Clinical trial NCT04241068
Conditions: Alzheimer's Disease
Sponsor: Biogen
Start date: 2020-03-02; Completion date: 2024-07-22
Enrollment: 1696 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective is to evaluate the safety and tolerability of aducanumab over 100 weeks of treatment after a wash-out period imposed by discontinuation of feeder studies in participants who had previously received aducanumab (i.e. previously treated participants) or who had previously received placebo (i.e. treatment-naïve participants).

Detailed description:

Arms: arm 1: Participants will be administered aducanumab 10 milligrams per kilogram (mg/kg) by intravenous (IV) infusions every four weeks (Q4W) for a duration of 100 weeks during the Core Treatment Period. Eligible participants will continue to receive aducanumab 10 mg/kg IV infusion, Q4W, for 52 weeks during the Long-Term Extension (LTE) Treatment Period.
Interventions: intervention 1: Aducanumab
Intervention descriptions: intervention 1: Administered as specified in the treatment arm.

Protocol documents:
Prot_000.pdf: 
Official Title: 
Phase 3b Open-Label, Multicenter, Safety Study of BIIB037 
(Aducanumab) in Subjects With Alzheimer’s Disease Who Had 
Previously Participated in the Aducanumab Studies 221AD103, 
221AD301, 221AD302, and 221AD205
NCT Number: 
NCT04241068 
Document Date: 
19 Jan 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: 
221AD304 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
 
PHASE OF DEVELOPMENT: 
3b  
 
PROTOCOL TITLE:  Phase 3b Open-Label, Multicenter, Safety Study of BIIB037 
(aducanumab) in Subjects With Alzheimer’s Disease Who Had Previously Participated in 
the Aducanumab Studies 221AD103, 221AD301, 221AD302, and 221AD205 
 
 
 
EUDRA CT NO: 
 
2019-004368-22 
 
 
DATE: 
19 JAN 2022 
Version 4.0 
FINAL 
 
Supersedes previous Version 3.0 dated 08 March 2021 
 
 


Protocol 221AD304 
Version 4.0 
Phase 3b Study of Aducanumab in 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 SIGNATURE 
 
Protocol 221AD304 was approved by: 
 
 
___________________________________________ 
 
_________________ 
, PhD 
 
 
 
 
Date (DD MMM YYYY) 
 
 
Biogen   


Protocol 221AD304 
Version 4.0 
Phase 3b Study of Aducanumab in Alzheimer’s Disease   
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
3 
TABLE OF CONTENTS 
SPONSOR SIGNATURE ................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................9 
LIST OF FIGURES .........................................................................................................................9 
1. 
SPONSOR INFORMATION .....................................................................................10 
2. 
LIST OF ABBREVIATIONS.....................................................................................11 
3. 
SYNOPSIS .................................................................................................................14 
4. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS FOR STUDY 
221AD304 ...................................................................................................................16 
4.1. 
Study Schematic .........................................................................................................16 
4.2. 
Schedule of Events .....................................................................................................17 
4.3. 
Additional Information ...............................................................................................32 
4.3.1. 
Site Staff .....................................................................................................................32 
5. 
INTRODUCTION ......................................................................................................33 
5.1. 
Previous Experience With Aducanumab ....................................................................34 
5.1.1. 
Nonclinical Experience ...............................................................................................34 
5.1.2. 
Clinical Experience .....................................................................................................34 
5.2. 
Study Rationale ...........................................................................................................37 
5.3. 
Rationale for Dose and Schedule Selection ................................................................41 
5.3.1. 
Dosing Scheme ...........................................................................................................41 
5.4. 
Benefit-Risk Assessment ............................................................................................41 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................43 
7. 
STUDY DESIGN .......................................................................................................46 
7.1. 
Study Overview ..........................................................................................................46 
7.2. 
Study Specifics ...........................................................................................................46 
7.2.1. 
Dose Suspension or Discontinuation for ARIA Events ..............................................46 
7.2.1.1. 
ARIA-E Events ...........................................................................................................47 
7.2.1.2. 
ARIA-H (Micro-hemorrhage) ....................................................................................49 
7.2.1.3. 
ARIA-H (Superficial Siderosis) .................................................................................51 
7.2.1.4. 
ARIA-H (Macro-hemorrhage) ....................................................................................53 


Protocol 221AD304 
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Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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7.2.1.5. 
Coincident ARIA-H and ARIA-E Events ...................................................................53 
7.2.1.6. 
Resumption of Study Treatment After Suspension due to ARIA...............................53 
7.2.1.7. 
Management After Recurrent ARIA (Dosing and MRI) ............................................54 
7.2.2. 
Infusion Interruption ...................................................................................................54 
7.3. 
Overall Study Duration and Follow-Up .....................................................................55 
7.3.1. 
Screening ....................................................................................................................56 
7.3.2. 
Treatment ....................................................................................................................56 
7.3.3. 
Follow-Up ...................................................................................................................56 
7.4. 
Study Stopping Rules .................................................................................................57 
7.5. 
Unscheduled Visits .....................................................................................................57 
7.6. 
End of Study ...............................................................................................................57 
8. 
SELECTION OF PARTICIPANTS ...........................................................................58 
8.1. 
Core Inclusion Criteria ...............................................................................................58 
8.2. 
Core Exclusion Criteria ..............................................................................................59 
8.3. 
LTE Inclusion Criteria ................................................................................................62 
8.4. 
LTE Exclusion Criteria ...............................................................................................63 
9. 
ENROLLMENT AND REGISTRATION .................................................................64 
9.1. 
Screening and Enrollment ...........................................................................................64 
9.2. 
Registration of Participants.........................................................................................64 
9.3. 
Blinding Procedures ....................................................................................................64 
10. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF PARTICIPANTS FROM THE STUDY..................................65 
10.1. 
Discontinuation of Study Treatment ...........................................................................65 
10.2. 
Lost to Follow-Up.......................................................................................................66 
10.3. 
Withdrawal of Participants From Study .....................................................................66 
11. 
STUDY TREATMENT ..............................................................................................67 
11.1. 
Regimen ......................................................................................................................67 
11.2. 
Modification of Dose and/or Treatment Schedule ......................................................67 
11.3. 
Precautions ..................................................................................................................67 
11.4. 
Compliance .................................................................................................................67 
11.5. 
Prior and Concomitant Therapy and Procedures ........................................................67 
11.5.1. 
Prior and Concomitant Therapy ..................................................................................67 


Protocol 221AD304 
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Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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11.5.1.1. 
Allowed Concomitant Therapy ...................................................................................67 
11.5.1.2. 
Disallowed Concomitant Therapy ..............................................................................68 
11.5.2. 
Concomitant Procedures .............................................................................................69 
11.6. 
Continuation of Treatment ..........................................................................................69 
12. 
STUDY TREATMENT MANAGEMENT ................................................................70 
12.1. 
Aducanumab ...............................................................................................................70 
12.1.1. 
Aducanumab Preparation ............................................................................................70 
12.1.2. 
Aducanumab Storage ..................................................................................................71 
12.1.3. 
Aducanumab Handling and Disposal .........................................................................71 
12.1.4. 
Aducanumab Accountability ......................................................................................71 
12.2. 
Additional Protocol-Designated Products ..................................................................71 
 
 
72 
 
72 
 
72 
 
72 
 
73 
 
74 
 
74 
 
74 
 
74 
 
75 
14. 
SAFETY ASSESSMENTS ........................................................................................76 
14.1. 
Clinical Safety Assessments .......................................................................................76 
14.2. 
Laboratory Safety Assessments ..................................................................................76 
14.3. 
Immunogenicity Assessments ....................................................................................77 
15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................78 
15.1. 
Definitions ..................................................................................................................78 
15.1.1. 
Adverse Event .............................................................................................................78 
15.1.2. 
Serious Adverse Event ................................................................................................78 
15.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................79 
15.2. 
Safety Classifications ..................................................................................................79 


Protocol 221AD304 
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Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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15.2.1. 
Investigator Assessment of Events .............................................................................79 
15.2.2. 
Relationship of Events to Study Treatment ................................................................80 
15.2.3. 
Severity of Events .......................................................................................................81 
15.2.4. 
Expectedness of Events ..............................................................................................81 
15.3. 
Monitoring and Recording Events ..............................................................................81 
15.3.1. 
Adverse Events ...........................................................................................................81 
15.3.2. 
Adverse Events of Special Interest .............................................................................81 
15.3.3. 
Serious Adverse Events ..............................................................................................82 
15.3.4. 
Immediate Reporting of Serious Adverse Events .......................................................82 
15.3.4.1. 
Deaths .........................................................................................................................83 
15.3.5. 
Suspected Unexpected Serious Adverse Reactions ....................................................83 
15.4. 
Procedures for Handling Special Situations ...............................................................83 
15.4.1. 
Pregnancy ...................................................................................................................83 
15.4.2. 
Overdose .....................................................................................................................83 
15.4.3. 
Medical Emergency ....................................................................................................84 
15.5. 
Contraception Requirements ......................................................................................84 
15.6. 
Safety Responsibilities ................................................................................................85 
15.6.1. 
The Investigator ..........................................................................................................85 
15.6.2. 
Biogen .........................................................................................................................85 
16. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........86 
16.1. 
Demography and Baseline Disease Characteristics ....................................................86 
 
86 
 
86 
 
86 
 
86 
 
86 
 
87 
 
87 
 
87 
16.4. 
Safety ..........................................................................................................................87 
16.4.1. 
Analysis Population ....................................................................................................87 
16.4.2. 
Methods of Analysis- Primary Endpoint ....................................................................87 


Protocol 221AD304 
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Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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16.4.2.1. 
Adverse Events ...........................................................................................................87 
16.4.2.2. 
Clinical Laboratory Results ........................................................................................87 
16.4.2.3. 
Vital Signs ..................................................................................................................88 
16.4.2.4. 
ECG ............................................................................................................................88 
16.4.2.5. 
Columbia Suicide Severity Rating Scale ....................................................................88 
16.5. 
Immunogenicity Data .................................................................................................88 
16.5.1. 
Analysis Population ....................................................................................................88 
16.5.2. 
Methods of Analysis- Primary Endpoint ....................................................................88 
16.6. 
Interim Analyses .........................................................................................................88 
16.7. 
Sample Size Considerations .......................................................................................88 
17. 
ETHICAL REQUIREMENTS ...................................................................................89 
17.1. 
Declaration of Helsinki ...............................................................................................89 
17.2. 
Ethics Committee/Institutional Review Board ...........................................................89 
17.3. 
Participant Information and Consent ..........................................................................89 
17.4. 
Participant Data Protection .........................................................................................90 
17.5. 
Compensation for Injury .............................................................................................90 
17.6. 
Conflict of Interest ......................................................................................................90 
17.7. 
Registration of Study and Disclosure of Study Results ..............................................91 
18. 
ADMINISTRATIVE PROCEDURES .......................................................................92 
18.1. 
Study Site Initiation ....................................................................................................92 
18.2. 
Quality Assurance .......................................................................................................92 
18.3. 
Monitoring of the Study..............................................................................................92 
18.4. 
Study Funding .............................................................................................................92 
18.5. 
Publications .................................................................................................................92 
19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................93 
19.1. 
External Contract Organizations .................................................................................93 
19.1.1. 
Contract Research Organization .................................................................................93 
19.1.2. 
Interactive Response Technology ...............................................................................93 
19.1.3. 
Electronic Data Capture ..............................................................................................93 
19.1.4. 
Central Laboratories for Laboratory Assessments .....................................................93 
19.1.5. 
Central Facility for Other Assessments ......................................................................93 
19.1.6. 
Central Review of Raters ............................................................................................94 


Protocol 221AD304 
Version 4.0 
Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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Biogen MA Inc. 
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19.1.7. 
Neurocognitive Assessments ......................................................................................94 
19.2. 
Study Committees .......................................................................................................94 
19.2.1. 
Advisory Committee ...................................................................................................94 
19.2.2. 
Independent Data Monitoring Committee ..................................................................94 
19.3. 
Changes to Final Protocol ...........................................................................................94 
19.4. 
Retention of Study Data ..............................................................................................95 
19.5. 
Study Report Signatory...............................................................................................95 
20. 
REFERENCES ...........................................................................................................96 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................98 
 


Protocol 221AD304 
Version 4.0 
Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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LIST OF TABLES 
Table 1: 
Core Treatment Period Schedule From Screening Through Week 48 of 
Treatment ....................................................................................................................17 
Table 2: 
Core Treatment Period Schedule From Week 50 to Week 102 ..................................21 
Table 3: 
LTE Treatment Schedule from Week 104 Through End of Treatment and 
Follow-Up ...................................................................................................................24 
Table 4: 
Brain MRI, ARIA Management, and Follow-Up Telephone Call Schedule 
During the Core and LTE Treatment Periods .............................................................27 
Table 5: 
Participants Who Discontinue Study Treatment During the Core Treatment 
and LTE Periods but Remain in the Study .................................................................29 
Table 6: 
Final Analysis of Primary and Secondary Endpoints From EMERGE 
(Study 221AD302) ......................................................................................................40 
Table 7: 
Final Analysis of Primary and Secondary Endpoints From ENGAGE 
(Study 221AD301) ......................................................................................................40 
Table 8: 
Disposition of ARIA-E Events ...................................................................................47 
Table 9: 
Disposition of ARIA-H (Micro-hemorrhage) Events .................................................49 
Table 10: Disposition of ARIA-H (Superficial Siderosis) Events ..............................................51 
Table 11: Resumption of Study Treatment Following Dose Suspension Due to ARIA 
During Titration ..........................................................................................................54 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................16 
 
 


Protocol 221AD304 
Version 4.0 
Phase 3b Study of Aducanumab in Alzheimer’s Disease   
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
10 
1. 
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 Australia Pty Ltd 
Suite 1, Level 3, 123 Epping Rd 
North Ryde, NSW 2113 
Australia 
 
Biogen Japan Ltd. 
Nihonbashi 1-chome Mitsui Building 14F 
4-1 Nihonbashi 1-chome 
Chuo-ku Tokyo 
103-0027 Japan  
For urgent medical issues in which the study Medical Director should be contacted, please refer 
to the Study Reference Manual’s Official Study Contact List for complete contact information. 
Biogen may transfer any or all of its study-related responsibilities to a CRO and other third 
parties; however, Biogen retains overall accountability for these activities. 
 


Protocol 221AD304 
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Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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2. 
LIST OF ABBREVIATIONS 
12F6A 
recombinant, human anti-amyloid beta immunoglobulin gamma 
1 monoclonal antibody with an amino acid sequence identical 
to aducanumab, produced in a different Chinese hamster ovary 
cell line 
Aβ 
amyloid beta (peptide derived from membrane bound amyloid 
precursor protein) 
ADA 
antidrug antibody 
ADAS-Cog 13 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
(13 items) 
ADCS-ADL-MCI 
Alzheimer’s Disease Cooperative Study - Activities of Daily 
Living Inventory – Mild Cognitive Impairment 
 
 
  
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
anti-HBc 
hepatitis B core antibody 
anti-HBs 
hepatitis B surface antibody 
 
 
  
 
ARIA 
amyloid-related imaging abnormalities 
ARIA-E 
amyloid-related imaging abnormality-edema  
ARIA-H 
amyloid-related imaging abnormality-hemorrhage or superficial 
siderosis 
AST 
aspartate aminotransferase 
 
 
CDR 
Clinical Dementia Rating 
CDR-SB 
Clinical Dementia Rating sum of boxes  
ch12F6A 
murine IgG2a chimeric version of 12F6A or aducanumab  
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale  
DBP 
diastolic blood pressure 
DCT 
discontinue treatment 
DHA 
Directions for Handling and Administration 
 
 
EC 
ethics committee 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EOT 
End of Treatment 


Protocol 221AD304 
Version 4.0 
Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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Biogen MA Inc. 
12 
 
 
 
 
 
 
 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
FU 
follow-up 
GCP 
Good Clinical Practice 
HbA1c 
glycosylated hemoglobin 
HbsAg 
hepatitis B surface antigen 
HCP 
health care provider 
HCV 
hepatitis C virus 
 
 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
independent data monitoring committee 
IgG 
immunoglobulin G 
IRB 
institutional review board 
IRT 
interactive response technology 
IV 
intravenous(ly) 
IWG 
International Working Group 
LP 
lumbar puncture 
LTE 
long term extension 
MCI 
mild cognitive impairment 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-model repeated measures 
MMSE 
Mini-Mental State Examination 
 
 
 
 
MRI 
magnetic resonance imaging 
NFT 
neurofibrillary tangle 
NIA-AA 
National Institute on Aging (NIA) at National Institutes of 
Health (NIH) and the Alzheimer’s Association (AA) 
 
 
PD 
pharmacodynamic(s) 
 
 
PK 
pharmacokinetic(s) 
Q4W 
every 4 weeks 
RNA 
ribonucleic acid 
 
 
SAE 
serious adverse event 
SBP 
systolic blood pressure 


Protocol 221AD304 
Version 4.0 
Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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SUSAR 
suspected unexpected serious adverse reaction 
SUVR 
Standard Uptake Value Ratio 
TEAE 
treatment-emergent adverse event 
UV 
Unscheduled Visit 


Protocol 221AD304 
Version 4.0 
Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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3. 
SYNOPSIS 
Protocol Number: 
221AD304 
Protocol Title: 
Phase 3b Open-Label, Multicenter, Safety Study of BIIB037 
(Aducanumab) in Subjects With Alzheimer’s Disease Who Had 
Previously Participated in the Aducanumab Studies 221AD103, 
221AD301, 221AD302, and 221AD205 
Version Number: 
4.0 
Name of Study 
Treatment: 
Aducanumab (BIIB037) 
Study Indication: 
Alzheimer’s disease 
Study Rationale: 
This open-label, single-arm clinical study is being conducted to assess 
the long-term safety and efficacy of aducanumab in participants with 
Alzheimer's disease who were actively participating in aducanumab 
clinical studies 221AD103, 221AD205, 221AD301, or 221AD302 (from 
now on named “feeder studies”) as of 21 March 2019. On that date, 
Biogen announced the discontinuation of the Phase 3 aducanumab 
clinical studies, based on results from a preplanned futility analysis; 
discontinuation of the other ongoing studies (Studies 221AD103 and 
221AD205) was also announced and implemented at the same time. The 
present study (221AD304) is being undertaken based on efficacy 
findings from additional analyses of the 2 Phase 3 studies. In these new 
analyses, Study 221AD302 showed that participants treated in the high-
dose arm of aducanumab had significantly slower cognitive and 
functional decline when compared to placebo at 18 months. Results from 
the low-dose arm of Study 221AD302 showed trends of slowing decline 
compared to placebo but did not reach significance. 
Phase of Development: 
3b 
Study Objectives and 
Endpoints: 
The primary objective of the study is to evaluate the long-term safety and 
tolerability of aducanumab after a wash-out period imposed by the 
discontinuation of the feeder studies in participants who had previously 
received aducanumab (i.e., previously treated participants) or who had 
previously received placebo (i.e., treatment-naïve participants). 


Protocol 221AD304 
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Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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15 
Protocol Number: 
221AD304 
The endpoints that relate to this objective are: 
• 
Incidence of AEs, SAEs, ARIA, and immunogenicity with 
long-term treatment and/or re-exposure to aducanumab. Safety 
and tolerability parameters including: 
− Incidence of all AEs, AEs leading to treatment 
discontinuation or study withdrawal, and all SAEs 
− Incidence of ARIA-E and ARIA-H  
− Incidence of anti-aducanumab antibodies (antidrug 
antibodies, ADA), in serum. 
   
Study Design: 
Single-arm, longitudinal, multicenter, open-label study with a 100-week 
Core Treatment Period followed by an LTE Treatment Period of an 
additional 52 weeks of treatment and a safety FU Visit 18 weeks after the 
last dose of study treatment. 
Study Location: 
Approximately 350 sites globally 
Number of Planned 
Participants: 
Approximately 2400 participants are planned to be enrolled. 
Study Population: 
This study will be conducted in participants who meet the following 
criteria: 
• 
Actively enrolled in an ongoing aducanumab clinical study at the 
time of the Sponsor’s decision to stop trials on 21 March 2019.  
• 
Diagnosed with Alzheimer’s disease, able to comply with study 
protocol-related tests and procedures, and with an 
 
  
Detailed inclusion and exclusion criteria are described in Section 8. 
Treatment Groups: 
All participants will receive aducanumab by IV infusion Q4W. The 
aducanumab target dose will be 10 mg/kg, after a titration period as 
follows: 1 mg/kg for the first 2 doses, 3 mg/kg for the next 2 doses, 
6 mg/kg for the next 2 doses, and 10 mg/kg thereafter. 
Duration of Study 
Participation: 
Study duration for each participant will be approximately 178 weeks: 
approximately 8-week Screening Period, a 100-week Core Treatment 
Period, a 52-week LTE Treatment Period, and a safety FU Visit 18 
weeks after the last dose of study treatment. 


Protocol 221AD304 
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Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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16 
4. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS FOR STUDY 221AD304 
4.1. 
Study Schematic  
Figure 1: 
Study Design 
 
 
 
         
                                
                                         
         
       
        
       
       
       
        
       
       
        
                              
  
  
 
  
 
  
 
 
 
 
 
  
  
  
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
   
 
                        
              
                      
        
                       
     
       
              
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
                                                
   


Protocol 221AD304 
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Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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4.2. 
Schedule of Events  
Table 1: 
Core Treatment Period Schedule From Screening Through Week 48 of Treatment 
Study Week 
Screening 
(≤ 60 days 
before 
Day 1)1 
Treatment Period 
UV for a 
Change in 
Alzheimer’s 
Disease 
Medication 
Wk 
1, 
Day 
1 
4 
8 
12 
16 
20 
24 
26 
28 
32 
36 
40 
44 
48 
Study Day 
 
1 
29± 5 
57± 5 
85± 5 
113± 5 
141± 5 
169± 5 
183± 5 
197± 5 
225± 5 
253± 5 
281± 5 
309± 5 
337± 5 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol/Drug 
Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV3/Hepatitis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Serum Pregnancy 
Test5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy 
Test5 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Aducanumab 
Infusion 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Hematology, Blood 
Chemistry, and 
Urinalysis 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alzheimer’s 
Disease Status7  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 221AD304 
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Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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Study Week 
Screening 
(≤ 60 days 
before 
Day 1)1 
Treatment Period 
UV for a 
Change in 
Alzheimer’s 
Disease 
Medication 
Wk 
1, 
Day 
1 
4 
8 
12 
16 
20 
24 
26 
28 
32 
36 
40 
44 
48 
Study Day 
 
1 
29± 5 
57± 5 
85± 5 
113± 5 
141± 5 
169± 5 
183± 5 
197± 5 
225± 5 
253± 5 
281± 5 
309± 5 
337± 5 
Physical 
Examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Neurological 
Examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Vital Signs8 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
12-Lead Paper ECG 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA9 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Aducanumab Serum 
Concentration9 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 


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19 
Study Week 
Screening 
(≤ 60 days 
before 
Day 1)1 
Treatment Period 
UV for a 
Change in 
Alzheimer’s 
Disease 
Medication 
Wk 
1, 
Day 
1 
4 
8 
12 
16 
20 
24 
26 
28 
32 
36 
40 
44 
48 
Study Day 
 
1 
29± 5 
57± 5 
85± 5 
113± 5 
141± 5 
169± 5 
183± 5 
197± 5 
225± 5 
253± 5 
281± 5 
309± 5 
337± 5 
C-SSRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Reporting 
 
Monitor and record continuously throughout the study 
Concomitant 
Therapy13 and 
Procedures 
Monitor and record continuously throughout the study 
SAE Reporting 
Monitor and record continuously throughout the study 
1 It is recommended that all screening procedures be completed within 60 days; however, the overall Screening Period may be extended up to 90 days in the event of 
 
 and/or other logistics restrictions due to major causes (i.e., institutional restrictions or participant disposition due to COVID-19 or other major disasters) and is 
subject to Sponsor approval. In order to ease participant burden, the Screening Visit may be carried out over 2 separate visits, at the Investigator’s discretion.  
2 All assessments must be completed prior to infusion. 
3 HIV testing is at the Investigator’s discretion after consideration of risk factors. 
 
5 Required for women of childbearing potential only (see Section 15.5). Must be performed prior to scans.  
6 Chemistry assessment at Screening Visit to include lipid panel. 
7 As judged by the Investigator. 
8 Vital signs will include body temperature, heart rate, SBP, DBP, and respiratory rate. Vital signs will be measured with the participant supine and after the participant has been 
resting for at least 10 minutes.  
 
  
 
 
 
 
 
 
 


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20 
 
. 
 
 
 
 
 
 
 
13 Participants who have a change in Alzheimer’s disease medication (other than study treatment) during the Treatment Period should have an unscheduled visit. A subset of the 
clinical efficacy assessments 
 should be performed prior to the change in medication if the participant alerts the 
Investigator before the change in medication occurs. In the event that 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 are performed within 30 days after the change 
in medication, the assessments do not have to be repeated. 
 


Protocol 221AD304 
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21 
Table 2: 
Core Treatment Period Schedule From Week 50 to Week 102 
Study Week 
Treatment Period 
FU 
50 
52 
56 
60 
64 
68 
72 
76 
78 
80 
84 
88 
92 
96 
100 
1021 
UV for a 
Change in 
Alzheimer’
s Disease 
Medication 
118 
(or 18 wks 
after last 
dose for 
participant
s who DCT 
early)2 
Study Day 
351 
± 5 
365 
± 5 
393 
± 5 
421 
± 5 
449 
± 5 
477 
± 5 
505 
± 5 
533 
± 5 
547 
± 5 
561 
± 5 
589 
± 5 
617 
± 5 
645 
± 5 
673  
± 5 
701 
± 5 
714 
± 5 
 
827± 5 
Body Weight 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Urine Pregnancy Test3 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Aducanumab Infusion 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Hematology, Blood 
Chemistry, and Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Alzheimer’s Disease 
Status4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Physical Examination 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Neurological Examination 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Vital Signs5 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-Lead Paper ECG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ADA6 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Aducanumab Serum 
Concentration6 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 


Protocol 221AD304 
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Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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22 
Study Week 
Treatment Period 
FU 
50 
52 
56 
60 
64 
68 
72 
76 
78 
80 
84 
88 
92 
96 
100 
1021 
UV for a 
Change in 
Alzheimer’
s Disease 
Medication 
118 
(or 18 wks 
after last 
dose for 
participant
s who DCT 
early)2 
Study Day 
351 
± 5 
365 
± 5 
393 
± 5 
421 
± 5 
449 
± 5 
477 
± 5 
505 
± 5 
533 
± 5 
547 
± 5 
561 
± 5 
589 
± 5 
617 
± 5 
645 
± 5 
673  
± 5 
701 
± 5 
714 
± 5 
 
827± 5 
C-SSRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
LTE IC/EC Eligibility 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
LTE Informed consent11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
AE Reporting 
Monitor and record continuously throughout the study 
Concomitant Therapy12 
and Procedures 
Monitor and record continuously throughout the study 
SAE Reporting 
Monitor and record continuously throughout the study 
1 Eligible participants who complete the Core Treatment Period and the Week 102 visit may enter the LTE period.  
2 For all participants who do not enter the LTE, a safety FU Visit is required 18 weeks after their last dose. 


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23 
3 Required for women of childbearing potential only (Section 15.5 ).  
4 As judged by the Investigator. 
5 Vital signs will include body temperature, heart rate, SBP, DBP, and respiratory rate. Vital signs will be measured with the participant supine and after the participant has been 
resting for at least 10 minutes. 
6 Will be performed prior to infusion (where applicable). 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
11 All participants who are eligible and continuing in the LTE must provide written informed consent. 
12 Participants who have a change in Alzheimer’s disease medication (other than study treatment) during the Treatment Period should have an unscheduled visit. A subset of the 
clinical efficacy assessments 
 should be performed prior to the change in medication if the participant alerts the 
Investigator before the change in medication occurs. In the event that 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 are performed within 30 days after the change 
in medication, the assessments do not have to be repeated. 
 


Protocol 221AD304 
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Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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24 
Table 3: 
LTE Treatment Schedule from Week 104 Through End of Treatment and Follow-Up 
Study Week 
LTE Treatment Period 
UV for a 
Change in 
Alzheimer’
s Disease 
Medication 
FU 
170 
(or 18 wks 
after last 
dose for 
participant
s who DCT 
early) 
104 
108 
112 
116 
120 
124 
128 
132 
136 
140 
144 
148 
152 
154/EO
T 
Study Day 
729± 
5 
757± 
5 
785± 
5 
813± 
5 
841± 
5 
869± 
5 
897± 
5 
925± 
5 
953± 
5 
981± 
5 
1009± 
5 
1037± 
5 
1065± 
5 
1078 ± 5 
1190 ± 5 
Body Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urine 
Pregnancy 
Test1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Aducanumab 
Infusion 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Hematology, 
Blood 
Chemistry, 
and Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Alzheimer’s 
Disease 
Status2 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Physical 
Examination 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Neurological 
Examination 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-Lead Paper 
ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ADA4 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Aducanumab 
Serum 
Concentration
4 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 


Protocol 221AD304 
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Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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25 
Study Week 
LTE Treatment Period 
UV for a 
Change in 
Alzheimer’
s Disease 
Medication 
FU 
170 
(or 18 wks 
after last 
dose for 
participant
s who DCT 
early) 
104 
108 
112 
116 
120 
124 
128 
132 
136 
140 
144 
148 
152 
154/EO
T 
Study Day 
729± 
5 
757± 
5 
785± 
5 
813± 
5 
841± 
5 
869± 
5 
897± 
5 
925± 
5 
953± 
5 
981± 
5 
1009± 
5 
1037± 
5 
1065± 
5 
1078 ± 5 
1190 ± 5 
C-SSRS 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
AE Reporting 
Monitor and record continuously throughout the study 
Concomitant 
Therapy9 and 
Procedures 
Monitor and record continuously throughout the study 


Protocol 221AD304 
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Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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26 
Study Week 
LTE Treatment Period 
UV for a 
Change in 
Alzheimer’
s Disease 
Medication 
FU 
170 
(or 18 wks 
after last 
dose for 
participant
s who DCT 
early) 
104 
108 
112 
116 
120 
124 
128 
132 
136 
140 
144 
148 
152 
154/EO
T 
Study Day 
729± 
5 
757± 
5 
785± 
5 
813± 
5 
841± 
5 
869± 
5 
897± 
5 
925± 
5 
953± 
5 
981± 
5 
1009± 
5 
1037± 
5 
1065± 
5 
1078 ± 5 
1190 ± 5 
SAE 
Reporting 
Monitor and record continuously throughout the study 
1 Required for women of childbearing potential only (see Section 15.5). Must be performed prior to scans.  
2 As judged by the Investigator 
3 Vital signs will include body temperature, heart rate, SBP, DBP, and respiratory rate. Vital signs will be measured with the participant supine and after the participant has been 
resting for at least 10 minutes.  
4 Will be performed prior to infusion (where applicable).  
 
 
 
 
 
 
 
 
 
 
 
 
 
.  
 
 
9 Participants who have a change in Alzheimer’s disease medication (other than study treatment) during the Treatment Period should have an unscheduled visit. a subset of the 
clinical efficacy assessments 
 should be performed prior to the change in medication if the participant alerts the 
Investigator before the change in medication occurs. In the event that 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 are performed within 30 days after the change 
in medication, the assessments do not have to be repeated. 
 


Protocol 221AD304 
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27 
Table 4: 
Brain MRI, ARIA Management, and Follow-Up Telephone Call Schedule During the Core and LTE Treatment 
Periods  
Study Week 
Screening 
(≤ 60 
days 
before  
Day 1)1 
Core Treatment Period 
Core 
Treatment 
Period FU2 
LTE 
Treatment 
Period FU3 
1 
2 
6 
10 
14 
18 
22 
26 
30 
42 
54 
66 
78 
102/ 
EOT4 
UV/MRI 
for 
ARIA5 
118 (or 18 
wks after 
last dose for 
participants 
who DCT 
early from 
core 
treatment 
period) 
170 (or 18 
wks after 
last dose for 
participants 
who DCT 
early from 
LTE 
treatment 
period) 
Study Day 
 
1 
15± 5 
43 
± 5 
71 
± 5 
99 
± 5 
127 
± 5 
155 
± 5 
183 
± 5 
211 
± 5 
295 
± 5 
379 
± 5 
463 
± 5 
547 
± 5 
714 
± 5  
827± 5 
1190 ± 5 
Follow-Up 
Telephone 
Call6 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Brain MRI 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Aducanumab 
Serum 
Concentration7 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
Physical 
Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Neurological 
Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Vital Signs8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
1 It is recommended that all screening procedures be completed within 60 days; however, the overall Screening Period may be extended up to 90 days in the event of 
 
 and/or other logistics restrictions due to major causes (i.e., institutional restrictions or participant disposition due to COVID-19 or other major disasters) and is 
subject to Sponsor approval. In order to ease participant burden, the Screening Visit may be carried out over 2 separate visits, at the Investigator’s discretion. 
2 Participants who complete the Core Treatment Period of the study and do not enter the LTE Treatment Period are to return to the site for a safety FU Visit at Week 118. 
Participants who discontinue or withdraw from the study early are to have a safety FU Visit 18 weeks after the last dose of study treatment. 


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3 Participants who complete the LTE Treatment Period of the study are to return to the site for a safety FU Visit at Week 170. Participants who DCT or withdraw from the LTE 
early are to have a safety FU Visit 18 weeks after the last dose of study treatment. 
4 Participants who discontinue prematurely are 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 2 Table 3 and Table 4 ) until the end of the study per the Schedule of Events (it is possible that a 
clinic visit will occur before the safety FU Visit). If the safety FU Visit will occur within 2 weeks of a scheduled clinic visit, then the safety FU Visit can be combined with the 
scheduled visit and all assessments required for both visits performed at this single visit. Participants who withdraw from study prematurely are to return to the site for an EOT 
Visit; for such participants, efficacy assessments specified at the EOT 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 in such cases. 
 
 
 
 
 
6 Telephone visit may be performed in person if the participant will be at the study site for clinical assessments. 
 
 
 
.  
8 Vital signs will include body temperature, heart rate, SBP, DBP, and respiratory rate. Vital signs will be measured with the participant supine and after the participant has been 
resting for at least 10 minutes.  
 
 
 


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29 
Table 5: 
Participants Who Discontinue Study Treatment During the Core Treatment and LTE Periods but Remain in the 
Study  
 
Post-Treatment Visit Schedule1 (Core Treatment and LTE Periods) 
Study Week 
12 
24 
26 
48 
50 
72 
78 
92 
102 2 
112 
128 
140 
152 
154/ 
EOT2 
UV for 
ARIA3 
Study Day 
85 ± 5 
169 ± 5 
183 ± 5 
337 ± 5 
351 ± 5 
505 ± 5 
547 ± 5 
645 ± 5 
714 ± 5 
785 ± 5 
897 ± 5 
981 ± 5 
1065 
± 5 
1078 
± 5 
Body Weight 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Hematology, Blood 
Chemistry, and 
Urinalysis 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Urine Pregnancy Test4 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Physical Examination 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
Neurological 
Examination 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
Vital Signs5 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
12-Lead Paper ECG 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Aducanumab Serum 
Concentration 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X6 
Brain MRI 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 


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30 
 
Post-Treatment Visit Schedule1 (Core Treatment and LTE Periods) 
Study Week 
12 
24 
26 
48 
50 
72 
78 
92 
102 2 
112 
128 
140 
152 
154/ 
EOT2 
UV for 
ARIA3 
Study Day 
85 ± 5 
169 ± 5 
183 ± 5 
337 ± 5 
351 ± 5 
505 ± 5 
547 ± 5 
645 ± 5 
714 ± 5 
785 ± 5 
897 ± 5 
981 ± 5 
1065 
± 5 
1078 
± 5 
C-SSRS 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
AE Reporting 
Monitor and record continuously throughout the study 
Concomitant Therapy 
and Procedures 
Monitor and record continuously throughout the study 
SAE Reporting 
Monitor and record continuously throughout the study 
1 Participants who discontinue study treatment prematurely are to remain in the study, attend a safety FU Visit 18 weeks after the last dose of study treatment as listed in Table 2 
Table 3 and Table 4 and immediately continue protocol-required tests and assessments at a subset of the clinic visits (Table 5 ) until the end of the study per the Schedule of 
Events (it is possible that a clinic visit will occur before the safety FU Visit). If the safety FU Visit will occur within 2 weeks of a scheduled clinic visit, then the safety FU Visit 
can be combined with the scheduled visit and all assessments required for both visits performed at this single visit. 
2 Participants who withdraw from study prematurely are to return to the site for an EOT Visit; for such participants, efficacy assessments specified at the EOT 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 in such cases. 
 
 
 
 
 
4 Required only if last dose of study treatment was less than 24 weeks before the clinic visit. 
5 Vital signs will include body temperature, heart rate, SBP, DBP, and respiratory rate. Vital signs will be measured with the participant supine and after the participant has been 
resting for at least 10 minutes.  
6 One sample will be collected within ± 2 days of the MRI visit. Exact collection date and time will be captured for all 
 on a specified CRF. 


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7 Sample may be collected within ± 2 days of the MRI visit. 
 
 
  
 
 
 
 
 
 
 
 
 
 


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4.3. 
Additional Information 
4.3.1. 
Site Staff  
A minimum of 2 separate HCPs are required for this study: 
1. A treating HCP (the Investigator may serve as a treating HCP) 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 if the participant’s study treatment should be temporarily 
withheld or permanently discontinued according to the criteria detailed in 
Section 10.1. 
2. An independent rating HCP (designated by the Investigator of the site) who is responsible 
for administering the 
 
, 
 
, and C-SSRS.  
To ensure consistency across sites, rating HCPs must complete the standardized study-specific 
qualification process on clinical efficacy assessment scoring prior to administration of the 
specific assessment at their site. All sites must attempt to maintain the same rating HCP 
throughout the study for specific assessments in an attempt to remain consistent. (*Each 
participant should have the same rating HCP perform the participant’s specific rating assessment 
throughout the study*). A qualified approved back-up rater should only conduct assessments in 
place of the primary rater due to extenuating circumstances resulting in unavailability (e.g., due 
to illness, vacation, or travel). If a rating HCP has to be replaced, the new rating HCP must 
undergo the study-specific qualification process prior to administration of the assessment. Please 
note that the treating HCPs and rating HCPs are NOT interchangeable at the participant level.  
A pharmacist (or authorized designee) will be responsible for the storage, distribution, 
preparation, and accountability of study treatment. The pharmacist will also be responsible for 
maintaining the pharmacy record.  
For further details about test administration and roles and responsibilities of HCPs and study 
personnel, please consult the Study Reference Manual.  
 


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33 
5. 
INTRODUCTION  
Alzheimer’s disease is the most common cause of dementia, accounting for 50% to 75% of all 
cases. Alzheimer’s Disease International estimates that as of 2016, there were 47 million people 
living with dementia worldwide, and that this figure will increase to 131 million by 2050 
[Alzheimer's Disease International 2016]. Globally, the greatest increase in dementia numbers 
through 2050 is expected to occur in countries in which the population is aging at an 
unprecedented rate [Alzheimer's Disease International 2015]. 
Clinically, Alzheimer’s disease is a progressive neurodegenerative disorder characterized by an 
insidious and unrelenting decline in cognition and behavioral disturbances that result in the 
person’s inability to perform usual activities of daily living [Jack 2013]. 
Pathologically, Alzheimer’s disease is defined by the presence in the brain of extracellular 
neuritic plaques containing Aβ peptide and intraneuronal neurofibrillary tangles composed of 
hyperphosphorylated tau proteins. The pathogenesis of these plaques and tangles and how they 
contribute to the clinical syndrome remain to be fully elucidated, but the leading hypothesis —
the “amyloid cascade”— proposes that the driving force behind the disease process is the 
accumulation of Aβ resulting from an imbalance between Aβ production and Aβ clearance in the 
brain [Hardy and Selkoe 2002]. 
Biomarker [Jack 2010], clinicopathologic [Delacourte 2002], and cohort [Amieva 2008] studies 
suggest that the disease process commences 10 to 20 years prior to the onset of symptoms, 
starting with the deposition of neocortical Aβ plaques and mesial temporal tau-containing NFTs 
followed years later by neocortical tau-containing NFTs, which best correlate with cognitive 
status and neuronal death [Nelson 2009]. As the disease progresses, cognitive impairments, 
behavioral changes, and functional disability manifest [Jack 2013]. Thus, it is hypothesized that 
removal of Aβ plaques and subsequent alteration of tau pathology may slow cognitive decline.  
Based on this understanding of the underlying disease process, with onset decades before 
symptom onset, the scientific community has focused on developing treatments for patients in 
the earlier stages of the Alzheimer’s disease continuum. This shift in focus was made possible in 
part by the development of diagnostic criteria for the diagnosis of earlier stages of Alzheimer’s 
disease in clinical research studies published by the NIA-AA [Albert 2011; McKhann 2011; 
Sperling 2011] and by an IWG [Dubois 2010]. These criteria address the need to define the 
clinical diagnosis of the predementia phases of Alzheimer’s disease (e.g., MCI due to 
Alzheimer’s disease) and to improve specificity of diagnosis by incorporating biomarkers of 
Alzheimer’s disease pathology into the diagnostic process. In 2014, IWG criteria were updated 
(IWG-2) [Dubois 2014]. The improved diagnostic framework, combined with the ability to 
confirm underlying disease pathology by use of CSF biomarkers or Aβ PET, enabled more 
accurate diagnosis of Alzheimer’s disease in predementia participants. Most recently, in 2018, 
the NIA-AA Research Framework for Alzheimer’s disease has further evolved the thinking on 
diagnosis of Alzheimer’s disease, recommending that Alzheimer’s disease is defined by its 
underlying pathologic processes that can be documented by postmortem examination or in vivo 
by biomarkers [Jack 2018] supporting the use of some imaging and CSF biomarkers (e.g., Aβ 
PET) as valid proxies for neuropathologic changes of Alzheimer’s disease.  


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5.1. 
Previous Experience With Aducanumab 
5.1.1. 
Nonclinical Experience  
Aducanumab (BIIB037) is a human anti-Aβ IgG1 monoclonal antibody derived from a 
de-identified library of B cells collected from healthy elderly subjects with no signs of cognitive 
impairment and cognitively impaired elderly subjects with unusually slow cognitive decline. 
In vitro characterization studies have shown that aducanumab binds with high affinity and 
selectivity to aggregated forms of Aβ, including soluble Aβ oligomers and protofibrils and 
deposited fibrillar Aβ. Additionally, the antibody binds amyloid plaques in human Alzheimer’s 
disease brain sections ex vivo. Data exist showing that both soluble oligomers and Aβ plaques 
are neurotoxic [Koffie 2009; Kuchibhotla 2008; Meyer-Luehmann 2008].   
In vivo characterization of aducanumab was conducted in Tg2576 transgenic mice, which 
overexpress human amyloid precursor protein and accumulate Aβ in the brain in an 
age-dependent manner. Binding of aducanumab to amyloid plaques in vivo (target engagement) 
was demonstrated after single systemic administration of the antibody in Tg2576 mice and was 
evidenced by immunohistochemistry of brain sections from the dosed animals after euthanasia. 
Target engagement was shown to be dose-dependent, i.e., a direct correlation was established 
between the brain drug levels and the amount of antibody decorating the amyloid plaques. 
Efficacy of aducanumab was evaluated following chronic treatment of Tg2576 mice with 
chaducanumab (a murine chimeric version of aducanumab that retains the antigen-binding 
fragment variable regions and was used for chronic dosing studies in mice) and resulted in a 
statistically significant and dose-dependent reduction in brain Aβ load. A minimum efficacious 
dose of 3 mg/kg was determined. Immunohistochemical data suggest that binding of 
chaducanumab to parenchymal Aβ plaques might trigger the recruitment of microglial cells, 
which might result in enhanced microglia-mediated phagocytosis of the plaques. 
The nonclinical safety assessment of aducanumab was conducted in accordance with ICH 
guidelines for a biotechnology-derived pharmaceutical intended for chronic administration. 
Aducanumab (and ch12F6A, murine chimeric analog of aducanumab, in aged Tg2576 mice 
only) was well tolerated in the repeat-dose toxicology studies. No target organs for toxicity were 
identified for aducanumab or ch12F6A. In fertility studies, embryo-fetal development, and 
pre- and postnatal development, there were no adverse toxicity findings up to the highest weekly 
dose tested. A tissue cross-reactivity study and whole blood hemolysis and plasma flocculation 
assays demonstrated expected tissue binding and no evidence of significant hemolysis. 
See the updated IB (Version 13.0) for detailed information on nonclinical studies. 
5.1.2. 
Clinical Experience 
The aducanumab clinical development program comprises 7 clinical studies, including 
1 completed study in healthy volunteers and 6 completed or terminated studies in subjects with 
Alzheimer’s disease. A summary of the clinical experience accumulated so far is provided 
below.  


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Study 221AD101 
This was a Phase 1, randomized, double-blind, placebo-controlled study of aducanumab in 
participants with mild or moderate Alzheimer’s disease. The primary objective was to evaluate 
the safety and tolerability of a range of aducanumab doses (0.3 to 60 mg/kg) when administered 
as single IV infusions. The secondary objectives were to assess the PK and immunogenicity of 
aducanumab after single-dose administration.   
Study 221AD103 
This was a Phase 1b study comprising a randomized, double-blind, placebo-controlled design in 
participants with prodromal or mild Alzheimer’s disease of 1 year in duration followed by an 
LTE in which all participants received aducanumab in an open-label fashion (yet dose-blinded). 
The study was designed to assess the safety, PK, and PD of aducanumab in participants with 
prodromal Alzheimer’s disease or mild Alzheimer’s disease dementia with brain Aβ pathology 
confirmed by 18F-florbetapir (Amyvid®) PET imaging. The main PD assessment (secondary 
endpoint) was the effect of aducanumab on brain Aβ levels as measured by PET and quantified 
by a composite SUVR. 
 
 At Screening, all participants were at the prodromal stage of Alzheimer’s 
disease (
 and a global CDR score of 0.5 or 
1.0) or in stages of mild dementia (
 and global CDR 
score between 0.5 and 1.0). Doses investigated in the placebo-controlled period included 1, 3, 6, 
and 10 mg/kg administered Q4W as a fixed dose, and 10 mg/kg administered after a titration 
period of 44 weeks.  
Placebo-Controlled Period Results 
Results from the 1-year placebo-controlled period showed that treatment with aducanumab 
resulted in a statistically significant, dose-dependent reduction in brain Aβ PET composite 
SUVR as compared with placebo at Week 26, and a further statistically significant, 
dose-dependent reduction at Week 54. In addition, a dose-dependent reduction of clinical decline 
was observed in the fixed-dose aducanumab groups, as well as the titration group, with a 
statistically significant treatment effect observed for both aducanumab 10 mg/kg fixed-dose and 
titration on the 
 and for 10 mg/kg fixed dosing on the 
, as compared with 
placebo. The impact of aducanumab on Aβ PET reduction was already evident at 26 weeks, 
while a difference was only observed on clinical measures at 1 year.  
Reduction in brain Aβ appears to be tightly associated with dose; the titration arm results are in 
line with the fixed-dose results based on the expected average dose in the titration arm (2.9 and 
5.3 mg/kg at 6 and 12 months, respectively), with the point estimate at Week 26 (-0.047) 
between that in the 1 and 3 mg/kg fixed-dose groups, and the point estimate at Week 54 (-0.171) 
between that in the 3 and 6 mg/kg fixed-dose groups. The results demonstrate engagement of 
aducanumab with amyloid plaques and a PD effect of dose- and time-dependent amyloid 
reduction.  
Safety analyses showed that aducanumab had an acceptable safety profile when given Q4W at 
doses up to 10 mg/kg for more than 5 years in Study 221AD103. The incidence and nature of 
fatal SAEs were consistent with underlying Alzheimer’s disease and associated comorbidities. 
No notable differences were observed between aducanumab and placebo in the overall incidence 


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of AEs or SAEs, except for ARIA events. The incidence of ARIA events (both ARIA-E and 
ARIA-H) appeared to be related to aducanumab dose and 
; the ARIA 
events were typically asymptomatic, monitorable, and clinically manageable.  
Participants with ARIA events who met certain criteria (for all clinical studies with aducanumab, 
including Study 221AD103) were required to temporarily suspend dosing with aducanumab. 
Therefore, certain participants with ARIA events experienced a transient interruption in dosing 
during prior clinical studies of aducanumab. In addition, only a small proportion of participants 
experienced more than 1 ARIA-E event during treatment.  
Long-Term Extension Period Results 
Data from the LTE of Study 221AD103 also provide insights relevant for the study population 
targeted in the present study (Study 221AD304). In the LTE period, those participants who 
started on active treatment at the beginning of the placebo-controlled period continued treatment 
(at the same dose as in the placebo-controlled period, except for the 1 mg/kg cohort who were 
switched to 3 mg/kg), while participants from the placebo arms initiated dosing with 
aducanumab. The main findings in Study 221AD103 during the LTE period regarding efficacy 
and safety for the high-dose groups (fixed-dose regimen of 10 mg/kg and titration to 10 mg/kg, 
which are the 2 relevant groups regarding the target dose in Study 221AD304) were the 
following:  
1. 
 
 
 
  
• At Week 222, the adjusted mean changes from baseline in the 10 mg/kg fixed-dose 
and 10 mg/kg titration groups (3.83 and 3.68, respectively) were numerically smaller 
than the adjusted mean changes in the 1, 3, and 6 mg/kg groups that continued dosing 
(range 5.48 to 8.43) and the group that switched from placebo to aducanumab after 
1 year (6.15). 
2. The safety profile of aducanumab in the LTE was similar to that seen in the 
placebo-controlled period: 
• Participants who began treatment with aducanumab during the placebo-controlled 
period had a low incidence of ARIA-E in the LTE (5% for 10 mg/kg fixed dose and 
17% for titration to 10 mg/kg). 
The incidence of ARIA-E in participants who began treatment with aducanumab in the LTE 
(22%) was similar to the incidence in participants who began treatment in the placebo-controlled 
period (24%). 
Studies 221AD301 and 221AD302 
These were large Phase 3 randomized, double-blind, placebo-controlled, parallel-group studies to 
evaluate the efficacy, PK, and safety of aducanumab in participants with early stages of 
Alzheimer’s disease. Refer to updated IB for details for re-analysis of efficacy, PK, and safety. 
Highlights of efficacy re-analysis are provided in Section 5.2. 


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Refer to the updated IB (Version 13.0) for further data from Studies 221AD103, 221AD301, and 
221AD302, as well as from other early phase aducanumab clinical studies. 
5.2. 
Study Rationale 
This open-label, single-arm clinical study is being conducted to assess the long-term safety and 
efficacy of aducanumab in participants with Alzheimer’s disease who were active in 
aducanumab clinical studies (Study 221AD103 [PRIME], Study 221AD205 [EVOLVE], 
Study 221AD301 [ENGAGE], and Study 221AD302 [EMERGE]), from now on named “feeder 
studies,” at the time of their early termination as of 21 March 2019. On that date, Biogen 
announced the discontinuation of the Phase 3 aducanumab clinical studies, based on results from 
a preplanned futility analysis; discontinuation of the other ongoing studies (221AD103 and 
221AD205) was announced and implemented at the same time. The present study (221AD304) is 
being undertaken based on efficacy findings from additional analyses of the 2 Phase 3 studies 
(results summarized below). In these new analyses, Study 221AD302 was statistically significant 
on the prespecified primary endpoint (p=0.01).  
Background: Interim Futility Analysis  
The 221AD301 and 221AD302 studies were 2 large Phase 3 randomized, double-blind, 
placebo-controlled, parallel-group studies to evaluate the efficacy and safety of aducanumab in 
participants with early Alzheimer’s disease (MCI due to Alzheimer’s disease and mild 
Alzheimer’s dementia). The duration was planned for 18 months of placebo-controlled period 
and up to 5 years of LTE. The preplanned futility analysis was performed on data collected as of 
26 December 2018, when approximately 50% of participants had the opportunity to complete the 
Week 78 Visit (57% [954 participants] from Study 221AD301 and 49% [803 participants] from 
Study 221AD302).  
Results based on data from these participants were provided to the IDMC who reviewed the data 
and confirmed that the prespecified futility criteria were met. Biogen reviewed the results and 
concurred with the IDMC and publicly announced the decision to discontinue the Phase 3 
program and the other ongoing clinical studies on 21 March 2019. 
On 21 March 2019, Biogen announced the early termination of the 2 Phase 3 studies 
(Studies 221AD301 and 221AD302) based on results of a prespecified interim futility analysis. 
No participant was dosed after 20 March 2019.  


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Analyses Conducted Postfutility Announcement 
Subsequent to these events, further analyses on the Phase 3 studies were conducted, using data 
from all randomized and dosed participants collected through 01 April 2019 and with data after 
20 March 2019 censored for efficacy analysis. These data comprised 63% of participants from 
both the 221AD301 and 221AD302 studies (66% from 221AD301 and 60% from 221AD302) 
who had the opportunity to complete the placebo-controlled period of the study. In both the 
221AD301 and 221AD302 studies, 87% of participants had the opportunity to reach Week 50 
and 100% with opportunity to complete Week 26. The results from this larger dataset differed 
markedly from the futility results: 
• In Study 221AD302, treatment with the aducanumab high dose regimen significantly 
reduced clinical decline compared with placebo on the primary endpoint, change from 
baseline to Week 78 on the CDR-SB (difference versus placebo -0.40 [-23%]; 
p=0.010). In addition, 2 of the 3 secondary endpoints, change from baseline to 
Week 78 on ADAS-Cog 13 (difference with placebo -1.395 [-27%]; p=0.0098) and 
ADCS-ADL-MCI (difference versus placebo 1.7 [-40%]; p=0.0009) were also 
positive, while the MMSE showed a positive trend but did not reach significance 
(difference with placebo 0.5 [-15%]; p=0.062). In the low-dose group, a 
nonsignificant numeric effect was observed for aducanumab-treated participants 
versus placebo. 
• Study 221AD301 did not meet the primary endpoint in the high-dose arm.  
• 
 
 consistent with findings in the Phase 1b study 
(Study 221AD103, PRIME). 
Given the above findings, the Sponsor undertook further analyses to understand the differences 
in the results of the 2 Phase 3 studies after consultation with external consultants and the FDA. 
Considering the different timing between studies in the enrollment and the implementation of 
2 critical study protocol amendments, a central hypothesis for further analyses is that differences 
in dose/exposure contributed to the disparity in the efficacy results. The Sponsor’s exploration of 
the dose-exposure relationship identified a heterogeneity in exposure to high dose aducanumab 
between the studies. Participants in Study 221AD301 who received high doses/exposure were 
found to have outcomes similar to the overall Study 221AD302 results. This finding was 
supported by multiple analyses directed at studying the multidimensional aspects of 
dose-exposure relationship. Additional factors such as baseline characteristics and ARIA were 
also considered, and they were not found to meaningfully contribute to the differences between 
studies. 
Together, these results led the Sponsor to determine that: (1) the conclusions based on the results 
of the futility analysis in March 2019 (based on a smaller, earlier dataset with less exposure to 
high dose aducanumab) were incorrect; (2) in Study 221AD302, based on the larger dataset, a 
statistically significant reduction in clinical decline was observed across multiple endpoints for 
aducanumab 10 mg/kg as compared with placebo; and (3) the differences between Study 
221AD302 and Study 221AD301 could mostly be accounted for by the greater exposure to 


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10 mg/kg in Study 221AD302. These conclusions were shared with the FDA on 21 October 2019 
at a Type C meeting. 
Given the significance of these results, the Sponsor has reinitiated the evaluation of aducanumab 
in this open-label, single-arm clinical trial, to evaluate the long-term safety and efficacy of the 
drug in participants previously enrolled in the studies that were ongoing at the time of the futility 
announcement (the 2 Phase 3 studies, the LTE study for the Phase 1b study [Study 221AD103], 
and the safety study [Study 221AD205]). This study will also assess the degree to which 
 and clinical measures of the treatment effect of aducanumab are maintained following 
a sustained interruption in dosing. 
Final database lock for both pivotal trials was only achieved in close temporal proximity to the 
finalization of this study protocol. Analyses of the final dataset for the primary and secondary 
efficacy endpoints were conducted after the final database lock and the results of these final 
analyses do not differ overall from the larger dataset results discussed above. The efficacy results 
for the 2 studies are presented in Table 6 and Table 7. 
Refer to the updated IB (Version 13.0) for further efficacy results of the Phase 3 studies 
(221AD301 and 221AD302). 
 
 


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Table 6: 
Final Analysis of Primary and Secondary Endpoints From EMERGE 
(Study 221AD302) 
 
Difference vs. placebo (%) 
p-value 
 
Placebo decline 
(n=548) 
Low dose 
(n=543) 
High dose 
(n=547) 
CDR-SB 
1.74 
-0.26 (-15%) 
0.0901 
-0.39 (-22%) 
0.0120 
MMSE 
-3.3 
-0.1 (3%) 
0.7578 
0.6 (-18%) 
0.0493 
ADAS-Cog 13 
5.162 
-0.701 (-14%) 
0.1962 
-1.400 (-27%) 
0.0097 
ADCS-ADL-MCI 
-4.3 
0.7 (-16%) 
0.1515 
1.7 (-40%) 
0.0006 
Table 7: 
Final Analysis of Primary and Secondary Endpoints From ENGAGE 
(Study 221AD301) 
 
Difference vs. placebo (%) 
p-value 
 
Placebo decline 
(n=545) 
Low dose 
(n=547) 
High dose 
(n=555) 
CDR-SB 
1.56 
-0.18 (-12%) 
0.2250 
0.03 (2%) 
0.8330 
MMSE 
-3.5 
0.2 (-6%) 
0.4795 
-0.1 (3%) 
0.8106 
ADAS-Cog 13 
5.140 
-0.583 (-11%) 
0.2536 
-0.588 (-11%) 
0.2578 
ADCS-ADL-MCI 
-3.8 
0.7 (-18%) 
0.1225 
0.7 (-18%) 
0.1506 


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5.3. 
Rationale for Dose and Schedule Selection 
The dose selected for this study (10 mg/kg IV Q4W after a 24-week titration period) is based on 
the findings that the high-dose arm in Study 221AD302 met its primary efficacy endpoint, which 
was a statistically significant difference on clinical decline as measured by the 
 
at 18 months compared to matching placebo. This finding was supported by dose-dependent 
reductions in 
 and in 
, both of which were 
statistically significant. These efficacy findings were supported by evidence from the subset of 
10 mg/kg-treated participants in the Phase 1b, Study 221AD103, and several post hoc analyses in 
Study 221AD301 evaluating dose-response. Safety and tolerability for this 10 mg/kg dosing 
regimen is consistent across aducanumab clinical studies and is being deemed acceptable after 
review of Study 221AD301 and 221AD302 safety data. 
5.3.1. 
Dosing Scheme 
Doses will be administered approximately 4 weeks apart, over approximately 100 weeks (a total 
of 26 doses) during the Core Treatment Period and 52 weeks during the LTE Treatment Period 
(an additional 13 doses). Participants will receive aducanumab 10 mg/kg under a titration 
regimen of 1 mg/kg for the first 2 doses, 3 mg/kg for the next 2 doses, 6 mg/kg for the next 
2 doses, and 10 mg/kg thereafter.  
5.4. 
Benefit-Risk Assessment 
There are currently no available therapies that modify the clinical course of Alzheimer’s disease. 
Analyses of data collected through the end of the study (Study 221AD301 database lock on 
15 November 2019 and Study 221AD302 database lock on 13 November 2019, with efficacy 
data after 20 March 2019 censored) in the 2 Phase 3 aducanumab clinical studies showed that, in 
Study 221AD302, treatment with aducanumab significantly reduced clinical decline in patients 
with early Alzheimer’s disease as measured by the prespecified primary endpoint (CDR-SB) and 
by the 3 secondary endpoints (MMSE, ADCS-ADL-MCI, and ADAS-Cog 13) in the high-dose 
group. In addition, Study 221AD301 contained supportive data, based on post-hoc analyses of 
subsets of participants who received sufficient exposure to the highest dose (10 mg/kg) of 
aducanumab. Additionally, data from the Study 221AD103 of aducanumab, with up to 4 years of 
FU data on treatment, suggested a continued benefit on the rate of clinical decline with continued 
aducanumab treatment (changes from baseline in the groups that received either 10 mg/kg fixed 
dose or 10 mg/kg titration since the beginning of the study were numerically smaller than those 
in the groups that switched from placebo to aducanumab). 
As of 04 May 2020, 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 (35.4%). The majority of 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, nausea, or rarely seizures, including prolonged seizures.. In the majority 


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of participants with ARIA-E, the first ARIA-E events were documented to have fully resolved 
(800 of 815 participants [98.2%]). In the clinical studies, some participants with an initial 
episode of ARIA-E that resolved subsequently experienced a second, later episode of ARIA-E. 
This was referred to as “recurrent ARIA-E” in the clinical studies. Recurrent ARIA-E events 
were less likely to be symptomatic than first ARIA-E events (recurrent: 13.1% versus first: 
23.6%). As with first ARIA-E events, in nearly all participants with second ARIA-E events, the 
events resolved during the study (231 of the 236 participants [97.9%] with second ARIA-E), and 
in the majority of participants with resolved second events, ARIA-E resolved within 12 weeks. 
Other frequent AEs, among participants from Studies 221AD301 and 221AD302 with a target 
dose of 10 mg/kg, included headache (20.5%), ARIA-H micro-hemorrhage (19.1%), fall 
(15.0%), nasopharyngitis (14.5%), and ARIA-H superficial siderosis (14.6%). Similar to ARIA-
E, the majority of participants with ARIA-H micro-hemorrhage and ARIA-H superficial 
siderosis were asymptomatic. Notably, transient treatment interruption has been routinely 
implemented in all aducanumab studies for participants with ARIA events meeting certain 
criteria. Resumption of dosing after this treatment-free period was not associated with an 
increased incidence of AEs or immunogenicity. 
The benefit-risk profile of aducanumab is considered positive for investigational use in both 
treatment-naïve participants as well as in previously treated participants who have had a 
treatment-free period.  


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
Core Primary Objective 
Core Primary Endpoints 
To evaluate the safety and tolerability of 
aducanumab over 100 weeks of treatment after 
a wash-out period imposed by discontinuation 
of feeder studies in participants who had 
previously received aducanumab (i.e., 
previously treated participants) or who had 
previously received placebo (i.e., treatment-
naïve participants) 
Incidence of AEs, SAEs, ARIA, and 
immunogenicity with over 100 weeks of treatment 
and/or re-exposure to aducanumab. Safety and 
tolerability parameters include the following: 
• Incidence of all AEs, AEs leading to 
treatment discontinuation or study 
withdrawal, and all SAEs 
• Incidence of ARIA-E and ARIA-H  
• Incidence of ADAs in serum 


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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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7. 
STUDY DESIGN 
7.1. 
Study Overview 
Study 221AD304 is an open-label, multicenter, longitudinal, single-arm, global Phase 3b study 
in participants with Alzheimer’s disease who had participated in feeder studies. It is calculated 
that up to approximately 2400 participants (see Section 16.7) will be enrolled across 
approximately 350 sites globally. The primary study objective is to evaluate the long-term safety 
and tolerability of a monthly dose (10 mg/kg) of aducanumab after a gap period imposed by 
discontinuation of feeder studies. 
After a Screening Period of approximately 8 weeks, participants who meet the eligibility criteria 
will receive open-label treatment. During the Core Treatment Period, participants will receive IV 
infusions of aducanumab approximately Q4W for a duration of 100 weeks (a total of 26 doses). 
The aducanumab dosing regimen will be 10 mg/kg following this titration: 1 mg/kg for the first 2 
doses, 3 mg/kg for the next 2 doses, 6 mg/kg for the next 2 doses, and 10 mg/kg thereafter. 
Eligible participants will then enter the LTE treatment period and continue dosing on 10 mg/kg 
aducanumab Q4W for an additional 52 weeks (a total of 152 weeks of continuous treatment). 
The EOT Visit will occur at Week 154. Participants will have a safety FU Visit 18 weeks after 
their last dose of study treatment.  
See Section 5.3.1 for details of dosing scheme.   
Individual dose adjustments may also be implemented in participants who develop ARIA. See 
Section 7.2.1. 
7.2. 
Study Specifics 
7.2.1. 
Dose Suspension or Discontinuation for ARIA Events 
Discontinuation of Dosing for a Given Participant 
The central MRI reading center will report incident events 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. All events of ARIA will be reviewed by the Sponsor and the 
Investigator; decisions on dosing continuation, interruption, or discontinuation will be based on 
clinical symptoms, and the radiographic severity scoring on the MRI report provided by the 
central reader. The Investigator must review the MRI report prior to next dosing. Guidelines on 
the management and disposition of ARIA-E and ARIA-H events (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. 
After each ARIA event, 
 will be collected at the time of the first 
unscheduled visit following the event. Dosing may also be terminated at the discretion of the 
Sponsor for medical reasons. See Section 10.1 for the full list of criteria for discontinuing study 
treatment.  


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7.2.1.1. 
ARIA-E Events 
Table 8: 
Disposition of ARIA-E Events 
Clinical Symptom 
Severity 
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 
Severe 
Serious “other 
medically important 
event” only1 
Serious, except for 
“other medically 
important event”2 
Discontinue dosing 
1 “Other medically important events” requiring dose suspension include SAEs that are not life-threatening (in the 
opinion of the Investigator), do not require inpatient hospitalization or prolongation of existing hospitalization, and 
do not result in significant/permanent disability or congenital anomalies/fetal defects, but may (in the opinion of 
the Investigator) jeopardize the participant or may require intervention to prevent one of the outcomes listed above 
and as described in Section 15.1.2. 
2 SAEs requiring permanent discontinuation of study treatment include those that are life-threatening (in the opinion 
of the Investigator), require inpatient hospitalization or prolongation of existing hospitalization, and/or result in 
persistent or significant disability/incapacity or a congenital anomaly/birth defect as described in Section 15.1.2. 
• Participants who develop mild ARIA-E, per central MRI reading, with no clinical 
symptoms during the episode of ARIA-E, may continue in the study at their current 
dose. Participants should complete all scheduled clinic visits for assessments and, in 
addition, have an unscheduled visit for an MRI and 
 until the 
ARIA-E has resolved per the centrally read MRI.   
• Participants who develop moderate or severe ARIA-E, per central MRI reading, 
with no clinical symptoms during the episode of ARIA-E will temporarily suspend 
treatment, but should complete all scheduled clinic visits for assessments and, in 
addition, have an unscheduled visit for an MRI and 
 until the 
ARIA-E has resolved per the centrally read MRI. If the ARIA-E resolves and the 
participant remains asymptomatic (in the Investigator’s opinion), the participant may 
resume treatment at the same dose.  
• Participants who develop mild, moderate, or severe ARIA-E, per central MRI 
reading, accompanied by clinical symptoms during the episode of ARIA-E will 
temporarily suspend treatment, but should complete all scheduled clinic visits for 
assessments and, in addition, have an unscheduled visit for an MRI and 
 
 until the ARIA-E has resolved per the centrally read MRI. If the ARIA-E 


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resolves and the clinical symptoms resolve (in the Investigator’s opinion), the 
participant may resume treatment at the same dose.  
• Participants who develop mild, moderate, or severe ARIA-E, per central MRI 
reading, accompanied by serious (except “other medically important event”) 
clinical symptoms related to the current episode of ARIA-E will permanently DCT 
but remain in the study. Participants should complete a safety FU Visit 18 weeks after 
the last dose of study treatment, protocol-required tests and assessments at a subset of 
the clinic visits (see Table 5), and, in addition, have an unscheduled visit for an MRI 
and 
 until the ARIA-E has resolved per centrally read MRI. 
See Section 7.2.1.6 for details on resumption of dosing when suspension occurs during the 
titration period and Section 7.2.1.7 for guidelines on resuming dosing after a recurrence of 
ARIA. 
 
 


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7.2.1.2. 
ARIA-H (Micro-hemorrhage) 
In this study, new incident micro-hemorrhages are defined as micro-hemorrhages that start after 
aducanumab infusion per this study (221AD304) and do not include micro-hemorrhages seen on 
the baseline MRI done for this study. 
Table 9: 
Disposition of ARIA-H (Micro-hemorrhage) Events 
Clinical 
Symptom 
Severity 
New Incident Micro-hemorrhages1 (Central Read) 
Mild 
Moderate 
Severe 
≥ 1 and ≤ 4 
≥ 5 and ≤ 9 
≥ 10 
Asymptomatic 
Continue dosing at current 
dose and schedule 
Suspend dosing. Once ARIA-H is 
stable, the participant may resume 
dosing at the same dose.   
Discontinue dosing 
Mild 
Suspend dosing. Once ARIA-H stabilizes and clinical symptoms 
resolve, the participant may resume dosing at the same dose.   
Moderate 
Severe 
Serious “other 
medically 
important 
event” only2 
Serious, except 
for “other 
medically 
important 
event”3 
Discontinue dosing 
1 New incidence of micro-hemorrhages = new micro-hemorrhages that start after aducanumab infusion per this 
study (221AD304), does not include micro-hemorrhages seen on the baseline MRI done for this study. 
2 “Other medically important events” requiring dose suspension include SAEs that are not life-threatening (in the 
opinion of the Investigator), do not require inpatient hospitalization or prolongation of existing hospitalization, and 
do not result in significant/permanent disability or congenital anomalies/fetal defects, but may (in the opinion of 
the Investigator) jeopardize the participant or may require intervention to prevent one of the outcomes listed above 
as described in Section 15.1.2. 
3 SAEs requiring permanent discontinuation of study treatment include those that are life-threatening (in the opinion 
of the Investigator), require inpatient hospitalization or prolongation of existing hospitalization, and/or result in 
persistent or significant disability/incapacity or a congenital anomaly/birth defect as described in Section 15.1.2. 
Asymptomatic ARIA-H (Micro-hemorrhage)  
• Participants who develop a ≥ 1 and ≤ 4 new incident micro-hemorrhage(s) [mild] 
at any time during the study may continue treatment at the current dose. Participants 
should complete all scheduled clinic visits for assessments and, in addition, have an 
unscheduled visit for an MRI and 
 until the ARIA-H 
micro-hemorrhage is confirmed stable per the centrally read MRI. 
Micro-hemorrhages are considered stable if there is no change or a decrease in the 
number, size, severity, or number of locations between 2 consecutive MRIs including 
the initial detection MRI and the MRI performed 4 weeks (± 5 days) later.  


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• Participants who develop ≥ 5 and ≤ 9 new incident micro-hemorrhages (moderate) 
at any time during the study will temporarily suspend treatment, but should complete 
all scheduled clinic visits for assessments and, in addition, have an unscheduled visit 
for an MRI and 
 until the micro-hemorrhage is confirmed as 
stable per the centrally read MRI. Once the micro-hemorrhage is deemed stable, 
participants may resume treatment at the same dose.  
• Participants who develop ≥ 10 new incident micro-hemorrhages (severe) at any 
time during the study will permanently DCT but remain in the study. Participants 
should complete a safety FU Visit 18 weeks after the last dose of study treatment, 
protocol-required tests and assessments at a subset of the clinic visits (see Table 5), 
and, in addition, have an unscheduled visit for an MRI and 
 
until the micro-hemorrhages are deemed stable per centrally read MRI.  
Symptomatic ARIA-H (Micro-hemorrhage) 
• Participants who develop ≤ 9 new incident micro-hemorrhages (mild or moderate) 
and associated mild, moderate, severe, or serious (“other medically important 
event” only [Section 15.1.2]) clinical symptoms will temporarily suspend treatment, 
but should complete all scheduled clinic visits for assessments and, in addition, have 
an unscheduled visit for an MRI and 
 until the ARIA-H 
micro-hemorrhage(s) is confirmed stable per the centrally read MRI. Once ARIA-H 
(micro-hemorrhage) is deemed stable and the clinical symptoms have resolved (in the 
Investigator’s opinion), the participant may resume treatment at the same dose. 
• Participants who experience serious (except “other medically important event” 
[Section 15.1.2]) clinical symptoms associated with micro-hemorrhage(s) 
(independent of the radiographic severity of the event) will permanently DCT but 
remain in the study. Participants should complete a safety FU Visit 18 weeks after the 
last dose of study treatment, protocol-required tests and assessments at a subset of the 
clinic visits (see Table 5), and, in addition, have an unscheduled visit for an MRI and 
 until the micro-hemorrhage(s) is confirmed stable per 
centrally read MRI. 
• Participants who develop ≥ 10 new incident micro-hemorrhages (severe), 
regardless of the presence of clinical symptoms, during the study, will permanently 
DCT but remain in the study. Participants should complete a safety FU Visit 18 
weeks after the last dose of study treatment, protocol-required tests and assessments 
at a subset of the clinic visits (see Table 5), and, in addition, have an unscheduled 
visit for an MRI and 
 until the micro-hemorrhages are 
deemed stable per centrally read MRI. 
See Section 7.2.1.6 for details on resumption of dosing when suspension occurs during the 
titration period and Section 7.2.1.7 for guidelines on resuming dosing after a recurrence of 
ARIA. 


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7.2.1.3. 
ARIA-H (Superficial Siderosis) 
In this study, for participants previously treated with aducanumab, new incident focal areas of 
superficial siderosis are defined as new incident focal areas of superficial siderosis that occur on 
treatment and do not include focal areas of superficial siderosis seen on baseline MRI. 
Table 10: 
Disposition of ARIA-H (Superficial Siderosis) Events 
Clinical 
Symptom 
Severity 
New Incident Areas of Superficial Siderosis1 (Central Read) 
Mild 
Moderate 
Severe 
1 
2 
>2 
Asymptomatic 
Continue dosing at 
current dose and schedule 
Suspend dosing. Once ARIA-H is 
stable the participant may resume 
dosing at the same dose.   
Discontinue dosing 
Mild 
Suspend dosing. Once ARIA-H stabilizes and clinical 
symptoms resolve, the participant may resume dosing at the 
same dose.   
Moderate 
Severe 
Serious “other 
medically 
important 
event” only2 
Serious, except 
for “other 
medically 
important 
event”3 
Discontinue dosing 
1 New incident superficial siderosis = new incident superficial siderosis on treatment. 
2 “Other medically important events” requiring dose suspension include SAEs that are not life-threatening (in the 
opinion of the Investigator), do not require inpatient hospitalization or prolongation of existing hospitalization, and 
do not result in significant/permanent disability or congenital anomalies/fetal defects, but may (in the opinion of 
the Investigator) jeopardize the participant or may require intervention to prevent one of the outcomes listed above 
as described in Section 15.1.2. 
3 SAEs requiring permanent discontinuation of study treatment include those that are life-threatening (in the opinion 
of the Investigator), require inpatient hospitalization or prolongation of existing hospitalization, and/or result in 
persistent or significant disability/incapacity or a congenital anomaly/birth defect as described in Section 15.1.2. 
Asymptomatic ARIA-H (Superficial Siderosis) 
• Participants who develop a single new incident focal area of hemosiderosis (also 
referred to as superficial siderosis) [mild] at any time during the study may 
continue treatment at the current dose, but must have an unscheduled visit for an MRI 
and 
 until the superficial siderosis is confirmed as stable per 
the centrally read MRI. Superficial siderosis is considered stable if there is no change 
or a decrease in the number, size, severity, or number of locations between 2 
consecutive MRIs, including the initial detection MRI and the MRI performed 
4 weeks (± 5 days) later.  


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• Participants who develop 2 new focal areas of hemosiderosis (superficial siderosis) 
[moderate] occurring at any time during the study will temporarily suspend 
treatment, but should complete all scheduled clinic visits for assessments and, in 
addition, have an unscheduled visit for an MRI and 
 until the 
ARIA-H (superficial siderosis) is confirmed as stable per the centrally read MRI. 
Once the superficial siderosis is deemed stable, the participants may resume treatment 
at the same dose.  
• Participants who develop > 2 new focal areas of hemosiderosis (superficial 
siderosis) [severe] at any time during the study must permanently DCT but remain in 
the study. Participants should complete a safety FU Visit 18 weeks after the last dose 
of study treatment, protocol-required tests and assessments at a subset of the clinic 
visits (see Table 5), and, in addition, have an unscheduled visit for an MRI and 
 until the ARIA-H (superficial siderosis) is confirmed as 
stable per the centrally read MRI.  
Symptomatic ARIA-H (Superficial Siderosis) 
• Participants who develop ≤ 2 new focal areas of superficial siderosis (mild or 
moderate) associated with mild, moderate, severe, or serious (“other medically 
important event” only) clinical symptoms will temporarily suspend treatment, but 
should complete all scheduled clinic visits for assessments and, in addition, have an 
unscheduled visit for an MRI and 
 until the ARIA-H 
superficial siderosis is confirmed stable per the centrally read MRI. Superficial 
siderosis is considered stable if there is no change or a decrease in the number, size, 
severity, or number of locations between 2 consecutive MRIs including the initial 
detection MRI and the MRI performed 4 weeks (± 5 days) later. Once the ARIA-H 
(superficial siderosis) is deemed stable and the clinical symptoms have resolved (in 
the Investigator’s opinion), the participants may resume treatment at the same dose. 
• Participants who experience serious (except “other medically important event” 
[Section 15.1.2]) clinical symptoms associated with ARIA-H (superficial 
siderosis) will permanently DCT but remain in the study. Participants should 
complete a safety FU Visit 18 weeks after the last dose of study treatment, 
protocol-required tests and assessments at a subset of the clinic visits (see Table 5), 
and, in addition, have an unscheduled visit for an MRI and 
 
until the superficial siderosis is confirmed stable per centrally read MRI.  
• Participants who develop >2 new focal areas of superficial siderosis (severe), 
regardless of the presence of clinical symptoms, will permanently DCT but remain in 
the study. Participants should complete a safety FU Visit 18 weeks after the last dose 
of study treatment, protocol-required tests and assessments at a subset of the clinic 
visits (see Table 5), and, in addition, have an unscheduled visit for an MRI and 
 until the superficial siderosis is confirmed stable per 
centrally read MRI.  


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See Section 7.2.1.6 for details on resumption of dosing when suspension occurs during the 
titration period and Section 7.2.1.7 for guidelines on resuming dosing after a recurrence of 
ARIA. 
7.2.1.4. 
ARIA-H (Macro-hemorrhage) 
Participants who develop any new incident of macro-hemorrhage (defined as > 1 cm in diameter 
on T2* MRI sequence), regardless of the presence of clinical symptoms, will permanently DCT, 
but should remain in the study. Participants should complete a safety FU Visit 18 weeks after the 
last dose of study treatment, protocol-required tests and assessments at a subset of the clinic 
visits (see Table 5) and, in addition, have an unscheduled visit for MRI and 
 
, or as clinically indicated, until the macro-hemorrhage is confirmed stable per 
centrally read MRI. A macro-hemorrhage is considered stable if there is no change or a decrease 
in the number, size, severity, or number of locations between 2 consecutive MRIs, including the 
initial detection MRI and the MRI performed 4 weeks (± 5 days) later.  
7.2.1.5. 
Coincident ARIA-H and ARIA-E Events  
Participants who develop ARIA-H coincident with ARIA-E at any time during the study will 
follow the most restrictive guidelines. Prior to resuming treatment, where applicable, ARIA-E 
must resolve, ARIA-H must be deemed stable, and the participant must be asymptomatic. For 
example, if a participant experiences radiographically mild ARIA-H (1 to 4 micro-hemorrhages) 
coincident with radiographically moderate ARIA-E, the participant will temporarily suspend 
treatment per the ARIA-E guidelines summarized in Table 8. In addition, unscheduled visits 
should occur as described in Section 7.2.1.1, Section 7.2.1.2, Section 7.2.1.3, and 
Section 7.2.1.4. 
7.2.1.6. 
Resumption of Study Treatment After Suspension due to ARIA 
7.2.1.6.1. MRI Monitoring 
When treatment resumes after a dose suspension due to ARIA, an MRI and 
 will be 
performed 2 weeks (± 5 days) after the second administration of the restarted dose.  This visit 
will also include a physical and neurological examination and collection of vital signs.  
In addition, if treatment was suspended during the dose titration prior to the participant reaching 
the 10 mg/kg dose, an MRI and 
 will be performed 2 weeks (± 5 days) after every second 
dose until completion of the titration period with a final MRI after the second dose at 10 mg/kg, 
not counting unscheduled MRI visits for monitoring of ongoing ARIA, MRIs will otherwise be 
performed as indicated in the Schedule of Events (Section 4.2).  
7.2.1.6.2. Dosing Upon Resumption of Study Treatment 
Participants who suspend treatment due to ARIA may resume treatment at the same dose if they 
meet the criteria as described in Section 7.2.1.1, Section 7.2.1.2, Section 7.2.1.3, Section 7.2.1.4, 
and Section 7.2.1.5. Participants who suspend and then resume dosing after having already 
reached 10 mg/kg are to continue dosing at that dose. However, if dosing is suspended prior to a 
participant reaching 10 mg/kg, the participant (1) must receive at least 2 doses at the restart dose 


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before titrating up to the next dose level and (2) must complete at least the required number of 
doses at that dose level per the titration schedule, as outlined in the right column of Table 11.  
Table 11: 
Resumption of Study Treatment Following Dose Suspension Due to ARIA 
During Titration 
Dose Level at Which 
ARIA Occurred 
Number of Doses 
Prior to ARIA 
Number of Doses at Current Dose Level Needed 
Before Going to the Next Higher Dose 
1 mg/kg 
1 
2 
1 mg/kg 
2 
2 
3 mg/kg 
1 
2 
3 mg/kg 
2 
2 
6 mg/kg 
1 
2 
6 mg/kg 
2 
2 
7.2.1.7. 
Management After Recurrent ARIA (Dosing and MRI) 
If the participant has more than one occurrence of ARIA (i.e., a second episode of ARIA-E or 
new incident ARIA-H micro-hemorrhages or superficial siderosis), after the ARIA resolves or 
stabilizes, the participant is to resume dosing at the same dose as that described in 
Section 7.2.1.6.2. Once dosing has resumed, the guidelines outlined in Table 11 apply if the 
participant is still in the titration period. If a participant resumes treatment after ARIA, an MRI 
and 
 will be performed 2 weeks (± 5 days) after the second administration of the restarted 
dose, and 2 weeks (± 5 days) after every second dose until the completion of titration (if 
applicable). MRIs will otherwise be performed as indicated in the Schedule of Events 
(Section 4.2). 
7.2.2. 
Infusion Interruption 
If any mild or moderate symptoms occur during a treatment 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 15.2.3. 


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7.3. 
Overall Study Duration and Follow-Up 
The study will consist of Screening, Core Treatment, LTE Treatment, and FU periods. A 
schematic of the study is presented in Figure 1.  
Study duration for each participant will be approximately 178 weeks: an approximately 8-week 
Screening Period, a 100-week Core Treatment Period, a 52-week LTE treatment period, and a 
safety FU Visit 18 weeks after the last dose of study treatment. 
Participants will have approximately 59 scheduled clinic visits during the study. All visits should 
be performed ± 5 days from the nominal visit day.  
• Screening Visits no more than 60 days before the first dose of study treatment on 
Day 1 (Screening Visits may be carried out over 2 separate visits, at the Investigator’s 
discretion). It is recommended that all screening procedures be completed within 
60 days; however, the overall Screening Period may be extended up to 90 days in the 
event of 
 and/or other logistics restrictions due to major causes 
(i.e., institutional restrictions or participant disposition due to COVID-19 or other 
major disasters) and is subject to Sponsor approval. 
• 39 outpatient dosing visits. 
• 8 telephone safety FU contacts approximately 2 weeks after each of the first 8 doses. 
• 7 visits for clinical assessments, including Screening and FU at Week 170 (or 
18 weeks after the last dose of study treatment for participants who DCT early). 
• 10 visits for brain MRI. 
• 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Participants who have a change in Alzheimer’s disease medication (other than study treatment) 
during either the Core or LTE Treatment Period should have an unscheduled visit; a subset of the 
clinical efficacy assessments 
 should 
be performed prior to the change in medication if the participant alerts the Investigator before the 


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change in medication occurs. In the event that 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 are 
performed within 30 days after the change in medication, the assessments do not have to be 
repeated.  
Participants who experience ARIA during the Treatment Period should have unscheduled visits 
per the guidelines in Section 7.2.1. 
7.3.1. 
Screening 
Participant eligibility for the study will be determined no more than 60 days prior to the first 
dose of study treatment on Day 1. It is recommended that all screening procedures be completed 
within 60 days (Screening Visits may be carried out over 2 separate visits, at the Investigator’s 
discretion); however, the overall Screening Period may be extended up to 90 days in the event of 
 and/or other logistics restrictions due to major causes (i.e., institutional 
restrictions or participant disposition due to COVID-19 or other major disasters) and is subject to 
Sponsor approval. Only in the event of inadequate tracer supplies or 
 availability, the 
Screening 
 may be performed after Day 1, upon Sponsor approval. The scan should 
be performed as close to the first infusion date as possible and must occur prior to the second 
infusion. In case the Screening Period is extended beyond 60 days, clinical efficacy assessments 
 will be re-assessed.  
Participants who fail screening will be permitted to be rescreened up to 2 times at the 
Sponsor’s/designee’s discretion. Rescreened participants will be assigned a new number. At 
rescreening, all assessments should be repeated except for 
 
  
7.3.2. 
Treatment 
After a Screening Period of approximately 8 weeks, participants who meet the eligibility criteria 
will receive an open-label treatment. During the Core Treatment Period, participants will receive 
IV infusions of aducanumab approximately Q4W for a  duration of 100 weeks (a total of 26 
doses). The aducanumab dosing regimen will be 10 mg/kg following this titration: 1 mg/kg for 
the first 2 doses, 3 mg/kg for the next 2 doses, 6 mg/kg for the next 2 doses, and 10 mg/kg 
thereafter. Eligible participants will then enter the LTE treatment period, and continue dosing 
with 10 mg/kg aducanumab Q4W for an additional 52 weeks (a total of 152 weeks of continuous 
treatment). 
7.3.3. 
Follow-Up 
All participants enrolled in the study are to return to the study site at Week 170 or 18 weeks after 
the last dose of study treatment for clinical assessments. For participants who do not enter the 
LTE, this FU visit will occur at Week 118. 
Participants who DCT are 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 5) until the end of the study or until withdrawal of consent. 


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Participants who withdraw from the study are encouraged to return for FU assessments 18 weeks 
after the last dose of study treatment.  
7.4. 
Study Stopping Rules 
Biogen may terminate this study at any time, after informing the Investigators. Biogen (or 
designee) will notify Investigators when the study is to be placed on hold, completed, or 
terminated. 
Dosing may be terminated by the Sponsor at the recommendation of the IDMC, based on safety 
and tolerability data, or at the discretion of the Sponsor; therefore, there are no study-specific 
stopping rules defined in this protocol.  
7.5. 
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. 
7.6. 
End of Study 
The end of study is last protocol-specified contact with the last participant. 


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8. 
SELECTION OF PARTICIPANTS 
8.1. 
Core Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Screening or at the timepoint specified in the individual eligibility criterion listed:  
1. Ability of the participant and/or his/her legally authorized representative (e.g., parent, 
spouse, or legal guardian), 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. 
• Participant was participating in an aducanumab clinical study at the time of the 
announcement of early termination (feeder studies). Note #1: Participants who 
formerly participated in feeder studies and had to permanently discontinue the 
investigational product and/or exited a feeder study due to protocol mandatory 
requirements for discontinuation  that are no longer applicable at the time of 
screening will be evaluated by the Sponsor on a case-by-case basis. Note #2: 
Participants who completed screening in Study 221AD205 and were confirmed 
eligible prior to 21 March 2019 but were not randomized due to the discontinuation of 
the trial may have the opportunity to screen on this study upon review/approval from 
the Sponsor. 
 
 
 
3. Has one care partner who, in the Investigator’s opinion, has adequate contact with the 
participant as to be able to provide accurate information about the participant’s cognitive 
and functional abilities. The care partner must be available to provide information to the 
Investigator and site staff about the participant and attend in-person clinic visits that 
require care partner input for clinic assessments. The care partner should be available for 
the duration of the study. 
4. Female participants 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. Refer to Section 15.5.  
5. Apart from a clinical diagnosis of Alzheimer’s disease, the participant must be in good 
health as determined by the Investigator, based on medical history and screening 
assessments. 


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8.2. 
Core 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 
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., substance abuse, vitamin B12 
deficiency, abnormal thyroid function, stroke or other cerebrovascular condition, Lewy 
body dementia, fronto-temporal dementia, head trauma). 
2. Clinically significant unstable psychiatric illness (e.g., uncontrolled major depression, 
uncontrolled schizophrenia, uncontrolled bipolar affective disorder) within 6 months 
prior to Screening.   
3. Stroke or any unexplained loss of consciousness within 1 year prior to Screening. 
4. Brain MRI (performed at Screening, centrally read) evidence of any of the following: 
• Acute or subacute hemorrhage. 
• Prior macro-hemorrhage (defined as > 1 cm in diameter on T2* sequence) or prior 
subarachnoid hemorrhage unless it can be documented that the finding is not due to 
an underlying structural or vascular abnormality (i.e., finding does not suggest 
participant is at risk of recurrent hemorrhage).  
• Greater than 4 (for treatment-naïve participants) or ≥ 10 (for aducanumab previously 
treated participants) micro-hemorrhages (defined as ≤ 1 cm in diameter on T2* 
sequence). 
• Cortical infarct (defined as > 1.5 cm in diameter; irrespective of anatomic location). 
• Any focal area of superficial siderosis (for treatment-naïve participants) or 3 or more 
focal areas of superficial siderosis (for aducanumab previously treated participants).  
5. History of bleeding disorder or predisposing conditions, blood clotting, or clinically 
significant abnormal results on coagulation profile at Screening, as determined by the 
Investigator. 
6. Presence of diabetes mellitus that, in the judgment of the Investigator, cannot be 
controlled or adequately managed.   
7. 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. 
8. Clinically significant 12-lead ECG abnormalities, as determined by the Investigator. 
9. 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 and/or DBP 


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readings > 180 mmHg and/or >100 mmHg, respectively, 3 months prior to treatment 
(Day 1) that, in the opinion of the Investigator, are indicative of chronic uncontrolled 
hypertension. 
10.  History of malignancy or carcinoma. The following exceptions may be made after 
discussion with the Sponsor:  
• Participants whose cancer is in remission according to the cancer specialist prior to 
Screening. 
• Participants with a history of excised or treated basal cell or squamous carcinoma of 
the skin.  
11. A seizure event that occurred after the last visit of the feeder study and before Screening 
for this study. 
12. Evidence 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). 
13. History or evidence of an autoimmune disorder considered clinically significant by the 
Investigator or requiring chronic use of systemic corticosteroids or other 
immunosuppressants. 
14. Recent history (within 1 year of Screening) of alcohol or substance abuse as determined 
by the Investigator, a positive urine drug (due to nonprescription drug) or alcohol test at 
Screening or use of cannabinoids (prescription or recreational). 
15. Clinically significant systemic illness or serious infection (e.g., pneumonia, septicemia) 
within 30 days prior to or during Screening. 
16. History of or known seropositivity for HIV. 
17. Current hepatitis C infection (defined as positive HCV antibody and detectable HCV 
RNA. Participants with positive HCV antibody and undetectable HCV RNA are eligible 
to participate in the study (Reference: United States Centers for Disease Control and 
Prevention). 
18. Current hepatitis B infection (defined as positive for HBsAg and/or 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. 
19. History of severe allergic or anaphylactic reactions, or history of hypersensitivity to any 
of the inactive ingredients in the drug product (refer to the IB for information on the 
clinical formulation). 
20. Any other medical conditions (e.g., renal disease) that are not stable or controlled, or, 
which in the opinion of the Investigator, could affect the participant’s safety or interfere 
with the study assessments. 


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Medications 
21. 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. 
22. Use of allowed medications for chronic conditions at doses that have not been stable for 
at least 4 weeks prior to 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 
up to Day 1. 
23. Chronic use of systemic immunosuppressive drugs (including systemic corticosteroids) 
as indicated in Section 11.5.1.2. Local and/or topical immunosuppressants will be 
allowed. 
24. Use of chemotherapeutic agents and checkpoint inhibitors. 
25. Use of parenteral immunoglobulin, blood products, plasma derivatives, plasma exchange, 
or plasmapheresis. 
26. Use of vaccinations within 10 days prior to Day 1.  
27. Use of medications with platelet anti-aggregant or anticoagulant properties (the use of 
aspirin at a dose ≤ 325 mg daily is allowed). 
28. Use of illicit narcotic medication. 
29. Participation in any study in which the participant is taking an investigational product for 
Alzheimer’s disease (with purported disease-modifying treatment or not) unless the 
participant has fulfilled a wash-out period of at least 5 half-lives for that particular 
investigational product or is able to provide documentation of having received placebo in 
that investigational product study.   
Study Procedures 
30. Contraindications to having a brain MRI (e.g., pacemaker; MRI-incompatible aneurysm 
clips, artificial heart valves, or other metal foreign body; claustrophobia that cannot be 
medically managed). 
 
 
 
 
 
 
 
 
 
 


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Others 
33. Female participants who are pregnant or currently breastfeeding. 
34. Participant currently living in an organized care facility with extensive intervention 
and/or support of daily living activities. 
35. Blood donation (≥ 1 unit) within 1 month prior to Screening. 
Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
participant unsuitable for enrollment.   
8.3. 
LTE Inclusion Criteria 
To be eligible to participate in the LTE period, participants must meet the following eligibility 
criteria at Week 102: 
1. Participant must have completed the Core study period (week 102) and adequately 
tolerated 10 mg/kg of aducanumab during the Core study period in the opinion of the 
Investigator. 
2. The participant will continue to derive clinical benefit from treatment with aducanumab, 
in the opinion of the Investigator. 
3. The participant (or the participant’s legally authorized representative) has the ability to 
understand the purpose and risks of the study and provide signed and dated informed 
consent (or assent) and authorization to use confidential health information in accordance 
with national and local subject privacy regulations. 
4. Female participants of childbearing potential and male participants must practice 
effective contraception during the study and for 24 weeks after their last dose of study 
treatment. 
5. Apart from a clinical diagnosis of AD, the participant must be in good health as 
determined by the Investigator, based on medical history. 
6. Must have the ability to comply with procedures for protocol-related tests. 
7. Has one informant/care partner who, in the Investigator’s opinion, has frequent and 
sufficient contact with the participant as to be able to provide accurate information about 
the participant’s cognitive and functional abilities.  The informant/care partner must 
minimally be available by phone to provide information to the Investigator and study 
staff about the participant and agrees to attend in person clinic visits that require partner 
input for scale completion.  An informant/care partner should be available for the 
duration of the study, and the use of the same informant/care partner for the duration of 
the study is encouraged. 


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8.4. 
LTE Exclusion Criteria 
Participants will be excluded from entering the LTE period if at Week 102 they have: 
1. Any medical or psychiatric contraindication or clinically significant abnormality that, in 
the opinion of the Investigator, will substantially increase the risk associated with the 
participant's enrollment in and completion of the study. 
2. Any other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
participant unsuitable for enrollment. 
 


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9. 
ENROLLMENT AND REGISTRATION 
9.1. 
Screening and Enrollment 
Participants (or their legally authorized representative, where applicable) must provide informed 
consent before any screening tests are performed (see Section 17.3). When a participant signs the 
ICF, that participant is considered to be enrolled in the study. 
 
  
Participating study sites are required to document all screened candidates initially considered for 
inclusion in this study. It is recommended that all screening procedures be completed within 
60 days; however, the overall Screening Period may be extended up to 90 days in the event of 
 and/or other logistics restrictions due to major causes (i.e., institutional 
restrictions or participant disposition due to COVID-19 or other major disasters) and is subject to 
Sponsor approval. Only in the event of inadequate tracer supplies or 
 availability, the 
Screening 
 may be performed after Day 1, upon Sponsor approval. The scan should 
be performed as close to the first infusion date as possible and must occur prior to the second 
infusion. 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. The total study 
duration for each enrolled participant will be approximately 178 weeks (approximately 8-week 
Screening Period, a Core Treatment Period of 100 weeks of aducanumab dosing (with clinical 
assessments at Week 102), an additional LTE Treatment Period of 52 weeks of aducanumab 
dosing, and a safety FU Visit 18 weeks after the last dose of study treatment).  
9.2. 
Registration of Participants 
Participants will be registered at the Screening Visit and enrolled only after all baseline 
assessments have been completed and the Investigator has verified that the participants are 
eligible per criteria in Section 8.1 and Section 8.2. No participant may begin treatment prior to 
assignment of a unique identification number (registration). Any participant identification 
numbers that are assigned will not be reused even if the participant does not receive treatment. 
Rescreened participants will be assigned a new number.   
Participants will receive aducanumab as per the treatment regimen. Participants who withdraw 
from the study may not be replaced. 
Refer to the Study Reference Manual for details on registration. 
9.3. 
Blinding Procedures 
This is an open-label study. 


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10. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF PARTICIPANTS FROM THE STUDY 
10.1. 
Discontinuation of Study Treatment 
A participant must permanently discontinue study treatment for any of the following reasons: 
• The participant develops any of the following: 
− ARIA-E accompanied by serious clinical symptoms except for “other medically 
important event” as defined in Table 8. 
− Symptomatic ARIA-H (micro-hemorrhages) with serious clinical symptoms 
except for “other medically important event” as defined in Table 9. 
− Symptomatic ARIA-H (superficial siderosis) with serious clinical symptoms 
except for “other medically important event” as defined in Table 10. 
− ARIA-H with ≥ 10 new incident micro-hemorrhages and/or > 2 new incident 
focal areas of superficial siderosis. (Note: Only new, treatment-emergent events 
occurring in the study are counted).  
− Any new incident macro-hemorrhage (defined as > 1 cm in diameter on T2* 
sequence). 
See Section 7.2.1 for full details regarding discontinuation due to ARIA-E or 
ARIA-H. 
• The participant becomes pregnant. Study treatment must be discontinued immediately 
and pregnancy must be reported according to the instructions in Section 15.4.1. 
• The participant withdraws consent to continue study treatment. 
• The participant experiences a medical emergency that necessitates permanent 
discontinuation of study treatment. 
• The participant experiences an AE that does not resolve or requires continued 
treatment that meets exclusionary criteria (see Section 11.5.1.2).   
• The participant experiences a severe infusion reaction. 
• At the discretion of the Investigator for medical reasons. 
• At the discretion of the Investigator or Sponsor for noncompliance or other reasons. 
The reason for discontinuation of study treatment must be recorded in the participant’s CRF. 
A participant who discontinues treatment is 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 5) until the end of the study per the 
Schedule of Events or until the participant withdraws consent.   


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10.2. 
Lost to Follow-Up 
Participants will be considered lost to FU 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 FU, 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 FU. 
10.3. 
Withdrawal of Participants From Study 
Participants must be withdrawn from the study for any one of the following reasons: 
• The participant withdraws consent. 
• 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 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 EOT Visit after the reason for withdrawal is identified. For such 
participants, efficacy assessments specified at the EOT 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 in such cases. Participants who are withdrawn from the study are also to return to the 
site for a safety FU Visit 18 weeks after the last dose of study treatment.  


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11. 
STUDY TREATMENT  
11.1. 
Regimen 
Refer to and follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.   
Please see Section 4.2 (Schedule of Events) for the study treatment infusion schedule during the 
Treatment Period of the study. 
Aducanumab is to be administered by IV infusion following dilution into saline. See Section 12 
for details of aducanumab study treatment. 
The Sponsor will provide aducanumab to study sites.   
11.2. 
Modification of Dose and/or Treatment Schedule 
Refer to Section 7.2.1 (dose suspension) and Section 7.2.2 (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. 
11.3. 
Precautions 
Not applicable. 
11.4. 
Compliance 
Compliance with treatment dosing is to be monitored and recorded by site staff. 
11.5. 
Prior and Concomitant Therapy and Procedures 
11.5.1. 
Prior and Concomitant Therapy 
Prior Alzheimer’s disease medication use within the gap period between 21 March 2019 and 
Screening will be captured. This includes any investigational drug for Alzheimer’s disease that 
the participant may have participated after 21 March 2019. 
A concomitant therapy is any drug or substance administered between the signing of the 
informed consent and until the participant’s final clinic visit (including the safety 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. 
11.5.1.1. Allowed Concomitant Therapy 
• 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 up to Day 1.  
• Symptomatic therapies for Alzheimer’s disease, including but not limited to 
donepezil, rivastigmine, galantamine, tacrine, and memantine, are allowed provided 


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that participants are receiving a stable dose for at least 8 weeks prior to Screening up 
to Day 1, and that they stay on a stable dose while in the study. 
• Vaccinations with live or attenuated vaccines are allowed during the study. 
Administration of any vaccination/booster should not be given < 10 days prior to any 
dosing visit and for 10 days after a dosing visit. 
Participants should be instructed to continue the medications that they were receiving at 
enrollment without any changes (see allowed concomitant therapy above) and avoid starting any 
new medications or herbal preparations during the study period, as it 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 Investigator needs 
to ensure pertinent communication with the study Medical Monitor if there are changes in 
medication of any nature that will have an effect on cognitive assessment. Medications used to 
treat AEs would not result in automatic permanent study treatment discontinuation. However, as 
noted in Section 10.1, if a participant requires continued use of a disallowed therapy, the 
participant must permanently discontinue study treatment. The Sponsor may be consulted if 
required. 
11.5.1.2. Disallowed Concomitant Therapy 
• Medications with platelet anti-aggregant or anticoagulant properties, except the use of 
aspirin at a dose of ≤ 325 mg per day. 
• Nonprescription narcotic medication. 
• Cannabinoids (prescription or recreational). 
• Systemic immunosuppressive drugs (including systemic corticosteroids). Local 
and/or topical immunosuppressants will be allowed. Local corticosteroids (including 
inhaled and topical corticosteroids) are allowed; certain systemic corticosteroids may 
be permitted at the Sponsor’s discretion.  
• Chemotherapeutic agents and checkpoint inhibitors.  
• Parenteral immunoglobulin, blood products, plasma derivatives, plasma exchange, 
and plasmapheresis. 
• Any investigational drug. 
Participants who have a change in Alzheimer’s disease medication (other than study treatment) 
during the Treatment Period should have an unscheduled visit; a subset of the clinical efficacy 
assessments 
 should be performed 
prior to the change in medication if the participant alerts Investigator before the change in 
medication occurs. In the event that 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 are performed 
within 30 days after the change in medication, the assessments do not have to be repeated. 
 


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11.5.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, routine colonoscopy, bacterial cultures) 
performed between the time the participant is enrolled in the study and until the participant’s 
final clinic visit (including safety FU Visit), unless the participants is being followed 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. 
11.6. 
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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12. 
STUDY TREATMENT MANAGEMENT 
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment. The DHA supersedes all other references 
(e.g., protocol). 
Study treatment will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice. Study treatment must be dispensed only by a pharmacist or 
appropriately qualified staff. Study treatment is to be dispensed only to participants enrolled in 
this study. Once study treatment is prepared for a participant, it can be administered only to that 
participant. Study treatment vials are for one-time use only; any study treatment remaining in the 
vial must not be used for another participant. 
12.1. 
Aducanumab   
Research Name: 
BIIB037  
Generic Name: 
Aducanumab 
Trade Name(s): 
Not applicable 
Synonyms: 
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 (excipients: L-histidine hydrochloride 
monohydrate, L-histidine, L-arginine hydrochloride, L-methionine, and 
polysorbate-80) 
The concentration for each vial (100 mg/mL) appears on the label. Aducanumab is manufactured 
in accordance with Good Manufacturing Practices. 
The contents of the label will be in accordance with all applicable regulatory requirements. 
Aducanumab should not be used after the expiration date. 
12.1.1. 
Aducanumab 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 Biogen. 


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12.1.2. 
Aducanumab 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. 
12.1.3. 
Aducanumab Handling and Disposal 
The Investigator must return all used and unused vials of aducanumab as instructed by Biogen 
(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 Biogen by providing, in writing, the destruction policy 
or details of the method of destruction. After such destruction, Biogen must be notified in writing 
of the details of the study treatment destroyed (e.g., lot or kit numbers, quantities), the date of 
destruction, and proof of destruction. 
12.1.4. 
Aducanumab 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 and/or lost.  
Unless otherwise notified, all vials both used and unused, must be saved for study treatment 
accountability. By the end of the study reconciliation must be made between the amount of 
aducanumab supplied, dispensed, and subsequently destroyed or returned to Biogen. A written 
explanation must be provided for any discrepancies. 
12.2. 
Additional Protocol-Designated Products 
Refer to the DHA for infusion-related supply specifications. 
 
 
 
  
 
 
  


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14. 
SAFETY ASSESSMENTS 
See Section 4.2 for the timing of assessments.  
If in-clinic visits are not able to occur, a remote visit via telephone or video call may be used to 
collect safety assessments (AEs, SAEs, concomitant medications, and C-SSRS) as deemed 
appropriate by the Sponsor (refer to the Study Reference Manual for details). 
14.1. 
Clinical Safety Assessments 
The following clinical assessments will be performed to evaluate the safety profile of 
aducanumab: 
• AE and SAE monitoring 
• Physical examination, including height and weight 
• Neurological examination 
• Vital signs (body temperature, heart rate, SBP, DBP, and respiratory rate) 
• 12-Lead ECG 
• Brain MRI 
• Concomitant medication, therapy, and procedure monitoring 
• 
 
• C-SSRS 
14.2. 
Laboratory Safety Assessments 
Samples will be analyzed using Good Laboratory Practice-validated assays. The following 
laboratory assessments will be performed to evaluate the safety profile of aducanumab:  
• Hematology: complete blood count with differential and 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. 
• Lipid panel: total cholesterol, high-density lipoproteins, low density lipoproteins, and 
triglycerides. 
• 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, virology (including HIV at the Investigator’s discretion after 
consideration of risk factors), HbA1c, and alcohol/drug screen at Screening. 


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14.3. 
Immunogenicity Assessments 
Presence of serum ADAs will be determined using a validated assay. A standard 3-tiered ADA 
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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15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES 
Throughout the course of the study, every effort must be made to remain alert to possible AEs. If 
an AE occurs, the first concern should be for the safety of the participant. If necessary, 
appropriate medical intervention should be provided. 
At the signing of the ICF, each participant or his/her legally authorized representative must be 
given the names and telephone numbers of study site staff for reporting AEs and medical 
emergencies. 
15.1. 
Definitions 
15.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation participant 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
Determination of whether an abnormal laboratory value meets the definition of an AE will be 
made by the Investigator. Although abnormal laboratory values are typically not considered AEs, 
the following considerations may result in an abnormal laboratory value being considered an AE: 
• A laboratory test result that meets the criteria for an SAE. 
• A laboratory test result that requires the participant to receive specific corrective 
therapy. 
• A laboratory abnormality that the Investigator considers to be clinically significant. 
Pretreatment, nonserious AEs that occur within 48 hours after receipt of a 
 will be 
recorded in the CRF.   
15.1.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death. 
• In the view of the Investigator, places the participant at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Results in a congenital anomaly/birth defect. 


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An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the participant or may require intervention to prevent one of the other outcomes 
listed in the definition above. (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.) 
15.1.3. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the participant is hospitalized. The study site must document all of the 
following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the 
participant’s consent to participate in the study. 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the participant’s consent to 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 15.1.2 is met. 
15.2. 
Safety Classifications 
15.2.1. 
Investigator Assessment of Events 
All events must be assessed to determine the following: 
• If the event meets the criteria for an SAE as defined in Section 15.1.2. 
• The relationship of the event to study treatment as defined in Section 15.2.2. 
• The severity of the event as defined in Section 15.2.3. 
 


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15.2.2. 
Relationship of Events to Study Treatment 
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment and, if applicable, the 
. 
Relationship of Event to Study Treatment 
Not related 
An AE will be considered “not related” to the use of the investigational drug if there is 
not a reasonable possibility that the event has been caused by the product under 
investigation. Factors pointing toward this assessment include but are not limited to: the 
lack of reasonable temporal relationship between administration of the drug and the 
event, the presence of a biologically implausible relationship between the product and 
the AE, or the presence of a more likely alternative explanation for the AE. 
Related 
An AE will be considered “related” to the use of the investigational drug if there is a 
reasonable possibility that the event may have been caused by the product under 
investigation. Factors that point toward this assessment include but are not limited to: a 
positive rechallenge, a reasonable temporal sequence between administration of the 
drug and the event, a known response pattern of the suspected drug, improvement 
following discontinuation or dose reduction, a biologically plausible relationship 
between the drug and the AE, or a lack of an alternative explanation for the AE. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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15.2.3. 
Severity of Events 
The following definitions should be considered when evaluating the severity of AEs and SAEs: 
Severity of Event 
Mild 
Symptom(s) barely noticeable to participant or does not make participant 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s) but may be given because of personality of 
participant. 
Moderate 
Symptom(s) of a sufficient severity to make participant uncomfortable; performance of 
daily activity is influenced; participant is able to continue in the study; treatment for 
symptom(s) may be needed. 
Severe 
Symptom(s) cause severe discomfort; symptoms cause incapacitation or significant 
impact on participant’s daily life; severity may cause cessation of treatment with study 
treatment; treatment for symptom(s) may be given and/or participant hospitalized. 
15.2.4. 
Expectedness of Events 
Expectedness of all AEs will be determined by the Sponsor according to the IB for aducanumab. 
15.3. 
Monitoring and Recording Events 
15.3.1. 
Adverse Events 
Any AE experienced by the participant between the time of first dose of study treatment and the 
participant’s final clinic visit (including the safety FU Visit) is to be recorded on the CRF, 
regardless of the severity of the event or its relationship to study treatment. At each study visit 
the Investigator will assess the participant for AEs and will record any new AEs or updates to 
previously reported AEs on the CRF Pretreatment, nonserious AEs that occur within 48 hours 
after receipt of a ligand will be captured by the sites on the AE form. AEs that are ongoing when 
the participant completes or discontinues the study will be followed by the Investigator until the 
event has resolved, stabilized, or returned to baseline status. AE outcome will be recorded on the 
CRF, as applicable. 
15.3.2. 
Adverse Events of Special Interest  
ARIA-E and ARIA-H are considered AEs of special interest and will be entered on the Adverse 
Event of Special Interest CRF within 72 hours following the receipt of abnormal MRI findings 
from the central MRI reader.   
AE reporting for ARIA-E and ARIA-H will be based on the following centrally read MRI 
sequences: fluid attenuated inversion recovery/T2 for ARIA-E and T2*/gradient echo for 
ARIA-H.   
If the event qualifies as an SAE, an SAE form should be submitted per the guidelines in 
Section 15.3.4. Investigators should include a copy of the centrally read MRI report when 
submitting the SAE form to IQVIA Lifecycle Safety.  


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15.3.3. 
Serious Adverse Events 
Any SAE experienced by the participant between signing of the ICF and the participant’s final 
clinic visit (including the safety FU Visit) will be recorded on an SAE form, regardless of the 
severity of the event or its relationship to study treatment. SAEs must be reported to Biogen (or 
designee) within 24 hours as described in Section 15.3.4. This also applies to SAEs that occur 
after administration of the ligand. FU information regarding an SAE also must be reported with 
24 hours. 
Events occurring after the participant’s final clinic visit (including the safety FU Visit) should be 
reported to Biogen only if the Investigator considers the SAE related to study treatment.   
Any SAE that is ongoing when the participant completes or discontinues the study will be 
followed by the Investigator until the event has resolved, stabilized, or returned to baseline 
status. 
15.3.4. 
Immediate Reporting of Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify IQVIA Lifecycle Safety within 24 hours of the study site staff becoming aware 
of the SAE. It is the Investigator’s responsibility to ensure that the SAE reporting information 
and procedures are used and followed appropriately. 
Reporting Information for SAEs 
Any SAE that occurs between the time that the participant has signed the ICF and the 
participant’s final clinic visit (including the safety FU Visit) must be reported to IQVIA 
Lifecycle Safety within 24 hours of the study site staff becoming aware of the event. 
Thereafter, the event should be reported only if the Investigator considers it related to study 
treatment. 
A report must be submitted to IQVIA Lifecycle Safety regardless of the following: 
• Whether or not the participant has undergone study-related procedures 
• Whether or not the participant has received study treatment 
• The severity of the event 
• The relationship of the event to study treatment 
To report initial or FU information on an SAE, fax or email a completed SAE form. Refer to 
the Study Reference Manual for complete contact information. 


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15.3.4.1. Deaths 
Death is an outcome of an event. The event that resulted in death should be recorded on the 
appropriate CRF. All causes of death must be reported as SAEs within 24 hours of the site 
becoming aware of the event. The Investigator should make every effort to obtain and send death 
certificates and autopsy reports to the Sponsor. The term death should be reported as an SAE 
only if the cause of death is not known and cannot be determined. 
15.3.5. 
Suspected Unexpected Serious Adverse Reactions 
Suspected SUSARs are SAEs that are unexpected and deemed by the Investigator or Biogen to 
be related to the study treatment administered. 
Biogen or designee will submit SUSARs to regulatory agencies and Investigators according to 
local law.   
15.4. 
Procedures for Handling Special Situations 
15.4.1. 
Pregnancy 
Female participants should not become pregnant during the study and for 5 times the 
half-life or 24 weeks (whichever is longer) 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 treatment to up to 24 weeks after last dose by faxing or emailing the appropriate form to 
IQVIA Lifecycle Safety within 24 hours of the study site staff becoming aware of the pregnancy. 
Refer to the Study Reference Manual's official study contact list for complete contact 
information. The Investigator or study site staff must report the outcome of the pregnancy to 
IQVIA Lifecycle Safety.  
Congenital abnormalities and birth defects in the offspring of female participants should be 
reported as an SAE if conception occurred during the study Treatment Period or up to 24 weeks 
after last dose. 
15.4.2. 
Overdose 
An overdose is any dose of study treatment given to a participant or taken by a participant that 
exceeds the dose described in 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 IQVIA Lifecycle Safety within 24 hours of the site becoming aware of 
the overdose. An overdose must be reported to IQVIA Lifecycle Safety 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 
IQVIA Lifecycle Safety. All study treatment-related dosing information must be recorded on the 
dosing CRF. 


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15.4.3. 
Medical Emergency 
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care. The Investigator (or designee) 
should contact the IQVIA 24-hour emergency medical support number. Refer to the Study 
Reference Manual’s Official Contact List for complete contact information. 
15.5. 
Contraception Requirements 
All women of childbearing potential must ensure that acceptable 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. In addition, participants should not donate 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 
− For women ≤ 55 years of age, 52 continuous weeks of natural (spontaneous) 
amenorrhea without an alternative medical cause and a serum FSH level 
≥ 40 mIU/mL. 
− For women > 55 years of age, 52 continuous weeks of natural (spontaneous) 
amenorrhea without an alternative medical cause and a serum FSH level 
≥ 40 mIU/mL, or at least 5 continuous years of natural (spontaneous) amenorrhea 
without an alternative medical cause. 
− 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Posthysterectomy. 
• Female surgical sterilization (e.g., bilateral tubal ligation). 
For the purposes of this study, acceptable contraception is defined as use of 1 of the following: 
• For females of childbearing potential: 
− Progesterone-only oral hormonal contraception, where inhibition of ovulation is 
not the primary mode of action. 
− Placement of an intrauterine device or intrauterine system. 
− Barrier methods of contraception with use of a spermicide: condom or occlusive 
cap (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 underwent surgical sterilization with the appropriate 
postvasectomy documentation of the absence of sperm in the ejaculate. 
− 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 


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the evaluation of the Investigator who should also take into consideration the 
duration of the clinical trial. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not considered 
acceptable methods of contraception. 
Pregnancy reporting is described in Section 15.4.1. 
15.6. 
Safety Responsibilities 
15.6.1. 
The Investigator 
The Investigator’s responsibilities include the following: 
• Monitor and record all AEs, including SAEs, on the 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 and FU on the outcome of the pregnancy in 
female participants. 
• Complete an SAE form for each SAE and fax it to Biogen (or designee) within 
24 hours of the site staff becoming aware of the event. 
• Pursue SAE FU information actively and persistently. FU information must be 
reported to Biogen (or designee) within 24 hours of the site staff becoming aware of 
new information. 
• 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 EC/IRBs, as required by local law. 
15.6.2. 
Biogen 
Biogen’s responsibilities include the following: 
• Before a site can enroll any participants, the Clinical Monitor (IQVIA) is responsible 
for reviewing with study site staff the definitions of AE and SAE, as well as the 
instructions for monitoring, recording, and reporting AEs and SAEs. 
• Biogen (or designee) is to notify all appropriate regulatory authorities, central 
EC/IRBs, and Investigators of SAEs, as required by local law, within required time 
frames. 


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16. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
The objectives of the study and the endpoints to be analyzed are listed in Section 6.  
16.1. 
Demography and Baseline Disease Characteristics 
Demographics and baseline data will be summarized with summary statistics (mean, SD, 
median, and range) or with frequency distributions. 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.4. 
Safety 
16.4.1. 
Analysis Population 
The safety population is defined as all participants who received at least 1 dose of aducanumab. 
16.4.2. 
Methods of Analysis- Primary Endpoint 
All AEs, laboratory data, ECG, neurological and physical examinations, and vital signs will be 
evaluated for safety. 
16.4.2.1. Adverse Events 
Only TEAEs will be presented in the summary tables for treatment-naïve participants and 
treatment-experienced participants. Treatment emergent 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. 
Incidence of TEAEs will be summarized 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. AEs will be coded using MedDRA.   
Incidence, severity, and symptomatology of ARIA will be summarized for treatment-naive and 
pretreated participants. The analysis of ARIA incidence will also be performed for all different 
types of ARIA (e.g., ARIA-E, ARIA-H).  
16.4.2.2. 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. In addition, the shift from baseline to the maximum postbaseline 
value and the shift from baseline to the minimum postbaseline status will be presented for each 
laboratory test. Also, summaries of laboratory values categorized based on common toxicity 
criteria grade will be created. Summary statistics for actual values and change from baseline will 
also be presented for quantitative laboratory data.   


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16.4.2.3. Vital Signs 
The analysis of vital signs will focus on clinically relevant abnormalities. 
16.4.2.4. ECG 
The number and percentage of participants with shifts to categorical values (abnormal not AE, or 
abnormal AE) will be summarized.   
16.4.2.5. Columbia Suicide Severity Rating Scale 
The baseline and postbaseline C-SSRS data will be summarized. C-SSRS data will be 
summarized using descriptive statistics (number of participants, mean, standard deviation, 
median, minimum, and maximum) for continuous variables, and using frequency and percentage 
for discrete variables. 
16.5. 
Immunogenicity Data 
16.5.1. 
Analysis Population 
The analysis population for immunogenicity is defined as all participants in the safety population 
who have at least 1 postdose sample evaluated for immunogenicity.   
16.5.2. 
Methods of Analysis- Primary Endpoint 
ADAs in serum will be summarized using shift tables. 
16.6. 
Interim Analyses 
The Sponsor plans to conduct interim analyses when appropriate milestones of the study are 
achieved. 
16.7. 
Sample Size Considerations 
Given that the study population depends on the feeder studies, no sample size was determined for 
this study.  
At the time that the feeder studies were stopped in March 2019, approximately 2600 participants 
had received treatment in 1 of those feeder studies. Approximately 400 participants were on 
placebo (“aducanumab treatment-naïve participants”) and approximately 2200 participants had 
received aducanumab (“aducanumab previously treated participants”). Biogen estimates that of 
these 2600 participants, 2400 participants could be eligible based on inclusion and exclusion 
criteria to participate in the current study.  


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17. 
ETHICAL REQUIREMENTS 
The Sponsor 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 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. 
17.1. 
Declaration of Helsinki 
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki. 
17.2. 
Ethics Committee/Institutional Review Board 
The Investigator must obtain EC/IRB approval of the protocol, ICF, and other required study 
documents prior to starting the study. Biogen will submit documents on behalf of the 
investigational sites worldwide in compliance with local requirements.  
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the EC. A copy of the approved ICF must be provided to Biogen. After 
approval, the ICF must not be altered without the agreement of the relevant EC and Biogen. 
It is the responsibility of the Investigator(s) to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations. 
Biogen must receive a letter documenting EC/IRB approval, which specifically identifies the 
protocol, protocol number, and ICF, prior to the initiation of the study. Protocol amendments will 
be participant to the same requirements as the original protocol. 
A progress report must be submitted to the EC/IRB at required intervals and not less than 
annually. 
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the EC/IRB and Biogen. 
17.3. 
Participant Information and Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the 
participant or participant’s legally authorized representative (e.g., legal guardian), as applicable, 
in accordance with local practice and regulations. Should the participant be under the care of a 
care partner, the care partner will sign a separate ICF. 
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the participant must be explained to the participant (or 
the participant’s legally authorized representative). The participant must be given sufficient time 
to consider whether to participate in the study. 


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Participants will be informed that their race and/or ethnicity will be collected and will be used 
during analysis of study results (only in countries where permitted by local law/regulation). 
These data will be used in the analysis of the safety and/or pharmacokinetic profile of the study 
treatment. 
A copy of the signed and dated ICF must be given to the participant, care partner, and/or 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 (wet signature) and copies of the signed and dated ICFs. 
Confirmation of informed consent must also be documented in the participant’s medical record. 
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. 
17.4. 
Participant Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by national and local law/privacy regulations (e.g., 
Protected Health Information authorization in North America). 
The participant will not be identified by name in the CRF or in any study reports and these 
reports will be used for research purposes only. Biogen, its partner(s) and designee(s), EC/IRBs, 
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. 
During the study, participants’ race and/or ethnicity will be collected (unless the collection is not 
permitted by applicable law or not approved by the governing ethics committee). These data may 
be used in the analysis of the safety, efficacy, and/or pharmacokinetic profile of the study 
treatment. It is unknown if the potency or effects of the study treatment are influenced by race or 
ethnicity. 
Study reports will be used for research purposes only. The participant will not be identified by 
name in CRFs, study-related forms, study reports, or any related publications. The Sponsor, its 
partners and designees, EC, 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. 
17.5. 
Compensation for Injury 
Biogen maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws. 
17.6. 
Conflict of Interest 
The Investigators should address any potential conflicts of interest (e.g., financial interest in 
Biogen or its partner[s]) with the participant before the participant makes a decision to 
participate in the study. 


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17.7. 
Registration of Study and Disclosure of Study Results 
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 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. 


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18. 
ADMINISTRATIVE PROCEDURES 
18.1. 
Study Site Initiation 
The Investigator must not screen any participants prior to completion of a study initiation visit, 
conducted by Biogen. This initiation visit will include a detailed review of the protocol and study 
procedures. 
18.2. 
Quality Assurance 
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits. The Investigator will be expected to 
cooperate with any audit and to provide assistance and documentation (including source data) as 
requested. 
18.3. 
Monitoring of the Study 
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the participants’ medical histories. Source data must be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data must be traceable, 
not obscure the original entry, and be explained if necessary (e.g., with an audit trail). The 
Investigator should maintain a record of the location(s) of essential documents. 
The Clinical Monitor(s) 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 and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.  
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, study treatment accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
18.4. 
Study Funding 
Biogen is the Sponsor of the study and is funding the study. All financial details are provided in 
the separate contract(s) between the institution, Investigator, and Biogen.  
18.5. 
Publications 
Details are included in the clinical trial agreement for this study. 


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19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
19.1. 
External Contract Organizations 
19.1.1. 
Contract Research Organization  
A CRO will be responsible for administrative aspects of the study including, but not limited to, 
study initiation, monitoring, and management of SAE reports. Before participants are screened at 
each study site, the CRO will review study responsibilities with the Investigators and other study 
site staff, as appropriate. 
19.1.2. 
Interactive Response Technology  
IRT will be used in this study. Before participants are screened, the IRT vendor will provide each 
study site with appropriate training, access rights, and a user manual. 
19.1.3. 
Electronic Data Capture 
Participant information will be captured and managed by study sites on electronic CRFs by a 
web-based EDC tool developed by IQVIA and 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  
19.1.4. 
Central Laboratories for Laboratory Assessments 
Biogen 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, 
 
 and ADA 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.   
19.1.5. 
Central Facility for Other Assessments 
A central imaging laboratory has been selected by Biogen 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. 
A central imaging laboratory will also be utilized to facilitate collection and analysis of 
 
. 


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19.1.6. 
Central Review of Raters 
Biogen has selected a rater management group to establish rater qualifications, provide 
study-specific 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. 
19.1.7. 
Neurocognitive Assessments 
Biogen 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 per project-specific plans. 
19.2. 
Study Committees 
19.2.1. 
Advisory Committee 
An advisory committee will be formed to provide scientific and medical direction for the study 
and to oversee the administrative progress of the study. 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. Biogen 
will designate one of the participating external experts to be the chairperson of the advisory 
committee. 
19.2.2. 
Independent Data Monitoring Committee  
The IDMC will be formed to review ongoing safety and tolerability data. 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 an AE(s) may recommend protocol modification(s), 
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. As of 5 Oct 2021, the 
meeting frequency of the IDMC was updated to ad hoc only.   
19.3. 
Changes to Final Protocol 
All protocol amendments must be submitted to the EC/IRB 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 EC/IRB before implementation of 
such modifications to the conduct of the study. If required by local law, such modifications must 
also be approved by the appropriate regulatory agency prior to implementation. 
However, Biogen may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a participant. In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification. 


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In the event of a protocol modification, the ICF may require similar modifications (see 
Section 17.2 and Section 17.3). 
19.4. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local, national, or regional laws or 
regulations. Prior to proceeding with destruction of records, the Investigator must notify Biogen 
in writing and receive written authorization from Biogen to destroy study records. In addition, 
the Investigator must notify Biogen of any changes in the archival arrangements including but 
not limited to archival at an offsite facility or transfer of ownership if the Investigator leaves the 
site. 
19.5. 
Study Report Signatory 
Biogen will designate one or more of the participating Investigators as a signatory for the study 
report. This determination will be made by several factors including but not limited to the 
Investigator's experience and reputation in the studied indication, the Investigator's contribution 
to the study in terms of design, management, and/or participant enrollment, or by other factors 
determined to be relevant by Biogen. 
 


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96 
20. 
REFERENCES 
Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to 
Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 
2011;7(3):270-9. 
Alzheimer's Disease International. World Alzheimer Report 2015: The Global Impact of 
Dementia. London: Alzheimer's Disease International (ADI); 2015. 
Alzheimer's Disease International. World Alzheimer Report 2016 Improving healthcare for 
people living with dementia coverage, Quality and costs now and in the future. London, United 
Kingdom: Alzheimer's Disease International (ADI); 2016. 
Amieva H, Le Goff M, Millet X, et al. Prodromal Alzheimer's disease: successive emergence of 
the clinical symptoms. Ann Neurol. 2008;64(5):492-8. 
Delacourte A, Sergeant N, Champain D, et al. Nonoverlapping but synergetic tau and APP 
pathologies in sporadic Alzheimer's disease. Neurology. 2002;59(3):398-407. 
Dubois B, Feldman HH, Jacova C, et al. Revising the definition of Alzheimer's disease: a new 
lexicon. Lancet Neurol. 2010;9(11):1118-27. 
Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer's 
disease: the IWG-2 criteria. Lancet Neurol. 2014;13(6):614-29. 
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on 
the road to therapeutics. Science. 2002;297(5580):353-6. Epub 2002 Jul 20. 
Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological 
definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-562. 
 
 
 
 
Koffie RM, Meyer-Luehmann M, Hashimoto T, et al. Oligomeric amyloid beta associates with 
postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl 
Acad Sci U S A. 2009;106(10):4012-7. 
Kuchibhotla KV, Goldman ST, Lattarulo CR, et al. Abeta plaques lead to aberrant regulation of 
calcium homeostasis in vivo resulting in structural and functional disruption of neuronal 
networks. Neuron. 2008;59(2):214-25. 


Protocol 221AD304 
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Phase 3b Study of Aducanumab in Alzheimer’s Disease   
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97 
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's 
disease: recommendations from the National Institute on Aging-Alzheimer's Association 
workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 
2011;7(3):263-9. 
Meyer-Luehmann M, Spires-Jones TL, Prada C, et al. Rapid appearance and local toxicity of 
amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature. 2008;451(7179):720-4. 
Nelson PT, Abner EL, Schmitt FA, et al. Brains with medial temporal lobe neurofibrillary 
tangles but no neuritic amyloid plaques are a diagnostic dilemma but may have pathogenetic 
aspects distinct from Alzheimer disease. J Neuropathol Exp Neurol. 2009;68(7):774-84. Epub 
2009 Jun 19. 
Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer's 
disease: recommendations from the National Institute on Aging-Alzheimer's Association 
workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 
2011;7(3):280-92. 
 


Protocol 221AD304 
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98 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “Phase 3b Open-Label, Multicenter, Safety Study of BIIB037 
(aducanumab) in Subjects With Alzheimer’s Disease Who Had Previously Participated in the 
Aducanumab Studies 221AD103, 221AD301, 221AD302 and 221AD205”, and agree to conduct 
the study according to the protocol and the applicable ICH guidelines and GCP regulations, and 
to inform all who assist me in the conduct of this study of their responsibilities and obligations. 
 
 
 
____________________________________________________ 
Investigator’s Signature 
 
 
 
Date 
 
 
____________________________________________________ 
Investigator’s Name (Print) 
 
 
 
____________________________________________________ 
Study Site (Print) 
 
 
 


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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 221AD304 
Phase 3b Open-Label, Multicenter, Safety Study of BIIB037 (aducanumab) in Subjects With 
Alzheimer’s Disease Who Had Previously Participated in the Aducanumab Studies 221AD103, 
221AD301, 221AD302, and 221AD205 
Version 4 
Date: 19 January 2022 
EUDRA CT Number: 2019-004368-22 
Version 4.0 of the protocol has been prepared for this amendment, which supersedes Version 3.0. 


Amendment Summary for Protocol 221AD304, Version 4.0 
 
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2 
PRIMARY REASON FOR AMENDMENT 
The primary reason for this amendment to Protocol 221AD304 is to add a 52-week long-term 
extension (LTE) period (13 additional doses) to the ongoing study. 
In combination with the phase 3 studies, the EMBARK study represents one of the largest and 
most comprehensive longitudinal clinical and 
 in early symptomatic AD. As 
such, Biogen remains committed, alongside the scientific community, to continue learning from 
this dataset. Rationale for continuation of the EMBARK study stems from the following: 
• Further characterization of the long-term safety of aducanumab 
• Further elucidation of the long-term efficacy of 10 mg/kg aducanumab in subjects as 
a continuation of the phase 3 studies 
• 
 
  
• Provision of additional data generation for aducanumab, as requested from all major 
global regulatory agencies 
• Continuation of treatment for patients who are deriving meaningful clinical benefit 
from aducanumab at no financial cost for an additional 12 months 
 
New text is shown in bold type; deleted text is shown with a strikethrough. 
Section 7.1, Study Overview 
Now reads: 
……… 
After a Screening Period of approximately 8 weeks, participants who meet the eligibility criteria 
will receive open-label treatment. During the Core Treatment Period, participants will receive IV 
infusions of aducanumab approximately Q4W for a total treatment duration of 100 weeks (a total 
of 26 doses). The aducanumab dosing regimen will be 10 mg/kg following this titration: 1 mg/kg 
for the first 2 doses, 3 mg/kg for the next 2 doses, 6 mg/kg for the next 2 doses, and 10 mg/kg 
thereafter. Eligible participants will then enter the LTE treatment period, and continue 
dosing on 10 mg/kg aducanumab Q4W for an additional 52 weeks (a total of 152 weeks of 
continuous treatment). The EOT Visit will occur at Week 154. Participants will have a safety 
FU Visit 18 weeks after their last dose of study treatment. The EOT Visit will occur at Week 
102. 


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3 
……. 
Rationale: These changes were made to include the 1-year LTE period for the Study 221AD304. 
This change also affects Section 4.2., Schedule of Events; Section 4.3.1., Site Staff; 
Section 5.3.1., Dosing Scheme; Section 7.3., Overall Study Duration and Follow-Up; 
Section 9.1., Screening and Enrollment; 
 
. 
 
 


Amendment Summary for Protocol 221AD304, Version 4.0 
 
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4 
SUMMARY OF MAJOR CHANGES TO THE PROTOCOL 
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough. 
Section 3., Synopsis 
The synopsis was revised to reflect changes made throughout the protocol. 
Section 4.2., Schedule of Events, Table 3 
Change: A new schedule of events table was added. 
Now reads:Table 1: LTE Treatment Schedule from Week 104 Through End of Treatment 
and Follow-Up 
Study 
Week 
LTE Treatment Period 
UV for 
a 
Chang
e in 
Alzhei
mer’s 
Diseas
e 
Medic
ation 
FU 
170 
(or 18 
wks 
after 
last 
dose 
for 
partici
pants 
who 
DCT 
early) 
104 
108 
112 
116 
120 
124 
128 
132 
136 
140 
144 
148 
152 
154/
EOT 
Study 
Day 
729
± 5 
757
± 5 
785
± 5 
813
± 5 
841
± 5 
869
± 5 
897
± 5 
925
± 5 
953
± 5 
981
± 5 
100
9± 5 
103
7± 5 
106
5± 5 
1078 
± 5 
1190 ± 
5 
Body 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urine 
Pregnan
cy Test1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Aducanu
mab 
Infusion 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Hematol
ogy, 
Blood 
Chemist
ry, and 
Urinalysi
s 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Alzheim
er’s 
Disease 
Status2 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Physical 
Examina
tion 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 


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5 
Study 
Week 
LTE Treatment Period 
UV for 
a 
Chang
e in 
Alzhei
mer’s 
Diseas
e 
Medic
ation 
FU 
170 
(or 18 
wks 
after 
last 
dose 
for 
partici
pants 
who 
DCT 
early) 
104 
108 
112 
116 
120 
124 
128 
132 
136 
140 
144 
148 
152 
154/
EOT 
Study 
Day 
729
± 5 
757
± 5 
785
± 5 
813
± 5 
841
± 5 
869
± 5 
897
± 5 
925
± 5 
953
± 5 
981
± 5 
100
9± 5 
103
7± 5 
106
5± 5 
1078 
± 5 
1190 ± 
5 
Neurolog
ical 
Examina
tion 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Vital 
Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
12-Lead 
Paper 
ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ADA4 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Aducanu
mab 
Serum 
Concent
ration4 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 


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6 
Study 
Week 
LTE Treatment Period 
UV for 
a 
Chang
e in 
Alzhei
mer’s 
Diseas
e 
Medic
ation 
FU 
170 
(or 18 
wks 
after 
last 
dose 
for 
partici
pants 
who 
DCT 
early) 
104 
108 
112 
116 
120 
124 
128 
132 
136 
140 
144 
148 
152 
154/
EOT 
Study 
Day 
729
± 5 
757
± 5 
785
± 5 
813
± 5 
841
± 5 
869
± 5 
897
± 5 
925
± 5 
953
± 5 
981
± 5 
100
9± 5 
103
7± 5 
106
5± 5 
1078 
± 5 
1190 ± 
5 
C-SSRS 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
AE 
Reportin
g 
Monitor and record continuously throughout the study 
Concomi
tant 
Therapy
9 and 
Procedu
res 
Monitor and record continuously throughout the study 
SAE 
Reportin
g 
Monitor and record continuously throughout the study 
1 Required for women of childbearing potential only (see Section 15.5). Must be performed prior to scans.  
2 As judged by the Investigator 
3 Vital signs will include body temperature, heart rate, SBP, DBP, and respiratory rate. Vital signs will be measured with the participant 
supine and after the participant has been resting for at least 10 minutes.  
4 Will be performed prior to infusion (where applicable).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.  
 
 
9 Participants who have a change in Alzheimer’s disease medication (other than study treatment) during the Treatment Period should 
have an unscheduled visit. a subset of the clinical efficacy assessments 
 should 
be performed prior to the change in medication if the participant alerts the Investigator before the change in medication occurs. In the 
event that 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 are performed within 30 
days after the change in medication, the assessments do not have to be repeated. 


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7 
 
Rationale: The new schedule of events table was included to reflect the addition of the LTE 
period and assessments during the LTE period.  
 
Section 4.2., Schedule of Events, Table 4 
Change: Table 4 was updated. 
Now reads:Table 2: Brain MRI, ARIA Management, and Follow-Up Telephone Call Schedule 
During the Core and LTE Treatment Periods  
Study 
Week 
Screen
ing (≤ 
60 
days 
before  
Day 
1)1 
Core Treatment Period 
Core 
Treatm
ent 
Period 
FU2 
LTE 
Treatme
nt 
Period 
FU3 
1 
2 
6 
1
0 
1
4 
18 
22 
26 
30 
42 
54 
66 
78 
102
/ 
EO
T4 
UV/M
RI for 
ARIA
5 
118 (or 
18 wks 
after 
last 
dose for 
particip
ants 
who 
DCT 
early 
from 
core 
treatme
nt 
period) 
170 (or 
18 wks 
after 
last dose 
for 
particip
ants 
who 
DCT 
early 
from 
LTE 
treatme
nt 
period) 
Study Day 
 
1 
15±
 5 
4
3 
± 
5 
7
1 
± 
5 
9
9 
± 
5 
12
7 
± 
5 
15
5 
± 
5 
18
3 
± 
5 
21
1 
± 
5 
29
5 
± 
5 
37
9 
± 
5 
46
3 
± 
5 
54
7 
± 
5 
714 
± 5  
827± 5 
1190 ± 5 
Follow-Up 
Telephone 
Call6 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Brain MRI 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Aducanum
ab Serum 
Concentrat
ion7 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
Physical 
Examinati
on 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Neurologi
cal 
Examinati
on 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 


Amendment Summary for Protocol 221AD304, Version 4.0 
 
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8 
Study 
Week 
Screen
ing (≤ 
60 
days 
before  
Day 
1)1 
Core Treatment Period 
Core 
Treatm
ent 
Period 
FU2 
LTE 
Treatme
nt 
Period 
FU3 
1 
2 
6 
1
0 
1
4 
18 
22 
26 
30 
42 
54 
66 
78 
102
/ 
EO
T4 
UV/M
RI for 
ARIA
5 
118 (or 
18 wks 
after 
last 
dose for 
particip
ants 
who 
DCT 
early 
from 
core 
treatme
nt 
period) 
170 (or 
18 wks 
after 
last dose 
for 
particip
ants 
who 
DCT 
early 
from 
LTE 
treatme
nt 
period) 
Study Day 
 
1 
15±
 5 
4
3 
± 
5 
7
1 
± 
5 
9
9 
± 
5 
12
7 
± 
5 
15
5 
± 
5 
18
3 
± 
5 
21
1 
± 
5 
29
5 
± 
5 
37
9 
± 
5 
46
3 
± 
5 
54
7 
± 
5 
714 
± 5  
827± 5 
1190 ± 5 
Vital 
Signs8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
1 It is recommended that all screening procedures be completed within 60 days; however, the overall Screening Period may be extended up to 90 
days in the event of 
 and/or other logistics restrictions due to major causes (i.e., institutional restrictions or participant 
disposition due to COVID-19 or other major disasters) and is subject to Sponsor approval. In order to ease participant burden, the Screening 
Visit may be carried out over 2 separate visits, at the Investigator’s discretion. 
2 Participants who complete the Core Treatment Period of the study and do not enter the LTE Treatment Period are to return to the site for a 
safety FU Visit at Week 118. Participants who discontinue or withdraw from the study early are to have a safety FU Visit 18 weeks after the 
last dose of study treatment. 
3 Participants who complete the LTE Treatment Period of the study are to return to the site for a safety FU Visit at Week 170. 
Participants who DCT or withdraw from the LTE early are to have a safety FU Visit 18 weeks after the last dose of study treatment 
4 Participants who DCT discontinue prematurely are 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 2, Table 3 and Table 4) 
until the end of the study per the Schedule of Events (it is possible that a clinic visit will occur before the safety FU Visit). If the safety FU 
Visit will occur within 2 weeks of a scheduled clinic visit, then the safety FU Visit can be combined with the scheduled visit and all 
assessments required for both visits performed at this single visit. Participants who withdraw from study prematurely are to return to the site for 
an EOT Visit; for such participants, efficacy assessments specified at the EOT 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 in such cases. 
 
 
 
 
 
 
 
 
 
 
  
8 Vital signs will include body temperature, heart rate, SBP, DBP, and respiratory rate. Vital signs will be measured with the participant supine 
and after the participant has been resting for at least 10 minutes.  
 
 
Rationale: The table was updated to include the MRI and other assessments at the follow-up 
visit after LTE treatment period (Week 170).  


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Section 4.2., Schedule of Events, Table 5 
Change: Table 5 was updated. 
Now reads:Table 5: Participants Who Discontinue Study Treatment During the Core 
Treatment and LTE Periods but Remain in the Study 
 
Post-Treatment Visit Schedule1 (Core Treatment and LTE Periods) 
Study Week 
12 
24 
26 
48 
50 
72 
78 
92 
102 2 
EOT 
112 
128 
140 
152 
154/ 
EO
T2 
UV for 
ARIA3 
Study Day 
85 
± 5 
169 
± 5 
183 
± 5 
337 
± 5 
351 
± 5 
505 
± 5 
547 
± 5 
645 
± 5 
714 
± 5 
785 
± 5 
897 
± 5 
981 
± 5 
106
5 
± 5 
107
8 
± 5 
Body Weight 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Hematology, 
Blood Chemistry, 
and Urinalysis 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Urine Pregnancy 
Test4 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Physical 
Examination 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
 
X 
 
Neurological 
Examination 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
Vital Signs5 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
12-Lead Paper 
ECG 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Aducanumab 
Serum 
Concentration 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X6 
Brain MRI 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 


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Post-Treatment Visit Schedule1 (Core Treatment and LTE Periods) 
Study Week 
12 
24 
26 
48 
50 
72 
78 
92 
102 2 
EOT 
112 
128 
140 
152 
154/ 
EO
T2 
UV for 
ARIA3 
Study Day 
85 
± 5 
169 
± 5 
183 
± 5 
337 
± 5 
351 
± 5 
505 
± 5 
547 
± 5 
645 
± 5 
714 
± 5 
785 
± 5 
897 
± 5 
981 
± 5 
106
5 
± 5 
107
8 
± 5 
C-SSRS 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
AE Reporting 
Monitor and record continuously throughout the study 
Concomitant 
Therapy and 
Procedures 
Monitor and record continuously throughout the study 
SAE Reporting 
Monitor and record continuously throughout the study 
1 Participants who discontinue study treatment prematurely are to remain in the study, attend a safety FU Visit 18 weeks after the last dose of 
study treatment as listed in Table 2, Table 3 and Table 3 Table 4 and immediately continue protocol-required tests and assessments at a subset 
of the clinic visits Table 4 (Table 5) until the end of the study per the Schedule of Events (it is possible that a clinic visit will occur before the 
safety FU Visit). If the safety FU Visit will occur within 2 weeks of a scheduled clinic visit, then the safety FU Visit can be combined with the 
scheduled visit and all assessments required for both visits performed at this single visit. 
2 Participants who withdraw from study prematurely are to return to the site for an EOT Visit; for such participants, efficacy assessments 
specified at the EOT 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 in such cases. 
3 For the frequency of required brain MRI and 
 assessments, 
 for participants who develop ARIA-E 
and/or ARIA-H, see Section 7.2.1.1, Section 7.2.1.2, Section 7.2.1.3, Section 7.2.1.4, and Section 7.2.1.5. This includes 
 
 at the first unscheduled visit for ARIA monitoring per episode only. For the frequency of brain MRI and 
 assessments 
following resolution of ARIA and resumption of dosing, see Section 7.2.1.6. For management of recurrent ARIA, see Section 7.2.1.7. 
4 Required only if last dose of study treatment was less than 24 weeks before the clinic visit. 
5 Vital signs will include body temperature, heart rate, SBP, DBP, and respiratory rate. Vital signs will be measured with the participant supine 
and after the participant has been resting for at least 10 minutes.  
6 One sample will be collected within ± 2 days of the MRI visit. Exact collection date and time will be captured for all 
 on a 
specified CRF. 
7 Sample may be collected within ± 2 days of the MRI visit. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Rationale: The table was updated to include the assessments during LTE period for participants 
who discontinue study treatment.  
 


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Section 6., Study Objectives and Endpoints 
Change: The study objectives and endpoints were updated, and 
 objectives and 
endpoints for the LTE period were added. 
Now reads:
Core Primary Objective 
Core Primary Endpoints 
To evaluate the long-term safety and tolerability of 
aducanumab over 100 weeks of treatment after a wash-
out period imposed by discontinuation of feeder studies 
in participants who had previously received 
aducanumab (i.e., previously treated participants) or 
who had previously received placebo (i.e., treatment-
naïve participants) 
Incidence of AEs, SAEs, ARIA, and immunogenicity with 
long-term over 100 weeks of treatment and/or re-exposure 
to aducanumab. Safety and tolerability parameters include 
the following: 
• 
Incidence of all AEs, AEs leading to treatment 
discontinuation or study withdrawal, and all 
SAEs 
• 
Incidence of ARIA-E and ARIA-H  
• 
Incidence of ADAs in serum 


Amendment Summary for Protocol 221AD304, Version 4.0 
 
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Amendment Summary for Protocol 221AD304, Version 4.0 
 
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Rationale: The study objectives and endpoints for the Core Treatment Period were updated to 
reflect changes in the duration of that study period and the 52-week LTE period was added. 
Separate LTE objectives and endpoints were added to the study. 
Section 8.3., LTE Inclusion Criteria 
Change: Inclusion criteria for the LTE Period were added. 
Now reads:8.3 
LTE Inclusion Criteria 
To be eligible to participate in the LTE period, participants must meet the following 
eligibility criteria at Week 102: 
1. Participant must have completed the Core study period (week 102) and adequately 
tolerated 10 mg/kg of aducanumab during the core study period in the opinion of 
the Investigator. 


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2. The participant will continue to derive clinical benefit from treatment with 
aducanumab, in the opinion of the Investigator. 
3. The participant (or the participant’s legally authorized representative) has the 
ability to understand the purpose and risks of the study and provide signed and 
dated informed consent (or assent) and authorization to use confidential health 
information in accordance with national and local subject privacy regulations. 
4. Female participants of childbearing potential and male participants must practice 
effective contraception during the study and for 24 weeks after their last dose of 
study treatment. 
5. Apart from a clinical diagnosis of AD, the participant must be in good health as 
determined by the Investigator, based on medical history. 
6. Must have the ability to comply with procedures for protocol-related tests. 
7. Has one informant/care partner who, in the Investigator’s opinion, has frequent and 
sufficient contact with the participant as to be able to provide accurate information 
about the participant’s cognitive and functional abilities.  The informant/care 
partner must minimally be available by phone to provide information to the 
Investigator and study staff about the participant and agrees to attend in person 
clinic visits that require partner input for scale completion.  An informant/care 
partner should be available for the duration of the study, and the use of the same 
informant/care partner for the duration of the study is encouraged. 
Rationale: The inclusion criteria for the 52-week LTE treatment period were added to the 
revised protocol. 
Section 8.4., LTE Exclusion Criteria 
Change: Exclusion criteria for the LTE period were added. 
Now reads:8.4 
LTE Exclusion Criteria 
Participants will be excluded from entering the LTE period if at Week 102 they have: 
1. Any medical or psychiatric contraindication or clinically significant abnormality 
that, in the opinion of the Investigator, will substantially increase the risk associated 
with the participant's enrollment in and completion of the study. 
2. Any other unspecified reasons that, in the opinion of the Investigator or Biogen, 
make the participant unsuitable for enrollment. 
Rationale: The exclusion criteria for the 52-week LTE treatment period was added to the revised 
protocol. 
 


Amendment Summary for Protocol 221AD304, Version 4.0 
 
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15 
SUMMARY OF MINOR CHANGES TO THE PROTOCOL 
The following minor changes were made to the protocol, as appropriate: 
• The version number and date were updated throughout the protocol. 
• Typographical errors and formatting were corrected. 
• Table and Figure numbers were updated. 
• The study schematic (Section 4.1.) was updated to include the 1-year LTE and other 
assessments. 
• The footnotes in Table 1., Core Treatment Period Schedule From Screening Through 
Week 48 of Treatment, were updated to exclude C-SSRS from the assessments 
needed to be completed prior to infusion, since that assessment was not relevant. 
• Table 2., Core Treatment Period Schedule From Week 50 to Week 102, was updated 
to include LTE eligibility and LTE informed consent. The table footnotes were 
updated accordingly. 
• The initial treatment period (Week 1 to Week 100) was renamed “Core Treatment 
Period” and the extension period was renamed “Long Term Extension (LTE)” 
throughout the protocol. 
• In Section 5.4. Benefit-Risk Assessment, symptoms related to ARIA-E episodes were 
updated (rarely seizures, including prolonged seizures). 
• In Section 7.2. Dose Suspension or Discontinuation for ARIA Events, the text was 
updated to include the review of MRI report by the Investigator prior to next dosing. 
• In Section 7.2.1.6.1. MRI Monitoring, the text was updated to include physical and 
neurological examination and collection of vital signs. 
• In Section 19.2.2. Independent Data Monitoring Committee, the occurrence of the 
IDMC meeting was updated to “ad-hoc only” as of 05 October 2021. 
 


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16 
LIST OF ABBREVIATIONS 
ADA 
antidrug antibody 
 
 
 
 
 
 
 
 
  
AE 
adverse event 
ARIA 
amyloid-related imaging abnormalities 
ARIA-E 
amyloid-related imaging abnormality-edema  
ARIA-H 
amyloid-related imaging abnormality-hemorrhage or superficial 
siderosis 
 
 
CDR 
Clinical Dementia Rating 
CDR-SB 
Clinical Dementia Rating Sum of Boxes  
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
 
 
C-SSRS 
Columbia Suicide Severity Rating Scale  
DBP 
diastolic blood pressure 
DCT 
discontinue treatment 
ECG 
electrocardiogram 
EOT 
End of Treatment 
 
 
 
 
 
 
 
FU 
follow-up 
 
 
ICH 
International Council for Harmonisation 
IDMC 
independent data monitoring committee 
IV 
intravenous(ly) 
LTE 
long term extension 
MCI 
mild cognitive impairment 
 
 
 
 
 
 
MRI 
magnetic resonance imaging 
 
 
 
 


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Q4W 
every 4 weeks 
 
 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
UV 
Unscheduled Visit 
 


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Biogen MA Inc. 
1 
 
 
 
 
 
 
Biogen MA Inc. 
225 Binney Street 
Cambridge, MA  02142 
United States 
 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead, Berkshire 
SL6 4AY 
United Kingdom 
 
 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Protocol 221AD304 
Phase 3b Open-Label, Multicenter, Safety Study of BIIB037 (aducanumab) in Subjects With 
Alzheimer’s Disease Who Had Previously Participated in the Aducanumab Studies 221AD103, 
221AD301, 221AD302, and 221AD205 
Version 3.0 
Date: 08 March 2021 
EUDRA CT Number: 2019-004368-22 
Version 3.0 of the protocol has been prepared for this amendment, which supersedes Version 2.0. 
 


Amendment Summary for Protocol 221AD304, Version 3.0 
 
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2 
PRIMARY REASON FOR AMENDMENT 
The primary reason for this amendment to Protocol 221AD304 is to revise text describing the 
rescreening criteria. 
New text is shown in bold type; deleted text is shown with a strikethrough. 
 
7.3.1, Screening 
 
Now reads: 
[…] 
Participants who fail screening will be permitted to be rescreened up to 2 times at the 
Sponsor’s/designee’s discretion in cases when a participant fails screening due to logistics 
restrictions due to major causes (i.e., institutional restrictions or participant disposition due to 
COVID-19 or other major disasters). Rescreened participants will be assigned a new number. At 
rescreening, all assessments should be repeated except for 
 
 
Rationale:  
The revision was made to remove text that had been included in error. 
 


Amendment Summary for Protocol 221AD304, Version 3.0 
 
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3 
SUMMARY OF MINOR CHANGES TO THE PROTOCOL 
The following minor changes were made to the protocol, as appropriate: 
• The version number and date were updated throughout the protocol. 
• Typographical errors and formatting were corrected. 
 


Amendment Summary for Protocol 221AD304, Version 3.0 
 
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Biogen MA Inc. 
4 
LIST OF ABBREVIATIONS 
 
 
 
 
 
 
 


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 221AD304 
Phase 3b Open-Label, Multicenter, Safety Study of BIIB037 (aducanumab) in Subjects With 
Alzheimer’s Disease Who Had Previously Participated in the Aducanumab Studies 221AD103, 
221AD301, 221AD302, and 221AD205 
Version 2.0 
Date: 26 August 2020 
EUDRA CT Number: 2019-004368-22 
Version 2.0 of the protocol has been prepared for this amendment, which supersedes Version 1.0. 
 


Amendment Summary for Protocol 221AD304, Version 2.0 
 
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Biogen MA Inc. 
2 
PRIMARY REASON FOR AMENDMENT 
The primary reason for this amendment to Protocol 221AD304 is to update the protocol with 
safety data from the Phase 3 Studies 221AD301 and 221AD302 and with additional supporting 
information on the efficacy of aducanumab at 10 mg/kg dosing from the Phase 1b study, 
Study 221AD103. The new pieces of information reinforce the benefit-risk assessment of the 
aducanumab 10 mg/kg dose, the one chosen in this study. 
New text is shown in bold type; deleted text is shown with a strikethrough. 
Section 5.4, Benefit-Risk Assessment 
Now reads: 
There are currently no available therapies that modify the clinical course of Alzheimer’s disease. 
Analyses of data collected through the end of the study (Study 221AD301 database lock on 
15 Novebmer November 2019 and Study 221AD302 database lock on 13 November 2019, with 
efficacy data after 20 March 2019 censored) in the 2 Phase 3 aducanumab clinical studies 
showed that, in Study 221AD302, treatment with aducanumab significantly reduced clinical 
decline in patients with early Alzheimer’s disease as measured by the prespecified primary 
endpoint (CDR-SB) and by the 3 secondary endpoints (MMSE, ADCS-ADL-MCI, and 
ADAS-Cog 13MMSE, and ADCS-ADL-MCI) in the high-dose group. In addition, Study 
221AD301 contained supportive data, based on post-hoc analyses of subsets of participants who 
received sufficient exposure to the highest dose (10 mg/kg) of aducanumab. Additionally, data 
from the Study 221AD103 of aducanumab, with up to 4 years of FU data on treatment, 
suggested a continued benefit on the rate of clinical decline with continued aducanumab 
treatment (changes from baseline in the groups that received either 10 mg/kg fixed dose or 
10 mg/kg titration since the beginning of the study were numerically smaller than those in 
the groups that switched from placebo to aducanumab). 
As of 01 April 2019 04 May 2020, an estimated a total of 3075 3078 participants have been 
exposed to aducanumab. These include 2755 Aducanumab-treated subjects from Studies 301 and 
302, of whom 1345 were assigned to a target dose of 10 mg/kg. 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 
adverse event AE, among subjects participants from Studies 221AD301 and 221AD302 with a 
target dose of 10 mg/kg, was ARIA-E (32.935.4%). The majority of participants who 
experienced with ARIA-E did not experience were asymptomatic, and participants with 
symptomatic ARIA-E had symptoms during an ARIA-E episode that were predominantly 
mild or moderate in clinical severity. Symptoms reported during ARIA-E episodes included 
headache, confusion confusional state, dizziness, visual disturbances, fatigue, and nausea, and 
vomiting. Such symptoms typically. In the majority of participants with ARIA-E, the first 


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3 
ARIA-E events were documented to have fully resolved and were generally not associated 
with long-term clinical sequelae.(800 of 815 participants [98.2%]). In the clinical studies, 
some participants with an initial episode of ARIA-E that resolved subsequently 
experienced a second, later episode of ARIA-E. This was referred to as “recurrent 
ARIA-E” in the clinical studies. Recurrent ARIA-E events were less likely to be 
symptomatic than first ARIA-E events (recurrent: 13.1% versus first: 23.6%). As with first 
ARIA-E events, in nearly all participants with second ARIA-E events, the events resolved 
during the study (231 of the 236 participants [97.9%] with second ARIA-E), and in the 
majority of participants with resolved second events, ARIA-E resolved within 12 weeks. 
Other frequent adverse events AEs, among subjects participants from Studies 221AD301 and 
221AD302 with a target dose of 10 mg/kg, included headache (18.720.5%), ARIA-H 
microhemorrhage micro-hemorrhage (17.019.1%), fall (15.0%), nasopharyngitis (14.5%), 
and ARIA-H superficial siderosis of the central nervous system (13.814.6%). Similar to 
ARIA-E, the majority of participants with ARIA-H microhemorrhage micro-hemorrhage and 
ARIA-H superficial siderosis were asymptomatic. Notably, transient treatment interruption 
has been routinely implemented in all aducanumab studies for participants with ARIA 
events meeting certain criteria. Resumption of dosing after this treatment-free period was 
not associated with an increased incidence of AEs or immunogenicity. 
The benefit-risk profile of aducanumab is considered positive for investigational use in both 
treatment-naïve participants as well as in previously treated participants who have had a 
treatment-free period.  
Rationale: Safety information from Phase 3 studies was updated to reflect the final high-level 
safety findings. These updated data are consistent with previous data from April 2019 and 
continue to support a positive benefit-risk profile of aducanumab. In addition, adding the 
observation from the LTE of the Phase 1b study helps in informing the efficacy of aducanumab 
in participants with long-term exposure to study treatment in an independent study. Providing 
this supporting information from previous studies is the main reason for this amendment. 


Amendment Summary for Protocol 221AD304, Version 2.0 
 
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4 
SUMMARY OF MAJOR CHANGES TO THE PROTOCOL 
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough. 
Section 3, Synopsis 
The synopsis was revised to reflect changes made throughout the protocol. 


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5 
Section 4.2, Schedule of Events, Table 1 
Change: Visit windows were updated to 5 days for all visits in Table 1.  
Now reads:  
Study 
Week 
Screening 
(≤ 60 
days 
before 
Day 1)1 
Treatment Period 
UV for a 
cChange in AD 
Alzheimer’s 
Disease 
mMedication 
Wk 
1, 
Day 
1 
4 
8 
12 
16 
20 
24 
26 
28 
32 
36 
40 
44 
48 
Study 
Day 
 
1 
29±3 5 
57±3 5 
85±3 5 
113±3 5 
141±3 5 
169±3 5 
183±3 5 
197±3 5 
225±3 5 
253±3 5 
281±3 5 
309±3 5 
337±3 5 
Rationale: Additional time for visits was allowed to accommodate institutional restrictions.  
This change also affects Section 4.2, Schedule of Events, Tables 2, 3, and 4.  
Section 4.2, Schedule of Events, Table 1 
Change: Timepoints for some assessments were removed.  
Now reads:  
Study Week 
Screening 
(≤ 60 days 
before 
Day 1)1 
Treatment Period 
UV for a 
cChange in AD 
Alzheimer’s 
Disease 
mMedication 
Wk 
1, 
Day 
1 
4 
8 
12 
16 
20 
24 
26 
28 
32 
36 
40 
44 
48 
Study Day 
 
1 
29±
3 5 
57±
3 5 
85±3 
5 
113±3
 5 
141±3 
5 
169±3
 5 
183±
3 5 
197±
3 5 
225±3 
5 
253±3
 5 
281±3
 5 
309±3 
5 
337±3
 5 
Hematology, Blood 
cChemistry, and 
uUrinalysis 
X6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AD Alzheimer’s 
Disease sStatus7  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical eExamination 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 


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6 
Study Week 
Screening 
(≤ 60 days 
before 
Day 1)1 
Treatment Period 
UV for a 
cChange in AD 
Alzheimer’s 
Disease 
mMedication 
Wk 
1, 
Day 
1 
4 
8 
12 
16 
20 
24 
26 
28 
32 
36 
40 
44 
48 
Study Day 
 
1 
29±
3 5 
57±
3 5 
85±3 
5 
113±3
 5 
141±3 
5 
169±3
 5 
183±
3 5 
197±
3 5 
225±3 
5 
253±3
 5 
281±3
 5 
309±3 
5 
337±3
 5 
Neurological 
eExamination 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Vital sSigns8 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
… 
C-SSRS 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Rationale: Hematology, blood chemistry, and urinalysis assessments were not needed at Day 1; Alzheimer’s disease status did not 
need to be re-established on Day 1; physical examination, neurological examination, and vital signs were not needed for the UV visit 
for change in Alzheimer’s disease medication; and C-SSRS was updated to be performed yearly.  
The change to the C-SSRS assessment timing also affects Section 4.2, Schedule of Events, Tables 2 and 4. 
Section 4.2, Schedule of Events, Table 1 
Change: 
.  
Now reads:  
Study Week 
Screening 
(≤ 60 days 
before 
Day 1)1 
Treatment Period 
UV for a 
cChange in AD 
Alzheimer’s 
Disease 
mMedication 
Wk 1, 
Day 1 
4 
8 
12 
16 
20 
24 
26 
28 
32 
36 
40 
44 
48 
Study Day 
 
1 
29±
3 5 
57±
3 5 
85±3 
5 
113±3
 5 
141±3 
5 
169±
3 5 
183
±3 5 
197±3 
5 
225±3
 5 
253±3
 5 
281±
3 5 
309±3 
5 
337±3
 5 


Amendment Summary for Protocol 221AD304, Version 2.0 
 
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7 
Rationale: 
 
 
 
 
 
 
 
 
 
 
 
 
Section 4.2, Schedule of Events, Table 1 
Change: Footnote 2 was updated. 
Now reads:  
2 All assessments, including the C-SSRS, must be completed before study treatment 
administration, except the postdose sample to measure aducanumab concentration prior to 
infusion. 
Rationale: Removed postdose sample for aducanumab concentration, as there is no plan to 
measure 
 in postdose samples. Language was adjusted to maintain consistency.  
Section 4.2, Schedule of Events, Table 1 
Change: Footnote 5 was updated. 
Now reads:  
5 Required for women of childbearing potential only (see Section 15.5). Must be performed 
prior to scans.  
Rationale: Clarified that serum pregnancy test must be performed before scans to ensure no 
pregnant participant undergoes the scans used for screening in the study.  


Amendment Summary for Protocol 221AD304, Version 2.0 
 
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8 
Section 4.2, Schedule of Events, Table 1 
Change: Footnotes 9, 10, and 11 were combined. 
Now reads:  
9 Sample collection for anti-aducanumab antibody willWill be performed prior to study treatment 
infusion (where applicable).  
10 Serum sampling for aducanumab concentration will be performed prior to infusion.  
 
  
Rationale: These footnotes were merged because the samplings for ADAs, serum aducanumab, 
and 
 each were to be performed prior to infusion. 
This change also affects Section 4.2, Schedule of Events (footnote numbers in Table 1, footnotes 
in Table 2, and footnote numbers in Table 2).  
Section 4.2, Schedule of Events, Table 1 
Change: Footnote 10 (previously Footnote 12 in Version 1.0) was updated. 
Now reads:  
 
 
 
 
 
 
 
 
 
Rationale: A
 
 
  
 
  


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Section 4.2, Schedule of Events, Table 1 
Change: Footnote 11 (previously Footnote 13 in Version 1.0) was updated. 
Now reads:  
 
 
 
 
 
 
 
 
 
 
 
 
Rationale: 
 
 
 
 
  


Amendment Summary for Protocol 221AD304, Version 2.0 
 
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10 
Section 4.2, Schedule of Events, Table 1 
Change: Footnote 12 (previously Footnote 14 in Version 1.0) was updated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale: 
 
 
 
 
 
  
Section 4.2, Schedule of Events, Table 2 
Change: New footnote 8 was added. 
Now reads:  
 
 
Rationale: 
  
 


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Section 4.2, Schedule of Events, Table 2 
Change: Footnote 10 was deleted. 
Now reads:  
 
 
 
 
 
Rationale: To avoid redundancy with footnotes 6 and 7.  
 


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12 
Section 4.2, Schedule of Events, Table 2 
Change: A timepoint for collecting body weight was added, and missing text that AE, concomitant therapy and procedures, and SAE 
reporting will be monitored continuously throughout the study was added.  
Now reads:  
Study Week 
Treatment Period 
FU 
50 
52 
56 
60 
64 
68 
72 
76 
78 
80 
84  
88 
92 
96 
100 
102/ 
EOT  
UV for a 
cChange in 
AD 
Alzheimer’s 
Disease 
mMedication 
118 
(or 18 wks 
after final 
last dose for 
participants 
who DCT 
early) 
Study Day 
351 
± 35 
365 
± 35 
393 
± 35 
421 
± 35 
449 
± 35 
477 
± 35 
505 
± 35 
533 
± 35 
547 
± 35 
561 
± 5 
589 
± 5 
617 
± 5 
645 
± 5 
673  
± 5 
701 
± 5 
714 
± 5 
 
827± 5 
Body Weight 
  
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
  
  
…… 
AE Reporting 
Monitor and record continuously throughout the study 
Concomitant Therapy9 
and Procedures 
Monitor and record continuously throughout the study 
SAE Reporting 
Monitor and record continuously throughout the study 
9 Participants who have a change in Alzheimer’s disease medication (other than study treatment) during the Treatment Period should have an unscheduled visit. A 
subset of the clinical efficacy assessments 
 should be performed prior to the change in medication if the 
participant alerts the Investigator before the change in medication occurs. In the event that 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 are 
performed within 30 days after the change in medication, the assessments do not have to be repeated. 
Rationale: Because body weight is part of the safety assessments, this assessment was added at EOT (Week 102). The text for AE, 
concomitant therapy and procedures, and SAE reporting was inadvertently not included in the previous version and is now added. 
Also added a footnote to provide guidance on changes in concomitant medication, specifically related to Alzheimer’s disease.  
This change also affects Section 7.3, Overall Study Duration and Follow-Up.


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Section 4.2, Schedule of Events, Table 3 
Change: Footnote 6 was modified to provide clarity on collection window for UV. 
Now reads:  
6 One sample will be collected within ±2 5 days of the MRI visit. Exact collection date and time 
will be captured for all 
 on a specified case report form CRF. Collection 
of aducanumab serum for 
 will also be performed at Weeks 1, 24, and 48 (see 
Table 1) and Week Weeks 72 and 102 (see Table 2). For UV due to ARIA, sample will be 
collected within ± 2 days of the MRI visit.  
Rationale: A missing timepoint for 
 was added. Text was added to clarify that the 
 time window in case of ARIA event will be within ± 2 days of the MRI visit to 
capture the change due to ARIA closer to the event.  
Clarified blood as serum for 
.  
This change also affects Section 4.2, Schedule of Events (footnotes of Table 4). 


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14 
Section 4.2, Schedule of Events, Table 3 
Change: 
 
Now reads:  
Study Week 
Screening 
(≤ 60 days 
before  
Day 1)1 
Treatment Period 
FU2 
1 
2 
6 
10 
14 
18 
22 
26 
30 
42 
54 
66 
78 
102/ 
EOT3 
UV/MRI 
for ARIA4 
118 (or 18 wks 
after final last 
dose for 
participants 
who DCT 
early) 
Study Day 
 
1 
15
±3 
5 
43 
±3 5 
71 
±3 5 
99 
±3 5 
127 
±3 5 
155 
±3 5 
183 
±3 5 
211 
±3 5 
295 
±3 5 
379 
±3 5 
463 
±3 5 
547 
±3 5 
714 
± 5  
827± 5 
Physical 
Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Neurological 
Examination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signs7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
7 Vital signs will include body temperature, heart rate, SBP, DBP, and respiratory rate. Vital signs will be measured with the participant supine and after the 
participant has been resting for at least 10 minutes.  
Rationale: 
Physical examination, neurological examination, and vital sign 
collection were added for UVs due to ARIA to monitor participants. A footnote was added to provide details about vital sign 
collection, for consistency with other occurrences. 


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Section 4.2, Schedule of Events, Table 3 
Change: Footnote 8 was modified (previously Footnote 7 in Version 1.0). 
Now reads:  
8 Sample may be collected within ± 2 days of the MRI visit at the same time as sample 
collection for aducanumab concentration. 
Rationale: Clarified that 
 collection time window in case of ARIA event will 
be ± 2 days of the MRI visit to capture the change due to ARIA closer to the event.  
This change also affects Section 4.2, Schedule of Events (footnotes of Table 4). 


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Section 4.2, Schedule of Events, Table 4 
Change: Urine pregnancy testing and 
 and corresponding footnotes were added.  
Now reads:  
 
Post-Treatment Visit Schedule1  
Study Week 
12 
24 
26 
48 
50 
72 
78 
92 
102 (EOT)2 
UV for ARIA3 
Study Day 
85 ± 35 
169 ± 35 
183 ± 35 
337 ± 35 
351 ± 35 
505 ± 35 
547 ± 35 
645 ± 5 
714 ± 5 
Urine Pregnancy Test4 
 
X 
 
X 
 
X 
X 
X 
 
 
…….. 
4 Required only if last dose of study treatment was less than 24 weeks before the clinic visit. 
Rationale: Urine pregnancy screening and a corresponding footnote were added to ensure that female participants are followed up 
until 24 weeks after the last dose of study treatment to abide by the protocol. 
 was added because it was inadvertently 
missed in the previous version.  


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Section 4.2, Schedule of Events, Table 4 
Change: Collection timepoints for some assessments were removed. 
Now reads: 
  
Post-Treatment Visit Schedule1  
Study Week 
12 
24 
26 
48 
50 
72 
78 
92 
102 (EOT)2 
UV for ARIA3 
Study Day 
85 ± 35 
169 ± 35 
183 ± 35 
337 ± 35 
351 ± 35 
505 ± 35 
547 ± 35 
645 ± 5 
714 ± 5 
Hematology, Blood 
Chemistry, and Urinalysis 
X 
X 
X 
 X 
X 
  
…… 
Physical Examination 
X 
X 
  
X 
  
X 
X 
X 
X 
  
Neurological Examination 
X 
X 
  
X 
  
X 
X 
X 
X 
  
… 
12-Lead Paper ECG  
 
 
 
X 
 
 
X 
 
X 
 
… 
Rationale: Timepoints for assessments were removed to maintain consistency with the Schedule of Events for participants receiving 
treatment. 
 


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18 
Section 4.2, Schedule of Events, Table 4 
Change: Footnote 4 regarding infusion was deleted. 
Now reads:  
4 Samples will be collected prior to infusion (where applicable).  
Rationale: Because this applies to participants who discontinue study treatment, this footnote 
was removed.  
Section 4.3.1, Site Staff 
Change: Language around treating HCPs was simplified. 
Now reads: 
A minimum of 2 separate HCPs are required for this study: 
1. A treating HCP (the PI or Sub-investigator Investigator may serve as a treating HCP) 
who is responsible for the following:  
Rationale: The terms “PI” and “Sub-investigator” were changed to “Investigator.”  
This was a global change made in the protocol to keep consistency in usage of the term 
“Investigator.”  
Section 4.3.1, Site Staff 
Change: 
 
Now reads: 
 
 
 
 
 
Rationale: 
 
  


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Section 4.3.1, Site Staff 
Change: Assessments to be administered and the role of the rating HCP were updated. 
Now reads:  
An independent rating HCP (designated by the Investigator of the site) who is responsible for 
administering the 
 
 
 and CAMC-SSRS.  
The independent rating HCPs must not be involved with any other aspect of subject care and 
management and must remain blinded to AEs, concomitant therapy, laboratory data, imaging 
data, or any other data that have the potential of introducing bias. 
Rationale: All 
 and C-SSRS were included to be administered by 
independent HCP raters to maintain consistency in assessments. Text that was not consistent 
with independent HCP rater responsibility was deleted.  
Section 4.3.1, Site Staff 
Change: Language regarding personnel involved in test administration was added.  
Now reads:  
A pharmacist (or authorized designee) will be responsible for the storage, distribution, 
preparation, and accountability of study treatment. The pharmacist will also be responsible for 
maintaining the pharmacy record.  
For further details about test administration and roles and responsibilities of HCPs and 
study personnel, please consult the Study Reference Manual.  
Rationale: This change was made to provide reference to roles and responsibilities of personnel 
administering tests.  
Section 5.1.2, Clinical Experience 
Change: Results from Studies 221AD103, 221AD301, and 221AD302 were added. 
Now reads:  
Aducanumab has been evaluated in one The aducanumab clinical development program 
comprises 7 clinical studies, including 1 completed single ascending dose study (221AD101) 
and one in healthy volunteers and 6 completed multiple ascending dose study (221AD103).or 
terminated studies in subjects with Alzheimer’s disease. A summary of the clinical 
experience accumulated so far is provided below. 


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Study 221AD101 
Study 221AD101 This was a Phase 1, randomized, double-blind, placebo-controlled, study of 
aducanumab in participants with mild or moderate AD Alzheimer’s disease. The primary 
objective was to evaluate the safety and tolerability of a range of aducanumab doses (0.3 to 
60 mg/kg) when administered as single IV infusions. The secondary objectives were to assess the 
PK and immunogenicity of aducanumab after single-dose administration. 
The tolerability, safety, PK, and PD of aducanumab given once every 4 weeks was first assessed 
in a Phase 1b study (Study 221AD103); 
 
. Interim data from this study informed the design of the Phase 3 program. 
Study 221AD103 
Study 221AD103 This was a Phase 1b study comprising a randomized, double-blind, 
placebo-controlled design in participants with prodromal or mild AD Alzheimer’s disease with 
a of 1 year in duration followed by a long-term extension an LTE in which all participants 
received aducanumab in an open-label fashion (yet dose-blinded). The study was designed to 
assess the safety, PK, and PD of aducanumab in participants with prodromal Alzheimer’s disease 
or mild Alzheimer’s disease dementia with brain Aβ pathology confirmed by [18F]-florbetapir 
(Amyvid®) PET imaging. The main PD assessment (secondary endpoint) was the effect of 
aducanumab on brain Aβ levels as measured by PET and quantified by a composite SUVR. 
 At 
Screening, all participants were at the prodromal stage of Alzheimer’s disease (
 
 and a global CDR score of 0.5 or 1.0) or in 
stages of mild dementia (
 and global CDR score 
between 0.5 and 1.0). Doses investigated in the Pplacebo-controlled Pperiod included: 1, 3, 6, 
and 10 mg/kg administered every 4 weeks Q4W as a fixed dose, and 10 mg/kg administered 
after a titration period of 44 weeks.  
Placebo-Controlled Period Results 
Results from the 1-year Placebo placebo-controlled Period period showed that treatment with 
aducanumab resulted in a statistically significant, dose-dependent reduction in brain Aβ PET 
composite SUVR as compared with placebo at Week 26, and a further statistically significant, 
dose-dependent reduction at Week 54. In addition, a dose-dependent reduction of clinical decline 
was observed in the fixed-dose aducanumab groups, as well as the titration group, with a 
statistically significant treatment effect observed for both aducanumab 10 mg/kg fixed-dose and 
titration on the 
 and for 10 mg/kg fixed dosing on the 
, as compared with 
placebo. The impact of aducanumab on Aβ PET reduction was already evident at 26 weeks, 
while a difference was only observed on clinical measures at 1 year.  
Reduction in brain Aβ appears to be tightly associated with dose; the titration arm results are 
in line with the fixed-dose results based on the expected average dose in the titration arm (2.9 
and 5.3 mg/kg at 6 and 12 months, respectively), with the point estimate at Week 26 (-0.047) 
between that in the 1 and 3 mg/kg fixed-dose groups, and the point estimate at Week 54 (-0.171) 


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21 
between that in the 3 and 6 mg/kg fixed-dose groups. The results demonstrate engagement of 
aducanumab with amyloid plaques and a PD effect of dose- and time-dependent amyloid 
reduction.  
Safety analyses showed that aducanumab had an acceptable safety and tolerability profile when 
given Q4W at doses up to 10 mg/kg for more than 5 years. Incidences and causes in 
Study 221AD103. The incidence and nature of death fatal SAEs were consistent with 
underlying Alzheimer’s disease and associated comorbidities. No notable differences were 
observed between aducanumab and placebo in the overall incidence of AEs or SAEs, except for 
ARIA events. The incidence of ARIA events (both ARIA-E and ARIA-H) appeared to be related 
to aducanumab dose and 
; the ARIA events were typically asymptomatic, 
monitorable, and clinically manageable. A small proportion of participants experienced more 
than 1 ARIA-E event during treatment, and ARIA was generally not associated with negative 
long-term clinical outcomes. 
Participants with ARIA events who met certain criteria (for all clinical studies with 
aducanumab, including Study 221AD103) were required to temporarily suspend dosing 
with aducanumab. Therefore, certain participants with ARIA events experienced a 
transient interruption in dosing during prior clinical studies of aducanumab. In addition, 
only a small proportion of participants experienced more than 1 ARIA-E event during 
treatment.  
Long-Term Extension Period Results 
Data from the LTE of Study 221AD103 also provide insights relevant for the study 
population targeted in the present study (Study 221AD304). In the LTE period, those 
participants who started on active treatment at the beginning of the placebo-controlled 
period continued treatment (at the same dose as in the placebo-controlled period, except 
for the 1 mg/kg cohort who were switched to 3 mg/kg), while participants from the placebo 
arms initiated dosing with aducanumab. The main findings in Study 221AD103 during the 
LTE period regarding efficacy and safety for the high-dose groups (fixed-dose regimen of 
10 mg/kg and titration to 10 mg/kg, which are the 2 relevant groups regarding the target 
dose in Study 221AD304) were the following:  
1. 
 
 
 
  
• At Week 222, the adjusted mean changes from baseline in the 10 mg/kg 
fixed-dose and 10 mg/kg titration groups (3.83 and 3.68, respectively) were 
numerically smaller than the adjusted mean changes in the 1, 3, and 6 mg/kg 
groups that continued dosing (range 5.48 to 8.43) and the group that switched 
from placebo to aducanumab after 1 year (6.15). 


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2. The safety profile of aducanumab in the LTE was similar to that seen in the 
placebo-controlled period: 
• Participants who began treatment with aducanumab during the 
placebo-controlled period had a low incidence of ARIA-E in the LTE (5% for 
10 mg/kg fixed dose and 17% for titration to 10 mg/kg). 
The incidence of ARIA-E in participants who began treatment with aducanumab in the 
LTE (22%) was similar to the incidence in participants who began treatment in the 
placebo-controlled period (24%). 
Studies 221AD301 and 221AD302 
Studies 221AD301 and 221AD302 These were large Phase 3 randomized, double-blind, 
placebo-controlled, parallel-group studies to evaluate the efficacy, PK, and safety of 
aducanumab in participants with early stages of Alzheimer’s disease. Preliminary results from 
these studies provide the rationale for the present study and are described Refer to the updated 
IB for details for re-analysis of efficacy, PK, and safety. Highlights of efficacy re-analysis 
are provided in Section 5.2. 
Refer to the updated IB (Version 13.0) for further data from Studies 221AD103, 221AD301, and 
221AD302, as well as from other early phase aducanumab clinical studies. 
Rationale: New information from Study 221AD103 was added to provide supporting 
information on the long-term efficacy of aducanumab. A reference to the most recent version of 
the IB was provided for final results from Studies 221AD301 and 221AD302 (these results were 
not added in the body of the protocol due to the extent of changes, but a clear reference to the IB 
was provided for Investigators).  
Section 5.2, Study Rationale 
Change: Study rationale was updated with new available information. 
Now reads: 
This open-label, single-arm clinical study is being conducted to assess the long-term safety and 
efficacy of aducanumab in participants with Alzheimer’s disease who were active in 
Aducanumab aducanumab clinical studies (Study 221AD103 [PRIME], Study 221AD205 
[EVOLVE], Study 221AD301 [ENGAGE], or and Study 221AD302 [EMERGE]), from now 
on named “feeder studies,” at the time of their early termination as of 21 March 2019. On 
that date, Biogen announced the discontinuation of the Phase 3 aducanumab clinical studies, 
based on results from a preplanned futility analysis; discontinuation of the other ongoing studies 
(Studies 221AD103 and 221AD205) was announced and implemented at the same time. The 
present study (221AD304) is being undertaken based on analyses efficacy findings from 
additional data analyses of the two 2 Phase 3 studies (results summarized below). In these new 
analyses, Specifically, the analysis of this larger dataset showed Study 221AD302 to be was 


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23 
statistically significant on the pre-specified prespecified primary endpoint (Pp=0.01). Study 301 
did not meet its primary endpoint; however, participants in Study 301 who received high 
aducanumab doses/exposure had outcomes similar to the Study 302 results and these Study 301 
data support the findings from Study 302. 
Background: Interim Futility Analysis  
The 221AD301 and 221AD302 studies were 2 large Phase 3 randomized, double-blind, 
placebo-controlled, parallel-group studies to evaluate the efficacy and safety of aducanumab in 
participants with early Alzheimer’s disease (MCI due to Alzheimer’s disease and mild 
Alzheimer’s dementia). The duration was planned for 18 months of placebo-controlled period 
and up to 5 years of long-term extension LTE. The preplanned futility analysis was performed 
on data collected as of 26 December 2018, when approximately 50% of participants had the 
opportunity to complete the Week 78 visit Visit (57% [954 participants] from Study 221AD301 
and 49% [803 participants] from Study 221AD302).  
Results based on data from these participants were provided to the independent data monitoring 
committee (IDMC) who reviewed the data and confirmed that the prespecified futility criteria 
were met. Biogen reviewed the results and concurred with the IDMC and publicly announced the 
decision to discontinue the Phase 3 program and the other ongoing clinical studies on 
21 March 2019. 
On 21 March 2019, Biogen announced the early termination of the 2 Phase 3 studies 
(Studies 221AD301 and 221AD302) based on results of a prespecified interim futility 
analysis. No participant was dosed after 20 March 2019.  
Analyses Conducted Postfutility Announcement 
Subsequent to these events, further analyses on the Phase 3 studies were conducted, using data 
from all randomized and dosed participants collected through 01 April 2019 and with data after 
20 March 2019 censored for efficacy analysis. These data comprised 63% of participants from 
both the 221AD301 and 221AD302 studies (66% from 221AD301 and 60% from 221AD302) 
who had the opportunity to complete the placebo-controlled period of the study. In both the 
221AD301 and 221AD302 studies, 87% of participants had the opportunity to reach Week 50 
and 100% with opportunity to complete Week 26. The results from this larger dataset differed 
markedly from the futility results: 
• In Study 221AD302, treatment with the aducanumab high-dose regimen significantly 
reduced clinical decline compared with placebo on the primary endpoint, - change 
from baseline to Week 78 on the CDR-SB (difference versus placebo -0.40 [-23%]; 
p=0.010). In addition, 2 of the 3 secondary endpoints, - change from baseline to 
Week 7978 on ADAS-Cog 13 (difference with placebo -1.395 [-27%]; p=0.0098) and 
ADCS-ADL-MCI (difference versus placebo 1.7 [-40%]; p=0.0009) were also 
positive, while the MMSE showed a positive trend but didn’t did not reach 
significance (difference with placebo 0.5 [-15%]; p=0.062). In the low-dose group, a 


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non-significant nonsignificant numeric effect was observed for aducanumab-treated 
participants versus placebo. 
• Study 221AD301 did not meet the primary endpoint in the high-dose arm, while non-
significant numeric advantages over placebo were seen for 2 of 3 secondary 
endpoints. Results for the low-dose group were similar to those in Study 302 low-
dose group.  
• 
 
 consistent with findings in the Phase 1b study 
(Study 221AD103, PRIME).  
……. 
Given the significance of these results, the Sponsor is reinitiating has reinitiated the evaluation 
of aducanumab in this open-label, single-arm clinical trial, to evaluate the long-term safety and 
efficacy of the drug in participants previously enrolled in the studies that were ongoing at the 
time of the futility announcement (the 2 Phase 3 studies, the long-term extension LTE study for 
the Phase 1b study [Study 221AD103], and the safety study [Study 221AD205]). This study will 
also assess the degree to which 
 and clinical measures of the treatment effect of 
aducanumab are maintained following a sustained interruption in dosing. 
Final database lock for both pivotal trials was only achieved in close temporal proximity to the 
finalization of this study protocol. Analyses of the final dataset for the primary and secondary 
efficacy endpoints were conducted after the final database lock and the results of these final 
analyses do not differ overall from the larger dataset results discussed above. The efficacy results 
for the two2 studies are presented in Table 5 and Table 6. 
Refer to the updated IB (Version 13.0) for further efficacy results of the Phase 3 studies 
(221AD301 and 221AD302). 
Rationale: Clarification that no dosing happened in feeder studies after 20 March 2019 was 
added. A reference to the most recent version of the IB was provided for final efficacy results 
from Studies 221AD301 and 221AD302 (these results were not added in the body of the protocol 
due to the extent of changes, but a clear reference to the IB was provided for Investigators). 
This change also affects Section 7.1, Study Overview, where the definition of feeder studies was 
removed.  


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Section 7.2.1, Dose Suspension or Discontinuation for ARIA Events  
Change: A general statement about 
 was added. 
Now reads: 
Discontinuation of Dosing for a Given Participant 
The central MRI reading center will report incident events 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. All events of ARIA will be reviewed by the Sponsor and the 
Investigator; decisions on dosing continuation, interruption, or discontinuation will be based on 
clinical symptoms, and the radiographic severity scoring on the MRI recport report provided by 
the central reader. Guidelines on the management and disposition of ARIA-E and ARIA-H 
events (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. After each ARIA event, 
 
will be collected at the time of the first unscheduled visit following the event. Dosing may 
also be terminated at the discretion of the Sponsor for medical reasons. See Section 10.1 for the 
full list of criteria for discontinuing study treatment.  
….… 
• Participants who develop mild ARIA-E, per central MRI reading, with no clinical 
symptoms during the episode of ARIA-E, may continue in the study at their current 
dose. Participants should complete all scheduled clinic visits for assessments and, in 
addition, have an unscheduled visit for an MRI and 
 every 4 weeks Q4W 
(± 5 days) until the ARIA-E has resolved per the centrally read MRI. In addition, 
 will be collected at the first unscheduled visit following 
an episode of ARIA. 
• Participants who develop moderate or severe ARIA-E, per central MRI reading, with 
no clinical symptoms during the episode of ARIA-E will have their treatment 
temporarily suspended suspend treatment, but should complete all scheduled clinic 
visits for assessments and, in addition, have an unscheduled visit for an MRI and 
 every 4 weeks Q4W (± 5 days) until the ARIA-E has resolved per the 
centrally-read centrally read MRI. In addition, 
 will be 
collected at the first unscheduled visit following an episode of ARIA. If the ARIA-E 
resolves and the participant remains asymptomatic (in the Investigator’s opinion), the 
participant may resume treatment at the same dose.  
• Participants who develop mild, moderate, or severe ARIA-E, per central MRI 
reading, accompanied by clinical symptoms during the episode of ARIA-E episode 
should will temporarily suspend treatment, but should complete all scheduled clinic 
visits for assessments and, in addition, have an unscheduled visit for an MRI and 


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 every 4 weeks Q4W (± 5 days) until the ARIA-E has resolved per the 
centrally-read centrally read MRI. In addition,
 will be 
collected at the first unscheduled visit following an episode of ARIA. If the ARIA-E 
resolves and the clinical symptoms resolve (in the Investigator’s opinion), the 
participant may resume treatment at the same dose.  
• Participants who develop mild, moderate, or severe ARIA-E, per central MRI 
reading, accompanied by serious (except “other medically important event”) clinical 
symptoms related to the current episode of ARIA-E will permanently discontinue 
treatment DCT but remain in the study. Participants should complete ana safety FU 
Visit 18 weeks after the final last dose of study treatment, protocol-required tests 
and assessments at a subset of the clinic visits (see Table 4), and, in addition, have an 
unscheduled visit for an MRI and 
 every 4 weeks Q4W (± 5 days) until the 
ARIA-E has resolved per centrally-read centrally read MRI. In addition, 
 
 will be collected at the first unscheduled visit following an episode 
of ARIA. 
Rationale: Language was rearranged to remove redundancy.  
This change also affects Section 7.2.1.2, ARIA-H (Micro-hemorrhage); Section 7.2.1.3, ARIA-H 
(Superficial Siderosis); and Section 7.2.1.4, ARIA-H (Macro-hemorrhage).  
Section 7.2.1.2, ARIA-H (Micro-hemorrhage) 
Change: Text was updated to clarify what will be considered micro-hemorrhages for the study. 
Now reads:  
In this study, new incident microhemorrhages micro-hemorrhages are defined as new incident 
microhemorrhages micro-hemorrhages that occur on treatment start after aducanumab 
infusion per this study (221AD304) and do not include microhemorrhages at 
micro-hemorrhages seen on the baseline MRI done for this study. 
Rationale: This change was made to clearly define the criteria for counting new ARIA-H 
(micro-hemorrhages) events that occur in this study. 
This change also affects Section 7.2.1.2, ARIA-H (Micro-hemorrhage) (footnote of Table 8); 
Section 10.1, Discontinuation of Study Treatment.  


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Section 7.2.1.2, ARIA-H (Micro-hemorrhage) 
Change: Collection of PBMCs and resuming treatment after ARIA-H is deemed stable were 
removed. 
Now reads: 
Asymptomatic ARIA-H (Microhemorrhage Micro-hemorrhage) 
• Participants who develop a ≥ 1 and ≤ 4 new incident microhemorrhage 
micro-hemorrhage(s) [mild] at any time during the study may continue treatment at 
the current dose. Participants should complete all scheduled clinic visits for 
assessments and, in addition, have an unscheduled visit for an MRI and 
 every 
4weeks Q4W (± 5 days) until the ARIA-H microhemorrhage micro-hemorrhage is 
confirmed stable per the centrally-read centrally read MRI. In addition, 
 
, and PBMC samples will be collected at the first unscheduled visit following an 
episode of ARIA. Microhemorrhages Micro-hemorrhages are considered stable if 
there is no change or a decrease in the number, size, severity, or number of locations 
between 2 consecutive MRIs including the initial detection MRI and the MRI 
performed 4 weeks (±5 days) later. Once ARIA-H (microhemorrhage) is deemed 
stable, the subject may resume treatment at the same dose. 
• …..... A microhemorrhage is considered stable if there is no change or a decrease in 
the number, size, severity, or number of locations between 2 consecutive MRIs 
including the initial detection MRI and the MRI performed 4 weeks (±5 days) later. 
……… 
• Participants who experience serious (except “other medically important event” 
[Section 15.1.2]) clinical symptoms associated with microhemorrhage(s) 
micro-hemorrhage(s) (independent of the radiographic severity of the event) will 
permanently discontinue treatment DCT but remain in the study. 
Rationale: PBMC collection for mild asymptomatic ARIA-H (micro-hemorrhage) was removed 
to keep management of this subtype of ARIA consistent with that of the other subtypes. Because 
there is no suspension of treatment in asymptomatic mild ARIA-H, the sentence about resuming 
treatment was removed. Text was deleted concerning what is considered a stable 
microhemorrhage to avoid redundancy. It was also added that for serious symptomatic ARIA-H, 
discontinuation is independent of radiographic correlation.  


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Section 7.2.1.3, ARIA-H (Superficial Siderosis) 
Change: Text was updated to clarify conditions for severe symptomatic superficial siderosis. 
Now reads: 
Participants who develop >2 new focal areas of superficial siderosis (severe), regardless of the 
presence of clinical symptom severitysymptoms, will permanently discontinue treatmentDCT 
but remain in the study. 
Rationale: Provided clarification that treatment should be discontinued for any radiographically 
severe superficial siderosis, regardless of the presence of clinical symptoms.  
Section 7.2.1.5, Coincident ARIA-H and ARIA-E Events 
Change: Clarification in an example situation was added. 
Now reads: 
Participants who develop ARIA-H coincident with ARIA-E at any time during the study will 
follow the most restrictive guidelines. Prior to resuming treatment, where applicable, ARIA-E 
must resolve, ARIA-H must be deemed stable, and the participant must be asymptomatic. For 
example, if a participant experiences radiographically mild, asymptomatic ARIA-H 
(1-4 microhemorrhages 1 to 4 micro-hemorrhages) coincident with ARIA-E assessed as 
radiographically moderate on MRI and accompanied by mild clinical symptoms, the dose 
ARIA-E, the participant will should be temporarily suspended suspend treatment per the 
ARIA-E guidelines summarized in Table 7. In addition, unscheduled visits should occur as 
described in Section 7.2.1.1, Section 7.2.1.2, Section 7.2.1.3, and through Section 7.2.1.4. 
Rationale: Text was updated for clarity regarding specifications for the instance in which 
participants develop ARIA-H coincident with ARIA-E. 
Section 7.3, Overall Study Duration and Follow-Up 
Change: Text was updated to clarify the number of weeks in the Treatment Period.  
Now reads:  
The study period will consist of Screening, Treatment, and FU periods. A schematic of the 
study is presented in Figure 1.  
Study duration for each participant will be approximately 126 weeks: an approximately 8-week 
screening period Screening Period, a 100102-week treatment period Treatment Period, and a 
18-week safety follow-up visit FU Visit 18 weeks after the last dose of study treatment. 


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Rationale: Treatment Period was clarified to last 102 weeks instead of 100 weeks so the EOT 
visit would be included as part of the Treatment Period. Added reference to study schematic.  
This change also affects Section 4.1, Study Schematic (Figure 1).  
Section 7.3, Overall Study Duration and Follow-Up 
Change: Adjusted number of scheduled clinical visits. 
Now reads: 
Participants will have up to 3338 scheduled clinic visits during the study. All visits should be 
performed ± 5 days from the nominal visit day.  
Rationale: MRI visits were also counted to update the number of clinical site visits. 
Section 7.3, Overall Study Duration and Follow-Up 
Change: A contingency plan for COVID-19 and/or other challenging circumstances for 
Screening Visit was added. 
Now reads: 
• Screening Visits no more than 60 days before the first dose of study treatment on 
Day 1 (visits Screening Visits may be conducted on multiple days) carried out over 
2 separate visits, at the Investigator’s discretion). It is recommended that all 
screening procedures be completed within 60 days; however, the overall screening 
period Screening Period may be extended up to 90 days in the event of logistical 
issues related to 
 and/or other logistics restrictions 
due major causes (i.e., institutional restrictions or participant disposition due to 
COVID-19 or other major disasters) and is subject to Sponsor approval. 
Rationale: Flexibility around Screening Visits was added to accommodate study participation 
restrictions owing to major disasters.  
This change also affects Section 4.2, Schedule of Events (Footnotes of Table 1 and Table 3); 
Section 7.3.1, Screening; and Section 9.1, Screening and Enrollment.  
Section 7.3, Overall Study Duration and Follow-Up 
Change: Updated clinical assessment visits.  
Now reads: 
• 46 visits for clinical assessments, including Screening and FU at Week 118 (or 18 
weeks after the last dose of study treatment for participants who DCT early). 


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• ….. 
• 1 FU safety visit at Week 118 (or 18 weeks after last dose of study treatment for those 
participants who discontinue early). 
Rationale: Updated clinical assessments visits to include Screening and FU Visits, and 
consequently deleted separate FU visit. 
Section 7.3, Overall Study Duration and Follow-Up 
Change: Rearranged and grouped visits for substudies.  
Now reads: 
 
 
  
 
 
 
 
 
 
. 
• 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Rationale: 
 
 
  
Section 7.3, Overall Study Duration and Follow-Up 
Change: Information regarding medication dose changes was added. 
Now reads: 
Participants who have a change in AD Alzheimer’s disease medication (other than study 
treatment) during the Treatment Period should have an unscheduled visit; a subset of the clinical 
efficacy assessments 
 should be 
performed prior to the change in medication if the participant alerts the Investigator before 
the change in medication occurs. In the event that 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 are performed within 30 days after the change in medication, the 
assessments do not have to be repeated. 
Rationale: Communication scenarios in case a participant has a change in Alzheimer’s disease 
medication (other than study treatment) were added.  
This change also affects Section 4.2, Schedule of Events (Table 1 and Table 2, added new 
footnotes) and Section 11.5.1.2, Disallowed Concomitant Therapy. 
Section 7.3.1, Screening 
Change: Details of re-assessing were added. 
Now reads:  
Participant eligibility for the study will be determined no more than 60 days prior to the first 
dose of study entry. treatment on Day 1. It is recommended that all screening procedures be 
completed within 60 days (Screening Visits may be carried out over 2 separate visits, at the 
Investigator’s discretion); however, the overall screening periodScreening Period may be 
extended up to 90 days in the event of logistical issues related to 
 
and/or other logistics restrictions due to major causes (i.e., institutional restrictions or 
participant disposition due to COVID-19 or other major disasters) and is dependent 
onsubject to Sponsor approval. Only in the event of inadequate tracer supplies or 
 
 
 
 
 
  


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Section 7.3.1, Screening 
Change: Details for rescreening were provided.  
Now reads: 
Participants who fail screening will be permitted to be rescreened once up to 2 times at the 
Sponsor’s discretion. Participants who fail in cases when a participant fails screening because 
allowed chronic medications have not been at stable doses for at least 4 weeks prior to Screening 
whose use of AD medications has not been at stable doses for at least 8 weeks prior to Screening 
Visit may return for due to logistics restrictions owing to major causes (i.e., institutional 
restrictions or disposition due to COVID-19 or other major disasters) rescreening after use 
of these medications has been stabilized for the required period. Rescreened participants will 
be assigned a new number. At rescreening, all assessments should be repeated except for 
.  
Rationale: Clarity was provided on 1) the number of allowed rescreens (up to 2) to account for 
COVID-19 situations (previously in aducanumab Phase 3 trials, 1 rescreening was allowed 
mainly due to medication washout per inclusion/exclusion criteria) and 2) assessments that need 
to be repeated when participants are rescreened. 
Section 7.5, Unscheduled Visits 
Change: An incorrect statement was removed. 
Now reads: 
Data collected during unscheduled visits should be recorded on CRFs only if the data support 
protocol objectives and/or are required for safety monitoring. 
If participants return for unscheduled visits, no study-related data should be collected. 
Rationale: A sentence that had inconsistent information regarding an UV was deleted.  
Section 8.1, Inclusion Criteria 
Change: Inclusion language in inclusion criterion 1 for participants from feeder studies was 
clarified. 
Now reads:  
Participant was participating in an aducanumab clinical study at the time of the announcement of 
early termination (Studies 221AD301, 221AD302, 221AD103, and 221AD205, referred to as 
“feeder studies”). Note #1: Participants who had formerly participated in feeder studies and had 


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to permanently discontinue the investigational product and/or exited a feeder study due to 
circumstances protocol mandatory requirements for discontinuation that are no longer 
applicable at the time of screening will be evaluated by the Sponsor on a case by case 
case-by-case basis. Note #2: Participants who completed screening on in Study 221AD205 and 
were confirmed eligible prior to 21 March 2019 but were not randomized due to the 
discontinuation of the trial, may have the opportunity to screen on this study upon 
review/approval from the Sponsor.  
Rationale: Text was revised to specify that participants who discontinued feeder studies can be 
considered for participation in Study 221AD304 if their discontinuation in the feeder study was 
due to protocol requirements and not general circumstances.  
Section 8.1, Inclusion Criteria 
Change: 
  
Now reads:  
 
 
 
Rationale: The inclusion criterion was updated to provide disease-specific inclusion criteria to 
assess disease stage.  
Section 8.1, Inclusion Criteria 
Change: Practice of effective contraception with respect to half-life of the study treatment was 
added to inclusion criterion 4.  
Now reads:  
4. Female participants of childbearing potential and male participants 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. Refer to Section 15.5. 
Rationale: To keep consistent with the required timeframe to maintain effective contraception 
mentioned in Section 15.5.  
This change also affects Section 15.4.1, Pregnancy.  


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Section 8.2, Exclusion Criteria 
Change: Exclusion criterion 4 was updated regarding MRI findings for the study. 
Now reads: 
4. Brain MRI (performed at screeningScreening, centrally-read centrally read) evidence of 
any of the following: 
• Acute or subacute hemorrhage. 
• Prior macrohemorrhage macro-hemorrhage (defined as ≥> 1 cm in diameter on T2* 
sequence) or prior subarachnoid hemorrhage unless it can be documented that the 
finding is not due to an underlying structural or vascular abnormality (i.e., finding 
does not suggest participant is at risk of recurrent hemorrhage).  
• Greater than 4 (for treatment-naïve participants) or ≥ 10 (for aducanumab 
previously-treated previously treated participants) microhemorrhages 
micro-hemorrhages (defined as ≤ 1 cm in diameter on T2* sequence). 
• Cortical infarct (defined as > 1.5 cm in diameter; irrespective of anatomic location). 
• 1 lacunar infarct (defined as  1.5 cm in diameter). 
• Any focal area of superficial siderosis (for treatment-naïve participants) or 3 or more 
focal areas of superficial siderosis (for aducanumab previously treated participants).  
Rationale: The definition of macro-hemorrhage was corrected for consistency. The occurrence 
of more than 1 lacunar infarct as exclusionary was removed. 
Section 8.2, Exclusion Criteria 
Change: Exclusion criterion 10 was updated to provide exception for cancer patients.  
Now reads: 
10. History of malignancy or carcinoma. The following exceptions may be made after 
discussion with the Sponsor:  
• Participants with whose cancer is in remission more than 2 years according to the 
cancer specialist prior to Screening. 
• Participants with a history of excised or treated basal cell or squamous carcinoma of 
the skin.  
• Participants with localized prostate cancer with treatment cycles that completed at 
least 6 months prior to Screening. 


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Rationale: Modified malignancy exclusion criteria and its exceptions to align with the conduct 
around intercurrent cancers during the Phase 3 trials. In these studies, participants with 
intercurrent cancers were able to reinitiate dosing once their cancer was treated without any 
stipulations/requirements for a cancer-free period. Therefore, the first sub-bullet was modified to 
request a report that confirms a “cancer in remission” status by the cancer specialist. The second 
sub-bullet was left intact because an excised basal cell or squamous cell carcinoma is de facto in 
remission. The third sub-bullet was deleted because it was a description of “localized prostate 
cancer” in remission and therefore was redundant with the first sub-bullet.  
Section 8.2, Exclusion Criteria 
Change: New exclusion criteria 23, 24, 25, and 26 were added to include additional medications 
that will not be allowed during the study. 
Now reads: 
22. Use of allowed chronic medications for chronic conditions at doses that have not been 
stable for at least 4 weeks prior to Screening up to Study Day 1, or use of AD 
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 up to Study Day 1. 
23. Chronic use of systemic immunosuppressive drugs (including systemic 
corticosteroids) as indicated in Section 11.5.1.2. Local and/or topical 
immunosuppressants will be allowed. 
24. Use of chemotherapeutic agents and checkpoint inhibitors. 
25. Use of parenteral immunoglobulin, blood products, plasma derivatives, plasma 
exchange, or plasmapheresis. 
26. Use of vaccinations within 10 days prior to Day 1.  
27. Use of medications with platelet anti-aggregant or anti-coagulant anticoagulant 
properties (the use of aspirin at a dose ≤ 325 mg daily is allowed). 
Rationale: Systemic immunosuppressants, chemotherapeutic agents and checkpoint inhibitors, 
and immunoglobulins were added to the exclusion criteria for consistency with disallowed 
concomitant medication and vaccination.  
This change also affects Section 11.5.1.2, Disallowed Concomitant Medication. 


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Section 8.2, Exclusion Criteria 
Change: Exclusion criterion 29 (exclusion criterion 25 in Version 1.0) was updated regarding 
investigational product use.  
Now reads: 
29. Participation in any study in which the participant is taking an investigational 
product for Alzheimer’s disease (with purported disease-modifying effect in AD 
treatment or not) unless the participant has fulfilled a wash out wash-out period of at 
least 5 half-lives for that particular investigational product or is able to provide 
documentation of having received placebo in that investigational product study. 
Rationale: Participation in other investigational studies while in the current study was restricted.  
Section 9, Enrollment and Registration 
Change: Updated section subheading.  
Now reads:  
Enrollment, and Registration, and Randomization 
Rationale: Corrected because there is no randomization. 
This change also affects Section 8.2, Exclusion Criterion (specifically #9).  
Section 11.5.1.1, Allowed Concomitant Therapy 
Change: Language about Investigator’s communication was changed. 
Now reads: 
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 needs to ensure pertinent communication with the study mMedical 
mMonitor to determine whether the participant’s study treatment should be suspended if there 
are changes in medication of any nature that will have an effect on cognitive assessment. 
Medications used to treat AEs would not result in automatic permanent study treatment 
discontinuation. 
Rationale: This update provided flexibility in terms of the Investigator’s communication with 
the Medical Monitor while implementing changes in medication that will have an impact on 
cognitive assessment.  


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Section 11.5.1.2, Disallowed Concomitant Therapy 
Change: Clarification on disallowed medications was provided.  
Now reads: 
• Nonprescription narcotic medication. 
• Immunosuppressive Cannabinoids (prescription or recreational). 
• Systemic immunosuppressive drugs (including systemic corticosteroids). Local or 
topical immunosuppressants will be allowed. Local corticosteroids (including inhaled 
and topical corticosteroids) are allowed; certain systemic corticosteroids may be 
permitted at the Sponsor’s discretion.  
• Chemotherapeutic agents and checkpoint inhibitors. 
Rationale: Text was updated to clarify that the excluded narcotics include cannabinoids and that 
systemic immunosuppressants are excluded (while local and topical immunosuppressants are 
allowed). 
 
Change: Added remote visit language. 
Now reads:  
Refer to Section 4.2 for the timing of assessments.  
If in-clinic visits are not able to occur, a remote visit via telephone or video call may be 
used to collect efficacy assessments as deemed appropriate by the Sponsor (refer to the 
Study Reference Manual for details). 
Rationale: Added information on how efficacy assessments will be collected during remote 
visits.  
 
Change: Added a sentence about audio recording of some scales.  
Now reads: 
Some tests will require the informant/care partner 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.  
Rationale: Added to indicate that there will be training and evaluation for some scales.  


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Change: 
  
Now reads:  
Where local regulations and EC approval allow, an optional 
 will be collected for 
future 
 from participants who did not previously consent for this collection in the 
feeder study. 
Rationale: Updated to clarify that all participants must provide consent for 
 
.  
 
Change: Updated to change the number of years samples will be stored. 
Now reads:  
The 
 will be coded with the participant’s identification number and stored for 
1525 years or a duration dictated by local, national, or regional laws or regulations. 
Rationale: Increased the number of years that the 
 can be stored. 
 
Change: This entire section was deleted. 
Now reads: 
 
 
  
 
 
 
 
 
 
 
 
 
Rationale: This section was deleted because this is not part of the current plan for this study. 


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Section 14, Safety Assessments 
Change: Added remote visit language. 
Now reads:  
Refer to Section 4.2 for the timing of assessments.  
If in-clinic visits are not able to occur, a remote visit via telephone or video call may be 
used to collect safety assessments (AEs, SAEs, concomitant medications, and C-SSRS) as 
deemed appropriate by the Sponsor (refer to the Study Reference Manual for details). 
Rationale: Added information on how safety assessments will be collected during remote visits.  
Section 15.5, Contraception Requirements 
Change: Information on postmenopausal status was updated.  
Now reads:  
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 
− For women ≤ 55 years of age, 52 continuous weeks of natural (spontaneous) 
amenorrhea without an alternative medical cause and a serum follicle-stimulating 
hormone (FSH) level >≥40 mIU/mL, or 6 weeks after surgical bilateral 
oophorectomy with or without hysterectomy. 
− For women > 55 years of age, 52 continuous weeks of natural (spontaneous) 
amenorrhea without an alternative medical cause and a serum FSH level 
≥ 40 mIU/mL, or at least 5 continuous years of natural (spontaneous) 
amenorrhea without an alternative medical cause. 
− 6 weeks after surgical bilateral oophorectomy with or without hysterectomy. 
• Posthysterectomy. 
• Female surgical sterilization (e.g., bilateral tubal ligation). 
Rationale: This update was made to clarify the postmenopausal FSH levels based on age.  


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Section 15.5, Contraception Requirements 
Change: Male contraception requirements and sperm donation were removed. 
Now reads:  
• For females of childbearing potential: 
− Progesterone-only oral hormonal contraception, where inhibition of ovulation is 
not the primary mode of action. 
− Placement of an intrauterine device or intrauterine system. 
− Barrier methods of contraception with use of a spermicide: condom or occlusive 
cap (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 underwent surgical sterilization with the appropriate 
postvasectomy documentation of the absence of sperm in the ejaculate. 
• For males: 
− Vasectomy with negative semen analysis at FU. 
− Use of condoms with spermicide (where applicable). 
− Female sexual partners who underwent surgical sterilization (e.g., bilateral tubal 
ligation), are postmenopausal, are posthysterectomy, or are using effective 
contraception as listed above for female participants. 
 For males and females of childbearing potential: 
− True abstinence, when this is consistent with the preferred and usual lifestyle of 
the participant, can be considered an acceptable method of contraception based on 
the evaluation of the Investigator who should also take into consideration the 
duration of the clinical trial. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not considered 
acceptable methods of contraception. 
Rationale: Based on the toxicology profile update for aducanumab (from Patient Safety 
Information), male contraception is no longer required per Clinical Trials Facilitation and 
Coordination Group guidelines. 
This change also affects other areas in Section 15.5, Contraception Requirements, and 
Section 8.1, Inclusion Criteria.  


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Change: 
  
Now reads: 
 
 
 
 
 
  
Rationale: 
 
  
Section 16.4.2.2, Clinical Laboratory Results 
Change: An inconsistent phrase was removed. 
Now reads: 
In addition, the shift from baseline to the maximum postbaseline value and the shift from 
baseline to the minimum postbaseline status will be presented for each laboratory test by 
treatment group. 
Rationale: Because all participants receive the same treatment, this phrase is not needed.  
Section 16.7, Sample Size Considerations 
Change: The projected sample size was added. 
Now reads: 
At the time that the feeder studies were stopped in March 2019, approximately 2600 participants 
had received treatment in 1 of those feeder studies. Approximately 400 participants were on 
placebo (“aducanumab treatment-naïve participants”) and approximately 2200 participants had 
received aducanumab (“aducanumab previously-treated previously treated participants”). 
Biogen estimates that of these 2600 participants, 2400 participants could be eligible based 
on inclusion and exclusion criteria to participate in the current study.  
Rationale: There was no sample size calculation because the sample size for this study is only a 
projected value from the feeder studies. 


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Section 18.3, Monitoring of the Study 
Change: Language to allow remote data verification was added. 
Now reads: 
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(s) 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. 
Rationale: This language was updated for consistency with the current template language. 


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SUMMARY OF MINOR CHANGES TO THE PROTOCOL 
The following minor changes were made to the protocol, as appropriate: 
• The version number and date were updated throughout the protocol. 
• The title of the sponsor signatory was updated. 
• Running headers were updated to be consistent with the present study design. 
• Clarified that the IB referenced is Version 13. 
• Change to use “care partner” throughout rather than “care giver” and “informant” (global 
change).  
• 
 
• Clarified FU Visits as safety FU Visits (except in Tables 1 and 2).  
• Clarified that safety FU is 18 weeks after last dose of study treatment (global change). 
• Change to use “telephone” instead of “phone” for consistency.  
• 
 
 
• Section 2, List of Abbreviations, was updated.  
• Section 4.2, Schedule of Events (Table 4), updated the order of assessments to keep 
consistency across the different Schedule of Events tables for participants who were on 
treatment or off treatment.  
• Section 12.1, Aducanumab, minor update to name of the drug to match updated style 
guide.  
• Section 15.5, Contraception Requirements, the term “effective” was added to 
contraception methods, to keep consistent with inclusion criterion 4.  
• Minor clarifications and editorial changes were made throughout the protocol.  
• Typographical errors and formatting were corrected. 
 


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LIST OF ABBREVIATIONS 
Aβ 
amyloid beta (peptide derived from membrane-bound amyloid 
precursor protein) 
ADA 
antidrug antibody 
ADAS-Cog 13 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
(13 items) 
ADCS-ADL-MCI 
Alzheimer’s Disease Cooperative Study – Activities of Daily 
Living Inventory – Mild Cognitive Impairment 
 
 
  
AE 
adverse event 
 
 
ARIA 
amyloid-related imaging abnormalities 
ARIA-E 
amyloid-related imaging abnormality-edema  
ARIA-H 
amyloid-related imaging abnormality-hemorrhage or superficial 
siderosis 
CDR 
Clinical Dementia Rating 
 
  
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
 
 
C-SSRS 
Columbia Suicide Severity Rating Scale  
DBP 
diastolic blood pressure 
DCT 
discontinue treatment 
 
 
EOT 
End of Treatment 
 
 
 
 
 
 
 
FDA 
Food and Drug Administration 


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FSH 
follicle-stimulating hormone 
FU 
follow-up 
HCP 
health care provider 
 
 
IB 
Investigator’s Brochure 
LTE 
long-term extension 
MCI 
mild cognitive impairment 
MMRM 
mixed-model repeated measures 
MMSE 
Mini-Mental State Examination 
 
 
 
 
MRI 
magnetic resonance imaging 
 
 
PBMC 
peripheral blood mononuclear cell 
PD 
pharmacodynamic(s) 
PET 
positron emission tomography 
PK 
pharmacokinetic(s) 
Q4W 
once every 4 weeks 
 
 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SUVR 
Standard Uptake Value Ratio 
UV 
Unscheduled Visit 
 

SAP_001.pdf: 
 
Official Title: 
Phase 3b Open-Label, Multicenter, Safety Study of BIIB037 
(Aducanumab) in Subjects With Alzheimer's Disease Who Had 
Previously Participated in the Aducanumab Studies 221AD103, 
221AD301, 221AD302 and 221AD205 
NCT Number: 
NCT04241068 
Document Date: 
10 May 2024 
 
 






Product: Aducanumab 
Study: 221AD304
Statistical Analysis Plan 
Version: 2.0
 
 
Page 3
 
 
 
VERSION HISTORY 
 
SAP Version 
Date 
Primary Reasons for Amendment 
1.0 
21-AUG-2020 
Not applicable. 
2.0 
10-MAY-2024 
Added 
 
 according protocol version 4.0. 
Added the core secondary objectives and 
endpoints according to interim analysis SAP. 
Added the description of the primary efficacy 
analysis results from the interim analysis in 
section 4.2. 
Modified for abbreviated CSR analysis. 
 
 
 


Product: Aducanumab 
Study: 221AD304
Statistical Analysis Plan 
Version: 2.0
 
 
Page 4
 
 
TABLE OF CONTENTS 
 
STATISTICAL ANALYSIS PLAN ...................................................................................................... 1 
APPROVAL .......................................................................................................................................... 2 
VERSION HISTORY............................................................................................................................ 3 
TABLE OF CONTENTS ...................................................................................................................... 4 
LIST OF ABBREVIATIONS................................................................................................................ 7 
1.
Introduction...................................................................................................................................9
2. 
Study Overview ............................................................................................................................ 10 
2.1. 
Study Objectives and Endpoints ...................................................................................... 10 
2.1.1. 
Core Primary Objective and Endpoints ...................................................................... 10 
2.1.2. 
Core Secondary Objectives and Endpoints.................................................................. 10 
 11 
 12 
2.2. 
Study Design ..................................................................................................................... 13 
2.3. 
Study Conduct Following Announcement of Study Termination ................................... 14 
2.4. 
Sample Size Considerations ............................................................................................. 18 
3. 
Definitions .................................................................................................................................... 18 
3.1. 
Dates and Points of Reference .......................................................................................... 18 
3.2. 
Study Treatment............................................................................................................... 20 
3.3.
Study Treatment Periods .................................................................................................20
3.4. 
Key Derived Variables ..................................................................................................... 21 
3.5. 
Stratification Factors and Subgroup Variables ............................................................... 21 
3.6. 
Analysis Population.......................................................................................................... 21 
4. 
List of Planned Study Analyses ................................................................................................... 22 
4.1. 
Interim Analysis ............................................................................................................... 22 
4.2. 
Primary Analysis .............................................................................................................. 23 
4.3. 
Final Analysis................................................................................................................... 24 
5. 
Statistical Methods for Planned Analyses ................................................................................... 24 


Product: Aducanumab 
Study: 221AD304
Statistical Analysis Plan 
Version: 2.0
 
 
Page 5
 
 
5.1. 
General Principles ............................................................................................................ 24 
5.2. 
Participant Accountability ............................................................................................... 25 
5.3. 
Demographic and Baseline Characteristics ..................................................................... 25 
5.4. 
Protocol Deviations........................................................................................................... 26 
5.5. 
Study Treatment Exposure and Concomitant Medications............................................ 26 
5.5.1. 
Study Treatment Exposure and Study Drug Compliance........................................... 26 
5.5.2. 
Concomitant Medications and Non-Drug Therapies ................................................... 26 
5.6. 
Efficacy Endpoints ........................................................................................................... 27 
5.7. 
Safety Endpoints............................................................................................................... 27 
5.7.1. 
General Considerations ................................................................................................ 27 
5.7.2. 
Clinical Adverse Events ................................................................................................ 28 
5.7.3. 
AE of Special Interest ................................................................................................... 31 
5.7.4. 
Other Significant AEs................................................................................................... 34 
5.7.5. 
Clinical Laboratory Data ............................................................................................. 36 
5.7.6. 
C-SSRS Data................................................................................................................. 39 
5.7.7. 
ECG Data...................................................................................................................... 40 
5.7.8. 
Vital Sign Data .............................................................................................................. 40 
5.7.9. 
Physical Examination and Neurological Examination ................................................ 40 
 40 
40 
5.10. 
Immunogenicity................................................................................................................ 41 
5.10.1. 
Background................................................................................................................... 41 
5.10.2. 
Immunogenicity Analysis ............................................................................................. 41 
6. 
Changes from Protocol-Specified Analyses ................................................................................. 42 
7. 
Summary of Changes from the Previous Version of the SAP .................................................... 43 
8. 
References .................................................................................................................................... 45 
9. 
APPENDICES.............................................................................................................................. 45 
9.1. 
Safety, 
, and Immunogenicity Analysis Display ................................. 45 
 


Product: Aducanumab 
Study: 221AD304
Statistical Analysis Plan 
Version: 2.0
 
 
Page 6
 
 
LIST OF TABLES
Table 1 
Summary of Updates on Last Dose Visit and Safety Follow-up Visit since the Announcement 
of Study Termination ............................................................................................................................. 15 
Table 2 
Revised Schedule of Assessments for the End of Treatment and Follow-up Visits .............. 17 
Table 3 
Summary of Interim Analysis ............................................................................................. 23 
Table 4 
List of Planned Analyses for AE ......................................................................................... 29 
Table 5 
Verbatim Terms and MedDRA terms for ARIA .................................................................. 31 
Table 6 
List of Planned Analyses for ARIA and Other Significant AEs ........................................... 34 
Table 7
Visit Windows for Laboratory by Visit Summaries.............................................................37
Table 8 
Criteria to Determine Potentially Clinically Significant (PCS) Laboratory Abnormalities.... 38 
Table 9 
Visit Windows for Immunogenicity by Visit Summaries..................................................... 42 
Table 10 
Summary of Changes from Protocol-Specified Analyses .................................................... 42 
Table 11 
Changes and Reasons for Changes from the Previous Version of the SAP........................... 43 
 
 
 






Product: Aducanumab 
Study: 221AD304
Statistical Analysis Plan 
Version: 2.0
 
 
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1. Introduction 
Study 221AD304 (EMBARK) is an open-label, single-arm clinical study that is being conducted 
to assess the long-term safety and efficacy of aducanumab in participants with Alzheimer's 
disease (AD) who were actively participating in aducanumab clinical studies 221AD103, 
221AD205, 
2019. Participants in an aducanumab clinical study at the time of the announcement of early 
termination of the feeder studies were eligible to enroll in Study 221AD304. 
Biogen initiated early termination of the Phase 3b study 221AD304 on 19 September 2023. At 
that time, all 221AD304 study participants had completed the core portion of the study, and 
therefore, the primary objective of assessing safety and tolerability of aducanumab and the core 
 of the study had been met. The decision to complete the study early was 
not based on any safety or efficacy concerns. Participants were notified that their next scheduled 
study visit would be their last dosing visit. Per protocol, participants were instructed to return to 
the site for the end of treatment visit followed by the safety follow-up visit (18 weeks after the 
last dose). 
As there was no available post-trial compassionate access mechanism in France, Biogen allowed 
French participants to remain on treatment beyond September 2023 as planned and to complete 
the EMBARK LTE in full. These data from the French participants will be added to the dataset 
for the LTE. As a result, the decision for early termination of EMBARK did not impact French 
participants in the study.  Following 
31 January 2024 decision to discontinue 
commercialization and development of aducanumab, study 221AD304 early termination was 
also initiated in France and the last dose for France participants occurred no later than 01 May 
2024. The study participants in France were required to perform a safety follow-up visit 12 
weeks after their last dose. The number of assessments conducted at the End of Treatment (EOT) 
and safety follow-up/End of Study Visit (EOS) visit were reduced to minimize the burden on site 
and study participants. 
 
 
  
The primary statistical analysis plan (SAP) version 1 was signed off on August 31, 2020. It 
described the analysis plan on the data by the end of the core treatment period as defined in 
protocol version 4. An interim analysis plan (SAP) version 2.0 was signed on 24 February 2023. 
This interim analysis was mainly focused on evaluating the efficacy of aducanumab versus an 
external control using clinical endpoints and 
 endpoints. 
Due to the early termination of the study, an abbreviated clinical study report is planned.  The 
focus of this SAP will be safety and tolerability of aducanumab in the core treatment period and 
the long-term extension period. The core primary endpoints, as well as the 
 
 related to safety and tolerability will be evaluated. All other 
 will 
not be included in this analysis. Disposition, baseline characteristics, demographics, exposure, 
and protocol deviation data will be also summarized to provide supporting information for the 
review of safety. 


Product: Aducanumab 
Study: 221AD304
Statistical Analysis Plan 
Version: 2.0
 
 
Page 10
 
 
2. Study Overview 
2.1. Study Objectives and Endpoints 
Given the context of the early study termination, two types of analyses will be performed: 1) the 
core primary endpoints (assessed over 100 weeks) and 
 
 
 
  
2.1.1. Core Primary Objective and Endpoints 
The core primary objective is to evaluate the safety and tolerability of aducanumab over 100 
weeks of treatment in participants from the aducanumab feeder studies (221AD301, 221AD302, 
221AD205 and 221AD103), which were the ongoing aducanumab trials at the time of program 
discontinuation on 21 March 2019. The study candidates had previously received aducanumab 
(i.e., previously treated participants) or had previously received placebo (i.e., treatment-naïve 
participants) after a wash-out period imposed by the discontinuation of the feeder studies. 
Primary endpoints include incidence of adverse events (AEs), SAEs, amyloid related imaging 
abnormality (ARIA) and immunogenicity with over 100 weeks of treatment and/or re-exposure 
to aducanumab. Safety and tolerability parameters include: 
 Incidence of all AEs; AEs leading to treatment discontinuation or study withdrawal, 
and all SAEs 
 Incidence of amyloid related imaging abnormality-edema (ARIA-E) and amyloid 
related imaging abnormality-hemorrhage or superficial siderosis (ARIA-H) 
 Incidence of anti-aducanumab antibodies (anti-drug antibodies, ADA) in serum. 
2.1.2. Core Secondary Objectives and Endpoints 
The core secondary objectives and endpoints are not described in the protocol but were 
developed as part of an interim statistical analysis plan (version 2.0) 
The core secondary objectives defined in the interim SAP are: 
 Evaluation of the efficacy of aducanumab versus an external control using clinical 
endpoints 
 Evaluation of the efficacy of aducanumab versus an external control using 
 
 
The corresponding primary clinical efficacy endpoint is change from baseline CDR-SB at Week  
78.  


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Additional core secondary clinical efficacy endpoints to be compared to an external control are: 
 
 
 
(ADAS-Cog 13) at Week 78 
 Change from baseline Mini-Mental State Examination (MMSE) at Week 78 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   


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2.2. Study Design 
Study 221AD304 is an open-label, multicenter, longitudinal, single-arm, global Phase 3b study 
at the time of their early termination. It is calculated that up to approximately 2400 participants 
will be enrolled across approximately 350 sites globally. The primary study objective is to 


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evaluate the long-term safety and tolerability of a monthly dose (10mg/kg) of aducanumab after 
a gap period imposed by discontinuation of feeder studies. 
The study consists of Screening, Core Treatment, LTE Treatment, and FU periods. A schematic 
of the study is presented in Figure 1 of protocol Section 4. According to the original protocol, 
study duration for each participant is approximately 178 weeks: an approximately 8-week 
Screening Period, a 100-week Core Treatment Period, a 52-week LTE treatment period, and a 
safety FU Visit 18 weeks after the last dose of study treatment. 
After the Screening Period, participants who meet the eligibility criteria will receive open-label 
treatment. During the Core Treatment Period, participants will receive IV infusions of 
aducanumab approximately every 4 weeks for a total treatment duration of 100 weeks (a total of 
26 doses). The aducanumab dosing regimen will be 10 mg/kg following this titration: 1 mg/kg 
for the first 2 doses, 3 mg/kg for the next 2 doses, 6 mg/kg for the next 2 doses, and 10 mg/kg 
thereafter. Eligible participants will then enter the LTE treatment period and continue dosing on 
10 mg/kg aducanumab Q4W for an additional 52 weeks (a total of 152 weeks of continuous 
treatment). The EOT Visit will occur at Week 102 for participants who do not enter the LTE 
treatment period and at Week 154 for participants who enter LTE treatment period. Participants 
will have a safety FU Visit 18 weeks after their last dose of study treatment. 
Individual dose adjustments may also be implemented in participants who develop ARIA. 
For Schedule of Events, see tables in protocol Section 4.2. 
 
 
 
 
 
  
 
 
  
 
 
 
2.3. Study Conduct Following Announcement of Study Termination   
On 19 September 2023, Biogen announced the decision to initiate early termination of the 
EMBARK study. At that time, all subjects had completed the core treatment period, and over 
600 subjects were in LTE treatment period.  
The requirement for scheduling the last dose visit and last safety follow-up visit was later 
updated as described in Table 1. Non-France participants were required to have the last-dose 


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visit prior to 31 October 2023, and the safety follow-up visit 18 weeks after their last dose (+/-5 
days) and no later than March 8th, 2024. 
As there was no available post-trial compassionate access mechanism in France, French 
participants were allowed to remain on treatment as planned and complete the EMBARK LTE in 
full. As a result, the decision for early termination of the EMBARK study did not impact French 
participants in the study. 
aducanumab program, EMBARK study 
termination activities were initiated in France on 31 January 2024.  Participants from France 
were required to have the last-dose visit prior to 01 May 2024, and the safety follow-up visit 12 
weeks after their last dose (+/-5 days) and no later than 24 July 2024.
Table 1 
Summary of Updates on Last Dose Visit and Safety Follow-up Visit since 
the Announcement of Study Termination 
 
Global excluding France 
France 
Date of 
study 
updates 
Last dose visit 
Follow-up visit  
Last dose visit 
Follow-up visit  
19Sep2023 
Prior to 
19Oct2023 
18 weeks after the 
last dose 
Prior to 
19Oct2023 
18 weeks after the last 
dose 
28Sep2023 
Prior to 
31Oct2023 
18 weeks after the 
last dose 
Study continues 
as originally 
planned 
31Jan2023   
No later than 
31Mar2024 
No later than 
01May2024
30 days after last dose 
and no later than 
01Jun2024 
22Feb2024   
18 weeks after their 
last dose (+/-5 days) 
and no later than 
08Mar2024 
  
12 weeks (90 days) 
after their last dose (+/-
5 days) and no later 
than 24Jul2024 
Changes to Study Execution Following Announcement of Study Termination  
The changes to study execution in France sites involve the following, as described in 221AD304 
Protocol Clarification Letter 13Feb2024. 
1. End of Treatment (EoT) visit (Section 4.2, Table 3)  
In Version 4 of the protocol, Section 4.2 Schedule of Events Table 3 currently includes 
timepoints for the 
 as well as clinical efficacy and 
safety assessments.  


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Clarification Statement 
Due to the discontinuation of the Aducanumab program and the early termination of the study, 
. 
Also, to reduce participant burden, the clinical efficacy assessments will be removed, leaving 
only safety assessments. 
2. Follow-up/End of Study (FU/EOS) Visit: assessments and timing (Section 4.2, Table 3) 
Version 4 of the current protocol mandates that participants return for a Follow-up/End of Study 
visit (also referred to as the safety follow-
152 weeks (see Section 4.2, Table 3, Schedule of Activities).
Clarification Statement 
Due to the discontinuation of the Aducanumab program and the early termination of the study, 
all participants will be asked to complete their Follow-up/End of Study Visit 12 weeks (+/  5 
Treatment Visit, the number of assessments that need to be completed is now reduced to lessen 
participant burden. These assessments are reported below in Table 2. If a participant has had 
their last dose of study treatment and it has been more than 12 weeks since their last dose and the 
participant has not had their safety follow-up, then they should complete a safety follow-up 
within the next 30 days, as defined in Table 2. 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 




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Study Assessments 
Week 154/End of Treatment 
Visit (within 2 weeks of last 
dose) 
Follow up/End of Study 
Visit (12 weeks after last 
dose +/- 5 days) 
C-SSRS 
X 
X 
This will now be completed
Brain MRI
X
AE Reporting
Monitor and record continuously throughout the study
Concomitant Therapy and
Procedures 
Monitor and record continuously throughout the study 
SAE Reporting
Monitor and record continuously throughout the study
2.4. Sample Size Considerations   
Given that the study population depends on the feeder studies, no sample size was determined for 
this study. 
At the time that the feeder studies were stopped in March 2019, approximately 2600 participants 
had received treatment in 1 of the feeder studies. At the time of study planning, Biogen estimated 
that of these 2600 participants, approximately 2400 participants could be eligible based on 
inclusion and exclusion criteria to participate in Study 221AD304.
A total of 1865 participants were screened in study 221AD304 and were from studies 
221AD301, 221AD302, 221AD103, and 221AD205. Of these, 1696 participants were enrolled 
across 305 sites globally.
3. Definitions 
3.1. Dates and Points of Reference 
1. Study Day 1: the date of the first dose of aducanumab in the study
2. Study Day 
a.
For a date on or after Study Day 1
Study Day = (Date of Interest)  (Study Day 1) + 1 
b. For a date before Study Day 1 
Study Day = (Date of Interest)  (Study Day 1) 
3. First dose date and last dose date 
The first dose date in the study is date of the first dose of aducanumab in 221AD304 
study, the last dose date in the study is the date of the last dose of aducanumab in 
221AD304 study.


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The first and last dose date in the core treatment period are the dates of the first and 
last dose of aducanumab received before scheduled Week 102 visit respectively.  
The first and last dose date in LTE treatment period are the dates of the first and the 
last dose of aducanumab received after scheduled Week 102 visit. 
4. End of Treatment (EOT) 
EOT date for the study is the last dose date in the core treatment period for subjects 
who did not receive any aducanumab in scheduled LTE visits, or the last dose date in 
the LTE treatment period if subject had received at least one dose of aducanumab in 
scheduled LTE visits.
EOT date for the core treatment period is the last dose date in core treatment period. 
EOT date for the LTE treatment period is the last dose date in LTE treatment period. 
5. End of Study (EOS) 
EOS date for the study is the End of Study date recorded on the End of Study eCRF 
page.  If the EOS date is missing, then the EOS date will be imputed using the very 
last date of any assessment done as completed in RAVE or in any vendor database if 
the EOS date is missing. 
For subjects who received the aducanumab in LTE visits, the EOS date for the core 
treatment period is defined as one day before the first dose date in LTE treatment 
period and those subjects will be considered as completer for the core treatment 
period. Otherwise, the EOS date for the core treatment period is the same as the EOS 
date for the study.
According to the eCRF Completion Guidelines, the End of Study eCRF must be 
completed for every subject enrolled in the study. For subjects who did not enter 
Long-Term Extension (LTE): A Completer is a subject who completed all visits as 
mandated by protocol inclusive of the Week 102 EOT visit and the Week 118 FU 
visit. A subject who discontinued treatment early and remains in study in the protocol 
specific follow schedule, inclusive of Week 102, is also considered as Complete. 
For subjects who entered LTE: A Completer is a subject who completed all visits as 
mandated by protocol inclusive of the Week 154 EOT visit and the Week 170 FU. A 
subject who discontinued treatment early and remains in study in the protocol specific 
follow schedule, inclusive of Week 154, is also considered as Complete.  
6. Visit window for by-visit analysis 
For data that are summarized by visit, assessment from all scheduled visits and 
unscheduled visits will be mapped to an appropriate analysis visit using a windowing 
scheme as described in each section. 
Unless otherwise specified, if there is more than 1 value in the same analysis visit 
window for a certain parameter for a participant, then the closest record to the target 


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visit day will be used for the by visit analysis. If there are 2 values in the same 
analysis visit window with the same distance from the target visit day for a certain 
parameter for a participant, then the record with the later date will be used for the by 
visit analysis.  If there are 2 values on the same day for a certain parameter for a 
participant, then the record with the later time will be used for the by visit analysis.  
7. Baseline values is defined as the most recent non-missing measurement collected 
prior to the first dose in the study or as the last non-missing measurement collected 
during screening for subjects not dosed. 
8. Change from 221AD304 baseline will be defined as post-baseline value minus 
221AD304 baseline value. 
9. Percent change from baseline will be defined as post-baseline value minus baseline 
value then divided by baseline value. 
10. Treatment Emergent 
An adverse event is regarded as treatment emergent if the event has onset date/time 
on or after the first dose date/time of study treatment, or was reported prior to the first 
dose and subsequently worsens in severity after first dose date. Additional criteria to 
determine treatment emergent are described in Section 5.7.2.1. 
3.2. Study Treatment 
During the Core Treatment Period, participants will receive IV infusions of aducanumab 
approximately Q4W for a duration of 100 weeks (a total of 26 doses). The aducanumab dosing 
regimen will be 10 mg/kg following this titration: 1 mg/kg for the first 2 doses, 3 mg/kg for the 
next 2 doses, 6 mg/kg for the next 2 doses, and 10 mg/kg thereafter. Eligible participants will 
then enter the LTE treatment period and continue dosing on 10 mg/kg aducanumab Q4W for an 
additional 52 weeks (a total of 152 weeks of continuous treatment). 
The safety analysis groups are defined based on historical exposure of BIIB037 in feeder studies 
including 0 dose of BIIB037, pre-treated with BIIB037 with 0 dose of 10 mg/kg, and with >0 
dose of 10 mg/kg. 
3.3. Study Treatment Periods
 Core period 
For subjects who received at least one dose of study treatment in LTE visits, core period is from 
the first dose of treatment in the study to before the first dose date in LTE period. For subjects 
who did not receive any dose in any LTE visits, core treatment period is from the first dose in 
study to the very last date of any assessment done as completed in RAVE or in any vendor 
database. 
 Long-term extension period 


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Long-term extension period, also called LTE period, is from the first dose date in LTE treatment 
period to the very last date of any assessment done as completed in RAVE or in any vendor 
database. 
3.4. Key Derived Variables 
This section is not applicable. 
3.5. Stratification Factors and Subgroup Variables 
3.5.1.  Stratification Factors 
This section is not applicable. 
  
 
 
 
3.6. Analysis Population
 Intent-to-treat and screen failure (ITTSF) population:  
The Intent-to-treat and screen failure population is defined as all subjects screened 
including both enrolled and screen failure subjects. 
 Enrolled population:  
The enrolled population is defined as all subjects who signed informed consent, were 
assigned a subject identification number, and met the eligibility criteria for study 
221AD304.
Modified Intent-to-treat (mITT) population: 
The modified Intent-to-treat population is defined as all subjects who received at least 
one dose of aducanumab in study 221AD304.  
 Modified Intent-to-treat (mITT) population for core period: 
The modified Intent-to-treat population for core treatment period is defined as all subjects 
who received at least one dose of aducanumab in the core period. 
 Modified Intent-to-treat (mITT) population for LTE period:  
The modified Intent-to-treat population is defined as all subjects who received at least 
one dose of aducanumab in the LTE period.  


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 Safety population:  
The safety population is defined as all subjects who received at least one dose of 
aducanumab in study 221AD304. 
 Safety population for the core period:  
The safety population is defined as all subjects who received at least one dose of 
aducanumab in the core period. 
 Safety MRI population:  
The safety MRI population is defined as all subjects who received at least one dose of 
aducanumab in study 221AD304 and had at least one post-baseline MRI assessment in 
study 221AD304.
 Safety MRI population for the core period:  
The safety MRI population is defined as all subjects who received at least one dose of 
aducanumab in the core period and had at least one post-baseline MRI assessment in the 
core period. 
 Immunogenicity population:  
The analysis population for immunogenicity is defined as all subjects who received at 
least one dose of aducanumab in study 221AD304 and had at least one post-dose sample 
evaluated for immunogenicity. 
 Immunogenicity population for the core period:  
The analysis population for immunogenicity is defined as all subjects who received at 
least one dose of aducanumab in the core period and had at least one post-dose sample 
evaluated for immunogenicity in the core period. 
 
4. List of Planned Study Analyses 
4.1. Interim Analysis 
According to the protocol, interim analyses may be conducted when the last patient is enrolled 
and when 50% of the enrolled patients have completed the study. Other interim analyses may be 
conducted at the discretion of the sponsor.  
The following interim analyses in Table 3 occurred prior to the completion of the core treatment 
period: 


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Table 3 
Summary of Interim Analysis 
Data  
Focus of analyses 
Amount of 221AD304 post-
baseline data 
Data cutoff of July 15th, 
2021 (Baseline Analysis) 
Gap period between feeder studies 
and 221AD304 baseline 
NA
Data cutoff of March 
15th, 2022 
221AD304 post-baseline data (No 
analyses comparing to external 
control were done)
420 of 1675 (25%) 
participants from feeder 
studies 221AD301 and 
221AD302 had an 
opportunity to complete the 
221AD304 Week-78 visit 
Data cutoff of August 
15th, 2022  
First analysis of 221AD304 versus 
external control: 
 221AD304 post-baseline 
data for participants from 
feeder studies 221AD301 
and 221AD302. 
 A selected number of 
analyses will be performed 
including participants from 
feeder studies 221AD103 
and 221AD205. 
 The focus of analyses will 
include the primary and 
secondary objectives as 
well as selected 
 
Approximately 1180 
of 1675 (70%) 
participants from 
feeder studies 
221AD301 and 
221AD302 will have 
had an opportunity to 
complete the 
221AD304 Week-78 
visit. 
All but one 
participant will have 
had an opportunity to 
complete the 
221AD304 Week-52 
visit.
4.2. Primary Analysis
The primary analysis of Study 221AD304 focuses on the core primary endpoints described in 
Section 2.1.1 and will be performed after all subjects have completed the core treatment period, 
either by completing the Week 118 follow-up visit or by entering the LTE treatment period. At 
the time of announcement of early study termination on 19 September 2023, all subjects had 
completed the Week 102 visit and only a few subjects had not completed the Week 118 follow-
up visit.   
As described in Section 2.1, the core primary and LTE 
 
 


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. However, the core primary endpoints assess these variables during the core 
period only (see Section 3.3 for further details), while the 
 
 
 
 
The core secondary objectives and endpoints (see Section 2.1.2) are not described in the protocol 
but were developed as part of an interim statistical analysis plan (version 2.0). This interim 
analysis used a data cutoff date of August 15th, 2022 (see Table 3) and comprised the primary 
efficacy analysis of study 221AD304 versus an external control using clinical endpoints and 
. The analysis of the secondary objectives and endpoints will be summarized 
in the 221AD304 (EMBARK) CSR addendum. 
4.3. Final Analysis
The final analysis of study 221AD304 will be performed at the end of the study after the last 
participant completes the last visit of the study and the final database is locked. The final 
analysis will include all data collected during the entire Study including both the core period and 
the LTE period.  
Following the decision to terminate the study early, an abbreviated CSR is planned. As such, the 
final analysis will focus on evaluating the long-term safety and tolerability of aducanumab as 
described in the 
 in Section 2.1.4. Disposition, baseline 
characteristics, demographics, exposure, and protocol deviation data will also be summarized to 
provide supporting information for the review of safety. 
5. Statistical Methods for Planned Analyses 
5.1.  General Principles 
This statistical analysis plan (SAP) defines the analysis scope for the Primary Analysis and the 
Final Analysis. 
Summary tables will be presented using descriptive summary statistics. For continuous variables, 
summary statistics will generally include: number of subjects with data, mean, standard 
deviation, median, 25% percentile, 75% percentile, minimum and maximum. For categorical 
variables, this will generally include: number of subjects randomized or dosed, number with 
data, and the percent of those with data in each category. 
All analyses will be summarized by safety analysis groups (0 dose of BIIB037, pre-treated with 
BIIB037 with 0 dose of 10 mg/kg, >0 dose of 10 mg/kg, subtotal of pre-treated with BIIB037, 
and overall total; analysis display SA in Appendix 9), unless otherwise specified. Where 
indicated, the analyses will be repeated by safety analysis group stratified by


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As noted in Section 1, due to the early termination of the study, an abbreviated CSR is planned. 
The data that will 
be summarized are full safety data, and data on disposition, baseline, demographics, exposure, 
and protocol deviations.  
All analyses will be done based on data collected during the entire study including the core and 
the LTE periods. Where specified, a subset of analyses will comprise the Primary Analysis and 
summarize safety and tolerability data from the core period only. 
There will be no statistical testing for any endpoints. 
The statistical software, SAS® version 9.4 or above will be used for all summaries and analyses.
5.2.  Participant Accountability  
Disposition will be summarized for all subjects enrolled by safety analysis groups (see Appendix 
9). The summary data will include number of subjects enrolled, number of subjects withdrawn 
prior to dosing, number (%) of subjects dosed, number (%) of subjects who completed the 
treatment/study, and number (%) of subjects who discontinued treatment and/or withdrew from 
the study. The denominator for all the percentage calculation is the number of subjects dosed. 
For subjects who discontinued treatment and/or withdrew from the study, the reasons for 
discontinuation and/or withdrawal, days on treatment and days on study will be listed.  The 
disposition will also be summarized by core period and LTE period separately.  
Number of subjects dosed will be summarized by feeder studies.  
5.3. Demographic and Baseline Characteristics 
Demographics, baseline characteristics, medical history and AD treatment history will be 
summarized for the mITT population.  
The demographic data including age, gender, ethnicity, race, height, weight, and body mass 
index (BMI) will be summarized. Age will also be categorized and presented using the following 
subgroups: <=60, 61-70, 71-80, 81-85, >85. In addition, Asian ethnicity will be summarized for 
the following subclassification: Chinese, Indian, Japanese, Korean, and other. 
, 221AD304 baseline clinical assessment including CDR global score, CDR-SB, 
CDR cognitive subscore, CDR functional subscore, MMSE, ADAS-Cog 13, 
, 
number of years of formal education, number of years since first AD symptom, number of years 
since diagnosis of AD, and AD symptomatic medication use at 221AD304 baseline (yes or no; 
see Section 5.5.2 for definition of AD symptomatic medication use at 221AD304 baseline). 
-20, 21-26, 27-30. Subject listings will be 
generated for demographics and baseline characteristics. 
Medical history collected at EMBARK baseline will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA version 26.1 or later). The number (%) of subjects with history 


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(including both ongoing and not ongoing medical conditions) will be summarized by system 
organ class and preferred term.
5.4.  Protocol Deviations 
Protocol deviations identified during site monitoring will be captured in a Protocol Deviation log 
and categorized as major or minor deviations based on Protocol Deviation Classification. The 
major protocol deviations will be summarized for the mITT population. Major and minor 
protocol deviations for all mITT subjects will be listed. Major protocol deviations related to 
COVID-19 will be summarized and all protocol deviations related to COVID-19 will be listed.  
Subjects with protocol alternations due to COVID-19 will be listed based on the data on the 
protocol alternations due to COVID-19 collected from the COVID-19 Impact log CRF page.   
5.5. Study Treatment Exposure and Concomitant Medications 
5.5.1.  Study Treatment Exposure and Study Drug Compliance 
Summary of study drug exposure and compliance will be provided. Number of infusions 
(aducanumab) received will be summarized as a categorical variable (categories of 1-5, 6-10, 11-
15, 16-20, 21-25, 26-30, 31-35, 36-39, and >39) as well as a continuous variable. Number of 
weeks on study treatment (aducanumab), calculated as (date of last dose  date of first dose 
+29)/7, will be summarized as a categorical variable (every 8 weeks) as well as a continuous 
variable. Percentage of study treatment taken up to the last dose, calculated as (the actual number 
of infusions / by the number of infusions a subject is expected to take until the date of last 
infusion) ×100, will be summarized as a continuous variable.  
Due to the use of titration regimen in the study and possible dose suspension due to ARIA, 
another summary table will be provided including the following information in the study: 
number of infusions at each dose level (1 mg/kg, 3 mg/kg, 6 mg/kg and 10 mg/kg, respectively) 
summarized as a categorical variable as well as a continuous variable, number of subjects with 
dose increase (1 to 3 mg/kg, 3 to 6 mg/kg and 6 to 10 mg/kg, respectively), maximum dose level 
received, and cumulative dose (as a continuous variable).  
Both drug exposure/compliance and titration summary tables will be repeated for the core period. 
A listing of study drug administration records, including dose level at each infusion, cumulative 
number of infusions and cumulative dose will be provided. 
5.5.2. Concomitant Medications and Non-Drug Therapies 
The number (%) of subjects taking concomitant medication and non-drug therapies will be 
summarized for the mITT population. Concomitant medications and non-drug therapies will be 
listed.  
All concomitant medications will be coded using the World Health Organization (WHO) 
medication dictionary. All concomitant non-drug therapies will be coded using the MedDRA 
dictionary (version 26.1 or later).  A concomitant medication/therapy will be defined as any 
therapy that was taken on or after the day of the first dose of study drug. This includes therapies 


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that start prior to the initiation of the first dose if their use continues on or after the date of first 
dose. To define concomitant use for therapies with missing start or stop dates, the following 
additional criteria will be used:
 if both the start and stop dates of a therapy are missing, that therapy will be considered 
concomitant. 
 if the start date of a therapy is missing and the stop date of that therapy fall on or after the 
date of the first dose, that therapy will be considered concomitant.  
 if the start date of a therapy is prior to the date of the first dose and the stop date of that 
therapy is missing and the therapy is listed as continuing, that therapy will be considered 
concomitant, or
 if the start date of a therapy is prior to the date of the first dose and the stop date of that 
therapy is missing and the therapy is not listed as continuing, that therapy will be 
considered non-concomitant. 
For a therapy with a partial start date, the year/month of the therapy date will be compared to that 
of the first dosing date to determine whether the therapy is concomitant.
AD symptomatic medications taken concomitantly at 221AD304 baseline are defined as AD 
symptomatic medications that were being taken at the time of the first dose in 221AD304 study, 
i.e., started prior to the first dose and continued until after the first dose. AD symptomatic 
medications are defined as anticholinesterase (cholinesterase inhibitors) and memantine drugs in 
the WHO medication dictionary (version: WHODrug Global B3 Sep2023 or later version if 
applicable). 
The number (%) of subjects taking concomitant AD symptomatic medications, number of 
subjects using Cholinesterase inhibitors only, Memantine only, or both at the 221AD304 baseline 
will be summarized. 
5.6. Efficacy Endpoints 
As discussed in Section 2.1, no efficacy analysis will be performed.
5.7. Safety Endpoints 
5.7.1. General Considerations 
The primary estimand employs the treatment-policy strategy to evaluate the safety of BIIB037 
determined by the following 4 attributes: 
 Population: Intended population for BIIB037 defined through the study 
inclusion/exclusion criteria. All subjects in the safety population will be used in 
analyzing this estimand
 Variable: adverse events 


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 Handling intercurrent events: regardless of intercurrent events including treatment 
discontinuation and use of concomitant therapies 
 Population-level summary: incidence of adverse events 
The Safety population will be used for safety analyses of AEs, clinical laboratory data, Columbia 
Suicide Severity Rating Scale (C-SSRS) data, ECG data and vital sign data (all the safety data 
except for ARIA data). Safety MRI population will be used for analyses of ARIA data. 
In general, AEs will be summarized based on incidence and incidence proportion. Incidence is 
defined as the number of subjects who experienced an event. Incidence proportion (%) is defined 
as the number of subjects who experienced an event divided by the total number of subjects in 
the analysis population, i.e., percentage. Each subject will be counted only once within each 
category.
All AEs will be coded using the MedDRA dictionary (version 26.1).
When analyzing data for the core period or LTE period, an event will be assigned to one period 
by the start date. The event duration will be based on the start date and the end date of that event.  
5.7.2. Clinical Adverse Events 
5.7.2.1. 
Treatment-emergent AEs (TEAEs) 
All AEs will be analyzed based on the principle of treatment emergence.  A treatment-emergent 
AE is defined as an AE that started or worsened after the start of first infusion of study treatment 
in 221AD304 study.  
To define treatment emergence for AEs with missing start or stop date or time the following 
additional criteria will be used:
 if both the start and stop dates for a particular AE are missing, then that AE is 
considered treatment emergent; 
 if the start date for a particular AE is missing and the stop date/time falls after the first 
dose date/time, then that AE is considered treatment emergent; 
 if the start date for a particular AE was the same as the first dose date, and the start 
time was missing, then that event is considered treatment emergent. 
For AEs with a partial start date, the year/month of the event date will be compared to that of the 
first dosing date to determine whether the event is treatment emergent. 
Only TEAEs will be included in the AE tables, unless otherwise specified. Listings of AEs will 
include all events, whether treatment-emergent or not. 
5.7.2.2. 
Summary and incidence analysis 
An overall summary of AE table will be presented by safety analysis group as well as safety 
summarized: the number of subjects with any AE, with any AE by maximum severity, the 






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5.7.3. AE of Special Interest 
5.7.3.1. 
Background 
ARIA-E and ARIA-H are considered AEs of special interest in this study. Protocol section 7.2.1 
describes ARIA management and dose disposition guidelines. Since ARIA is a brain MRI 
finding, ARIA data are collected under two data sources: (1) safety MRI data as recorded on 
brain MRI worksheet by central MRI reader; (2) AE eCRF. For each ARIA event, the 
information of start/end date, severity, locations in brain regions and status on MRI scan is 
collected on the brain MRI worksheet by central MRI reader. ARIA severity is determined by the 
central MRI reader based on number and size of the ARIA regions on imaging. An AE record is 
then entered into the eCRF by the investigator with the start/end date and severity information 
from brain MRI worksheet, and with information on the symptomatic status and action taken 
towards study drug. If ARIA is symptomatic, the symptoms will be entered into AE eCRF and 
the severity of the symptoms will be determined by the investigator. AE eCRF data will be used 
as the primary source for ARIA analysis as it contains the complete information of ARIA as well 
as associated symptoms. Safety MRI data will also be used to show the consistency between two 
data sources, provide details on MRI assessments, and for any specific analysis that requires 
information from MRI.
ARIA includes ARIA-E (vasogenic edema) and ARIA-H (hemorrhage). ARIA-H includes 
ARIA-H microhemorrhage, ARIA-H macrohemorrhage and ARIA-H superficial siderosis. Table 
5 shows the reported term on MRI worksheet, the corresponding reported term on AE eCRF, and 
the MedDRA preferred term for each type of ARIA. 
Table 5 
Verbatim Terms and MedDRA terms for ARIA 
AESI 
Verbatim term 
MedDRA preferred term 
ARIA-E 
Asymptomatic ARIA-E or 
Symptomatic ARIA-E
Amyloid related imaging 
abnormality-oedema/effusion 
ARIA-H  
microhemorrhage
Asymptomatic ARIA-H 
(Microhemorrhage) or 
Symptomatic ARIA-H 
(Microhemorrhage) 
Amyloid related imaging 
abnormality-microhaemorrhages and 
haemosiderin deposits 
ARIA-H superficial 
siderosis 
Asymptomatic ARIA-H 
(Superficial Siderosis) or 
Symptomatic ARIA-H 
(Superficial Siderosis)
Superficial siderosis of the central 
nervous system 
ARIA-H  
macrohemorrhage 
Asymptomatic ARIA-H 
(Macrohemorrhage) or 
Symptomatic ARIA-H 
(Macrohemorrhage) 
ARIA-H macrohemorrhages could be 
coded to various preferred terms, 
depending on type of hemorrhage and 
location of hemorrhage. 
Example: cerebral haemorrhage


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Events of ARIA-H macrohemorrhage have been added to the analysis of ARIA events based on 
historical considerations for the aducanumab program. These AEs were reported by Investigators 
brain MRI worksheet. Because of the limitations of the MedDRA coding for such events (there is 
no MedDRA PT that is consistently used for ARIA-H macrohemorrhage), the event reporting 
included additional free text to describe other pertinent details of the event, such as the 
hemorrhage location. 
For any specific ARIA event, the start date of the duration is the date of the MRI assessment that 
initially identifies the ARIA event, and the end date of the duration is the date of the MRI 
assessment that shows the complete resolution of this ARIA event (in the case of ARIA-E), or 
the date of the MRI assessment that shows ARIA being stable (in the case of ARIA-H). Stable is
a decrease in number, size, severity, or number of locations between 2 
consecutive MRIs including the initial detection MRI and the follow-up MRIs performed 4 
weeks (±5 days) later.  
If the severity increases, or the event changes from asymptomatic to symptomatic, or from non-
serious to serious, more AE records will be added to eCRF to capture the change with new 
start/end AE dates (the end date of the previous record will be the start date of the next record). 
For analysis, records with changes in severity or symptomatic status or seriousness are 
considered as a single ARIA event. The severity/symptomatic status/seriousness for that event is 
defined as the worst level among all the AE records that belong to that event. 
If the same type of ARIA event happens again after the previous event has ended and both events 
occurred within the 221AD304 study, then it is considered a recurrent event of ARIA of that 
type. Recurrent events will be referred as the second event, the third event, etc.  
If the duration based on MRI of an ARIA-E event overlaps with the duration based on MRI of an 
ARIA-H event, then these 2 ARIA events are considered as concurrent events. 
All planned analyses described below are listed in Table 6. All analyses will be presented by 
safety analysis groups for the overall study. Where indicated, the analyses will be repeated by 
safety analysis groups stratified by 
 or for the core period.   
5.7.3.2. 
Incidence and summary of ARIA 
Incidence of ARIA-E, ARIA-H, ARIA-E and ARIA-H (not necessarily concurrent), concurrent 
ARIA-E and ARIA-H, ARIA-E or ARIA-H, isolated ARIA-H (only ARIA-H, no ARIA-E), 
ARIA-H microhemorrhage, ARIA-H macrohemorrhage and ARIA-H superficial siderosis will 
be summarized based on both AE eCRF and MRI data, which will be stratified by ARIA-E status 
(No ARIA-E vs Had ARIA-E) in the feeder study when applicable. If there is any discrepancy in 
incidence between the two data sources, a listing of the subjects and ARIA events with 
discrepancy will be provided.  
Number of subjects with each type of ARIA, maximum severity and worst symptomatic status of 
the type of ARIA will be summarized based on AE eCRF by safety analysis groups and safety 
ity and worst 


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symptomatic status of each type of ARIA will also be summarized by safety analysis groups 
among subjects with ARIA in the study.   
Onset of ARIA events will be summarized to present number of first and total ARIA and ARIA-
E events, number of first and total symptomatic ARIA and ARIA-E events, and number of first 
and total serious ARIA and ARIA-E events. 
ARIA-E resolution and ARIA-H stabilization will be summarized, and the following information 
will be presented: number of subjects with ARIA-E and ARIA-H, total number of ARIA-E and 
ARIA-H events, number of ARIA-E and ARIA-H events resolved and not resolved while on 
study, and MRI duration of the resolved ARIA-E and ARIA-H events. The MRI duration will be 
summarized as categorical variable (categories of 0-4, 0-8, 0-12, 0-16, 0-20, and >20 weeks). 
An incidence table of AEs considered by the investigator to be related to ARIA by system organ 
class and preferred term will be provided, as well as a listing of these AEs.  
Symptomatic ARIA will also be summarized. Number of subjects with symptomatic ARIA, 
number of symptomatic ARIA events, and MRI severity and symptomatic severity will be 
presented.  
Number of subjects with serious or severe ARIA, or serious or severe ARIA symptoms will be 
summarized. Serious or severe ARIA-related AEs will be summarized by preferred term. 
Summary of first ARIA-E events table based on AE eCRF will summarize the number of 
subjects with a first event of ARIA-E, the MRI severity of the events, the symptomatic status of 
the events, the severity of the symptoms for symptomatic events, whether the event is an SAE, 
number of resolved and unresolved events, duration of the resolved events, time from first 
infusion in study to onset, number of doses received since the start of the study to onset, dose 
level of the last infusion received prior to onset, dosing status (continue as planned, dose 
interrupted, dose reduced, or dose discontinued) after the events, and the number of subjects with 
recurrent ARIA-E events.   
Summary of recurrent ARIA-E events based on AE eCRF will present the following 
information: number of ARIA-E event per subject, number of cumulatively ARIA-E events per 
subject, number of subjects with a first ARIA-E event and at least 1 dose and MRI after 
resolution of the first ARIA-E event, number of subjects experienced recurrent ARIA-E. 
A listing of subjects who withdrew from the study with unresolved ARIA-E will be provided 
with the details of the event including the duration from onset to last follow-up.  
A summary of ARIA-H will be provided for participants with or without ARIA-E in the study. 
MRI assessments for subjects with ARIA-E, ARIA-H microhemorrhage, ARIA-H superficial 
siderosis, ARIA-H macrohemorrhage, other MRI abnormalities at postbaseline, and other 
ischemic abnormalities at postbaseline will be listed. The last dose level received before the MRI 
scan will be provided in those listings. 








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5.7.5.1. 
Quantitative analyses 
For numeric laboratory parameters, actual values will be summarized by visit. Number of 
evaluable subjects, mean, standard deviation, median, 25% and 75% quartiles, minimum and 
maximum values will be presented at each visit.  
Plots of mean actual values (with standard error) for numeric laboratory parameters at each visit 
will be provided.  
Summary of change from 221AD304 baseline and percent change from 221AD304 baseline for 
numeric laboratory parameters will be presented at each visit. Number of evaluable subjects, 
mean, standard deviation, median, 25% and 75% quartiles, minimum and maximum values will 
be presented at each visit.  
Visit windows for by visit summaries 
For laboratory by visit summaries, the analysis visit should be defined using visit windows (see 
Table 7).   
Table 7 
Visit Windows for Laboratory by Visit Summaries
Analysis visit 
Target visit day 
Analysis visit window 
221AD304 baseline
1 
Last value prior to the first dose of aducanumab 
Week 52
365
[2, 539] 
Week 102
714
[540, 896] 
Week 154
1078 
>=897 
5.7.5.2. 
Qualitative analyses 
visit window in the quantitative analyses). 
Shift analyses 
 
Shifts from 221AD304 baseline to high/low status will be presented for hematology, blood 
chemistry and urinalysis numeric parameters, and shifts from 221AD304 baseline to abnormal 
(positive) will be presented for urinalysis categorical parameters.  Shift to low includes normal to 
low, high to low, and unknown to low; Shift to high includes normal to high, low to high, and 
unknown to high. Subjects need to have at least one post-baseline evaluation and a baseline value 
not low or high or positive (including missing) to be included in the analysis. 






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a) Listing of C-SSRS for subjects with post-baseline suicidal ideation, suicidal behavior, or 
non-suicidal self-injurious behavior 
b) Listing of C-SSRS for subjects with post-baseline suicidal ideation 
c) Listing of C-SSRS for subjects with post-baseline suicidal behavior 
5.7.7. ECG Data 
The 12-lead electrocardiograms (ECG) data will be summarized using shift table based on 
subjects with at least one post-baseline ECG assessment and whose baseline ECG assessment 
was not abnormal. This includes shift from normal or unknown at baseline to abnormal post-
baseline, shift from normal or unknown at baseline to not adverse event or abnormal post-
baseline, and shift from normal or unknown at baseline to adverse event post-baseline. 
The number and percentage of subjects with shifts to abnormal ECG, not adverse events, and 
subjects with shift to abnormal ECG, adverse events at any time during post-baseline will be 
summarized. 
5.7.8. Vital Sign Data 
Vital sign parameters include body temperature, systolic blood pressure, diastolic blood pressure, 
heart rate, respiration rate and weight. Vital signs will be measured with the subject supine and 
after the subject has been resting for at least 10 minutes.  
Clinically relevant post-baseline abnormalities in vital signs will be presented with criteria 
defined below:  
 
< 36 °C and > 38°C for body temperature  
 
< 60 bpm and > 100 bpm for pulse  
 
< 90 mmHg, > 140 mmHg and > 160 mmHg for systolic blood pressure  
 
< 50 mmHg, > 90 mmHg and > 100 mmHg for diastolic blood pressure  
 
  
< 12 breaths/min and > 20 breaths/min for respiratory rate
5.7.9. Physical Examination and Neurological Examination  
Clinically significant abnormalities found at a physical examination or neurological examination 
will be reported as AEs and will be included in the analyses of AEs.  
 
 
 
 


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5.10. Immunogenicity 
5.10.1. Background 
Definition of baseline value
221AD304 baseline value is defined as the latest immunogenicity data collected prior to the first 
dose. If no immunogenicity data are collected prior to the first dose, 221AD304 baseline value is 
missing and will be treated as anti-drug antibody negative for immunogenicity analyses.  
Treatment-emergent anti-aducanumab antibody positive responses 
Post-baseline positive anti-aducanumab antibody responses are defined as treatment-emergent if 
(1) a subject is antibody negative at 221AD304 baseline; or (2) a subject is antibody positive at 
221AD304 baseline but the post-baseline antibody response is more than 2-fold increase in titer 
compared to the 221AD304 baseline response.
Persistent and transient positive responses:  
Subjects with treatment-emergent positive anti-aducanumab antibody responses will be further 
classified as transient positive under the following conditions:  
 if only a single positive evaluation occurs which is not at the last available time point  
 or if more than 1 positive evaluation occurs < 112 days (16 weeks) apart and there is at 
least 1 negative evaluation that occurs thereafter 
Subjects with treatment-emergent positive anti-aducanumab antibody responses will be further 
classified as persistent positive under the following conditions:  
 
 
 or if a single positive evaluation occurs at the last available time point with no further 
negative results available 
5.10.2. Immunogenicity Analysis 
Immunogenicity population will be used to analyze immunogenicity data. An immunogenicity 
summary table will be presented showing the number of subjects with anti-aducanumab antibody 
positive response at any time (including baseline), the number of subjects with treatment-
emergent anti-aducanumab antibody positive response at each scheduled test visit, the number of 
subjects with transient positive response, and the number of subjects with persistent positive 
response. A listing of immunogenicity data for subjects with anti-aducanumab antibody positive 
results will also be provided. The immunogenicity summary table will be repeated for the core 
period. 
Visit windows for by visit summaries 
For immunogenicity by visit summaries, the analysis visit should be defined using visit windows 
(see Table 9 below).  










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0 dose of BIIB037
Pre-treated with BIIB037 
 
0 dose of 10 mg/kg 
>0 dose of 10 mg/kg 
 
 
Total 
 
 
Total 
 
Total