau pathology, neurodegeneration and 
ultimately slowing of clinical decline. 
The aducanumab safety database exceeds the minimum ICH 
guidance, and risk management can be achieved through monitoring 
for ARIA, as described in the protocol. Most of the safety data from 
the aducanumab clinical program are derived from Studies 
221AD301 and 221AD302. A total of 2757 participants with MCI 
due to Alzheimer’s disease or mild Alzheimer’s disease received 
aducanumab in Studies 221AD301 and 221AD302, accounting for 
approximately 3983.5 person-years of exposure and 4736.1 total 
person-years of FU. In the pooled analysis of the placebo-controlled 
periods of the Phase 3 studies, AEs experienced by participants in the 
10 mg/kg IV dose group with an incidence of at least 5% and that 
were observed at a 2% or greater incidence than in the placebo group 
were ARIA-E, headache, ARIA-H microhemorrhage, fall, ARIA-H 
superficial siderosis, and diarrhea. These AEs are ADRs of 
aducanumab.  
ARIA is the most common safety finding observed with 
aducanumab. ARIA includes ARIA-E, which can be observed on 
MRI as brain edema or sulcal effusions, and ARIA-H, which includes 
microhemorrhage and superficial siderosis. ARIA-E was observed in 
35.2% of the 10 mg/kg dose group, compared to 2.7% of the placebo 
group. The incidence of ARIA-E was higher in ApoE ε4 carriers than 
in ApoE ε4 noncarriers (43.0% and 20.3%, respectively). The 
majority of ARIA-E radiographic events occurred early in treatment 
(within the first 8 doses), although ARIA can occur at any time. In 
the 10 mg/kg group, the majority of ARIA-E events resolved within 
12 to 16 weeks of detection (68.9% and 82.8%, respectively) and 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
18 
98% of ARIA-E resolved radiographically. In the 10 mg/kg group, 
10.0% of aducanumab-treated participants experienced symptoms in 
the setting of ARIA, which included headache, confusion, dizziness, 
visual disturbances, nausea, and vomiting, with most symptoms being 
mild or moderate and transient in nature. Seizures, including status 
epilepticus, can be a severe symptom of ARIA-E.  
The potential risks related to participation in this study are justified 
by the anticipated benefit to participants. However, given the partial 
discrepancies between the 2 pivotal trials, and while acknowledging 
that this drug has been approved at this time in the US under 
accelerated approval, the benefit profile of aducanumab at 10 mg/kg 
IV will be further verified in this study.  
General risk mitigation against COVID-19 will be implemented in 
accordance with the study site’s IRB-approved monitoring and 
prevention control measures. The risk mitigation measures, where 
applicable, will be amended based on emerging local, regional, and 
national guidance. 
Detailed information about the known and expected benefits and 
risks and reasonably expected AEs of aducanumab is provided in the 
Investigator’s Brochure and ICF. 










Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
23 
recommended that all screening procedures be completed within 60 days before Day 1; however, the overall screening period may be extended up to 90 days in 
the event of logistical issues related to PET scans and/or due to other major causes (i.e., institutional restrictions or participant disposition due to COVID-19 or 
other major disasters/disruptions) and is subject to Sponsor approval. 
2 Participants who have a change in Alzheimer’s disease medication (other than study treatment) should have a UV. A subset of the clinical efficacy assessments 
(CDR, MMSE, ADCS-ADL-MCI, and ADAS-Cog13) should be performed prior to the change in medication if the participant alerts the Investigator before the 
change in medication occurs. If the change in medication occurs before clinical efficacy assessments are performed, the clinical efficacy assessments must be 
performed within 30 days of the Investigator being notified about the change. If clinical efficacy assessments have been performed within 30 days of the change 
in medication, the assessments do not have to be repeated. 
3 For the frequency of required brain MRI assessments and of PK 
 sample collection for participants who develop ARIA-E and/or ARIA-H, see 
Section 5.3.1. This includes PK 
 sample collection at the first unscheduled visit for ARIA monitoring per episode only.  For the frequency of brain 
MRI assessments following resolution of ARIA and resumption of dosing, see Section 5.3.1.6. For management of recurrent ARIA, see Section 5.3.1.7. 
4 This written full informed consent allows for completion of all assessments necessary for screening, treatment, and FU of participants: collection of 
demographic data (including ethnic and racial data), medical and cognitive status history, sample collection for ApoE genotyping, confirmation of amyloid 
positivity, and completion of cognitive and functional scales. Additional separate informed consents will be used for the 3 longitudinal substudies involving 
imaging and CSF sampling over time (see Section 9.4), and for optional future scientific research assessments (see Section 9.6).  
5 All eligibility criteria must be confirmed, and all assessments must be completed, before study treatment infusion. 
6 Medical history should be assessed up until predose on Day 1.  
7 HIV testing is at the Investigator’s discretion after consideration of risk factors. 
 
 
 
 
 
 
10 Pregnancy testing will be required for women of childbearing potential only. See Section 11.4.2. 
11 FSH determination will only be required in women at Screening to confirm postmenopausal status. If the participant’s status as menopausal is confirmed, no 
subsequent pregnancy testing of that participant is required. 
12 ECGs will be read locally. 
13 Vital signs will include SBP, DBP, heart rate, body temperature, and respiratory rate. Vital signs will be measured with the participant supine and after the 
participant has been resting for at least 10 minutes. 
14 If SBP is below 165 mmHg and DBP is below 100 mmHg at Screening, only 1 BP reading needs to be conducted. If either parameter is exceeded, 
3 measurements should be taken to determine the average. 
15 The preceding centralized MRI report must have been received and reviewed by the Investigator before continuing with study treatment infusions. 
16 Sample collection for anti-aducanumab Abs will be performed prior to study treatment infusion (where applicable). 
17 Blood sampling for aducanumab concentration will be performed prior to infusion. When collected for ARIA management, a sample will be collected ± 2 days 
of the MRI visit. Exact collection date and time will be captured for all PK blood samples on a specified CRF. 
 
 
19 Coagulation panels, including PT, PTT, INR, and platelet count, must be performed within 35 days before the LP. If a participant, in the opinion of the 
Investigator, is at increased bleeding risk, the coagulation panel should be repeated within 7 days before the LP, if necessary. These repeat tests may be 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
24 
performed locally to facilitate timely review of the results. Before any LP can be performed, the results of the most recent coagulation panel, concomitant 
medications, and overall general bleeding risk must be reviewed by the Investigator and must indicate that the LP can be performed safely. When the coagulation 
panel is performed at a visit that includes hematology testing, the platelet count should be done only once. 
20 Screening CSF should only be collected after the participant meets all other eligibility criteria, including MRI criteria, at Screening Visits 1 and 2. An LP 
should not be performed if the Investigator suspects the presence of intracranial hypertension clinically or radiologically. Before any LP can be performed, the 
results of the most recent coagulation panel, concomitant medications, and overall general bleeding risk must be reviewed by the Investigator and must indicate 
that the LP can be performed safely. For participants of the longitudinal CSF substudy, the sample must be taken at Screening using study-specific procedures. If 
a participant enters the study based on amyloid PET positivity, as determined by a previous amyloid PET scan, and also enters the 
 with 
a negative baseline CSF result, the PET result takes precedence for the purposes of determining eligibility. 
21 Amyloid PET is limited to selected sites with access to the Sponsor-approved amyloid PET radiotracer(s). For participants who are not enrolled in the 
longitudinal amyloid PET substudy, a historical amyloid PET scan previously obtained within 18 months of Screening Visit 1 is permissible and must be 
submitted to the central imaging vendor to confirm that study inclusion criteria are met. A historical amyloid PET scan will not be accepted for participants who 
enroll in the longitudinal amyloid PET substudy. If a participant enters the study based on amyloid PET positivity, as determined by a previous amyloid PET 
scan, and also enters the 
 with a negative baseline CSF result, the PET result takes precedence for purposes of determining eligibility. 
Screening amyloid PET scan should only be conducted after meeting all other eligibility criteria, including MRI criteria, at Screening Visits 1 and 2. The 
Screening Period may be extended up to 90 days in the event of logistical issues related to PET scans and/or due to other major causes (i.e., institutional 
restrictions or participant disposition due to COVID-19 or other major disasters/disruptions) and is subject to Sponsor approval. For all women of childbearing 
potential, a pregnancy test must be performed within 24 hours prior to every PET scan. 
22 Tau PET will be performed in a subset of participants at selected sites with access to the Sponsor-approved tau PET radiotracer(s). A Screening tau PET scan is 
mandatory for all participants at sites with tau PET scanning capabilities; a historical tau PET scan will not be accepted. Screening tau PET will not contribute to 
eligibility determination. The tau PET scan should only be performed at Screening Visit 3 after the participant has confirmation of a positive amyloid result 
(either PET or CSF) from Screening Visits 1 or 2, and after meeting all other eligibility criteria, including MRI criteria, at Screening Visits 1 and 2. Screening tau 
PET scan should be performed prior to randomization. Only in the event of inadequate radiotracer supplies or PET camera availability can the Screening tau PET 
scan be performed after Day 1, with Sponsor approval; the scan should be performed as close to the first infusion date as possible and must occur prior to the 
second infusion. The Screening Period may be extended up to 90 days in the event of logistical issues related to PET scans and/or due to other major causes (i.e., 
institutional restrictions or participant disposition due to COVID-19 or other major disasters/disruptions) and is subject to Sponsor approval. For all women of 
childbearing potential, a pregnancy test must be performed within 24 hours prior to every PET scan. 
23 Brain MRI (Screening Visit 2) will not be performed until the participant has met the eligibility criteria and has acceptable laboratory tests from Screening 
Visit 1. 
24 Safety FU telephone contacts occur during dose escalation. These FU contacts may be performed in person if the participant will be at the site for clinical 
assessments.  
25The Research Diagnostic Verification Form is used at Screening Visit 1 for initial diagnosis, and the Diagnostic Staging Form is used at subsequent visits to 
help standardize diagnostic change across the study. These forms should be completed after the CDR is performed (see the Study Reference Guide). 
26 The baseline ADAS-Cog13 and the ADCS-ADL-MCI must be performed within 20 days of Screening Visit 1, but not on the same day as the screening of CDR 
or MMSE. These scales can also be performed on Day 1 prior to randomization and study treatment infusion. 
27 The NPI-10 must be performed after the CDR but can be performed at any time during Screening or on Day 1. 
28 At Screening, the Lifetime/Recent C-SSRS will be used. At all postscreening visits, the C-SSRS-SLV version will be used.  
 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
25 
30 Two versions of the EQ-5D-5L questionnaire will be completed only at baseline: the participant’s self-reported version and the informant-reported version 
describing the participant. 
31 Two versions of the QoL-AD questionnaire will be completed: the participant’s self-reported version and the informant-reported version describing the 
participant. 
32 AEs and SAEs related to the PET radiotracer will also be monitored and reported. 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab (BIIB037) in Early Alzheimer’s Disease  
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
26 
Table 2: 
Schedule of Activities From Week 36 to End of Study 
Study 
Week 
 
106 
ET1 
UV 
AD 
Meds2 
UV 
ARIA3 
FU4 
EOS 
36 
40 
42 
44 
48 
50 
52 
56 
60 
64 
68 
72 
76 
78 
80 
84 
88 
92 
96 
100 
104 
122 
Study Day 
253 
± 3 
281 
± 3 
295 
± 3 
309 
± 3 
337 
± 3 
351 
± 3 
365 
± 3 
393 
± 3 
421 
± 3 
449 
± 3 
477 
± 3 
505 
± 3 
533 
± 3 
547 
± 3 
561 
± 3 
589 
± 3 
617 
± 3 
645 
± 3 
673 
± 3 
701 
± 3 
729  
± 3 
743 
± 3 
855± 3 
Body Weight 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
Urine 
Pregnancy 
Test5 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
Physical 
Exam 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
Neurological 
Exam 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
12-Lead ECG 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
Vital Signs6 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
Hematology, 
Blood 
Chemistry, 
and 
Urinalysis 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
Study 
Treatment 
Infusion7 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Anti-
Aducanumab 
Ab8 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
X 
Aducanumab 
Concentratio
n9 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
CSF 
Collection11 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
Coagulation 
Panel12 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
Amyloid 
PET13 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
Tau PET14 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
Brain MRI 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
X 




Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
28 
occur at each UV for ARIA management. For the frequency of brain MRI assessments following resolution of ARIA and resumption of dosing, see 
Section 5.3.1.6.  For management of recurrent ARIA, see Section 5.3.1.7.  
4 A safety FU Visit is required 18 weeks after the participant’s last dose at 104 weeks. Similarly, participants who discontinue treatment and do not agree to 
continue in the study (withdrawn participants) should return to sites for a final assessment 18 weeks after their final dose. Participants who discontinue treatment 
prematurely but agree to remain in the study should continue assessments at a subset of the clinic visits until the end of the study per the Schedule of Activities in 
Table 3. It is possible that a clinic visit will occur before the FU Visit 18 weeks after the participant’s final dose. If the FU Visit occurs within 2 weeks of a 
scheduled clinic visit, then the FU Visit can be combined with the scheduled visit and all assessments required for both visits performed at this single visit. 
5 Pregnancy testing will only be required for women of childbearing potential. Section 11.4.2. 
6 Vital signs will include SBP, DBP, heart rate, body temperature, and respiratory rate. Vital signs will be measured with the participant supine and after the 
participant has been resting for at least 10 minutes. 
7 The preceding centralized MRI report must have been received and reviewed by the Investigator before continuing with study treatment infusions.  
8 Sample collection for anti-aducanumab Abs will be performed prior to study treatment infusion (where applicable).  
9 Blood sampling for aducanumab concentration will be performed prior to infusion. When collected for ARIA management, a sample will be collected ± 2 days 
of the MRI visit. Exact collection date and time will be captured for all PK blood samples on a specified CRF. 
 
  
11  Before any LP can be performed, the results of the most recent coagulation panel, concomitant medications, and overall general bleeding risk must be 
reviewed by the Investigator and must indicate that the LP can be performed safely.  An LP should not be performed if the Investigator suspects the presence of 
intracranial hypertension clinically or radiologically. 
12 Coagulation panels, including PT, PTT, INR, and platelet count, must be performed within 35 days before the LP. If a participant, in the opinion of the 
Investigator, is at increased bleeding risk, the coagulation panel should be repeated within 7 days before the LP, if necessary. These repeat tests may be 
performed locally to facilitate a timely review of the results. Before any LP can be performed, the results of the most recent coagulation panel, concomitant 
medications, and overall general bleeding risk must be reviewed by the Investigator and must indicate that the LP can be performed safely. When the coagulation 
panel is performed at a visit that includes hematology testing, the platelet count should be done only once. 
13 FU amyloid PET scans at Weeks 78 and 104 will only be conducted at selected sites for participants enrolled in the longitudinal amyloid PET substudy and 
may be scheduled within a window of -21 to +7 days. Amyloid PET must be conducted using only the Sponsor-approved radiotracer and the same radiotracer 
used for baseline amyloid PET scan. A QC-passing Screening amyloid PET scan is required to continue in the longitudinal amyloid PET substudy. For 
participants consenting to both amyloid and tau PET substudies, the amyloid and tau PET scans should be performed on separate days (cannot be performed on 
the same day). For participants consenting to both CSF and PET substudies, if collected on the same day as a PET scan, CSF should be collected prior to PET. 
For participants in the amyloid PET longitudinal substudy who withdraw before Week 78, PET assessment will be collected at ET Visit only if withdrawal 
occurs > 6 months after the previous amyloid PET scan. For all women of childbearing potential, a pregnancy test must be performed within 24 hours prior to 
every PET scan. 
14 FU tau PET scans at Weeks 78 and 104 should be collected in a subset of participants in the longitudinal tau PET substudy at selected sites and may be 
scheduled within a window of -21 to +7 days. Tau PET must be conducted using only the Sponsor-approved radiotracer and the same tracer used for baseline tau 
PET scan. A QC-passing screening tau PET scan is required to continue in the longitudinal tau PET substudy. For participants consenting to both amyloid and 
tau PET substudies, the amyloid and tau PET scans must be performed on different days (cannot be performed on the same day). For participants consenting to 
both CSF and PET substudies, if collected on the same day as a PET scan, CSF should be collected prior to PET. For participants in the tau PET longitudinal 
substudy who withdraw before Week 78, PET assessment will be collected at ET Visit only if withdrawal occurs > 6 months after the previous amyloid PET 
scan. For all women of childbearing potential, a pregnancy test must be performed within 24 hours prior to every PET scan. 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
29 
 
 
16 Two versions of the QoL-AD questionnaire will be completed: the participant’s self-reported version and the informant-reported version describing the 
participant. 
17 AEs and SAEs related to the PET radiotracer will also be monitored and reported. 
 






Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab in Early Alzheimer’s Disease 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
32 
baseline amyloid PET scan. A QC-passing screening amyloid PET scan is required to continue in the longitudinal amyloid PET substudy. For participants 
consenting to both amyloid and tau PET substudies, the amyloid and tau PET scans must be performed on different days (cannot be performed on the same day). 
For participants consenting to both CSF and PET substudies, if collected on the same day as a PET scan, CSF should be collected prior to PET. For participants 
in the amyloid PET longitudinal substudy who withdraw before Week 78, PET assessment will be collected at ET Visit only if withdrawal occurs > 6 months 
after the previous amyloid PET scan. For all women of childbearing potential, a pregnancy test must be performed within 24 hours prior to every PET scan. 
9 FU tau PET scan at Weeks 78will only be collected in a subset of participants enrolled in the longitudinal tau PET substudy at selected sites and may be 
scheduled within a window of -21 to +7 days. Tau PET must be conducted using only the Sponsor-approved radiotracer. A QC-passing Screening tau PET scan 
is required to continue in the longitudinal tau PET substudy. For participants consenting to both amyloid and tau PET substudies, the amyloid and tau PET scans 
must be performed on different days (cannot be performed on the same day). For participants consenting to both CSF and PET substudies, if collected on the 
same day as a PET scan, CSF should be collected prior to PET. For participants in the tau PET longitudinal substudy who withdraw before Week 78, PET 
assessment will be collected at ET Visit only if withdrawal occurs > 6 months after the previous amyloid PET scan. For all women of childbearing potential, a 
pregnancy test must be performed within 24 hours prior to every PET scan. 
  
 
 
12 Two versions of the QoL-AD questionnaire will be completed: the participant’s self-reported version and the informant-reported version describing the 
participant. 
13 AEs and SAEs related to the PET radiotracer will also be monitored and reported. 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab (BIIB037) in Early Alzheimer’s Disease  
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
33 
2. 
LIST OF ABBREVIATIONS 
Aβ 
amyloid beta 
Ab 
antibody 
AD 
Alzheimer’s disease 
ADAS-Cog13 
Alzheimer’s Disease Assessment Scale, Cognitive subscale 
ADCS-ADL-MCI 
Alzheimer’s Disease Cooperative Study Scale for Activities of Daily Living 
in Mild Cognitive Impairment 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
anti-HBc 
hepatitis B core antibody 
anti-HBs 
hepatitis B surface antibody 
ApoE 
apolipoprotein E 
ApoE ε4 
apolipoprotein E ε4 
ARIA 
amyloid-related imaging abnormality 
ARIA-E 
amyloid-related imaging abnormality-edema 
ARIA-H 
amyloid-related imaging abnormality-hemorrhage 
AST 
aspartate aminotransferase 
CBD 
cannabidiol 
CDR 
Clinical Dementia Rating scale 
CDR-GS 
Clinical Dementia Rating scale - Global Score 
CDR-SB 
Clinical Dementia Rating scale - Sum of Boxes 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
C-SSRS-SLV 
Columbia Suicide Severity Rating Scale - Since Last Visit 
DBP 
diastolic blood pressure 
 
 
DMI 
delayed memory index on RBANS 
 
 
DSST 
digit symbol substitution test 
ECG 
electrocardiogram 
EMACC 
Early Alzheimer’s Disease/Mild Cognitive Impairment Alzheimer’s 
Cognitive Composite 
EQ-5D-5L 
health-related EuroQoL 5-dimension instrument 
ET 
early termination 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FU 
follow-up 
GST 
global statistical test 
HbA1c 
glycated hemoglobin 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HEOR 
health economic and outcomes research 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab (BIIB037) in Early Alzheimer’s Disease 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
34 
HIV 
human immunodeficiency virus  
iADRS 
Integrated Alzheimer’s Disease Rating Scale 
ICE 
intercurrent event 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
independent data monitoring committee 
INR 
international normalized ratio 
IRB 
institutional review board 
IRT 
interactive response technology 
IV 
intravenous 
IVIG 
intravenous immune globulin 
LP 
lumbar puncture 
LS 
least squares 
MCI 
mild cognitive impairment 
MMRM 
mixed-effect model repeated measure 
MMSE 
Mini-Mental State Examination 
 
 
MRI 
magnetic resonance imaging 
NIA-AA 
National Institute on Aging and Alzheimer’s Association 
NPI-10 
Neuropsychiatric Inventory-10 
PET 
positron emission tomography 
PI 
Principal Investigator 
PK 
pharmacokinetics 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
PV4 
protocol version 4 
Q4W 
every 4 weeks 
QoL 
quality of life 
QoL-AD 
Quality of Life in Alzheimer’s Disease 
RBANS 
Repeatable Battery for the Assessment of Neuropsychological Status 
RNA 
ribonucleic acid 
RUD-Lite 
Resource Utilization in Dementia – Lite Version 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SBP 
systolic blood pressure 
SD 
standard deviation 
SLV 
since last visit 
THC 
tetrahydrocannabinol 
US 
United States 
USPI 
United States Prescribing Information 
UV 
unscheduled visit 
 
 
 
 
 


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35 
3. 
INTRODUCTION  
Aducanumab is a human IgG1 monoclonal antibody targeting soluble and insoluble aggregated 
forms of amyloid beta. Aducanumab modifies the underlying pathophysiological disease course 
by removing amyloid plaques, which are considered one of the hallmarks of Alzheimer’s 
disease. Treatment effects observed on both CSF p-tau and tau PET suggest that aducanumab 
also has a downstream effect on tau pathology, the other major hallmark protein of the disease.  
3.1. 
Study Rationale  
The purpose of this confirmatory study is to verify the clinical benefit of aducanumab compared 
with placebo in participants with Alzheimer’s disease, including participants with either MCI 
due to Alzheimer’s disease or mild Alzheimer’s disease.  
In June 2021, aducanumab was approved by the US FDA under the accelerated approval 
pathway as a treatment for Alzheimer’s disease. Approval was based on evidence that 
aducanumab reduces brain amyloid, coupled with evidence that the reduction in amyloid 
identified in aducanumab clinical studies is reasonably likely to predict clinical benefit in 
Alzheimer’s disease. 
Consistent with the accelerated approval regulations, this study is being conducted to fulfill a 
postmarketing requirement from the FDA to verify the clinical benefit of aducanumab. The study 
is required to be a randomized, controlled trial to evaluate the efficacy of aducanumab compared 
with an appropriate control for the treatment of Alzheimer’s disease and to be of sufficient 
duration to observe changes on an acceptable endpoint in the enrolled study population. 
In accordance with the stated requirements, the study design largely conforms to that of the 
aducanumab Phase 3 Studies 221AD301 and 221AD302, namely, that it is a multicenter, 
randomized, double-blind, placebo-controlled, parallel-group study.  
Relevant nonclinical and clinical data (including from the Phase 3 program) are summarized in 
Section 3.2.3. 
3.1.1. Rationale for Study Population 
The study population will include participants with MCI due to Alzheimer’s disease and 
participants with mild Alzheimer’s disease [Albert 2011; McKhann 2011]. Enrollment will be 
monitored so that the population of participants with mild Alzheimer’s disease represents 
approximately 50% of the total number of participants enrolled in the study. Aducanumab is 
expected to provide the most benefit to patients in these early stages of Alzheimer’s disease.  
3.1.2. Rationale for Dosing Regimen 
Participants will be assigned to 1 of 2 treatment groups in a 2:1 ratio of aducanumab to placebo 
administered IV every 4 weeks.  Treatment is initiated via titration, which has been demonstrated 
to result in a lower incidence of ARIA. Titration will start at 1 mg/kg and will escalate to 3, 6 
and 10 mg/kg.   


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36 
3.2. 
Background 
3.2.1. Overview of Alzheimer’s Disease 
Alzheimer’s disease is an irreversible, progressive neurodegenerative disorder that slowly 
destroys memory and thinking skills. Initial impairment in memory may be followed by 
behavioral and neuropsychiatric symptoms and, finally, the inability to perform usual daily life 
activities. Alzheimer’s disease is the most common cause of dementia among older adults and is 
ultimately fatal. 
In the US, more than 5.8 million people are living with Alzheimer’s disease. By 2050, this 
number is projected to more than double [Alzheimer's Association 2020]. Alzheimer’s disease 
was the sixth leading cause of death in the US and the fifth leading cause for people aged 
65 years and older in 2018 [Alzheimer's Association 2020].   
Life expectancy after an Alzheimer’s disease diagnosis depends on various factors, including age 
at onset and severity at diagnosis [Brodaty 2012; Guehne 2007; Guehne 2005; Xie 2008]. An 
important distinction for Alzheimer’s disease patients is that a significant period of their 
remaining lives may be spent in the severe disabling disease state, adding to the burden on the 
health care system [Rizzuto 2012].   
In addition to the effect on patients, Alzheimer’s disease places a burden on families and 
caregivers. Informal caregiving for patients with Alzheimer’s disease or dementia has been 
estimated at 18 billion hours per year in the US, valued at $230 billion annually [Alzheimer's 
Association 2020; Dunbar 2018]. Increased care demands result in increased financial, 
psychological, and physical stress for the caregiver [Alzheimer's Association 2020; Suehs 2014].   
Alzheimer’s disease is a pathophysiological and clinical continuum in which specific 
pathological changes in the brain that occur as a continuous process throughout the course of the 
disease precede by many years the eventual emergence of clinical symptoms of cognitive decline 
that also progress continuously over a long period [Jack 2018].  
Alzheimer’s disease is defined biologically by the presence of 2 abnormal protein deposits: 
extracellular deposits of brain amyloid plaques (comprising amyloid beta peptides) and 
neurofibrillary tangles (comprising abnormal tau protein) [Hyman 2012]. 
Deposition of amyloid beta peptides into amyloid plaques begins decades prior to observable 
clinical symptoms [Vermunt 2019]. Deposition of amyloid beta is followed sequentially by 
markers of neurodegeneration [Hardy and Selkoe 2002], accumulation of tau pathology 
[Hanseeuw 2019], and brain volume loss [Jonsson 2012], all of which initiate prior to the onset 
of clinical symptoms. This presymptomatic phase of Alzheimer’s disease precedes the 
emergence of clinical symptoms by 10 to 20 years [Villemagne 2013]. At the time of the 
emergence of the earliest clinical findings, Alzheimer’s disease has already been present in the 
individual for decades, and there is already an advanced pathological disease state in the brain.  
The most salient known risk factors for Alzheimer’s disease are the unmodifiable contributors of 
older age, genetics, and family history. Of these, increasing age has the largest known impact on 


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37 
risk of developing Alzheimer’s disease. While several genes have been found to increase the risk 
of Alzheimer’s disease, the ε4 allele of the ApoE gene is the strongest known genetic risk factor 
[Elias-Sonnenschein 2011; Mattsson 2018]. Compared with the most common ApoE genotype of 
ε3/ε3, ε4 heterozygosity increases risk of Alzheimer’s disease by 3 to 4 times, and ε4 
homozygosity increases risk by 8 to 12 times [Alzheimer's Association 2020]. Approximately 
two-thirds of pathology-confirmed Alzheimer’s disease cases are ε4 positive (homozygous or 
heterozygous), compared with about 15% to 20% of the general population [Mattsson 2018]. 
Autosomal dominant genetic mutations are estimated to account for fewer than 1% of 
Alzheimer’s disease cases [Bekris 2010]. 
Developing treatments to halt, slow, or reverse the course of disease is a goal for the scientific 
community, the clinical health care system, long-term care services, community/support 
environments serving patients and caregivers, and the federal government [U.S. Department of 
Health and Human Services 2019].  
With pathophysiological changes in the brain starting a decade or more before clinical symptom 
onset, treatments directed at this goal must begin prior to the development of irreversible 
neurodegeneration and well before there are advanced clinical symptoms [FDA 2018; U.S. 
Department of Health and Human Services 2019; Vermunt 2019]. 
3.2.2. Other Current Therapies for Alzheimer’s Disease 
Until the approval of aducanumab in 2021 in the US, the only approved Alzheimer’s disease 
treatments included the cholinesterase inhibitors donepezil, rivastigmine, and galantamine, and 
the N-methyl-D-aspartate antagonist memantine.   
None of these other agents address the underlying pathology of the disease. Their effects are 
reversible and lessen over time due to the continued progression of the disease process [Birks 
2006; McShane 2006]. 
3.2.3. Profile of Previous Experience With Aducanumab 
3.2.3.1. 
Nonclinical Experience 
Unlike any other anti-Aβ monoclonal antibody in development, aducanumab was derived from 
human B cells collected from healthy elderly individuals with no signs of cognitive impairment 
and from cognitively impaired elderly individuals with unusually slow clinical decline. The 
screening of libraries of human memory B cells for reactivity against aggregated Aβ led to 
molecular cloning, sequencing, and recombinant expression of aducanumab [Sevigny 2016]. 
Aducanumab is a human IgG1 anti-Aβ monoclonal antibody selective for Aβ aggregates, 
including soluble oligomers and insoluble fibrils, but not monomers, as demonstrated in a variety 
of biochemical and structural analyses.  
Binding of aducanumab to aggregated Aβ promotes the removal of amyloid from the brain, 
through a microglia-mediated phagocytosis mechanism. Experimental evidence has shown that 


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38 
removal of amyloid stops or reduces neurotoxicity [Rozkalne 2009; Spires-Jones 2009] that 
might otherwise lead to neurodegeneration and, ultimately, cognitive impairment.  
Nonclinical studies have confirmed in vivo dose-dependent target engagement and 
dose-dependent reduction in brain amyloid burden for aducanumab [Sevigny 2016]. 
See the Investigator’s Brochure for detailed information on relevant nonclinical and clinical 
studies. 
3.2.3.2. 
Clinical Experience 
The aducanumab clinical development program comprises studies in healthy volunteers and in 
subjects with Alzheimer’s disease. See the Investigator’s Brochure for detailed information on 
the clinical efficacy and safety of aducanumab. 
The Phase 3 Study 221AD302 demonstrated a statistically significant treatment benefit (smaller 
increase in the CDR-SB) for aducanumab 10 mg/kg, compared to placebo (-0.39 [-22%], 
p = 0.0120). Statistically significant treatment effects in favor of aducanumab 10 mg/kg were 
also observed for all 3 ranked secondary clinical endpoints (MMSE, ADAS-Cog13, and ADCS-
ADL-MCI) and the tertiary endpoint (NPI-10). The effect of aducanumab on clinical endpoints 
was supported by statistically significant dose- and time-dependent reductions of markers of 
brain amyloid beta plaques, and dose-dependent reductions of relevant markers of downstream 
Alzheimer’s tau pathophysiology and neurodegeneration. The changes on measures of Aβ were 
correlated with changes on clinical outcomes. The Phase 3 Study 221AD301 did not contribute 
to the evidence of effectiveness on clinical outcomes for aducanumab; however, the study did 
further demonstrate that aducanumab reduces amyloid beta plaques, as the PET subset 
demonstrated statistically significant time- and dose-dependent decreases in amyloid beta 
plaques. Supportive data were also provided from the Phase 1b Study 221AD103, a smaller 
randomized, placebo-controlled, dose-finding study conducted in a similar population and using 
many of the same endpoints that were used in Studies 221AD301 and 221AD302. A dose-related 
numerical reduction in decline was observed relative to placebo for CDR-SB and MMSE, as well 
as dose- and time-dependent reduction of markers of brain amyloid beta plaques.  
As of March 2022, a total of 3078 participants have been exposed to aducanumab across 
completed or terminated clinical studies (including 3050 participants with Alzheimer’s disease 
and 28 healthy volunteers). Of those, 2757 participants were enrolled in the Phase 3, placebo-
controlled studies (Studies 221AD301 and 221AD302), for approximately 3983.5 person-years 
of exposure and totaling 4736.1 person-years of FU. The most frequent AE among participants 
from Studies 221AD301 and 221AD302 with a target dose of 10 mg/kg was ARIA-E (35.2%). 
Most participants with ARIA-E were asymptomatic, and participants with symptomatic ARIA-E 
had symptoms that were predominantly mild or moderate in clinical severity. Symptoms reported 
during ARIA-E episodes included headache, confusional state, dizziness, fatigue, and nausea. In 
the majority of participants with ARIA-E, the first ARIA-E events were documented to have 
fully resolved (800 of 815 participants [98.2%]). Similar to ARIA-E, the majority of participants 
with ARIA-H microhemorrhage and ARIA-H superficial siderosis were asymptomatic and 
stabilized radiographically. Other AEs observed at an incidence of at least 5% among 
participants from Studies 221AD301 and 221AD302 with a target dose of 10 mg/kg and at a 2% 


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39 
or greater incidence than placebo included headache (20.5%), ARIA-H microhemorrhage 
(19.1%), fall (15.0%), ARIA-H superficial siderosis (14.6%), and diarrhea (8.9%). Seizures, 
including status epilepticus, occurred more frequently in aducanumab-treated participants who 
experienced ARIA: 0.4% of all participants in the 10 mg/kg group had a seizure event compared 
with 0.8% of aducanumab-treated participants who experienced ARIA-E. These events are 
ADRs of aducanumab. 
3.3. 
Benefit-Risk Assessment 
Alzheimer’s disease is a major public health issue that imposes immense burden on patients and 
caregivers.  
The Phase 3 Study 221AD302 met its prespecified primary and secondary endpoints. The 
statistically significant effect of aducanumab on clinical endpoints was supported by statistically 
significant dose- and time-dependent reductions of markers of brain amyloid beta plaques, and 
dose-dependent reductions of relevant markers of downstream Alzheimer’s tau pathophysiology 
and neurodegeneration. Supportive efficacy data were provided from the Phase 1b Study 
221AD103, a smaller randomized, placebo-controlled, dose-finding study that demonstrated a 
dose-related numerical reduction in decline relative to placebo for CDR-SB and MMSE, as well 
as dose- and time-dependent reduction of markers of brain amyloid beta plaques. Although the 
Phase 3 Study 221AD301 did not contribute to the evidence of effectiveness on clinical 
outcomes for aducanumab, the study did further demonstrate that aducanumab reduces amyloid 
beta plaques, as the PET subset demonstrated statistically significant time- and dose-dependent 
decreases in amyloid beta plaques. There is also extensive scientific evidence of the role of 
amyloid in Alzheimer’s disease. Collectively, the imaging, fluid biomarker results, the 
correlation analysis, and the exposure-response modeling are all consistent with a direct effect of 
aducanumab on lowering brain Aβ pathology with a subsequent effect on reducing tau 
pathology, neurodegeneration, and ultimately slowing of clinical decline. 
The aducanumab safety database exceeds the minimum ICH guidance, and risk management can 
be achieved through monitoring for ARIA, as described in the protocol. Most of the safety data 
from the aducanumab clinical program are derived from Studies 221AD301 and 221AD302.  
ARIA is the most common safety finding observed with aducanumab. ARIA includes ARIA-E, 
which can be observed on MRI as brain edema or sulcal effusions, and ARIA-H, which includes 
microhemorrhage and superficial siderosis. ARIA-E was observed in 35.2% of the 10 mg/kg 
dose group, compared with 2.7% of the placebo group. The incidence of ARIA-E was higher in 
ApoE ε4 carriers than in ApoE ε4 noncarriers (43.0% and 20.3%, respectively). The majority of 
ARIA-E radiographic events occurred early in treatment (within the first 8 doses), although 
ARIA can occur at any time. In the 10 mg/kg group, the majority of ARIA-E events resolved 
within 12 to 16 weeks of detection (68.9% and 82.8%, respectively) and 98% of ARIA-E 
resolved radiographically. In the 10 mg/kg group, 10.0% of aducanumab-treated participants 
experienced symptoms in the setting of ARIA; these included headache, confusion, dizziness, 
visual disturbances, nausea, and vomiting, with most symptoms being mild or moderate and 
transient in nature. Seizures, including status epilepticus, can be a severe symptom of ARIA-E.  


Protocol 221AD305, Version 2.0 
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40 
The potential risks related to participation in this study are justified by the anticipated benefit to 
participants. However, given the partial discrepancies between the 2 pivotal trials, and while 
acknowledging that this drug has been approved at this time in the US via accelerated approval, 
the benefit profile of aducanumab at 10 mg/kg IV will be further verified in this study.  
General risk mitigation against COVID-19 will be implemented in accordance with the study 
site’s IRB-approved monitoring and prevention control measures. The risk mitigation measures, 
where applicable, will be amended based on emerging local, regional, and national guidance. 
Detailed information about the known and expected benefits and risks and reasonably expected 
AEs of aducanumab is provided in the Investigator’s Brochure and ICF.  
 








Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab (BIIB037) in Early Alzheimer’s Disease 
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44 
 
 
 
 
 
 
 
 
 
 
 
 
  
This clinical study collects samples that, under separate optional consent, may be used for future 
scientific and genetic research. Objectives related to this future research have not been 
determined. 


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Biogen MA Inc. 
45 
5. 
STUDY DESIGN 
5.1. 
Study Overview 
Study 221AD305 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study in participants with early Alzheimer’s disease, including those with MCI due to 
Alzheimer’s disease or mild Alzheimer’s disease dementia. Enrollment will be monitored via the 
IRT system so that the population of participants with mild Alzheimer’s disease represents 
approximately 50% of the total number of participants enrolled in the study. The study will 
include up to 24 months of treatment as well as screening and post-treatment FU periods. 
Approximately 1512 participants will be enrolled across an estimated 220 centers globally.   
The primary study objective is to verify the clinical benefit of monthly doses of aducanumab on 
CDR-SB relative to placebo at Week 78. Key secondary objectives include assessment of the 
effect of monthly doses of aducanumab on clinical decline as compared to placebo at Week 78 as 
measured by a variety of cognitive and functional scales such as those implemented in the Phase 
3 studies (i.e., ADCS-ADL-MCI, ADAS-Cog13, MMSE, and NPI-10), as well as the composite 
scale iADRS, which is a linear combination of the ADAS-Cog13 and the ADCS-ADL-MCI. 
Other secondary objectives include assessment of the effect of monthly doses of aducanumab on 
change in amyloid PET and tau PET signal at Week 78 and 104 as compared with placebo, as 
well as all clinical endpoints (i.e., CDR-SB, iADRS, ADCS-ADL-MCI, ADAS-Cog13, MMSE, 
and NPI-10) assessed at the Week 106 timepoint. Secondary objectives also include an 
assessment of the effect of monthly doses of aducanumab on the GST composite z-score, defined 
as the average of standardized z scores of the CDR-SB, ADCS-ADL-MCI, and ADAS-Cog13, at 
Weeks 78 and 106. Tertiary objectives include confirmation of the safety, tolerability, and 
associated immunogenicity of aducanumab and its PK characteristics, and HEOR and QoL 
metrics. 
 
 
 
 
 
 
Participants will receive IV infusions of aducanumab or placebo approximately Q4W for 104 
weeks. Participants will be randomized to receive aducanumab:placebo in a 2:1 ratio. The 
randomization will be stratified by geographical region, baseline disease stage (MCI due to 
Alzheimer’s disease or mild Alzheimer’s disease dementia), and ApoE ε4 status (carrier or 
noncarrier). Randomization will be performed using IRT. Aducanumab will be initiated with a 6-
dose titration period prior to reaching the target dose of 10 mg/kg, as detailed in Section 3.1.2. 
Investigators, outcome assessors, study site staff (except for the designated unblinded 
pharmacist/technician), study participants, and informants will be blinded to the randomized 
treatment assignment.  


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The total duration of the study for each participant will be approximately 130 weeks, including a 
series of screening visits within 8 weeks before administration of the first dose, and a 104-week 
placebo-controlled treatment period. Participants will additionally undergo a safety FU Visit 
18 weeks after the final dose of aducanumab.  
See Figure 1 for schematic of the study design. 
Substudies 
Three optional longitudinal substudies will be completed within this study in subsets of 
consenting participants, as follows:  
• An amyloid PET substudy involving assessments of amyloid by PET scan at Screening 
and at Weeks 78 and 104 
• A tau PET substudy involving assessments of tau by PET scan at Screening and at 
Weeks 78 and 104  
 
  
For participants of these substudies, study-specific procedures are required for provision of 
baseline PET scans 
 
5.2. 
Study Duration for Participants 
The total duration of the study for each participant will be approximately 130 weeks, including a 
series of screening visits within 8 weeks before administration of the first dose, and a 104-week 
placebo-controlled treatment period. Additionally, participants will undergo a safety FU Visit 
18 weeks after the final dose of aducanumab.  
Participants will have approximately 39 scheduled clinic visits, 27 of which are dosing visits, as 
well as up to 8 telephone safety FU contacts, as follows: 
• Screening Visits 1 to 3 will occur no more than 60 days before the first dose of study 
treatment on Day 1. Visits will be conducted on multiple days. All screening procedures 
should be completed within 60 days; however, with Sponsor approval, the overall 
screening period may be extended up to 90 days in the event of logistical issues related 
to PET scans (and/or due to other major causes [i.e., institutional restrictions or 
participant disposition due to COVID-19 or other major disasters/disruptions]). These 
screening visits will include baseline brain MRI, clinical scales of cognition and 
function, biological fluid sampling (including CSF), amyloid and tau PET scans (where 
available), physical and neurological examinations, and all other safety and efficacy 
assessments. See Section 1.3 for the Schedules of Activities. 
• Twenty-seven dosing visits (Day 1 and Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 
52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, and 104). 


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47 
• Eight telephone safety FU contacts after each of the first 8 doses. 
• Four visits separate from dosing for clinical functional and cognitive assessments 
(Weeks 26, 50, 78, and 106). 
• One safety FU visit at Week 122, 18 weeks after the last dose at Week 104, or 18 weeks 
after administration of the last dose for participants who discontinue treatment early. 
• A minimum of 6 MRI visits, with 4 during treatment (Week 14 [before escalation to 
6 mg/kg, before at the fifth dose], Week 22 [before escalation to 10 mg/kg, before the 
seventh dose], Week 30 [before the third dose at 10mg/kg], and Week 42 [before the 
sixth dose at 10 mg/kg]. Two additional MRIs will be performed at Week 106 and at 
Week 122 [EOS] 18 weeks after the final-dose safety FU) or 18 weeks after 
administration of the last dose for participants who discontinue treatment early. 
5.3. 
Monitoring and Management of ARIA 
5.3.1. Dose Suspension or Permanent Discontinuation for ARIA Events 
Guidelines on the management and disposition of ARIA cases (including the criteria to be met 
for the continuation, suspension/resumption, permanent discontinuation of dosing due to ARIA, 
resumption of dosing after dose suspension due to ARIA [including rules for titrating up to the 
assigned dose], and management of recurrent ARIA) are provided in the following subsections.  
The central MRI reading center will report incident cases of ARIA-E and ARIA-H to both the 
Sponsor and the Investigator within a specified time after observing the finding on MRI per the 
imaging manual procedures, with an assessment of severity. All cases of ARIA must be reviewed 
by the Investigator; decisions on dosing continuation, interruption, or discontinuation will be 
based on the Investigator’s clinical assessment of the participant and the MRI information 
provided by the central reader. Dosing may also be terminated at the discretion of the Sponsor 
for medical reasons. 
If a participant experiences symptoms that could be suggestive of ARIA, clinical evaluation 
should be performed, including MRI testing if indicated. 
See Section 8.1 for the full list of criteria for discontinuing study treatment. 


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48 
5.3.1.1. 
ARIA-E 
Table 4: 
Disposition of ARIA-E Cases 
Clinical 
Symptom 
Severity1 
ARIA-E Severity on MRI (Central Read)  
Mild 
Moderate 
Severe 
Asymptomatic 
Continue dosing at 
current dose and 
schedule 
Suspend dosing. Once ARIA-E resolves, the participant may resume 
dosing at the same dose.  
Mild 
Suspend dosing. Once ARIA-E and clinical symptoms resolve, the 
participant may resume dosing at the same dose. 
Moderate 
Suspend dosing. Once ARIA-E and clinical symptoms resolve, the participant may resume dosing 
at the same dose. 
Severe 
1 Nonserious symptoms only. If serious symptoms of ARIA-E (according to the definition of serious adverse events 
in Section 11.1.2), treatment should be permanently discontinued. 
The following study activities must be followed for participants with ARIA-E:  
• Participants with ARIA-E should complete all scheduled clinic visits for assessments 
and, in addition, have an unscheduled visit for an MRI every 4 weeks (± 5 days) until the 
ARIA-E has resolved per the centrally read MRI. In addition, 
 and PK 
samples will be collected at the first visit, scheduled or unscheduled, following an 
episode of ARIA-E.  
For nonserious ARIA-E and ARIA-E with nonserious symptoms (according to the definition of 
serious adverse events in Section 11.1.2): 
• Participants who develop ARIA-E that is radiographically mild, per central MRI 
reading, and who have no symptoms or symptoms that are mild may continue 
dosing per protocol. Participants should complete all scheduled clinic visits for 
assessments and have an unscheduled visit for an MRI Q4W (± 5 days) until the ARIA-
E has resolved per the centrally read MRI.  
− If moderate or severe symptoms develop during follow-up of the ARIA-E event, 
dosing should be suspended. 
− If a follow-up MRI demonstrates radiographically moderate or severe ARIA-E, 
per central MRI reading, dosing should be suspended.  
If dosing is suspended, once the ARIA-E has resolved per the centrally read MRI and 
once the clinical symptoms have resolved (in the Investigator’s opinion), the participant 
may resume treatment at the same dose (see Section 5.3.1.6 for dose resumption rules).  
• Participants who develop ARIA-E that is radiographically mild, per central MRI 
reading, accompanied by moderate or severe clinical symptoms, should suspend 
dosing. Once the ARIA-E has resolved per the centrally read MRI and once the clinical 


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49 
symptoms have resolved (in the Investigator’s opinion), the participant may resume 
treatment at the same dose. See Section 5.3.1.6 for dose resumption rules. 
• Participants who develop ARIA-E that is radiographically moderate or severe, per 
central MRI reading, with or without symptoms, should suspend dosing. Dosing may 
be resumed at the same dose once the ARIA-E has resolved per the centrally read MRI 
and once the clinical symptoms, if any, have resolved (in the Investigator’s opinion). See 
Section 5.3.1.6 for dose resumption rules. 
For serious ARIA-E events or ARIA-E events with serious symptoms (according to the 
definition of serious adverse events in Section 11.1.2): 
• Participants who develop ARIA-E (of any radiographic severity) that is considered 
serious or that is accompanied by serious clinical symptoms (according to the 
definition of serious adverse events in Section 11.1.2), at any time during the study, 
should permanently discontinue treatment.   
See Section 5.3.1.6 for details on resumption of dosing when suspension occurs during the 
titration period and Section 5.3.1.7 for guidelines on resuming dosing after a recurrence of 
ARIA. 
5.3.1.2. 
ARIA-H (Microhemorrhage) 
Treatment-emergent microhemorrhages are defined as microhemorrhages that occur while the 
participant is on study treatment and do not include microhemorrhages at baseline. 
Table 5: 
Disposition of ARIA-H (Microhemorrhage) Cases 
Clinical 
Symptom 
Severity1 
Treatment-emergent Microhemorrhages (Central Read)  
Mild 
Moderate 
Severe 
≥ 1 and ≤ 4 
≥ 5 and ≤ 9 
≥ 10 
Asymptomatic 
Continue dosing at current 
schedule 
Suspend dosing. Once ARIA-H is stable, the 
participant may resume dosing at the same 
dose. 
Permanently 
discontinue 
treatment 
Symptomatic 
Suspend dosing. Once ARIA-H stabilizes and clinical symptoms resolve, 
the participant may resume dosing at the same dose. 
1 Nonserious symptoms only. If serious symptoms of ARIA-H (according to the definition of serious adverse events 
in Section 11.1.2), treatment should be permanently discontinued. 
The following study activities must be followed for participants with ARIA-H 
(microhemorrhage):  
• Participants with ARIA-H microhemorrhage should complete all scheduled clinic visits 
for assessments. In addition, if ARIA-H microhemorrhage is radiographically moderate, 
or if symptoms are present, participants should have an unscheduled visit for an MRI 
every 4 weeks (± 5 days) until the ARIA-H has stabilized per the centrally read MRI. 


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ARIA stabilization is defined as no change or a decrease in the number or size of 
microhemorrhages on 2 consecutive MRIs, including the initial detection MRI. In 
addition, 
 and PK samples will be collected at the first visit, scheduled or 
unscheduled, following an episode of ARIA. .  
For nonserious ARIA-H microhemorrhages and ARIA-H microhemorrhages with nonserious 
symptoms (according to the definition of serious adverse events in Section 11.1.2): 
• 
Participants who develop between 1 and 4 (≥ 1 and ≤ 4) treatment-emergent 
microhemorrhages (mild radiographic per central MRI reading), and who have no 
symptoms may continue dosing per protocol. 
• Participants who develop between 1 and 4 (≥ 1 and ≤ 4) treatment-emergent 
microhemorrhages (mild radiographic per central MRI reading), accompanied by 
clinical symptoms of any severity, should suspend dosing. Dosing may be resumed at 
the same dose once the ARIA-H is radiographically stable on follow-up MRI and 
clinical symptoms have resolved (in the Investigator’s opinion). See Section 5.3.1.6 for 
dose resumption rules. 
• Participants who develop between 5 and 9 (≥ 5 and ≤ 9) treatment-emergent 
microhemorrhages (moderate radiographic per central MRI reading), with or 
without symptoms of any severity, should suspend dosing. Dosing may be resumed at 
the same dose once the ARIA-H is radiographically stable on follow-up MRI and 
clinical symptoms, if any, have resolved (in the Investigator’s opinion). See 
Section 5.3.1.6 for dose resumption rules. 
• Participants who develop 10 or more (≥ 10) treatment-emergent microhemorrhages 
(severe radiographic per central MRI reading), should permanently discontinue 
treatment. 
For serious ARIA-H microhemorrhages or ARIA-H microhemorrhages with serious symptoms 
(according to the definition of serious adverse events in Section 11.1.2): 
• Participants who develop ARIA-H microhemorrhage (of any radiographic severity) that 
is accompanied by serious clinical symptoms (according to the definition of serious 
adverse events in Section 11.1.2) should permanently discontinue treatment. 
See Section 5.3.1.6 for details on resumption of dosing when suspension occurs during the 
titration period and Section 5.3.1.7 for guidelines on resuming dosing after a recurrence of 
ARIA. 


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5.3.1.3. 
ARIA-H (Superficial Siderosis) 
Table 6: 
Disposition of ARIA-H (Superficial Siderosis) Cases 
Clinical 
Symptom 
Severity1 
Treatment-Emergent Superficial Siderosis (Central Read)  
Mild 
Moderate 
Severe 
1 
2 
> 2 
Asymptomatic 
Continue dosing at current 
schedule 
Suspend dosing. Once ARIA-H is 
stable, the participant may resume 
dosing at the same dose. 
Permanently discontinue 
treatment 
Symptomatic 
Suspend dosing. Once ARIA-H stabilizes and clinical symptoms 
resolve, the participant may resume dosing at the same dose. 
1 Nonserious symptoms only. If serious symptoms of ARIA-H (according to the definition of serious adverse events 
in Section 11.1.2), treatment should be permanently discontinued. 
The following study activities must be followed for participants with ARIA-H (superficial 
siderosis):  
• Participants with ARIA-H superficial siderosis should complete all scheduled clinic 
visits for assessments and should have an unscheduled visit for an MRI every 4 weeks 
(± 5 days) until the ARIA-H has stabilized per the centrally read MRI. ARIA 
stabilization is defined as no change or a decrease in the number, size, or location of 
superficial siderosis on 2 consecutive MRIs, including the initial detection MRI. In 
addition, 
 and PK samples will be collected at the first visit, scheduled or 
unscheduled, following an episode of ARIA.  
For nonserious ARIA-H superficial siderosis or ARIA-H superficial siderosis with nonserious 
symptoms (according to the definition of serious adverse events in Section 11.1.2): 
• Participants who develop 1 treatment-emergent focal area of superficial siderosis 
(mild radiographic per central MRI reading), and who have no symptoms may 
continue dosing per protocol. Participants should complete all scheduled clinic visits for 
assessments and have an unscheduled visit for an MRI Q4W (± 5 days) until the ARIA-
H has stabilized per the centrally read MRI. 
• Participants who develop 1 treatment-emergent focal area of superficial siderosis 
(mild radiographic per central MRI reading), with symptoms of any severity, 
should suspend dosing. Dosing may be resumed at the same dose once the ARIA-H is 
radiographically stable on follow up MRI and once clinical symptoms, if any, have 
resolved (in the Investigator’s opinion). See Section 5.3.1.6 for dose resumption rules. 
• Participants who develop 2 treatment-emergent focal areas of superficial siderosis 
(moderate radiographic per central MRI reading), with or without symptoms of 
any severity, should suspend dosing. Dosing may be resumed at the same dose once the 
ARIA-H is radiographically stable on follow-up MRI and clinical symptoms have 
resolved (in the Investigator’s opinion). See Section 5.3.1.6 for dose resumption rules. 


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• Participants who develop more than 2 (> 2) treatment-emergent focal area of 
superficial siderosis (severe radiographic per central MRI reading), with or 
without clinical symptoms of any severity, should permanently discontinue treatment. 
For serious ARIA-H superficial siderosis or ARIA-H superficial siderosis with serious symptoms 
(according to the definition of serious adverse events in Section 11.1.2):   
• Participants who develop ARIA-H superficial siderosis (of any radiographic severity) 
accompanied by serious clinical symptoms (according to the definition of serious 
adverse events in Section 11.1.2), should permanently discontinue treatment. 
See Section 5.3.1.6 for details on resumption of dosing when suspension occurs during the 
titration period and Section 5.3.1.7 for guidelines on resuming dosing after a recurrence of 
ARIA. 
5.3.1.4. 
Cerebral Hemorrhage > 1 cm  
Participants who develop any new treatment-emergent cerebral hemorrhage > 1 cm in diameter 
on T2* sequence, regardless of symptom severity during the study, will permanently discontinue 
treatment but should be encouraged to remain in the study. Participants should complete a FU 
Visit 18 weeks after the final dose, protocol-required tests and assessments at a subset of the 
clinic visits (see Table 3), and in addition, have an unscheduled visit for MRI every 4 weeks 
(± 5 days) until the cerebral hemorrhage is confirmed stable per centrally read MRI. A cerebral 
hemorrhage is considered stable if there is no change or a decrease in the size or number of 
locations between 2 consecutive MRIs, including the initial detection MRI and the MRI 
performed 4 weeks (± 5 days) later.  
5.3.1.5. 
Coincident (Concurrent) ARIA-H and ARIA-E Cases 
Participants who develop ARIA-H coincident with ARIA-E at any time during the study will 
follow the most restrictive guidelines. For ARIA events, prior to resuming treatment, where 
applicable, ARIA-E must not be radiographically severe, ARIA-H must be deemed stable, and 
the participant must be asymptomatic.  
5.3.1.6. 
Resumption of Study Treatment and MRI Monitoring After Suspension Due to 
ARIA 
Participants who suspend treatment due to ARIA may resume treatment if they meet the criteria 
as described in Sections 5.3.1.1, Section 5.3.1.2, Section 5.3.1.3, Section 5.3.1.4, and 
Section 5.3.1.5. The preceding centralized MRI report must be received and reviewed by the 
Investigator before continuing with study treatment infusions. 
• Participants who suspend and then resume dosing after having reached the 10 mg/kg dose 
level (e.g., dose 7 or later) are to resume dosing at the 10 mg/kg dose level.  


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• If dosing is suspended prior to a participant reaching the 10 mg/kg dose level (e.g., during 
the first 6 doses), the participant should resume dosing per the titration schedule (e.g., if 
dosing was suspended after 3 doses, the next dose should be 3 mg/kg).  
Routine MRI monitoring should be conducted as follows in the context of dose suspension. 
If dosing was suspended prior to completion of the 4 routine monitoring MRIs for asymptomatic 
ARIA, these should be completed at the same time points in titration, allowing for the number of 
weeks that dosing was suspended, and any repeated dose during titration. 
• If dosing was suspended prior to the fourth dose, the participant should undergo routine 
MRIs prior to the first dose at 6 mg/kg, and prior to the first, third, and sixth doses at the 
10 mg/kg dose level. 
•  If dosing was suspended prior to the sixth dose, the participant should undergo routine 
MRIs prior to the first, third, and sixth dose at the 10 mg/kg dose level. 
• If dosing was suspended prior to the eighth dose, the participant should undergo routine 
MRIs prior to the third and sixth doses at the 10 mg/kg dose level. 
• If dosing was suspended prior to the eleventh dose, the participant should undergo a 
routine MRI prior to the sixth dose at 10 mg/kg. 
5.3.1.7. 
Management After Recurrent ARIA  
Recurrent ARIA is managed identically to the first ARIA occurrence with respect to dosing and 
MRI. Consideration should be given to permanent discontinuation in the event of 3 or more 
recurrent episodes of ARIA. 
5.3.2. 
Infusion Interruption 
If any mild or moderate infusion-related reactions (e.g., headache, chills/rigors, and 
nausea/vomiting) occur during an infusion, the infusion should be slowed or interrupted, and 
supportive treatment should be instituted at the discretion of the Investigator. After resolution of 
symptoms, if the infusion had been slowed, the original infusion rate may be resumed; if the 
infusion had been interrupted, the infusion may be restarted at a rate that does not exceed the 
original infusion rate. An infusion must be discontinued if not completed within 3 hours. 
Refer to the DHA for infusion rate information. 
If a severe infusion-related reaction occurs during an infusion, or an allergic reaction such as 
urticaria or anaphylaxis occurs, the participant will be discontinued from study treatment but 
may remain in the study. The participant must be appropriately treated in accordance with local 
practice. 
Severity of events is described in Section 11.2.3. 


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5.4. 
Study Termination 
The Sponsor may terminate this study at any time, after informing Investigators. The Sponsor 
will notify Investigators when the study is to be placed on hold, completed, or terminated. 
5.5. 
Unscheduled Visits 
Data collected during unscheduled visits should be recorded on CRFs only if the data support 
protocol objectives and/or are required for safety monitoring. Unscheduled visits specifically 
prompted by a change in Alzheimer’s disease medication or ARIA events are specified in 
Table 1 Table 2, and Table 3.  
5.6. 
End of Study 
The end of study is last participant, last visit.  


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6. 
STUDY POPULATION 
6.1. 
Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Screening, or at the timepoint specified in the individual eligibility criterion listed: 
1. The participant and/or his/her legally authorized representative (e.g., parent, spouse, or 
legal guardian, where local regulations and institutional practices permit) must be able, as 
appropriate and applicable, to understand the purpose and risks of the study, to provide 
signed and dated informed consent, and to authorize the use of confidential health 
information in accordance with national and local privacy and ethics regulations. 
2. The participant must be 60 to 85 years old, inclusive, at the time of informed consent.  
3. All women of childbearing potential must practice effective contraception during the study 
and for 5 times the half-life or 24 weeks (whichever is longer) after their last dose of study 
treatment. For further details of contraceptive requirements for this study, refer to 
Section 11.5. 
4. The participant must have a minimum of 9 years of education or vocational training or the 
equivalent education/vocational training until the age of 15 or, per Investigator judgment, 
work experience that indicates a lack of mental deficits other than early-stage dementia. 
5. The participant must have confirmed amyloid beta pathology by CSF (historical CSF test 
results not allowed) or amyloid PET. If providing only a screening amyloid PET scan for 
amyloid positivity, a historical, amyloid PET scan obtained within 18 months of Screening 
Visit 2 is permissible. Sponsor-approved tracers must be used and scans must be 
submitted to the central imaging vendor to confirm that study inclusion criteria are met. In 
the case of discordant results between CSF and PET, PET results will be used to assess 
eligibility. 
6. The participant must have a history of subjective memory decline with gradual onset and 
slow progression over the last 6 months before Screening, confirmed by study partner. 
7. The participant must meet all of the following clinical criteria for MCI due to Alzheimer’s 
disease or mild Alzheimer’s disease according to NIA-AA criteria  [Albert 2011; 
McKhann 2011]: 
• Have an MMSE score between 22 and 30 inclusive 
• Have a CDR memory score ≥ 0.5 
• Have a CDR-GS of 0.5 or 1.0 
• Have an RBANS score of 85 or lower indicative of objective cognitive impairment 
(based upon the DMI score) 
8. The participant must be in good health, apart from a clinical diagnosis of early 
Alzheimer’s disease, as determined by the Investigator based on medical history and 
screening assessments. 


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9. The participant must consent to ApoE genotyping.  
10. The participant must have 1 informant/care partner who, in the Investigator’s opinion, has 
frequent and sufficient contact with the participant (at least 10 hours/week in person or by 
phone) as to be able to provide accurate information about the participant’s cognitive and 
functional abilities over time. The informant/care partner ideally has known the participant 
prior to their cognitive decline to have a reference point for change across time. The 
informant/care partner must be available by phone to provide information to the 
Investigator and study staff about the participant as well as agree to attend in-person clinic 
visits that require partner input for scale completion. The informant/care partner must be 
literate and provide informed consent and should be available for the duration of the study. 
The same informant/care partner is required to be consistent across all study visits except 
under rare, unavoidable circumstances (e.g., unexpected informant health crisis) that are 
approved by the Investigator and Sponsor. 
6.2. 
Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Screening, or at the timepoint specified in the individual criterion listed: 
Medical History and Current Health Status 
1. Any uncontrolled medical or neurological/neurodegenerative condition (other than 
Alzheimer’s disease) that, in the opinion of the Investigator, might be a contributing cause 
of the participant’s cognitive impairment (e.g., Lewy body dementia, head trauma, 
substance abuse, frontotemporal dementia, vitamin B12 deficiency, abnormal thyroid 
function, stroke, or other cerebrovascular condition). 
2. Clinically significant and/or unstable psychiatric illness within 6 months prior to 
Screening. 
3. Any documented prior history of chronic schizophrenia. 
4. History of long-term major depression or bipolar affective disorder with an active episode 
in the past 5 years. 
5. Transient ischemic attack or stroke or any unexplained loss of consciousness within 1 year 
prior to Screening. 
6. Brain MRI performed at Screening (per centrally read MRI) that shows evidence of any of 
the following: 
• 
Acute or subacute hemorrhage 
• 
Prior cerebral hemorrhage > 1 cm in diameter on T2* sequence or prior 
subarachnoid hemorrhage unless it can be documented that the finding is not due 


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to an underlying structural or vascular abnormality (i.e., finding does not suggest 
participant is at risk of recurrent hemorrhage) 
• 
4 or more microhemorrhages (defined as ≤ 1 cm in diameter on T2* sequence) 
• 
1 or more localized superficial siderosis findings 
• 
Cortical infarct (defined as > 1.5 cm in diameter irrespective of anatomic 
location) 
• 
> 1 lacunar infarct (defined as ≤ 1.5 cm in diameter) 
• 
History of 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 participant’s dementia, might pose a risk to the participant, or might prevent a 
satisfactory MRI assessment for safety monitoring 
7. History of bleeding disorder or predisposing conditions, blood clotting, or clinically 
significant abnormal results on coagulation profile at Screening as determined by the 
Investigator. 
8. Presence of diabetes mellitus that, in the judgment of the Investigator, cannot be 
controlled or adequately managed. 
9. 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. 
10. Clinically significant 12-lead ECG abnormalities as determined by the Investigator. 
11. Uncontrolled hypertension defined as: average of 3 SBP/DBP readings > 165 mmHg 
and/or > 100 mmHg 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 mmHg and/or > 100 mmHg 3 months prior to randomization (Day 1) that, in the 
opinion of the Investigator, are indicative of chronic uncontrolled hypertension. 
12. History of malignancy or carcinoma.  The following exceptions may be made 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. 


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• Participants with localized prostate cancer with treatment cycles that completed at 
least 6 months prior to Screening Visit 1. 
13. History of seizures or new-onset seizures within 10 years prior to Screening. 
14. Indication of impaired liver function as shown by an abnormal liver function profile at 
Screening (e.g., repeated values of AST and ALT ≥ 2 × the upper limit of normal). 
15. History or evidence of an autoimmune disorder considered clinically significant by the 
Investigator. 
16. Recent history (within 1 year of Screening) of alcohol or substance abuse as determined 
by the Investigator, or a positive urine drug test (due to a nonprescription drug and without 
a clear justification of the results according to the Investigator) at Screening.  
17. Within 30 days of Screening, clinically significant systemic illness or infection that 
requires hospitalization or that, in the opinion of the Investigator, is impacting the 
patient’s usual performance in function or cognition.  
18. History of or known seropositivity for HIV. 
19. Current hepatitis B infection (defined as positive for HBsAg and total anti-HBc). 
Participants with immunity to hepatitis B from previous natural infection (defined as 
negative HBsAg, positive anti-HBc, and positive anti-HBs) or vaccination (defined as 
negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in 
the study. 
20. Current hepatitis C virus infection (defined as positive HCV antibody and detectable HCV 
RNA). Participants with positive HCV Ab and undetectable HCV RNA are eligible to 
participate in the study. 
21. History of severe allergic or anaphylactic reactions or of hypersensitivity to any of the 
inactive ingredients in the drug product. (Refer to the Investigator’s Brochure for 
information on the clinical formulation.) 
22. Symptoms consistent with SARS-CoV-2 infection, per the judgment of the Investigator, 
within 14 days prior to Day 1, including but not limited to fever (temperature > 37.5°C), 
sore throat, new and persistent cough, shortness of breath, diarrhea, muscle aches, or loss 
of taste or smell. 
23. Any other medical conditions (e.g., renal disease) that are not stable or controlled or, in 
the opinion of the Investigator, could affect the participant’s safety or interfere with the 
study assessments. 


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Medications 
24. Participation in any active immunotherapy study targeting Aβ unless documentation of 
receipt of placebo is available. 
25. Participation in any passive immunotherapy study targeting Aβ within 12 months of 
Screening unless documentation of receipt of placebo is available. 
26. Participation in any study with purported disease-modifying effect in Alzheimer’s disease 
within 12 months prior to Screening unless documentation of receipt of placebo is 
available.  
27. Current use or previous use of medications with a purported disease‑modifying effect in 
Alzheimer’s disease, outside of investigational studies. 
28. 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. 
29. Use of allowed chronic concomitant medications (see Section 7.7.1.1) at doses that have 
not been stable for at least 4 weeks prior to Screening Visit 2 and during Screening up to 
Day 1, or use of Alzheimer’s disease 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 2 and during Screening up to Day 1. 
30. Use of allowed chronic concomitant medications that affect cognition (e.g., 
antidepressants, anticonvulsants, atypical and typical antipsychotics, short-/medium-acting 
benzodiazepines; see Section 7.7.1.2.1) at doses that have not been stable for at least 8 
weeks prior to Screening Visit 2 and during Screening up to Day 1. 
31. Use of long-acting benzodiazepines (allowed only for sedation prior to MRI/PET scans or 
LP for participants requiring sedation).  
32. Use of medications with antiplatelet or anticoagulant properties (acetylsalicyclic acid 
[aspirin] is allowed at a dose ≤ 325 mg per day). 
33. Use of chemotherapeutic agents and checkpoint inhibitors. 
34. Chronic use of systemic immunosuppressive drugs (including systemic corticosteroids) as 
indicated in Section 7.7.1.2. Local immunosuppressants and local corticosteroids 
(including inhaled or topical corticosteroids) are allowed; short-term courses of systemic 
corticosteroids may also be permitted at the Sponsor’s discretion. 
35. Use of parenteral immunoglobulin (i.e., IVIG), blood products, plasma derivatives, plasma 
exchange, or plasmapheresis. 
36. Use of active or passive immunotherapy agents targeting the CNS. 


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37. Use of any drug of abuse (prescription or recreational), including but not limited to, 
amphetamine, cocaine, opiates, methadone, phencyclidine, or barbiturates. 
38. Use of THC-containing cannabinoids (products containing only CBD are allowed). 
39. Use of opioid medications within 4 weeks prior to Screening Visit 1.  
40. Use of anticholinergics, such as benztropine. 
41. Use of any investigational drug. 
42. Vaccinations (including COVID-19 vaccines and boosters) within 5 days prior to 
randomization (Day 1).  
43. Prior exposure to aducanumab either commercially or by participation in a previous study 
with aducanumab. (Participants are eligible if they did not receive active aducanumab.) 
Study Procedures 
44. Contraindications to having a brain MRI (e.g., pacemaker; MRI-incompatible aneurysm 
clips, artificial heart valves, or other metal foreign body; or claustrophobia that cannot be 
medically managed). 
45. Any of the following contraindications to having an amyloid PET scan or LP if CSF 
testing is used for amyloid confirmation: 
• Contraindications to PET (e.g., inability to lie flat or still for the duration of the scan) 
or intolerance to previous PET scans (i.e., previous hypersensitivity reactions to any 
PET ligand or imaging agent or failure to participate in and comply with previous 
PET scans); the participant has had or plans to have exposure to experimental 
radiation within 12 months prior to Screening such that radiodosimetry limits would 
be exceeded by participating in this study. 
• Contraindications to having a LP (e.g., presence of risk for increased or uncontrolled 
bleeding, anatomical factors at or near the LP site). Any symptoms caused by or 
related to the optional LP during Screening must be resolved prior to randomization 
(Day 1).  
46. A negative PET scan result with any amyloid-targeting ligand within 12 months prior to 
Screening. 
Other 
47. Female participants who are pregnant or currently breastfeeding. 
48. Participant currently lives in an organized care facility with extensive intervention and/or 
support of daily living activities. 
49. Blood donation (≥ 1 unit) within 1 month prior to Screening. 


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50. Inability to comply with study requirements. 
51. Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the 
participant unsuitable for enrollment. 
6.3. 
Screening, Rescreening, and Screen Failures 
6.3.1. Screening Visits 1 to 3 
Participants (or their legally authorized representative where local regulations and institutional 
practices permit) must provide full written informed consent before any screening tests are 
performed.  
Screening Visits 1 to 3 will be conducted no more than 60 days before receiving the first dose of 
study treatment. All screening procedures should be completed within 60 days; however, with 
Sponsor approval, the overall screening period may be extended up to 90 days in the event of 
logistical issues related to PET scans (and/or due to other major causes [i.e., institutional 
restrictions or participant disposition due to COVID-19 or other major disasters/disruptions]). A 
minimum of 2 weeks should separate Screening Visits 1 and 2 to minimize learning effects.  
ApoE genotyping may be performed at Visit 1 prior to other screening assessments. 
During Screening Visits 1 to 3, participants will complete functional and neurocognitive 
assessments. These will include the primary clinical scales required for eligibility, CDR, MMSE, 
RBANS, and may include ADAS-Cog13, ADCS-ADL-MCI, and NPI-10. The clinical scales that 
are not required for eligibility (i.e., ADAS-Cog13, ADCS-ADL-MCI, and NPI-10), as well as 
 and quality-of-
life and health economic assessments (RUD-Lite, EQ-5D-5L, 
, and QoL-AD) may be 
completed at Day 1. The C-SSRS will be completed at Screening and at every subsequent visit.  
Participating study sites are required to document all screened candidates initially considered for 
inclusion in this study. If a participant is excluded from the study, the reasons for exclusion will 
be documented in the participant’s source documents and on the screening log.  
If a participant fulfills all inclusion and none of the exclusion criteria for study eligibility and the 
full written ICF is signed, the participant is considered enrolled in the study. 
For participants who are not enrolled in the longitudinal amyloid PET substudy, and if providing 
a historical amyloid PET scan for screening amyloid positivity, the scan obtained within 18 
months prior to Screening Visit 2 must be submitted to the central imaging vendor to confirm 
that study inclusion criteria are met. 
6.3.2. Rescreening and Screen Failures 
Screen failures are defined as participants who sign the ICF but are not subsequently 
randomized. Screen failures will be allowed to rescreen under the conditions described below; 


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however, a minimum of 60 days must pass between the initial and subsequent screening 
evaluations.  
If a participant fails screening due to exclusion criteria that are not indicative of uncontrolled 
disease, the participant may be allowed to rescreen on 2 occasions if the disease is controlled at a 
later date, at the discretion of the Investigator and approval of the Medical Monitor.  
• If ineligibility is due to unstable medications, rescreening is allowed when permitted 
chronic medications are at stable doses for at least 4 weeks prior to Screening Visit 2. 
• When Alzheimer’s disease medications are at stable doses for at least 8 weeks prior to 
Screening Visit 2 (see Section 7.7.1.1). 
Participants are also allowed to rescreen if ineligibility is due to unforeseen nonclinical reasons, 
such as weather or public health directives. 
Participants who fail Screening due to meeting the following exclusionary criteria will not be 
allowed to rescreen: 
• Amyloid negative PET scan or amyloid negative CSF sample 
• Exclusionary MRI findings 
• Outside of the MMSE score requirements of 22 to 30 inclusive 
• Current hepatitis B or C (as described in Section 6.2, exclusion criteria 19 and 20) 
Note: Participants who meet all other entry criteria but fail Screening due to not meeting the 
threshold inclusion criteria for early Alzheimer’s disease as assessed by CDR (i.e., with a global 
score of 0) or RBANs (i.e., with an RBANs DMI score > 85) may be allowed to rescreen once 
only after at least 6 months from the initial screening evaluation and after review and approval of 
the Medical Monitor. Participants who fail screening due to a CDR global score > 1 will not be 
permitted to rescreen. 
At rescreening, all assessments should be repeated with the following exceptions:  
• Amyloid PET if done < 12 months since last assessment for participants consenting to the 
longitudinal substudy (amyloid PET for eligibility is acceptable within 18 months) 
• Amyloid CSF if done < 6 months from last assessment 
• Tau PET if done < 6 months from last assessment  
• MRI if done < 3 months from last assessment  
 
 


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If a participant is considered a screen failure, the reasons for exclusion must be documented in 
the participant’s source documents and on the screening log. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAEs. 
 


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7. 
STUDY TREATMENT  
7.1. 
Regimen 
Following titration, participants will receive either aducanumab 10 mg/kg or placebo IV every 4 
weeks. 
At each applicable visit, the preceding centralized MRI report must have been received and 
reviewed by the Investigator before continuing with dose administration. 
Refer to and follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.  
Aducanumab is to be administered by IV infusion following dilution into saline. 
There are no fasting or food intake requirements/restrictions associated with this intravenously 
administered treatment.  
See Section 1.3 for the study treatment infusion schedule during the study. See Section 7.3 for 
details about aducanumab study treatment. 
7.1.1. Aducanumab 
The Sponsor will provide aducanumab to study sites. 
7.1.2. Placebo 
Placebo (0.9% sterile sodium chloride for injection) will be supplied by the study site. 
7.2. 
Modification of Dose and/or Treatment Schedule 
Refer to Section 5.3.1 (dose suspension) and Section 5.3.2 (infusion interruption). Doses should 
be administered at least 21 days apart. If the dosing interval cannot be met, the dose 
administration should be assessed by the study Medical Monitor. 
7.3. 
Study Treatment Management 
Study treatment will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice. 
Site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment. The DHA aligns with all other references, 
including the protocol.  
Study treatment must be dispensed only by a pharmacist or appropriately qualified staff and 
ensuring blinding is maintained. 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 


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that participant. Study treatment are for one-time use only; do not use any study treatment 
remaining in the vial for another participant. 
7.3.1. Aducanumab 
Research Name: 
BIIB037 
Generic Name: 
Aducanumab-avwa 
Trade Names:  
Aduhelm™ 
Synonyms: 
 
Fully human, IgG1, anti-A monoclonal antibody 
Aducanumab is a human antibody expressed in a Chinese hamster ovary cell line, purified to a 
high degree of purity, and formulated as a liquid. Aducanumab is an IgG1 consisting of 2 heavy 
and 2 kappa light chains connected by inter-chain disulfide bonds. Aducanumab has 1 
carbohydrate moiety linked to Asn-304. Aducanumab is purified from the media and formulated 
as a liquid. 
Aducanumab is supplied as a liquid drug product containing aducanumab 100 mg/mL as well as 
the excipients L-histidine hydrochloride, L-histidine free base, L-arginine hydrochloride, 
L-methionine, and polysorbate 80. 
The concentration appears on the label. Aducanumab is manufactured in accordance with Good 
Manufacturing Practice. 
The contents of the label will be in accordance with all applicable regulatory requirements. 
Aducanumab should not be used after the expiration date. 
At a minimum, the label will include a study reference code, study treatment identifier, quantity 
of dosage units, lot number, and other pertinent information in accordance with local law. The 
expiry or use-by date is stored in the IRT system, and printable assignment reports are available 
to site staff. 
7.3.1.1. 
Preparation 
The individual preparing aducanumab should carefully review the instructions provided in the 
DHA. 
Aducanumab is to be administered by IV infusion following dilution into saline. 
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the vials or drug, it should not be used. The vial in question should be saved at the study site, and 
the problem immediately reported to the Sponsor. 
Contact information for reporting a problem is provided in the Official Study Contact List in the 
Study Reference Manual. 


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7.3.1.2. 
Storage 
Study treatment must be stored in a secure location. Aducanumab is to be stored at 2○C to 8○C 
(36○F to 46○F), in a locked storage container with limited access. Aducanumab should be 
protected from light, protected from freezing, and should not be shaken. If administration of the 
prepared aducanumab is delayed for more than 4 hours, then it should be kept at 2°C to 8ºC until 
use. If administration of the prepared aducanumab is delayed for more than 24 hours, it must be 
discarded. For the most up-to-date storage requirements, follow the instructions provided in the 
DHA. 
7.3.1.3. 
Handling and Disposal 
The Investigator must return all used and unused vials of aducanumab as instructed by the 
Sponsor (or its designee) unless approved for onsite destruction. 
If any aducanumab supplies are to be destroyed at the study site, the institution or appropriate 
site staff must obtain prior approval from the Sponsor, by providing, in writing, the destruction 
policy or details of the method of destruction. After such destruction, the Sponsor must be 
notified, in writing, of the details of the study treatment destroyed (e.g., lot or kit numbers and 
quantities), the date of destruction, and proof of destruction. 
7.3.1.4. 
Accountability 
Accountability for study treatment is the responsibility of the Investigator. The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (participant-by-participant accounting), and accounts of any study treatment 
accidentally or deliberately destroyed.  
Unless otherwise notified, all vials both used and unused, must be saved for study treatment 
accountability. By the end of the study, reconciliation must be made between the amount of 
aducanumab supplied, dispensed, and subsequently destroyed or returned to the Sponsor. A 
written explanation must be provided for any discrepancies. 
7.3.2. Placebo 
The placebo (0.9% sterile sodium chloride for injection) will be provided by the site in the form 
of 100 mL saline IV bags. 
7.4. 
Blinding Procedures 
This is a multicenter, randomized study with a 24-month double-blind, placebo-controlled, 
parallel-group treatment period. 
All study staff who conduct participant assessments will be blinded to the participant treatment 
assignments. See Section 14.1 for details. The rating HCPs should remain blinded to treatment 
assignment as well as participant care management and only have access to the information 
necessary to carry out their responsibilities as detailed in Section 14.1. Since a placebo match is 
not provided for the study, unblinded pharmacy staff are required to manage all aspects of study 


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treatment receipt, dispensing, and preparation. To maintain the study blind, it is imperative that 
participant treatment assignments are not shared with the participants, their families, or any 
member of the blinded study team, either at the study site or at the Sponsor or its representatives, 
except the unblinded pharmacist (or designee), the unblinded pharmacy monitor, and the 
unblinded CRO or Sponsor safety staff. 
The CDR Raters and the Independent Non-CDR Raters must remain blinded to knowledge of a 
participant’s AEs and SAEs. 
To maintain rater blinding, it is imperative that participant treatment assignments, dosing dates, 
and laboratory data are not shared with the CDR Rater or Independent Non-CDR rater. 
Post-baseline medical imaging (including MRI, ARIA findings, and PET) should not be shared 
with participants or raters. Local reads of post-baseline amyloid or tau PET scans should not be 
conducted. Details will be specified in the blinding charter. See Section 14.1 for further details. 
At the end of the study (i.e., once the clinical study report is finalized), if unblinding will not 
jeopardize the results of ongoing related studies, the Sponsor will provide the randomization 
codes to Investigators, who then can inform their participants about the treatment received.  
In the event of a medical emergency that requires unblinding of a participant’s treatment 
assignment, refer to Section 11.4.4. 
7.5. 
Precautions 
Not applicable. 
7.6. 
Compliance 
Compliance with treatment dosing is to be monitored and recorded by unblinded site staff. 
Study treatment will be administered by the site staff. 
7.7. 
Concomitant Therapy and Procedures 
7.7.1. Concomitant Therapy 
A concomitant therapy is any drug or substance administered between the informed consent and 
until the participant’s final clinic visit (including the FU Visit). 
No premedication (e.g., anti-allergy drugs, antipyretic analgesics) should be used prior to the 
start of study treatment infusion unless discussed with the study Medical Monitor in advance. 
Participants should be instructed to contact their Investigators before taking any new 
medications, including nonprescription drugs and herbal preparations. 


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7.7.1.1. 
Allowed Concomitant Therapy 
The following medications are allowed: 
• With the exceptions described below, under Section 7.7.1.2, medications for chronic 
conditions are allowed at a stable dose during the study as long as the participant has 
been stable on the medication(s) for at least 4 weeks prior to Screening Visit 2 and 
during the screening period. 
• Symptomatic therapies for Alzheimer’s disease, 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 2 and 
during the screening period and that they stay on a stable dose while in the study. 
• Vaccinations are allowed during the study. Administration of any vaccination/booster 
should not be given < 5 days prior to any dosing visit and for 10 days after a dosing 
visit. 
7.7.1.2. 
Disallowed Concomitant Therapy 
The following medications are not allowed for the duration of the study: 
• Medications with antiplatelet or anticoagulant properties (acetylsalicylic acid [aspirin] at 
a dose ≤ 325 mg per day is allowed)  
• Chemotherapeutic agents and checkpoint inhibitors 
• Chronic use of immunosuppressive drugs (including systemic corticosteroids). Local 
immunosuppressants and local corticosteroids (including inhaled or topical 
corticosteroids) are allowed; short-term courses of systemic corticosteroids may also be 
permitted at the Sponsor’s discretion. 
• Parenteral immunoglobulin (e.g., IVIG), blood products, plasma derivatives, plasma 
exchange, and plasmapheresis 
• Active or passive immunotherapy agents targeting the CNS  
• Any drug of abuse (prescription or recreational), including but not limited to 
amphetamine, cocaine, opiates, propoxyphene, methadone, methaqualone, 
phencyclidine, or barbiturates 
• THC-containing cannabinoids (products containing CBD only are allowed) 
• Anticholinergics such as benztropine; anticholinergics for bladder control with limited 
cognitive effects are permitted but should be avoided if possible.  
• Any investigational drug 


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7.7.1.2.1. Medications with Limitations of Use 
• Benzodiazepines:  
− Long-acting benzodiazepines are only permitted for sedation prior to MRI or PET 
scans or LP for those participants requiring sedation. These medications should 
not be taken within 12 hours before cognitive testing.  
− Short- and medium-acting benzodiazepines (e.g., alprazolam, lorazepam, 
oxazepam, temazepam) are allowed if used chronically on a stable dose for 
8 weeks prior to Screening Visit 1 and during the Screening Period up to Day 1. If 
they are newly prescribed after randomization on Day 1, it is recommended that 
the medication is stable for at least 1 week before a cognitive testing visit. If used 
intermittently, these medications should not be taken within 12 hours before 
cognitive testing.  
• Chronic use of sedating antihistamines is allowed on a stable dose for 8 weeks prior to 
Screening Visit 1 and during the Screening Period up to Day 1 is allowed. If used 
intermittently, these medications should not be taken within 12 hours before cognitive 
testing. Nonsedating antihistamines (e.g., fexofenadine, cetirizine) are allowed.  
• Opioid medications are not allowed within 4 weeks prior to Screening Visit 1. After 
randomization on Day 1, short-term, intermittent use of prescription narcotics are 
allowed only in specific situations (e.g., after surgical procedures) and should not be 
taken within 12 hours before cognitive testing.  
• Antidepressants with known effects on cognition (e.g., tricyclic antidepressants) are not 
allowed. Mild depression or depressive mood arising in the context of Alzheimer’s 
disease is not a criterion for study withdrawal. Use of other antidepressants that do not 
affect cognition is allowed if at stable doses for 8 weeks prior to Screening Visit 1 and 
during the Screening Period up to Day 1. If participants are newly prescribed acceptable 
antidepressants after randomization on Day 1, it is recommended that the medication is 
stable for at least 1 week before a cognitive testing visit.  
• Anticonvulsants that have significant effects on cognition are not allowed. 
Anticonvulsants with limited cognitive effects, such as lamotrigine, pregabalin, and 
levetiracetam are allowed if, in the opinion of the Investigator, they are not producing 
sedation or contributing to cognitive impairment. The participant must be on a stable 
dose for 8 weeks prior to Screening Visit 1 and during the Screening Period up to Day 1. 
If participants are newly prescribed acceptable anticonvulsants after randomization on 
Day 1, it is recommended that the medication is stable for at least 1 week before a 
cognitive testing visit and that, in the opinion of the Investigator, they are not producing 
sedation or contributing to cognitive impairment. 
• Atypical and typical antipsychotics that have significant effects on cognition are not 
allowed. Behavioral symptoms arising during the course of the study in the context of 
Alzheimer’s disease are not criteria for study withdrawal. Per the Investigator’s opinion, 


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use of atypical and typical antipsychotics is allowed if at stable doses for 8 weeks prior 
to Screening Visit 1 and during the Screening Period up to Day 1 or used on an as-
needed basis. If participants are newly prescribed acceptable atypical and typical 
antipsychotics after randomization on Day 1, or if used intermittently during the study, it 
is recommended that the medication is stable for at least 1 week before a cognitive 
testing visit.   
• Intermittent or occasional use of any other sedating medications (e.g., melatonin, 
zolpidem, eszopiclone) is not allowed within 12 hours before cognitive testing.  
Participants should be instructed to continue the medications that they were receiving at 
enrollment without any changes (see allowed concomitant therapy, Section 7.7.1.1) and avoid 
starting any new medications or herbal preparations during the study period, since 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 changes in medication. The 
change should be reviewed by the Investigator and, if needed, by the Medical Monitor to 
determine whether the participant’s study treatment should be suspended. Medications used to 
treat AEs would not result in automatic permanent study treatment discontinuation. However, if 
a participant requires continued use of a disallowed therapy, the participant must permanently 
discontinue study treatment. The Sponsor may be consulted if required. 
Participants who have a change in Alzheimer’s disease medication (other than study treatment) 
should have an unscheduled visit. A subset of the clinical efficacy assessments (CDR-SB, 
MMSE, ADCS-ADL-MCI, and ADAS-Cog13) should be performed prior to the change in 
medication if the participant alerts the Investigator before the change in medication occurs. If the 
change in medication occurs before clinical efficacy assessments are performed, the clinical 
efficacy assessments must be performed within 30 days of the Investigator being notified about 
the change. If an unscheduled visit for a change in Alzheimer’s disease medication occurs within 
30 days of the previous efficacy assessment visit and the Investigator suspects no significant 
changes in cognitive status, efficacy assessments specified at this visit are not required. 
7.7.2. Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy, 
nocturnal-assisted breathing device) or diagnostic assessment (e.g., blood gas measurement, 
bacterial cultures) performed between the time the participant is enrolled in the study and the 
participant’s final clinic visit (including FU Visit), unless the participant is being monitored for 
study-related toxicity. 
The use of concomitant therapies or procedures defined above must be recorded on the 
participant’s CRF. AEs related to administration of these therapies or procedures must be 
documented on the appropriate AE CRF. 
7.8. 
Continuation of Treatment  
No further provisions are made for access to the study treatment. If aducanumab is proven to be 
beneficial, all regulatory requirements regarding poststudy access will be met. 


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8. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF PARTICIPANTS FROM THE STUDY 
8.1. 
Discontinuation of Study Treatment 
A participant must permanently discontinue aducanumab for any of the following reasons: 
• The participant develops any new acute or subacute hemorrhage. 
• The participant develops any treatment-emergent incident of cerebral hemorrhage > 1 cm 
in diameter on T2* sequence.  
• The participant develops a radiographically severe ARIA-H (10 or more treatment-
emergent microhemorrhage or more than 2 treatment-emergent superficial siderosis) 
• The participant develops any radiographic type of ARIA- E or ARIA-H accompanied by 
serious symptoms (according to the definition of serious adverse events in Section 11.1.2). 
• The participant develops a cortical infarct (defined as > 1.5 cm in diameter irrespective of 
anatomic location). 
• The participant develops more than 1 (> 1) lacunar infarct (defined as ≤ 1.5 cm in 
diameter). 
• 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 that necessitates treatment discontinuation or requires 
continued treatment that meets exclusionary criteria. 
• The participant experiences a severe infusion reaction. 
• The participant initiates treatment of Alzheimer’s disease with a commercially available 
disease-modifying drug. 
• At the discretion of the Investigator for medical reasons, including treatment-emergent 
ARIA events. 
• At the discretion of the Sponsor for safety or other reasons.  
• At the discretion of the Investigator or Sponsor for noncompliance. 
• The participant becomes pregnant; study treatment must be discontinued immediately, and 
pregnancy must be reported according to protocol instructions. 


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The primary reason for discontinuation of study treatment must be recorded in the participant’s 
CRF. 
Participants who discontinue treatment are encouraged to remain in the study, attend a safety FU 
Visit 18 weeks after the last dose of study treatment, and immediately continue protocol required 
tests and assessments at a subset of the clinic visits (see Table 3) until the end of the study per 
the Schedule of Activities or until the participant withdraws consent. 
8.2. 
Lost to Follow-Up 
Participants will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and are unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the study site for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study. 
• In cases in which the participant is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the participant. These contact attempts 
should be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, that participant will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
8.3. 
Withdrawal of Participants From Study 
Participants must be withdrawn from the study for any one of the following reasons: 
• The participant withdraws consent for participation in the study.  
• The participant enrolls into another interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered. 
• The participant is unwilling or unable to comply with the protocol. 
• At the discretion of the Investigator or Sponsor. 
Note: A participant who discontinues study treatment will not be automatically withdrawn from 
the study, regardless of the number of doses missed. The participant is to remain in the study, 
and continue with a FU Visit 18 weeks after the participant’s last dose of study treatment, and 
protocol-required tests and assessments at a subset of the clinic visits (see Table 3) until the end 
of the study or until the participant withdraws consent. 


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The primary reason for the participant’s withdrawal from the study must be recorded in the 
participant’s CRF. 
Participants who are withdrawn from the study after receiving ≥ 1 doses of study treatment 
should complete the ET Visit after the reason for withdrawal is identified. For such participants, 
efficacy assessments specified at the ET Visit are not required if the participant discontinues 
treatment within 3 months of the previous efficacy assessment visit, and no significant changes 
in cognitive status are suspected by the Investigator; the site should notify the Sponsor and 
Medical Monitor in such cases. Participants who are withdrawn from the study are also to return 
to the site for a FU Visit 18 weeks after receiving their last dose of study treatment. 
Participants should undergo an ET visit unless withdrawal is due to death or withdrawal of 
consent. 
Participants who withdraw from the study may be replaced if enrollment is still open. 
 


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9. 
EFFICACY, PHARMACOKINETIC, AND 
PHARMACODYNAMIC ASSESSMENTS 
See Section 1.3 for the timing of all assessments. 
Tests and evaluations affecting primary endpoints and/or analyses may need to be repeated if the 
original results are lost or damaged. In these cases, participants will be asked to return to the 
study site to have the evaluations repeated. 
Where available, and with permission from the Sponsor, home visits may be permitted, with 
limitations. For visits that involve cognitive assessments, such as the CDR and ADAS-Cog13, 
the same in-person site rater must also perform the home visit. Note: The Week 78 visit is never 
permitted to be a home assessment. Refer to the Study Reference Manual for details. 
9.1. 
Clinical Efficacy Assessments 
The following clinical scales will be assessed to verify the clinical benefit of aducanumab: 
Clinical Assessments 
• CDR 
The CDR is a 5-point scale used to stage Alzheimer’s disease by characterization of the 6 
domains of cognitive and functional performance: memory, orientation, judgment and 
problem solving, community affairs, home and hobbies, and personal care. This 
information is collected through a semistructured interview of the participant and the 
informant. Scores range from 0 to 3, with a higher score indicating greater impairment. 
The CDR-SB score is obtained by summing each of the CDR domain box scores, with 
scores ranging from 0 to 18. The CDR-SB is a more detailed quantitative index than the 
global score, providing more precise information on participants with MCI and early 
Alzheimer’s disease, as well as improved tracking of changes over time. 
• ADCS-ADL-MCI 
The ADCS-MCI-ADL is a functional evaluation scale for MCI participants, based on the 
information provided by an informant who rates 18 areas of daily living. Higher scores 
indicate greater independent and healthy functioning, with total score ranging from 0 to 
53. 
• ADAS-Cog13 
The ADAS-Cog13 is a brief objective cognitive assessment of the severity of cognitive 
symptoms of Alzheimer’s disease. The composite scale was developed to include both 
participant-completed tests and informant-based assessments that measure the cognitive 
domains of memory, language, and praxis. The original ADAS-Cog11 version of the scale 
included the specific tasks of word recall, naming objects and fingers, commands, 
constructional praxis, ideational praxis, orientation, word recognition, and language. The 


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ADAS-Cog13 revised version was adapted to include delayed memory and number 
cancellation tasks to more sensitively capture the memory and executive functioning 
deficits seen in early-stage Alzheimer’s disease. The ADAS-Cog13 scores range from 0 to 
85, with higher scores indicating worse performance. 
• MMSE 
The MMSE is a brief cognitive screening tool that provides clinicians the ability to rapidly 
assess cognitive ability in less than 10 minutes. It is an 11-question measure that tests 
orientation, registration, attention and calculation, recall, language, and visuospatial skills. 
The MMSE scores range from 0 to 30, with higher scores indicating better performance. 
• NPI-10 
The NPI-10 is a questionnaire administered to the informant and is designed to obtain 
information on the presence of neuropsychiatric symptoms and behaviors in a patient with 
Alzheimer’s disease. The presence and severity of 10 areas are assessed: delusions, 
hallucinations, agitation/aggression, depression, anxiety, elation/euphoria, 
apathy/indifference, disinhibition, irritability, and aberrant motor behavior. Higher scores 
indicate greater impairment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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It is recommended that clinical assessments be performed at the same time of day for participants 
during their study visits.  
Some tests will require the informant to participate and answer questions regarding the 
participant’s daily activities and cognitive capabilities. Some scales will be audio recorded for 
training and evaluation purposes.  
The recommended order of administration of the clinical assessments is described in the Study 
Reference Manual. 
The key secondary endpoint, the modified iADRS, is a composite endpoint that combines the 
ADAS-Cog13 and ADCS-ADL-MCI to capture decline of both cognition and daily function. 
The 
 cognitive functioning tests include the following neuropsychological tests: word 
retrieval from the ADAS-Cog13, 
 
. These are calculated to form the EMACC 
composite [Jaeger 2021; Jaeger 2017]. The GST composite z-score is calculated by averaging the 
standardized z-scores for the CDR-SB, ADCS-ADL-MCI, and ADAS-Cog13. 
9.2. 
Laboratory Efficacy Assessments 
Samples will be analyzed using Good Laboratory Practice validated assays.  


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9.3. 
Pharmacokinetic Assessments 
The following parameters will be calculated to assess the PK of aducanumab: 
• Serum concentrations of aducanumab will be measured using a validated assay. 
9.4. 
Pharmacodynamic Assessments 
Serial measurements of disease- or treatment-related 
 will be assessed in all 
participants.  
The pharmacodynamic properties of aducanumab will be confirmed through analyses of blood 
samples that will include, but are not limited to, 
 
 
Optional Substudies 
The following substudies will be conducted in a subset of sites and participants, where available. 
Investigator participation in these substudies is optional and contingent upon approval by the 
ethics committee or IRB. If the Investigator is not participating in a substudy, or if the tests 
described below are not approved by the Investigator’s ethics committee and/or IRB, the relevant 
section of the ICF will not be applicable to that site. Informed consents must be recorded in the 
CRF. Approximately 400 participants are expected to enroll in each of the 3 
 
. Participating in multiple substudies (where available) is highly encouraged. 
Historical CSF samples or PET scans are not acceptable for participants in the longitudinal 
. 
The pharmacodynamic properties of aducanumab will be confirmed through the following 
longitudinal substudies: 
1. Measurement of amyloid plaque burden in certain areas of the brain as measured by 
amyloid PET 
Participants who consent to this optional longitudinal PET substudy will undergo 3 PET 
scans (Screening, Week 78, and Week 104). Only sites with capabilities to perform 
amyloid PET with Sponsor-approved tracer will be allowed to perform this assessment. 
Detailed PET scanning protocols will be described in a separate procedural manual for 
PET.  
2. Measurement of neurofibrillary tangle burden in certain areas of the brain as measured by 
tau PET  
Participants who consent to this optional longitudinal PET substudy will undergo 3 PET 
scans (Screening, Week 78, and Week 104). Only sites with capabilities to perform tau 
PET with Sponsor-approved tracer will be allowed to perform this assessment. Detailed 
PET scanning protocols will be described in a separate procedural manual for PET.  


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9.6. 
Future Scientific Research Assessments 
 
 
Participants will sign a separate, written ICF if they agree to their samples being used in this 
way. 
The residual samples may be utilized to identify or verify putative, prognostic, and predictive 
markers associated with disease and markers of therapeutic response to treatment, and/or to 
develop diagnostic and analytical tests. Background and dynamic clinical disease characteristics 
and associated 
 data may be utilized to predict subsequent disease worsening 
(severity), identify high-risk patient subgroups, and identify predictors of response to treatment. 
9.7. 
Additional Assessments 
The following assessments will be performed to evaluate the effect of aducanumab in 
participants and informants: 
• EQ-5D-5L (for both participant and informant) 
• QoL-AD (for both participant and informant) 
 
 
• RUD-Lite (for informant only) 
Some tests will require the informant/care partner to participate and answer questions regarding 
the participant’s daily activities and cognitive capabilities. 
The recommended order of administration of the clinical assessments is described in the Study 
Reference Manual. 


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10. 
SAFETY ASSESSMENTS 
See Section 1.3 for the timing of all safety assessments. 
Tests and evaluations affecting primary endpoints and/or analyses may need to be repeated if the 
original results are lost or damaged. In these cases, participants will be asked to return to the 
study site to have the evaluations repeated. 
If in-clinic visits are not able to occur, a remote visit via telephone or video call may be used to 
collect safety assessments as deemed appropriate by the Sponsor (refer to the Study Reference 
Manual for details). 
10.1. 
Clinical Safety Assessments 
The following clinical assessments will be performed to confirm the safety profile of 
aducanumab: 
• AE and SAE monitoring 
• Physical examination, including height and body weight 
• Neurological examination 
• Vital signs (body temperature, heart rate, SBP, DBP, and respiratory rate) 
• 12-lead ECG 
• Brain MRI 
• Concomitant therapy and procedures 
• C-SSRS Lifetime/Recent at screening and the C-SSRS-SLV for postscreening visits 
The C-SSRS assesses the patient’s risk of suicide and aids in stratifying patients into 
categories of low, moderate, or high risk. The C-SSRS separates ideation and behavior by 
using 4 constructs (severity of ideation, intensity of ideation, behavior, and lethality), 
based on factors identified in previous studies as predictive of suicide attempts and 
completed suicide. Higher scores indicate greater risk of suicide. The Lifetime/Recent 
version allows practitioners to gather lifetime history of suicidality, as well as any recent 
suicidal ideation/behavior. The Since Last Visit (C-SSRS-SLV) version of the scale 
assesses suicidality since the patient’s last visit.  
10.2. 
Laboratory Safety Assessments 
Samples will be analyzed using Good Laboratory Practice validated assays. 


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The following laboratory assessments will be performed to evaluate the safety profile of 
aducanumab: 
• Hematology: complete blood count with platelet count, and absolute neutrophil count. 
• Blood chemistry: total protein, albumin, creatinine, blood urea nitrogen, 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, blood, ketones, and microscopic 
examination (if abnormal). 
• Serum and urine pregnancy test for women of childbearing potential only. 
• Coagulation (panel [PT, aPTT, INR, platelet count] also conducted prior to LP), 
virology (including hepatitis B, hepatitis C, and HIV [the latter at the Investigator’s 
discretion after consideration of risk factors]), HbA1c, and alcohol/drug screen at 
Screening. 
10.3. 
Immunogenicity Assessments 
Presence of serum anti-aducanumab will be determined using a validated assay. A standard 3-tier 
antidrug antibody approach will be used (i.e., screening assay, confirmatory assay, and titration 
assay). Additional characterization of the immune response may be performed. 


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11. 
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 (where 
local regulations and institutional practices permit) must be given the names and telephone 
numbers of site staff for reporting SAEs, pregnancies, overdoses, and medical emergencies. 
Throughout the protocol, the Sponsor is named, but reporting may be done through a CRO. 
11.1. 
Definitions 
11.1.1. 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 assessment such as an abnormal laboratory value), 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 assessment (e.g., laboratory value, vital sign, and ECG) 
result meets the definition of an AE will be made by the Investigator. Abnormal results are not 
considered AEs unless 1 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. 
11.1.2. 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.) 
11.1.3. 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 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 
be 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 be 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. 
− 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 11.1.2 is met. 
11.2. 
Safety Classifications 
11.2.1. 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 11.1.2. 
• The relationship of the event to study treatment as defined in Section 11.2.2. 
• The severity of the event as defined in Section 11.2.3. 








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effort to obtain and send death certificates and autopsy reports to the Sponsor. The term death 
should be reported as an SAE only if the cause of death is not known and cannot be determined. 
11.3.5. Suspected Unexpected Serious Adverse Reactions 
SUSARs are SAEs that are unexpected and judged by the Investigator or the Sponsor to be 
related to the study treatment administered. 
Appropriate Sponsor personnel will unblind SUSARs for the purpose of regulatory reporting. 
The Sponsor will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies 
according to local law. The Sponsor will submit SUSARs to Investigators in a blinded fashion. 
11.4. 
Procedures for Handling Special Situations 
11.4.1. Public Health Emergencies 
In the event of a public health emergency that results in site closure, travel restrictions, and/or the 
study being deprioritized at the site such that clinic visit(s) cannot occur, a protocol deviation 
would be incurred for any deviation from the protocol-specified visits and assessments, with 
additional notation that this protocol deviation is due to the public health emergency.  
If a protocol-specified clinical visit cannot occur due to a public health emergency, the following 
mitigating options should be pursued, in order of preference (in which the highest preference 
option that is feasible should be done): 1) transfer to another active study site that is open, 2) 
home visit, 3) telemedicine visit (e.g., by telephone or web conference), and 4) local laboratory 
visit. These mitigating options only apply in the setting of a public health emergency in which a 
protocol-specified clinic visit cannot occur and should not be pursued solely due to participant’s 
preference. If the participant does not participate in one of these options, a Safety Telephone call 
must be conducted within 14 days of the last dosing visit.  
Details on which visits and procedures are eligible to be performed at alternative medical 
facilities will be provided by the Sponsor in writing. All procedures performed at alternative 
medical facilities will need to be performed as described in this protocol and medical staff will 
need to be trained accordingly. If a participant cannot attend the study site visit for 
administration of study drug, a home visit or a visit to an alternative medical facility may be 
appropriate. Study treatment administration outside of the study site may require appropriately 
delegated study site staff or a home healthcare service with Sponsor approval. 
The Sponsor will determine appropriate start and end dates for each contingency measure, where 
the duration of the mitigations may begin at the onset of site restrictions for a specific site and/or 
country and may end once those restrictions are lifted and in accordance with local laws and 
regulations. The adaptations to the visits and procedures described are alternatives or deviations 
to the main protocol procedures. 
These contingency measures will only be implemented in exceptional cases and after the site has 
received written notification from the Sponsor. The Sponsor will have the final authority to 
decide what mitigations can be implemented, in accordance with local laws and regulations. 


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The Sponsor will communicate decisions to the Principal Investigator(s) and study site(s) via 
protocol clarification letters. The protocol clarification letter will include details such as which 
visits are eligible to be conducted via televisits. Study sites will be responsible for notifying any 
required boards or committees.  
11.4.2. Pregnancy 
Participants should not become pregnant during the study and for 24 weeks after their last 
dose of study treatment. If a female participant becomes pregnant, study treatment must be 
discontinued immediately. 
The Investigator must report a pregnancy occurring in a female participant from first dose of 
study drug to 24 weeks after her last dose by faxing or emailing the appropriate form to the 
Sponsor within 24 hours of the study site staff’s becoming aware of the pregnancy. Refer to the 
Official Study Contact List in the Study Reference Manual for complete contact information. 
The Investigator or site staff must report the outcome of the pregnancy to the Sponsor. 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 or within 
24 weeks after last dose of study treatment. 
11.4.3. Overdose 
An overdose is any dose of study treatment administered to 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 or emailed to the Sponsor within 24 hours of the site staff becoming 
aware of the overdose. An overdose must be reported to the Sponsor even if the overdose does 
not result in an AE. If an overdose results in an AE, the AE must be recorded. If an overdose 
results in an SAE, both the SAE and overdose forms must be completed and faxed or emailed to 
the Sponsor. All study treatment-related dosing information must be recorded on the dosing 
CRF. 
11.4.4. 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) 
should contact the Sponsor-designated Medical Services. Refer to the Official Study Contact List 
in the Study Reference Manual for complete contact information.  
11.4.4.1. Unblinding for Medical Emergency 
In this study, emergency decoding will be made available to the Investigator and designated 
personnel at the Sponsor through IRT. 


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In a medical emergency, when knowledge of the participant’s treatment assignment may 
possibly influence the participant’s clinical care, the Investigator may access the participant’s 
treatment assignment by IRT. However, prior to unblinding, the Investigator can refer to the 
Official Study Contact List in the Study Reference Manual for complete contact information. 
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.  
11.5. 
Contraception Requirements 
All women of childbearing potential must ensure that effective contraceptive methods are used 
during the study and for 5 times the half-life or 24 weeks (whichever is longer) after their last 
dose of study treatment. For all women of childbearing potential, a pregnancy test must be 
performed 24 hours prior to every PET scan. In addition, participants should not donate sperm or 
eggs for the duration of the study and for at least 24 weeks after their last dose of study 
treatment. 
For the purposes of this study, women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant UNLESS they meet one of the following 
conditions: 
• Postmenopausal 
− 12 months of natural (spontaneous) amenorrhea without an alternative medical 
cause or 6 weeks after surgical bilateral oophorectomy with or without 
hysterectomy 
− 52 continuous weeks of natural (spontaneous) amenorrhea without an alternative 
medical cause and a serum follicle-stimulating hormone level ≥ 40 mIU/mL, or at 
least 5 continuous years of natural (spontaneous) amenorrhea without an alternative 
medical cause 
• Posthysterectomy 
• Female surgical sterilization (e.g., bilateral tubal ligation)  
For the purposes of this study, effective contraception is defined as use of one of the following: 
For females:  
• Progesterone-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action. 
• Placement of an intrauterine device or intrauterine hormone-releasing system. 


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• The following barrier methods of contraception with use of a spermicide: condom or 
occlusive cap (i.e., diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream suppository; the use of barrier contraceptives should always be 
supplemented with the use of a spermicide (where applicable). 
• Male sexual partners who underwent surgical sterilization with the appropriate 
postvasectomy documentation of the absence of sperm in the ejaculate. If documentation 
is not available, the participant must use contraception. 
For males: 
• Vasectomy with negative semen analysis at follow-up. If documentation is not available, 
the participant must use contraception.  
• Intercourse with a woman who uses the methods described for females if she is of 
childbearing potential. 
For males or females: 
• 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 trial. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not considered acceptable methods of 
contraception. 
Pregnancy reporting is described in Section 11.4.2 . 
11.6. 
Safety Responsibilities 
11.6.1. 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, and severity of each event. 
• 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 report it to the Sponsor (or designee) within 
24 hours of the site staff becoming aware of the event or according to national law. 


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• Pursue SAE FU information actively and persistently. FU information must be reported 
to the Sponsor (or designee) within 24 hours of the site staff becoming aware of new 
information or according to national law. 
• Ensure all AE and SAE reports are supported by documentation in the participants’ 
medical records. 
• Pursue AE FU information, if possible, until the event has resolved or become stable. 
Record AE FU information, including resolution, on the CRF as applicable. 
• Report SAEs to local ethics committees as required by local law. 
11.6.2. The Sponsor  
The Sponsor’s responsibilities include the following: 
• Before a study site activation and participant enrollment, the Clinical Monitor is 
responsible for reviewing with site staff the definitions of AE and SAE as well as the 
instructions for monitoring, recording, and reporting AEs and SAEs. 
• The Sponsor (or designee) is to notify all appropriate regulatory authorities, central 
ethics committees, and Investigators of SAEs, as required by local law, within required 
timeframes. 
 


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12. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
The objectives of the study and the endpoints to be analyzed are listed in Section 4. 
12.1. 
Demography and Baseline Disease Characteristics 
Demographics and baseline data will be summarized with summary statistics (mean, SD, 
median, and range) or with frequency distributions. 
12.2. 
Efficacy and Pharmacodynamics 
12.2.1. Analysis Sets 
The FAS includes all participants who are randomized and received at least 1 dose of study 
treatment (aducanumab or placebo). The FAS will be used for efficacy analyses. 
12.2.2. Methods of Analysis 
12.2.2.1. General Considerations 
Summary statistics will be presented. For continuous endpoints, summary statistics will 
generally include the following: number of participants with data, mean, SD, median, and range. 
For categorical endpoints, these will generally include number of participants randomized or 
dosed, number with data, and the percent of those with data in each category. Statistical testing 
for efficacy endpoints will be made between aducanumab and placebo. All statistical tests will be 
2-sided. 
12.2.2.2. General Considerations for Analyses of Week 78 Endpoints 
Analyses of Week 78 endpoints will only include data up to the Week 78 visit.  See Section 12.7 
for additional information. 
12.2.2.3. Considerations for Multiple Comparison Adjustments 
The primary endpoint will be tested at a 2-sided alpha level of 0.05. If the primary endpoint is 
statistically significant, then the key secondary endpoints will be tested in the following order. 
• iADRS 
• ADCS-ADL-MCI 
• ADAS-Cog13 
• MMSE 
• NPI-10 


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Each test will be performed at a 2-sided alpha level of 0.05 and will only be performed if the 
preceding test is statistically significant. 
12.2.2.4. Considerations for Efficacy Endpoint Analysis 
In analyses performed on the FAS, participants will be analyzed based on the intent-to-treat 
principle according to their randomized treatment assignment regardless of treatment received. 
The primary estimand on the treatment effect of aducanumab is for the primary endpoint based 
on the continuous variable of change from baseline scores in CDR-SB. This analysis is 
conducted for an estimand with a treatment policy strategy to handle all ICEs, with the following 
attributes as outlined by ICH E9 (R1): 
• Analysis set: all participants in the FAS 
• Variable: the change from baseline scores in CDR-SB at Week 78 regardless of ICEs 
• Analysis set level summary: LS mean difference from MMRM model in change from 
baseline between aducanumab dose and placebo 
• ICEs and strategies for addressing ICEs: all observed data to be included regardless of 
ICEs 
The ICEs include treatment discontinuation or a change in concomitant use of Alzheimer’s 
disease symptomatic medication. 
12.2.2.5. Analysis of the Primary Endpoint 
The primary analysis of the primary endpoint is based on a rank ANCOVA and an MMRM 
model. Non-normality of data is a key analytic consideration. A rank ANCOVA model of the 
change from baseline CDR-SB at Week 78 adjusting for treatment group, baseline CDR-SB, 
baseline MMSE, baseline disease stage, Alzheimer’s disease symptomatic medication use at 
baseline, region, and laboratory ApoE ε4 status will be used to test the statistical significance of 
the difference between aducanumab and placebo-treated groups at Week 78. Missing data will be 
imputed using multiple imputation assuming missing at random before performing the rank 
ANCOVA. The following covariates will be included in the imputation model: treatment group, 
baseline CDR-SB, baseline MMSE, baseline disease stage, AD symptomatic medication use at 
baseline (yes/no), region, and laboratory ApoE ε4 status (carrier/noncarrier). An MMRM model 
will be used to estimate the difference in change from baseline CDR-SB between treatment 
groups using fixed effects of treatment, time, treatment-by-time interaction, baseline CDR-SB, 
baseline CDR-SB by time, baseline MMSE, baseline disease stage, Alzheimer’s disease 
symptomatic medication use at baseline, region, and laboratory ApoE ε4 status. An unstructured 
covariance matrix will be used to model the within-participant variance-covariance errors. If the 
unstructured covariance structure matrix results in a lack of convergence, the heterogeneous 
Toeplitz covariance structure followed by the heterogeneous first-order autoregressive 
covariance structure will be used. The Kenward-Roger approximation will be used to estimate 
the denominator degrees of freedom. In the primary analysis, missing data are assumed to be 
missing at random [Rubin 1976]. 


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A sensitivity analysis will be performed to assess the robustness of the primary analysis to 
deviations from the missing-at-random assumption. Imputation for missing data will be 
conducted to have outcomes that enable an estimand with a treatment policy strategy. The 
sensitivity analysis will be conducted for the FAS population. The copy increment from 
reference method will be applied to impute the postwithdrawal data for any aducanumab-treated 
participant who withdraws from study early based on data from the placebo group rather than the 
participant’s own randomized treatment group  [Carpenter 2013]. This method assumes that any 
benefit gained from previous treatment will be retained, but participants progress as if they were 
on placebo after withdrawal from study. For any participant on placebo who withdraws early, 
their postwithdrawal profile will be imputed following the missing-at-random principle.  
Supplementary analyses will include repeating the primary analysis twice with the data censored 
after each of the following intercurrent events: 
• premature discontinuation of the study treatment 
• any change to concomitant AD symptomatic medications during the study (if multiple 
events occur to the same participant, data after the earliest event will be censored) 
12.2.2.6. Key Secondary Endpoints 
The key secondary endpoints are described in Section 4. An MMRM model will be used as the 
primary analysis to analyze change from baseline in all key secondary endpoints using fixed 
effects of treatment, time, treatment-by-time interaction, a given key secondary endpoint score at 
baseline, a baseline key secondary endpoint score by time interaction, baseline MMSE, baseline 
disease stage, Alzheimer’s disease symptomatic medication use at Baseline, region, and 
laboratory ApoE ε4 status. 
12.2.2.7. Secondary Endpoints 
The secondary endpoints are described in Section 4. 
An MMRM model will be used also as the primary analysis to analyze change from baseline in 
all secondary endpoints using fixed effects of treatment, time, treatment-by-time interaction, a 
given secondary endpoint score at baseline, a baseline secondary endpoint score by time 
interaction, baseline MMSE, baseline disease stage, Alzheimer’s disease symptomatic 
medication use at Baseline, region, and laboratory ApoE ε4 status. 
12.2.2.8. Tertiary and 
 Endpoints  
Analyses of the tertiary and 
 endpoints regarding quality-of-life questionnaires, health 
economic metrics, as well as the 
, if 
performed, will be prespecified in the SAP. 


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12.3. 
Methods of Analysis for Pharmacokinetic Endpoints 
12.3.1. Analysis Set 
The PK analysis set is defined as all participants who are dosed with aducanumab and had at 
least 1 measurable aducanumab concentration in serum.   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
12.5. 
Analysis of Safety Endpoints 
12.5.1. Analysis Set 
The safety analysis set is defined as all participants who are randomized and received at least 
1 dose of study treatment (aducanumab or placebo). 
12.5.2. Methods of Analysis  
All AEs, laboratory data, and vital signs will be evaluated for safety. 
12.5.3. Adverse Events 
AEs will be coded using MedDRA.  
Only TEAEs will be presented in the summary tables. Treatment emergence is defined as having 
an onset date that is on or after the start of study treatment or as worsening after the start of study 
treatment. 


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Incidence of TEAEs will be summarized by treatment groups, overall, by severity and by 
relationship to aducanumab. The summary tables will include incidence estimates for overall 
system organ class as well as for preferred terms within each system organ class.   
Incidence, severity, and symptomatology of ARIA will be summarized by treatment group. The 
analysis of ARIA incidence will also be performed for all different types of ARIA (e.g., ARIA-E 
and ARIA-H).  
12.5.4. Clinical Laboratory Results 
Laboratory data will be summarized using shift tables. Shifts from baseline to high/low status for 
hematology and blood chemistry parameters and shifts from baseline to high/positive status for 
urinalysis will be presented. Summary statistics for actual values and change from baseline will 
also be presented for quantitative laboratory data. 
12.5.5. Vital Signs 
The analysis of vital signs will focus on clinically relevant abnormalities. 
12.5.6. ECGs 
The number and percentage of participants with shifts to categorical values (abnormal not AE, or 
abnormal AE) will be summarized by treatment groups. 
12.5.7. C-SSRS 
Baseline C-SSRS and postbaseline C-SSRS-SLV data will be summarized using descriptive 
statistics (i.e., number of participants, mean, SD, median, minimum, and maximum) for 
continuous variables and using frequency and percentage for discrete variables. 
12.6. 
Methods of Analysis for Immunogenicity Data 
12.6.1. Analysis Set 
The immunogenicity analysis set is defined as all participants in the safety analysis set who 
have at least 1 postdose sample evaluated for immunogenicity.   
12.6.2. Methods of Analysis 
Treatment-emergent ADAs in serum will be summarized. 
12.7. 
Interim Analyses 
Interim analyses for superiority may be performed after approximately 60% of the participants 
have completed the 18-month visit (or discontinued). The alpha level at the interim analysis will 
be determined using the O'Brien-Fleming boundary approach. The alpha level for the final 
analysis will be adjusted to achieve an overall type I error of 0.05.  


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If an interim analysis is performed, the interim analysis will be performed by an independent 
group external to the Sponsor that will not be involved in the conduct of the study after 
unblinding. A potential role for the IDMC in this interim analysis will be fully described in the 
IDMC charter. The aim of this interim analysis is to allow the possibility to verify the clinical 
treatment benefit of aducanumab early. The analysis will be discussed in detail in the SAP. 
After all participants have had an opportunity to complete the Week 78 visit, the Sponsor will 
perform an unblinded analysis. This unblinded analysis will performed by a small internal 
independent team (separate from the study team). Analyses of Week 78 endpoints will only 
include data up to the Week 78 visit (see Section 12.2.2.2). 
12.8. 
Sample Size Considerations 
The sample size is mainly based on results from the primary analysis of Study 221AD302. 
Results from the post-PV4 population (i.e., the 221AD302 and 221AD301 protocol amendment 
in which the high dose of aducanumab was increased from 6 mg/kg to 10 mg/kg) in pooled data 
from Studies 221AD302 and 221AD301 were also considered. A total sample size of 
1512 participants is planned to have approximately 90% power to detect a mean difference of 
0.48 in change from baseline CDR-SB at Week 78 between the 2 treatment groups. This power 
calculation is based on a 2-sided t-test assuming equal variance with a final significance level of 
0.05, an SD of 2.33, a dropout rate through Week 78 of 27%, and a randomization ratio of 2:1. 
The assumed mean difference of 0.48 between the 2 treatment groups represents an 
approximately 24% reduction in the placebo mean change from baseline at Week 78 if the 
placebo mean change is estimated to be 2.  
A blinded assessment of the pooled SD for the primary efficacy endpoint may be performed 
approximately 3 months prior to the completion of enrollment and the sample size may be 
increased as a result. The sample size could also be increased using internal and external clinical 
study results that become available after the start of this study.  In addition, the sample size may 
be increased if the dropout rate through Week 78 is estimated to exceed 27%.  The sample size 
will not be reduced based on this assessment. 


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13. 
ETHICAL AND REGULATORY REQUIREMENTS 
The Sponsor, any contracted third party, and the Investigator must comply with all instructions, 
regulations, and agreements in this protocol and applicable ICH and GCP guidelines and conduct 
the study according to local regulations. 
The Investigators are responsible for demonstrating timely oversight of all clinical trial data from 
their site, including data external to the EDC system, such as laboratory, imaging, and electronic 
clinical outcomes assessment data. Investigators must approve all their data on completed CRFs 
by signing electronically, at the participant, visit, or casebook level, at any time prior to an 
interim lock or database lock as well as before any subsequent relock. The EDC system does not 
prohibit Investigator approval or signing in any way. 
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. 
13.1. 
Declaration of Helsinki 
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki. 
13.2. 
Ethics Committee 
The Investigator must obtain ethics committee approval of the protocol, ICF, and other required 
study documents prior to starting the study. The Sponsor or designated CRO will submit 
documents on behalf of the study sites in countries other than the US. 
If the Investigator makes any changes to the ICF, the Sponsor must approve the changes before 
the ICF is submitted to the ethics committee. A copy of the approved ICF must be provided to 
the Sponsor. After approval, the ICF must not be altered without the agreement of the relevant 
ethics committee and the Sponsor. 
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations. 
The Sponsor must receive a letter documenting ethics committee approval that 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. 


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13.3. 
Changes to Final Protocol 
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law. Protocol modifications that affect participant safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
before implementation of such modifications to the conduct of the study. If required by local 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation. 
However, the Sponsor may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a participant. In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification. 
In the event of a protocol modification, the ICF may require similar modifications (see 
Section 13.4). 
13.4. 
Informed Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent must be obtained with the approved ICFs.  
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the participant must be explained to the participant and/or 
the participant’s legally authorized representative (where local regulations and institutional 
practices permit). The participant and/or the participant’s legally authorized representative must 
be given sufficient time to consider whether to participate in the study. 
The Investigator must reassess the participant’s capacity to provide informed consent 
periodically over the course of the study. In the event the participant is no longer cognitively 
intact and loses capacity to provide informed consent, the Investigator must obtain participant 
consent by the participant’s legally authorized representative (in accordance with local laws and 
regulations) or withdraw the participant from the study. 
A separate informed consent will be used for the 3 longitudinal substudies involving imaging and 
CSF sampling over time. 
The level of information provided to participants should match their level of understanding as 
determined by the Investigator and in accordance with applicable regulations and guidelines. 
A copy of the signed and dated ICF must be given to the participant and/or the participant’s 
legally authorized representative. The original signed and dated ICF will be retained with the 
study records. Local regulations must be complied with in respect to the final disposition of the 
original and copies of the signed and dated ICFs. 
Confirmation of informed consent must also be documented in the participant’s medical record. 


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When additional information that may affect participants’ willingness to continue in the study 
becomes available, the Investigators will be notified in a timely manner, according to all local 
and applicable law. An updated ICF may be required. 
13.5. 
Participant Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by applicable national and local privacy regulations 
(e.g., Protected Health Information authorization in North America). 
During the study, participants’ race and ethnicity and year of birth will be collected (unless the 
collection is not permitted by applicable law or not approved by the governing ethics 
committee). These data will be used in the analysis of the safety and/or PK profile of the study 
treatment. It is unknown whether the effects of the study treatment are influenced by race or 
ethnicity.  
In the US only, where permitted by applicable law and governing ethics committees, a code for 
environmental health will be obtained using the participant’s address. The address will not be 
stored on source documents, study records or CRFs, nor stored in the University of Wisconsin 
website where the code is obtained (see Study Reference Manual for more information). These 
data will be used in the 
 of the impacts of social determinants of health on 
treatment efficacy. It is unknown whether the effects of the study treatment are influenced by 
social determinants of health, but they are believed to be important to our scientific 
understanding of Alzheimer’s disease. 
In the US only, where permitted by applicable law and governing ethics committees, participants 
will have the option to report gender identity and sexual orientation information. These data will 
be used in an 
 of the disease course and treatment impacts of gender identity, 
which are currently unknown but are believed to be important to our scientific understanding of 
Alzheimer’s disease.  
Biogen will not disclose the result of ApoE testing to the participants. The investigator is 
responsible to ensure participant’s full understanding of the potential safety risks associated with 
genotyping, cognizant of the ethical and legal issues of disclosing results without appropriate 
genetic counselling. 
Study reports will be used for research purposes only. The participant will not be identified by 
name in CRFs, study-related forms, study reports, or any related publications. The Sponsor, its 
partners and designees, ethics committees, and various government health agencies may inspect 
the records of this study. Every effort will be made to keep the participant’s personal medical 
data confidential. 
13.6. 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws. 


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13.7. 
Conflict of Interest 
The Investigators should address any potential conflicts of interest (e.g., financial interest in the 
Sponsor with the participant before the participant makes a decision to participate in the study). 
13.8. 
Study Report Signatory 
The Sponsor will designate one 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 the Sponsor. 
The Sponsor will follow all applicable local regulations pertaining to study report signatories. 
13.9. 
Registration of Study and Disclosure of Study Results 
The Sponsor will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 
The Sponsor also will notify, when required, the regulatory authorities and ethics committees 
about the completion or termination of this study and send a copy of the study synopsis in 
accordance with necessary timelines. 
13.10. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site as dictated by any institutional requirements or local, national, or regional laws or 
regulations. Prior to proceeding with destruction of records, the Investigator must notify the 
Sponsor in writing and receive written authorization from the Sponsor to destroy study records. 
In addition, the Investigator must notify the Sponsor of any changes in the archival arrangements 
including but not limited to archival at an offsite facility or transfer of ownership if the 
Investigator leaves the site. 


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14. 
KEY ROLES AND STUDY GOVERNANCE COMMITTEES 
14.1. 
Site Staff 
Refer to the Study Reference Manual for further details regarding site staff responsibilities, 
including key blinding procedures for the 3 study roles.  
A minimum of 3 separate HCPs are required:   
1. A treating Investigator or Subinvestigator who is responsible for the following: 
− Management of routine neurological care of the participant. 
− Assessment (including assignment of causality) and treatment of AEs.   
− Review of selected hematology and blood chemistry results from the central 
laboratory to assess whether the participant’s study treatment should be 
temporarily withheld or permanently discontinued according to the criteria 
detailed in Section 8.1. 
2. The CDR Rater (designated by the Investigator of the site) who is an independent rater 
responsible for administering the CDR.  
3. The Independent Non-CDR Rater (designated by the Investigator of the site) who will 
administer the remainder of the clinical scales of cognition and function as well as the 
QoL questionnaires and health economic metrics. 
The CDR Rater and the Independent Non-CDR Rater must not be involved with any other aspect 
of participant care and management and must remain blinded to AEs, concomitant therapy, 
laboratory data, imaging data, or any other data that have the potential of revealing the treatment 
assignment. The CDR Rater and Independent Non-CDR Rater must not share any information 
about participants. Treating Investigators should not serve as raters, with the exception of the 
Research Diagnostic Verification and subsequent Disease Staging Forms. Treating Investigators 
must not discuss AEs (e.g., ARIA) or ARIA-related MRI-monitoring scheduling matters with the 
CDR Rater or Independent Non-CDR Rater.   
To ensure consistency across sites, all study raters must complete the standardized study-specific 
qualification and training process prior to administering clinical efficacy assessments. All sites 
must attempt to maintain the same rater for a given participant throughout the study. A qualified, 
approved back-up rater should conduct assessments in place of the primary rater only if 
extenuating circumstances (e.g., illness, vacation, or travel) result in unavailability of the primary 
rater. If a rater has to be replaced, the new rater must undergo the study-specific qualification 
process prior to administration of the assessment. 
Hematology and blood chemistry data will be sent to the investigational sites to aid in 
management of the participant. As with other laboratory and clinical information, these data 
should NOT be reviewed by the raters.   


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The roles of the CDR Rater, the Independent Non-CDR Rater, and treating Investigator are not 
interchangeable. In addition, the CDR Rater is not interchangeable with the Independent Non-
CDR Rater at the participant level. For example, if a rater has administered the CDR to a 
participant, they may not administer the other neurocognitive assessments to that participant at 
any point during the study. 
An unblinded pharmacist (or authorized designee) will be responsible for the storage, 
distribution, preparation, and accountability of study treatment. The unblinded pharmacist will 
also be responsible for maintaining the unblinded pharmacy record separate from the main study 
file in order to support the study blind. 
14.2. 
Vendors 
The Sponsor will ensure oversight of any study-related duties and functions carried out on its 
behalf and will specify in writing all duties and functions that are transferred.  
14.2.1. 
Contract Research Organization  
A CRO will be responsible for administrative aspects of the study, including but not limited to 
study initiation, monitoring, and management of SAE reports. Before participants are screened at 
each study site, the CRO will review study responsibilities with the Investigators and other study 
site staff, as appropriate.  
14.2.2. 
Interactive Response Technology 
IRT will be used in this study. Before participants are screened or enrolled, the IRT vendor will 
provide each study site with the necessary training, a user manual, and access rights to the 
system. 
14.2.3. 
Electronic or Remote Data Capture 
Participant information will be captured and managed by study sites on electronic CRFs by a 
Web-based EDC tool configured by the EDC vendor. Electronic Clinical Outcome Assessment 
will be entered by site staff on a Web-based tool. The site staff will monitor data via a secure 
Web portal.  
14.2.4. 
Central Laboratories for Laboratory Assessments 
The Sponsor has selected a central laboratory service to perform all standard hematology, blood 
chemistry, and urinalysis testing for the study. This central laboratory will also receive, track, 
and ship all urine, blood, CSF samples, and 
, PK, 
, and antidrug antibody testing, including aliquots from these samples retained as 
backup in case original samples are lost or not evaluable. 
 
 
Laboratories performing specialized testing will be identified in regulatory documentation. These 
laboratories will use appropriately validated or qualified assays to test study samples. 


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14.2.5. 
Central Facility for Other Assessments 
A central imaging laboratory has been selected by the Sponsor to read and interpret all MRIs for 
this study within the timeframe specified in the procedural manual for MRI. In cases of ARIA-E 
and ARIA-H, the central imaging laboratory must expedite notification to the Investigator and 
the Sponsor. For the purposes of study conduct, the MRI interpretations from the central reader 
will prevail over those from the local radiologist. 
The central imaging laboratory will also be utilized to facilitate collection and analysis of PET 
scans. 
14.2.6. 
Central Review of Raters 
The Sponsor has selected a rater management group to establish rater qualifications, provide 
studyspecific training about the rater process, and provide oversight. As part of the oversight 
process, the rater management group will incorporate a central review of the raters to ensure that 
data are consistently rated across sites. 
14.2.7. 
Neurocognitive Assessments 
The Sponsor has selected a rater management group to establish rater qualification, study-
specific training, and oversight. The study raters are required to complete qualifications steps and 
required training prior to administering study assessments. The rater management group will 
oversee the assessments in accordance with project-specific plans. 
14.3. 
Study Committees 
14.3.1. 
Advisory Committee 
An advisory committee will be formed to provide scientific and medical direction for the study 
and to oversee the administrative progress of the study. The advisory committee will meet 
periodically to monitor participant accrual and oversee study conduct, including advising on 
study design and execution.  
Members of the advisory committee will include external experts in Alzheimer’s disease. The 
Sponsor will designate one of the participating external experts to be the chairperson of the 
advisory committee. 
14.3.2. 
Independent Data Monitoring Committee  
The IDMC will be formed to review ongoing safety and tolerability data. The IDMC may also 
participate in a review of efficacy data only during interim analysis.  Members of the IDMC will 
not be allowed to participate as Investigators in this study. The IDMC will review safety data on 
an ongoing basis to ensure safe and proper treatment of participants. The IDMC, based on the 
nature, frequency, and/or severity of AEs, may recommend protocol modifications, dose 
suspension, dose termination, or study termination. An IDMC charter will provide full guidance 
on the function and practices to be followed by the IDMC.  


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15. 
ADMINISTRATIVE PROCEDURES 
15.1. 
Study Site Initiation 
The Investigator must not screen any participants prior to the Sponsor completing a study 
initiation visit. This initiation visit with the Investigator and other site staff, as appropriate, will 
include a detailed review of the protocol, study procedures, and study responsibilities. 
15.2. 
Quality Control and Quality Assurance 
Quality control procedures will be implemented at each stage of data handling to ensure that all 
data are reliable and have been processed correctly. Data anomalies will be communicated to the 
sites for clarification and resolution, as appropriate. The Investigator is responsible for endorsing 
all CRF data prior to any interim or final database lock. 
During and/or after completion of the study, quality assurance officers named by the Sponsor 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. 
15.3. 
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 Monitor will visit the study site at regular intervals during the study and after the 
study has completed, as appropriate. A clinical site monitoring plan will detail who performs the 
monitoring, how often, and the extent of 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. Documentation of 
results will be provided to the Sponsor in a timely fashion to allow FU and verification of 
compliance with the monitoring plan. Remote evaluation of data (centralized monitoring) may 
also be conducted and reported as defined in the monitoring plan. 
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure the protection of participant rights and well-being, protocol adherence, quality of data 
(accurate, complete, and verifiable), study treatment accountability, compliance with regulatory 
requirements, and continued adequacy of the investigational site and its facilities. 


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15.4. 
Study Funding 
The Sponsor is responsible for setting up the funding of the study. All financial details are 
provided in the separate contracts between the institution, Investigator, and the Sponsor 
organization. 
15.5. 
Publications 
Details are included in the clinical trial agreement for this study. 


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16. 
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population based cohort study with 14 year follow-up. BMJ. 2008;336(7638):258-62. 
 


Protocol 221AD305, Version 2.0 
Phase 3b/4 Study of Aducanumab (BIIB037) in Early Alzheimer’s Disease 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
110 
17. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “A Phase 3b/4 Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group Study to Verify the Clinical Benefit of Aducanumab (BIIB037) in 
Participants with 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) 


CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
1 
 
 
 
 
 
 
Biogen MA Inc. 
225 Binney Street 
Cambridge, MA  02142 
United States 
 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead, Berkshire 
SL6 4AY 
United Kingdom 
 
 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Protocol 221AD305 
A Phase 3b/4 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Verify 
the Clinical Benefit of Aducanumab (BIIB037) in Participants with Alzheimer’s Disease  
For Global Protocol Amendment: Version 2 
Date: 15 April 2022 
Version 2.0 of the protocol has been prepared for this amendment, which supersedes Version 1.0. 
 




Amendment Summary for Protocol 221AD305, Version 2 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
3 
SUMMARY OF MAJOR CHANGES TO THE PROTOCOL 
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted text is shown with a strikethrough. 
Table 2, Schedule of Activities From Week 36 to End of Study 
Change: Aducanumab autoantibody assessment was included in Version 1 of the protocol as assessed at the unscheduled visit for 
ARIA and not at the End-of-Study visit.  This was a transpositional error. Autoantibody assessment is now removed from this visit 
and added to the End-of-Study visit.  
Now reads: 
Study Week 
 
106 
ET1 
UV 
AD 
Meds2 
UV 
ARIA3 
FU4 
EOS 
36 
40 
42 
44 
48 
50 
52 
56 
60 
64 
68 
72 
76 
78 
80 
84 
88 
92 
96 
100 
104 
122 
Study Day 
253 
± 3 
281 
± 3 
295 
± 3 
309 
± 3 
337 
± 3 
351 
± 3 
365 
± 3 
393 
± 3 
421 
± 3 
449 
± 3 
477 
± 3 
505 
± 3 
533 
± 3 
547 
± 3 
561 
± 3 
589 
± 3 
617 
± 3 
645 
± 3 
673 
± 3 
701 
± 3 
729  
± 3 
743 
± 3 
855± 
3 
Anti-
Aducanumab 
Ab5 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
Rationale: In light of the amendment being triggered for correction of typographical errors, this error was also corrected.  
 
 

SAP_001.pdf: 
COVER PAGE 
Official Title: A Phase 3b/4 Randomized, Double-Blind, Placebo-Controlled, 
Parallel- Group Study to Verify the Clinical Benefit of Aducanumab 
(BIIB037) in Participants with Alzheimer’s Disease  
NCT Number: NCT05310071  
Document Date: 06 May 2024