Conditions: Parkinson's Disease
Keywords: BIIB054 Alpha-synuclein
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 357
Healthy volunteers: no

Brief summary:
The primary objective of the study is to evaluate the clinical efficacy of BIIB054 via dose response using the change from baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Total Score.

The secondary objectives of the study are to evaluate the dose-related safety of BIIB054, to evaluate the clinical efficacy of BIIB054 via MDS-UPDRS total score, to assess the pharmacokinetic (PK) profile of BIIB054, to evaluate the clinical efficacy of BIIB054 based on MDS-UPDRS subparts, to evaluate the pharmacodynamic effects of BIIB054 on the integrity of nigrostriatal dopaminergic nerve terminals and to evaluate the immunogenicity of BIIB054.

Detailed description:

Arms:
arm 1: Year 1: Participants will receive matching placebo to BIIB054 on Day 1 and then every 4 weeks.

Year 2: Participants who received placebo in year 1 will be randomized into one of the active treatment arms in year 2 and will receive BIIB054 intravenous (IV) infusion on Week 52 and then every 4 weeks. arm 2: Participants will receive BIIB054 250 milligrams (mg) intravenous (IV) infusion on Day 1 and then every 4 weeks. arm 3: Participants will receive BIIB054 1250 mg IV infusion on Day 1 and then every 4 weeks. arm 4: Participants will receive BIIB054 3500 mg IV infusion on Day 1 and then every 4 weeks.

Interventions: intervention 1: Placebo intervention 2: BIIB054
Intervention descriptions: intervention 1: Administered as specified in the treatment arm intervention 2: Administered as specified in the treatment arm.

Protocol document:
Prot_000.pdf: 




Protocol 228PD201
Version 8
Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
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TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ....................................................................................................2
1.
SPONSOR INFORMATION .....................................................................................10
2.
LIST OF ABBREVIATIONS.....................................................................................11
3.
SYNOPSIS .................................................................................................................13
4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR STUDY
228PD201 ...................................................................................................................17
4.1.
Study Schematic .........................................................................................................17
4.2.
Schedule of Activities.................................................................................................20
5.
INTRODUCTION......................................................................................................40
5.1.
Overview of Parkinson’s Disease...............................................................................40
5.2.
Current Therapies for Parkinson’s Disease ................................................................41
5.3.
Profile of Previous Experience with BIIB054............................................................42
5.3.1.
Nonclinical Experience...............................................................................................42
5.3.2.
Clinical Experience.....................................................................................................43
5.4.
Study Rationale...........................................................................................................43
5.5.
Rationale for Dosing Regimen ...................................................................................44
5.5.1.
Rationale for Comparator/Reference Product or Placebo ..........................................46
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................47
7.
STUDY DESIGN .......................................................................................................52
7.1.
Study Overview ..........................................................................................................52
7.1.1.
Year 1 (Placebo-Controlled Portion of the Study) .....................................................52
7.1.2.
Years 2 through 4 (Active-Treatment Dose-Blinded Portion of the Study)...............52
7.2.
Overall Study Duration and Follow-Up .....................................................................53
7.2.1.
Screening ....................................................................................................................53
7.2.2.
Study Treatment..........................................................................................................54
7.2.2.1.
Year 1..........................................................................................................................54
7.2.2.2.
Years 2 through 4........................................................................................................54
7.2.2.3.
Treatment with Parkinson’s Disease Medications......................................................54
7.2.3.
Follow-Up Visits and Final Visit................................................................................55
7.2.3.1.
Cohort A, Year 1.........................................................................................................55
7.2.3.2.
Cohort B, Year 1.........................................................................................................55


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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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7.2.3.3.
Cohorts A and B, Years 2 through 4...........................................................................56
7.2.4.
Unscheduled Visits .....................................................................................................57
7.2.5.
Early Termination.......................................................................................................57
7.2.6.
Study Stopping Rules .................................................................................................58
7.3.
End of Study ...............................................................................................................58
8.
SELECTION OF SUBJECTS ....................................................................................59
8.1.
Inclusion Criteria ........................................................................................................59
8.2.
Exclusion Criteria.......................................................................................................60
9.
ENROLLMENT, REGISTRATION, AND RANDOMIZATION ............................65
9.1.
Screening and Enrollment...........................................................................................65
9.2.
Randomization and Registration of Subjects..............................................................65
9.3.
Blinding Procedures....................................................................................................66
10.
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY...........................................67
10.1.
Discontinuation of Study Treatment...........................................................................67
10.2.
Withdrawal of Subjects From Study...........................................................................67
11.
STUDY TREATMENT USE .....................................................................................69
11.1.
Regimen......................................................................................................................69
11.1.1.
Year 1 (Placebo-Controlled Portion of the Study) .....................................................69
11.1.2.
Years 2 through 4 (Active-Treatment Dose-Blinded Portion of the Study)...............69
11.2.
Modification of Dose and/or Treatment Schedule......................................................69
11.3.
Concomitant Therapy and Procedures........................................................................69
11.3.1.
Concomitant Therapy .................................................................................................69
11.3.1.1.
Allowed Concomitant Therapy...................................................................................70
11.3.1.2.
Disallowed Concomitant Therapy..............................................................................71
11.3.2.
Concomitant Procedures.............................................................................................72
11.4.
Continuation of Treatment..........................................................................................72
11.5.
Compliance.................................................................................................................72
12.
STUDY TREATMENT MANAGEMENT................................................................73
12.1.
BIIB054 ......................................................................................................................73
12.1.1.
BIIB054 Preparation...................................................................................................73
12.1.2.
BIIB054 Storage.........................................................................................................73


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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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12.1.3.
BIIB054 Handling and Disposal.................................................................................74
12.1.4.
BIIB054 Accountability..............................................................................................74
12.2.
Placebo........................................................................................................................74
13.
CLINICAL FUNCTION, PHARMACOKINETIC, AND 
PHARMACODYNAMIC ASSESSMENTS..............................................................75
13.1.
Clinical Function Assessments...................................................................................75
13.1.1.
Motor Function and Related Activities of Daily Living.............................................75
13.1.1.1.
Movement Disorder Society Sponsored Revision of the Unified Parkinson’s 
Disease Rating Scale (Including Modified Hoehn and Yahr Scale)...........................75
.76
76
.77
77
77
77
78
78
78
78
78
78
78
79
13.2.
Pharmacokinetic Assessments....................................................................................79
13.3.
Pharmacodynamic Assessments.................................................................................79
13.3.1.
Imaging Assessments..................................................................................................80
13.3.1.1.
Single-Photon Emission Computed Tomography Scan of the Dopamine 
Transporter..................................................................................................................80
80
80
81
82
14.
SAFETY ASSESSMENTS ........................................................................................83


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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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14.1.
Clinical Safety Assessments.......................................................................................83
14.2.
Laboratory Safety Assessments..................................................................................84
14.3.
Immunogenicity Assessments ....................................................................................85
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................86
15.1.
Definitions ..................................................................................................................86
15.1.1.
Adverse Event.............................................................................................................86
15.1.2.
Serious Adverse Event................................................................................................86
15.1.3.
Prescheduled or Elective Procedures or Routinely Scheduled Treatments................87
15.2.
Safety Classifications..................................................................................................87
15.2.1.
Investigator Assessment of Events.............................................................................87
15.2.2.
Relationship of Events to Study Treatment, to the Lumbar Puncture 
Procedure, and to the Radioligand..............................................................................88
15.2.3.
Severity of Events.......................................................................................................89
15.2.4.
Expectedness of Events ..............................................................................................89
15.3.
Monitoring and Recording Events..............................................................................89
15.3.1.
Adverse Events ...........................................................................................................89
15.3.2.
Serious Adverse Events..............................................................................................90
15.3.3.
Immediate Reporting of Serious Adverse Events.......................................................90
15.3.3.1.
Deaths .........................................................................................................................90
15.3.4.
Suspected Unexpected Serious Adverse Reactions....................................................91
15.4.
Procedures for Handling Special Situations ...............................................................91
15.4.1.
Pregnancy ...................................................................................................................91
15.4.2.
Overdose.....................................................................................................................91
15.4.3.
Medical Emergency....................................................................................................91
15.4.3.1.
Unblinding for Medical Emergency...........................................................................92
15.5.
Contraception Requirements ......................................................................................92
15.6.
Safety Responsibilities................................................................................................93
15.6.1.
The Investigator..........................................................................................................93
15.6.2.
Biogen.........................................................................................................................94
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........95
16.1.
Safety..........................................................................................................................95
16.1.1.
Analysis Population....................................................................................................95


Protocol 228PD201
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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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16.1.2.
Methods of Analysis...................................................................................................95
16.1.2.1.
Adverse Events ...........................................................................................................95
16.1.2.2.
Clinical Laboratory Results........................................................................................96
16.1.2.3.
Vital Signs ..................................................................................................................96
16.1.2.4.
Electrocardiogram.......................................................................................................96
16.1.2.5.
Physical and Neurological Examinations...................................................................96
16.1.2.6.
Columbia Suicide Severity Rating Scale....................................................................96
16.1.2.7.
Magnetic Resonance Imaging.....................................................................................96
16.2.
Pharmacodynamics – Imaging Analyses....................................................................96
16.2.1.
Analysis Population....................................................................................................96
16.2.2.
Methods of Analysis...................................................................................................97
16.3.
Pharmacokinetics........................................................................................................97
16.3.1.
Analysis Population....................................................................................................97
16.3.2.
Methods of Analysis...................................................................................................97
16.4.
Immunogenicity Data .................................................................................................98
16.4.1.
Analysis Population....................................................................................................98
16.4.2.
Methods of Analysis...................................................................................................98
16.5.
Clinical Function ........................................................................................................98
16.5.1.
Analysis Population....................................................................................................98
16.5.2.
Methods of Analysis...................................................................................................98
16.5.2.1.
Year 1 (Placebo-Controlled Portion of the Study) .....................................................99
16.5.2.2.
Years 2 through 4 (Active-Treatment Dose-Blinded Portion of the Study) 
and Overall Experience.............................................................................................100
101
101
101
101
102
102
16.8.
Interim Analyses.......................................................................................................102
16.9.
Sample Size Considerations .....................................................................................103
17.
ETHICAL REQUIREMENTS .................................................................................106


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17.1.
Declaration of Helsinki.............................................................................................106
17.2.
Ethics Committee......................................................................................................106
17.3.
Subject Information and Consent .............................................................................107
17.4.
Subject Data Protection ............................................................................................107
17.5.
Compensation for Injury...........................................................................................108
17.6.
Conflict of Interest....................................................................................................108
17.7.
Registration of Study and Disclosure of Study Results............................................108
18.
ADMINISTRATIVE PROCEDURES.....................................................................109
18.1.
Study Site Initiation..................................................................................................109
18.2.
Quality Control and Quality Assurance....................................................................109
18.3.
Monitoring of the Study............................................................................................109
18.4.
Study Funding...........................................................................................................110
18.5.
Publications...............................................................................................................110
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION......................111
19.1.
External Contract Organizations...............................................................................111
19.1.1.
Contract Research Organization...............................................................................111
19.1.2.
Interactive Response Technology.............................................................................111
19.1.3.
Electronic or Remote Data Capture..........................................................................111
19.1.4.
Central Laboratories for Laboratory Assessments ...................................................111
19.1.5.
Central Facility for Other Assessments ....................................................................112
19.1.6.
Clinical Assessments ................................................................................................112
19.2.
Study Committees.....................................................................................................112
19.2.1.
Advisory Committee.................................................................................................112
19.2.2.
Independent Data Monitoring Committee................................................................112
19.3.
Changes to Final Study Protocol ..............................................................................112
19.4.
Ethics Committee Notification of Study Completion or Termination......................113
19.5.
Retention of Study Data............................................................................................113
19.6.
Study Report Signatory.............................................................................................113
20.
REFERENCES .........................................................................................................114
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.......................................117
APPENDIX 1.
REMOTE VISITS – SCHEDULE OF ACTIVITIES ......................................118


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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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LIST OF TABLES
Table 1:
Cohort A: Infusions 1–3 (Year 1)...............................................................................20
Table 2:
Cohort A: Infusions 4–13 (Year 1).............................................................................24
Table 3:
Cohort B: Infusions 1–13 (Year 1).............................................................................27
Table 4:
Cohorts A and B:  Infusions 14–25 (Year 2)..............................................................32
Table 5:
Cohorts A and B:  Infusions 26–41 (Years 3 and 4)...................................................35
Table 6:
Cohorts A and B Early Termination and End of Study: 4 Weeks After Last 
Dose Through Final Visit ...........................................................................................38
Table 7:
Projected Median Steady-State Serum AUCtau, Steady-State Cmax and Safety 
Margins for Proposed Phase 2a Doses, Based on Simulations of 1000 PD 
Subjects.......................................................................................................................45
Table 8:
Estimated Sample Size Per Group (Planned) ...........................................................104
Table 9:
Estimated Sample Size Per Group Based on Actual Enrollment (Before 
Drop-Outs)................................................................................................................105
Table 10:
Estimated Sample Size Per Group Based on Actual Enrollment (After 
Adjusting for 10% Drop-Out At Week 52................................................................105
Table 11:
Estimated Sample Size Per Group Based on Actual Enrollment (After 
Adjusting for 15% Drop-Out At Week 72................................................................105
Table 12:
Cohorts A and B: Remote Visits in Year 2...............................................................118
Table 13:
Cohorts A and B: Remote Visits in Years 3 and 4 ...................................................120
Table 14:
Cohorts A and B Remote Early Termination and End of Study: 4 Weeks 
After Last Dose Through Final Visit........................................................................122
LIST OF FIGURES
Figure 1:
Study Design...............................................................................................................17
Figure 2:
Overview of Study Dosing .........................................................................................19
Figure 3:
Simulated Cerebrospinal Fluid Concentration – Time Profiles for Proposed 
Doses in the Phase 2a Study.......................................................................................46
Figure 4:
Flowchart for Week 96 to End of Study for Subjects Eligible to be Treated in 
Years 3 and 4 ..............................................................................................................57
Figure 5:
Candidate Models for Dose-Response......................................................................104


Protocol 228PD201
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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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1.
SPONSOR INFORMATION
Biogen MA Inc. is the Sponsor of the study. 
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
For urgent medical issues in which the study’s 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 contract research 
organization (CRO) and other third parties; however, Biogen retains overall accountability for 
these activities.


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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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2.
LIST OF ABBREVIATIONS
α-syn
alpha-synuclein
AE
adverse event
Anti-HBc
hepatitis B core antibody
Anti-HBs
hepatitis B surface antibody
APTT
activated partial thromboplastin time
AUC
area under the concentration-time curve 
AUCtau
area under the concentration-time curve within a dosing interval
CI
confidence interval
Cmax
maximum observed concentration
COMT
catechol-O-methyltransferase
CRO
contract research organization
C-SSRS
Columbia Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
DaT
dopamine transporter
DaTscan™
ioflupane I123 radioligand for imaging of dopamine transporter
DBP
diastolic blood pressure
DHA
Directions for Handling and Administration
eCRF
electronic case report form
EC50
concentration at 50% of maximum observed biologic effect
EC90
concentration at 90% of maximum observed biologic effect
ECG
electrocardiogram
Emax
maximum effect
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide-1
HBsAg
hepatitis B surface antigen
HCVAb
hepatitis C virus antibody
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
independent data monitoring committee
IgG
immunoglobulin G
INR
international normalized ratio
IRT
interactive response technology


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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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ISF
interstitial fluid
ITT
intent-to-treat
IV
intravenous
LB
Lewy body
LN
Lewy neurite
LP
lumbar puncture
LSmeans
least-squares means
mAb
monoclonal antibody
MAO-B
monoamine oxidase type B
MCP-MOD
multiple comparison procedure-modelling
MDS-UPDRS
Movement Disorder Society Sponsored Revision of the Unified 
Parkinson’s Disease Rating Scale
MMRM
mixed model for repeated measures
MRI
magnetic resonance imaging
NOAEL
no observed adverse effect level
NSAID
nonsteroidal anti-inflammatory drug
PD
Parkinson’s disease
PK
pharmacokinetic(s)
PT
prothrombin time
QALY
quality-adjusted life year
 
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SBR
striatal binding ratio
SD
standard deviation
SNCA
alpha-synuclein gene
SNRI
serotonin norepinephrine reuptake inhibitor
SPECT
single-photon emission computed tomography
SSRI
selective serotonin reuptake inhibitors
SUSAR
suspected unexpected serious adverse reaction


Protocol 228PD201
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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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3.
SYNOPSIS
Protocol Number:
228PD201
Protocol Title:
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study, with an Active-Treatment 
Dose-Blinded Period, to Evaluate the Efficacy, Safety, 
Pharmacokinetics, and Pharmacodynamics of BIIB054 in 
Subjects with Parkinson’s Disease
Version Number
8
Name of Study Treatment:
BIIB054
Study Indication:
Parkinson’s disease (PD)
Study Rationale
BIIB054 is a human monoclonal antibody that targets 
aggregated forms of alpha-synuclein (α-syn), and is being 
developed by Biogen for the treatment of PD.
Neuropathological, genetic, and functional animal studies all 
point to a causative role of α-syn in the pathogenesis of PD.  
Alpha-synuclein is a primary structural component of Lewy 
bodies (LBs) and Lewy neurites, which are the pathological 
hallmarks of PD.  Anatomical distribution, density, and 
severity of LB pathology are associated with clinical disease 
severity. Owing to the strong links between α-syn and PD 
pathogenesis, it has become an important target for potential 
disease-modifying treatments.
BIIB054 binds with subnanomolar affinity to the N-terminal 
region (aa 4-10) of α-syn and does not bind to other 
homologous members of the synuclein family.  The murine 
chimeric version of BIIB054 improved synuclein pathology 
in transgenic animal models that either overexpress α-syn or 
express mutated α-syn.  This version of BIIB054 also 
improved motor performance in 2 different transgenic 
animal models that express mutated α-syn.
Early stage PD patients were selected as the test population 
in this study, as binding of α-syn may be more effective in 
modifying the course of the disease when less neuronal 
damage is evident and the spread of disease pathology is 
more limited.




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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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the last dose at Week 96.
Study Location:
Approximately 85 sites are planned globally.
Number of Planned Subjects:
Approximately 311 subjects will be enrolled.
Study Population:
This study will be conducted in subjects aged 40 to 80 years 
at the time of informed consent, who have been diagnosed 
with clinically established PD within a maximum of 3 years 
prior to Screening, with no other known or suspected cause 
of Parkinsonism.  Subjects must not receive any treatment 
for PD within 12 weeks prior to Day 1, and total duration of 
any previous PD treatment regimens should not exceed 
30 days.  Subjects should have a score of ≤2.5 on the 
Modified Hoehn and Yahr Scale, and should have screening 
DaT/SPECT results demonstrating activity consistent with 
neurodegenerative Parkinsonism.  Detailed criteria are 
described in Section 8.
Treatment Groups:
In Year 1 (the placebo-controlled portion of the study), 
subjects will be randomized into the following 4 parallel 
dosing arms, to receive treatment every 4 weeks:

Arm 1:  Placebo

Arm 2:  BIIB054 250 mg

Arm 3:  BIIB054 1250 mg

Arm 4:  BIIB054 3500 mg 
Subjects will be enrolled in 2 cohorts.  Cohort A will be 
randomized first and will include approximately 24 subjects.  
Cohort B will be randomized after all subjects in Cohort A 
complete Week 12 assessments and will include 
approximately 287 subjects.  Dose levels, number of 
treatment arms, and number of subjects per arm in Cohort B 
may be adjusted based on the safety and PK data from 
Cohort A and on review by the independent data monitoring 
committee (IDMC).  Any changes will be documented in a 
protocol amendment.  Per this protocol amendment 
(Version 8), the actual enrollment is 357 subjects with 
29 subjects randomized to Cohort A and 328 subjects 
randomized to Cohort B.
After all subjects in Cohort A complete Week 12 
assessments (28 days after their third infusion) and before 


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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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dosing any subjects in Cohort B, all available safety and PK 
data will be reviewed by the IDMC.  Only the IDMC will 
review unblinded data.  The Sponsor, site staff, and subjects 
will remain blinded.  No subjects in Cohort B may be dosed 
until the IDMC review is complete.  During the review 
period, subjects in Cohort A will continue to be dosed every 
4 weeks. 
Subjects will continue treatment in Year 2 (the 
active-treatment dose-blinded portion of the study).  
Subjects who received placebo in Year 1 will be randomized 
to 1 of the active-treatment arms to receive BIIB054 in 
Year 2.  Subjects who received BIIB054 (250, 1250, or 
3500 mg) in Year 1 will continue with the same dose 
regimen in Years 2 through 4.  
Duration of Treatment and 
Follow-up:
The total duration of study participation for each subject 
will be at most 178 weeks, including a 6-week Screening 
period, a 48-week placebo-controlled treatment period, up to 
a 112-week active-treatment dose-blinded period, and a 
12-week follow-up period.  Not all subjects will have the 
opportunity for dosing past Year 2/Week 96. 


Protocol 228PD201
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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR STUDY 228PD201
4.1.
Study Schematic
Figure 1:
Study Design


Protocol 228PD201
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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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DaT = dopamine transporter; IDMC = independent data monitoring committee; PK = pharmacokinetic(s); SPECT = single-photon emission computed 
tomography
a Prior to Infusion 14 (first dose of Year 2), subjects who received placebo in Year 1 will be randomized to 1 of the active-treatment groups; these subjects will 
receive BIIB054 in Year 2.  Subjects who received BIIB054 in Year 1 will continue with the same dose regimen in Years 2 through 4.  Dosing will continue until 
the last subject in the study has had his or her Week 96 Visit.  Not all subjects will have the opportunity for dosing past Year 2/Week 96.
Note: As of Protocol Version 8, actual enrollment was 357 subjects with 29 subjects randomized to Cohort A and 328 subjects randomized to Cohort B.




Protocol 228PD201
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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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20
4.2.
Schedule of Activities
Table 1:
Cohort A: Infusions 1–3 (Year 1)
Tests and assessments
Screening
≤42 days 
before 
Day 11
Infusions 1-3
Day 1/Baseline, Day 29 (±1 day), & Day 57 (±1 day)
Clinic Visits
Day 43
(Safety 
Telephone 
Call)
Day 2, 30, 
58
Day 4, 60
Day 8, 36, 
64
Day 15, 71
Pre-
infusion2
0m
Time after End of Last Infusion
≤10m
1h
±15m
2h
±15m
4h
±30m
24h
±2h
72h
-2h/+1d
168h
±24h
336h
±24h
336h
±24h
Informed consent
X
Verification of eligibility
X3
Medical history
X
X3
Body weight
X
X
Height
X
Physical/neurological examination4
X
X3
12-lead ECG5
X
X
X
X
Vital signs6
X
X
X
X
X
X
X
X
X
HbA1c
X
Urine pregnancy test7
X
Serum pregnancy test7
X
FSH test8
X
Coagulation panel including platelet count
X
Hematology, blood chemistry, urinalysis
X
X
X
X
HBsAg, anti-HBc, anti-HBs, HCVAb, HIV
X
Drug screen
X
X3


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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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21
Tests and assessments
Screening
≤42 days 
before 
Day 11
Infusions 1-3
Day 1/Baseline, Day 29 (±1 day), & Day 57 (±1 day)
Clinic Visits
Day 43
(Safety 
Telephone 
Call)
Day 2, 30, 
58
Day 4, 60
Day 8, 36, 
64
Day 15, 71
Pre-
infusion2
0m
Time after End of Last Infusion
≤10m
1h
±15m
2h
±15m
4h
±30m
24h
±2h
72h
-2h/+1d
168h
±24h
336h
±24h
336h
±24h
Brain MRI12
X
DaT/SPECT12
X
Randomization
X3
Study treatment infusion13
X
BIIB054 serum PK sampling
X14
X
X15
X15
X15
X16
X
X17
X
Serum for anti-BIIB054 antibodies
X
X18
MDS-UPDRS (full scale), includes 
Modified Hoehn and Yahr Scale20
X
X 
X
X






Protocol 228PD201
Version 8
Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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24
Table 2:
Cohort A: Infusions 4–13 (Year 1) 
Tests and assessments
Infusions 4-13, 
Week (±3d) 
PK Visits,
Week 
(±3d)
Year 1
Week 52,
(±3d)2
12
16 20 24 28 32 36 40 44
48
22, 34, or 
461
Physical/neurological examination3,4
X
Body weight3
X
X
X
X
X
X
X
X X
X
X
12-lead ECG3,5 
X
X
X
X
Vital signs3,6
X
X
X
X
X
X
X
X X
X
X
Urine pregnancy test3,7
X
X
X
X
X
X
X
X X
X
Coagulation panel including platelet count8
X
X
Hematology, blood chemistry, urinalysis3
X
X
X
X
X
X
X
X X
X
X
Brain MRI10 
X
X
DaT/SPECT10
X
X
Study treatment infusion11
X
X
X
X
X
X
X
X X
X
BIIB054 serum PK sampling
X12 X12
X13
X12
X
X12
Serum for anti-BIIB054 antibodies3
X
X
X
MDS-UPDRS (full scale), includes Modified Hoehn and Yahr Scale3,14 
X
X
X
X
X
X






Protocol 228PD201
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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
27
Table 3:
Cohort B: Infusions 1–13 (Year 1)
Tests and assessments
Screening
≤42d 
Before
Day 11
Day 12
Baseline/ 
Infusion 1
Safety 
Telephone 
Calls
1d & 7d 
after 
Infusion 12
Infusions 2-13, Week (±3d)
PK 
Visits,
Week 
(±3d)
Year 1
Week 52,
(±3d)4
42
Safety 
Telephone 
Calls
1d & 7d 
after 
Infusion 22
82
Safety 
Telephone 
Calls
1d & 7d 
after 
Infusion 32
12 16
20
24
28
32 36 40
44
48
22, 34, 
or 463
Informed consent
X
Verification of eligibility
X5
Medical history
X
X5
Body weight6
X
X5
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Physical/neurological examination7
X
X5
X
12-lead ECG6,8
X
X5
X
X
X
X
Vital signs6,9
X
X5
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c
X
Urine pregnancy test 6,10
X5
X
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy test10
X
FSH test11
X
Coagulation panel including platelet count
X
X12,13
X12,13
Hematology, blood chemistry, urinalysis6
X
X5
X
X
X
X
X
HBsAg, anti-HBc, anti-HBs, HCVAb, 
HIV
X
Drug screen
X
X5


Protocol 228PD201
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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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28
Tests and assessments
Screening
≤42d 
Before
Day 11
Day 12
Baseline/ 
Infusion 1
Safety 
Telephone 
Calls
1d & 7d 
after 
Infusion 12
Infusions 2-13, Week (±3d)
PK 
Visits,
Week 
(±3d)
Year 1
Week 52,
(±3d)4
42
Safety 
Telephone 
Calls
1d & 7d 
after 
Infusion 22
82
Safety 
Telephone 
Calls
1d & 7d 
after 
Infusion 32
12 16
20
24
28
32 36 40
44
48
22, 34, 
or 463
Brain MRI16
X17
X
X
DaT/SPECT16
X17
X
X
Randomization
X5
Study treatment infusion18
X
X
X
X
X
X
X
X
X
X
X
X
X
BIIB054 serum PK sampling19
X5
X
X
X
X
X
X
X
X
Serum for anti-BIIB054 antibodies6
X5
X
X
X
X
MDS-UPDRS (full scale), includes 
Modified Hoehn and Yahr Scale6,23
X
X5
X
X
X
X
X
X
X






Protocol 228PD201
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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc.
31
 
 
The “Since Last Visit” version of the C-SSRS will be administered at all clinic visits following the Day 1/Baseline assessment.  If the Investigator has any 
concern regarding the completed C-SSRS, the subject should be referred to psychiatric evaluation based on local standards of care.
26Nonserious AEs that occur during the Screening period and that are assessed by the Investigator as related to the ligand will be captured by the sites on the AE 
electronic case report form. After the first dose of study treatment, all AEs are collected, both related and unrelated to the ligand (see Section 15.3.1).


Protocol 228PD201
Version 8
Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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32
Table 4:
Cohorts A and B:  Infusions 14–25 (Year 2)
Tests and assessments
Year 2
Week 
52
(±3d)1
Safety 
Telephone 
Calls 1d & 
7d after 
Infusion 142
Infusions 15-253
Week (±3d)
Unsched 
Visit3,4
Infus-
ion 14
56
60
64
68
72
76
80
84
88
92
965
Body weight6
X
X
X
X
X
Physical/neurological examination7
X
X
X
12-lead ECG6,8
X
X
X
Vital signs6,9
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test 6,10
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, blood chemistry, urinalysis6
X
X
X
Brain MRI12
X
DaT/SPECT12
X
Randomization13
X
Study treatment infusion14
X
X
X
X
X
X
X
X
X
X
X
X
BIIB054 serum PK sampling15
X
X
X
X
Serum for anti-BIIB054 antibodies6
X
X
X
MDS-UPDRS (full scale), includes 
Modified Hoehn and Yahr Scale6,17
X
X
X
X
X






Protocol 228PD201
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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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35
Table 5:
Cohorts A and B:  Infusions 26–41 (Years 3 and 4)
Tests and Assessments1
Year 32, 3
Infusions 26-38, 
Week (±3d)
(13 monthly doses)
Year 42, 3
Infusions 39-41, 
Week (±3d)
(3 monthly doses)
Unsched 
Visit3, 4
100
104
108
112
116
120
124
128
132
136
140
144
148
152
156
160
Body weight5
X
X
X
X
X
Physical/neurological examination6
X
X
X
12-lead ECG5,7
X
X
Vital signs5, 8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test5,9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, blood chemistry, urinalysis5
X
X
X
Brain MRI11
X
DaT/SPECT11
X
Study treatment infusion12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BIIB054 serum PK sampling13
X
X
Serum for anti-BIIB054 antibodies5
X
X
MDS-UPDRS (full scale), includes 
Modified Hoehn and Yahr Scale5,15
X
X
X
X
X
X










Protocol 228PD201
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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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40
5.
INTRODUCTION 
BIIB054 is a human monoclonal antibody (mAb) that targets aggregated forms of 
alpha-synuclein (α-syn), and is being developed by Biogen for the treatment of Parkinson’s 
disease (PD).  
5.1.
Overview of Parkinson’s Disease 
PD is the second most common neurodegenerative disease in the world [Bertram and Tanzi 
2005].  In the United States, estimates of its prevalence vary, ranging from 430,000 to 
approximately 1 million affected persons [Beck 2016].  In Europe, available estimates of PD
prevalence in recent generalizable studies of populous European Union countries [Hobson 2005; 
Morgante 2008; Totaro 2005; Wickremaratchi 2009] range from 0.11% in the United Kingdom 
[Hobson 2005] to 0.16% in central Italy [Totaro 2005]; these would correspond to a range of 
600,000 to 800,000 persons living with PD in the European Union in 2016.  In Israel, prevalence 
varies depending on the population studied, and is markedly higher among Israeli Jews (0.33%, 
or 28,000 cases in 2016) [Chillag-Talmor 2011] compared to the Israeli Arab population (0.04%, 
or 3400 cases) [Masalha 2010].  Across the world, the prevalent burden of PD is expected to 
double from 2005 to 2030, from approximately 4.5 million to 9 million cases [Dorsey 2007].  
The incidence of PD increases with age; the disease is rare before age 50 years but affects up to 
4% of the population in the oldest age groups [de Lau and Breteler 2006].  Men may be 1.5 times 
more likely to be affected than women, especially among patients older than 70 years of age, in 
western populations [Twelves 2003].  Severe disability or death may be expected in 35% of the 
patients within 5 years, in 65% of patients within 10 years, and in 80% of patients within 
15 years of onset [Poewe 2006; Schrag and Banks 2006; Schrag 2000; Shulman 2006].  The
economic burden of PD in the United States was approximately $15 billion in 2010 [Kowal 
2013].
PD is clinically diagnosed by the constellation of rest tremor, bradykinesia, and rigidity.  Other 
frequent symptoms include stooped posture, hypomimia, hypophonia, micrographia, and loss of 
postural stability.  Although diagnosis of PD by clinicians is reasonably accurate [Jellinger 
2016], pathologic hallmarks seen postmortem are required to make a definitive diagnosis.  These 
include the loss of dopaminergic neurons in the pars compacta in the substantia nigra, and the 
presence of Lewy bodies (LBs) and Lewy neurites (LNs), which are α-syn-containing inclusions 
[Gelb 1999].  Cross-sectional and longitudinal studies show a relationship between the 
anatomical distribution of LB pathology and the presence or absence of key motor, psychiatric, 
autonomic, and cognitive symptoms.  Similarly, the density and severity of LB pathology are 
associated with the severity of motor and cognitive impairment [Beach 2009] and the number of 
late-stage PD complications (falls, residential care, cognitive impairment, and psychosis) 
[Kempster 2010].
The motor syndrome of PD is related to the degeneration of dopaminergic neurons, although 
catecholaminergic and serotonergic brain stem neurons may also degenerate.  The discovery of 


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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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genes related to PD has helped elucidate the molecular mechanism involved in the pathogenesis 
of PD.  Genetic studies have identified point mutations, as well as duplications and triplications 
of the α-syn gene (SNCA) that are associated with familial, early onset, and aggressive PD 
[Nuytemans 2010].  There is a link between seemingly sporadic PD and α-syn gene expression in 
that polymorphisms in the promoter region and reduced epigenetic silencing are associated with 
an increased risk of PD [Jowaed 2010].  Taken together, these genetic studies suggest a 
dose-response relationship and argue for a gain of function in PD [Martin 2011].  The current 
view of the molecular mechanism suggests that aggregation of α-syn is influenced by both 
genetic and environmental factors.  The main pathological finding associated with PD is 
formation of protein aggregates in the brain, which are composed mostly of fibrillar α-syn.  
Further, it is believed that synuclein abnormalities in the brain trigger or are otherwise related to 
a series of dysfunctions at the cellular level, including abnormalities of vesicular trafficking, 
mitochondrial function, autophagy, and consequent inflammation [Olanow and Kordower 2009]. 
5.2.
Current Therapies for Parkinson’s Disease
Current treatment for PD is directed at providing relief from motor symptoms associated with the 
disease.  There is no neuroprotective therapy that halts or delays disease progression [Connolly 
and Lang 2014].  Motor impairment is most closely linked to reductions in dopamine in the basal 
ganglia of the brain.  Most treatments that are specifically approved for PD increase 
dopaminergic transmission within the brain.  The primary treatments for PD include 
administration of levodopa, often in conjunction with inhibitors of dopamine metabolism, 
including monoamine oxidase type B (MAO-B) and catechol-O-methyltransferase (COMT) 
inhibitors, or dopamine agonists.  Levodopa is the mainstay of treatment in PD and is the most 
effective treatment for motor symptoms.  It is typically given in combination with a dopamine 
decarboxylase inhibitor (benserazide or carbidopa).  Dopamine agonists (pramipexole, 
ropinirole, and rotigotine) are frequently used as first-line agents, especially in younger patients.  
Other first-line therapies include MAO-B inhibitors (selegiline and rasagiline) and amantadine.  
Other agents are used in an off-label fashion to treat particular symptoms, e.g., anticholinergics 
such as trihexyphenidyl and benztropine for tremors.  All these agents offer varying levels of 
success in treating motor symptoms, but none of them seem to change the rate of PD progression 
and all of them have adverse effects that limit their use.  
In later stages of PD, motor fluctuation and dyskinesia may limit the effectiveness of medical 
treatment despite combining the first-line agents plus COMT inhibitors to try and increase 
dopamine levels through various pathways.  Apomorphine, a fast-acting dopamine agonist, can 
be used as rescue therapy during off periods.  Dopaminergic therapies are also administered via 
routes other than oral administration to tackle the issue of motor fluctuations by continuous 
delivery (e.g., levodopa-carbidopa intestinal gel given through gastrojejunostomy and 
subcutaneous apomorphine pump).  Surgical treatment using different techniques (generally deep 
brain stimulation) targeting various locations in the brain (thalamus, globus pallidus, and 
subthalamic nucleus) can alleviate adverse motor symptoms and has become more common, but 
it also poses unique challenges and has limitations.  Treatment options for presumptively 
nondopaminergic symptoms, such as loss of balance and freezing of gait, remain scarce.  
Rivastigmine has been approved for treatment of cognitive symptoms in PD.  Droxidopa was 


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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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42
recently approved for the treatment of orthostatic hypotension.  However, there is currently no 
approved disease-modifying therapy used to halt or delay disease progression of PD.  All 
existing treatments for PD provide only partial relief of motor symptoms and may worsen other 
symptoms.  Thus, there remains a high unmet medical need for neuroprotective agents that can 
slow or halt the progression of disease-related pathology in patients with PD.
5.3.
Profile of Previous Experience with BIIB054
5.3.1.
Nonclinical Experience
Nonclinical pharmacology, pharmacokinetic (PK), and toxicology studies have been performed 
to support clinical development of BIIB054.  In vitro and in vivo studies were conducted using 
BIIB054, a human mAb consisting of 2 immunoglobulin G (IgG) 1 heavy and 2 lambda () light 
chains connected by inter-chain disulfide bonds, or a chimeric mouse IgG2a/analog (ch12F4).  
Mouse, rat, and cynomolgus monkey were chosen as pharmacologically relevant species because 
BIIB054 binds similarly to -syn from the human, mouse, rat, and monkey. 
The binding of BIIB054 to α-syn was evaluated using purified recombinant proteins and human 
brain tissue extracts.  These studies established that BIIB054 binds to both soluble monomeric 
and aggregated forms of α-syn, with preferential binding to aggregated α-syn in diseased brain 
tissue, and is highly specific for α-syn (concentration at 50% of maximum observed biologic 
effect [EC50] of ~0.25 nM for fibrillar and EC50 of ~39 nM for soluble monomeric α-syn) relative 
to the closely related β- and γ-synucleins (no detectable binding).  Immunohistochemistry 
showed BIIB054 staining of LB pathology in brain tissue from patients with PD and dementia 
with LB. 
In vivo pharmacology studies demonstrated significant treatment effects on brain α-syn burden 
and/or motor performance with BIIB054 and ch12F4.  These studies were performed in 
transgenic mouse models, which overexpress either wild-type or mutant human α-syn under 
central nervous system-specific promoters, and, with aging, accumulate α-syn in the brain and 
develop motor function deficits.  ch12F4 also reduced α-syn pathology and restored motor 
performance in mouse models of α-syn spreading induced by intracerebrally inoculated α-syn 
fibrils.  These models recapitulate important aspects of α-syn pathology in the brain, and these 
animals exhibit motor deficits that may be directly linked to reduced dopamine.  Penetration of 
BIIB054 into the brain, binding to pathology, and a short-term rise in plasma α-syn were 
demonstrated following systemic administration.  
The PK profile of BIIB054 was determined in single-dose studies in mice, rats, and cynomolgus 
monkeys.  The toxicokinetic characteristics of BIIB054 were evaluated in 4-week, repeat-dose 
toxicology studies in monkeys and rats, and a 26-week, repeat-dose toxicology study in rats.
The following Good Laboratory Practice studies were conducted to assess the nonclinical safety 
of BIIB054:  an in vitro evaluation in human blood, two 4-week repeat-dose general toxicology 
studies in rats and monkeys, and one 26-week, repeat-dose chronic toxicology study in rats.  
Safety pharmacology assessments were conducted as part of the repeat-dose studies.  


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The treatment duration of the chronic toxicology study was 26 weeks, with an additional 
12-week recovery period.  There were no clinical observations and no drug-related animal 
deaths.  There were no clinical signs or changes in body weight, food consumption, or clinical 
pathology (serum chemistry, hematology, coagulation, or urinalysis) at the end of the 26-week 
treatment or 12-week recovery periods.  There were no gross lesions, organ weight changes, or 
microscopic observations.  BIIB054 was not immunogenic in rats; no anti-drug antibody 
response was noted under the conditions of the study.  At 13 weeks and 26 weeks, higher mean 
total protein levels and globulin levels, as well as lower mean albumin/globulin ratios, were 
present in males and females in the 150 and 450 mg/kg groups.  These findings were attributed to 
the increased levels of BIIB054 (a protein and immunoglobulin) and not considered a 
toxicological effect.  There were no BIIB054-related changes in blood chemistry after the 
12-week recovery period.  No adverse effect level for this chronic toxicology study was detected 
at the highest dose, 450 mg/kg (maximum feasible dose level based on drug concentration and 
dosing volume). 
See the Investigator’s Brochure for detailed information on nonclinical studies.
5.3.2.
Clinical Experience
A Phase 1, first-in-human study (228HV101) to evaluate single-ascending doses in healthy 
volunteers and subjects with PD was completed.  This was a randomized, placebo-controlled 
study designed to evaluate the safety, tolerability, and PK of single doses of BIIB054.
Healthy volunteers were assigned to 1 of 6 cohorts and randomized to receive a single 
intravenous (IV) dose of BIIB054 (1, 5, 15, 45, 90, or 135 mg/kg) or placebo.  Cohort 7 included 
subjects with PD, who received a single dose of BIIB054 (15 or 45 mg/kg) or placebo.
As of 19 May 2019, 48 healthy volunteers had received BIIB054 (up to a single dose of 
135 mg/kg) or placebo, and 18 subjects with PD had received BIIB054 (up to 45 mg/kg) or 
placebo.
Study 228HV101 is complete and indicated that BIIB054 was well tolerated at single doses, 
including dose levels similar to and higher than those in Study 228PD201.  See the Investigator’s 
Brochure for the most up-to-date information.
5.4.
Study Rationale
BIIB054 is a novel, human-derived mAb that targets primarily aggregated forms of α-syn and is 
being developed by Biogen for the treatment of PD.
Neuropathological, genetic, and functional animal studies all point to a causative role of α-syn in 
the pathogenesis of PD; α-syn is a primary structural component of LBs and LNs, which are the 
pathological hallmarks of PD.  The distribution of this pathology is associated with clinical 
disease severity.  Mutations and multiplications of the α-syn gene are associated with early onset 
and aggressive PD [Nuytemans 2010], and changes in expression can increase the risk for 
sporadic PD [Jowaed 2010].  Transgenic mouse models expressing mutated α-syn or exogenous 


Protocol 228PD201
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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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Biogen MA Inc.
44
wild-type α-syn recapitulate aspects of PD [Luk 2012a; Luk 2012b; Masliah 2000].  Based on the 
link between α-syn and risk for and progression of PD, interventions that reduce α-syn pathology 
may slow the clinical progression of disease; therefore, α-syn has become an important target for 
potential disease-modifying treatments.
BIIB054 binds with subnanomolar affinity to the N-terminal region (aa 4-10) of α-syn and does 
not bind to other highly homologous members of the synuclein family.  The murine chimeric 
version of BIIB054 improved synuclein pathology in transgenic animal models that either 
overexpress α-syn or express mutated α-syn.  This version of BIIB054 also improved motor 
performance in 2 different transgenic animal models that express mutated α-syn.  The ability of 
BIIB054 to bind preferentially to aggregated forms of α-syn and reduce pathology in nonclinical 
studies suggests that BIIB054 may have the potential to slow the progression of PD, and perhaps 
delay the onset of severe disability.  BIIB054 has the potential to be the first-in-class disease-
modifying therapy in PD that would fulfill a high unmet need.
This study will be conducted in subjects with PD to enable characterization of the efficacy, 
safety and PK profile of BIIB054, as well as the effect of BIIB054 on pharmacodynamic markers 
in the presence of the biological target, α-syn.  
Early stage PD patients were selected as the test population in this study and will likely be the 
target population in subsequent studies.  Binding of α-syn may be more effective in modifying 
the course of the disease and, thus, is more likely to delay disease progression when less 
neuronal damage is evident and the spread of disease pathology is more limited [Braak 2002].  
5.5.
Rationale for Dosing Regimen 
In this study, subjects will receive an IV infusion of study treatment (placebo [Year 1 only] or 
BIIB054 250 mg, 1250 mg, or 3500 mg) once every 4 weeks.  Subjects will receive a total of up 
to 41 doses: 13 doses in Year 1 (placebo-controlled portion of the study) and up to 28 doses in 
Years 2 through 4 (active-treatment dose-blinded portion of the study).  The dose levels of 
BIIB054 were selected based on in vitro data on the affinity of BIIB054 to aggregated α-syn, 
nonclinical toxicology data, and BIIB054 safety, tolerability, and PK data from healthy 
volunteers in the Phase 1 human study.
In vitro studies established that BIIB054 binds to both soluble and aggregated forms of α-syn, 
with a higher apparent binding affinity for aggregates.  The EC50 of BIIB054 for aggregated 
α-syn was estimated at approximately 0.25 nM, and the EC90 was estimated at approximately 
2.1 nM (0.0375 and 0.315 μg/mL, respectively).  These EC50 and EC90 concentrations were used 
as target values for dose selection.  See the BIIB054 Investigator’s Brochure for further details.
In the Phase 1, first-in-human study (228HV101), serum and cerebrospinal fluid (CSF) 
concentrations in healthy volunteers were described using a population PK model.  
Subsequently, estimated PK parameters as well as between subject variability and residual 
variability estimates from healthy volunteers were used to simulate 1000 serum and CSF 
steady-state profiles.  Emerging data from the PD cohort suggests that PK is similar between 
healthy volunteer and PD subjects.  To account for weight differences between healthy 


Protocol 228PD201
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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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Biogen MA Inc.
45
volunteers and the target Phase 2a population of PD subjects, the Parkinson’s Progression 
Markers Initiative study database was used as a source of weight distribution data in PD patients. 
Simulations of CSF profiles in PD subjects were conducted for several dose levels to enable dose 
selection.  CSF and brain interstitial fluid (ISF) concentrations of BIIB054 were assumed to be 
equal.  Given the favorable safety profile of BIIB054 in the previous study 228HV101 and based 
on PK modeling from that study, a fixed-dose approach is to be implemented in this study. 
Simulations based on preliminary serum and CSF data from the first-in-human study 228HV101 
indicate that for the 250 mg dose, the BIIB054 concentration in CSF and ISF at steady state is 
projected to be above EC50 for the majority of subjects (Figure 3).  The highest dose (3500 mg) 
was selected to maintain these levels above EC90, to increase the likelihood of demonstrating 
efficacy for BIIB054.  An intermediate dose of 1250 mg is expected to maintain a CSF and ISF 
level at or above EC90, as well as provide adequate separation between doses to elucidate the 
exposure-response relationship.  
Nonclinical pharmacology data also suggest that the dose of 250 mg is expected to provide 
minimal efficacy based on studies in the D-Line synuclein transgenic mouse (see the BIIB054 
Investigator’s Brochure for further details).  The estimated efficacious exposure in the mouse 
was approximately 1317 day*μg/mL.  Clearance of BIIB054 in healthy volunteers is on average 
0.1248 L/day.  Thus, using Dose = Clearance × area under the concentration-time curve (AUC), 
the projected mean minimum pharmacologically efficacious dose is approximately 164 mg.
Overall, all 3 doses are expected to be safe and well tolerated in humans.  The highest planned 
dose (3500 mg) is expected to yield median steady-state area under the concentration-time curve 
within a dosing interval (AUCtau) and maximum observed concentration (Cmax) values 
approximately 8- to 9-fold lower than those observed at the no observed adverse effect level in 
the 26-week toxicology study in rats (Table 7).  
Table 7:
Projected Median Steady-State Serum AUCtau, Steady-State Cmax and Safety 
Margins for Proposed Phase 2a Doses, Based on Simulations of 1000 PD 
Subjects
Dose (mg)
Projected parameters
Safety marginsa
AUCtau
(h*µg/mL)
Cmax (µg/mL) 
AUCtau
Cmax
250
42700
175
131
114
1250
214000
882
26
23
3500
612000
2480
9
8
AUCtau = area under the concentration-time curve within a dosing interval; Cmax = maximum observed 
concentration; NOAEL = no observed adverse effect level.
a  Calculated based on mean AUC0-168h and Cmax after the last dose of BIIB054 in the 26-week rat toxicology 
study.  AUCtau at NOAEL = AUC0-168h*4 = 5,580,000 h*µg/mL.


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Figure 3:
Simulated Cerebrospinal Fluid Concentration – Time Profiles for Proposed 
Doses in the Phase 2a Study
CSF = cerebrospinal fluid; EC50 = half-maximal effective concentration
Solid line = population median; shaded area = 5th-95th percentile
5.5.1.
Rationale for Comparator/Reference Product or Placebo 
As no disease-modifying therapy for PD is currently available, placebo is deemed to be an 
appropriate comparator.
The use of placebo does not increase the risk to subjects, since subjects are being selected for this 
study on the basis of the presence of PD symptoms of insufficient impact to demand institution 
of medical treatment at the initiation of the study.  Subjects will be allowed to start treatment for 
PD should symptom severity warrant treatment during the study. 














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received placebo in Year 1 will be randomized into 1 of the active-dosing arms for Year 2; these 
subjects will receive BIIB054 in Year 2.  Subjects who received BIIB054 (1250 mg or 3500 mg) 
in Year 1 of the study will continue with the same dose regimen in Year 2.  Subjects receiving 
the 250-mg dose in Year 1 may be randomized to 1 of the 2 highest doses of BIIB054 in Year 2 
based on IDMC review of data. No specific action related to randomization is required of 
investigators or study sites at Year 2 Week 52.
Subjects will receive 12 additional doses of BIIB054 (250, 1250, or 3500 mg) in Year 2 and up 
to 16 additional doses in Years 3 and 4.  Up until the last subject in the study has had his or her 
last dose in Year 2 of the study (Week 96 Visit), eligible subjects will be able to continue 
treatment once every 4 weeks.  
Subjects who complete dosing through Week 96 and the Final Visit 12 weeks after the last visit 
will be considered Year 2 completers in the eCRF. 
See Figure 2 for a depiction of the duration of dosing in Years 3 and 4 for subjects continuing 
dosing past Week 96.
Figure 4 presents a flowchart for dosing and procedures from Week 96 through end of study, 
including how to determine which subjects are eligible to continue dosing past Week 96.
7.2.
Overall Study Duration and Follow-Up
The total duration of study participation for each subject will be up to approximately 178 weeks, 
including a 6-week Screening period before the first study treatment infusion, a 48-week 
placebo-controlled treatment period, up to a 112-week active-treatment dose-blinded period, and 
a 12-week follow-up period.
Note: In the event of a public health emergency that results in site closure, travel restrictions, or 
the study being deprioritized at the site such that clinic visit(s) cannot occur, Remote Visits will 
be done. Use of a Remote Visit will not be done in place of an onsite visit simply due to subject 
preference. If a subject does not participate in a remote or clinic visit, a Safety Telephone Call 
must be conducted. Refer to Table 12, Table 13, and Table 14 for Remote Visit assessments.
7.2.1.
Screening
Subject eligibility for the study will be determined within 42 days prior to study randomization 
on Day 1. 
The Screening Visit assessments (excluding imaging) may be performed over 1 to 2 days, which 
need not be consecutive, to minimize subject burden.  The imaging assessments (DaT/SPECT 
and brain MRI) should be done after all other eligibility criteria have been met and before Day -7 
for Cohort A and at least 8 business days before Day 1/randomization for Cohort B, to allow 
adequate time for evaluation of the results.  


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7.2.2.
Study Treatment
Eligible subjects will report to the study site to receive study treatment administered by IV 
infusion every 4 weeks.  The infusion duration will be 1 hour (± 10 minutes).  Subjects will be 
under observation for at least 1 hour after the end of each infusion.  The Investigator or designee 
must contact the study’s Medical Monitor in advance if they would like to adjust the infusion 
duration or administration conditions based on the subject’s ability to tolerate infusion.  
7.2.2.1.
Year 1
In Year 1 (placebo-controlled portion) of the study, subjects will receive study treatment for 
48 weeks, for a total of 13 dosing visits, beginning on Day 1.
Specified assessments on Day 1, Week 24, and Week 48 in both cohorts (and on Day 29 and 
Day 57 in Cohort A only) may be completed on the day before dosing or the day of dosing (e.g., 
Day -1 or Day 1 for the Day 1 Baseline Visit), at the discretion of the Investigator, except as 
noted in the Schedule of Assessments (e.g., randomization, pregnancy test, vital signs, and 
electrocardiogram [ECG]) must be obtained pre-infusion on the day of dosing).
7.2.2.2.
Years 2 through 4
In Years 2 through 4 (active-treatment dose-blinded portion) of the study, subjects will receive 
BIIB054 every 4 weeks until the last subject in the study receives the Week 96 dose (up to 
112 weeks [28 doses]).
7.2.2.3.
Treatment with Parkinson’s Disease Medications 
Medications used to treat the symptoms of PD (hereafter referred to as symptomatic PD 
medications) will be listed in the Study Reference Manual.  Subjects should refrain from using 
symptomatic PD medications for as long as possible, and in particular for at least 6 months 
following Day 1.
The entire MDS-UPDRS assessment (Parts I to IV) should be performed as close as possible 
before subjects receive their first dose of symptomatic PD medication, either at a scheduled visit 
or included in an unscheduled visit.
It is recommended that subjects who plan to start symptomatic PD medication either outside of a 
visit window or outside of the DaT/SPECT window wait, if possible, until after the next 
DaT/SPECT to start the medication, provided that a DaT/SPECT visit is planned within 1 month.  
(As an alternative, if the subject cannot wait to start symptomatic PD medication, the 
DaT/SPECT window of ±7 days, except for Week 52 MRI and DaT/SPECT which has a -7 day 
window only to allow Year 2 dosing to be appropriately scheduled, may be expanded so that it 
extends from -28 days to +7 days.)  If the subject is not due for DaT/SPECT at the next 
scheduled visit per the Schedule of Activities, it is not necessary to have this scan performed 
prior to starting symptomatic PD medications.  


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Once they have started symptomatic PD medication, subjects should refrain from taking the PD 
medication for approximately 12 hours prior to study visits at which MDS-UPDRS 
 
assessments will be conducted (see Section 4.2).  At those visits, subjects taking PD medication 
should come to the clinic prior to taking their morning dose, and should refrain from taking their 
PD medication until after completion of the MDS-UPDRS Part III assessment 
.
See Section 13.1 for a description of the timing of clinical function assessments relative to 
administration of the symptomatic PD medication.
During Year 1 of the study (up to and including the Year 1 Week 52 Visit), subjects taking 
levodopa (preferred symptomatic PD medication) or other symptomatic PD medications should 
be encouraged to manage their symptoms with a single medication (e.g., levodopa/carbidopa or 
levodopa/benserazide).  Once subjects enter Year 2 (active-treatment dose-blinded portion of the 
study), there will be no restrictions on the number or classes of symptomatic PD medications to 
be introduced, although use of PD medications that may affect interpretation of DaT/SPECT is to 
be discouraged until the final DaT/SPECT assessment (Week 96/148 Visit).  See 
Section 11.3.1.1 for further description of the recommended PD medications.  
7.2.3.
Follow-Up Visits and Final Visit
Follow-up visits are described in the following subsections.
Subjects who withdraw prematurely from the study will be asked to return to complete an Early 
Termination Visit within 4 weeks (±3 days) of their last study treatment and a Final Visit 12 
weeks (±3 days) after their last study treatment.
7.2.3.1.
Cohort A, Year 1
During Year 1, in addition to dosing day visits, subjects in Cohort A will return to the study site 
for 12 follow-up clinic visits on Days 2, 30, and 58 (24 hours after infusions 1-3); Days 4 and 60 
(72 hours after infusions 1 and 3); Days 8, 36, and 64 (168 hours after infusions 1-3); Days 15 
and 71 (336 hours after infusions 1 and 3); 1 visit only at Week 22, 34, or 46; and at the 
Week 52 Visit.  
A subject will return to the clinic for only 1 of the 3 visits at Week 22, 34, or 46 for PK 
sampling; the timing of the visit will be randomly assigned at the time of treatment assignment.  
However, should any subject have a scheduling conflict on the assigned date, the Investigator 
may reschedule to 1 of the other 2 timeslots. 
During Year 1, subjects in Cohort A will have 1 Safety Telephone Call, on Day 43 (336 hours 
after the second infusion). 
7.2.3.2.
Cohort B, Year 1
During Year 1, in addition to dosing day visits, subjects in Cohort B will have 2 follow-up clinic 
visits:  1 visit only at Week 22, 34, or 46; and the Week 52 Visit.  


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A subject will return to the clinic for only 1 of the 3 visits at Week 22, 34, or 46 for PK 
sampling; the timing for the visit will be randomly assigned at the time of treatment assignment.  
However, should any subject have a scheduling conflict on the assigned date, the Investigator 
may reschedule to 1 of the other 2 timeslots.
During Year 1, subjects in Cohort B will have 6 Safety Telephone Calls, on Days 2, 8, 30, 36,
58, and 64 (24 hours and 168 hours after each of the first 3 doses). 
7.2.3.3.
Cohorts A and B, Years 2 through 4 
At the beginning of Year 2, in addition to the dosing visits, subjects will have 2 Safety 
Telephone Calls, 1 day and 7 days after Infusion 14 (the first infusion in Year 2).  
For the purposes of this section, Last Subject will be defined as the final subject in the study to 
complete a Week 96 Visit.  The date of the Last Subject’s Week 96 Visit will be communicated 
to all sites. As shown in Figure 4, subjects whose Week 96 Visit is more than 1 month before the 
Last Subject’s Week 96 Visit should continue dosing every 4 weeks; all other subjects should 
receive their last study dose at the Week 96 Visit. 
Following the final dose of study treatment at any time during the study, all subjects will follow 
end of study procedures as shown in Table 6: an additional visit/Early Termination Visit 4 weeks 
after the last dose, a Safety Telephone Call 8 weeks after the last dose, and the Final Visit 
12 weeks after the last dose.  Final Visit procedures should be performed at the subject’s last 
study visit, even in the case of scheduling difficulties.


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Figure 4:
Flowchart for Week 96 to End of Study for Subjects Eligible to be Treated in 
Years 3 and 4
EOS = end of study; LS = last subject; W = week.
7.2.4.
Unscheduled Visits
Unscheduled clinic visits may occur at any time, at the discretion of the Investigator, for safety-
related issues.  They may also occur to administer the MDS-UPDRS prior to the first dose of 
symptomatic PD medication, for subjects who start their medication outside of a scheduled visit.  
Assessments specified in Table 4 (Year 2) and Table 5 (Years 3 and 4) should be performed at 
every unscheduled visit; additional assessments may be performed at the Investigator’s 
discretion.
7.2.5.
Early Termination
For subjects terminating (i.e., discontinuing both study treatment and study assessments) early, it 
is recommended that the assessments of the Early Termination Visit be performed within 
4 weeks after the last dose of study treatment.  The Safety Telephone Call should be performed 


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approximately 8 weeks after the last dose, and the assessments of the Final Visit should be 
performed approximately 12 weeks after the last dose.  Final Visit procedures should be 
performed at the subject’s last study visit, even in the case of scheduling difficulties.  For Early 
Termination and end of study procedures, see Table 6.
7.2.6.
Study Stopping Rules
Biogen may terminate this study at any time, after informing Investigators.  Biogen will notify 
Investigators if the study is to be placed on hold, completed, or terminated.
For Cohort A until initiation of dosing in Cohort B: 
After evaluation of the safety, tolerability, and PK data by the IDMC, further dosing may be 
terminated if any of the following is observed:

Two similar SAEs or clinically significant AEs, unless clearly unrelated to BIIB054, are 
reported for subjects on active study treatment.

Three or more similar AEs are reported for subjects on active study treatment (unless 
these events are clearly unrelated to BIIB054) that are not tolerable, as reported by the 
subject (e.g., severe dizziness) and/or deemed a medically unacceptable risk by the 
IDMC and/or Sponsor.

Sponsor requests that dosing be terminated.
For both cohorts after initiation of dosing in Cohort B: 
Conditions that may warrant termination of the study include, but are not limited to, the 
following: 

The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study.

A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product.
7.3.
End of Study
The end of study is last subject, last visit.


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8.
SELECTION OF SUBJECTS
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Screening, or at the timepoint specified in the individual eligibility criterion listed:  
1. Able to understand the purpose and risks of the study and to provide signed and dated 
informed consent and authorization to use confidential health information in accordance 
with national and local subject privacy regulations.
2. Diagnosed with PD within a maximum of 3 years (based on month and year of diagnosis) 
prior to Screening.  Subjects must have:  
a.
An asymmetric or bilateral presentation of one of the following: 

resting tremor and bradykinesia

bradykinesia and rigidity

rigidity and resting tremor
OR 

either asymmetric resting tremor or asymmetric bradykinesia.
b. No known or suspected cause of Parkinsonism other than neurodegenerative PD.  
Subjects with drug-induced Parkinsonism (e.g., metoclopramide and flunarizine), 
metabolic identified neurogenetic disorders (e.g., Wilson’s disease), encephalitis, 
or Parkinson Plus syndromes, other forms of atypical Parkinsonian syndromes 
(e.g., progressive supranuclear palsy and multiple system atrophy), or Lewy body 
dementia are not allowed in the study.  
3. Has not received any medication for the treatment of the motor symptoms of PD 
(including, but not limited to, levodopa and levodopa-containing products, dopamine 
agonists, monoamine oxidase inhibitors, centrally-acting anticholinergics, amantadine, 
zonisamide; see list of PD medications in the Study Reference Manual) for at least 
12 weeks prior to Day 1 and, in the opinion of the Investigator, is not expected to require 
PD treatment for at least 6 months following Day 1.  Maximum total duration of prior PD 
regimens should not exceed 30 days.  Stable (at least 8 weeks) dosages of medications 
that are used to treat conditions other than PD tremor (e.g., beta-blockers, 
benzodiazepines, and barbiturates) are allowed.  Further guidance will be provided by the 
study’s Medical Monitor on a case by case basis.
4. Aged 40 to 80 years, inclusive, at the time of the main informed consent. 
5. Body mass index from 19 kg/m2 to 35 kg/m2.


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6. For Cohort A only, nonsmoker during the 6 months prior to Day 1 and willing to abstain 
from smoking throughout the study period.
7. Score of ≤2.5 on the Modified Hoehn and Yahr Scale.
8. Screening DaT/SPECT results demonstrating activity in the striatum is either 
asymmetric, absent in the putamen and/or one or both caudate nuclei, consistent with 
neurodegenerative Parkinsonism, as assessed with qualitative, visual assessment.  
DaT/SPECT images will be reviewed by a central reader to confirm eligibility.  
9. All women of childbearing potential and all men must practice highly effective 
contraception during the study and for 6 months after their last dose of study treatment. 
For further details of contraceptive requirements for this study, please refer to 
Section 15.5.
8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Screening, or at the timepoint specified in the individual criterion listed:
Medical History
1. History of or positive test result at Screening for human immunodeficiency virus (HIV).  
The requirement for testing at Screening may be omitted if it is not permitted by local 
regulations.
2. History of, or positive test result at Screening for, hepatitis C virus antibody (HCVAb).
3. Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] 
and/or total hepatitis B core antibody [anti-HBc]).  Subjects with immunity to hepatitis B
from previous natural infection (defined as negative HBsAg, positive anti-HBc, and 
positive hepatitis B surface antibody [anti-HBs]) or vaccination (defined as negative 
HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study.
4. Presence of freezing of gait.
5. MoCA score <23 or other significant cognitive impairment or clinical dementia that, in 
the opinion of the Investigator, would interfere with study evaluation.
6. Unstable psychiatric illness, including psychosis, suicidal ideation, or untreated major 
depression within 90 days before Screening, as determined by the Investigator.
7. History or Screening MRI results showing evidence of structural abnormalities that could 
contribute to the subject’s clinical state, or any finding that might pose a risk to the 
subject, or might prevent a satisfactory MRI assessment for safety monitoring.  MRI 
results will be reviewed by a central reader to confirm eligibility at Screening.


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8. History of drug or alcohol abuse within the past 5 years (as defined by the Investigator), a 
positive urine drug test, or an unwillingness to abstain from these substances during clinic 
visit days.  Subjects who test positive for cannabinoids due to occasional marijuana use, 
as determined by the Investigator, and who agree to refrain from using marijuana for the 
duration of the study may be enrolled at Investigator’s discretion, after a consultation 
with the Sponsor.  The use of cannabinoids other than marijuana (e.g., cannabinoid cream 
or gel) is acceptable, unless the use is considered to be drug abuse by the Principal 
Investigator, which is exclusionary.
9. History of severe allergic or anaphylactic reactions, or history of hypersensitivity to 
BIIB054 or any of the inactive ingredients in the drug product (refer to the Investigator’s 
Brochure for information on the clinical formulation) or to radioligands or iodine used in 
the study.  
10. Transient ischemic attack or stroke, or any unexplained loss of consciousness within 
1 year before Screening.
11. 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 before Screening.
12. History of malignancy or carcinoma.  The following exceptions may be made after 
discussion with the Sponsor: 

Subjects with cancers in remission for more than 5 years prior to Screening

Subjects with a history of basal cell or squamous cell carcinomas of the skin that 
have been completely excised and are considered cured.
13. History of any clinically significant endocrinologic, hematologic, hepatic, immunologic, 
metabolic, urologic, pulmonary, neurologic, dermatologic, renal, ischemic or 
cardiovascular, or other major diseases, as determined by the Investigator.
14. History of any brain surgery for PD (e.g., pallidotomy, deep brain stimulation, or fetal 
tissue transplant).
15. Surgery within 12 weeks before Day 1 (other than minor cosmetic surgery and minor 
dental surgery, as determined by the Investigator).
16. Clinically significant abnormal laboratory test values at Screening, as determined by the 
Investigator.
17. Chronic, uncontrolled hypertension (average of 3 systolic blood pressure [SBP] readings 
at Screening >165 mmHg or average diastolic blood pressure [DBP] ≥100 mmHg, or any 
documented SBP reading >180 mmHg or DBP ≥100 mmHg within the 3 months before 
Day 1), or orthostatic hypotension that is clinically significant as determined by the 
Investigator.


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18. Clinically significant (as determined by the Investigator) 12-lead ECG abnormalities,
including but not limited to confirmed demonstration of corrected QT interval using the 
Fridericia correction method of >460 msec [men] and >470 msec [women] before study 
treatment administration, if considered clinically significant by the Investigator. 
19. Poorly controlled diabetes mellitus, as defined by having dosage adjustment of diabetic 
medication within 3 months before dosing (Day 1) or glycated hemoglobin value ≥8% at 
Screening.
20. Screening value for hemoglobin <12 g/dL for men or <11 g/dL for women.
21. Indication of impaired liver function as shown by an abnormal liver function profile at 
Screening (e.g., values of aspartate aminotransferase, or alanine aminotransferase, or total 
bilirubin ≥2 times the upper limit of normal).
22. Indication of impaired renal function at Screening (estimated glomerular filtration rate 
<60 mL/min). 
23. Screening values of coagulation parameters including platelet count, international 
normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time 
(APTT) that are not generally within normal ranges.  Subjects with nonclinically 
significant and stable out-of-range values may be allowed in the study at the discretion of 
the Investigator, and only after a consultation with the Medical Monitor.
24. Currently active infection or serious infection (e.g., pneumonia, septicemia) within 
8 weeks before Day 1, as determined by the Investigator.
25. Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that is not 
managed optimally and could place a subject at an increased risk for bleeding.  These 
could include, but are not limited to, known underlying disorders of the coagulation 
cascade, platelet function, or platelet count (e.g., hemophilia, Von Willebrand’s disease, 
liver disease).
26. For subjects enrolling at sites where LPs will be performed:  Subjects with the 
following characteristics will be excluded from participation in LP procedures:

Any history of lumbar surgery for any reason (e.g., herniated disc) that in the 
opinion of the Investigator would interfere with or pose risks to the LP 
procedure

Other contraindications to having a LP (at Screening and prior to subsequent 
LPs), including but not limited to: 

Low platelet count (below 50,000 cells/μL), or Screening values of INR, PT, or 
APTT that indicate that a LP cannot be performed safely in the opinion of the 
Investigator 


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
Taking any antiplatelet medication (e.g., aspirin >100 mg daily, clopidogrel, or 
nonsteroidal anti-inflammatory drugs [NSAIDs]) within 7 days prior to the 
planned LP or anticipated need for antiplatelet medication within 48 hours after 
an LP

Taking anticoagulant medication (warfarin, heparinoids, and direct coagulation 
factor inhibitors, e.g., apixaban, dabigatran, rivaroxaban) within 7 days prior to 
the planned LP or anticipated need for antiplatelet medication with 48 hours after 
an LP 

X-ray, MRI, or myelographic evidence of significant lumbar spine abnormalities 
or other anatomical factors at or near the LP site that might interfere with 
performance of LP
Treatment History
27. Participation in any passive immunotherapy study targeting α-syn, other than the 
BIIB054 Phase 1 study 228HV101.  Subjects who participated in Study 228HV101 must 
meet all entry criteria for the present study, and cannot have received BIIB054 within 
24 weeks before Day 1 of Study 228PD201. 
28. Participation in any active immunotherapy study targeting α-syn. 
29. Use of any of the following medications within 180 days before Day 1:  typical or 
atypical antipsychotics (including, but not limited to, clozapine, olanzapine, flunarizine, 
and aripiprazole), metoclopramide, or alpha methyldopa.
30. Use of any of the following medications within 90 days before Day 1:  methylphenidate, 
cinnarizine, tetrabenazine, reserpine, amphetamine, memantine, cholinesterase inhibitors 
(rivastigmine, donepezil, galantamine, and tacrine), or monoamine oxidase type A 
inhibitors (pargyline, phenelzine, and tranylcypromine).
31. Use of medicines that strongly bind to the dopamine transporter and may interfere with 
DaT/SPECT including amphetamine, benztropine, bupropion, cocaine, mazindol, 
methylphenidate, phentermine, and sertraline within 30 days before the Screening 
DaT/SPECT.
32. Use of any glucagon-like peptide-1 (GLP-1) agonists (e.g., exenatide, liraglutide, 
lixisenatide, albiglutide, and dulaglutide) within 90 days before Day 1.
33. Use of nilotinib within 90 days before Day 1.
34. Use of allowed medications not previously specified at doses that have not been stable for 
at least 8 weeks before Day 1, and/or that are not expected to remain stable for the 
duration of the study.


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35. Use of selective serotonin reuptake inhibitors (SSRIs) (with the exception of sertraline, 
which is prohibited) or serotonin norepinephrine reuptake inhibitors (SNRIs) at doses that 
have not been stable for at least 3 months before Day 1 and/or that are not expected to 
remain stable for the duration of the study.
36. Vitamins, supplements, herbal/alternative health preparations, and other over-the-counter 
medications at doses that are not expected to remain stable from Screening through 
Day 1.  
37. Participation or planned enrollment in any other clinical study or treatment with any 
investigational drug or investigational use of an approved therapy within 30 days (or 
5 half-lives, whichever is longer) before Screening.
Other
38. Contraindication for MRI (pacemaker, ferromagnetic objects in the body, claustrophobia, 
etc.). 
39. Presence of a ventriculoperitoneal shunt.
40. Female subjects who are pregnant, currently breastfeeding, or attempting to conceive 
during the study.
41. Blood donation (1 unit or more) within 8 weeks before Day 1 (must also refrain from 
donating blood for the duration of the study).
42. Unwillingness or inability to comply with study requirements, including the presence of 
any condition (physical, mental, or social) that prevents the subject from participating in 
visits as scheduled.
43. Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the 
subject unsuitable for enrollment.
44. Previous registration in this study.  Subjects previously enrolled in Study 228HV101 are 
eligible provided they meet the criteria of Study 228PD201 and were not administered 
BIIB054 within 24 weeks before Day 1.


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9.
ENROLLMENT, REGISTRATION, AND RANDOMIZATION
9.1.
Screening and Enrollment
Subjects must provide informed consent before any screening tests are performed (see 
Section 17.3).  When a subject signs the main informed consent form (ICF), that subject 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.  
Individuals who do not meet the criteria for participation in this study (i.e., a screen failure) may 
not be rescreened, except in the following circumstances:
Subjects with urinary tract infection detected on screening urinalysis may be rescreened once 
after the infection has been treated and resolved.
Rescreening for other reasons may be allowed after consultation with the Sponsor.  In addition, 
eligible subjects who are not able to complete the Day 1 Visit within 42 days of starting their 
screening assessments may be rescreened at the discretion of the Sponsor.  All screening 
assessments will be repeated except for the main ICF, 
, 
confirmation of PD diagnosis, height measurement, blood sampling for ribonucleic acid (RNA), 
MRI, and DaT/SPECT unless determined otherwise by the sponsor.  For female subjects, if 
initial follicle-stimulating hormone (FSH) level confirmed postmenopausal state, it does not need 
to be repeated.  
Coagulation, blood chemistry, and hematology tests may be repeated once if, in the opinion of 
the Investigator, values of the initial tests are only slightly out of range.  For central laboratory 
normal ranges, please refer to the Study Reference Manual.  Subjects who have other 
nonclinically significant out-of-range laboratory results may be retested 1 time only after 
discussion with the Medical Monitor. 
The rescreen and repeat parameters apply to any subject that was screened under any version of 
this protocol. 
9.2.
Randomization and Registration of Subjects
Subjects will be registered and randomized at Day 1, after all baseline assessments have been 
completed.  In particular, prior to randomization at Day 1, the Investigator must verify that the 
subjects are eligible according to criteria in Section 8.1 and Section 8.2 (including confirmation 
of DaT deficit by central reader) and that the MDS-UPDRS results from Day 1 are available.  No 
subject may begin treatment prior to assignment of a unique identification number (registration) 
and randomization.  The identification number will be used on study-related documents 
pertaining to the subject.  Any subject identification numbers that are assigned will not be reused 
even if the subject does not receive treatment.


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Subjects will be randomized at Day 1 into 1 of 4 parallel dosing arms to receive placebo or 
BIIB054 (250 mg, 1250 mg, and 3500 mg).  Cohort A (approximately 24 subjects) will be 
enrolled and randomized first in a 1:1:1:1 ratio.  Randomization and dosing for Cohort B 
(approximately 287 subjects) will start after all subjects in Cohort A complete Week 12 
assessments, and all available safety and PK data are reviewed by the IDMC.  Randomization of 
subjects in Cohort B will be stratified by baseline (Day 1) MDS-UPDRS Part I + II + III total 
scores (≤35 and >35) and striatum SBR (≤1.2 and >1.2), and subjects will be randomized at 
Day 1 into 1 of 4 parallel dosing arms to receive placebo (n=82) or BIIB054 (250 mg [n=41], 
1250 mg [n=82], or 3500 mg [n=82]) in each stratum.
All subjects who were randomized to receive placebo in Year 1 will be randomized, in equal 
ratio, to 1 of the active BIIB054 treatments for Year 2.  For subjects receiving placebo in Cohort 
A, this randomization will occur prior to Infusion 14; for subjects receiving placebo in Cohort B, 
this randomization will occur at the time of the baseline Day 1 randomization (Year 1).  Subjects 
who received BIIB054 (1250 mg or 3500 mg) in Year 1 will continue with the same dose 
regimen in Year 2.  In addition, the decision of whether to randomize subjects who receive the 
250-mg dose in Year 1 to 1 of the 2 highest doses of BIIB054 in Year 2 will be made after the 
IDMC review of Cohort A Week 12 data.
Per this protocol amendment (Version 8), the actual enrollment is 357 subjects based on the same 
randomization ratio as described above for Cohort A (n=29) and Cohort B (n=328).
Refer to the Study Reference Manual for details on registration and randomization.
9.3.
Blinding Procedures
This is a 2-part randomized, double-blinded study.  Year 1 is the placebo-controlled portion of 
the study; Years 2 through 4 are the active-treatment dose-blinded portion of the study.  
All study staff (Sponsor and study site staff) will be blinded to the subject treatment assignments.  
During Year 1, subjects will be administered either placebo or 1 of 3 dose levels of BIIB054.  In 
Years 2 through 4, all subjects will receive BIIB054, but subjects, Investigators, and study staff 
will remain blinded as to the dose level assignment.  To maintain the study blind, it is imperative 
that subject treatment assignments are not shared with the subjects, their families, or any member 
of the study team, either at the study site or at Biogen, except the unblinded Pharmacist (or 
designee) and the unblinded Pharmacy Monitor.  At the end of the study (i.e., after the clinical 
study report is finalized), if unblinding will not jeopardize the results of ongoing related studies, 
Biogen will provide the randomization codes to Investigators, who then can inform their subjects 
about the treatment received.


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10.
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY
10.1.
Discontinuation of Study Treatment
A subject must permanently discontinue BIIB054 for any of the following reasons:

The subject becomes pregnant.  Study treatment must be discontinued immediately.  
Report the pregnancy according to the instructions in Section 15.4.1.

The subject withdraws consent to continue study treatment.  

The subject experiences an AE that necessitates permanent discontinuation of study 
treatment.

The subject experiences a medical emergency that necessitates unblinding of the 
subject’s treatment assignment. 

The subject is unwilling or unable to comply with the protocol.

At the discretion of the Investigator for medical reasons.
The primary reason for discontinuation of study treatment must be recorded in the subject’s 
electronic case report form (eCRF).
Subjects who discontinue study treatment will be encouraged to remain in the study and 
complete all appropriate protocol-specified tests and assessments.  At a minimum, the following 
assessments should be performed at the timepoints shown on the schedule of assessments tables 
in Table 1 through Table 6:  MDS-UPDRS, 
. 
For subjects terminating early (i.e., discontinuing both study treatment and study assessments 
before Week 96), it is recommended that the assessments of the Early Termination Visit be 
performed within 4 weeks after the last dose of study treatment.  The Safety Telephone Call 
should be performed approximately 8 weeks after the last dose, and the assessments of the Final 
Visit should be performed approximately 12 weeks after the last dose. Final Visit procedures 
should be performed at the subject’s last study visit, even in the case of scheduling difficulties.  
For Early Termination/Follow-up and end of study procedures, see Table 6.
10.2.
Withdrawal of Subjects From Study
Subjects must be withdrawn from the study for any one of the following reasons:

The subject withdraws consent.  


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
The subject enrolls into another interventional clinical study in which an investigational 
treatment or approved therapy for investigational use is administered.

The subject is unwilling or unable to comply with the protocol.
The primary reason for the subject’s withdrawal from the study must be recorded in the subject’s 
eCRF.  
For subjects terminating early (i.e., discontinuing both study treatment and study assessments), it 
is recommended that the assessments of the Early Termination Visit be performed within 
4 weeks after the last dose of study treatment.  The Safety Telephone Call should be performed 
approximately 8 weeks after the last dose, and the assessments of the Final Visit should be 
performed approximately 12 weeks after the last dose.  Final Visit procedures should be 
performed at the subject’s last study visit, even in the case of scheduling difficulties.  For Early 
Termination and end of study procedures, see Table 6.
Subjects in Cohort A only who withdraw from the study prior to completing the Final Visit may 
be replaced at the discretion of the Sponsor.  A replacement subject will receive the same study 
treatment and dosage as the subject who discontinued treatment.  


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11.
STUDY TREATMENT USE
11.1.
Regimen
Refer to and follow the Directions for Handling and Administration (DHA).
Study treatment will be administered by the study site staff via IV infusion once every 4 weeks.  
If there is a deviation from this schedule, there should be at least 7 days between infusions.  The 
duration of the infusion will be approximately 1 hour.  The Investigator or designee must contact 
the study’s Medical Monitor in advance if they would like to adjust the infusion duration or 
administration conditions based on the subject’s ability to tolerate infusion.
11.1.1.
Year 1 (Placebo-Controlled Portion of the Study)
Prior to the first dose of Year 1, subjects will be randomized into 4 parallel dosing arms as 
follows: 

Arm 1:  placebo

Arm 2:  BIIB054 250 mg 

Arm 3:  BIIB054 1250 mg

Arm 4:  BIIB054 3500 mg
11.1.2.
Years 2 through 4 (Active-Treatment Dose-Blinded Portion of the Study)
Prior to Infusion 14 (first dose of Year 2), subjects who received placebo in Year 1 will be 
randomized to 1 of the active-treatment arms for Year 2; these subjects will receive BIIB054 in 
Years 2 through 4. Subjects who received BIIB054 (250, 1250, or 3500 mg) in Year 1 will 
continue to receive the same dose regimen of BIIB054 in Years 2 through 4.  
11.2.
Modification of Dose and/or Treatment Schedule
Dose levels, number of treatment arms, and number of subjects per arm for Cohort B may be 
modified based on emerging Cohort A safety and PK data, and review by the IDMC.  
Any changes will be documented in a protocol amendment. 
11.3.
Concomitant Therapy and Procedures
11.3.1.
Concomitant Therapy
A concomitant therapy is any drug or substance administered between the time a subject is 
screened for the study and the Final Visit.


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11.3.1.1.
Allowed Concomitant Therapy

Symptomatic PD treatment may be initiated during a subject’s participation in the 
study at the discretion of the Investigator, although subjects should refrain from 
taking symptomatic PD medications for as long as possible (in particular, for at least 
6 months following Day 1).  For subjects who do require PD treatment, it is 
recommended that treatment start with immediate-release levodopa/carbidopa at a 
dose of 25/100 mg 3 times a day (or equivalent dosage of levodopa/benserazide in 
locations where levodopa/carbidopa is not available).  The dose of 
levodopa/carbidopa may be titrated until satisfactory symptomatic relief is achieved.  
Subjects receiving levodopa/carbidopa should remain on their initially established 
dose as long as possible.  Adjunctive use of COMT inhibitors, sustained-release 
levodopa/carbidopa preparations, dopamine agonists, MAO-B inhibitors, and 
zonisamide is discouraged, and use of amantadine and anticholinergic medications is 
prohibited in Year 1 of the study.  For subjects who do require PD treatment, it is 
recommended that treatment start with immediate-release levodopa/carbidopa at a 
dose of 25/100 mg 3 times a day (or equivalent dosage of levodopa/benserazide in 
locations where levodopa/carbidopa is not available).  The dose of 
levodopa/carbidopa may be titrated until satisfactory symptomatic relief is achieved. 
Subjects receiving levodopa/carbidopa should remain on their initially established 
dose as long as possible. Adjunctive use of COMT inhibitors, sustained-release 
levodopa/carbidopa preparations, dopamine agonists, MAO-B inhibitors, and 
zonisamide is discouraged, and use of amantadine and anticholinergic medications is 
prohibited in Year 1 of the study.  Prior to initiating treatment with symptomatic PD 
medication, the Investigator should provide the 
 Medical Monitor with a 
description of the Parkinsonian manifestations that require treatment and a rationale 
for the choice of medication.
During Year 1 of the study (up to and including the Year 1 Week 52 Visit), subjects 
taking levodopa (preferred symptomatic PD medication) or other symptomatic PD 
medications should be encouraged to manage their symptoms with a single 
medication (e.g., levodopa/carbidopa or levodopa/benserazide).  Once subjects enter 
Year 2 (active-treatment dose-blinded portion of the study), there will be no 
restrictions on the number or classes of symptomatic PD medications to be 
introduced, although use of PD medications that may affect interpretation of 
DaT/SPECT is to be discouraged until the final DaT/SPECT assessment 
(Week 96/148 Visit).  
Further guidance on allowed and disallowed concomitant medications will be 
provided by the study’s Medical Monitor on a case by case basis.  See Section 7.2.2.3
for a description of timing of the start of symptomatic PD medications relative to 
scheduled study visits.  See Section 13.1 for a description of the timing of clinical 
function assessments relative to administration of PD medication. 


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
SSRIs (with the exception of sertraline, which is prohibited) and SNRIs are allowed 
provided that the subject is on a stable dose for at least 3 months prior to Day 1 and 
the dose is expected to remain stable for the duration of the study.

Medications for chronic conditions are allowed provided that the subject is on a stable 
dose for at least 8 weeks prior to Day 1 and the dose is expected to remain stable for 
the duration of the study.

Aspirin ≤100 mg daily.

Acetaminophen and NSAIDs are allowed if used according to the local label 
guidelines.  NSAIDs and clopidogrel must be avoided before and after LP procedures, 
as described in Section 11.3.1.2.

Vaccinations with live or attenuated vaccines are allowed during the study; however, 
administration of any vaccination/booster should not be given within 10 days before a 
dosing visit and for 10 days after a dosing visit.

Routine vitamin therapy is allowed.  Subjects should not change administration of 
vitamins, supplements, herbal/alternative health preparations, or over-the-counter 
medications unless required for symptom management (e.g., pain) during the study; 
such medications and preparations must be recorded on the appropriate eCRF page. 
11.3.1.2.
Disallowed Concomitant Therapy

Typical or atypical antipsychotics (including clozapine, olanzapine, flunarizine, and 
aripiprazole), metoclopramide, and alpha methyldopa.

Tricyclic antidepressants.

Amantadine or anticholinergic medications for PD in Year 1 of the study.

Amphetamine, benztropine, bupropion, cocaine, mazindol, methylphenidate, 
phentermine, sertraline, cinnarizine, tetrabenazine, reserpine, memantine, 
cholinesterase inhibitors (rivastigmine, donepezil, galantamine, and tacrine) or 
monoamine oxidase type A inhibitors (pargyline, phenelzine, and tranylcypromine).

GLP-1 agonists, e.g., exenatide, liraglutide, lixisenatide, albiglutide, and dulaglutide.

Nilotinib.

Immunosuppressive drugs (including systemic corticosteroids).  Short-term 
corticosteroids for the treatment of reversible conditions and local corticosteroids may 
be permitted, following a consultation with the Sponsor.


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
Parenteral immunoglobulin, blood products, plasma derivatives, plasma exchange, 
and plasmapheresis.

Any investigational drug.

For subjects who are participating in LPs: Any antiplatelet medication (e.g., aspirin 
>100 mg daily, clopidogrel, or NSAIDs) or any anticoagulant medication (warfarin, 
heparinoids, and direct coagulation factor inhibitors, e.g., apixaban, dabigatran, 
rivaroxaban) is prohibited from 7 days before to 48 hours after each LP procedure.  
Subjects should be instructed to continue the medications that they were receiving at enrollment 
(see Section 11.3.1.1 for allowed concomitant therapy) and to avoid starting any new 
medications or herbal preparations during the study period, since they may confound the results 
of the study.  However, medically indicated medication or treatment should not be withheld.  
Subjects should inform the Investigator of any changes in medication. 
11.3.2.
Concomitant Procedures
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is screened for the study and the Final Visit.  
Subjects should be encouraged to continue their prior physical activity regimen without 
interruption or change throughout the study. 
Transcranial magnetic stimulation and brain surgery for PD are disallowed concomitant 
procedures.  
11.4.
Continuation of Treatment 
Subjects who complete this study and do not discontinue study treatment may be offered the 
option to enter an extension study (under a separate protocol), provided they meet all eligibility 
criteria for that study.  
11.5.
Compliance
Compliance with treatment dosing is to be monitored and recorded by site staff.
Subjects who complete dosing through Week 96 and the Final Visit 12 weeks after the last visit 
will be considered Year 2 completers in the eCRF.


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12.
STUDY TREATMENT MANAGEMENT
Study site staff will administer study treatment and 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 must be dispensed only by a pharmacist or appropriately qualified staff.  Study 
treatment is to be dispensed only to subjects enrolled in this study.  Once study treatment is 
prepared for a subject, it can be administered only to that subject.  Study treatments are for 
one-time use only; do not use any study treatment remaining in the vial for another subject.
12.1.
BIIB054
BIIB054 is supplied as a liquid drug product in 5-mL vials containing 250 mg BIIB054 per vial.  
The drug product is formulated using sodium citrate dihydrate, citric acid monohydrate, 
L-arginine hydrochloride, and polysorbate 80.  BIIB054 is manufactured, handled, and stored in 
accordance with applicable Good Manufacturing Practices.
The contents of the BIIB054 label will be in accordance with all applicable regulatory 
requirements.  At a minimum, the label will include a study reference code, study treatment 
identifier, quantity of dosage units, lot number, and other pertinent information in accordance 
with local law.  The expiry or use-by date is stored in the interactive response technology (IRT) 
system, and printable assignment reports are available to site personnel.  BIIB054 should not be 
used after the expiration, expiry, or use-by date. 
12.1.1.
BIIB054 Preparation
The individual preparing BIIB054 should carefully review the instructions provided in the DHA.
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the vials or study treatment, do not use the study treatment.  The vial in question should be saved 
at the study site and the problem immediately reported to Biogen.
12.1.2.
BIIB054 Storage
Study treatment must be stored in a secure location.  
BIIB054 is to be stored at 2C to 8C (36F to 46F), in a monitored, locked refrigerator with 
limited access.  For the most up-to-date storage requirements, follow the instructions provided in 
the DHA.  BIIB054 is to be protected from light, protected from freezing, and should not be 
shaken.


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12.1.3.
BIIB054 Handling and Disposal
The Investigator must return all used and unused vials of BIIB054 as instructed by Biogen unless 
approved for onsite destruction.
If any BIIB054 supplies are to be destroyed at the study site, the institution or appropriate site 
personnel must obtain prior approval from Biogen, by providing, in writing, the destruction 
policy or details of the method of destruction.  After such destruction, Biogen must be notified, 
in writing, of the details of the study treatment destroyed (e.g., lot or kit numbers, quantities), the 
date of destruction, and proof of destruction.
12.1.4.
BIIB054 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 (subject-by-subject accounting), and accounts of any study treatment accidentally or 
deliberately destroyed or lost.  
Unless otherwise notified, all vials both used and unused must be saved for study treatment 
accountability.  At the end of the study, reconciliation must be made between the amount of 
BIIB054 supplied, dispensed, and subsequently destroyed, lost, or returned to Biogen.  A written 
explanation must be provided for any discrepancies.
12.2.
Placebo 
Commercially available saline, provided by the site, will be used as placebo.  The manufacturer’s 
directions for material storage and handling are to be followed, as are standard clinical practices 
for ensuring sterility of the material.


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13.
CLINICAL FUNCTION, PHARMACOKINETIC, AND 
PHARMACODYNAMIC ASSESSMENTS
See Section 4 for the timing of all assessments; further detail regarding the order of the 
assessments will be provided in the Study Reference Manual.
See Section 7.2.2.3 for further information on the timing of the start of symptomatic PD 
medications relative to scheduled study visits.  See Section 11.3.1.1 for further information on 
the recommended PD medications.
Remote Visits will be done in the event of a public health emergency that results in site closure, 
travel restrictions, or the study being deprioritized at the site such that visit(s) cannot occur. Use 
of a Remote Visit will not be done in place of an onsite visit simply due to subject preference. 
Refer to Table 12, Table 13, for Table 14 for clinical function assessments to be conducted 
during the Remote Visit.
13.1.
Clinical Function Assessments
Clinical function assessments are performed by qualified raters, preferably those who are not 
involved in other aspects of subject clinical care and management, including clinical safety 
assessments.  The same rater should perform a given assessment across all visits.
The following assessments will be performed to evaluate effects of BIIB054 on clinical function:  
13.1.1.
Motor Function and Related Activities of Daily Living
13.1.1.1.
Movement Disorder Society Sponsored Revision of the Unified Parkinson’s 
Disease Rating Scale (Including Modified Hoehn and Yahr Scale)
MDS-UPDRS is a multimodal scale assessing impairment and disability.  It is separated into 
4 subscales:

Part I assesses nonmotor experiences of daily living.

Part II assesses motor experiences of daily living that reflect the patients' subjective 
perception of their own condition. 

Part III assesses the motor signs of PD and is administered by the Investigator.

Part IV assesses motor complications, dyskinesias, and motor fluctuations using historical 
and objective information. 
Hoehn and Yahr Scale is included within the MDS-UPDRS, and is a commonly used system for 
describing PD manifestation, severity, and progression.  The scale allocates stages from 0 to 5 to
indicate the relative level of disability. 
















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14.
SAFETY ASSESSMENTS
Refer to Section 4 for the timing of all safety assessments; further details regarding the order of 
the assessments will be provided in the Study Reference Manual.
Remote Visits will be done in the event of a public health emergency that results in site closure, 
travel restrictions, or the study being deprioritized at the site such that visit(s) cannot occur. Use 
of a Remote Visit will not be done in place of an onsite visit simply due to subject preference. If 
a subject does not participate in a remote or clinic visit, a Safety Telephone Call must be 
conducted to collect AEs, SAEs, concomitant medications and any procedures. Refer to 
Table 12, Table 13, and Table 14 for Remote Visit assessments.
14.1.
Clinical Safety Assessments
The following clinical assessments will be performed to evaluate the safety profile of BIIB054:

AE and SAE recording.

Physical and neurological examinations performed by the Investigator, Subinvestigator, 
or qualified designated personnel.  

Columbia Suicide Severity Rating Scale (C-SSRS).

Vital sign measurements:  temperature, pulse rate, SBP, DBP, and respiratory rate will be 
measured after the subject has been resting in a supine position for at least 10 minutes.  
Orthostatic vital sign measurements will be obtained whenever blood pressure is read, in 
the following manner:  after supine blood pressure and pulse rate are measured, the 
subject should stand, and blood pressure and pulse rate should be measured after standing 
1 minute and 3 minutes.
To determine eligibility at the Screening Visit, after a 10-minute rest period, the supine 
SBP/DBP and pulse reading should be performed 3 separate times, at least 15 minutes 
apart, with the last supine measurement followed by 1 orthostatic SBP/DBP and pulse 
measurement each at 1 minute and 3 minutes after standing.  At subsequent visits, supine 
vital signs need to be measured only once, followed by orthostatic vital sign 
measurements at 1 and 3 minutes after standing. 

Weight measurements.

12-lead ECGs must be performed after the subject has been resting in a supine position 
for at least 10 minutes.  The ECGs will be read by the Investigator at collection.  Copies 
of all raw ECG data must be made available to Biogen.

Concomitant therapy and procedure recording.






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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 subject.  If necessary, 
appropriate medical intervention should be provided.
At the signing of the main ICF, each subject 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 subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.  
Determination of whether an abnormal laboratory value, vital sign result, MRI result, 
physical/neurological examination finding, and/or ECG result meet the definition of an AE will 
be made by the Investigator.  Abnormal results are not considered AEs unless 1 or more of the 
following criteria are met:

The result meets the criteria for an SAE.

The result requires the subject to receive specific corrective therapy.

The result is considered by the Investigator to be clinically significant.
15.1.2.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:

Results in death

In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred in a 
more severe form, might have caused death

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity


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
Results in a congenital anomaly/birth defect

Is a medically important event
A medically important event is an AE that, in the opinion of the Investigator, may jeopardize the 
subject 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 subject 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 subject’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 subject’s consent to participate in the study and the time of the 
procedure or treatment.

The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission.

If a subject 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, to the LP procedure, and to the DaTscan 
(ioflupane I123 Injection) radioligand (hereafter referred to as the radioligand), as defined 
in Section 15.2.2.

The severity of the event as defined in Section 15.2.3.








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death certificates and autopsy reports to Biogen.  The term death should be reported as an SAE 
only if the cause of death is not known and cannot be determined.
15.3.4.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or Biogen to be related to the study treatment administered.
Appropriate personnel at Biogen will unblind SUSARs for the purpose of regulatory reporting.  
Biogen will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies according 
to local law.  Biogen will submit SUSARs to Investigators in a blinded fashion.
15.4.
Procedures for Handling Special Situations
15.4.1.
Pregnancy
Subjects should not become pregnant or impregnate their partners during the study and 
for 6 months after their last dose of study treatment.  If a female subject becomes pregnant, 
study treatment must be discontinued immediately.
The Investigator must report a pregnancy occurring in a female subject from first dose of study 
treatment up to 6 months after the last dose, by faxing the appropriate form to Biogen within 
24 hours of the study site staff becoming aware of the pregnancy; refer to the Study Reference 
Manual for complete contact information.  The Investigator or study site staff must report the 
outcome of the pregnancy to Biogen.  A pregnancy is not considered an AE and should not be 
recorded on the AE eCRF.
Congenital abnormalities and birth defects in the offspring of male or female subjects should be 
reported as an SAE if conception occurred during the study treatment period.
15.4.2.
Overdose
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol.  Overdoses are not considered 
AEs and should not be recorded as an AE on the eCRF; however, all overdoses must be recorded 
on an Overdose form and faxed to Biogen within 24 hours of the site becoming aware of the 
overdose.  An overdose must be reported to Biogen even if the overdose does not result in an 
AE.  If an overdose results in an AE, the AE must be recorded.  If an overdose results in an SAE, 
both the SAE and Overdose forms must be completed and faxed to Biogen.  All study treatment-
related dosing information must be recorded on the dosing eCRF.
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 inform the study’s Medical Monitor of the event as soon as it is feasible to do so.  Refer 
to the Study Reference Manual’s Official Study Contact List for complete contact information.


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15.4.3.1.
Unblinding for Medical Emergency
In a medical emergency when knowledge of the subject’s treatment assignment may influence 
the subject’s clinical care, the Investigator or designee may access the subject’s treatment 
assignment by IRT.  When possible, the Investigator or designee should attempt to contact the 
study’s Medical Monitor to discuss the emergency.  The Investigator must document the reasons 
for unblinding in the subject’s source documents.  The Investigator is strongly advised not to 
divulge the subject’s treatment assignment to any individual not directly involved in managing 
the medical emergency, nor to personnel involved with the analysis and conduct of the study.  
The Investigator can contact Biogen to discuss such situations.
15.5.
Contraception Requirements
All women of childbearing potential and all men must practice highly effective contraception 
during the study and for 6 months after their last dose of study treatment.  In addition, male 
subjects should not donate sperm for the duration of the study and for at least 6 months after their 
last dose of study treatment.
For the purposes of this study, women who do not meet one of the following criteria listed below 
are considered to be physiologically capable of becoming pregnant and are, therefore, defined as 
women of childbearing potential:

Postmenopausal

12 continuous months of natural (spontaneous) amenorrhea without an alternative 
medical cause and a serum follicle stimulating hormone level >40 mIU/mL 

6 weeks after surgical bilateral oophorectomy with or without hysterectomy

Posthysterectomy

Female surgical sterilization (e.g., bilateral tubal ligation)
For the purposes of the study, highly effective contraception is defined as use of 1 of the 
following:
For female subjects:

Established use of oral, intravaginal, or transdermal combined (estrogen and progestogen 
containing) hormonal methods of contraception associated with the inhibition of 
ovulation.

Established use of oral, injected, or implanted progestogen-only hormonal methods of 
contraception. 

Placement of an intrauterine device or intrauterine hormone-releasing system.


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
Bilateral tubal occlusion.

Sex with a male partner who has undergone surgical sterilization (with the appropriate 
postvasectomy documentation of the absence of sperm in the ejaculate).
For male subjects:

A vasectomy with subsequent negative semen analysis.

Sex with a woman who uses the methods described for female subjects if she is of 
childbearing potential.
True abstinence, when this is consistent with the preferred and usual lifestyle of the subject, 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.
Pregnancy reporting is described in Section 15.4.1.
15.6.
Safety Responsibilities
15.6.1.
The Investigator
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, on the eCRF regardless of the severity, 
relationship to study treatment, relationship to the LP procedure, or relationship to the 
radioligand.

Determine the seriousness, relationship to study treatment, relationship to the LP 
procedure, relationship to the radioligand, and severity of each event.

Determine the onset and resolution dates of each event.

Monitor and record all pregnancies in female subjects and follow up on the outcome of 
all pregnancies.

Complete an SAE form for each SAE and fax it to Biogen within 24 hours of the study 
site staff becoming aware of the event.

Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to Biogen within 24 hours of the study site staff becoming aware of new 
information.

Ensure all AE and SAE reports are supported by documentation in the subjects’ medical 
records.


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
Pursue AE follow-up information, if possible, until the event has resolved or become 
stable.  Record AE follow-up information, including resolution, on the eCRF, as 
applicable.

Report SAEs to local ethics committees, as required by local law.
15.6.2.
Biogen 
Biogen’s responsibilities include the following:

Before study site activation and subject enrollment, the Clinical Monitor is responsible 
for reviewing with study site staff the definitions of AE and SAE, as well as the 
instructions for monitoring, recording, and reporting AEs and SAEs.

Biogen is to notify all appropriate regulatory authorities, central ethics committees, 
central institutional review boards 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.
Safety
16.1.1.
Analysis Population
The safety population is defined as all subjects who received at least 1 dose of study treatment 
(BIIB054 or placebo).  The same definition applies to Years 1 through 4.
16.1.2.
Methods of Analysis
AEs will be coded using the Medical Dictionary for Regulatory Activities.  In general, safety 
endpoints will be summarized using descriptive statistics.
Safety analyses will be done separately, as follows:

Year 1 (placebo-controlled portion of the study):  All data will be summarized by 
treatment group (e.g., placebo; 250 mg, 1250 mg, and 3500 mg of BIIB054; and total 
BIIB054).

Years 2 through 4 (active-treatment dose-blinded portion of the study) and overall 
experience:  Data from Years 2 through 4 and combined data from Years 1 through 4
(active-treatment dose-blinded portion of the study as well as overall experience on 
BIIB054 from the combined placebo-controlled portion and active-treatment dose-
blinded portion of the study) will be summarized by treatment group.  
The primary evaluation of safety will cover Year 1 of the study (placebo-controlled period, from 
baseline to Week 52).
Any safety data collected from in-clinic or remote visits will be included in the statistical 
analysis.
16.1.2.1.
Adverse Events
All analyses of AEs will be based on the principle of treatment emergence.  An AE is considered 
to be treatment emergent if it has an onset date on or after the date of first dosing, or if it was 
present prior to the first dose and subsequently worsened.  Incidences of all AEs will be 
presented by system organ class and preferred term by treatment group and overall active group.  
In addition, incidence of all AEs by severity, by relationship to study treatment, and by 
relationship to LP procedure will be presented.  Data after subjects started symptomatic PD 
medications will be analyzed both ways (included and excluded).


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16.1.2.2.
Clinical Laboratory Results
Clinical laboratory evaluations include hematology, blood chemistry, and urinalysis.  Analyses 
of clinically significant abnormalities, shifts from baseline to post-baseline relative to the normal 
range, as well as change from baseline by visit will be presented by treatment group and overall 
active group.
16.1.2.3.
Vital Signs
The analysis of vital signs will focus on clinically relevant abnormalities, which will be defined 
in more detail in the statistical analysis plan (SAP).  Incidence of clinically relevant 
abnormalities in vital signs will be summarized by treatment group and overall active group.  
16.1.2.4.
Electrocardiogram
The analysis of ECGs will focus on clinically relevant abnormalities, which will be defined in 
more detail in the SAP.  ECG changes from baseline will be summarized using descriptive 
statistics and presented by treatment group, overall active group, and timepoint.
16.1.2.5.
Physical and Neurological Examinations
Abnormal findings during physical and neurological examinations will be recorded as AEs and 
will be reflected in the summary of AEs.  
16.1.2.6.
Columbia Suicide Severity Rating Scale
C-SSRS data will be summarized using descriptive statistics and presented by treatment group 
and overall active group.
16.1.2.7.
Magnetic Resonance Imaging
Subjects’ brain MRIs will be categorized by normal and abnormal.  Shift tables for MRI results 
will be presented by visit for each treatment group and overall active group.
16.2.
Pharmacodynamics – Imaging Analyses
16.2.1.
Analysis Population
The pharmacodynamic population is defined as a subset of the intent-to-treat (ITT) population 
with at least 1 post-baseline pharmacodynamic measurement.  The ITT population is defined in 
Section 16.5.2.1.




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Atypical serum drug concentrations (such as very low or very high) will be excluded from the 
analysis if no apparent explanation exists.  Concentration observations will also be removed from 
the data set if corresponding dosing or sampling times are missing or cannot be reconstructed.  
Concentration data with below limit of quantification value will be removed from analysis.  All 
deletions of data points will be appropriately documented.
Population PK analysis may be conducted to estimate BIIB054 population PK parameters and to 
identify potential covariates (e.g., demographics, body weight, and anti-BIIB054 mAb) on the 
variability of BIIB054 PK.  Results will be presented in a separate report.
16.4.
Immunogenicity Data
16.4.1.
Analysis Population
Immunogenicity analysis will be performed for all subjects in the safety population.
16.4.2.
Methods of Analysis
The incidence of anti-BIIB054 antibody will be summarized by visit and by treatment group.
16.5.
Clinical Function
16.5.1.
Analysis Population
The ITT population is defined as all randomized subjects who receive at least 1 dose of study 
treatment.  Data from corresponding dose levels in Cohort A and Cohort B will be pooled for all 
analyses.
The per protocol population, mainly for the purpose of Year 1 analyses, is defined as a subset of 
the ITT population who receives at least 70% (10 doses) of study treatment during Year 1 and 
has not missed consecutive doses. 
16.5.2.
Methods of Analysis
In general, analyses for clinical function will be done in 2 ways: (1) Year 1 (placebo-controlled 
portion of the study) and (2) Years 2 through 4 (active-treatment dose-blinded portion of the 
study) and overall experience (combined data from Years 1 through 4).
In general, all data collected from in-clinic or remote visits will be included in the statistical 
analyses. The impact of remote assessments on the statistical analyses may be assessed.
Missing data due to the impact of the COVID-19 public health emergency will be considered 
missing at random in the statistical analyses. Analysis to evaluate the impact of the current 
COVID-19 emergency and any future public health emergency will be described in the SAP.










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A blinded sample size re-estimation may be conducted when approximately 10% of subjects 
have completed the Week 52 Visit or approximately 1 month before enrollment is projected to be 
completed, whichever is earlier.  The study sample size may be increased based on this blinded
data review.  There may be small adjustments to the percentage depending on actual enrollment 
rate.  Details will be provided in the SAP.  
16.9.
Sample Size Considerations
The sample size calculation is based on changes in MDS-UPDRS Part I + II + III total score at 
Week 52 and at Week 72 of treatment.  Based on data from the Parkinson’s Progression Markers 
Initiative study, the placebo subject’s mean and standard deviation (SD) at Week 52 and 
Week 72 are assumed to be 8.0 (10.64) and 9.6 (13.7) respectively. Assuming a maximum of 
55% reduction in the change from baseline in the active group with maximum response relative 
to placebo group, the mean (SD) for this active group will be 3.2 (10.64) and 3.84 (13.7) 
respectively at Week 52 and Week 72, and the responses for other active groups are assumed to 
be somewhere between 0 and the maximum response.  The primary analysis will be based on the 
MCP-MOD method to detect a dose-response trend while controlling for multiplicity.  Optimal 
contrasts will be constructed to detect potential dose-response trend under common dose-
response curves (e.g., Emax, exponential, logistic, linear in log dose, and quadratic model, which 
are illustrated with parameters shown in Figure 5 which will be used for both Week 52 and Week 
72).  The planned enrollment is 311 subjects total (24 subjects in Cohort A and 287 subjects in 
Cohort B, Table 8).  Actual enrollment is 357 subjects.  In Cohort A, 29 subjects were 
randomized in a 1:1:1:1 ratio to each of the treatment groups, while in Cohort B 328 subjects 
were randomized in 2:1:2:2 ratio to the placebo, 250 mg, 1250 mg, and 3500 mg groups.  Based 
on the actual enrollment, the estimated number of subjects by cohort and treatment groups are 
given in Table 9 below.  After accounting for dropout rate of 10% and 15% at Week 52 and 
Week 72, respectively, the estimated sample sizes are given in Table 10 and Table 11.  With the 
updated sample size, the study will provide an average power of approximately 80% to detect the 
dose-response trend over 1 year of treatment, based on a 2-sided type I error of 0.05 and 
approximately 73% of power at the Week 72 analyses, based on a 2-sided type I error of 0.05.  
Overall, the sample size in the study will provide approximately 89% power.  If there are any 
modifications to the candidate dose-response curves/models or parameters, the final candidate 
models for the MCP-MOD will be prespecified and described in the SAP.  
With an estimated sample size of 100 subjects dosed per arm in the 1250 mg and 3500 mg arms, 
the study has 80% probability of detecting AEs with a rate of 1.2% or greater in these 2 arms, 
and a 90% probability of detecting AEs occurring with a rate of 2.1% or greater.  


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Figure 5:
Candidate Models for Dose-Response
Table 8:
Estimated Sample Size Per Group (Planned)
Treatment Group
Placebo
BIIB054
250 mg
BIIB054
1250 mg
BIIB054
3500 mg
Total
Cohort
Cohort A
6
6
6
6
24
Cohort B
82
41
82
82
287
Total
88
47
88
88
311


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Table 9:
Estimated Sample Size Per Group Based on Actual Enrollment (Before 
Drop-Outs)
Treatment Group
Placebo
BIIB054
250 mg
BIIB054
1250 mg
BIIB054
3500 mg
Total
Cohort
Cohort A
8
7
7
7
29
Cohort B
93
47
94
94
328
Total
101
54
101
101
357
Table 10:
Estimated Sample Size Per Group Based on Actual Enrollment (After 
Adjusting for 10% Drop-Out At Week 52
Treatment Group
Placebo
BIIB054
250 mg
BIIB054
1250 mg
BIIB054
3500 mg
Total
Cohort
Cohort A
7
6
6
6
25
Cohort B
84
42
84
84
294
Total
91
48
90
90
319
Table 11:
Estimated Sample Size Per Group Based on Actual Enrollment (After 
Adjusting for 15% Drop-Out At Week 72
Treatment Group
Placebo
BIIB054
250 mg
BIIB054
1250 mg
BIIB054
3500 mg
Total
Cohort
Cohort A
7
6
6
6
25
Cohort B
79
40
80
80
279
Total
86
46
86
86
304


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17.
ETHICAL REQUIREMENTS
Biogen, 
 and the Investigator must comply with all instructions, regulations, and 
agreements in this protocol and applicable International Council for Harmonisation (ICH) and 
Good Clinical Practice (GCP) guidelines and conduct the study according to local regulations.
The Investigator is responsible for endorsing all data on completed eCRFs via signature prior to 
any interim lock or database lock.  
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated.  The Investigator 
is responsible for supervising those individuals and for implementing procedures to ensure the 
integrity of the tasks performed and any data generated.
17.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
17.2.
Ethics Committee
The Investigator must obtain ethics committee approval of the protocol, ICFs, and other required 
study documents prior to starting the study.  
 will submit documents on behalf of the 
investigational sites with central institutional review boards.  Investigational sites with local 
institutional review boards will submit documents themselves, and 
 will provide the 
necessary documentation. 
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the ethics committee or institutional review board.  A copy of the approved 
ICF must be provided to Biogen.  After approval, the ICF must not be altered without the 
agreement of the relevant ethics committee or institutional review board, and Biogen.
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations.
Biogen must receive a letter documenting ethics committee or institutional review board 
approval, which specifically identifies the protocol, protocol number, and ICF, prior to the 
initiation of the study.  Protocol amendments will be subject to the same requirements as the 
original protocol.
A progress report must be submitted to the ethics committee or institutional review board at 
required intervals and not less than annually.




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more thorough evaluation of the safety profile, the pharmacokinetics/ pharmacodynamics, 
, and benefit of the study treatment in the target population.
Study reports will be used for research purposes only.  The subject will not be identified by name 
in eCRFs, study-related forms, study reports, or any related publications.  Biogen, its partners 
and designees, ethics committees, institutional review boards, and various government health 
agencies may inspect the records of this study.  Every effort will be made to keep the subject’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) with the subject before the subject makes a decision to participate in the study.
17.7.
Registration of Study and Disclosure of Study Results
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.


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18.
ADMINISTRATIVE PROCEDURES
18.1.
Study Site Initiation
The Investigator must not screen any subjects prior to completion of a study initiation visit, 
conducted by Biogen.  This initiation visit will include a detailed review of the protocol and 
study procedures.
18.2.
Quality Control and Quality Assurance
Quality control procedures will be implemented at each stage of data handling to ensure that all 
data are reliable and have been processed correctly.  Data anomalies will be communicated to the 
sites for clarification and resolution, as appropriate.  The Investigator is responsible for 
endorsing all eCRF data prior to any interim or final database lock.
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits or inspections.  The Investigator will be 
expected to cooperate with any audit or inspection and to provide assistance and documentation 
(including source data) as requested.
18.3.
Monitoring of the Study
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories.  Source data must be attributable, legible, 
contemporaneous, original, accurate, and complete.  Changes to source data must be traceable, 
not obscure the original entry, and be explained if necessary (e.g., with an audit trail).  The 
Investigator should maintain a record of the location(s) of essential documents.
The Clinical Monitor will visit the Investigator 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 subject safety, data integrity, and critical data and processes.
During these visits, eCRFs, supporting documentation, and essential documentation related to the 
study will be reviewed and any discrepancies or omissions will be resolved. 
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure the protection of subject rights and well-being, protocol adherence, quality of data 
(accurate, complete, and verifiable), study treatment accountability, compliance with regulatory 
requirements, and continued adequacy of the investigational site and its facilities.


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18.4.
Study Funding
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contracts between the institution, Investigator, and Biogen.  
18.5.
Publications
Details are included in the clinical trial agreement for this study.






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approved by the ethics committee and/or institutional review board 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 subject.  In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification.
In the event of a protocol modification, the ICFs may require similar modifications (see 
Section 17).
19.4.
Ethics Committee Notification of Study Completion or Termination
Where required, the regulatory authorities and ethics committees and/or institutional review 
board must be notified of completion or termination of this study, and sent a copy of the study 
synopsis in accordance with necessary timelines.
19.5.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local, regional, or national 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.
19.6.
Study Report Signatory
Biogen will designate one of the participating Study 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 subject enrollment; or by other factors 
determined to be relevant by Biogen.


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114
20.
REFERENCES
Beach TG, Adler CH, Lue L, et al. Unified staging system for Lewy body disorders: correlation 
with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol. 
2009;117(6):613-34.
Beck JC, Alcalay RN, Bower JH, et al. Prevalence of Parkinson’s disease in North America: A 
nationwide epidemiological study sharing available databases. Presented at the Fourth World 
Parkinson Congress; Portland, Oregon. 2016
Bertram L, Tanzi RE. The genetic epidemiology of neurodegenerative disease. J Clin Invest. 
2005;115(6):1449-57.
Braak H, Del Tredici K, Bratzke H, et al. Staging of the intracerebral inclusion body pathology 
associated with idiopathic Parkinson's disease (preclinical and clinical stages). J Neurol. 
2002;249 Suppl 3:III/1-5.
Chillag-Talmor O, Giladi N, Linn S, et al. Use of a refined drug tracer algorithm to estimate 
prevalence and incidence of Parkinson's disease in a large israeli population. J Parkinsons Dis. 
2011;1(1):35-47.
Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA. 
2014;311(16):1670-83.
de Lau LM, Breteler MM. Epidemiology of Parkinson's disease. Lancet Neurol. 2006;5(6):525-
35.
Dorsey ER, Constantinescu R, Thompson JP, et al. Projected number of people with Parkinson 
disease in the most populous nations, 2005 through 2030. Neurology. 2007;68(5):384-6.
Gan-Or Z, Amshalom I, Kilarski LL, et al. Differential effects of severe vs mild GBA mutations 
on Parkinson disease. Neurology. 2015;84(9):880-7.
Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol. 
1999;56(1):33-9.
Healy DG, Falchi M, O'Sullivan SS, et al. Phenotype, genotype, and worldwide genetic 
penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 
2008;7(7):583-90.
Hobson P, Gallacher J, Meara J. Cross-sectional survey of Parkinson's disease and parkinsonism 
in a rural area of the United Kingdom. Mov Disord. 2005;20(8):995-8.
Jellinger KA, Logroscino G, Rizzo G, et al. Accuracy of clinical diagnosis of Parkinson disease: 
A systematic review and meta-analysis. Neurology. 2016;87(2):237-8.


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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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115
Jowaed A, Schmitt I, Kaut O, et al. Methylation regulates alpha-synuclein expression and is 
decreased in Parkinson's disease patients' brains. J Neurosci. 2010;30(18):6355-9.
Kempster PA, O'Sullivan SS, Holton JL, et al. Relationships between age and late progression of 
Parkinson's disease: a clinico-pathological study. Brain. 2010;133(Pt 6):1755-62.
Kowal SL, Dall TM, Chakrabarti R, et al. The current and projected economic burden of 
Parkinson's disease in the United States. Mov Disord. 2013;28(3):311-8.
Luk KC, Kehm V, Carroll J, et al. Pathological alpha-synuclein transmission initiates Parkinson-
like neurodegeneration in nontransgenic mice. Science. 2012a;338(6109):949-53.
Luk KC, Kehm VM, Zhang B, et al. Intracerebral inoculation of pathological alpha-synuclein 
initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice. The Journal of 
experimental medicine. 2012b;209(5):975-86.
Martin I, Dawson VL, Dawson TM. Recent advances in the genetics of Parkinson's disease. 
Annu Rev Genomics Hum Genet. 2011;12:301-25.
Masalha R, Kordysh E, Alpert G, et al. The prevalence of Parkinson's disease in an Arab 
population, Wadi Ara, Israel. Isr Med Assoc J. 2010;12(1):32-5.
Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusion body formation in 
alpha-synuclein mice: implications for neurodegenerative disorders. Science. 
2000;287(5456):1265-9.
Morgante L, Nicoletti A, Epifanio A, et al. Prevalence of Parkinson's disease and other types of 
parkinsonism in the Aeolian Archipelago, Sicily. Parkinsonism Relat Disord. 2008;14(7):572-5. 
Epub 2008/03/05.
Nalls MA, Pankratz N, Lill CM, et al. Large-scale meta-analysis of genome-wide association 
data identifies six new risk loci for Parkinson's disease. Nat Genet. 2014;46(9):989-93.
Nuytemans K, Theuns J, Cruts M, et al. Genetic etiology of Parkinson disease associated with 
mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum 
Mutat. 2010;31(7):763-80.
Olanow CW, Kordower JH. Modeling Parkinson's disease. Ann Neurol. 2009;66(4):432-6.
Poewe W. The natural history of Parkinson's disease. J Neurol. 2006;253 Suppl 7:VII2-6.
Schrag A, Banks P. Time of loss of employment in Parkinson's disease. Mov Disord. 
2006;21(11):1839-43.
Schrag A, Jahanshahi M, Quinn N. How does Parkinson's disease affect quality of life? A 
comparison with quality of life in the general population. Mov Disord. 2000;15(6):1112-8.


Protocol 228PD201
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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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116
Shulman LM, Pretzer-Aboff I, Anderson KE, et al. Subjective report versus objective 
measurement of activities of daily living in Parkinson's disease. Mov Disord. 2006;21(6):794-9.
Totaro R, Marini C, Pistoia F, et al. Prevalence of Parkinson's disease in the L'Aquila district, 
central Italy. Acta neurologica Scandinavica. 2005;112(1):24-8.
Twelves D, Perkins KS, Counsell C. Systematic review of incidence studies of Parkinson's 
disease. Mov Disord. 2003;18(1):19-31.
Wickremaratchi MM, Perera D, O'Loghlen C, et al. Prevalence and age of onset of Parkinson's 
disease in Cardiff: a community based cross sectional study and meta-analysis. J Neurol 
Neurosurg Psychiatry. 2009;80(7):805-7.


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117
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Study, with an Active-Treatment Dose-Blinded Period, to Evaluate the 
Safety, Pharmacokinetics, and Pharmacodynamics of BIIB054 in Subjects with Parkinson’s 
Disease,” and agree to conduct the study according to the protocol and the applicable ICH 
guidelines and GCP regulations, and to inform all who assist me in the conduct of this study of 
their responsibilities and obligations.
____________________________________________________
Investigator’s Signature
Date
____________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)




Protocol 228PD201
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Phase 2a Study of BIIB054 in Subjects with Parkinson’s Disease
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119
1 Unscheduled Visit can occur for safety-related issues at any time (as determined by the Investigator) or for administering the MDS-UPDRS prior to starting 
symptomatic PD medications outside of a scheduled visit.  Additional tests may be performed at the Investigator’s discretion.
2 Consult Figure 4 to see if subject qualifies to continue dosing in Years 3 and 4 (if applicable).
3 Subjects who have started symptomatic PD medication during this study should refrain from taking the PD medication for approximately 12 hours prior to 
MDS-UPDRS visits.  MDS-UPDRS Part III will be administered before subjects take the PD medication, 
 
5 The “Since Last Visit” version of the C-SSRS will be administered at all Remote Visits.  If the Investigator has any concern regarding the completed C-SSRS, 
the subject should be referred to psychiatric evaluation based on local standards of care.




Protocol 228PD201
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121
1 Unscheduled Visit can occur for safety-related issues at any time (as determined by the Investigator) or for administering the MDS-UPDRS prior to starting 
symptomatic PD medications outside of a scheduled visit.  Additional tests may be performed at the Investigator’s discretion.
2 Subjects who have started symptomatic PD medication during this study should refrain from taking the PD medication for approximately 12 hours prior to 
MDS-UPDRS visits.  MDS-UPDRS Part III will be administered before subjects take the PD medication, 
 
4 The “Since Last Visit” version of the C-SSRS will be administered approximately every 60 days. If the Investigator has any concern regarding the completed 
C-SSRS, the subject should be referred to psychiatric evaluation based on local standards of care.




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 228PD201
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study, with an Active-Treatment 
Dose-Blinded Period, to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of 
BIIB054 in Subjects with Parkinson’s Disease
Version 7
Date: 03 February 2020
EUDRA CT Number: 2016-004610-95
Version 7 of the protocol has been prepared for this amendment, which supersedes Version 6.


Amendment Summary for Protocol 228PD201, Version 7
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
2
PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 228PD201 is to specify the timing of 
DaT/SPECT scans for certain participants, as requested by the German Radiology Authority.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 4.2, Schedule of Activities, Table 6, footnote 5
Now reads:
Performed only for subjects who have not had the assessment at Week 96 (if withdrawing after 
Year 2) or Week 148 (if withdrawing after Year 3). Further, DaT/SPECT is only to be 
performed if the time interval since the previous DaT/SPECT examination exceeds 23 
weeks. This >23-week time interval restriction does not apply to MRI. The MRI and 
DaT/SPECT assessment windows for all visits are ±7 days.  The MRI results will be read by the 
local radiologist at collection.  Both MRI and DaT/SPECT results will be sent within 24 hours to 
a central reader for further evaluation.  Subjects will be contacted by telephone within 7 days 
following the DaT/SPECT procedure to monitor for AEs.
Rationale: This text was added in order to specify the minimum time interval required between 
SPECT visits to ensure that participant radiation exposures are kept at a safe limit, at the request 
of the German Radiology Authority.


Amendment Summary for Protocol 228PD201, Version 7
CONFIDENTIAL
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Biogen MA Inc.
3
SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 3, Synopsis
The synopsis was revised to reflect changes made throughout the protocol.
Section 4.2, Schedule of Activities, Table 1
Change: AE reporting and concomitant medications/procedures reporting were split into 
separate rows and the timing of these activities was updated. Footnote 23 was updated 
accordingly.Now reads:
Tests and assessments
Screening
≤42 days 
before 
Day 11
Infusions 1-3
Day 1/Baseline, Day 29 (±1 day), & Day 57 (±1 day)
Clinic Visits
Day 43
(Safety 
Telephone 
Call)
Day 
2, 
30, 
58
Day 4, 
60
Day 
8, 
36, 
64
Day 
15, 
71
Pre-
infusion2
0m
Time after End of Last Infusion
≤10m
1h
±15m
2h
±15m
4h
±30m
24h
±2h
72h
-2h/+1d
168h
±24h
336h
±24h
336h
±24h
AE reporting23
ongoing
Concomitant 
therapy and 
procedures
reporting
ongoing
Footnote 23 now reads:
23Nonserious AEs that occur during the Screening period and that are assessed by the 
Investigator as related to the ligand will be captured by the sites on the AE electronic case report 
form (eCRF). After the first dose of study treatment, all AEs are collected, both related and 
unrelated to the ligand (see Section 15.3.1).
Rationale: This change clarifies that reporting of concomitant therapy and procedures should 
begin during screening, while reporting of AEs not related to the radioligand should not start 
until study treatment has been administered.
This change also affects Section 4.2, Schedule of Activities, Table 3 and footnote 26.
Section 4.2, Schedule of Activities, Table 4


Amendment Summary for Protocol 228PD201, Version 7
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4
Change: An X was added in the BIIB054 serum PK sampling row under Year 2 Week 52. 
Footnote 1 was added to the Year 2 Week 52 column heading, and subsequent footnote 
numbering was updated accordingly. Now reads:
Tests and assessments
Year 2
Week 
52
(±3d)1
Safety 
Telephone
Calls 1d & 
7d after 
Infusion 142
Infusions 15-25, 
Week (±3d)
Unsched 
Visit3
Infus-
ion 14
56
60
64
68
72
76
80
84
88
92
964
Body weight5
X
X
X
X
X
Physical/neurological examination6
X
X
X
12-lead ECG5,7
X
X
X
Vital signs5,8
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test 5,9
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, blood chemistry, urinalysis5
X
X
X
Whole blood for RNA5,10
X
X
Brain MRI11
X
DaT/SPECT11
X
Randomization12
X
Study treatment infusion13
X
X
X
X
X
X
X
X
X
X
X
X
BIIB054 serum PK sampling14
X
X
X
X
Rationale: Because the BIB054 serum PK sampling box for Year 2 Week 2 was not marked in 
this Schedule of Activities, sites were not consistently obtaining the required Week 52 post-dose 
PK sample. This change was made to help prevent future protocol deviations and ensure 
adequate PK sample collection. The table now matches Table 3.


Amendment Summary for Protocol 228PD201, Version 7
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5
Section 7.1.2, Years 2 through 4 (Active-Treatment Dose-Blinded Portion of the Study)
Change: Language was added to clarify that both clinic visits scheduled for Week 52 can be 
conducted as a single visit.
Now reads: The Year 1 Week 52 and Year 2 Week 52 visits (first visit of Year 2) can be 
conducted as a single visit. Prior to Infusion 14 (the first dose of Year 2; Year 2 Week 52
visit), subjects who received placebo in Year 1 will be randomized into 1 of the active-dosing 
arms for Year 2; these subjects will receive BIIB054 in Year 2.
Rationale: Allowing these temporally proximal visits to be combined reduces the burden on 
participants without sacrificing data collection and provides clarity for study sites.
This change also affects Section 4.2, Schedule of Activities, Table 2, footnote 2; Table 3, 
footnote 4; and Table 4, footnote 1.
Section 7.2.2.3, Treatment with Parkinson’s Disease Medications
Change: Language was added to clarify that the Week 52 MRI and DaT/SPECT scans have a 
window of only -7 days (rather than ±7).
Now reads: It is recommended that subjects who plan to start symptomatic PD medication either 
outside of a visit window or outside of the DaT/SPECT window wait, if possible, until after the 
next DaT/SPECT to start the medication, provided that a DaT/SPECT visit is planned within 1 
month.  (As an alternative, if the subject cannot wait to start symptomatic PD medication, the 
DaT/SPECT window of ±7 days, except for Week 52 MRI and DaT/SPECT which has a -7 
day window only to allow Year 2 dosing to be appropriately scheduled, may be expanded so 
that it extends from -28 days to +7 days.)  If the subject is not due for DaT/SPECT at the next 
scheduled visit per the Schedule of Activities, it is not necessary to have this scan performed 
prior to starting symptomatic PD medications.
Rationale: This change was made to prevent disruption of a timely start to Year 2 dosing that 
could result from waiting to conduct the Week 52 MRI and DaT/SPECT scans up to 7 days after 
the Week 52 visit.
This change also affects Section 4.2, Schedule of Activities, Table 2, footnote 10; Table 3, 
footnote 16; Table 4, footnote 11; Table 5, footnote 10; and Table 6, footnote 5.


Amendment Summary for Protocol 228PD201, Version 7
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6
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.

In Section 7.2.3, Follow-Up Visits and Final Visit, the window for the Early 
Termination and Final Visits was corrected to ± 3 days to be consistent with the 
Schedule of Activities.

Figure 1, Study Design, was updated with the correct maximum numbers of doses 
(41) and study weeks (178). 

Table 4 footnotes were renumbered to accommodate the addition of a footnote.

The PK sampling collection window for the Year 1 Week 52 visit by participants in 
Cohort A was clarified by adding footnote 12 to that box in Table 2.

In Section 7.1.2, Years 2 through 4 (Active-Treatment Dose-Blinded Portion of the 
Study), language was added from Table 4, footnote 12 to remind sites that
randomization of participants who received BIIB054 in Year 1 is unnecessary at the 
start of Year 2.


Amendment Summary for Protocol 228PD201, Version 7
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7
LIST OF ABBREVIATIONS
AE
adverse event
DaT/SPECT
dopamine transporter/single-photon emission computed tomography
MRI
magnetic resonance imaging
PK
pharmacokinetic(s)


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 228PD201
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study, with an Active-Treatment 
Dose-Blinded Period, to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of 
BIIB054 in Subjects with Parkinson’s Disease 
Version 6
Date: 11 July 2019
EUDRA CT Number: 2016-004610-95
Version 6 of the protocol has been prepared for this amendment, which supersedes Version 5.


Protocol 228PD201, Version 6
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc.
2
PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 228PD201 is to extend the active treatment 
dose-blinded period from Year 2 into Years 3 and 4. Dosing will end when the last subject has 
received the last dose in Year 2 (at Week 96), and the study will end when the last subject has 
had the Final Visit in Year 2 (12 weeks after the last dose [Week 108 visit]).
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 7.1, Study Overview 
Now reads:
This Phase 2a, randomized, double-blind, parallel-group, placebo-controlled study (Year 1) with 
an active-treatment dose-blinded period (Years 2 through 4) will examine the safety, PK, and 
pharmacodynamics of BIIB054, administered every 4 weeks via IV infusion to adult subjects 
with PD.  Approximately 311 subjects will be enrolled at about 85 sites globally.  
Rationale: The active-treatment dose-blinded period was extended to collect additional data. 
This change also affects Section 4.1, Study Schematic (Figure 1 and Figure 2 [new figure]); 
Section 4.2, Schedule of Activities (Table 4, Table 5 [new table], and Table 6 [new table]); 
Section 5.5, Rationale for Dosing Regimen; Section 6.3.2, Years 2 through 4 (Active-Treatment 
Dose-Blinded Portion of the Study); Section 7.1.2, Years 2 through 4 (Active-Treatment Dose-
Blinded Portion of the Study); Section 7.2, Overall Study Duration and Follow-up; 
Section 7.2.2.2, Years 2 through 4; Section 7.2.3.3, Cohorts A and B, Years 2 through 4 
(including addition of Figure 4); Section 7.2.4, Unscheduled Visits; Section 7.2.5, Early 
Termination; Section 9.3, Blinding Procedures; Section 10.2, Withdrawal of Subjects from 
Study; Section 11.1.2, Years 2 through 4 (Active-Treatment Dose-Blinded Portion of the Study);  
Section 11.5, Compliance; Section 16.1.1, Analysis Population; Section 16.1.2, Methods of 
Analysis; Section 16.2.2, Methods of Analysis; Section 16.5.2, Methods of Analysis; 
Section 16.5.2.2, Years 2 through 4 (Active-Treatment Dose-Blinded Portion of the Study) and 
Overall Experience; Section 19.1.4, Central Laboratories for Laboratory Assessments. 


Protocol 228PD201, Version 6
CONFIDENTIAL
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Biogen MA Inc.
3
SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 3, Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 10.1, Discontinuation of Study Treatment
Change: Procedures for subjects discontinuing study treatment but remaining in the study were 
clarified.
Now reads:
[…]
Subjects who discontinue study treatment will be encouraged to remain in the study and 
complete all appropriate protocol-specified tests and assessments.  At a minimum, the 
following assessments should be performed at the timepoints shown on the schedule of 
assessments in Table 1 through Table 6:  MDS-UPDRS, 
, DaTScan, 
, and 
.     
For It is recommended that subjects terminatingwho terminate early (i.e., 
discontinuingdiscontinue both study treatment and study assessments before Week 96), it is 
recommended that ) perform the assessments of the Early Termination Visit be performed 
within 4 weeks after the last dose of study treatment.  The Safety Telephone Call should be 
performed approximately 8 weeks after the last dose, and the assessments of the Final Visit 
should be performed approximately 12 weeks after the last dose.  Final Visit procedures should 
be performed at the subject’s last study visit, even in the case of scheduling difficulties.  For 
Early Termination/Follow-up and end of study procedures, see Table 6.
Rationale: The changes provide additional clarity to study sites for study conduct.
Section 11.1, Regimen
Change: Guidance was added for subjects whose dose of study treatment is substantially 
delayed or missed. 
Now reads:
Study treatment will be administered by the study site staff via IV infusion once every 4 weeks.  
If there is a deviation from this schedule there should be at least 7 days between infusions.  
The duration of the infusion will be approximately 1 hour.  The Investigator or designee must 


Protocol 228PD201, Version 6
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Biogen MA Inc.
4
contact the study’s Medical Monitor in advance if they would like to adjust the infusion duration 
or administration conditions based on the subject’s ability to tolerate infusion.    
Rationale:  The change protects subject safety and provides clarity to study sites.
Section 11.3.1.1, Allowed Concomitant Therapy
Change: Dosing of subjects requiring symptomatic treatment with levodopa preparations was 
clarified.
Now reads:
Symptomatic PD treatment may be initiated during a subject’s participation in the study at the 
discretion of the Investigator, although subjects should refrain from taking symptomatic PD 
medications for as long as possible (in particular, for at least 6 months following Day 1).  For 
subjects who do require PD treatment, it is recommended that treatment start with immediate-
release levodopa/carbidopa at a dose of 25/100 mg 3 times a day (or equivalent dosage of 
levodopa/benserazide in locations where levodopa/carbidopa is not available).  The dose of 
levodopa/carbidopa may be titrated until satisfactory symptomatic relief is achieved.  Subjects 
receiving levodopa/carbidopa should remain on their initially established dose as long as 
possible.  Adjunctive use of COMT inhibitors, sustained-release levodopa/carbidopa 
preparations, dopamine agonists, MAO-B inhibitors, and zonisamide is discouraged, and use of 
amantadine and anticholinergic medications is prohibited in Year 1 of the study.  For subjects 
who do require PD treatment, it is recommended that treatment start with immediate-
release levodopa/carbidopa at a dose of 25/100 mg 3 times a day (or equivalent dosage of 
levodopa/benserazide in locations where levodopa/carbidopa is not available). The dose of 
levodopa/carbidopa may be titrated until satisfactory symptomatic relief is achieved. 
Subjects receiving levodopa/carbidopa should remain on their initially established dose as 
long as possible. Adjunctive use of COMT inhibitors, sustained-release levodopa/carbidopa 
preparations, dopamine agonists, MAO-B inhibitors, and zonisamide is discouraged, and 
use of amantadine and anticholinergic medications is prohibited in Year 1 of the study.  
Prior to initiating treatment with symptomatic PD medication the Investigator should 
provide the 
 Medical Monitor with a description of the Parkinsonian manifestations 
that require treatment and a rationale for the choice of medication.
[…]
Rationale: The change protects subject safety and provides clarity to study sites.




Protocol 228PD201, Version 6
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6

Section 11.3.1.2, Disallowed Concomitant Therapy, subjects participating in lumbar 
punctures were clarified.

Section 11.4, Continuation of Treatment, potential future study was clarified.

Section 15.2.3, Severity of Events, the version of the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) was updated to reflect 
the most recent version.

Typographical errors and formatting were corrected.


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 228PD201 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study, with an Active-Treatment 
Dose-Blinded Period, to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of 
BIIB054 in Subjects with Parkinson’s Disease  
Version 5 
Date: 12 February 2019 
EUDRA CT Number: 2016-004610-95 
Version 5 of the protocol has been prepared for this amendment, which supersedes Version 4. 
 


Protocol 228PD201, Version 5 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
2 
PRIMARY REASON FOR AMENDMENT 
The primary reason for this amendment to Protocol 228PD201is to extend the screening period 
by 1 week (7 days). 
New text is shown in bold type; deleted text is shown with a strikethrough. 
Section 7.2, Overall Study Duration and Follow-Up  
Now reads: 
The total duration of study participation for each subject will be up to approximately 113 
114 weeks, including a 5 6-week Screening period before the first study treatment infusion, a 
48-week placebo-controlled treatment period, a 48-week active-treatment dose-blinded period, 
and a 12-week follow-up period. 
Rationale: The screening window was increased by 1 week in order to ease the burden of 
screening procedures on subjects and to allow the sites a sufficient amount of time to complete 
the screening assessments.  
This change also affects Section 4.1, Study Schematic; Section 4.2, Schedule of Activities 
(Tables 1 and 3); Section 7.2.1, Screening; and Section 9.1, Screening and Enrollment.  
 
 


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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL 
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough. 
Section 3, Synopsis 
The Synopsis was revised to reflect changes made throughout the protocol. 
Section 4.2, Schedule of Activities  
Change: In Table 2 and Table 3, coagulation panel assessment edited to take place at Week 48 
instead of Week 44 
.  
Now reads: 
Table 2:  
Cohort A: Infusions 4−13 (Year 1) 
Tests and assessments 
Infusions 4-13,  
Week (±3 d)  
PK Visits, 
Week  
(±3 d) 
Year 1 
Week 52,  
(±3 d)2 
12 16 20 24 28 32 36 40 44 48 
22, 34, or 
461 
 
 
Coagulation panel including platelet count8 
 
 
X 
 
 
 
 
 X X 
 
 
 
 
  
 
 
Table 3 
Cohort B: Infusions 1−13 (Year 1) 
Tests and 
assessments 
Screening 
≤35 42 d 
Before 
Day 11 
Day 12 
Baseline/ 
Infusion 1 
Safety 
Telephone 
Calls 
1d & 7d 
after 
Infusion 12 
Infusions 2-13, Week (±3 d) 
PK 
Visits, 
Week 
(±3 d) 
Year 1 
Week 
52, 
(±3 d)4 
42
Safety 
Telephone 
Calls 
1d & 7d 
after 
Infusion 22 
82
Safety 
Telephone 
Calls 
1d & 7d 
after 
Infusion 32 
1216 20 2428323640 44 
48 22, 34, 
or 463 
Coagulation 
panel 
including 
platelet count 
X 
 
 
 
 
 
 
 
 X12,13  
 
 
 
 X12,13X12,13 
 
 
 
 
 


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This change also affects Section 14.2, Laboratory Safety Assessments.  
Section 15.3.1, Adverse Events 
Change: Text was added to clarify that any nonserious adverse events that occur during the 
Screening period and are related to the ligand will be captured on the electronic case report form 
(eCRF). 
Now reads: 
Any AE (including SAEs) experienced by the subject between the time of first dose of study 
treatment and the Final Visit is to be recorded on the eCRF, regardless of the severity of the 
event, its relationship to study treatment, its relationship to the LP procedure, or its relationship 
to the radioligand.  Nonserious AEs that occur during the Screening period and that are 
assessed by the Investigator as related to the ligand will be captured by the sites on the AE 
eCRF.  At each study visit, the Investigator will assess the subject for AEs and will record any 
new AEs or updates to previously reported AEs on the eCRF.   
Rationale: This text was added to fulfill the terms of the safety data exchange with the company 
that provides the ligand. 
This change also affects Section 4.2, Schedule of Activities (Table 1, footnote 23 and Table 3, 
footnote 26). 
Section 16.8, Interim Analyses  
Change: A second interim analysis was added for when all subjects complete their Week 72 
Visits.  
Now reads: 
… 
For the purpose of planning for future studies, Aan administrative interim analysis may be 
performed for the purpose of planning future studies after when approximately 60% of the 
subjects have completed the Week 52 Visit, and a second interim analysis when all subjects 
have completed the Week 72 Visit. 
… 


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Rationale: This data cut is being added to assess primary endpoint readout after subjects have 
received BIIB054 for approximately 6 months since the previous interim analysis.  
Change: Blinded sample size re-estimation was decreased from 25% to 10% of subject 
completion at Week 52 or 1 month prior to the completion of enrollment, whichever is first.  
Now reads: 
… 
A blinded sample size re-estimation may be conducted when approximately 25 10% of subjects 
have completed the Week 52 Visit or approximately 1 month before enrollment is projected 
to be completed, whichever is earlier. 
… 
Rationale: The timing of the sample size re-estimation is being changed as the study is enrolling 
faster than anticipated and the data need to be analyzed prior to closing enrollment out for the 
study in case sample size changes are warranted.  
 


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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. 
• Text was clarified throughout the protocol to specify the use of electronic case report 
forms. 
• Section 4.2, Schedule of Activities, Table 1 (footnote 20), Table 2 (footnote 14), 
Table 3 (footnote 23) and Table 4 (footnote 17); Section 7.2.2.3, Treatment with 
Parkinson’s Disease Medications; Section 13.1.1.1, Movement Disorder Society 
Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (Including 
Modified Hoehn and Yahr Scale); and 
 
, text was added to ease restrictions on time frame for subjects to take 
Parkinson’s disease medication prior to study visits at which Movement Disorder 
Society Sponsored Revision of the United Parkinson’s Disease Rating Scale or 
quantitative movement assessment will be conducted. 
• Section 5.3.2, Clinical Experience, text was updated with current subject dosing 
information for Study 228HV101. 
• Section 7.1.1, Year 1 (Placebo-Controlled Portion of the Study), and Section 11.2, 
Modification of Dose and/or Treatment Schedule, text was added to clarify that any 
changes to these sections will be documented in a protocol amendment.  
• Section 8.2, Exclusion Criteria (criterion 26), text was added to allow the Investigator 
discretion as to when a LP can be safely performed based on laboratory values.  
• Section 8.2, Exclusion Criteria (criterion 26); Section 11.3.1.1, Allowed Concomitant 
Therapy; and Section 11.3.1.2, Disallowed Concomitant Therapy, the minimum dose 
of aspirin use allowed by subjects was increased from 81 to 100 mg.  
• Section 9.1, Screening and Enrollment, text was added to clarify that rescreen and 
repeat parameters apply to any subject under any version of the protocol.  
• Section 11.3.1.1, Allowed Concomitant Therapy, zonisamide was added as a drug 
whose adjunctive use is discouraged.  
• Section 11.3.1.2, Disallowed Concomitant Therapy, benztropine, bupropion, cocaine, 
mazindol, phentermine, and sertraline were added as disallowed concomitant 
medications. 
• Typographical errors and formatting were corrected. 


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1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 228PD201
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study, with an Active-
Treatment Dose-Blinded Period, to Evaluate the Safety, Pharmacokinetics, and 
Pharmacodynamics of BIIB054 in Subjects with Parkinson’s Disease 
Version 4
Date:  15 August 2018
EUDRA CT Number: 2016-004610-95
Version 4 of the protocol has been prepared for this amendment, which supersedes Version 3.


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PRIMARY REASON FOR AMENDMENT
The primary reason the sponsor has initiated this amendment to Protocol 228PD201 is to add 
retesting and rescreening flexibility for subjects with nonclinically significant out-of-range 
laboratory results as well as those who cannot complete the Day 1 visit within the designated 
screening period.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 9.1, Screening and Enrollment
Now reads:
Rescreening for other reasons may be allowed after consultation with the Sponsor.  In 
addition, eligible subjects who are not able to complete the Day 1 Visit within 35 days of 
starting their screening assessments may be rescreened at the discretion of the Sponsor.  
All screening assessments will be repeated except for the main ICF, 
 
, confirmation of PD diagnosis, height measurement, blood sampling 
for ribonucleic acid (RNA), MRI, and DaT/SPECT unless determined otherwise by the 
sponsor. For female subjects, if initial follicle-stimulating hormone (FSH) level confirmed 
postmenopausal state, it does not need to be repeated.  
Coagulation, blood chemistry, and hematology tests may be repeated once if, in the opinion of 
the Investigator, values of the initial tests are only slightly out of range.  For central laboratory
normal ranges, please refer to the Study Reference Manual.  Subjects who have other 
nonclinically significant out-of-range laboratory results may be retested 1 time only after 
discussion with the Medical Monitor.  
Rationale:  This language was added to support study enrollment.  It allows for more flexibility 
for rescreening and lessens the probability that subjects will be unnecessarily excluded from the 
study for nonclinically significant laboratory results.  It also, gives subjects who are taking study 
prohibited medications the opportunity to stop these treatments and rescreen after an appropriate 
washout period.  Additionally, this new text makes all sections of the protocol consistent with 
regards to retesting of samples. 


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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 3, Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 4.2, Schedule of Activities 
Change: Testing of hepatitis B surface antibodies (anti-HBs) was added to the list of viral 
screens in Table 1.
Now reads:
Tests and 
assessments
Screeni
ng
≤35 day
s before
Day 11
Infusions 1-3
Day 1/Baseline, Day 29 (1 day), & Day 57 (1 day)
Clinic Visits
Day 43
(Safety 
Telephone 
Call)
Day 
2, 
30, 
58
Day 4, 
60
Day 
8, 
36, 
64
Day 
15, 71
Pre-
infusion2
0m
Time after End of Last Infusion
≤10m
1h
±15m
2h
±15m
4h
±30m
24h
±2h
72h
-2h/+1d
168h
±24h
336h
±24h
336h
±24h
HBsAg, anti-HBc, 
anti-HBs, 
HCVAb, HIV
X
Rationale:  anti-HBs are a diagnostic marker of hepatitis B infection, the presence of which is an 
exclusion criterion for the study. 
This change also affects Section 4.2, Schedule of Activities, Table 3.
Section 4.2, Schedule of Activities 
Change:  Reference to a 7-day follow-up phone call following DaT/SPECT was add to Table 1,
Footnote 12. 
Now reads:
12 The MRI results will be read by the local radiologist at collection.  Both MRI and 
DaT/SPECT results will be sent within 24 hours to a central reader for further evaluation and to 
confirm eligibility at Screening.  Screening imaging assessments should be completed after all 
other eligibility criteria have been met, and before Day -7, to allow adequate time for evaluation 
of the results.  Subjects will be contacted by telephone within 7 days following the 
DaT/SPECT procedure to monitor for AEs.




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Rationale:  For Cohort B, it was determined that 7 days did not provide enough time to complete 
the evaluation of imaging results, which are required for enrollment in the study.  An extension 
of this period to at least 8 business days will provide adequate turnaround time for this to be 
completed before randomization.     
This change also affects Section 7.2.1, Screening.
Section 4.2, Schedule of Activities 
Change:  Changed text in Table 4 Footnote 1 to indicate that Year 2 randomization will be 
performed prior to Year 2 Week 52 Visit. 
Now reads:
1  Randomization for Year 2 will be performed prior to the Year 2 Week 52 Visit.  Study 
treatment infusion and the assessments shown will be considered part of Year 2 of the study and 
will be performed after all assessments for the Year 1 Week 52 Visit are completed (see Table 2 
and Table 3)., with the exception that randomization for Year 2 may be performed prior to the 
Year 2 Week 52 Visit.  The Year 2 Week 52 assessments may be performed on the same day as 
the Year 1 Week 52 Visit or on the next day; however, pregnancy test, vital signs, and ECG must 
be obtained predose on the same day as dosing for Infusion 14, and randomization for Year 2 
must be performed prior to Infusion 14.  
Rationale:  The wording of this footnote was adjusted slightly for clarity.  Section 9.2 was 
changed to specify that Year 2 randomization will be performed prior to Infusion 14 for Cohort 
A and on Day 1 for Cohort B.  Therefore, it is now more accurate to definitively state that 
randomization will occur prior to Year 2.   
Section 6.1, Primary Objective and Endpoint
Change: The incidence of abnormalities or changes in a variety of assessments and measures
was removed as a safety endpoint.
Now reads:

Incidence of abnormalities or change from baseline in clinical laboratory test data, 
vital sign measurements, neurological and physical examination findings, 
electrocardiograms (ECGs), and brain magnetic resonance imaging (MRI) safety 
findings (may include T1, fluid attenuated inversion recovery, and gradient echo)
Rationale:  
The language has been modified to enable Biogen to better comply with clinical trial 
transparency reporting requirements.  Because these assessments were individually listed as a 
separate endpoint, clinical trial registries required reporting of any and all abnormalities, 
regardless of their clinical significance, at all timepoints where they were observed.  This was 
found to be complicated and unnecessary, as in most cases, only clinically significant 
abnormalities would be considered important.  Further, any such clinically significant 
abnormalities would also get documented as AEs or SAEs making their reporting duplicative.  




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prior PD regimens should not exceed 30 days.  Stable (at least 8 weeks) dosages of 
medications that are used to treat conditions other than PD tremor (e.g., beta-
blockers, benzodiazepines, and barbiturates) are allowed.  Further guidance will be 
provided by the study’s Medical Monitor on a case by case basis.
Rationale: In order to properly evaluate the effect of BIIB054 on clinical study endpoints it is 
critical that the medications being utilized by study subjects do not have substantial effects on 
the motor symptoms of PD.  
This change also affects Section 11.3.1.1, Allowed concomitant Therapy
Section 8.2, Exclusion Criteria
Change: In exclusion criterion 3, the language and abbreviations defining hepatitis B virus 
infection were revised.
Now reads:
3.
Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] 
and/or total hepatitis B core antibody [HBcAb anti-HBc]).  Subjects with immunity to hepatitis 
B from previous natural infection (defined as negative HBsAg, positive hepatitis B surface 
antibody immunoglobulin G, and positive HBcAb) or vaccination (defined as positive anti HBs)
defined as negative HBsAg, positive anti-HBc, and positive hepatitis B surface antibody 
[anti-HBs]) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive 
anti-HBs) are eligible to participate in the study.
Rationale:  The language was updated to conform to new language and abbreviations used by
the United States Centers for Disease Control and Prevention.  
This change also affects Section 2, List of Abbreviations; Section 4.2, Schedule of Activities,
Tables 1 and 3; and Section 19.1.4, Central Laboratories for Laboratory Assessments.
Section 8.2, Exclusion Criteria
Change:  Exclusion criterion 18 was updated with new language on electrocardiogram (ECG)
abnormalities.
Now reads:
18.
Clinically significant (as determined by the Investigator) 12-lead ECG abnormalities, 
including prolongation of confirmed demonstration of corrected QT interval (e.g., repeated 
demonstration of a corrected QT interval using the Fridericia correction method of >460 msec 
[men] and >470 msec [women] before study treatment administration).  
Rationale:  Criteria for assessing ECG abnormalities were updated to harmonize with that of 
other studies.
Section 8.2, Exclusion Criteria


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Change:  Exclusion criterion 26 and 34, pertaining to anticoagulant medication, was changed.
Now reads:
26.
For subjects enrolling at sites where LPs will be performed:  Subjects with the following 
characteristics will be excluded from participation in LP procedures:
•
Any history of lumbar surgery for any reason (e.g., herniated disc) that in the opinion of 
the Investigator would interfere with or pose risks to the LP procedure 
•
Other contraindications to having a LP, including but not limited to: 

Low platelet count (below 50,000 cells/μL), or Screening values of INR, PT, or APTT 
that are not within normal ranges     

Taking any antiplatelet medication (e.g., aspirin >81 mg daily, clopidogrel, or 
nonsteroidal anti-inflammatory drugs [NSAIDs]) within 7 days prior to the planned LP or 
anticipated need for antiplatelet medication within 48 hours after an LP

Taking anticoagulant medication (warfarin, heparinoids, and direct coagulation factor 
inhibitors, e.g., apixaban, dabigatran, rivaroxaban) within 7 days prior to the planned 
LP or anticipated need for antiplatelet medication with 48 hours after an LP.   

X-ray, MRI, or myelographic evidence of significant lumbar spine abnormalities or other 
anatomical factors at or near the LP site that might interfere with performance of LP                
34.
Use of anticoagulant medications within 90 days before Day 1 (warfarin, heparinoids, 
and direct coagulation factor inhibitors e.g., apixaban, dabigatran, rivaroxaban).
Rationale:  The exclusion of anticoagulant medications for all subject throughout the study was 
determined to be too restrictive.  The use of anticoagulants is primarily a safety concern for those 
who are undergoing a lumbar puncture (LP) procedure.  Because LPs will only be performed on 
a subset of subjects at particular timepoints, the restriction on these medications was limited to 
the time immediately before and after a scheduled LP procedure.   
This change also affects Section 11.3.1.2, Disallowed Concomitant Therapy  
Section 8.2, Exclusion Criteria
Change: Exclusion criterion 36 was updated to include serotonin norepinephrine reuptake 
inhibitors (SNRIs) and specifically exclude the selective serotonin reuptake inhibitor (SSRI), 
sertraline.
Now reads:
36.
Use of selective serotonin reuptake inhibitors (SSRIs), (with the exception of sertraline, 
which is prohibited) or serotonin norepinephrine reuptake inhibitors (SNRIs) at doses that 
have not been stable for at least 3 months before Day 1 and/or that are not expected to remain 
stable for the duration of the study.


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Rationale:  There is published evidence to suggest that like SSRIs, SNRIs may also have a small 
effect on DaT/SPECT results.  For this reason, it would be necessary for subjects to maintain 
stable doses during the study to allow for accurate assessment of BIIB054 treatment-induced 
changes.  Additionally, even though sertraline is an SSRI, it is specifically excluded in exclusion 
criterion 31 due to its ability to interfere with DaT/SPECT.
This change also affects Section 11.3.1.1, Allowed Concomitant Therapy 
Section 9.2, Randomization and Registration of Subjects
Change: Part numbers were added to the description of the Movement Disorder Society 
Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) assessment 
score.  
Now reads:
Randomization of subjects in Cohort B will be stratified by baseline (Day 1) MDS-UPDRS Part 
I, II, and III total scores (≤35 and >35) and striatum SBR (≤1.2 and >1.2), and subjects will be 
randomized at Day 1 into 1 of 4 parallel dosing arms to receive placebo (n=82) or BIIB054 (250 
mg [n=41], 1250 mg [n=82], or 3500 mg [n=82]) in each strata.
Rationale:  The text was updated to clarify that the MDS-UPDRS scores for each subject will be 
derived from Parts I, II, and III of that assessment.   
This change also affects Section 16.9, Sample Size Considerations.
Section 9.2, Randomization and Registration of Subjects
Change:  The DaT/SPECT striatal binding ratio (SPR) value was updated.
Now reads:
Randomization of subjects in Cohort B will be stratified by baseline (Day 1) MDS-UPDRS Part 
I, II, and III total scores (≤35 and >35) and striatum SBR (≤1.11.2 and >1.11.2), and subjects will 
be randomized at Day 1 into 1 of 4 parallel dosing arms to receive placebo (n=82) or BIIB054 
(250 mg [n=41], 1250 mg [n=82], or 3500 mg [n=82]) in each strata.
Rationale:   Striatal SBR values will be used to improve randomization across treatment arms in 
Cohort B. The striatal SBR value in the original protocol (1.1) was determined using an 
evaluation of a large data set of publicly available baseline DaT/SPECT scans of PD patients 
(n=~300; Parkinson's Progression Markers Initiative [PPMI]). Direct comparison of the PPMI 
and SPARK reconstruction/processing pipelines revealed a small, albeit significant, increase in 
SBR values with application of our standardized and scalable SPARK DaT/SPECT pipeline, 
resulting in a rightward shift in the overall distribution across the population. To account for this, 
the SBR cutoff value will be amended to 1.2 so as to allow a more equal separation of subjects 
based on DaT/SPECT values.
Section 9.2, Randomization and Registration of Subjects


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Change:  Language was added to allow flexibility to randomize the lowest (250 mg) BIIB054 
dosing cohort to a higher dosing cohort in Year 2 of the study.  It also clarifies the timing of the 
Year 2 randomization.     
Now reads:
Prior to receiving Infusion 14, which will be the first infusion of Year 2 (active treatment dose 
blinded portion of the study), subjects who received placebo in Year 1 will be randomized to 1 of 
the active arms to receive BIIB054 in Year 2.  Subjects who received BIIB054 in Year 1 will 
continue with the same dose regimen in Year 2.  All subjects who were randomized to receive 
placebo in Year 1 will be randomized, in equal ratio, to one of the active BIIB054 
treatments for Year 2.  For subjects receiving placebo in Cohort A, the randomization will 
occur prior to Infusion 14.  For subjects receiving placebo in Cohort B, this randomization 
will at the time of the baseline Day 1 randomization (Year 1). Subjects who received 
BIIB054 (1250 mg or 3500 mg) in Year 1 will continue with the same dose regimen in Year 
2. In addition, the decision of whether or not to randomize subjects who receive the 
250-mg dose in Year 1 to 1 of the 2 highest doses of BIIB054 in Year 2 will be made after 
the IDMC review of Cohort A Week 12 data.
Rationale:  Language was added to allow for greater flexibility in establishing Year 2 dosing 
assignments.  Previous language in the protocol only allowed for placebo subjects from Year 1 to 
be randomized to active BIIB054 treatment arms in Year 2.  Because the 250-mg dose of 
BIIB054 may be too low to achieve clinical effect, language was added to allow flexibility to 
also randomize the 250-mg dosing cohort subjects to a higher dosing cohort in Year 2 of the 
study.  This new language also clarifies the timing of the subject’s randomization to their Year 2 
treatment assignment.
This change also affects Section 4.1, Study Schematic; Section 4.2, Schedule of Activities, Table 
4 (Footnote 13); Section 7.1.2, Year 2 (Active-Treatment Dose-Blinded Portion of the Study); 
Section 11.1.2,Year 2 (Active-Treatment Dose-Blinded Portion of the Study).    
Section 11.2, Modification of Dose and/or Treatment Schedule
Change:  Removed language requiring changes to be documented in a protocol amendment and 
restricting dose level changes after randomization.  
Now reads:
Dose levels, number of treatment arms, and number of subjects per arm for Cohort B may be 
modified based on emerging Cohort A safety and PK data, and review by the IDMC.  Any 
changes will be documented in a protocol amendment.  No changes in dose level are permitted 
for an individual subject once randomized.
Rationale:   Section 9.2 of the protocol was updated to allow for potential rerandomization of 
subjects to higher dose levels in Year 2 of the study.  Consequently, dose changes should not be 
strictly prohibited in the protocol.  Further, the need for a protocol amendment for such study
changes should be evaluated on a case-by-case basis.  


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This change also affects Section 7.1.1, Year 1 (Placebo-Controlled Portion of the Study); and 
Section 7.2.2, Study Treatment.
Section 11.5, Compliance
Change:  A section pertaining to compliance with treatment was added.
Now reads:
11.5.
Compliance
Compliance with treatment dosing is to be monitored and recorded by site staff.
Rationale:   Compliance with dosing is necessary to allow for accurate assessment of the effects 
of BIIB054 treatment.  The original template under which this protocol was written did not 
include such language.  Therefore, this section was added to clarify site staff’s role in ensuring 
and documenting treatment compliance.  
Section 13.1, Clinical Function Assessments
Change:  Language was added to specify Biogen’s preferred procedures regarding the rating of 
the clinical function assessments.  
Now reads:
Clinical function assessments are performed by qualified raters, preferably those who are 
not involved in other aspects of subject clinical care and management, including clinical 
safety assessments.  The same rater should perform a given assessment across all visits.
Rationale:   Biogen is recommending these rating procedures to better maintain study blinding, 
reduce the chance of bias, and improve the constancy of data collection.  
Section 13.3.1.1, Single-Photon Emission Computed Tomography Scan of the Dopamine 
Transporter
Change:  The sentence pertaining to additional imaging at phenoconversion in previously 
asymptomatic subjects was deleted.
Now reads:
Biological effects of BIIB054 on brain dopamine neurons and nerve terminals will be assessed 
using DaT/SPECT imaging.  Subjects will undergo DaT/SPECT imaging at Baseline and at 
specified timepoints.  Subjects may also undergo an additional imaging at the time of    
phenoconversion to motor PD in previously asymptomatic subjects.  The DaT/SPECT imaging 
procedure will be performed using DaTscan, administered IV.  Before the DaTscan injection, 
subjects will be pretreated with stable iodine (10 drops of a saturated solution of potassium 
iodide) to reduce the uptake of DaTscan by the thyroid.  Subjects will be injected with 3 to 5 mCi 
of DaTscan.  Within a 4-hour (±30 minutes) window following the injection, subjects will 
undergo SPECT imaging on the camera.  Subjects will be monitored by study site staff for AEs 


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on the day that a DaT/SPECT scan is obtained.  Subjects will also be contacted by telephone 
within 7 days following the injection/scan.
Rationale:  The deleted sentence is not necessary as this study is only open to subjects who 
already have a PD diagnosis.  Asymptomatic subjects would not have been eligible to participate.  
This statement was originally included in error.
Section 14.2, Laboratory Safety Assessments
Change:  The language regarding coagulation testing was changed to allow for the use of 
samples collected at non-study visits
Now reads:

Coagulation panel, including platelet count, INR, PT, and APTT will be measured no 
more than 35 days before performing an LP.  Before an LP can be performed, results of 
the most recent (i.e., performed at previous visit within 35 days) coagulation tests, 
including platelet count, must be reviewed by the Investigator and must indicate that an 
LP can be performed safely.  If repeat tests are clinically indicated in the opinion of the 
Investigator, then these tests may be performed locally The most recent tests may be 
those completed by the central laboratory from a previous study visit within 35 days 
(i.e., Screening) or may be performed by a local laboratory if needed to facilitate 
timely review., and. rResults must be reviewed before an LP can be performed.
Rationale:   This change was made to clarify to sites that it is allowable for coagulation samples 
to be collected at non-study visits (as an unscheduled sample) and tested at local laboratories on 
occasions when the subject’s latest study visit was beyond the acceptable time range.  
This change also affects Section 4.2, Schedule of Activities, Table 2, Footnote 8; and Table 3,
Footnote 13.
Section 15.1.1, Adverse Event
Change:  Magnetic resonance imaging (MRI) and physical/neurological examination were
added to the list of abnormal results that could constitute an adverse event.   
Now reads:
Determination of whether an abnormal laboratory value, vital sign result, MRI result, 
physical/neurological examination finding, and/or ECG result meet the definition of an AE 
will be made by the Investigator.
Rationale:  This was added to provide a more complete listing of results that could be reported 
as an adverse event.  
Section 16.8, Interim Analysis




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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.

Section 2, List of Abbreviations, was updated, and some abbreviations throughout 
document were changed.

The Table of Contents, List of Tables, and List of Figures were updated to reflect 
changes throughout the text.

Minor grammatical corrections were made to Section 4.1, Study Schematic Figure 1 
and Section 4.2, Schedule of Activities Table 3 

The name of the contract research organization was changed from 
 to 

Typographical errors and formatting were corrected.


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1
Biogen MA Inc.
225 Binney Street
Cambridge, MA  02142
United States
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
______________________________________________________________________
AMENDMENT SUMMARY
Biogen Protocol 228PD201
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study, with an Active-Treatment
Dose-Blinded Period, to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of 
BIIB054 in Subjects with Parkinson’s Disease
  Version 3
Date:  22 October 2017 
EUDRA CT Number:  2016-004610-95 
Version 3 of the protocol has been prepared for this amendment, which supersedes Version 2.




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Section 11.1, Regimen.  The change to subject randomization and treatment assignments also 
affects Section 7.1.2, Year 2 (Active-Treatment Dose-Blinded Portion of the Study); Section 9.2, 
Randomization and Registration of Subjects; and Section 9.3, Blinding Procedures.






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Section 7.2.6, Study Stopping Rules
Change:  The timing was modified for the study stopping rules.
Now reads:
Biogen may terminate this study at any time, after informing Investigators.  Biogen will notify 
Investigators if the study is to be placed on hold, completed, or terminated.
For Cohort A until initiation of dosing in Cohort B: 
After evaluation of the safety, tolerability, and PK data by the IDMC, further dosing may be 
terminated if any of the following is observed:

Two similar SAEs or 2 clinically significant AEs, unless clearly unrelated to 
BIIB054, are reported for subjects on active study treatment.

Three or more similar AEs are reported for subjects on active study treatment (unless 
these events are clearly unrelated to BIIB054) that are not tolerable, as reported by 
the subject (e.g., severe dizziness) and/or deemed a medically unacceptable risk by 
the IDMC and/or Sponsor.

Sponsor requests that dosing be terminated.
For both cohorts after initiation of dosing in Cohort B: 
cConditions that may warrant termination of the study include, but are not limited to, the 
following: 

The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled 
in the study.

A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product.
Rationale:  The more comprehensive stopping criteria for Cohort A are only necessary until 
dosing has begun in Cohort B.
Section 8.2, Exclusion Criteria
Change:  The reference to uncorrected QT interval was removed from Exclusion Criterion 18 
for ECG abnormalities.
Now reads:
18. Clinically significant (as determined by the Investigator) 12-lead ECG abnormalities,
including prolongation of corrected QT interval (e.g., repeated demonstration of a QT or 
corrected QT interval using the Fridericia formula >460 msec [men] and >470 msec 
[women] before study treatment administration).  
Rationale:  This change was made for accuracy.  Only the corrected QT interval applies here.










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by the need to administer the MDS-UPDRS prior to starting symptomatic PD 
medications outside of a scheduled visit, and to clarify the tests to be performed.  In 
addition, this text for unscheduled visits was moved to a new Section 7.2.4,
Unscheduled Visits.  The title for the remaining text in Section 7.2.3 was modified to 
Follow-Up Visits and Final Visit, and the sentence regarding the timing of the final 
follow-up visit was moved to Section 7.2.3.3, Cohorts A and B, Year 2, for clarity.

The title of Section 7.2.5 was modified from “Early Termination Visit and Final 
Visit” to “Early Termination” to coordinate with the text in that section, which 
includes the Early Termination Visit, a Safety Telephone Call, and the Final Visit.

The text for the first study stopping rule in Section 7.2.6, Study Stopping Rules, was 
modified to clarify that it applies to 2 events, either serious adverse events (SAEs) or 
clinically significant AEs.

The text in Section 8.2, Exclusion Criteria, for the exclusion criterion for participation 
in another clinical study or treatment with an investigational drug or therapy, was 
modified for clarity.

Guidance on potential modifications to infusion duration and guidance on the 
requirement to maintain dose levels in Section 7.2.2, Study Treatment, have been 
repeated in Section 11.1, Regimen, and Section 11.2, Modification of Dose and/or 
Treatment Schedule, respectively, for clarity and completeness.

The text in Section 11.4, Continuation of Treatment, has been modified to indicate 
that further treatment may be offered in an open-label extension study under a 
separate protocol.

The description of coordination of symptomatic Parkinson’s Disease medications 
with clinical function assessments has been modified in Section 13.1.1.1, Movement 
Disorder Society Sponsored Revision of the Unified Parkinson’s Disease Rating 
Scale, Including Modified Hoehn and Yahr Scale, and 
 
 for clarity and consistency with Section 7.2.2.3, Treatment 
with Parkinson’s Disease Medications. 


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APPENDIX A. SCHEDULE OF ACTIVITIES TABLES
The following tables show the changes in the Schedule of Activities tables from Protocol V2 to V3.
For ease of readability, changes to the tables are shown using images of tracked changes from the amended protocol rather than with 
bolding and strikethrough.
Table 1:
Cohort A: Infusions 1–3 (Year 1)
Table 2:
Cohort A: Infusions 4–13 (Year 1)
Table 3:
Cohort B: Infusions 1-13 (Year 1)
Table 4:
Cohorts A and B:  Infusions 14–25 (Year 2) and Follow-Up






























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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 228PD201
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, 
Pharmacokinetics, and Pharmacodynamics of BIIB054 in Subjects with Parkinson’s Disease
Version 2 
Date:  09 August 2017
EUDRA CT Number:  2016-004610-95 
Version 2 of the protocol has been prepared for this amendment, which supersedes Version 1.


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PRIMARY REASON FOR AMENDMENT
The primary reasons for this amendment to Protocol 228PD201 are as follows:

The length of the treatment period and total duration of subject participation in the study 
have been reduced.  

The number of subjects in the study has been increased and the sample size 
considerations supporting that change have been updated.

Key inclusion criteria were modified as follows:
-
Inclusion criterion 2 was modified to reduce the time from past diagnosis with 
PD, to clarify clinical presentation details, and to indicate that subjects with Lewy 
body dementia would not be included in the study.
-
Inclusion criterion 3 was modified to lengthen the washout duration for levodopa 
treatment before entry into the study from 4 weeks to 12 weeks, to describe PD 
medications excluded, and to shorten the maximum duration of allowed prior PD 
treatment regimens from 3 months to 30 days.

The dose levels were changed from 3 mg/kg, 15 mg/kg, and 45 mg/kg (dosing based on 
body weight) to 250 mg, 1250 mg, and 3500 mg (fixed dosing) for both cohorts.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 7.2, Overall Study Duration and Follow-Up
Now reads:  
The total duration of study participation for each subject will be approximately 89 weeks 65 
weeks, including a 5-week Screening period before the first study treatment infusion, a 72 week 
48-week treatment period, and a 12-week follow–up period n.
Rationale:  The shorter treatment duration will allow earlier data collection and acceleration to a 
future Phase 3 study.
This change also affects Section 4.1, Study Schematic; Section 4.2, Schedule of Activities; and 
Section 7.2.2, Study Treatment.
To coordinate with this change, there has been a corresponding decrease in the number of study 
treatment doses (from 19 to 13 doses).  The change in number of doses affects Section 4.1, Study 
Schematic; Section 4.2, Schedule of Activities; Section 7.1, Study Overview; Section 7.2.2, 
Study Treatment; and Section 16.5.1, Clinical Function (under Analysis Population).
There has also been a corresponding change in the number and naming of study visits during the 
treatment period.  The change in visit descriptions affects Section 4.2, Schedule of Activities; 
Section 7.2.4, Unscheduled Visits and Follow-Up; Section 16.2.2, Pharmacodynamic – Imaging 
Analyses (under Methods of Analysis); and Section 16.5.2, Clinical Function (under Methods of
Analysis). 


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Section 16.9, Sample Size Considerations
Now reads:  
The sample size calculation is based on changes in SBR observed using pharmacologic 
parameters, i.e., DaT/SPECT with DaTscan.  Based on re-analysis of data from the Parkinson’s
Progression Markers Initiative study, putamen ipsilateral to the clinically more severely affected 
side was selected as the region of interest for the purpose of sample size calculation, as it shows 
one of the highest mean to standard deviation (SD) ratios and most rapid rates of change over 
time.  Based on mean changes from baseline to 12-month and 24 month SBR from the 
Parkinson’s Progression Markers Initiative study, it is assumed, by linear extrapolation, that the 
mean change (SD) from baseline to Week 76 52 for the placebo group will be 0.18 (0.167) 0.138
(0.156).  Assuming a maximum 40% reduction in the change from baseline of the active group 
with maximum response relative to placebo group, the mean (SD) for this active group will be 
0.108 (0.167) 0.083 (0.156) and the responses for other active groups are assumed to be 
somewhere between placebo and the maximum response.  The primary analysis will be based on 
the MCP-MOD method to detect a dose-response trend while controlling for multiplicity.  
Optimal contrasts will be constructed to detect potential dose-response trend under common 
dose-response curves (e.g., Emax, exponential, logistic, linear in log dose, and quadratic model, 
which are illustrated with parameters shown in Figure 3 Figure 2).  It has also been determined 
that in Cohort A, 24 subjects will be randomized in a 1:1:1:1 ratio to each of the treatment 
groups, while in Cohort B, subjects will be randomized in 2:1:2:2 ratio to the placebo, 3 mg/kg 
250 mg, 15 mg/kg 1250 mg, and 45 mg/kg 3500 mg groups.  A sample size of 52:26:52:52 
82:41:82:82 in the respective treatment groups in Cohort B, together with the sample size in 
Cohort A, will provide an average power of approximately 80% to detect the dose-response 
trend, based on a 2-sided type I error of 0.2.  If the 2-sided type I error is 0.1, the power is 
approximately 68% 70%.  The sample size will be 58:32:58:58 88:47:88:88 placebo:3 
mg/kg250 mg:15 mg/kg1250 mg:45 mg/kg3500 mg, with a total of 206 311 subjects to be 
enrolled for the study (Table 5 and Table 6).  A 15% dropout rate has been adjusted assumed
for in this calculation.  If there are any modifications to the candidate dose-response 
curves/models or parameters, the final candidate models for the MCP-MOD will be 
prespecified and described in the SAP.  
With a sample size of 88 subjects per arm in the 1250 mg and 3500 mg arms, the study has 
approximately 70% power to detect a 40% reduction in the active group relative to placebo 
in the change from baseline to Week 52 MDS-UPDRS total score, assuming the placebo 
mean change (SD) is 8.0 (10.64), based on the Parkinson’s Progression Markers Initiative 
study data and a 2-sided alpha of 0.2.
With a sample size of 88 subjects per arm in the 1250 mg and 3500 mg arms, the study has 
80% probability of detecting AEs with a rate of 1.8% or greater in these 2 arms, and a 
90% probability of detecting AEs occurring with a rate of 2.6% or greater.


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Figure 32:
Response Shapes
[original figure replaced with the one below]
Table 5:
Sample Size Before Adjusting for 15% Dropout Rate
Treatment Group
Placebo
BIIB054
250 mg
BIIB054
1250 mg
BIIB054
3500 mg
Total
Cohort
Cohort A
5
5
5
5
20
Cohort B
69
34
69
69
241
Total
74
39
74
74
261
Table 4 Table 6:
Sample Size After Adjusting for 15% Dropout Rate
Dose
Treatment Group
Placebo
BIIB054
3 mg/kg250 
mg
BIIB054
15 mg/kg1250 
mg
BIIB054
45 mg/kg3500 
mg
Total
Cohort
Cohort A
6
6
6
6
24
Cohort B
5282
2641
5282
5282
182287
Total
5888
3247
5888
5888
206311


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Rationale:  The number of subjects in the study was increased in order to allow enough power 
for statistical analyses based on DaT/SPECT with a shorter treatment duration.  The updated 
response shape diagram (now Figure 3) and tables support the sample size calculations.  Power 
to detect changes in MDS-UPDRS score and AE incidence has also been provided.
This change also affects Section 4.1, Study Schematic; Section 7.1, Study Overview; Section 9.2,
Randomization and Registration of Subjects; and Section 11.1, Regimen. 
To coordinate with this change, there was a corresponding increase in the number of study sites.  
The change in the number of study sites affects Section 7.1, Study Overview.
Section 8.1, Inclusion Criteria 
Inclusion criterion 2:
Now reads:  
2.  Diagnosed with idiopathic PD within the last a maximum of 5 3 years without motor 
fluctuations or dyskinesia prior to Screening.  Subjects must have:  
a.
An asymmetric or bilateral presentation of Oone of the following: 

resting tremor and bradykinesia

bradykinesia and rigidity

rigidity and resting tremor
OR 

either asymmetric resting tremor or asymmetric bradykinesia.
b. No known or suspected cause of Parkinsonism other than idiopathic 
neurodegenerative PD.:  i.e., no presence of  Subjects with drug-induced 
Parkinsonism (e.g., metoclopramide and flunarizine), metabolic identified 
neurogenetic disorders (e.g., Wilson’s disease), encephalitis, or Parkinson Plus 
syndromes, or other forms of atypical Parkinsonian syndromes (e.g., progressive 
supranuclear palsy and multiple system atrophy), or Lewy body dementia are not 
allowed in the study.
Rationale:  The change to inclusion criterion 2 was made because subjects with a longer time 
from diagnosis would likely have static disease or even be starting to decline, and BIIB054 is 
unlikely to be effective for them.  The shorter time from diagnosis is also consistent with that in 
the majority of other studies of disease-modifying therapies for PD.  Clinical presentation of 
symptoms has been modified for accuracy and clarity.
The changes to inclusion criterion 2b clarify that Lewy body dementia would rule out 
neurodegenerative PD and is not included in the intended subject population.  


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Inclusion criterion 3:
Now reads:  
3.   Has not received levodopa for at least 4 weeks, or any other treatment for PD 
symptoms (dopamine agonists, amantadine, anticholinergics, MAO-B inhibitors, 
or safinamide) for at least 12 weeks before Screening prior to Day 1 and, in the 
opinion of the Investigator, is not expected to require symptomatic therapy PD 
treatment for at least 6 months following Day 1.  Maximum total duration of 
previous levodopa treatment prior PD regimens should not exceed 3 months 30 
days.
Rationale:  The longer washout of prior levodopa and the shorter maximum duration of prior PD 
regimens are intended to avoid inclusion of subjects with slowly progressing disease, as well as 
those with atypical Parkinsonian syndromes, who could dilute the outcomes signal in the study.  
In addition, the washout period was defined relative to Day 1 in order to provide a fixed 
reference point and for consistency with other inclusion and exclusion criteria.
Section 7.1, Study Overview
Now reads:  
…All subjects in the study will be randomized into 4 arms, to receive 19 13 doses of BIIB054 (3, 
15, or 45 mg/kg 250, 1250, or 3500 mg) or placebo.  
Rationale:  Given the favorable safety profile of BIIB054 in the first-in-human Study 
228HV101 and based on PK modeling from that study, a fixed-dose approach was chosen for 
this study. Fixed doses will result in greater compliance and reduced potential for medication 
errors.  Projected safety margins for both approaches are similar and on average are estimated to 
be 9 (AUCtau) and 8 (Cmax) for the 3500 mg fixed dose, and 7 (AUCtau) and 14 (Cmax) for a
45 mg/kg dose.
This change also affects Section 4.1, Study Schematic; Section 5.5, Rationale for Dosing 
Regimen; Section 9.2, Randomization and Registration of Subjects; Section 11.1, Regimen; and 
Section 16.8, Sample Size Considerations.




















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Section 4.2, Schedule of Activities
Change:  A new footnote was added to the Week 52/ET Visit, the Safety Telephone Call
(Week 56), and the Final Visit (Week 60) columns of Table 2 (Cohort A: Infusions 4-13 and 
Follow-Up) and Table 3 (Cohort B: Schedule of Assessments) to indicate the recommended 
timing of assessments for subjects who terminate early.
Now reads for Table 2 (same text for Table 3, footnote 5):
2
For subjects terminating early, it is recommended that the assessments of the Early 
Termination Visit be performed within 4 weeks after the last dose of study treatment, a 
Safety Telephone Call be performed approximately 8 weeks after the last dose, and the 
Final Visit be performed approximately 12 weeks after the last dose.
Rationale:  This change was made to provide the recommended timing of the Early Termination
Visit, Safety Telephone Call, and Final Visit assessments for subjects who terminate early.
This change coordinates with changes in the new Section 7.2.4 (Early Termination Visit and 
Final Visit), and corresponding changes in Section 10.1 (Discontinuation of Study Treatment) 
and Section 10.2 (Withdrawal of Subjects from the Study).
Section 4.2, Schedule of Activities
Change:  An MDS-UPDRS assessment has been added to the Unscheduled Visit in Table 2 
(Cohort A: Infusions 4-13 and Follow-Up) and Table 3 (Cohort B: Schedule of Assessments).
The footnote for the Unscheduled Visit has been modified to indicate that additional tests may be 
performed at the Investigator’s discretion.
Now reads for Table 2 (same text for Table 3, footnote 6):  
23    Unscheduled Visit can occur at any time, as determined by the Investigator, for safety-related 
issues.  Additional tests may be performed at the Investigator’s discretion.
Rationale:  The MDS-UPDRS assessment provides valuable data on clinical function for 
subjects who are seen at the clinic between scheduled visits.  The footnote change allows for 
flexibility in the additional tests to monitor subject safety depending on the subject’s condition.
Section 4.2, Schedule of Activities
Change:  Body weight has been added as an assessment at the Week 22, 34, or 46 clinic visit in 
Table 2 (Cohort A: Infusions 4-13 and Follow-Up) and Table 3 (Cohort B: Schedule of 
Assessments).
Rationale:  Body weight has been added at this visit for safety monitoring and to support PK 
analyses.




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preliminary serum and cerebrospinal fluid (CSF) data from the first in human SAD study, at the 
3 mg/kg dose, BIIB054 concentration in CSF and brain interstitial fluid (ISF) at steady state is 
projected to be above EC50 for the majority of subjects.  An intermediate dose of 15 mg/kg is 
expected to maintain a CSF and ISF target at or above EC90, as well as provide adequate 
separation between doses to elucidate the exposure response relationship.
In vitro studies established that BIIB054 binds to both soluble and aggregated forms of α-
syn, with a higher apparent binding affinity for aggregates.  The half-maximal effective 
concentration (EC50) of BIIB054 for aggregated α-syn was estimated at approximately 
0.25 nM, and the EC90 estimated at approximately 2.1 nM (0.0375 and 0.315 μg/mL, 
respectively).  These EC50 and EC90 concentrations were used as target values for dose 
selection.  See the BIIB054 Investigator’s Brochure for further details.
In the Phase 1, first-in-human study (228HV101), serum and cerebrospinal fluid (CSF)
concentrations in healthy volunteers were described using a population PK model.  
Subsequently, estimated PK parameters as well as between subject variability and residual 
variability estimates from healthy volunteers were used to simulate 1000 serum and CSF 
steady-state profiles.  Emerging data from the PD cohort suggests that PK is similar 
between healthy volunteer and PD subjects.  To account for weight differences between 
healthy volunteers and the target Phase 2 population of PD subjects, the Parkinson’s 
Progression Markers Initiative study database was used as a source of weight distribution 
data in PD patients. 
Simulations of CSF profiles in PD subjects were conducted for several dose levels to enable 
dose selection.  CSF and brain interstitial fluid (ISF) concentrations of BIIB054 were 
assumed to be equal.  Given the favorable safety profile of BIIB054 in the previous study 
228HV101 and based on PK modeling from that study, a fixed-dose approach is to be 
implemented in this study. 
Simulations based on preliminary serum and CSF data from the first-in-human study 
228HV101 indicate that for the 250 mg dose, the BIIB054 concentration in CSF and ISF at 
steady state is projected to be above EC50 for the majority of subjects (Figure 2).  The 
highest dose (3500 mg) was selected to maintain these levels above EC90, to increase the 
likelihood of demonstrating efficacy for BIIB054.  An intermediate dose of 1250 mg is 
expected to maintain a CSF and ISF level at or above EC90, as well as provide adequate 
separation between doses to elucidate the exposure-response relationship.  
Nonclinical pharmacology data also suggest that the dose of 250 mg is expected to provide 
minimal efficacy based on studies in the D-Line synuclein transgenic mouse (see the 
BIIB054 Investigator’s Brochure for further details).  The estimated efficacious exposure in 
the mouse was approximately 1317 day*μg/mL.  Clearance of BIIB054 in healthy 
volunteers is on average 0.1248 L/day. Thus, using Dose = Clearance × area under the 
concentration-time curve (AUC), the projected mean minimum pharmacologically 
efficacious dose is approximately 164 mg.
Overall, all 3 doses are expected to be safe and well tolerated in humans.  The highest 
planned dose (3500 mg) is expected to yield median steady-state area under the 
concentration-time curve within a dosing interval (AUCtau) and maximum observed 








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Section 7.2.2, Study Treatment
Change:  An observation period of 1 hour has been added after each infusion.  The text 
regarding infusion duration has been modified and text has been added regarding adjustments to 
infusion duration or administration conditions.  
Now reads:  
Eligible subjects will report to the study site to receive study treatment, administered by IV
infusion, every 4 weeks for 72 weeks 48 weeks, for a total of 19 13 dosing visits, beginning on 
Day 1.  The infusion duration will be approximately 1 hour ±5 minutes.  Subjects will be 
under observation for at least 1 hour after the end of each infusion.  The Investigator or 
designee must contact the study’s Medical Monitor in advance if they would like to adjust 
the infusion duration or administration conditions based on the subject’s ability to tolerate 
infusion.  No changes in dose level are permitted.
Rationale:  The additional monitoring allows further assessment of subject safety following the 
infusion, as appropriate, given that this is the first multiple-dose clinical study.  The infusion 
duration has been modified for additional flexibility at the study site.  Changes in dose level are 
not allowed, but guidance is provided for adjustment to the infusion duration or other 
administration conditions.
This change also affects Section 4.2, Schedule of Activities, and Section 11.1, Regimen.
Section 7.2.2.1, Treatment with Parkinson’s Disease Medications
Change:  A new section has been added to describe timing recommendations for treatment with 
PD medications.
Now reads:  
Medications used to treat the symptoms of PD (hereafter referred to as symptomatic PD 
medications) will be listed in the Study Reference Manual. Subjects should refrain from 
using symptomatic PD medications for as long as possible, at least 6 months following 
Day 1.  For subjects who do require PD treatment, see Section 11.3.1.1 for a description of 
the recommended medications.
The entire MDS-UPDRS assessment (Parts I to IV) should be performed before subjects 
receive their first dose of symptomatic PD medication, either at a scheduled visit or 
included in an unscheduled visit.
It is recommended that subjects who plan to start symptomatic PD medication either 
outside of a visit window or outside of the DaT/SPECT window wait, if possible, until after 
the next DaT/SPECT to start the medication, provided that a DaT/SPECT visit is planned 
within 1 month.  (As an alternative, if the subject cannot wait to start symptomatic PD 
medication, the DaT/SPECT window may be expanded so that it extends from -28 days to 
+7 days.)  
Once they have started symptomatic PD medication, subjects should refrain from taking 
the PD medication for 12 hours prior to study visits at which MDS-UPDRS assessments 


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will be conducted (see Section 4.2).  At those visits, subjects taking PD medication should 
come to the clinic prior to taking their morning dose, and should refrain from taking their 
PD medication until after completion of the MDS-UPDRS Part III assessment and 
.
See Section 13.1 for a description of the timing of clinical function assessments relative to 
administration of the symptomatic PD medication.
Rationale:  The new text was added to explicitly state the timing recommendations and to 
describe coordination of the PD medication with key clinical function assessments (DaT/SPECT 
and MDS-UPDRS).
This change also affects Section 4.2, Schedule of Activities.
Section 7.2.4, Early Termination Visit and Final Visit
Change:  A new section was added to indicate the recommended timing of the assessments at 
this visit for subjects who terminate early.  In addition, the former Final/ET Visit was divided 
into 2 separate visits, an Early Termination Visit and a Final Visit.
Now reads:  
7.2.4. Early Termination Visit and Final Visit
For subjects terminating early (i.e., discontinuing both study treatment and study 
assessments), it is recommended that the assessments of the Early Termination Visit be 
performed within 4 weeks after the last dose of study treatment.  The Safety Telephone 
Call should be performed approximately 8 weeks after the last dose, and the assessments of 
the Final Visit should be performed approximately 12 weeks after the last dose.    
Rationale:  This change was made to allow appropriate monitoring of subjects who terminate 
early and to clarify the procedures and timing of the assessments for those subjects.
This change also affects Section 7.2.3, Unscheduled Visits and Follow-Up; Section 10.1,
Discontinuation of Study Treatment; and Section 10.2, Withdrawal of Subjects From the Study.  
This change coordinates with changes to Section 4.2, Schedule of Activities, Table 2 (footnote 3) 
and Table 3 (footnote 6).
Section 7.2.5, Study Stopping Rules
Change:  Specific AE criteria for terminating dosing have been added for Cohort A.  
Now reads:  
Biogen may terminate this study at any time, after informing Investigators.  Biogen will notify 
Investigators if the study is to be placed on hold, completed, or terminated.
For Cohort A: 
After evaluation of the safety, tolerability, and PK data by the IDMC, further dosing may 
be terminated if any of the following is observed:


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
Two similar SAEs or 2 clinically significant AEs, unless clearly unrelated to 
BIIB054, are reported for subjects on active study treatment.

Three or more similar AEs are reported for subjects on active study treatment 
(unless these events are clearly unrelated to BIIB054) that are not tolerable, as 
reported by the subject (e.g., severe dizziness) and/or deemed a medically 
unacceptable risk by the IDMC and/or Sponsor.

Sponsor requests that dosing be terminated.
For Cohort B:
Cconditions that may warrant termination of the study include, but are not limited to, the 
following:
…
Rationale:  The new text was added to provide more detailed guidance on terminating dosing for 
Cohort A, since this is the first group of subjects to receive multiple doses of BIIB054.  
Section 8.1, Inclusion Criteria
Change:  Inclusion criterion 8 was modified to clarify the criteria for inclusion based on 
DaT/SPECT results.
Now reads:  
8.  Screening DaT/SPECT with DaTscan results demonstrating activity in the 
striatum is either asymmetric, absent in the putamen and/or one or both caudate 
nuclei, consistent with dopamine transporter deficit based on high probability of
neurodegenerative pParkinsonism, as assessed with qualitative, visual assessment.  
DaT/SPECT results images will be sent to reviewed by a central reader to confirm 
eligibility.
Rationale:  This criterion was modified for consistency with the approved DaTscan label.
Section 8.2, Exclusion Criteria 
Change:  Exclusion criterion 1 regarding history of or positive test results for human 
immunodeficiency virus was modified to provide an exception for local regulations.
Now reads:
1. History of or positive test result at Screening for human immunodeficiency virus (HIV).  
The requirement for testing at Screening may be omitted if it is not permitted by 
local regulations.


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Rationale:  This change was made to allow flexibility depending on local regulations and for 
consistency with updates to the Sponsor’s protocol template.
Section 8.2, Exclusion Criteria 
Change:  Exclusion criterion 2 regarding history of or positive hepatitis B or C results was 
divided into 2 exclusion criteria and modified for hepatitis B to refer to current hepatitis B 
infection and immunity to hepatitis B.  
Now reads:  
2. History of, or positive test result at Screening for, hepatitis C virus antibody (HCVAb).
3. or hepatitis B virus (defined as positive for hepatitis B surface antigen [HBsAg] or 
hepatitis B core antibody [HBcAb]).Current hepatitis B infection (defined as positive 
for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]).  
Subjects with immunity to hepatitis B from previous natural infection (defined as 
negative HBsAg, positive hepatitis B surface antibody immunoglobulin G, and 
positive HBcAb) or vaccination (defined as positive anti-HBs) are eligible to 
participate in the study.
Rationale:  This change was made for accuracy and for consistency with updates to the 
Sponsor’s protocol template.
Section 8.2, Exclusion Criteria
Change:  Exclusion criterion 9 regarding allergic reaction or hypersensitivity has been modified 
to focus on study treatments and reagents used during the study.
Now reads:  
8.9. History of Clinically significant severe allergiesc or anaphylactic reactions, as 
determined by the Investigator, including or history of hypersensitivity to BIIB054 or
any of the inactive ingredients in the drug product (refer to the Investigator’s 
Brochure for information on the clinical formulation) or to radioligands to be or 
iodine used in the study, a broad range of anesthetics, or iodine.  
Rationale:  These changes were made to clarify that the types of allergic or hypersensitivity 
reactions of concern are those associated with agents administered during the study, including 
BIIB054 and inactive ingredients in the drug product, as well as the radioligand and iodine.  This 
approach is consistent with that of other Sponsor studies.
Section 8.2, Exclusion Criteria 
Change:  Exclusion criterion 17 was modified to clarify the criteria for excluding hypertension 
and orthostatic hypotension.


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Now reads:  
17.  Chronic, uncontrolled hypertension (average of 3 systolic blood pressure 
[SBP]/diastolic blood pressure [DBP] readings at Screening >165 mmHg/ or 
average diastolic blood pressure [DBP] ≥100 mmHg, or any documented 
SBP/DBP reading >180 mmHg/ or DBP ≥100 mmHg within the 3 months before 
Day 1), or severe orthostatic hypotension that is clinically significant as 
determined by the Investigator.
Rationale:  This change was made to specify that the exclusion criterion for hypertension 
applies to either elevated SBP or elevated DBP, and to clarify the exclusion criterion for 
orthostatic hypotension.
Section 8.2, Exclusion Criteria 
Change:  In exclusion criterion 19, the glycated hemoglobin cutoff value for poorly controlled 
diabetes mellitus has been increased.
Now reads:  
19. Poorly controlled diabetes mellitus, as defined by having dosage adjustment of 
diabetic medication within 3 months before dosing (Day 1) or glycated hemoglobin 
value ≥78% at Screening.
Rationale: This change was made to allow greater flexibility in enrolling subjects without 
affecting overall safety.
Section 8.2, Exclusion Criteria 
Change:  In exclusion criterion 20, the units for hemoglobin values were changed from mg/dL to 
g/dL.
Now reads:  
20.  Screening value for hemoglobin <12 mg/dL for men or <11 mg/dL for women.  
Rationale:  This change was made to correct an error in the units for the hemoglobin exclusion 
criterion.  
Section 8.2, Exclusion Criteria 
Change:  The criteria for excluded liver function test values were clarified in exclusion criterion 
21, and the exclusion criterion for impaired renal function was clarified and made into a separate 
exclusion criterion.
Now reads:  
21.  Indication of impaired liver function as shown by an abnormal liver function profile at 
Screening (e.g., values of aspartate aminotransferase, and or alanine aminotransferase, 
or total bilirubin ≥2 times the upper limit of normal).


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20.22. and/or Iindication of impaired renal function at Screening (e.g., estimated glomerular 
filtration rate [calculated according to the Modification of Diet in Renal Disease equation]
<60 mL/min) and corroborating history and physical examination.
Rationale:  The exclusion for elevated liver function tests was modified to clarify that it would 
apply to either aspartate aminotransferase or alanine aminotransferase, and to add a criterion for 
exclusion of elevated total bilirubin levels.  The exclusion for impaired renal function was 
clarified to remove the requirement for a specific calculation and the requirement for 
corroborating history and physical examination.
Section 8.2, Exclusion Criteria
Change:  Additional guidance was added for coagulation parameters in exclusion criterion 23.
Now reads:
21.23. Screening values of coagulation parameters including platelet count, international 
normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin 
time (APTT) that are not generally within normal ranges.  Subjects with 
nonclinically significant and stable out-of-range values may be allowed in the 
study at the discretion of the Investigator, and only after a consultation with the 
Medical Monitor.
Rationale: This change was made to allow greater flexibility in enrolling subjects with 
nonclinically significant abnormal values for coagulation parameters.
Section 8.2, Exclusion Criteria
Change:  The criteria for exclusion of risk factors for bleeding were clarified in exclusion 
criterion 25.
Now reads:
23.25. Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that 
is not managed optimally and could place a subject at an increased risk for 
intraoperative or postoperative bleeding.  These could include, but are not limited to, 
anatomical factors at or near the LP site (e.g., vascular abnormalities, neoplasms, or 
other abnormalities) and known underlying disorders of the coagulation cascade, 
platelet function, or platelet count (e.g., hemophilia, Von Willebrand’s disease, liver 
disease).
Rationale:  The criterion was modified to broadly refer to bleeding rather than operative 
bleeding, since only some subjects will get an LP.  A shortened version of the text regarding 
anatomical factors at or near the LP site was moved to exclusion criterion 26 for subjects 
enrolled at sites where LPs will be performed, in order to group the LP items together.


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Section 8.2, Exclusion Criteria
Change:  Text for exclusion criterion 26 for lumbar surgery has been modified to exclude only 
lumbar surgery that would interfere with or pose a risk to the LP procedure, and to clarify 
contraindications to having an LP.
Now reads:     
24.26. For subjects enrolling at sites where LPs will be performed:  Subjects with the 
following characteristics will be excluded from participation in LP procedures:

Any Hhistory of lumbar surgery for any reason (e.g., herniated disc) that in 
the opinion of the Investigator would interfere with or pose risks to the 
LP procedure or

oOther contraindications to having a LP, including but not limited to,:

Low platelet count (below 50,000 cells/μL), or Screening values of 
INR, PT, or APTT that are not within normal ranges       

Taking any antiplatelet medication (e.g., aspirin >81 mg daily, 
clopidogrel, or nonsteroidal anti-inflammatory drugs [NSAIDs]) 
within 7 days prior to the planned LP or anticipated need for 
antiplatelet medication within 48 hours after an LP

Taking anticoagulant medication (warfarin, heparinoids, and direct 
coagulation factor inhibitors, e.g., apixaban, dabigatran, rivaroxaban)    
chronic back pain sufficient to interfere with ADL on a regular basis;
prominent scoliosis; X-ray, MRI, or myelographic evidence of significant 
lumbar spine abnormalities or other anatomical factors at or near the 
LP site that might interfere with performance of LP; history of chronic 
tension or migraine headaches; or a refractory or prolonged headache or 
other complication after a prior LP, including that performed at the 
Screening Visit that did not resolve with conservative treatment.  Note:  all 
clinically significant (in the opinion of the Investigator) post LP 
symptoms must have resolved prior to dosing on Day 1.
…
32.  For subjects enrolling at sites where LPs will be performed:  Anticipated need, in the 
opinion of the Investigator, for administration of any antiplatelet or anticoagulant 
medication (e.g., clopidogrel, aspirin >81 mg daily) for 7 days before or 48 hours 
after an LP.  Aspirin ≤81 mg daily is permitted.
Rationale: This change was made because, given the high frequency of degenerative disease of 
the spine in the elderly population, previous lumbar surgery is common and will not necessarily 
interfere with the LP.   
Exclusion based on low platelet count and current administration of antiplatelet medication 
allows integration of this exclusion criterion with former exclusion criterion 32; the description 


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of the washout period for these medications has also been clarified.  The exclusion of abnormal 
coagulation test results at Screening allows coordination with the modifications to exclusion 
criterion 23 for coagulation test results. 
Wording has been added to clarify that subjects taking anticoagulant medications should not 
receive an LP procedure due to the risk to these subjects when they suspend those medications.
Exclusion due to chronic back pain has been removed due to the likelihood of nonspecific 
reasons for chronic back pain. Other anatomical factors at or near the LP site were added to the 
exclusion criterion for X-ray, MRI, or myelographic evidence of significant lumbar spine 
abnormalities in order to group similar items together (this text was moved from the former 
exclusion criterion 23).  Prominent scoliosis was removed as an explicit item in the list because it 
would be covered by this more general exclusion criterion for lumbar spine abnormalities or 
anatomical factors that might interfere with an LP. 
History of chronic tension or migraine headaches and refractory or prolonged post-LP headache 
were removed as exclusion criteria to avoid unnecessary exclusion of subjects with other causes 
for these events.
This change also affects Section 11.3.1.1, Allowed Concomitant Therapy; and Section 11.3.1.2, 
Disallowed Concomitant Therapy.
Section 8.2, Exclusion Criteria
Change:  The former exclusion criterion 25 regarding PD symptom response to levodopa was 
removed.
Now reads:  
25.
PD symptoms (except tremor) did not respond to levodopa, if previously treated.
Rationale:  Because the duration of prior levodopa treatment has been reduced, this exclusion 
criterion is no longer relevant.
Section 8.2, Exclusion Criteria
Change:  The former Exclusion criterion 26 regarding vaccination was removed.
Now reads:  
26.
Administration of any vaccination/booster within 10 days before a dosing visit 
and for 10 days after a dosing visit.
Rationale:  This criterion was removed because the corresponding text in Section 11.3.1.1,
Allowed Concomitant Therapy, sufficiently describes the restrictions for vaccination.
Section 8.2, Exclusion Criteria
Change:  Two new exclusion criteria were added for immunotherapy that targets α-syn.


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Now reads:  
27. Participation in any passive immunotherapy study targeting α-syn, other than the 
BIIB054 Phase 1 study 228HV101.  Subjects who participated in Study 228HV101 
must meet all entry criteria for the present study, and cannot have received BIIB054 
within 24 weeks before Day 1 of Study 228PD201.        
28. Participation in any active immunotherapy study targeting α-syn.    
Rationale:  This change was made because immunotherapy that targets α-syn other than 
BIIB054 may confound the results of the study.
Section 8.2, Exclusion Criteria
Change:  A new exclusion criterion was added for medicines that strongly bind to the dopamine 
transporter and may interfere with DaT/SPECT.
Now reads:  
31. Use of medicines that strongly bind to the dopamine transporter and may 
interfere with DaT/SPECT including amphetamine, benztropine, bupropion, 
cocaine, mazindol, methylphenidate, phentermine, and sertraline within 30 days 
before the Screening DaT/SPECT.
Rationale:  This change was made because the use of medicines that interfere with DaT/SPECT  
may confound data contributing to the secondary endpoint of change in striatal binding ratio.
Section 8.2, Exclusion Criteria
Change:  A new exclusion criterion was added for use of glucagon-like peptide-1 agonists.  
Now reads:  
32. Use of any glucagon-like peptide-1 (GLP-1) agonists (e.g., exenatide, liraglutide, 
lixisenatide, albiglutide, and dulaglutide) within 90 days before Day 1.
Rationale:  This change was made because these agonists may confound the effects of study 
treatment on measures of PD progression.
This change also affects Section 11.3.1.2, Disallowed Concomitant Therapy.
Section 8.2, Exclusion Criteria
Change:  A new exclusion criterion was added for use of anticoagulant medications.
Now reads:  
33. Use of anticoagulant medications within 90 days before Day 1 (warfarin, 
heparinoids, and direct coagulation factor inhibitors e.g., apixaban, dabigatran, 
rivaroxaban).


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Rationale:  Anticoagulant medications are disallowed at study entry and during the study 
(previous text in the prior exclusion criterion 32 allowed these medications with a washout 
period, but these medications should be avoided completely) in order to prevent risk of bleeding 
due to multiple blood draws and, as applicable, for LP. 
Section 8.2, Exclusion Criteria
Change:  The time period required for stable doses of selective serotonin reuptake inhibitors 
(SSRIs) in exclusion criterion 35 has been shortened from 6 months to 3 months.
Now reads:  
29.35.  Use of selective serotonin reuptake inhibitors (SSRIs) at doses that have not been 
stable for at least 6 3 months before Day 1 and/or that are not expected to remain 
stable for the duration of the study.
Rationale:  This change was made because stable SSRI doses for 3 months are now considered 
sufficient for and allow greater flexibility in enrolling subjects.
This change also affects Section 11.3.1.1, Allowed Concomitant Therapy.
Section 8.2, Exclusion Criteria
Change: The exclusion criterion regarding over-the-counter medications, including vitamins 
and herbal/alternative health preparations, has been clarified.
Now reads:  
30.36. Subjects who have used over the counter medication, including megadose (intake 
of 20 to 600 times the recommended daily dose) vitamin therapy within 7 days 
before Day 1, or herbal/alternative health preparations or procedures within 14 days 
before Day 1, unless agreed as not clinically relevant by the Investigator and 
Sponsor.  Routine vitamin therapy is allowed. Vitamins, supplements, 
herbal/alternative health preparations, and other over-the-counter medications 
at doses that are not expected to remain stable from Screening through Day 1.
Rationale:  This change was made because vitamins, supplements, herbal/alternative health 
preparations, and other over-the-counter medications are allowed for this study provided the dose 
is stable prior to entry and during the study.  Routine safety monitoring will detect adverse 
events associated with these medications. 
This change also affects Section 11.3.1.1, Allowed Concomitant Therapy; and Section 11.3.1.2, 
Disallowed Concomitant Therapy.
Section 9.1, Screening and Enrollment
Change:  Text was added to define screen failures and to state what information should be 
recorded for screen failures.


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Now reads:  
Subjects must provide informed consent before any screening tests are performed (see Section 
17.3).  When a subject signs the main informed consent form (ICF), that subject 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.  If a subject is excluded from the study, 
the reasons for exclusion will be documented in the subject’s source documents and on the 
screening log.
Individuals who do not meet the criteria for participation in this study (i.e., a screen 
failure) may not be rescreened, except in the following circumstances:
Subjects with urinary tract infection detected on screening urinalysis may be rescreened once 
after the infection has been treated and resolved.
Coagulation tests may be repeated once if, in the opinion of the Investigator, values of the initial 
tests are only slightly out of range.  For normal ranges please refer to the Study Reference Guide
Manual.
Rationale: This change was made to clarify the definition of a screen failure and the procedures 
for recording information on screen failure subjects.
This change also affects Section 4.2, Schedule of Activities, Table 1, footnote 1 and Table 3, 
footnote 1. 
Section 11.3.1.1, Allowed Concomitant Therapy
Change:  Text was added or modified regarding the allowed use of symptomatic PD 
medications, aspirin, acetaminophen, and NSAIDs, as well as the use of vitamins, supplements, 
herbal/alternative health preparations, and over-the-counter medications.
Now reads:  

Symptomatic PD treatment (e.g., MAO B inhibitors, levodopa, and dopaminergic 
agonists) may be initiated during a subject’s participation in the study at the 
discretion of the Investigator, although subjects should be encouraged to refrain from 
taking symptomatic PD medications for as long as possible; (at least 6 months 
following Day 1).  For subjects who do require PD treatment, it is recommended 
that treatment start with immediate-release levodopa/carbidopa at a dose of 
25/100 mg 3 times a day (or equivalent dosage of levodopa/benserazide in 
locations where levodopa/carbidopa is not available).  The dose of 
levodopa/carbidopa may be titrated until satisfactory symptomatic relief is 
achieved.  Subjects receiving levodopa/carbidopa should remain on their initially 
established dose as long as possible.  Adjunctive use of catechol-O-
methyltransferase (COMT) inhibitors, sustained-release levodopa/carbidopa 
preparations, dopamine agonists, and MAO-B inhibitors is discouraged, and use 
of amantadine and anticholinergic medications is prohibited.  


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See Section 7.2.2.1 for a description of timing of the start of symptomatic PD 
medications relative to scheduled study visits.  See Section 13.1 for a description 
of the timing of clinical function assessments relative to administration of PD 
medication. 

SSRIs are allowed provided that the subject is on a stable dose for at least 6 3 months
prior to Day 1 and the dose is expected to remain stable for the duration of the study.

Medications for chronic conditions are allowed provided that the subject is on a stable 
dose for at least 8 weeks prior to Day 1 and the dose is expected to remain stable for 
the duration of the study.

Aspirin ≤81 mg daily (will need a 7 14 day washout before LP).

Routine vitamin therapy is allowed.

Acetaminophen and nonsteroidal anti inflammatory drugs NSAIDs are allowed if 
used according to the local label guidelines.  NSAIDs and clopidogrel must be 
avoided before and after LP procedures, as described in Section 11.3.1.2.

Vaccinations with live or attenuated vaccines are allowed during the study; however, 
administration of any vaccination/booster should not be given within 10 days before a 
dosing visit and for 10 days after a dosing visit.

Routine vitamin therapy is allowed.  Subjects should not change administration 
of vitamins, supplements, herbal/alternative health preparations, or over-the-
counter medications unless required for symptom management (e.g., pain) 
during the study; such medications and preparations must be recorded on the 
appropriate CRF page.
Rationale: Text was added to clarify and expand guidance regarding the types and doses for 
permitted symptomatic PD medications.  Low-dose aspirin does not require a washout before 
LP.  Conditions for use of NSAIDs and clopidogrel were clarified by referring to excluded uses 
in the Disallowed Concomitant Therapy section.  Vitamin, supplements, herbal/alternative health 
preparations, and over-the-counter medications should stay on a stable dose unless changes are 
needed to manage symptoms.
Section 11.3.1.2, Disallowed Concomitant Therapy
Change:  Text was added regarding conditions for use of short-term corticosteroids, 
anticoagulant medications, and NSAIDs during the study.  GLP-1 agonists were added as 
disallowed medications.  Megadose vitamins were removed as disallowed medications.  
Additional guidance has been provided for subjects continuing prior medications or starting new 
medications during the study.


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Now reads:  
Subjects should be instructed to contact their Investigators before taking any new medications, 
including nonprescription drugs and herbal preparations. 

Typical or atypical antipsychotics (including clozapine, olanzapine, flunarizine, and 
aripiprazole), metoclopramide, and alpha methyldopa.

Tricyclic antidepressants.

Amantadine or anticholinergic medications for Parkinson’s diseasePD.

Methylphenidate, cinnarizine, tetrabenazine, reserpine, amphetamine, memantine, 
cholestinerase inhibitors (rivastigmine, donepezil, galantamine, and tacrine) or 
monoamine oxidase type A inhibitors (pargyline, phenelzine, and tranylcypromine).

GLP-1 agonists, e.g., exenatide, liraglutide, lixisenatide, albiglutide, and 
dulaglutide.

Immunosuppressive drugs (including systemic corticosteroids).  Short-term 
corticosteroids for the treatment of reversible conditions and Llocal
corticosteroids may be permitted, at following a consultation with the Sponsor 
discretion.  

Parenteral immunoglobulin, blood products, plasma derivatives, plasma exchange, 
and plasmapheresis.

Any investigational drug.

Megadose (intake of 20 to 600 times the recommended daily dose) vitamin therapy. 

For subjects enrolling at sites performing LPs: Any antiplatelet or anticoagulant 
medication (e.g., aspirin >81 mg daily, clopidogrel, or NSAIDswarfarin, and Factor 
IX and X antagonists) is prohibited from 7 days before to 48 hours after each LP 
procedure.  

Anticoagulant medications (warfarin, heparinoids, and direct coagulation factor 
inhibitors, e.g., apixaban, dabigatran, rivaroxaban).
Subjects should be instructed to continue the medications that they were receiving at 
enrollment (see Section 11.3.1.1 for allowed concomitant therapy) and to avoid starting any 
new medications or herbal preparations during the study period, since they may confound 
the results of the study. However, medically indicated medication or treatment should not 
be withheld.  Subjects should inform the Investigator of any changes in medication.
Rationale: These changes were made for clarity. Use of short-term corticosteroids is permitted 
for the treatment of reversible conditions at the Sponsor’s discretion.  No long-term 
immunosuppression is expected from this type of corticosteroid usage.  
Use of NSAIDs is allowed if suspended prior to and after an LP procedure.  Use of 
anticoagulants is prohibited under all conditions, to prevent possible bleeding that could result 
from blood sample collection or LPs. Use of GLP-1 agonists is not allowed during the study, 
since they may confound effects of study treatment on measures of PD progression.














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Rationale: This change was made because the data recorded for an adverse event (AE) and the 
analyses performed will include the event’s relationship to the LP procedure and relationship to 
the radioligand, as well as the relationship to the study treatment.  The AE relationship to the LP 
procedure and relationship to the radioligand are both recorded in the CRF (and if applicable in 
the SAE forms).  
Summaries of both the AE relationship to study treatment and relationship to the LP procedure
will be presented in the study results and included in the safety analyses for the study.  The AE
relationship to the radioligand will be reported to the radioligand manufacturer but will not be 
included in the presentation of the study results or the safety analyses.
This change also affects Section 15.2.2, Relationship of Events to Study Treatment, to the 
Lumbar Puncture Procedure, and to the Radioligand; Section 15.3.1, Adverse Events; Section 
15.3.2, Serious Adverse Events; Section 15.3.3, Immediate Reporting of Serious Adverse 
Events; Section 15.6.1, The Investigator; and Section 16.1.2.1, Adverse Events.
Section 15.5, Contraception Requirements
Change:  Two items were added and additional modifications were made to the list of possible 
definitions of highly effective contraception for females.
Now reads:  
For females subjects:

Established use of oral, intravaginal, or transdermal combined (estrogen and 
progestogen containing) hormonal methods of contraception associated with the 
inhibition of ovulation.

Established use of oral, injected, or implanted progestogen-only hormonal methods 
of contraception. 

Placement of an intrauterine device or intrauterine hormone-releasing system.

Bilateral tubal occlusion.

Sex with a male partner who has undergone surgical sterilization (with the 
appropriate postvasectomy documentation of the absence of sperm in the ejaculate).
Rationale:  The changes clarify the definition of highly effective contraception for female 
subjects, consistent with the Sponsor’s protocol template.
Section 15.5, Contraception Requirements
Change:  A new item was added to the definition of highly effective contraception for males.  
Now reads:  
For males subjects:

A vasectomy with subsequent negative semen analysis at follow up.








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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.

Minor typographical errors were corrected throughout the protocol.

In Section 4.2 (Schedule of Activities), the following changes were made to correct 
errors, maintain consistency, or emphasize information already provided in the body 
of the protocol:

A cross-reference to Section 14.1 (Clinical Safety Assessments) was added to the 
vital signs footnotes for Table 1 (Cohort A: Infusions 1-3), footnote 6; Table 2 
(Cohort A: Infusions 4-13 and Follow-Up), footnote 7; and Table 3 (Cohort B:
Schedule of Assessments), footnote 10, for additional detail about the orthostatic 
vital sign measurements.

Text was added to the C-SSRS footnotes for Table 1 (Cohort A: Infusions 1-3)
stating that subjects should be referred for psychiatric evaluation if the 
Investigator has any concern regarding the C-SSRS results, for consistency with 
text already present for the C-SSRS footnote in Table 2 (Cohort A: Infusions 4-13
and Follow-Up) and Table 3 (Cohort B: Schedule of Assessments).

Footnotes in Table 1 (Cohort A: Infusions 1-3), starting with the former 
footnote 19, were renumbered to correct an error in use of footnote numbers.

In Table 3 (Cohort B: Schedule of Assessments), an incorrect footnote (the former 
footnote 5) for alternate visit timing was removed from the drug screen 
assessment at Day 1 Baseline/Infusion 1.

Minor clarifications were made throughout the protocol, including the following:

In Section 5.1 (Overview of Parkinson’s Disease), the prevalence data for PD was 
updated to reflect the global population.

In Section 5.3.2 (Clinical Experience), the summary of the first-in-human Phase 1 
Study 228HV101 has been updated, including an update to reflect current 
enrollment data.

In Section 6.1 (Primary Objective and Endpoint), the brain MRI endpoint was 
moved to the list of clinical laboratory items.

In Section 6.3 (Additional Objectives and Endpoints), the endpoint for time to 
start of medications for PD symptoms was moved to clarify that it is not a change 
in health-related quality of life or a mental health endpoint.






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48
AEs will be monitored until the event resolves, stabilizes, or returns to baseline 
status, and that the outcome will be recorded on the CRF.

Section 15.4.1 (Pregnancy):  The text regarding recording of a pregnancy was 
clarified.

Section 15.6.1 (The Investigator):  The text was modified to clarify and explicitly 
state the Investigator’s responsibilities for recording AE and AE follow-up 
information.

Section 17 (Ethical Requirements):  The text was modified to clarify and 
explicitly state that the Investigator is responsible for endorsing data on 
completed CRFs prior to any interim or database lock.  The Investigator is also 
responsible for supervising delegates and implementing procedures to ensure 
integrity of study conduct and data.

Section 18.2 (Quality Control and Quality Assurance) and Section 18.3 
(Monitoring of the Study):  These sections have been updated to clarify the 
relevant responsibilities and processes for these tasks.


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APPENDIX A. SCHEDULE OF ACTIVITIES TABLES
The following tables show the changes in the Schedule of Activities tables from Protocol V1 to V2.
For ease of readability, changes to the tables are shown using images of tracked changes from the amended protocol rather than with 
bolding and strikethrough.
Table 1:
Cohort A: Infusions 1–3 
Table 2:
Cohort A: Infusions 4–13 and Follow-Up 
Table 3:
Cohort B:  Schedule of Assessments 

























SAP_001.pdf: 




 
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Table of Contents 
LIST OF ABBREVIATIONS .............................................................................................................. 5 
1 
SCOPE OF WORK IN THE STATISTICAL ANAYSIS PLAN ............................................. 7 
2 
DESCRIPTION OF OBJECTIVES AND ENDPOINTS ......................................................... 7 
3 
STUDY DESIGN ........................................................................................................................ 11 
3.1 
STUDY OVERVIEW ............................................................................................................... 11 
3.1.1 
Year 1 (Placebo-Controlled Portion of the Study) .......................................................... 12 
3.1.2 
Years 2 Through 4 (Active-Treatment Dose-Blinded Portion of the Study) .................. 12 
3.2 
STUDY SCHEMATIC .............................................................................................................. 13 
3.3 
SCHEDULE OF EVENTS ......................................................................................................... 15 
4 
SAMPLE SIZE JUSTIFICATION ........................................................................................... 15 
5 
STATISTICAL ANALYSIS METHODS ................................................................................ 17 
5.1 
GENERAL CONSIDERATIONS ................................................................................................ 17 
5.1.1 
End of Study (EOS) and End of Treatment (EOT) ......................................................... 17 
5.1.2 
Analysis Population ........................................................................................................ 18 
5.2 
BACKGROUND CHARACTERISTICS ....................................................................................... 18 
5.2.1 
Accounting of Subjects ................................................................................................... 18 
5.2.2 
Demographics and Baseline Characteristics ................................................................... 19 
5.2.3 
Concomitant Medications and Non-drug Therapies ....................................................... 19 
5.2.4 
Protocol Deviations ......................................................................................................... 20 
5.2.5 
Study Drug Exposure and Study Drug Compliance ........................................................ 20 
5.3 
EFFICACY ENDPOINTS ......................................................................................................... 21 
5.3.1 
General Consideration ..................................................................................................... 21 
5.3.2 
MDS-UPDRS .................................................................................................................. 22 
 
Primary efficacy endpoint ........................................................................................................................ 22 
 
Secondary endpoints and additional 
 MDS-UPDRS based endpoints .................................... 23 
 
Sensitivity analysis ................................................................................................................................... 24 
 
-RPS) measure .......................................................... 25 
 
Time to start of PD medication, or an increase of MDS-UPDRS Part III total 
 MCID (4.63), whichever 
comes earlier ............................................................................................................................................................ 26 
 
Time to start of PD medication ................................................................................................................ 26 
 
Time to disease progression and DCR (Disease Control Rate) ................................................................ 26 
 
Subgroup analysis .................................................................................................................................... 27 
 
Per-protocol analysis ................................................................................................................................ 28 
5.3.3 
Other clinical efficacy endpoints ..................................................................................... 28 
 
 29 
5.3.5 
Assessment of the Impact of Covid-19 on the clinical outcome analyses ...................... 31 
5.4 
SAFETY ANALYSIS ............................................................................................................... 31 
5.4.1 
General Considerations ................................................................................................... 31 
5.4.2 
Clinical Adverse Events .................................................................................................. 32 
5.4.3 
Clinical Laboratory Data ................................................................................................. 34 
 
Quantitative laboratory analyses .............................................................................................................. 35 
 
Qualitative laboratory analyses ................................................................................................................ 35 
5.4.4 
Vital Sign Data ................................................................................................................ 37 
5.4.5 
ECG Data ........................................................................................................................ 38 
5.4.6 
Physical and Neurological Examination ......................................................................... 39 
5.4.7 
C-SSRS Data ................................................................................................................... 39 
5.4.8 
MRI Safety Data ............................................................................................................. 40 
5.5 
PHARMACODYNAMIC -IMAGING ANALYSIS ........................................................................ 41 
5.5.1 
Type of imaging techniques and imaging outcomes ....................................................... 41 


 
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5.5.2 
Analysis population ......................................................................................................... 41 
5.5.3 
Baseline value ................................................................................................................. 41 
5.5.4 
Outlier of percent change from baseline ......................................................................... 41 
5.5.5 
Analysis methods ............................................................................................................ 41 
5.5.6 
Sensitivity analysis .......................................................................................................... 42 
5.5.7 
Correlation analysis ......................................................................................................... 43 
 
 43 
 
 43 
 
 43 
 
 43 
 
 44 
5.7 
PHARMACOKINETICS ANALYSIS .......................................................................................... 44 
5.7.1 
PK Concentration Profile ................................................................................................ 45 
5.7.2 
Serum PK Parameters ..................................................................................................... 45 
5.8 
IMMUNOGENICITY ANALYSIS .............................................................................................. 45 
5.8.1 
Analysis Methods for Immunogenicity Data .................................................................. 45 
6 
INTERIM ANALYSIS ............................................................................................................... 46 
7 
REFERENCES ........................................................................................................................... 48 
8 
APPENDIX ................................................................................................................................. 49 
8.1 
APPENDIX I: QUESTIONNAIRES ............................................................................................ 49 
8.2 
APPENDIX II: VISIT WINDOW MAPPING .............................................................................. 49 
8.3 
APPENDIX III: DESCRIPTION OF MCP-MOD METHOD ........................................................ 49 
8.4 
APPENDIX IV: DEFINITION OF THE EARLY PARKINSON S REGIONAL PROGRESSION SCORE 
(EP-RPS) .......................................................................................................................................... 50 
 
 
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to adult subjects with PD. Approximately 311 subjects will be enrolled at about 85 sites 
globally. 
3.1.1 Year 1 (Placebo-Controlled Portion of the Study) 
Prior to the first dose in Year 1, all subjects in the study will be randomized into 4 arms, to 
receive 13 doses of BIIB054 (250, 1250, or 3500 mg) or placebo. 
Subjects will be enrolled into 2 cohorts. Cohort A will be randomized first, in a 1:1:1:1 ratio 
into each of th e4 treatment arm and will include approximately 24 subjects.  Randomization 
and dosing for Cohort B (approximately 287 planned subjects) will start after all subjects in 
Cohort A complete Week 12 assessments, and all available safety and PK data are reviewed 
by the IDMC.  Randomization of subjects in Cohort B will be stratified by baseline (Day 1) 
MDS-UPDRS 
and subjects will be randomized at Day 1 into 1 of 4 parallel dosing arms in each stratum. 
After all subjects in Cohort A complete Week 12 assessments (28 days after their third 
infusion), and before dosing any subjects in Cohort B, all available safety and PK data will be 
reviewed by the IDMC. No subjects in Cohort B may be dosed until the IDMC review is 
complete. The study schematic is presented in Figure 1. After IDMC review is complete, 
subjects in Cohort B will be randomized, and dosing may begin. During the review period, 
subjects in Cohort A will continue to be dosed on a schedule of once every 4 weeks. 
The first IDMC meeting will occur after the last subject in Cohort A completes Week 12 
assessments, or approximately 6 months after the first subject has been enrolled in Cohort A, 
whichever comes first. Regular IDMC meetings will occur approximately every 3 months 
after the first meeting.   
 
 
 
THe Week 48 infusion is the last infusion of the placebo-controlled period, and Week 52 is 
the first dosing of the Dose-blinded portion of the study.  
3.1.2 Years 2 Through 4 (Active-Treatment Dose-Blinded Portion of the Study) 
Prior to Infusion 14 (the first dose of Year 2) at Week 52, subjects who received placebo in 
Year 1 will be randomized into 1 of the active-dosing arms for Year 2; these subjects will 
receive BIIB054 in Year 2. Subjects who received BIIB054 (1250 mg or 3500 mg) in Year 1 
of the study will continue with the same dose regimen in Year 2. Subjects receiving the 250-
mg dose in Year 1  continued on their original dose assignement. 
 
Subjects will receive 12 additional doses of BIIB054 (250, 1250, or 3500 mg) in Year 2 and 
up to 16 additional doses in Years 3 and 4. Up until the last subject in the study has had his or 
her last dose in Year 2 of the study (Week 96 Visit), eligible subjects will be able to continue 
treatment once every 4 weeks. 
 
Subjects who complete dosing through Week 96 and the Final Visit 12 weeks after the last 
visit will be considered Year 2 completers in the eCRF. 
 


 
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See Figure 2 for a depiction of the duration of dosing in Years 3 and 4 for subjects continuing 
dosing past Week 96. 
 
Figure 4 on protocol presents a flowchart for dosing and procedures from Week 96 through 
end of study, including how to determine which subjects are eligible to continue dosing past 
Week 96. 
3.2 Study Schematic 
Figure 2: Overview of Study Dosing: 




 
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3.3 Schedule of Events 
See Protocol Section 4.2. 
 
4 SAMPLE SIZE JUSTIFICATION 
The sample size calculation is based on changes in MDS-UPDRS Part I + II + III total score 
SD) at Week 52 
and Week 72 are assumed to be 8.0 (10.64) and 9.6 (13.7) respectively. Assuming a 
maximum of 55% reduction in the change from baseline in the active group with maximum 
response relative to placebo group, the mean (SD) for this active group will be 3.2 (10.64) 
and 3.84 (13.7) respectively at Week 52 and Week 72, and the responses for other active 
groups are assumed to be somewhere between 0 and the maximum response.  The primary 
analysis will be based on the MCP-MOD method to detect a dose-response trend while 
controlling for multiplicity.  Optimal contrasts will be constructed to detect potential dose-
response trend under common dose-response curves (e.g., Emax, exponential, logistic, linear in 
log dose, and quadratic model, which are illustrated with parameters shown in Figure 4.1 
which will be used for both Week 52 and Week 72).  The planned enrollment is 311 subjects 
total (24 subjects in Cohort A and 287 subjects in Cohort B, 4.1).  Actual enrollment is 357 
subjects.  In Cohort A, 29 subjects were randomized in a 1:1:1:1 ratio to each of the treatment 
groups, while in Cohort B 328 subjects were randomized in 2:1:2:2 ratio to the placebo, 250 
mg, 1250 mg, and 3500 mg groups.  Based on the actual enrollment, the estimated number of 
subjects by cohort and treatment groups are given in Table 4.4.2 below.  After accounting for 
dropout rate of 10% and 15% at Week 52 and Week 72, respectively, the estimated sample 
sizes are given in Table  and Table 1.  With the updated sample size, the study will provide 
an average power of approximately 80% to detect the dose-response trend over 1 year of 
treatment, based on a 2-sided type I error of 0.05 and approximately 73% of power at the 
Week 72 analyses, based on a 2-sided type I error of 0.05.  Overall, the sample size in the 
study will provide approximately 89% power, taking into consideration success at either 
Week 52 or Week 72.   The final candidate models for the MCP-MOD are prespecified and 
described below.   
With an estimated sample size of 100 subjects dosed per arm in the 1250 mg and 3500 mg 
arms, the study has 80% probability of detecting AEs with a rate of 1.6% or greater in these 
2 arms, and a 90% probability of detecting AEs occurring with a rate of 2.3% or greater.   
 
 
 




 
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Figure 4.1: 
Candidate Models for Dose-Response 
 
 
5 STATISTICAL ANALYSIS METHODS 
5.1 General Considerations 
Summary tables will be presented using descriptive summary statistics. For continuous 
variables, summary statistics will generally include: number of subjects with data, mean, 
standard deviation, median, and range (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.  
Unless otherwise specified, baseline value is defined as the most recent non-missing 
measurement collected prior to the first dose. Change from baseline will be defined as post-
baseline value minus baseline value.  
Statistical testing will be performed to assess efficacy endpoints by conducting pairwise 
comparison between each BIIB054 group and placebo, and no multiplicity will be adjusted. 
Unless stated otherwise, all the statistical tests will be 2-sided with a statistical significance 
level of 0.05 . 
The statistical software, SAS® will be used for all summaries and analyses.  
5.1.1 End of Study (EOS) and End of Treatment (EOT) 
For subjects who complete the placebo-controlled period of the study, EOS visit is defined as 
Week 52 visit; for subjects who are early terminated, EOS visit is defined as the scheduled 


 
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follow-up visit after EOT visit. For subjects who complete the treatment, EOT visit is defined 
as Week 48.  
5.1.2 Analysis Population 
 Intent-to-treat (ITT) population:  
The intent-to-treat population is defined as all randomized subjects who received at least 
one dose of study treatment (BIIB054 or placebo).  
 
 Per-protocol (PP) population:  
The per-protocol population is defined as a subset of the ITT population who received at 
least 70% (10 doses) of study treatment (BIIB054 or placebo). 
  
 Safety population:  
The safety population is defined as all subjects who received at least one dose of study 
treatment (BIIB054 or placebo).  
 
 PK population:  
The PK population is defined as all subjects in the ITT population who had at least one 
measurable BIIB054 concentration in serum 
. 
 
 Pharmacodynamic population:  
The pharmacodynamic population is defined as all subjects in the ITT population who 
had at least one post-baseline pharmacodynamic measurement. 
 
 Immunogenicity population:  
The analysis population for immunogenicity is defined as all subjects in the safety 
population. 
 
 
 
 
 
 
5.2 Background Characteristics 
The summaries in this section will be based on the ITT population. Unless otherwise 
specified, all the summary tables and listings will be presented by treatment group.  
5.2.1 Accounting of Subjects 
The summary of subject disposition will include number (%) of subjects randomized, number 
(%) subjects randomized but not dosed, number (%) of subjects who completed the 
treatment/study, and number (%) of subjects who discontinued treatment and/or withdrew 
from study. For subjects who discontinued treatment and/or withdrew from study, the reasons 
for discontinuation and/or withdrawal, and days on treatment and days on study will be 
summarized and listed. The pattern (time and rate) of treatment discontinuation and study 


 
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withdrawal will be displayed by Kaplan-Meier plot. The number of subjects in each analysis 
population will be summarized.  
In addition, number of subjects dosed and number of subjects who completed the 
treatment/study will be summarized by country (region) and site.  
The categorization of region is based not only on consideration of geography but also on type 
of health care system and access to health care in each country. The categories for regions 
will be: 
o Region 1: United States (US); 
o Region 2: European countries (including Austria, France, Germany, Israel, 
Italy, Poland, Spain and United Kingdom) and Canada. 
 
5.2.2 Demographics and Baseline Characteristics 
Demographic data, including age (in years), age category (40-50, 51-60, 61-70, 71-80 years), 
gender, race, ethnicity, height, weight, body mass index (BMI), country (region) and year of 
education at baseline will be summarized by treatment groups and overall.  
Baseline PD history will be summarized by treatment groups and overall, using descriptive 
statistics. Time since onset of PD symptoms (in years), time since PD diagnosis (in years), 
subtype of PD (PIGD, TD or indeterminate), side predominately affected at disease onset, 
Disease will be summarized. MDS-UPDRS total and subtotal scores, PIGD, TD, and LE 
subscore, Hoehn and Yahr stage, 
 
 will be 
summarized. DaT/SPECT imaging outcomes, 
 
 outcomes will also be summarized. Baseline MDS-UPDRS score is defined as the 
Day 1 visit, if Day 1 visit score is not available, screening visit will be used. Baseline PD 
history data will be listed. 
Number (%) of subjects with any PD treatment history will be summarized by treatment 
groups and overall. Total duration of previous therapies and reason for stopping therapies will 
be summarized. Number (%) of subjects who had taken MAO-B inhibitors, Dopamine 
Agonist, Levodopa and other PD medications will be displayed by treatment groups and 
overall. A listing of PD treatment history will be generated. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number (%) of subjects with history (including both ongoing and not 
ongoing medical conditions) will be summarized by system organ class and preferred term, 
and by preferred term only. A listing of medical history will be generated. 
 
5.2.3 Concomitant Medications and Non-drug Therapies 
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.  A concomitant medication/therapy will be defined as any therapy that was taken 


 
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on or after the day of the first dose of study drug. This include therapies that start prior to the 
initiation of the first dose if their use continues on or after the date of first dose. To determine 
whether medications and/or non-drug therapies with missing start or stop dates are 
concomitant with study treatment, the following additional criteria will be used: 
 If both the start and stop dates of a therapy are missing, then the therapy will be 
considered concomitant; 
 If the start date is missing and the stop date of the therapy falls on/after the first dose 
date, then the therapy will be considered concomitant; 
 If the start date is missing and the stop date of the therapy falls before the first dose 
date, then the therapy will be considered non-concomitant; 
 If the start date of a therapy is prior to the date of the first dose and the stop date of 
the therapy is missing and the therapy is listed as ongoing, that therapy will be 
considered concomitant; 
 If the start date of a therapy is prior to the date of first dose and the stop date of that 
therapy is missing and the therapy is not listed as ongoing, that therapy will be 
considered non-concomitant. 
 If the start date of a therapy is on/after the date of first dose but in the treatment period 
(last dosing date+28 days) and the stop date of that therapy is missing, then that 
therapy will be considered concomitant. 
 If the start date of a therapy is on/after the treatment period (last dosing date+28 days) 
and the stop date of that therapy is missing, then that therapy will be considered non-
concomitant. 
For a record with a partial start/end date, the year/month of the partial date will be compared 
to that of the date of first dose to determine whether it is concomitant. 
The number and percent of subjects taking concomitant medication and non-drug treatments 
will be summarized by treatment group and overall. Concomitant PD medication will be 
summarized separately from the other concomitant medication. 
 
5.2.4 Protocol Deviations 
Protocol deviations identified during site monitoring will be captured in a Protocol Deviation 
log and categorized as major or minor deviations. The major protocol deviations will be 
summarized and listed. The minor protocol deviations will also be listed. Number (%) of 
subjects with at least one major deviation will be summarized by category. The protocol 
deviation related to COVID-19 will be listed. 
 
5.2.5 Study Drug Exposure and Study Drug Compliance 
The number of infusions administered will be summarized as both continuous and category 
variables (categories as integers from 1 to 13, and 1-3, 4-6, 7-9, 10-13). The number of weeks 
on study drug, calculated as (date of last dose  date of first dose +1)/7, will be summarized 


 
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as a categorical variable (every 8 weeks from 0 to 48 Weeks) as well as a continuous 
variable. Overall compliance, which is the percentage of drug infusions actually received 
over 13 planned doses, will be summarized regardless of study completion for all subjects. 
Percentage of study treatment taken up to the last dose, calculated as (the actual number of 
infusions / the number of infusions a subject is expected to take until the date of last 
infusion), will be summarized as a continuous variable. This table will be presented by 
treatment group. For subjects who completed study, the number of expected infusions is 13. 
For subjects who withdrew from study early, the number of expected infusions is the planned 
number of infusions before the time of withdrawal.  
A listing of study drug administration records, including infusion start date and time, infusion 
stop date and time, total volume prepared, total volume administered, location of infusion, 
initial infusion rate, dose interruption or rate change or not, time of interruption or rate 
change, infusion rate after interruption or rate of change, reason for interruption or rate 
change will be provided. 
 
5.3 
Efficacy Endpoints 
5.3.1 General Consideration 
Clinical efficacy (clinical function) Assessments include Movement Disorder Society Sponsored 
Revision of the Unified 
-UPDRS), 
 
 
 
 
 The questionnaire as well as the scoring 
algorithm for all these clinical assessments are described in Appendix I. 
 
Unless otherwise noted, the analysis will be performed based on all the subjects in both 
Cohort A and B and the common visits. For numerical outcomes, the actual value and the 
change from baseline will be presented by treatment group and visit. For categorical 
outcome, the count and frequency will be summarized by treatment group and visit. 
 
Analysis population 
All clinical function endpoints will be evaluated in the ITT population as defined in Section 
5.1.2. MDS-UPDRS 
 may also be analyzed in the per protocol population as 
defined in Section 5.1.2. 
 
Baseline value 
MDS-UPDRS, 
 are assessed at both screening visit and Day 1 
visit. 
 
 


 
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. For all of them, the baseline values are defined as the 
latest data collected prior to or on the first dose date. 
 
Visit windows for mapping clinical function endpoint 
Assessments from all scheduled visits, EOT visit and EOS visit, and unscheduled visits will 
be mapped to an appropriate analysis visit using a windowing scheme (Appendix II). 
 
Handling missingness of itemed question score 
For MDS-UPDRS, the maximum number of missing item allowable to provide a valid 
standard score for each part are: 2 for Part I, 2 for Part II, 9 for Part III, and 0 for Part IV. For 
each part, if no item is missing, the total score is the sum of all the item scores in the part. If 
some items are missing, the total score is the sum of all available item scores multiplied by 
the total number of items in the part and then divided by the number of items with available 
scores. MDS-UPDRS Part I+II+III (II+III) total score is the sum of all relevant part scores. 
As subjects were not guided to enter 0 to the Part IV questionnaire before they start 
symptomatic PD medication, some subjects left blank to the Part IV items at applicable visits. 
Therefore, we will impute the missing item in Part IV as 0. The total score is missing if and 
only if any relevant part score is missing (Stebbins et. al. 2015). For all other clinical 
endpoints, if more than half of the items are missing, then the total score is set to be missing. 
Otherwise, the missing item score will be imputed and used to derive the total score. In 
particular, if an item score is missing at a post baseline visit, it will be imputed by last 
observation carried forward method. And if an item score is missing at baseline, it will be 
imputed by the median of the item score among all the subjects of the same PD subtype 
(PIGD-dominant, Tremor-dominant, Indeterminate) in the study who have a baseline score in 
the item.  
 
5.3.2 MDS-UPDRS 
 Primary efficacy endpoint  
Estimand:  
The estimand of the primary analysis is the mean difference of the change from baseline in 
MDS-UPDRS I+II+III total score at Week 52 between treatment groups in the ITT 
population in a hypothetical setting where subjects do not start PD medication. MDS-UPDRS 
data collected after the intercurrent events, i.e., subjects start PD medication will be excluded 
in the primary analysis. Specifically, the estimand takes the following into consideration: 
A. Population: ITT population as defined in Section 5.1.2 
B. Variable: change from baseline to Week 52 in MDS-UPDRS score 
C. Intercurrent events: had PD medication not been made available to subjects prior 
to Week 52  
D. Population-level summary: difference in variable means between treatment 
conditions. 


 
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MMRM will be used as the primary analysis to analyze the change from baseline in MDS-
UPDRS score. The model includes the fixed effects of treatment group, time (categorical), 
baseline PD subtype (categorical; PIGD vs TD vs indeterminate), prior use of PD medication 
(categorical), treatment group-by-time interaction, region (categorical), baseline MDS-
UPDRS I+II+III total (continuous), baseline MDS-UPDRS I+II+III total by time interaction 
and baseline striatum SBR values (continuous), and baseline striatum SBR by time 
interaction. A random intercept and slope will be included in the model to model the random 
effects within subjects.  If small sample size in subgroups of PD types causes lack of model 
convergence, the indeterminate group will be combined with the TD group.  The Kenward-
Roger approximation will be used to estimate the denominator degrees of freedom. Least 
square means (LSmeans) of each treatment group as well as treatment difference between 
BIIB054 groups and placebo will be displayed with 95% CI and p-value at Week 52. If the 
distribution of the outcome is highly skewed, p-value will be generated from the MMRM 
model based on ranked data. In the primary analysis, missing data are assumed to be missing 
at random (Rubin 1976), and MDS-UPDRS I+II+III score is impacted by PD medication. 
The multiple comparison procedure-modelling (MCP-MOD) method will be used to assess 
the dose-response relationship while controlling for multiplicity (Pinheiro 2013). The dose-
response parameter of interest for MCP-MOD are the least-squares means (LSmeans) at 
Week 52 for each treatment group from the MMRM model. The underlying models to be 
tested are specified in Figure 4.1. P-value of dose response will be presented. Details of 
MCP-MOD procedure are specified in Appendix III. 
A multiple comparison adjustment method will be applied to control the overall type I error 
at 0.05 in the study, due to the primary endpoint of change from baseline in MDS-UPDRS 
total score being analyzed at Week 52 and Week 72, and superiority against placebo is 
considered reached in the study if statistically significant result is achieved at either timepoint 
at the respective adjusted alpha-level.  This will be applied to the p-value from the MCP-
 
Nominal p-values for pair-wise comparison of each active group vs placebo will be reported, 
no additional multiple comparison adjustment will be applied.  
Item 1.6 of features of dopamine dysregulation syndrome will be excluded to calculate all the 
scores. 
 
 Secondary endpoints and additional 
 MDS-UPDRS based endpoints 
The analysis approach and the MMRM model as described for the primary endpoint will be 
performed for additional MDS-UPDRS based endpoints as listed below, except that, 1) the 
baseline MDS-UPDRS I+II+III total score term in the model will be replaced by the 
corresponding baseline value of MDS-UPDRS total or sub-part score being analyzed, 2) 
MCP-MOD dose-response may be performed, 3) no additional multiple comparison 
adjustment will be applied for secondary efficacy 
 endpoints 
 MDS-UPDRS Parts I, II, III (Secondary Efficacy Endpoints),  
 MDS-UPDRS Parts II+III, Ib+II+III 








 
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27 
 
 
 
  
 
 Subgroup analysis 
Subgroup analyses will be performed for the outcomes of MDS-UPDRS part III and I+II+III 
respectively in the subgroups of the following baseline covariates. The MMRM model is the 
same as the one in the primary analyses. If the MMRM model of a specific subgroup does not 
converge, no results will be displayed for that subgroup. A forest plot will be generated to 
present the results of all subgroups together.  
 Age (above v.s. below median) 
 Gender (male v.s. female) 
 region, (US v.s. Other)  
 prior use of PD medication (Yes v.s. No)  
 time since onset of PD symptoms (above v.s. below median) 
 baseline type of PD (tremor-dominant v.s PIGD-dominant v.s. Indeterminate)  
 baseline MDS-UPDRS III (above v.s. below median) 
 baseline MDS-UPDRS I+II+III (above v.s. below median),  
 baseline modified H&Y stage (<=1.5 v.s. >=2)  
 
 
 baseline total striatum SBR measure, occipital reference (<=mean-sd v.s >mean-sd to 
<=mean+sd v.s. >mean+sd)  
 baseline contralateral putamen SBR measure, occipital reference (<=mean-sd v.s 
>mean-sd to <=mean+sd v.s. >mean+sd) 
 baseline ipsilateral putamen SBR measure, occipital reference (<=mean-sd v.s >mean-
sd to <=mean+sd v.s. >mean+sd) 
 
 
 
 
 
 
 baseline total striatum volume (above v.s. below median), 
 baseline lateral ventricle volume (above v.s. below median), 
 
 
 
  
 baseline stride time variability (above v.s. below median), 
Subgroup analysis will be performed respectively by including and excluding data after PD 
medication. The forest plot will be generated respectively as well. Besides, subgroup analysis 
of time to start of PD medication will be performed for the subgroup of regions (US v.s. Italy 
v.s Other) 


 
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 Per-protocol analysis 
The per-protocol analysis will be performed in the same fashion as the primary analysis for 
MDS-UPDRS I+II+III, but by applying in the per-protocol population as defined in Section 
4.1. If the per-
subjects included in the ITT population are also included in the per-protocol population, then 
the per-protocol analysis will not be performed. 
 
5.3.3 Other clinical efficacy endpoints 
Other clinical efficacy (function) and quality of life assessments are listed as below. The 
questionnaire as well as the scoring algorithm for these clinical assessments are described in 
Appendix I. 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
   
 
  
  
   
 Clinical Global Impressions Improvement (CGI-I) Scale (collected at Week 52 in the 
US sites only)*, 
  Patient Global Impression of Change (PGI-C) (collected at Week 52 in the US sites 
only)*.  
Data after PD medication will be included in the analysis for all the outcomes except 
. 
For each clinical assessments that are collected longitudinally, an MMRM model will be used 
to analyze the change from baseline in the continuous clinical outcome, with addition of 
adjustment for the corresponding baseline outcome value and its interaction with time.  i.e. 
the model will include fixed effects of treatment group (categorical), time (categorical), 
region (categorical), treatment group-by-time interaction, baseline value of the corresponding 
outcome (continuous), baseline value of the outcome by time interaction, baseline MDS-
UPDRS I+II+III total score (continuous), baseline MDS-UPDRS I+II+III total score-by-time 
interaction, baseline striatum SBR values (continuous), and baseline striatum SBR by time 
interaction.  
nally include the 
baseline PD subtype (categorical) as a covariate.  An unstructured covariance matrix will be 
used to model the within-subject variance-covariance errors. If the unstructured covariance 
structure matrix results in a lack of convergence, the heterogeneous Toeplitz covariance 
structure followed by the heterogeneous first-order autoregressive covariance structure will 


 
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be used.  Least square means (LSmeans) of each treatment group as well as treatment 
difference between BIIB054 groups and placebo will be displayed with 95% CI and p-value 
at Week 52.  
For CGI-I and PGI-C that are only collected at Week 52, an ANCOVA model will be used to 
analyze the data and adjust for the covariates of baseline MDS-UPDRS I+II+III (continuous) 
and baseline straiatum SBR values (continuous), and baseline PD subtype (categorical). 
with that of the MDS-UPDRS I+II+III, EP-RPS 
 will be 
computed by including and excluding data after PD medication respectively  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 




 
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5.3.5 Assessment of the Impact of Covid-19 on the clinical outcome analyses 
As this study is on-going when the Covid-19 public health emergency (PHE) occurred, 
subject  visits and data collection were impacted, including missing visits, missed 
assessments, delayed visits and/or some visits were performed via remote assessments, e.g. 
telephone/video visits.  Every effort was made to document these impacted study activities 
systematically on the eCRF and othe electronic source  data.   
 
A complete listing of all visits impacted (e.g. missed visits, delayed or assessment done via 
remote visits) will be listed in the clinical study report.  
   
In addition, subgroup analyses of the selected key clinical outcome MDS-UPDRS will be 
performed on a subset of subjects who did not have >=3 consecutive missing doses 
throughout the study to further evaluate the impact of Covid-19 on the study. The same 
MMRM model for the primary analyses will be used for the subgroup analyses.  
 
In addition, due to Covid-19, some visits were delayed.  A few subjects will have their Week 
52 imaging done at later visits up to Week 72 and these will still be considered as Week 52 
visit data in the analyses for Week 52.  These data were not included in the Week 52 database 
lock in time, but will be included in the Week 72 database, and the related Week 52 imaging 
analyses will be updated at the time of the Week 72 interim analyses.  
 
5.4 Safety Analysis  
5.4.1 General Considerations 
Analysis population 
All safety endpoints will be evaluated in the safety population (all subjects dosed) as defined 
in Section 5.1.2.  
Methods of analysis 
All adverse events (AEs) and serious adverse events (SAEs), clinical laboratory 
abnormalities, vital sign measurements, physical and neurological examination findings, 12-
lead ECG readings, disease activity by brain MRI metrics, body weight and Columbia 
Suicide Severity Rating Scale (C-SSRS) will be evaluated for safety. Safety data collected by 
EOS defined in Section 5.1.1 will be used for the safety analyses. The main safety analysis 
will include data after PD medication. Additional analyses may be performed by excluding 


 
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32 
 
data after PD medication. Unless mentioned otherwise, all safety data will be summarized by 
treatment group and overall active group. 
Although treatment assignment error is not expected, if some subjects received different 
study treatment than the randomization allocation, the safety analyses will be based on the 
actual treatment allocation. Specifically, if a subject who was assigned placebo received 
BIIB054 at any visit at the same dose level by mistake, this subject will be included in the 
BIIB054 group of that dose in the safety statistical analyses; if a subject was assigned placebo 
or BIIB054 of certain dose level, but  received BIIB054 at multiple dose level by mistake, 
this subject will be included in the BIIB054 group of the dose level that were taken the most 
frequently in the safety statistical analyses; on the other hand, if a subject who was assigned 
BIIB054 does receive placebo by mistake, this subject will be included under placebo group 
in the safety statistical analyses only when this subject received placebo at all study visits. 
For the clinical laboratory assessments, vital sign measurements and 12-lead ECG readings, 
subjects in Cohort A have additional post-baseline visits between Day 1 and Week 12, 
comparing to Cohort B. The summary of numerical changes over time, i.e., the quantitative 
analysis will be based on the pooled data of both Cohort A and Cohort B and the common 
visits. All the qualitative analyses including the shift analysis, grade analysis and so on will 
be based on all the data of Cohort A and Cohort B of all visits. All the listings will be based 
on all the data of Cohort A and Cohort B of all visits.  
Visit windows for mapping safety endpoint 
For safety data that are summarized by visit, assessment from all scheduled visits, EOT visit, 
EOS visit and unscheduled visits will be mapped to an appropriate analysis visit using a 
windowing scheme (Appendix II). 
 
5.4.2 Clinical Adverse Events 
For this study, any AE experienced by a subject between the time of first dose of study 
treatment (Day 1/Baseline) and the end of study visit is to be recorded on the CRF, regardless 
of the severity of the event or its relationship to study treatment. Any SAE experienced by the 
subject between the time the subject has signed the ICF and the end of study visit is to be 
recorded, regardless of the severity of the event or its relationship to study treatment.   
All AEs will be coded using the MedDRA and will be analyzed based on the principle of 
treatment emergence.  An AE will be regarded as treatment-emergent if it was present prior 
to the first dose and subsequently worsened in severity or was not present prior to first dose 
but subsequently appeared.  
In order to define treatment emergence for AE with missing start or stop dates, the following 
additional criteria will be used: 
 If both the start and stop dates for a particular event are missing, then that event is 
considered treatment-emergent; 
 If the start date for a particular event is missing and the stop date/time falls after the 
first dose date/time, then that event is considered treatment-emergent; 


 
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 If the start date is the same as the first dose date, and the start time is missing, then 
that event is considered treatment-emergent. 
For events 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 and TESAEs will be summarized in the tables, unless otherwise specified. All 
SAEs (including pre-dosing SAEs) will be included in the listing of SAEs, with an indicator 
of pre-dosing or treatment-emergent. Only TEAEs will be included in other AE listings, if not 
otherwise specified. 
The overall summary table of AEs will present the number of subjects with the following 
events for each treatment group, BIIB054 total and overall. A subject is counted only once in 
each category. 
 Any AE; 
 AE by severity as measured in CTCAE grade of version 5.0: 1 (mild), 2 (moderate), 3 
(severe or medically significant), 4 (life-threatening), 5 (death) 
 Study drug-related AE; 
 
 
 Radioligand related AE; 
 Any SAE; 
 Study drug-related SAE; 
 
; 
 Radioligand related SAE; 
 AE leading to discontinuation of study treatment; and  
 AEs leading to withdrawal from study 
 Death 
The incidence of AEs will be summarized using the primary system organ class (SOC) or 
preferred term (PT) or both, sorted by decreasing frequency and alphabetical order, 
respectively. Additionally, AEs at least 5% higher in incidence for any active group 
compared to placebo group will be summarized by SOC and PT. 
The incidence of AEs will also be summarized by severity as measured in CTCAE grade of 
version 5.0 using system organ class and preferred term. Within each system organ class 
or/and preferred term, the same subject will be counted only once.  Under the same system 
organ class or/and preferred term, the occurrence of the adverse event with the greatest 
severity will be used in the calculation of incidence by severity.  
The study drug related AEs, 
 and radioligand related AEs will be 
summarized by SOC, PT and treatment group as well.  
The incidence of SAEs will be summarized by primary system organ class, preferred term 
and treatment group. Study drug related SAEs, 
 and radioligand 
related SAEs will be summarized in the same fashion as well. 
Tables of AEs that led to study drug discontinuation and AEs that led to study withdrawal by 
SOC, PT and treatment group will be presented. 


 
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Listings of all AEs, SAEs, AEs that led to study drug discontinuation, and AEs that led to 
study withdrawal will be presented. Listing of death will be provided if applicable.  
In some AE/SAE listings, complete AE start and end dates are needed to calculate the relative 
study days of AE start and end. Therefore, any partial date will be imputed for these listings. 
Specifically, the partial AE start date will be imputed as the earliest possible date on or after 
the first dose based on the partial information, and the partial AE end date will be imputed as 
the latest possible date on or before the EOS. 
 
AEs around the time of infusion 
The incidence of AEs within 2 hours from infusion start will be summarized by preferred 
term and visit for each treatment group. At each visit, the same subject will be counted only 
once within each preferred term. Preferred terms will be ordered by decreasing frequency of 
AEs in the BIIB054 total column. Listings of such AEs within 2 hours from infusion start 
will be provided by treatment group. 
 
5.4.3 Clinical Laboratory Data 
The following clinical laboratory parameters are assessed in the protocol: 
 Hematology: Complete blood count with differential and platelet count, INR, 
prothrombin time, and APTT 
 Blood chemistry: total protein, albumin, creatinine, blood urea nitrogen, uric acid, 
bilirubin (total and direct), alkaline phosphatase, alanine aminotransferase, aspartate 
aminotransferase, gamma-glutamyl transferase, glucose, calcium, phosphorus, 
bicarbonate, chloride, sodium, and potassium 
 Urinalysis: dipstick for blood, protein, and glucose (microscopic examination may 
also be performed)  
 
 
 
 
 
 
         
 
 
  
 
 
 
 
 
  
 
 
 


 
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All the laboratory tables and listings, unless otherwise specified, will be presented by 
treatment group.  
 
 Quantitative laboratory analyses  
For numeric laboratory parameters, actual values, change and percent change from baseline 
will be summarized by visit. Number of evaluable subjects, mean, standard deviation, 
median, min and max values will be presented at each visit.  
Plots of mean values (with standard deviation) for key numeric laboratory parameters by visit 
will be provided.  
 
Visit windows for by visit summaries 
For laboratory by visit summaries, the analysis visit should be defined using visit windows in 
Appendix II.  If there is more than 1 value in the same analysis visit window (>1 value for the 
same analysis visit) for a certain parameter for a subject, then the closest record to the target 
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 subject, 
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 subject, then the record with the later time will 
be used for the by visit analysis. If there are 2 records on the same date and time, then use the 
average value for quantitative parameters and the worse value for qualitative parameters. 
 
 
 Qualitative laboratory analyses 
each visit window in the quantitative analyses). 
 
Shift analyses 
hematology, blood chemistry and urinalysis numeric 
categorical values will be flagged as 
, 
 no value is available. Shifts from baseline to 
high/low status will be presented for hematology, blood chemistry and urinalysis numeric 
parameters, and shifts from baseline to abnormal (positive) will be presented for urinalysis 
categorical parameters.   
In the hematology, blood chemistry and urinalysis numeric values shift summary tables, 
entries are numbers of subjects shift to low (or high) divided by number of subjects at risk 






 
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Table 5.2. Criteria Used to Clinically Relevant Abnormalities in Vital Signs 
Variable 
Low 
High 
Body temperature 
<36 degrees C 
>38 degrees C 
Pulse Rate 
<60 bpm  
>100 bpm 
Systolic Blood Pressure 
(Supine) 
<90 mm Hg or a decrease from 
baseline of >30 mm Hg  
>140 mm Hg or an increase from 
baseline of >40 mm Hg 
Orthostatic Systolic Blood 
Pressure  
> 20 mm Hg decrease from supine 
to 3-minute standing measure 
 
 
 
 
Diastolic Blood Pressure 
< 50 mm Hg or a decrease from 
baseline of > 20 mm Hg  
>90 mm Hg or an increase from 
basleine of >30 mm Hg 
Orthostatic Diastolic Blood 
Pressure 
>10 mm Hg decrease from supine to 
3-minute standing measure 
 
Respiration Rate 
< 12 breaths per minute  
>20 breaths per minute  
Weight 
>7% decrease from BL 
>7 % increase from BL 
 
 
 
BL= baseline; bpm = beats per minute 
Note: the clinically relevant abnormality criteria will be evaluated based on the supine measure unless otherwise 
mentioned. 
 
A summary table for subjects with any clinically relevant post-baseline abnormalities will be 
provided. In the summary table, entries are numbers of subjects with an abnormality divided 
by number of subjects evaluated followed by corresponding percentages. Number evaluated 
is the number of subjects who had a baseline assessment and at least one post-baseline 
assessment for that vital sign.  
The descriptive statistics for actual values and change from baseline will be summarized over 
time for each treatment group and overall active group. The line of mean vital sign over time 
by treatment group will be graphed.  
A subject listing will be presented for subjects with any post-baseline clinically relevant 
abnormalities in vital sign
screening to last study visit will be listed with abnormalities labeled. 
 
Visit windows for by visit summaries 
For vital sign visit summaries, the analysis visit will be defined by visit window in Appendix 
II. For the same parameter for a subject, if there is more than 1 record in the same analysis 
visit window), then select the record closest to the target visit day.  If there are 2 records in 
the same analysis visit window with the same distance from the target visit day, then select 
the record with the later date. If there are 2 records on the same date, then use the average 
value for quantitative parameters and the worse value for qualitative parameters. 
 
5.4.5 ECG Data 
Actual value and change from Baseline in ECG will be summarized using descriptive 
statistics and presented by treatment group, overall active group and visit. 
The ECG result is classified as normal or abnormal. The post baseline abnormal ECG result 
is further classified as abnormal AE or Abnormal but not AE. Shift table from normal or 


 
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unknown ECG at baseline to abnormal post-baseline ECG will be summarized. The worst 
post-baseline record of each subject is selected.  Subjects with abnormal post-baseline ECG 
status will be listed.  
In addition, the number of subjects with potential QTcF interval outlier post-baseline will be 
summarized by treatment group. The criteria of defining QTcF interval outliers is specified in 
Table 5.3. 
Table 5.3. Criteria used for QTcF interval outlier 
Variable 
Low 
High 
QTcF interval (msec.) 
NA 
>450; >480; >500 
Increase in QTcF interval 
(msec.) 
NA 
>30; >60 
 
Visit windows for by visit summaries 
For ECG visit summaries, the analysis visit will be defined by visit window in Appendix II. 
For the same subject, if there is more than 1 record in the same analysis visit window, then 
the record closest to the target visit day is selected. If there are 2 records in the same analysis 
visit window with the same distance from the target visit day, then the record with the later 
date is selected. If there are 2 records on the same date, then the worse record is selected.   
 
5.4.6 Physical and Neurological Examination 
Abnormal findings during physical and neurological examinations are captured as adverse 
events and will be reflected in the summary of AEs.  
 
5.4.7 C-SSRS Data 
The Columbia Suicide Severity Rating Scale (C-SSRS) is an assessment that evaluates 
suicidal ideation and behavior. C-SSRS measurements are collected with respect to 
 
 
 
-baseline visit. 
-baseline visits. Five questions 
on suicidal ideation and five questions on suicidal behavior are re-ordered and follow 
increasing severity order respectively as shown in Table 5.4; another question on self-
injurious behavior without suicidal intent is listed separately. In particular, only subjects who 
, and the questions in the 
section of intensity of ideation
 
used to record if subject had committed suicide in post-baseline visits. 
Table 5.4: C-SSRS re-ordered questions 
Suicidal Ideation
Question 1 
Wish to be dead 
Question 2 
Non-specific active suicidal thoughts 


 
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Question 3 
Active suicidal ideation with any methods (not plan) 
without intent to act 
Question 4 
Active suicidal ideation with some intent to act, without 
specific plan 
Question 5 
Active suicidal ideation with specific plan and intent 
Suicidal Behavior 
Question 6 
Preparatory acts or behavior 
Question 7 
Aborted attempt 
Question 8 
Interrupted attempt 
Question 9 
Actual attempt  
Question 10 
Suicidal behavior 
Question 11 (post-baseline visits 
only) 
Suicide 
Self-Injurious Behavior without Suicidal Intent 
Question 12 
Self-injurious behavior without suicidal intent 
 
A subject is considered to have suicidal ideation 
answered to any of the five suicidal ideation questions (Question 1-5). A subject is 
considered to have suicidal behavior 
the five suicidal behavior questions (Question 6-
of the six suicidal behavior questions (Question 6-11) at post-baseline visit.  
Suicidal Ideation Score is defined as the maximal suicidal ideation question 
number (maximal of 1-
 
The following analyses on C-SSRS measurements will be conducted: 
 
-12 as well as 
subjects who had suicidal ideation or suicidal behavior at baseline and at any post-
baseline visit. the denominator for summary is the number of subjects who were 
dosed and had a baseline assessment and at least one post-baseline assessment for 
each question. 
Listing of subjects having a post-baseline suicidal ideation will be provided. The listing will 
display both baseline and post-baseline suicidal ideation scores for each subject.  
 
5.4.8 MRI Safety Data 
Brain MRI safety finding (may include T1, fluid-attenuated inversion recovery, gradient 
echo) or other modalities and sequences (to be detailed in Imaging/MRI manual) are assessed 
at Screening visit, Week 24 and 52 visits.  
The MRI safety result is classified as normal or abnormal. Shift table from normal or 
unknown MRI at baseline to abnormal post-baseline MRI will be summarized. The worst 
post-baseline record of each subject is selected. A listing of details for abnormal brain MRI 
findings will also be presented. 
 


 
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5.5 Pharmacodynamic -Imaging Analysis 
5.5.1 Type of imaging techniques and imaging outcomes 
There are three types of imaging techniques used in the study:  
(1) DaT/SPECT imaging, 
(2) 
 
  
(3) 
   
 
DaT/SPECT imaging assesses the biological effects of BIIB054 on brain dopamine neurons 
and nerve terminals. DaT-associated outcome measures include the estimates of anterior and 
posterior putamen, caudate, as well as total striatum striatal binding ratio (SBR), a measure 
that compares signal intensity in the region of interest to that in the occipital cortex, a region 
relatively devoid of dopamine nerve terminals.  Measurements are obtained both ipsilateral 
and contralateral to the side of worst motor symptoms, anterior, posterior as well as 
combining both sides.  
 
 
  
 
 
 
5.5.2 Analysis population 
All pharmacodynamic imaging endpoints will be evaluated based on the Pharmacodynamics 
population as defined in Section 5.1.2. 
 
5.5.3 Baseline value 
Baseline value is defined as the latest data collected at any time prior to the first dose, or if 
collected only after dosing the earliest data on the first dose date, given the data is collected 
within 1 week after first dose date. 
 
5.5.4 Outlier of percent change from baseline 
If the percent change from baseline in a post-baseline value of a DaT/SPECT SBR measure is 
greater than 50% or less than -50%, the post-baseline value of the DaT/SPECT measures is 
considered as physiologically implausible, and therefore will be excluded in the analysis. 
5.5.5 Analysis methods 
The estimand of the primary analysis for imaging outcome measure is the mean difference of 
the change from baseline in the imaging measure at Week 52 between treatment groups in the 


 
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pharmacodynamics population regardless of whether start of PD medication had occurred or 
not. Specifically, the estimand takes the following into consideration: 
A. Population: pharmacodynamics population as defined in Section 5.1.2; 
B. Variable: change from baseline to Week 52 in the imaging measure; 
C. Intercurrent events: regardless of whether start of PD medication had occurred or not; 
D. Population-level summary: difference in variable means between each active 
treatment and placebo group 
A set of DaT/SPECT measures and 
 have been 
selected for the statistical anlayses based on literature review and clinical inputs before the 
DBL. Please see Appendix VI for the listed measures.  
Data collected after subjects who have begun taking PD medication will be included in the 
primary analysis. Change and percent change from baseline will be summarized by visit and 
treatment groups using descriptive statistics. Change or percent change from baseline in the 
imaging measures will be analyzed using the mixed model for repeated measures (MMRM), 
which includes the fixed effect of the treatment group (categorical), time (categorical), 
interaction between treatment group and time, region (categorical), baseline imaging values 
(continuous), baseline imaging values by time interaction, baseline MDS-UPDRS I+II+III 
total score (continuous) and baseline MDS-UPDRS I+II+III total score by time interaction. 
An unstructured covariance matrix will be used to model the within-subject variance-
covariance errors. If the unstructured covariance structure matrix results in a lack of 
convergence, the heterogeneous Toeplitz covariance structure followed by the heterogeneous 
first-order autoregressive covariance structure will be used.  The Kenward-Roger 
approximation will be used to estimate the denominator degrees of freedom. Least square 
means (LSmeans) of each treatment group as well as treatment difference between each 
BIIB054 groups and placebo will be displayed with 95% CI and p-value at Week 52. If the 
distribution of the outcome is highly skewed, p-value will be generated from the MMRM 
model based on the rank data. In the primary analysis, missing data are assumed to be 
missing at random (Rubin 1976), and the PD medication is assumed to have minimal impact 
on the imaging measures.  
The same MCP-MOD method as used in the primary analyses of MDS-UPDRS I+II+III may 
be used to assess and model dose-response relationship of the imaging outcomes.  
 
5.5.6 Sensitivity analysis 
A sensitivity analysis will be performed using the same MMRM model in the primary 
analysis, but by excluding DaT/SPECT values that are collected after subjects starting PD 
medications.  
The sensitivity analysis will be performed only for the key DaT/SPECT measures as 
specified in the Appendix VI.  


 
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5.5.7 Correlation analysis 
will be computed for the 
following imaging and MDS-UPDRS parameters. For the pairs with MDS-UPDRS III, 
I+II+III and EP-RPS correlation will be computed respectively by including and excluding 
data after PD medication. For the other pairs, correlation will be compuated by including the 
data after PD medication only. 
 
DaT-SPECT Striatum total SBR (25. STR_SBR) x MDS-UPDRS III 
 
DaT-SPECT Striatum total SBR (25. STR_SBR) x MDS-UPDRS I+II+III 
 
DaT-SPECT Striatum total SBR (25. STR_SBR) x 
Progression Score (EP-RPS) 
 
DaT-SPECT Striatum total SBR (25. STR_SBR) x structural MRI Striatum total volume (13. 
STR_VOL) 
 
DaT-SPECT Striatum total SBR (25. STR_SBR) x SNc total volume via GRE (23. 
GRE_NM_VOL) 
 
DaT-SPECT Striatum total SBR (25. STR_SBR) x SNc total intensity ref 4 via GRE (98. 
GRE_NM_NMSIG_R4)  
 
NM-MRI SNc total volume via GRE (23. GRE_NM_VOL) x NM-MRI SNc total volume via 
TSE (9. TSE_NM_VOL) 
 
NM-MRI SNc total intensity ref 4 via GRE (98. GRE_NM_NMSIG_R4) x NM-MRI SNc 
total intensity ref 4 via TSE (37. TSE_NM_NMSIG_R4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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5.7 Pharmacokinetics Analysis 
The PK analysis population as defined in Section 5.1.2 will be used for the description of the 
concentration-time profiles and for the estimation of PK parameters.  
A serum drug concentration that is deemed inconsistent with dosing (very low or very high) 
will be excluded from the analysis if no apparent explanation exists. Concentration 
observations may also be removed from the data set if corresponding dosing or sampling 
times are missing or cannot be imputed. Concentration data with below limit of quantification 
value will be excluded. All exclusions of data points or subjects from the analysis will be 
appropriately documented. 
In addition, a detailed listing of sampling time (actual and nominal) and corresponding 
concentration at each time point for all subjects in the PK population will be provided. 
Presence of anti-BIIB054 antibody will also be listed and summarized. Additional listings 
may be generated as deemed necessary. 




 
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For immunogenicity, baseline value is defined as the latest data collected at any time prior to 
the first dose, or if collected only after dosing the earliest data on the first dose date. More 
specifically, if samples are only available prior to the first dose, or samples are available both 
prior to first dose date and on the first dose date, baseline is the latest sample prior to the first 
dose date. However, if samples are only available on the first dose date but not prior to the first 
date, baseline is the earliest sample on the first dose date. 
positive sample result at any time during the treatment or post-treatment evaluation periods. A 
study subject will be g
are antibody negative.  
Anti-BIIB054 antibody responses in antibody-positive subjects are defined as treatment 
emergent if a subject is: 
- ADA-negative at baseline and ADA-positive post-baseline, or  
- ADA-positive at baseline and had a greater than 2-fold increase in antibody titer post-
baseline. 
Summary table of the number and percentage of treatment-emergent anti- BIIB054-positive 
and -negative antibody events by visit will be displayed for each active treatment groups. A 
listing of all anti- BIIB054 antibody results will also be provided. 
 
6 INTERIM ANALYSIS 
Safety and PK data only will be reviewed by the IDMC after subjects in Cohort A have 
completed Week 12 Visit assessments, and before dosing any subjects in Cohort B.  
After subjects in Cohort A complete the Week 24 Visit, 
, all available serum PK, 
from Cohort A will be analyzed by a statistical/PK team independent of the study.  The 
grouped level summary statistics will be reviewed only by a limited number of individuals at 
Biogen who are not involved in the management of the subjects or subject-level data for the 
study.  No changes to the study design are expected based on this review. 
For the purpose of planning for future studies, an administrative interim analysis may be 
performed when approximately 60% of the subjects have completed the Week 52 Visit. A 
small unblinded team from Biogen, separate from the study management team, will have 
access to the unblinded interim analysis results. As of the finalization of protocol Version 8 
and all subjects have completed Week 52 visits, this analyses was not conducted 
A full analysis of the 1-year data will be performed after all subjects have completed the 
Week 52 Visit.  A small unblinded team from Biogen, separate from the study management 
team, will have access to the unblinded 1-year analysis results.  All efficacy endpoints will be 
analyzed at the Week 52 analyses.  All available safety data will also be summarized.  
An interim analysis when all subjects have completed the Week 72 Visit is planned to be 
conducted.  A small unblinded team from Biogen, separate from the study management team, 
will have access to the unblinded interim analysis results.  All efficacy endpoints and 
available 
 will be analyzed at the Week 72 analyses.  Selected key safety data (e.g. 
summary of AE and SAE, summary of MRI safety findings and incidence of anti-drug 


 
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antibodies) will be summarized, as this is only a snapshort of the safety profile at the time of 
the Week 72 interim analysis, and the comprehensive safety profile will be presented at the 
End of Study   
A multiple comparison adjustment method will be applied to control the overall type I error 
at 0.05 in the study, due to the primary endpoint of change from baseline in MDS-UPDRS 
total score being analyzed at Week 52 and Week 72, and superiority against placebo is 
considered reached in the study if statistically significant result is achieved at either timepoint 
at the respective adjusted alpha-level.    
An improved fall-back procedure will be used to control the overall type I error at 0.05 level 
due to multiple-testing.  An alpha of 0.04 will be allocated to the Week 52 primary endpoint 
analyses and an alpha of 0.01 will be allocated to the Week 72 primary endpoint analysis.  
 If the Week 52 analysis is statistically significant at the 0.04 level (i.e. p-
, 
the alpha of 0.04 will be transferred (recycled) to the Week 72 analysis, and Week 72 
will have alpha=0.05.  
 If the Week 52 analysis is not statistically significant at the 0.04 level, alpha of 0.01 
will be used for the Week 72 analysis.  Statistically significance is considered 
achieved if the p-value is 0.01 at Week 72.    
 If statistically significance is achieved at the Week 72, in either scenarios above, then 
the alpha of 0.01 will be transferred (recycled ) back to Week 52, and the Week 52 
primary analysis will be re-evaluated for statistically signifance at the 0.05 level.  This 
will only change the conclusion of the Week 52 results if the initial p-value is greater 
than 0.04 and 0.05. 
 
 No additional multiplicity adjustments will be made for secondary or 
 endpoint 
analyses.  
A blinded sample size re-estimation may be conducted when approximately 10% of subjects 
have completed the Week 52 Visit or approximately 1 month before enrollment is projected 
to be completed, whichever is earlier (description of method is below).  The study sample 
size may be increased based on this blinded data review.  There may be small adjustments to 
the percentage depending on actual enrollment rate.  As of the finaliation of protocol Version 
8 (Aug 2020), all subjects have completed Week 52 visits, this analyses was not conducted.  
 
Blind sample size re-estimation 
The sample size for this study may be reassessed in a blinded manner in a cutoff date of 
February 2020, by which time approximately 78/311 (25%) of subjects will complete the 
Week 52 visit.  
The standard deviation (SD) of the change from baseline to Week 52 in the putamen 
ipsilateral side SBR will be estimated based on the blinded data using a modified version of 
Gould-Shih simple adjustment on sample variance (Zucker et al. 1999): 
 


 
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where  denotes the number of subjects included in the analysis for blinded sample size re-
estimation (subjects with both baseline and Week 52 data of the putamen ipsilateral side SBR 
available at the time of sample size re-
atment effect 
(same treatment effect assumed for high, medium and low dose group in this analysis), and 
 is the unadjusted one sample variance of the estimate of the change from baseline to 
Week 52 in the putamen ipsilateral side SBR from the pooled blinded data.  
The recommendation of sample size increase depends on the comparison of 
 with 0.156, 
the assumed value of SD for the current sample size (see Section 4). If 
 is less than or 
equal to 0.156, the value used for sample size calculation when planning the study, the study 
will continue with the original planned sample size 311. If 
 is greater than 0.156, the 
study will continue with an increased sample size. The increased sample size will be 
calculated by using the same MCP-MOD method as specified in Protocol 16.9, subject to a 
maximum of 413, which is a 30% increase on the original sample size.  
 
7 References  
Donald B.Rubin. Inference and missing data. Biometrika. 1976;63: 581 592. 
 
Jose Pinheiro, Bjorn Bornkamp, Ekkehard Glimm and Frank Bretz. Model-based dose 
finding under model uncertainty using general parametric models. Statistics in Medicine. 
2013;33: 1646 1661. 
 
Stacy M, Hauser R (2007) Development of a Patient Questionnaire to facilitate recognition of 
motor and non-motor wearing-off in 
J Neural Transm 114:211 217 
 
Washburn RA, Smith KW, Jette AM, Janney CA. The physical activity scale for the elderly 
(PASE): Development and evaluation. Journal of Clinical Epidemiology. 1993 Feb 
1;46(2):153 62. 
 
Christopher G. Goetz, Sheng Luo, Lu Wang, Barbara C. Tilley, Nancy R. LaPelle, Glenn T. 
Stebbins. Handling Missing Values in the MDS-UPDRS. Mov Disord. 2015 October; 30(12): 
1632-1638. 
 
K. Horvath, Z. Aschermann, P. Acs, G. Deli, J. Janszky, S. Komoly, E. Balazs, K. Takacs, K. 
Karadi, N. Kovacs. Minimal clinically important difference on the Motor Examination part of 
MDS-UPDRS. Parkinsonism and Related Disorders 2015. 21: 1421-1426. 
 
K. Horvath, Z. Aschermann, M. Kovacs, A. Makkos, M. Harmat, J. Janszky, S. Komoly, K. 
Karadi, N. Kovacs. Minimal clinically important difference on the Experiences of Daily 
Living Parts of Movement Disorder Society-
Scale. Movement Disorders 2017. Vol. 32, No. 5. 
 
L. M. Shulman, A. L. Gruber-Baldini, K. E. Anderson, P. S. Fishman, S. G. Reich, W. J. 
Scale. Arch Neurol. 2010; 67 (1): 64-70 


 
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49 
 
 
Zucker, D. M., Wittes, J. T., Schabenberger, O. and Brittain, E. Internal pilot studies II: 
comparison of various procedures. Statistics in Medicine. 1999;18: 3493 3509. 
 
 
8 Appendix 
8.1 Appendix I: Questionnaires 
Please refer to the separate Appendix document for the details of the questionnaire as well as 
the corresponding scoring algorithm.  
 
8.2 Appendix II: Visit Window Mapping 
Please refer to the separate Appendix document for the details of the visit window mapping 
rule for all the study endpoints.  
 
8.3 Appendix III: Description of MCP-MOD method 
MCP-MOD method works in the following steps.  
Step 1: Set of candidate models 
Candidate models include Emax (ED50
(ED50
0.5), linear-log (off=237.5), quadratic 
-0.0002), Exponential 
Figure 4.1 in the SAP. 
Step 2: Optimal model contrast 
The LSmeans at Week 52 and the covariance matrix of the LSmeans will be estimated 
from the MMRM model and used to determine the optimal contrasts. The coefficients of 
the contrasts are pre-specified during the design stage once the candidate models are 
selected in Step 1. 
Step 3: Testing for dose response signal 
A multiple contrast test will be used to test the overall dose response signal and to 
identify all contrasts that have adjusted p-values less than or equal to the pre-specified 
alpha controlling for multiplicity at Week 52 and Week 72. As a result, the significance 
of the dose response signal will be established. 
Step 4: Model selection 
Value of AIC will be presented together with the p-values for the dose response models in 
Step 3.   


 
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8.4 
Progression Score (EP-RPS) 
EP-RPS is derived in the following steps based on MDS-UPDRS Part III motor assessments. 
 
Step 1: group the 30 MDS-UPDRS Part III items into 7 body regions as below (item 3.11 of 
freezing of gait, item of 3.13 of posture and item 3.18 of constancy of rest are excluded.) 
 
Body region 
Question items in UPDRS Part III 
questionnaire 
Variable names in 
SAS data set 
Right hand 
3.3b Rigidity-RUE 
3.4a Finger Tapping-Right hand 
3.5a Hand movements-Right hand 
3.6a Pronation-supination movements-
Right hand 
3.15a Postural tremor-Right hand 
3.16a Kinetic tremor-Right hand 
3.17a Rest tremor amplitude-RUE 
3.3b NP3RIGRU 
3.4a NP3FTAPR 
3.5a NP3HMOVR 
3.6a NP3PRSPR 
3.15a NP3PTRMR 
3.16a NP3KTRMR 
3.17a NP3RTARU 
Left hand 
3.3c Rigidity-LUE 
3.4b Finger Tapping-Left hand 
3.5b Hand movements-Left hand 
3.6b Pronation-supination movements-
Left hand 
3.15b Postural tremor-Left hand 
3.16b Kinetic tremor-Left hand 
3.17b Rest tremor amplitude-LUE 
3.3c NP3RIGLU 
3.4b NP3FTAPL 
3.5b NP3HMOVL 
3.6b NP3PRSPL 
3.15b NP3PTRML 
3.16b NP3KTRML 
3.17b NP3RTALU 
Right leg 
3.3d Rigidity-RLE 
3.7a Toe tapping-Right foot 
3.8a Leg agility-Right leg 
3.17c Rest tremor amplitude-RLE 
3.3d PN3RIGRL 
3.7a NP3TTAPR 
3.8a NP3LGAGR 
3.17c NP3RTARL 
Left leg 
3.3e Rigidity-LLE 
3.7b Toe tapping-Left foot 
3.8b Leg agility-Left leg 
3.17d Rest tremor amplitude-LLE 
3.3e NP3RIGLL 
3.7b NP3TTAPL 
3.8b NP3LGAGL 
3.17d NP3RTALL 
Trunk 
3.3a Rigidity-Neck 
3.9 Arising from chair 
3.10 Gait 
3.12 Postural Stability 
3.13 Posture 
3.3a NP3RIGN 
3.9 NP3RISNG 
3.10 NP3GAIT 
3.12 NP3PSTBL 
3.13 NP3POSTR 
Speech 
3.1 Speech 
3.1 NP3SPCH 
Face 
3.2 Facial expression 
3.17e Rest tremor amplitude-Lip/jaw 
3.2 NP3FACXP 
3.17e NP3RTALJ 
 
 


 
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Step 2: For each body region, derive the region score as the maximum score of all the items 
included in the region. As a result, a score will be derived per subject per visit per body 
region. 
 
Step 3: For each subject at each visit, count the total number of progressed body region. A 
body region is progressed at visit t if and only if the change from baseline in the body region 
score is greater than or equal to 1 at visit t, and the change is confirmed by the next visit after 
visit t. A body region is progressed by visit s, if and only if the body region is progressed 
prior to or at visit s. 
 
Step 4: For each subject at each visit, derive the body region progression AUC as the 
weighted average of the number of progressed body regions of all the visits before the current 
visit. The weight of each visit is proportional to the time elapsed from the previous visit to the 
current visit. Alternatively, the body region progression AUC at visit t can be computed as 
the area from baseline to visit t under the trajectory curve of the number of progressed body 
regions by time, divided by the total number of years elapsed from baseline to visit t. Missing 
data will be imputed by linear interpolation for the intermediate missing visits and by linear 
extrapolation for the trailing missing visits. 
 
For illustration purpose, suppose a subject had 0, 1, 2, 2, 3, 3 and 4 body regions with 
progression AUC value is as shown in the following plot. 
 










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VERSION HISTORY 
 
SAP Version 
Date 
Primary Reasons for 
Amendment 
1.0 
25-SEP-2020 
First version of the SAP 
2.0 
23-JUNE-2021 
Update links within sample 
size section 
Update SMT job titles 
 
 


 
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Table of Contents 
1 
DESCRIPTION OF OVERALL STUDY  (INCLUDING DOSE-BLINDED EXTENSION (DBE)) 
OBJECTIVES AND ENDPOINTS ..................................................................................................................... 7 
2 
STUDY DESIGN ....................................................................................................................................... 12 
2.1 
STUDY OVERVIEW .................................................................................................................................. 12 
2.1.1 
Year 1 (Placebo-Controlled Portion of the Study) ........................................................................ 12 
2.1.2 
Years 2-4 (Active-Treatment Dose-Blinded Portion of the Study) ................................................ 12 
2.2 
STUDY SCHEMATIC ................................................................................................................................. 13 
2.3 
SCHEDULE OF EVENTS ............................................................................................................................ 15 
3 
SAMPLE SIZE JUSTIFICATION .......................................................................................................... 15 
4 
STATISTICAL ANALYSIS METHODS ............................................................................................... 18 
4.1 
GENERAL CONSIDERATIONS ................................................................................................................... 18 
4.1.1 
Analysis Population ...................................................................................................................... 20 
4.1.2 
Analyses period ............................................................................................................................. 20 
4.2 
BACKGROUND CHARACTERISTICS .......................................................................................................... 21 
4.2.1 
Accounting of Subject ................................................................................................................... 21 
4.2.2 
Demographics and Baseline Characteristics ................................................................................ 22 
4.2.3 
Concomitant Medications and Non-Drug Therapies .................................................................... 22 
4.2.4 
Protocol Deviations ...................................................................................................................... 22 
4.2.5 
Study Drug Exposure and Study Drug Compliance ...................................................................... 23 
4.3 
EFFICACY ANALYSES .............................................................................................................................. 23 
4.3.1 
General Consideration ................................................................................................................. 23 
4.3.2 
Primary efficacy endpoint analysis ............................................................................................... 24 
4.3.3 
Secondary efficacy endpoints and additional endpoints analysis ................................................. 26 
 
MDS-UPDRS based endpoints ................................................................................................................ 26 
 
Other clinical efficacy measures .............................................................................................................. 26 
4.4 
PHARMACODYNAMICS ANALYSES ........................................................................................................... 27 
4.5 
SAFETY ANALYSES ................................................................................................................................. 28 
4.5.1 
General Considerations ................................................................................................................ 28 
4.5.2 
Clinical Adverse Events ................................................................................................................ 29 
 
Summary and incidence analysis.............................................................................................................. 29 
 
Incidence and incidence rate analysis for active treatment (placebo-controlled and DBE) period ........... 30 
4.5.3 
Clinical Laboratory Data ............................................................................................................. 32 
 
Quantitative analyses ............................................................................................................................... 32 
 
Qualitative analyses ................................................................................................................................. 33 
4.5.4 
Vital Sign Data ............................................................................................................................. 34 
4.5.5 
ECG Data ..................................................................................................................................... 35 
4.5.6 
Physical and Neurological Examination ...................................................................................... 35 
4.5.7 
C-SSRS Data ................................................................................................................................. 35 
4.5.8 
MRI Safety Data ........................................................................................................................... 36 
4.6 
PHARMACODYNAMIC -IMAGING ANALYSIS ............................................................................................. 36 
4.6.1 
General Consideration ................................................................................................................. 36 
4.6.2 
By Visit Summary and MMRM Model .......................................................................................... 37 
4.6.3 
Additional analyses of placebo-controlled period due to COVID-19 ........................................... 37 
 
 38 
 
.. 38 
 
 38 
4.8 
PHARMACOKINETICS ANALYSIS .............................................................................................................. 38 
4.9 
IMMUNOGENICITY ANALYSIS .................................................................................................................. 38 
4.9.1 
Analysis population....................................................................................................................... 38 
4.9.2 
Method of analysis ........................................................................................................................ 39 
4.10 
INTERIM ANALYSES ........................................................................................................................... 39 
5 
ASSESSMENT OF THE IMPACT OF COVID-19 ON STATISTICAL ANALYSES ...................... 40 
















 
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2 STUDY DESIGN 
2.1 
Study Overview 
This Phase 2a, randomized, double-blind, parallel-group, placebo-controlled study (Year 1) 
with an active-treatment dose-blinded period (Year 2 through 4) will examine the efficacy, 
safety, PK, and pharmacodynamics of BIIB054, administered every 4 weeks via IV infusion 
to adult subjects with PD. Approximately 311 subjects will be enrolled at about 85 sites 
globally. 
2.1.1 Year 1 (Placebo-Controlled Portion of the Study) 
Prior to the first dose in Year 1, all subjects in the study will be randomized into 4 arms, to 
receive 13 doses of BIIB054 (250, 1250, or 3500 mg) or placebo. 
Subjects will be enrolled into 2 cohorts. Cohort A will be randomized first, in a 1:1:1:1 ratio 
into each of the 4 treatment arm and will include approximately 24 subjects. Randomization 
and dosing for Cohort B (approximately 287 planned subjects) will start after all subjects in 
Cohort A complete Week 12 assessments, and all available safety and PK data are reviewed 
by the IDMC.  Randomization of subjects in Cohort B will be stratified by baseline (Day 1) 
MDS-
and subjects will be randomized at Day 1 into 1 of 4 parallel dosing arms in each stratum. 
After all subjects in Cohort A complete Week 12 assessments (28 days after their third 
infusion), and before dosing any subjects in Cohort B, all available safety and PK data will be 
reviewed by the IDMC. No subjects in Cohort B may be dosed until the IDMC review is 
complete. The study schematic is presented in Figure 1. After IDMC review is complete, 
subjects in Cohort B will be randomized, and dosing may begin. During the review period, 
subjects in Cohort A will continue to be dosed on a schedule of once every 4 weeks. 
The first IDMC meeting will occur after the last subject in Cohort A completes Week 12 
assessments, or approximately 6 months after the first subject has been enrolled in Cohort A, 
whichever comes first. Regular IDMC meetings will occur approximately every 3 months 
after the first meeting.  
 
 
 
The Week 48 infusion is the last infusion pf the placebo-controlled period, and Week 52 is 
the first dosing of the Dose-blinded portion of the study. 
Any changes will be documented in a protocol amendment. 
2.1.2 Years 2-4 (Active-Treatment Dose-Blinded Portion of the Study) 
Prior to Infusion 14 (the first dose of Year 2) at Week 52, subjects who received placebo in 
Year 1 will be randomized into 1 of the active-dosing arms for Year 2; these subjects will 
receive BIIB054 in Year 2. Subjects who received BIIB054 (250mg, 1250 mg or 3500 mg) in 
Year 1 of the study will continue with the same dose regimen in Year 2. Subjects receiving 
the 250-mg dose in Year 1  continued on their original dose assignement. 
 


 
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Subjects will receive 12 additional doses of BIIB054 (250, 1250, or 3500 mg) in Year 2 and 
up to 16 additional doses in Years 3 and 4. Up until the last subject in the study has had his or 
her last dose in Year 2 of the study (Week 96 Visit), eligible subjects will be able to continue 
treatment once every 4 weeks. 
 
Subjects who complete dosing through Week 96 and the Final Visit 12 weeks after the last 
visit will be considered Year 2 completers in the eCRF. 
 
See Figure 2 for a depiction of the duration of dosing in Years 3 and 4 for subjects continuing 
dosing past Week 96. 
 
Figure 4 in the protocol presents a flowchart for dosing and procedures from Week 96 
through end of study, including how to determine which subjects are eligible to continue 
dosing past Week 96. 
    
 
2.2 
Study Schematic 
 
 
 
 


 
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Figure 2: Overview of Study Dosing: 
 


 
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2.3 
Schedule of Events 
See Protocol Section 4.2. 
3 SAMPLE SIZE JUSTIFICATION 
The sample size calculation is based on changes in MDS-UPDRS Part I + II + III total score 
SD) at Week 52 
and Week 72 are assumed to be 8.0 (10.64) and 9.6 (13.7) respectively. Assuming a 
maximum of 55% reduction in the change from baseline in the active group with maximum 
response relative to placebo group, the mean (SD) for this active group will be 3.2 (10.64) 
and 3.84 (13.7) respectively at Week 52 and Week 72, and the responses for other active 
groups are assumed to be somewhere between 0 and the maximum response.  The primary 
analysis will be based on the MCP-MOD method to detect a dose-response trend while 
controlling for multiplicity.  Optimal contrasts will be constructed to detect potential dose-
response trend under common dose-response curves (e.g., Emax, exponential, logistic, linear in 
log dose, and quadratic model, which are illustrated with parameters shown in Figure 3.1 
which will be used for both Week 52 and Week 72).  The planned enrollment is 311 subjects 
total (24 subjects in Cohort A and 287 subjects in Cohort B, 3.1).  Actual enrollment is 357 
subjects.  In Cohort A, 29 subjects were randomized in a 1:1:1:1 ratio to each of the treatment 
groups, while in Cohort B 328 subjects were randomized in 2:1:2:2 ratio to the placebo, 250 
mg, 1250 mg, and 3500 mg groups.  Based on the actual enrollment, the estimated number of 
subjects by cohort and treatment groups are given in Table 3.2 below.  After accounting for 
dropout rate of 10% and 15% at Week 52 and Week 72, respectively, the estimated sample 
sizes are given in Table 3.3 and Table 3.4.  With the updated sample size, the study will 
provide an average power of approximately 80% to detect the dose-response trend over 1 
year of treatment, based on a 2-sided type I error of 0.05 and approximately 73% of power at 
the Week 72 analyses, based on a 2-sided type I error of 0.05.  Overall, the sample size in the 
study will provide approximately 89% power, taking into consideration success at either 
Week 52 or Week 72.      
With an estimated sample size of 100 subjects dosed per arm in the 1250 mg and 3500 mg 
arms, the study has 80% probability of detecting AEs with a rate of 1.6% or greater in these 
2 arms, and a 90% probability of detecting AEs occurring with a rate of 2.3% or greater.   


 
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Figure 3.1: 
Candidate Models for Dose-Response 
 
 
 
 
 




 
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4 STATISTICAL ANALYSIS METHODS 
4.1 
General Considerations 
This statistical analysis plan (SAP) covers the analyses of the dose-blinded extension (i.e., 
long term extension) period (Years 2-4) and the analyses across both the placebo-controlled 
period and the DBE period (analyses integrating the data for Years 1-4).   
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. Pharmacokinetics (PK) 
summaries will also include Geometric mean and geometric CV. 
Statistical testing will be performed to assess efficacy endpoints by conducting pairwise 
comparison between each BIIB054 group and the delayed-start group (i.e. subjects who were 
randomized to placebo in Year-1),. Dose-response relationship may also be tested.  Unless 
stated otherwise, all the statistical tests will be 2-sided with a statistical significance level of 
0.05 . 
The statistical software, SAS® will be used for all summaries and analyses.  
 
 
Analysis displays 
Unless otherwise specified, the analysis of the DBE period and the analyses across both the 
placebo-controlled period and the DBE period will be displayed by DBE treatment groups as 
shown below, separate for early and delayed start treatment group) including tables, listings 
and figures, unless otherwise specified. 
Unless otherwise specified, analyses for efficacy data (e.g., pharmacodynamics of imaging, 
, clinical efficacy, 
) will be 
displayed by the following treatment groups according to randomization assignment at the 
start of the placebo-controlled period: 
 
BIIB054 early start: subjects who are assigned to (1) receive BIIB054 in the 
placebo-controlled period and (2) continue receiving BIIB054 in the DBE period 
 
BIIB054 late start: subjects who are assigned to (1) receive placebo in the 
placebo-controlled period and (2) switch to BIIB054 in the DBE period  
Unless otherwise specified, analyses for safety, PK, and ADA data will be displayed by the 
following treatment groups according to dose received: 
 
BIIB054 early start: subjects who receive BIIB054 in the placebo-controlled 
period (regardless of randomization assignment)  


 
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BIIB054 late start: subjects who receive only placebo in the placebo-controlled 
period (regardless of randomization assignment) and switch to receive BIIB054 in 
the DBE period  
 
BIIB054 total: subjects in either BIIB054 early or late start treatment groups 
. 
If all subjects received study treatment according to their randomization assignments during 
the placebo-controlled period (i.e. no subject assigned to placebo received BIIB054, and no 
subject assigned to BIIB054 received only placebo), then the assignment of subjects to 
treatment groups in efficacy related tables will be the same as those in safety related tables.  
For efficacy, pharmacodynamic of imaging, 
, clinical, 
 
 and PK and ADA outcomes. Each BIIB054 early start dose group may be 
compared with the corresponding delay-start dose group, as well as the pooled delay-start 
group. Outputs will be presented in the following two ways:  
 
BIIB054 delayed start 
(N = xx) 
 
 
BIIB054 early start 
(N = xx) 
 
Placebo to 
250 mg 
(N = xx) 
Placebo to 
1250mg 
(N = xx) 
Placebo to 
3500 mg 
(N = xx) 
 
 
250 mg 
(N = xx) 
1250 mg 
(N = xx) 
3500 mg 
(N = xx) 
 
 
 
 
BIIB054 delayed start 
(N = xx) 
 
 
BIIB054 early start 
(N = xx) 
 
Placebo to BIIB054 
(N = xx) 
 
250 mg 
(N = xx) 
1250 mg 
(N = xx) 
3500 mg 
(N = xx) 
 
For baseline and safety related outputs: 
BIIB054 delayed start 
(N = xx) 
BIIB054 early start 
(N = xx) 
BIIB054 
Total 
(N=xx) 
Placebo 
to 250 
mg 
(N = xx)
Placebo 
to 
1250mg 
(N = xx)
Placebo 
to 3500 
mg 
(N = xx)
Total 
(N=xx) 
250 mg 
(N = xx) 
1250 mg 
(N = xx) 
3500 mg 
(N = xx) 
Total 
(N=xx) 
 
For all listings the start and stop day in the listing will be computed based on the placebo-
controlled baseline. 
Baseline for all the analyses across the SAP  
Unless otherwise specified, baseline refers to the baseline value for the placebo-controlled 
period and is defined as the most recent non-missing measurement collected prior to the first 


 
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dose in Year 1. DBE baseline is defined as the last non-missing measurement collected prior 
to the first dose of the DBE period in Year 2.  
For analyses on the DBE period or on the active treatment (placebo-controlled and DBE) 
period, DBE baseline will be used for delayed start subjects who are assigned to receiving 
BIIB054 in the DBE period. Change from baseline will be defined as post-baseline value 
minus baseline value.  
 
 
4.1.1 Analysis Population 
 Intent-to-treat (ITT) population:  
The Intent-to-treat population is defined as all randomized subjects who received at least 
one dose of study treatment (BIIB054 or placebo).  
 
 Safety population:  
The safety population is defined as all subjects who received at least one dose of study 
treatment (BIIB054 or placebo).  
 
 Pharmacodynamic analysis population:  
The pharmacodynamic population is defined as a subset of the ITT population with at 
least 1 post-baseline pharmacodynamic measurement.   
 
 PK analysis population:  
The PK population is defined as a subset of the ITT population who have at least 1 
measurable BIIB054 concentration in serum 
   
 
 
 
 
 
 Immunogenicity population:  
Immunogenicity analysis will be performed for all subjects in the safety population. 
 
4.1.2 Analyses period 
Depending on the purpose, different analyses will be conducted on the following study 
periods: 
1. DBE period. Only data in the DBE period will be included in these analyses. For 
example, incidence table of adverse events in the DBE period.  
2. Placebo-controlled and DBE period. All the data in the placebo-controlled and DBE 
periods will be included in these analyses. For example, mean plot of actual 
laboratory values in the placebo-controlled and DBE period. 


 
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3. Active treatment (placebo-controlled and DBE) period (i.e., Total BIIB054 
experience) period. Active treatment period is defined as the study period(s) that a 
subject is assigned to BIIB054. For early start subjects  subjects who are assigned to 
BIIB054 in both placebo-controlled and DBE period, all the data (placebo-controlled 
and DBE periods) will be included in the analyses. For delayed start subjects  
subjects who are assigned to placebo in Year 1 and BIIB054 in the DBE period, only 
data in the DBE period will be included. For example, incidence table of adverse 
events in the active treatment (placebo-controlled and DBE) period will not include 
the AEs started on placebo treatment in year 1.     
Subjects to be included in a certain output is determined by both the analysis population and 
the analysis period. For example, the incidence table of adverse events in the DBE period will 
include subjects in the safety population for the DBE period, i.e., all randomized subjects 
who received at least one dose of study treatment in the DBE period. The incidence table of 
adverse events in the active treatment (placebo-controlled and DBE) period will include 
subjects in the safety population for the active treatment period, i.e., all randomized subjects 
who received at least one dose of study treatment in the active treatment period. In this SAP 
we do not separately define the analysis population in each analysis period. 
 
4.2 
Background Characteristics 
The summaries in this section will be based on the ITT population. Analysis period will be 
specified for each table or figure. Unless otherwise specified, summary tables will be 
presented by DBE treatment group. Listings will include all data in the placebo-controlled 
and DBE periods (all data in the study), with an indicator of the study period in a column 
(pre-dosing, placebo-controlled, or DBE) for each record to indicate when the event occurred. 
Listings will be presented by DBE treatment group. 
 
4.2.1 Accounting of Subject 
Disposition in the DBE period will be summarized for subjects enrolled in DBE. The 
summary data will include number (%) of subjects dosed in the DBE period, number (%) of 
subjects who completed the first year of treatment/study of DBE (i.e., year 2 of the study), 
number (%) of subject who discontinued treatment and/or withdrew from study in the first 
year of DBE (i.e., year 2 of the study), the reason for treatment discontinuation and/or study 
withdrawal for in the first year of DBE (i.e., year 2 of the study), number (%) of subjects who 
completed the treatment/study in DBE (i.e., year 2-4 of the study), and number (%) of 
subjects who discontinued treatment and/or withdrew from study in DBE (i.e., year 2-4 of the 
study), the reason for treatment discontinuation and/or study withdrawal in DBE (i.e., year 2-
4 of the study).  
For subject who discontinued treatment and/or withdrew from the study in the first year of 
DBE (i.e., year 2 of the study), days on treatment and days on study will be summarized.  
For subjects who discontinued treatment and/or withdrew from study in DBE (i.e., year 2-4 
of the study), days on treatment and days on study will be summarized and listed. In the 
listing, the subjects who discontinued treatment and/or withdrew from study in the first year 


 
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of DBE will be flagged. Time to treatment discontinuation and time to study withdrawal in 
the DBE period may be displayed by Kaplan-Meier plot (presented by DBE treatment group). 
Disposition in the placebo-controlled and DBE period will be also summarized in the same 
fashion. Number (%) of subjects dosed in the placebo-controlled period, number (%) subject 
who completed the placebo-controlled period, number (%) of subjects who entered the DBE 
period, number (%) of subjects who completed the first year of DBE period, number (%) of 
subjects who completed the whole study will be displayed. Number of subjects who 
discontinued treatment or study and reason of discontinuation will be summarized for each 
period and for the whole study. 
 
4.2.2 Demographics and Baseline Characteristics 
Demographics, baseline characteristics, medical history and PD treatment history will be 
summarized for subjects enrolled in the DBE period and subjects not enrolled in the DBE 
period, respectively. Please refer to the SAP of placebo-controlled period for more details.  
 
4.2.3 Concomitant Medications and Non-Drug Therapies 
All medications will be coded using the World Health Organization Drug (WHODrug March 
2020 B3 or higher) dictionary. All non-drug therapies (defined as diagnostic procedures or 
medical treatment procedures) will be coded using the MedDRA dictionary version 23.0 or 
higher.   
The number (%) of subjects taking concomitant general medication (excluding PD 
medications) and non-drug therapies in the DBE period will be summarized by DBE 
treatment group for subjects enrolled in the DBE period. In addition, number of subjects in 
the ITT population that have taken any concomitant medications in the active treatment 
(placebo-controlled and DBE) period will be summarized. Concomitant non-PD medications 
and non-drug therapies will be listed in the placebo-controlled and DBE treatment period.  
Start and stop day in the listing will be computed based on the placebo-controlled baseline. 
For subjects enrolled in the DBE period, the number (%) of subjects taking any concomitant 
PD symptomatic medications, number of subjects taking Dopamine, MAO-B inhibitor, 
Dopamine Agonist at the baseline of the placebo-controlled period and at the baseline of 
DBE period will be summarized respectively by DBE treatment group. The placebo-
controlled and DBE period data will be summarized in the same fashion. Concomitant PD 
symptomatic medication will be listed for all subjects in the placebo-controlled and DBE 
periods. Start and stop day in the listing will be computed based on the placebo-controlled 
baseline. Please refer to the placebo-controlled SAP for definitions of concomitant therapies 
and PD symptomatic medication use at baseline. 
 
4.2.4 Protocol Deviations 
Protocol deviations identified during site monitoring will be captured in a Protocol Deviation 
log and categorized as major or minor deviations. The major protocol deviations occurred in 


 
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the DBE period will be summarized for subjects enrolled in DBE. The major protocol 
deviations for all ITT subjects in the combined placebo-controlled and DBE periods will also 
be summarized.  Major and minor protocol deviations for all ITT subjects will be listed, 
respectively, across the placebo-controlled period and the DBE period. All summaries for 
protocol deviations will be presented by DBE treatment group.  A separate Covid-19 related 
protocol deviation category will be shown in the protocol deviation listings.  
 
4.2.5 Study Drug Exposure and Study Drug Compliance 
A summary table of study drug exposure and compliance in the DBE period will be provided. 
Number of infusions of BIIB054 received will be summarized as a continuous variable as 
well as a categorical variable (categories as 1-5, 6-10 and 11-15, 16-20, 20-25, >=26) as well 
as a continuous variable. Number of weeks on study treatment, calculated as (date of last 
dose  date of first dose +1)/7, will be summarized as a categorical variable (categories as 
<0.5 years, >=0.5 years, >=1 year, >=2 years, >=3 years) as well as a continuous variable. 
Percentage of study treatment taken up to the last dose, calculated as (the actual number of 
infusions / the number of infusions a subject is expected to take until the date of last 
infusion)*100, will be summarized as a continuous variable. This table will be presented by 
DBE treatment group. A similar table will also be provided on the active treatment (placebo-
controlled and DBE) period in order to summarize the exposure data while subjects are on 
BIIB054.  
A listing of study drug administration records, including infusion start date and time, infusion 
stop date and time, total volume prepared, total volume administered, location of infusion, 
initial infusion rate, dose interruption or rate change or not, time of interruption or rate 
change, infusion rate after interruption or rate change, reason for interruption or rate change 
will be provided for the placebo-controlled and DBE period. A listing of subjects who 
received the wrong treatment compared to what they were randomized to will be provided for 
the placebo-controlled and DBE period. 
4.3 
Efficacy analyses 
4.3.1 General Consideration 
The analysis population for the efficacy analyses are defined in Section 4.2.1. The analysis 
period includes data from both placebo-controlled and DBE period combined.  That is, data 
from both the placebo-controlled and DBE periods will be included in the analysis.  
The following three comparisons will be evaluated for the long-term efficacy analyses of 
BIIB054: 
 The early start 250 mg compared with the pooled delayed start group; 
 The early start 1250 mg compared with the pooled delayed start group; 
 The early start 3500 mg compared with the pooled delayed start group 
The following comparisons may also be evaluated: 
 The early start 250 mg compared with the delayed start 250 mg; 


 
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 The early start 1250 mg compared with the delayed start 1250 mg. 
 The early start 3500 mg compared with the delayed start 3500 mg. 
The pooled delayed start group contains all the subjects who were randomized to placebo 
treatment in the placebo-controlled period including those who did and who did not enter into 
the DBE period.  There will be no multiple comparison adjustments.  Data after subjects start 
PD symptomatic treatment will be included in the analyses, since the majority of subjects are 
expected to take PD medication after Week 52. 
Subjects who were randomized to placebo group but accidentally received one or more doses 
of the active treatment during the placebo-controlled period will be classified as delayed start  
for all the efficacy, pharmacodynamic, and 
 analyses. 
 
Visit Windows for by visit analyses 
For the by visit summaries and MMRM models, the analysis visit should be defined using 
visit windows (see Tables 6-16 in the Appendix).  If there is more than 1 value in the same 
analysis visit window (>1 value for the same analysis visit) for a certain parameter for a 
subject, then the closest record to the target visit day will be used for the by visit analysis.  If 
they are with the same distance from the target visit day, then the record with the later time 
will be used for the by visit analysis.   
 
Handling of missing items for scales 
Please refer to the placebo-controlled SAP for the imputation method.The same method will 
be applied to efficacy endpoints collected in the DBE period. 
 
4.3.2 Primary efficacy endpoint analysis  
The estimand of the primary analysis for MDS-UPDRS Part I+II+III total score at Week 72 is 
the mean difference of the change from baseline at Week 72 between treatment groups in the 
ITT population regardless of whether start of PD medication had occurred or not. 
Specifically, the estimand takes the following into consideration: 
A. Population: ITT population as defined in Section 4.1.1; 
B. Variable: change from baseline to Week 72 in the MDS-UPDRS Part I+II+III total 
score; 
C. Intercurrent events: regardless of whether start of PD medication had occurred or not; 
D. Population-level summary: difference in variable means between each early start 
group and delayed start group 
Change from baseline in the MDS-UPDRS Part I+II+III total score at Week 72 will be 
analyzed using an MMRM model for all the visits in the placebo-controlled and DBE period.  
Data after subjects start PD medication will be included in the primary analyses.   
For details on the model to be used please refer back to the Year 1 SAP, for the analyses of 
MDS-UPDRS including data after PD medication. Adjusted means for each treatment group, 


 
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pairwise adjusted differences for the comparisons, 95% confidence intervals for the 
differences will be presented at each visit, and p-values will be presented for the key visits of 
week 24, 52, and 72.  Dose-response testing will be done using the adjusted mean with the 
pre-specified MCP-MOD procedure with pre-specified candidate models (refer to Year 1 
SAP Sample Size Consideration section).   If the distribution of the outcome is highly 
skewed, p-value will be generated from the MMRM model based on the rank data. Missing 
data are assumed to be missing at random behind the MMRM model.   
 
A multiple comparison adjustment method (graphical procedure) will be applied to control 
the overall type I error at 0.05 in the study, due to the primary endpoint of MDS-UPDRS total 
score being analyzed at Week 52 and Week 72, and superiority against placebo is considered 
reached in study if statistically significant result is achieved at either timepoint. Please refer 
versus delayed-start group(s) will also be conducted, however, no additional multiplicity 
adjustment will be made, and nominal p-values will be reported.   The primary comparison is 
between each of the early-start BIIB054 dose group, with the pooled delayed-start BIIB054 
group.    
The following three comparisons will be evaluated for the long-term efficacy analyses of 
BIIB054: 
 The early start 250 mg compared with the pooled delayed start group; 
 The early start 1250 mg compared with the pooled delayed start group; 
 The early start 3500 mg compared with the pooled delayed start group 
The following comparisons may also be evaluated: 
 The early start 250 mg compared with the delayed start 250 mg; 
 The early start 1250 mg compared with the delayed start 1250 mg. 
 The early start 3500 mg compared with the delayed start 3500 mg. 
  
Per design, a subset of subjects will enter year 3 and 4 for a limited time. There will be some 
visits with too few data in year 3 and 4. If this is the case, the visits with too few data will be 
excluded from the MMRM analyses, Otherwise, the MMRM model will not converge. In 
addition, since most patients will start PD medication by year 1, most data in year 2-4 will be 
after PD medication. Therefore, data after subject start PD medication will be included in the 
MMRM analyses. Otherwise, the MMRM model will not converge. 
Data at the common visits of cohort A and cohort B will be included in the by visit summary 
and MMRM model. Data at all visits will be listed. 
  


 
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4.3.3 Secondary efficacy endpoints and additional endpoints analysis  
Secondary endpoints, e.g., change from baseline in the MDS-UPDRS subscores (e.g., Part I, 
II, or III score, Part II and III total score) will be analyzed in a similar model, but no 
additional multiplicity adjustment will be made or for other secondary endpoints.    
 MDS-UPDRS based endpoints 
 
The analysis approaches and the MMRM model described will be performed for additional 
MDS-UPDRS based endpoints as listed below, except that, 1) the baseline MDS-UPDRS 
total score term in the model will be replaced by the corresponding baseline value of MDS-
UPDRS total or sub-part score being analyzed, 2) MCP-MOD dose-response may be 
performed, 3) no additional multiple comparison adjustment will be applied for secondary 
efficacy and exploratory efficacy endpoints 
 MDS-UPDRS Parts I, II, III (Secondary Efficacy Endpoints), 
 MDS-UPDRS Total Score (I+II+III) at the end of the study  
 MDS-UPDRS Parts II+III, Ib+II+III 
 MDS-UPDRS Part IV 
 Postural Instability -Gait Difficulty (PIGD) score (mean score of MDS-UPDRS items 
2.12+2.13+3.10+3.11+3.12), 
 Lower Extremity (LE) score (mean score of MDS-UPDRS items 
3.10+3.11+3.12+3.13+3.3d+3.3e+3.7a+3.7b +3.8a+3.8b+3.17c+3.17d+2.12+2.13), 
and Tremor score (mean score of MDS-UPDRS items 
2.10+3.15a+3.15b+3.16a+3.16b+3.17a+3.17b+3.17c+3.17d+3.17e+3.18).  
 Other clinical efficacy measures  
 
 
  
  
  
  
  
  
  
  
  
  
  


 
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4.4 
Pharmacodynamics analyses 
There are three types of imaging outcomes in the study: DaT/SPECT imaging, 
 
. Please refer to the placebo-controlled SAP for 
details. 
The analysis population for pharmacodynamic analyses is defined in Section 3.1.1. The 
analysis period is placebo-controlled and DBE period combined.  That is, data from both the 
placebo-controlled and DBE periods will be included in the analyses.  
Similar analyses will be conducted for the pharmacodynamic analyses as for the clinical 
outcome analysis.  The main comparison will be between the early and delayed-start groups. 
The pooled delayed start group contains all the subjects who were randomized to placebo 
treatment in the placebo-controlled period including those who did and who did not enter to 
the DBE period.  There will be no multiple comparison adjustments.  Data after subjects start 
PD symptomatic treatment will be included in the analyses.  
 
Visit Windows for by visit analyses 


 
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For the by visit summaries and MMRM models, the analysis visit should be defined using 
visit windows (see Table 3 in the Appendix).  If there is more than 1 value in the same 
analysis visit window (>1 value for the same analysis visit) for a certain parameter for a 
subject, then the closest record to the target visit day will be used for the by visit analysis.  If 
they are with the same distance from the target visit day, then the record with the later time 
will be used for the by visit analysis.   
A prespecified set of imaging measures as well as the change from baseline will be 
summarized by DBE treatment groups by visit for all the visits in the placebo-controlled and 
DBE period.  
MMRM model analyses: 
Similar MMRM model will be used to conduct the pharmacodynamic analyses as for the 
clinical outcome analysis, with the same terms included in the model.   
 
4.5 
Safety Analyses 
4.5.1 General Considerations 
Analysis population 
Safety population will be used for safety analyses of AEs, clinical laboratory data, vital sign 
data, ECG data, physical and neurological examination findings, Columbia Suicide Severity 
Rating Scale (C-SSRS) data and MRI safety data.  
 
DBE safety treatment groups  
Please refer to Section 3.1 for the safety treatment groups. Subjects who were randomized to 
placebo group but accidentally received one or more doses of BIIB054 during the placebo-
controlled period will be classified as early start  for all the safety analyses that involves 
DBE, and their applicable safety data in the placebo-controlled period will be included in the 
analysis for active treatment (placebo-controlled and DBE) period. 
 
Safety analysis period  
Analysis period will be specified for each output. Analyses periods in this SAP are 
 Long-term extension period  for AE analyses 
 Active treatment (placebo-controlled and DBE) period - for AE analyses and analyses of 
hematology/blood chemistry/urinalysis, hepatotoxicity, vital sign, ECG, MRI. 
Safety data in the specified analysis period will be included in the analysis. Listings will 
include all data in the placebo-controlled and DBE period, unless otherwise specified. 
 
Incidence, incidence proportion and incidence rate 
 Incidence and incidence proportion will be provided in incidence tables. Incidence is 
defined as the number of subjects who experienced an event. Incidence proportion is 


 
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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. 
 Incidence and incidence rate will be provided in incidence rate tables. Incidence rate is 
defined as the number of subjects who experienced an event divided by the total follow-
up time among the subjects in the analysis population (e.g., incidence rate per 100 
subject-years). The total follow-
-up time. The 
follow-up time for a subject is defined as the number of days (inclusive) from the first 
dose of treatment until the last day on study divided by 365.25. For active treatment 
(placebo-controlled and DBE) period analyses, the first dose of treatment is considered as the 
first dose received in the study period (PC or OLE) in which a subject first receives BIIB054. 
Each subject will be counted only once within each category.  
 
4.5.2 Clinical Adverse Events  
Treatment emergent AEs (TEAEs) 
All AEs will be coded using the MedDRA dictionary version 23.0 or higher.   
All AEs will be analyzed based on the principle of treatment emergence.  A treatment 
emergent AE is defined as an AE that started or worsened after the start of first infusion of 
study treatment.  
To define treatment emergence for AEs with missing start or stop date or time the following 
additional criteria will be used: 
 if both the start and stop dates for a particular AE are missing, then that AE is considered 
treatment emergent. 
 if the start date for a particular AE is missing and the stop date/time falls after the first 
dose date/time, then that AE is considered treatment emergent. 
 if the start date for a particular AE was the same as the first dose date, and the start time 
was missing, then that event is considered treatment emergent. 
For AEs with a partial start date, the year/month of the event date will be compared to that of 
the first dosing date to determine whether the event is treatment emergent. 
In addition, SAEs that occurred since a subject was screened in the study and prior to the first 
infusion of study treatment, which by definition are not treatment emergent, will be analyzed 
separately. 
Only TEAEs will be included in the AE tables, unless otherwise specified. Listings of AEs 
will include all events, whether treatment emergent or not.  
 
 Summary and incidence analysis 
Overall summary of AE table will be done for the following periods, by DBE treatment 
groups: 
 DBE period, and, 


 
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 the active treatment (placebo-controlled and DBE) period  
 The following information will be summarized: the number of subjects with any AE, with 
any AE by maximum severity, with any related AE (related to study drug as assessed by 
investigator), with radioligand rated AE, with SAE, with related SAE, with radioligand rated 
SAE, with AE leading to study drug discontinuation, with AE leading to study withdrawal 
and the number of deaths.  
The sorting order of AE incidence tables, unless otherwise specified, will be by decreasing 
DBE treatment group. A subject is counted only once within each category in each table. For 
example, for the table of AEs by system organ class and preferred terms sorted by decreasing 
frequency presented by DBE treatment group, system organ class will be presented in 
decreasing frequency order of BIIB054 total column, and within each system organ class, 
preferred terms will be presented in decreasing frequency order of BIIB054 total column. A 
subject is counted only once within each system organ class and preferred term.  
 
The severity of AEs and SAEs is graded using the  CTCAE grade, version 5.0. The 
categorisation of severity is as follows: grade 1 (mild), 2 (moderate), 3 (severe or medically 
significant), 4 (life-threatening) and 5 (death),  Severe AEs and SAEs are classed as CTCAE 
grade >=3. 
 
The following AE incidence tables will be provided for the DBE period: 
1. AEs by system organ class and preferred term sorted by decreasing frequency  
2. AEs by preferred term  
3. Severe AEs by system organ class and preferred term 
4. Severe AEs by preferred term  
5. Study drug related AEs by system organ class and preferred term  
6. SAEs by system organ class and preferred term sorted by decreasing frequency 
7. SAEs by preferred term  
8. Study drug related SAEs by system organ class and preferred term 
9. AEs that led to discontinuation of study treatment by system organ class and preferred 
term  
10. AEs that led to withdrawal from study by system organ class and preferred term  
 
 Incidence and incidence rate analysis for active treatment (placebo-controlled 
and DBE) period 
Due to the different length of active treatment (placebo-controlled and DBE) period in early 
start versus delayed start subjects, both incidence (proportion) tables and incidence rate tables 
will be used for AE analyses in this period. The entire follow-up time is from the first dose in 


 
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active treatment period (first dose in placebo-controlled period for early start subjects and 
first dose in DBE period for delayed start subjects) until the last day in the study.  
The following incidence (proportion) will be provided for the active treatment (placebo-
controlled and DBE) period. The follow-up adjusted incidence rate table will be provided for 
1, 10, 12, 14, 16 and 17. 
1. AEs by system organ class and preferred term sorted by decreasing frequency  
2. AEs by system organ class and preferred term sorted by alphabetical order analysis  
3. AEs by system organ class  
4. AEs by preferred term  
5. AEs with an incidence of 5% or more in any treatment group by preferred term  
6. Severe AEs by system organ class and preferred term  
7. Severe AEs by preferred term  
8. AEs by maximum severity by system organ class and preferred term (System organ 
class will be presented alphabetically. Preferred term will be presented in decreasing 
frequency order.  
9. AEs by maximum severity by preferred term (Preferred term will be presented in 
decreasing frequency order) 
10. Study drug related AEs by system organ class and preferred term  
11. Radioligand related AEs by system organ class and preferred term 
12. SAEs by system organ class and preferred term  
13. SAEs by preferred term  
14. Study drug related SAEs by system organ class and preferred term  
15. Radioligand related SAEs by system organ class and preferred term 
16. AEs that led to discontinuation of study treatment by system organ class and preferred 
term  
17. AEs that led to withdrawal from study by system organ class and preferred term  
18. AEs that occurred within 2 hours from infusion start by system organ class and 
preferred term  
The following listings will be provided for the placebo-controlled and DBE period: 
1. Listing of AEs 
2. Listing of SAEs  
3. Listing of AEs that led to discontinuation of study treatment 
4. Listing of AEs that led to withdrawal from study 
5. Listing of AEs that occurred within 2 hours from infusion start 
6. Listing of study drug related AEs 
7. Listing of radioligand related AEs 


 
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8. Listing of deaths 
 
 
4.5.3 Clinical Laboratory Data 
The following laboratory assessments will be performed in Year 2-4 to evaluate the safety 
profile of BIIB054: 
 Hematology:  Complete blood count with differential and platelet count, INR, PT, 
and APTT 
 Blood chemistry:  total protein, albumin, creatinine, blood urea nitrogen, uric acid, 
bilirubin (total and direct), alkaline phosphatase, alanine aminotransferase, 
aspartate aminotransferase, gamma-glutamyl transferase, glucose, calcium, 
phosphorus, bicarbonate, chloride, sodium, and potassium 
 Urinalysis:  dipstick for blood, protein, and glucose (microscopic examination 
may also be performed) 
 
  
 
 Quantitative analyses  
For quantitative analyses, analysis period is active treatment (placebo-controlled and DBE) 
period. For numeric laboratory parameters, actual values will be summarized by visit for all 
the common visits in both Cohort A and B in the active treatment (placebo-controlled and 
DBE) period. 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 key numeric laboratory parameters at each visit for all 
the visits in the active treatment (placebo-controlled and DBE) period will be provided.  
Plots of mean actual values (with standard error) for numeric laboratory parameters at each 
visit for all the visits in the active treatment (placebo-controlled and DBE) period may be 
provided. 
Change from baseline and percent change from baseline for numeric laboratory parameters 
will be summarized in the active treatment (placebo-controlled and DBE) period. Placebo-
controlled baseline will be used for early start subjects and DBE baseline will be used for 
delayed start subjects. Change and percent change from baseline will be calculated based on 
the DBE baseline for delayed start subjects. Number of evaluable subjects, mean, standard 
deviation, median, 25% and 75% quartiles, minimum and maximum values will be presented 
at each visit.  
Listings of individual laboratory measurements by patients for all the parameters will be 
provided for placebo-controlled and DBE period.  
 


 
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Visit windows for by visit summaries 
For laboratory by visit summaries, the analysis visit should be defined using visit windows 
(see Table 1 in the Appendix).  Visit windows are generally from mid-points between the 
visit before to the current, and the midpoint from the current visit to the next visit.  If there is 
more than 1 value in the same analysis visit window for a certain parameter for a subject, 
then the closest record to the target 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 subject, 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 subject, then 
the record with the later time will be used for the by visit analysis. 
 
 Qualitative analyses 
For qualitative analyses, all available 
within each visit window in the quantitative analyses). Analysis period is active treatment 
(placebo-controlled and DBE) period.  
 
Shift analyses 
Laboratory data will be summarized using shift tables where appropriate for the active 
treatment (placebo-controlled and DBE) 
 
Shifts from baseline to high/low status will be presented for hematology, blood chemistry and 
urinalysis numeric parameters, and shifts from 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) in order to be included in the analysis. 
For early start subjects, the placebo-controlled baseline will be used and shifts that occurred 
in either placebo-controlled or DBE period will be included. For delayed start subjects, the 
DBE baseline will be used and shifts that occurred in the DBE period based on DBE baseline 
will be included.  
 
Potentially Clinically Significant (PCS) laboratory abnormalities analyses 
Please refer to the placebo-controlled SAP for the parameters and criteria for potentially 
clinically significant laboratory abnormalities analyses.  
The number of subjects with potentially clinically significant laboratory abnormalities post-
baseline will be summarized for the active treatment (placebo-controlled and DBE) period.  


 
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Subjects need to have at least one post-baseline evaluation in the active treatment period in 
order to be included in the analysis. For early start subjects, the placebo-controlled baseline 
will be used and abnormalities that occurred in either placebo-controlled or DBE period will 
be included. For delayed start subjects, the DBE baseline will be used and PCS abnormalities 
that occurred in the DBE period based on DBE baseline will be included. 
A listing of subjects with PCS laboratory abnormalities in the active treatment (placebo-
controlled and DBE) period will also be provided, with all the data in the placebo-controlled 
and DBE period will be listed. 
 
Potential serious hepatotoxicity 
Potential serious hepatotoxicity is defined as ALT or AST > 3x ULN and total bilirubin > 2x 
ULN at any time post-baseline, not necessarily concurrent, in the active treatment (placebo-
controlled and DBE) period. A scatterplot of the maximum post-baseline ALT or AST value 
relative to ULN and maximum post-baseline total bilirubin value relative to ULN (not 
necessarily concurrent) will be provided. In addition, a line plot of ALT, AST, ALP and total 
bilirubin values over time for each subject with potential serious hepatotoxicity will be 
provided. 
A listing of subjects with potential serious hepatotoxicity in the active treatment (placebo-
controlled and DBE) period will be provided with the concurrent records labeled. All the data 
in the placebo-controlled and DBE period will be listed. Concurrent is defined as on the same 
day. Subjects with ALT > 1x ULN, > 3x ULN, > 5x ULN, > 10x ULN or > 20x ULN, 
subjects with AST > 1x ULN, > 3x ULN, > 5x ULN, > 10x ULN or > 20x ULN, subjects 
with total bilirubin > 1x ULN, >1.5x ULN or > 2x ULN, subjects with ALP >1x ULN or 
>1.5x ULN, and subjects with AST or ALT > 3x ULN post-baseline accompanied by 
concurrently elevated total bilirubin > 1.5x ULN or > 2x ULN will be labeled.  
 
4.5.4 Vital Sign Data 
For vital sign data analyses, the analysis period is active treatment (placebo-controlled and 
DBE) period. 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. The 
descriptive statistics for actual values will be summarized at each visit in the active treatment 
(placebo-controlled and DBE) period.  Plot of mean vital sign values in the active treatment 
(placebo-controlled and DBE period) may be provided.  
Summary of change from baseline including number of evaluable subjects, mean, standard 
deviation, median, 25% and 75% quartiles, minimum, and maximum values will be 
summarized at each visit in the active treatment (placebo-controlled and DBE) period. 
Placebo-controlled baseline will be used for early start subjects and DBE baseline will be 
used for delayed start analysis.  
The analysis of vital signs will also focus on the incidence of clinically relevant abnormalities 
at any post-baseline visit in the active treatment (placebo-controlled and DBE) period. Please 
refer to the placebo-controlled SAP for the criteria to assess potential clinically relevant 
abnormalities in vital sign. The incidence and percentage of clinically relevant abnormalities 


 
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determined by each criterion will be summarized in the active treatment (placebo-controlled 
and DBE) period.  
A listing of subjects with clinically relevant abnormalities at any post-baseline visit in the 
active treatment (placebo-controlled and DBE) period will also be provided. All the data in 
the placebo-controlled and DBE period will be listed. 
 
Visit windows for by visit summaries 
For vital sign by visit summaries, the analysis visit should be defined using windows (see 
Table 2 in the Appendix). For the same parameter for a subject, if there is more than 1 record 
in the same analysis visit window, then select the record closest to the target visit day. If there 
are 2 records in the same analysis visit window with the same distance from the target visit 
day, then select the record with the later date. 
 
4.5.5 ECG Data 
For ECG data analyses, the analysis period is active treatment (placebo-controlled and DBE) 
period. The descriptive statistics for actual values will be summarized at each visit in the 
active treatment (placebo-controlled and DBE) period.  Plot of mean ECG values in the 
active treatment (placebo-controlled and DBE) period may be provided. 
Shift from normal or unknown ECG at baseline to abnormal post-baseline ECG, will be 
summarized in the active treatment (placebo-controlled and DBE) group. The number of 
subjects with potential QTcF interval outlier post-baseline will also be summarized in the 
active treatment (placebo-controlled and DBE) period. The criteria of defining QTcF interval 
outliers is specified in the placebo-controlled SAP. For early start subjects, the placebo-
controlled baseline will be used. For delayed start subjects, the DBE baseline will be used.  
A listing of subjects with abnormal ECG status post-baseline in the active treatment (placebo-
controlled and DBE) period will be provided. All data in the placebo-controlled and DBE 
period will be listed. 
 
4.5.6 Physical and Neurological Examination 
Abnormal findings during physical and neurological examinations are captured as adverse 
events and will be reflected in the summary of AEs. 
  
4.5.7 C-SSRS Data 
The Columbia Suicide Severity Rating Scale (C-SSRS) is an assessment that evaluates 
following the increasing severity order: (1) Wish to be dead, (2) Non-specific active suicidal 
thoughts, (3) Active suicidal ideation with any methods (not plan) without intent to act, (4) 
Active suicidal ideation with some intent to act, without specific plan, (5) Active suicidal 
ideation with specific plan and intent, and 


 
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following the increasing severity order: (6) Preparatory acts or behavior, (7) Aborted attempt, 
(8) Interrupted attempt, (9) Actual attempt, (10) Suicidal behavior, (11) Suicide (only at post-
baseline visits).  An
-
suicidal self-injurious behavior is also collected.  
The summary table for C-SSRS will be conducted for the active treatment (placebo-
controlled and DBE) period. Number of subjects who answe
questions post-
subjects who have engaged in non-suicidal self-injurious behavior will be presented.  
A listing of subjects with any suicidal ideation or behavior at baseline or post-baseline will be 
provided for the placebo-controlled and DBE period. 
 
4.5.8 MRI Safety Data 
Brain MRI safety finding are assessed at Screening visit, Week 24, 52, 96, 148 and 4 weeks 
after last dose/ET visits.   
The MRI safety result is classified as normal or abnormal. Shift table from normal or 
unknown MRI at baseline to abnormal post-baseline MRI will be summarized in the active 
treatment (placebo-controlled and DBE) period. The worst post-baseline record of each 
subject is selected. A listing of details for abnormal brain MRI findings will be presented for 
placebo-controlled and DBE period. 
 
4.6 
Pharmacodynamic -Imaging analysis 
4.6.1 General Consideration 
There are three types of imaging outcomes in the study: DaT/SPECT imaging, Neuromelanin 
MRI imaging and Structural MRI imaging. Please refer to the placebo-controlled SAP for 
details. 
The analysis population for pharmacodynamic analysis is defined in Section 3.1.1. The 
analysis period is placebo-controlled and DBE period. That is, data from both the placebo-
controlled and DBE periods will be included in the analysis. All pharmacodynamic analyses 
will be presented by DBE treatment group.  
The following three comparisons will be evaluated for the long-term pharmacodynamic 
analyses of BIIB054: 
 The early start 250 mg compared with the delayed start 250 mg; 
 The early start 1250 mg compared with the delayed start 1250 mg. 
 The early start 3500 mg compared with the delayed start 3500 mg. 
The following comparisons may also be evaluated: 
 The early start 250 mg compared with the pooled delayed start group; 


 
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 The early start 1250 mg compared with the pooled delayed start group; 
 The early start 3500 mg compared with the pooled delayed start group 
The pooled delayed start group contains all the subjects who were randomized to placebo 
treatment in the placebo-controlled period including those who did and who did not enter to 
the DBE period.  There will be no multiple comparison adjustments.  Data after subjects start 
PD symptomatic treatment will be included in the analyses.  
 
Visit Windows for by visit analyses 
For the by visit summaries and MMRM models, the analysis visit should be defined using 
visit windows (see Table 3 in the Appendix).  If there is more than 1 value in the same 
analysis visit window (>1 value for the same analysis visit) for a certain parameter for a 
subject, then the closest record to the target visit day will be used for the by visit analysis.  If 
they are with the same distance from the target visit day, then the record with the later time 
will be used for the by visit analysis.   
 
4.6.2 By Visit Summary and MMRM Model  
A prespecified set of imaging measures as well as the change from baseline will be 
summarized by DBE treatment groups by visit for all the visits in the placebo-controlled and 
DBE period.  
Change or percent change from baseline in the imaging measures will be analyzed using an 
MMRM model for all the visits in the placebo-controlled and DBE period. For details of the 
model to be used please see the 1 year SAP. Adjusted means for each treatment group, 
pairwise adjusted differences for the comparisons, 95% confidence intervals for the 
differences will be presented at each visit, and p-values will be presented for the key visits of 
week 24, 52, 96 and 148. If the distribution of the outcome is highly skewed, p-value will be 
generated from the MMRM model based on the rank data. Missing data are assumed to be 
missing at random behind the MMRM model. 
Per design, a subset of subjects will enter year 3 and 4 for a limited time. There will be some 
visits with too few data in year 3 and 4. If this is the case, the visits with too few data will be 
excluded from the MMRM analyses, Otherwise, the MMRM model will not converge. In 
addition, since most patients will start PD medication by year 1, most data in year 2-4 will be 
after PD medication. Therefore, data after subject start PD medication will be included in the 
MMRM analyses. Otherwise, the MMRM model will not converge. 
Data at the common visits of cohort A and cohort B will be included in the by visit summary 
and MMRM model. Data at all visits will be listed. 
 
4.6.3 Additional analyses of placebo-controlled period due to COVID-19 
Due to COVID-19 public health emergency, considerations were made to allow week 52 
assessments to be delayed up to 4 weeks. If this occurs, some of the data may not be included 
in the all patient week 52 analyses, as they may miss the timeline of the corresponding 


 
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interim database lock. However, these data are still considered in the placebo-controlled 
period because they are before the first dose of DBE period. Depending how much data are 
missing in the all patient week 52 analyses database lock, the MMRM analyses in the 
placebo-controlled period may be repeated by including all the available data in the placebo-
controlled period. 
 
 
 
 
 
 
 
 
 
 
 
 
4.8 
Pharmacokinetics Analysis 
Per protocol, sparse PK data are collected in the DBE period. Therefore, the PK analyses will 
be focused on summarizing the PK concentration over time. The PK analysis population as 
defined in Section 3.1.1 and data from both placebo-controlled and DBE periods will be 
included. All the PK analyses will be presented by DBE treatment group. In addition, an 
exposure-response (ER) analysis from both placebo-controlled and DBE periods will be 
conducted, to detect any ER relationship trend and potential covariate using any primary or 
secondary endpoint and BIIB054 exposure metrics as deemed appropriate.  Other tables and 
figures based on the population PK and ER analyses will be generated by Clinical 
Pharmacology and Pharmacometrics (CPP) team and will be included in a separate report 
from CPP. 
 
 
  
 
4.9 
Immunogenicity Analysis 
4.9.1 Analysis population 
All immunogenicity data will be analyzed based on the immunogenicity population, which is 
same as the safety population as defined in Section 3.1.1. 
 


 
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4.9.2 Method of analysis 
A summary table of subjects with treatment-emergent positive anti-BIIB054 antibody 
responses in the placebo-controlled and DBE active treatment period will be displayed by 
DBE treatment group and by visit. Please refer to the placebo-controlled SAP for the 
definition of treatment-emergent positive anti-BIIB054 antibody responses. In this summary, 
DBE baseline will be used for delayed start subjects who are assigned to receiving BIIB054 
in the DBE period. A listing of immunogenicity data in the placebo-controlled and DBE 
period for subjects with anti-BIIB054 antibody positive responses will be provided. 
 
Visit Windows for by visit analyses 
For immunogenicity by visit summaries, the analysis visit should be defined using visit 
windows (see Table 12 in the Appendix). If there is more than 1 value in the same analysis 
visit window for a subject, then the closest record to the target 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 subject, 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 subject, then the record with the later time will be used for the by visit 
analysis. 
 
4.10 Interim Analyses 
Safety and PK data only will be reviewed by the IDMC after subjects in Cohort A have 
completed Week 12 Visit assessments, and before dosing any subjects in Cohort B.  
After subjects in Cohort A complete the Week 24 Visit, 
, all available serum PK, 
-syn levels and complex formation data, if available) 
from Cohort A will be analyzed by a statistical/PK team independent of the study.  The 
grouped level summary statistics will be reviewed only by a limited number of individuals at 
Biogen who are not involved in the management of the subjects or subject-level data for the 
study.  No changes to the study design are expected based on this review. 
For the purpose of planning for future studies, an administrative interim analysis may be 
performed when approximately 60% of the subjects have completed the Week 52 Visit. A 
small unblinded team from Biogen, separate from the study management team, will have 
access to the unblinded interim analysis results. As of the finalization of protocol Version 8 
and all subjects have completed Week 52 visits, this analyses was not conducted. 
A full analysis of the 1-year data will be performed after all subjects have completed the 
Week 52 Visit.  A small unblinded team from Biogen, separate from the study management 
team, will have access to the unblinded 1-year analysis results. 
An interim analysis when all subjects have completed the Week 72 Visit is planned to be 
conducted.  A small unblinded team from Biogen, separate from the study management team, 
will have access to the unblinded interim analysis results. All efficacy endpoints 
 
 will be analyzed at the Week 72 analyses.  Selected key safety data (e.g. 
summary of AE and SAE, summary of MRI safety findings and incidence of anti-drug 
antibodies) will be summarized, as this is only a snapshort of the safety profile at the time of 


 
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the Week 72 interim analysis, and the comprehensive safety profile will be presented at the 
End of Study   
 
A multiple comparison adjustment method will be applied to control the overall type I error 
at 0.05 in the study, due to the primary endpoint of change from baseline in MDS-UPDRS 
total score being analyzed at Week 52 and Week 72, and superiority against placebo is 
considered reached in the study if statistically significant result is achieved at either timepoint 
at the respective adjusted alpha-level.    
A graphical procedure will be used to control the overall type I error at 0.05 level due to 
multiple-testing.  An alpha of 0.04 will be allocated to the Week 52 primary endpoint 
analyses and an alpha of 0.01 will be allocated to the Week 72 primary endpoint analysis.  
 If the Week 52 analysis is statistically significant at the 0.04 level (i.e. p-
0.04), the alpha of 0.04 will be transferred (recycled) to the Week 72 analysis, and 
Week 72 will have alpha=0.05.  
 If the Week 52 analysis is not statistically significant at the 0.04 level, alpha of 0.01 
will be used for the Week 72 analysis.  Statistically significance is considered 
achieved if the p-
 
 If statistical significance is achieved at the Week 72, in either scenarios above, then 
the alpha of 0.01 will be transferred (recycled) back to Week 52, and the Week 52 
primary analysis will be re-evaluated for statistically signifance at the 0.05 level.  This 
will only change the conclusion of the Week 52 results if the initial p-value is greater 
 
 
 No additional multiplicity adjustments will be made for secondary or exploratory endpoint 
analyses.  
A blinded sample size re-estimation may be conducted when approximately 10% of subjects 
have completed the Week 52 Visit or approximately 1 month before enrollment is projected 
to be completed, whichever is earlier.  The study sample size may be increased based on this 
blinded data review.  There may be small adjustments to the percentage depending on actual 
enrollment rate.  As of the finalization of protocol Version 8 and all subjects have completed 
Week 52 visits, this analyses was not conducted.  
 
5 Assessment of the impact of Covid-19 on statistical analyses 
As this study is on-going when the Covid-19 public health emergency (PHE) occurred, 
subject visits and data collection were impacted, including missing visits, delayed visits, 
missed assessments and/or some visits were performed via remote assessments, e.g. 
telephone/video visits.  Every effort was made to document these impacted study activities 
systematically on the eCRF and other electronic source data.   
 


 
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A complete listing of all visits impacted (e.g. missed visits, delayed or assessment done via 
remote visits) will be listed in the clinical study report. Missing data due to Covid-19 is 
considered as missing at random. 
   
Impact of COVID-19 on the clinical outcome analyses 
 
In addition, subgroup analyses of the selected key clinical outcome MDS-UPDRS will be 
performed on a subset of subjects who did not have >=3 consecutive missing doses 
throughout the study to further evaluate the impact of Covid-19 on the study. The same 
MMRM model for the primary analyses will be used for the subgroup analyses.  
 
In addition, due to Covid-19, some visits were delayed.  A few subjects will have their Week 
52 imaging done at later visits up to Week 72 and these will still be considered as Week 52 
visit data in the analyses for Week 52.  These data were not included in the Week 52 database 
lock in time, but will be included in the Week 72 database, and the related Week 52 imaging 
analyses will be updated at the time of the Week 72 interim analyses.  
 
Impact of COVID-19 on the safety analyses 
 
During the COVID-19 pandemic period, subjects may be prone to a high risk of getting 
depressed or anxiety. As a result, the analyses below will be performed to evaluate the impact 
of the COVID-19 pandemic on the safety analyses. 
 
1. An overall summary of AE in DBE period based on data after March 7th, 2020, the 
start date when subjects in SPARK get impacted by COVID-19  
2. An overall summary of AE in the active treatment (placebo-controlled and DBE) 
period based on data after March 7th, 2020, the start date when subjects in SPARK get 
impacted by COVID-19 
3. AEs by system organ class and preferred term sorted by decreasing frequency in DBE 
period based on data after March 7th, 2020, the start date when subjects in SPARK get 
impacted by COVID-19 
4. AEs by system organ class and preferred term sorted by decreasing frequency in 
active treatment (placebo-controlled and DBE) period based on data after March 7th, 
2020, the start date when subjects in SPARK get impacted by COVID-19 
5. C-SSRS data summary based on data after March 7th, 2020, the start date when 
subjects in SPARK get impacted by COVID-19  
 
















 
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VERSION HISTORY 
 
SAP Version 
Date 
Primary Reasons for 
Amendment 
1.0 
25-SEP-2020 
First version of the SAP 
2.0 
23-JUNE-2021 
Update links within sample 
size section 
Update SMT job titles 
 
 


 
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Table of Contents 
1 
DESCRIPTION OF OVERALL STUDY  (INCLUDING DOSE-BLINDED EXTENSION (DBE)) 
OBJECTIVES AND ENDPOINTS ..................................................................................................................... 7 
2 
STUDY DESIGN ....................................................................................................................................... 12 
2.1 
STUDY OVERVIEW .................................................................................................................................. 12 
2.1.1 
Year 1 (Placebo-Controlled Portion of the Study) ........................................................................ 12 
2.1.2 
Years 2-4 (Active-Treatment Dose-Blinded Portion of the Study) ................................................ 12 
2.2 
STUDY SCHEMATIC ................................................................................................................................. 13 
2.3 
SCHEDULE OF EVENTS ............................................................................................................................ 15 
3 
SAMPLE SIZE JUSTIFICATION .......................................................................................................... 15 
4 
STATISTICAL ANALYSIS METHODS ............................................................................................... 18 
4.1 
GENERAL CONSIDERATIONS ................................................................................................................... 18 
4.1.1 
Analysis Population ...................................................................................................................... 20 
4.1.2 
Analyses period ............................................................................................................................. 20 
4.2 
BACKGROUND CHARACTERISTICS .......................................................................................................... 21 
4.2.1 
Accounting of Subject ................................................................................................................... 21 
4.2.2 
Demographics and Baseline Characteristics ................................................................................ 22 
4.2.3 
Concomitant Medications and Non-Drug Therapies .................................................................... 22 
4.2.4 
Protocol Deviations ...................................................................................................................... 22 
4.2.5 
Study Drug Exposure and Study Drug Compliance ...................................................................... 23 
4.3 
EFFICACY ANALYSES .............................................................................................................................. 23 
4.3.1 
General Consideration ................................................................................................................. 23 
4.3.2 
Primary efficacy endpoint analysis ............................................................................................... 24 
4.3.3 
Secondary efficacy endpoints and additional endpoints analysis ................................................. 26 
 
MDS-UPDRS based endpoints ................................................................................................................ 26 
 
Other clinical efficacy measures .............................................................................................................. 26 
4.4 
PHARMACODYNAMICS ANALYSES ........................................................................................................... 27 
4.5 
SAFETY ANALYSES ................................................................................................................................. 28 
4.5.1 
General Considerations ................................................................................................................ 28 
4.5.2 
Clinical Adverse Events ................................................................................................................ 29 
 
Summary and incidence analysis.............................................................................................................. 29 
 
Incidence and incidence rate analysis for active treatment (placebo-controlled and DBE) period ........... 30 
4.5.3 
Clinical Laboratory Data ............................................................................................................. 32 
 
Quantitative analyses ............................................................................................................................... 32 
 
Qualitative analyses ................................................................................................................................. 33 
4.5.4 
Vital Sign Data ............................................................................................................................. 34 
4.5.5 
ECG Data ..................................................................................................................................... 35 
4.5.6 
Physical and Neurological Examination ...................................................................................... 35 
4.5.7 
C-SSRS Data ................................................................................................................................. 35 
4.5.8 
MRI Safety Data ........................................................................................................................... 36 
4.6 
PHARMACODYNAMIC -IMAGING ANALYSIS ............................................................................................. 36 
4.6.1 
General Consideration ................................................................................................................. 36 
4.6.2 
By Visit Summary and MMRM Model .......................................................................................... 37 
4.6.3 
Additional analyses of placebo-controlled period due to COVID-19 ........................................... 37 
 
 38 
 
.. 38 
 
 38 
4.8 
PHARMACOKINETICS ANALYSIS .............................................................................................................. 38 
4.9 
IMMUNOGENICITY ANALYSIS .................................................................................................................. 38 
4.9.1 
Analysis population....................................................................................................................... 38 
4.9.2 
Method of analysis ........................................................................................................................ 39 
4.10 
INTERIM ANALYSES ........................................................................................................................... 39 
5 
ASSESSMENT OF THE IMPACT OF COVID-19 ON STATISTICAL ANALYSES ...................... 40 
















 
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2 STUDY DESIGN 
2.1 
Study Overview 
This Phase 2a, randomized, double-blind, parallel-group, placebo-controlled study (Year 1) 
with an active-treatment dose-blinded period (Year 2 through 4) will examine the efficacy, 
safety, PK, and pharmacodynamics of BIIB054, administered every 4 weeks via IV infusion 
to adult subjects with PD. Approximately 311 subjects will be enrolled at about 85 sites 
globally. 
2.1.1 Year 1 (Placebo-Controlled Portion of the Study) 
Prior to the first dose in Year 1, all subjects in the study will be randomized into 4 arms, to 
receive 13 doses of BIIB054 (250, 1250, or 3500 mg) or placebo. 
Subjects will be enrolled into 2 cohorts. Cohort A will be randomized first, in a 1:1:1:1 ratio 
into each of the 4 treatment arm and will include approximately 24 subjects. Randomization 
and dosing for Cohort B (approximately 287 planned subjects) will start after all subjects in 
Cohort A complete Week 12 assessments, and all available safety and PK data are reviewed 
by the IDMC.  Randomization of subjects in Cohort B will be stratified by baseline (Day 1) 
MDS-
and subjects will be randomized at Day 1 into 1 of 4 parallel dosing arms in each stratum. 
After all subjects in Cohort A complete Week 12 assessments (28 days after their third 
infusion), and before dosing any subjects in Cohort B, all available safety and PK data will be 
reviewed by the IDMC. No subjects in Cohort B may be dosed until the IDMC review is 
complete. The study schematic is presented in Figure 1. After IDMC review is complete, 
subjects in Cohort B will be randomized, and dosing may begin. During the review period, 
subjects in Cohort A will continue to be dosed on a schedule of once every 4 weeks. 
The first IDMC meeting will occur after the last subject in Cohort A completes Week 12 
assessments, or approximately 6 months after the first subject has been enrolled in Cohort A, 
whichever comes first. Regular IDMC meetings will occur approximately every 3 months 
after the first meeting.  
 
 
 
The Week 48 infusion is the last infusion pf the placebo-controlled period, and Week 52 is 
the first dosing of the Dose-blinded portion of the study. 
Any changes will be documented in a protocol amendment. 
2.1.2 Years 2-4 (Active-Treatment Dose-Blinded Portion of the Study) 
Prior to Infusion 14 (the first dose of Year 2) at Week 52, subjects who received placebo in 
Year 1 will be randomized into 1 of the active-dosing arms for Year 2; these subjects will 
receive BIIB054 in Year 2. Subjects who received BIIB054 (250mg, 1250 mg or 3500 mg) in 
Year 1 of the study will continue with the same dose regimen in Year 2. Subjects receiving 
the 250-mg dose in Year 1  continued on their original dose assignement. 
 


 
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Subjects will receive 12 additional doses of BIIB054 (250, 1250, or 3500 mg) in Year 2 and 
up to 16 additional doses in Years 3 and 4. Up until the last subject in the study has had his or 
her last dose in Year 2 of the study (Week 96 Visit), eligible subjects will be able to continue 
treatment once every 4 weeks. 
 
Subjects who complete dosing through Week 96 and the Final Visit 12 weeks after the last 
visit will be considered Year 2 completers in the eCRF. 
 
See Figure 2 for a depiction of the duration of dosing in Years 3 and 4 for subjects continuing 
dosing past Week 96. 
 
Figure 4 in the protocol presents a flowchart for dosing and procedures from Week 96 
through end of study, including how to determine which subjects are eligible to continue 
dosing past Week 96. 
    
 
2.2 
Study Schematic 
 
 
 
 


 
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Figure 2: Overview of Study Dosing: 
 


 
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2.3 
Schedule of Events 
See Protocol Section 4.2. 
3 SAMPLE SIZE JUSTIFICATION 
The sample size calculation is based on changes in MDS-UPDRS Part I + II + III total score 
SD) at Week 52 
and Week 72 are assumed to be 8.0 (10.64) and 9.6 (13.7) respectively. Assuming a 
maximum of 55% reduction in the change from baseline in the active group with maximum 
response relative to placebo group, the mean (SD) for this active group will be 3.2 (10.64) 
and 3.84 (13.7) respectively at Week 52 and Week 72, and the responses for other active 
groups are assumed to be somewhere between 0 and the maximum response.  The primary 
analysis will be based on the MCP-MOD method to detect a dose-response trend while 
controlling for multiplicity.  Optimal contrasts will be constructed to detect potential dose-
response trend under common dose-response curves (e.g., Emax, exponential, logistic, linear in 
log dose, and quadratic model, which are illustrated with parameters shown in Figure 3.1 
which will be used for both Week 52 and Week 72).  The planned enrollment is 311 subjects 
total (24 subjects in Cohort A and 287 subjects in Cohort B, 3.1).  Actual enrollment is 357 
subjects.  In Cohort A, 29 subjects were randomized in a 1:1:1:1 ratio to each of the treatment 
groups, while in Cohort B 328 subjects were randomized in 2:1:2:2 ratio to the placebo, 250 
mg, 1250 mg, and 3500 mg groups.  Based on the actual enrollment, the estimated number of 
subjects by cohort and treatment groups are given in Table 3.2 below.  After accounting for 
dropout rate of 10% and 15% at Week 52 and Week 72, respectively, the estimated sample 
sizes are given in Table 3.3 and Table 3.4.  With the updated sample size, the study will 
provide an average power of approximately 80% to detect the dose-response trend over 1 
year of treatment, based on a 2-sided type I error of 0.05 and approximately 73% of power at 
the Week 72 analyses, based on a 2-sided type I error of 0.05.  Overall, the sample size in the 
study will provide approximately 89% power, taking into consideration success at either 
Week 52 or Week 72.      
With an estimated sample size of 100 subjects dosed per arm in the 1250 mg and 3500 mg 
arms, the study has 80% probability of detecting AEs with a rate of 1.6% or greater in these 
2 arms, and a 90% probability of detecting AEs occurring with a rate of 2.3% or greater.   


 
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Figure 3.1: 
Candidate Models for Dose-Response 
 
 
 
 
 




 
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4 STATISTICAL ANALYSIS METHODS 
4.1 
General Considerations 
This statistical analysis plan (SAP) covers the analyses of the dose-blinded extension (i.e., 
long term extension) period (Years 2-4) and the analyses across both the placebo-controlled 
period and the DBE period (analyses integrating the data for Years 1-4).   
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. Pharmacokinetics (PK) 
summaries will also include Geometric mean and geometric CV. 
Statistical testing will be performed to assess efficacy endpoints by conducting pairwise 
comparison between each BIIB054 group and the delayed-start group (i.e. subjects who were 
randomized to placebo in Year-1),. Dose-response relationship may also be tested.  Unless 
stated otherwise, all the statistical tests will be 2-sided with a statistical significance level of 
0.05 . 
The statistical software, SAS® will be used for all summaries and analyses.  
 
 
Analysis displays 
Unless otherwise specified, the analysis of the DBE period and the analyses across both the 
placebo-controlled period and the DBE period will be displayed by DBE treatment groups as 
shown below, separate for early and delayed start treatment group) including tables, listings 
and figures, unless otherwise specified. 
Unless otherwise specified, analyses for efficacy data (e.g., pharmacodynamics of imaging, 
, clinical efficacy, 
) will be 
displayed by the following treatment groups according to randomization assignment at the 
start of the placebo-controlled period: 
 
BIIB054 early start: subjects who are assigned to (1) receive BIIB054 in the 
placebo-controlled period and (2) continue receiving BIIB054 in the DBE period 
 
BIIB054 late start: subjects who are assigned to (1) receive placebo in the 
placebo-controlled period and (2) switch to BIIB054 in the DBE period  
Unless otherwise specified, analyses for safety, PK, and ADA data will be displayed by the 
following treatment groups according to dose received: 
 
BIIB054 early start: subjects who receive BIIB054 in the placebo-controlled 
period (regardless of randomization assignment)  


 
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BIIB054 late start: subjects who receive only placebo in the placebo-controlled 
period (regardless of randomization assignment) and switch to receive BIIB054 in 
the DBE period  
 
BIIB054 total: subjects in either BIIB054 early or late start treatment groups 
. 
If all subjects received study treatment according to their randomization assignments during 
the placebo-controlled period (i.e. no subject assigned to placebo received BIIB054, and no 
subject assigned to BIIB054 received only placebo), then the assignment of subjects to 
treatment groups in efficacy related tables will be the same as those in safety related tables.  
For efficacy, pharmacodynamic of imaging, 
, clinical, 
 
 and PK and ADA outcomes. Each BIIB054 early start dose group may be 
compared with the corresponding delay-start dose group, as well as the pooled delay-start 
group. Outputs will be presented in the following two ways:  
 
BIIB054 delayed start 
(N = xx) 
 
 
BIIB054 early start 
(N = xx) 
 
Placebo to 
250 mg 
(N = xx) 
Placebo to 
1250mg 
(N = xx) 
Placebo to 
3500 mg 
(N = xx) 
 
 
250 mg 
(N = xx) 
1250 mg 
(N = xx) 
3500 mg 
(N = xx) 
 
 
 
 
BIIB054 delayed start 
(N = xx) 
 
 
BIIB054 early start 
(N = xx) 
 
Placebo to BIIB054 
(N = xx) 
 
250 mg 
(N = xx) 
1250 mg 
(N = xx) 
3500 mg 
(N = xx) 
 
For baseline and safety related outputs: 
BIIB054 delayed start 
(N = xx) 
BIIB054 early start 
(N = xx) 
BIIB054 
Total 
(N=xx) 
Placebo 
to 250 
mg 
(N = xx)
Placebo 
to 
1250mg 
(N = xx)
Placebo 
to 3500 
mg 
(N = xx)
Total 
(N=xx) 
250 mg 
(N = xx) 
1250 mg 
(N = xx) 
3500 mg 
(N = xx) 
Total 
(N=xx) 
 
For all listings the start and stop day in the listing will be computed based on the placebo-
controlled baseline. 
Baseline for all the analyses across the SAP  
Unless otherwise specified, baseline refers to the baseline value for the placebo-controlled 
period and is defined as the most recent non-missing measurement collected prior to the first 


 
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dose in Year 1. DBE baseline is defined as the last non-missing measurement collected prior 
to the first dose of the DBE period in Year 2.  
For analyses on the DBE period or on the active treatment (placebo-controlled and DBE) 
period, DBE baseline will be used for delayed start subjects who are assigned to receiving 
BIIB054 in the DBE period. Change from baseline will be defined as post-baseline value 
minus baseline value.  
 
 
4.1.1 Analysis Population 
 Intent-to-treat (ITT) population:  
The Intent-to-treat population is defined as all randomized subjects who received at least 
one dose of study treatment (BIIB054 or placebo).  
 
 Safety population:  
The safety population is defined as all subjects who received at least one dose of study 
treatment (BIIB054 or placebo).  
 
 Pharmacodynamic analysis population:  
The pharmacodynamic population is defined as a subset of the ITT population with at 
least 1 post-baseline pharmacodynamic measurement.   
 
 PK analysis population:  
The PK population is defined as a subset of the ITT population who have at least 1 
measurable BIIB054 concentration in serum 
   
 
 
 
 
 
 Immunogenicity population:  
Immunogenicity analysis will be performed for all subjects in the safety population. 
 
4.1.2 Analyses period 
Depending on the purpose, different analyses will be conducted on the following study 
periods: 
1. DBE period. Only data in the DBE period will be included in these analyses. For 
example, incidence table of adverse events in the DBE period.  
2. Placebo-controlled and DBE period. All the data in the placebo-controlled and DBE 
periods will be included in these analyses. For example, mean plot of actual 
laboratory values in the placebo-controlled and DBE period. 


 
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3. Active treatment (placebo-controlled and DBE) period (i.e., Total BIIB054 
experience) period. Active treatment period is defined as the study period(s) that a 
subject is assigned to BIIB054. For early start subjects  subjects who are assigned to 
BIIB054 in both placebo-controlled and DBE period, all the data (placebo-controlled 
and DBE periods) will be included in the analyses. For delayed start subjects  
subjects who are assigned to placebo in Year 1 and BIIB054 in the DBE period, only 
data in the DBE period will be included. For example, incidence table of adverse 
events in the active treatment (placebo-controlled and DBE) period will not include 
the AEs started on placebo treatment in year 1.     
Subjects to be included in a certain output is determined by both the analysis population and 
the analysis period. For example, the incidence table of adverse events in the DBE period will 
include subjects in the safety population for the DBE period, i.e., all randomized subjects 
who received at least one dose of study treatment in the DBE period. The incidence table of 
adverse events in the active treatment (placebo-controlled and DBE) period will include 
subjects in the safety population for the active treatment period, i.e., all randomized subjects 
who received at least one dose of study treatment in the active treatment period. In this SAP 
we do not separately define the analysis population in each analysis period. 
 
4.2 
Background Characteristics 
The summaries in this section will be based on the ITT population. Analysis period will be 
specified for each table or figure. Unless otherwise specified, summary tables will be 
presented by DBE treatment group. Listings will include all data in the placebo-controlled 
and DBE periods (all data in the study), with an indicator of the study period in a column 
(pre-dosing, placebo-controlled, or DBE) for each record to indicate when the event occurred. 
Listings will be presented by DBE treatment group. 
 
4.2.1 Accounting of Subject 
Disposition in the DBE period will be summarized for subjects enrolled in DBE. The 
summary data will include number (%) of subjects dosed in the DBE period, number (%) of 
subjects who completed the first year of treatment/study of DBE (i.e., year 2 of the study), 
number (%) of subject who discontinued treatment and/or withdrew from study in the first 
year of DBE (i.e., year 2 of the study), the reason for treatment discontinuation and/or study 
withdrawal for in the first year of DBE (i.e., year 2 of the study), number (%) of subjects who 
completed the treatment/study in DBE (i.e., year 2-4 of the study), and number (%) of 
subjects who discontinued treatment and/or withdrew from study in DBE (i.e., year 2-4 of the 
study), the reason for treatment discontinuation and/or study withdrawal in DBE (i.e., year 2-
4 of the study).  
For subject who discontinued treatment and/or withdrew from the study in the first year of 
DBE (i.e., year 2 of the study), days on treatment and days on study will be summarized.  
For subjects who discontinued treatment and/or withdrew from study in DBE (i.e., year 2-4 
of the study), days on treatment and days on study will be summarized and listed. In the 
listing, the subjects who discontinued treatment and/or withdrew from study in the first year 


 
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of DBE will be flagged. Time to treatment discontinuation and time to study withdrawal in 
the DBE period may be displayed by Kaplan-Meier plot (presented by DBE treatment group). 
Disposition in the placebo-controlled and DBE period will be also summarized in the same 
fashion. Number (%) of subjects dosed in the placebo-controlled period, number (%) subject 
who completed the placebo-controlled period, number (%) of subjects who entered the DBE 
period, number (%) of subjects who completed the first year of DBE period, number (%) of 
subjects who completed the whole study will be displayed. Number of subjects who 
discontinued treatment or study and reason of discontinuation will be summarized for each 
period and for the whole study. 
 
4.2.2 Demographics and Baseline Characteristics 
Demographics, baseline characteristics, medical history and PD treatment history will be 
summarized for subjects enrolled in the DBE period and subjects not enrolled in the DBE 
period, respectively. Please refer to the SAP of placebo-controlled period for more details.  
 
4.2.3 Concomitant Medications and Non-Drug Therapies 
All medications will be coded using the World Health Organization Drug (WHODrug March 
2020 B3 or higher) dictionary. All non-drug therapies (defined as diagnostic procedures or 
medical treatment procedures) will be coded using the MedDRA dictionary version 23.0 or 
higher.   
The number (%) of subjects taking concomitant general medication (excluding PD 
medications) and non-drug therapies in the DBE period will be summarized by DBE 
treatment group for subjects enrolled in the DBE period. In addition, number of subjects in 
the ITT population that have taken any concomitant medications in the active treatment 
(placebo-controlled and DBE) period will be summarized. Concomitant non-PD medications 
and non-drug therapies will be listed in the placebo-controlled and DBE treatment period.  
Start and stop day in the listing will be computed based on the placebo-controlled baseline. 
For subjects enrolled in the DBE period, the number (%) of subjects taking any concomitant 
PD symptomatic medications, number of subjects taking Dopamine, MAO-B inhibitor, 
Dopamine Agonist at the baseline of the placebo-controlled period and at the baseline of 
DBE period will be summarized respectively by DBE treatment group. The placebo-
controlled and DBE period data will be summarized in the same fashion. Concomitant PD 
symptomatic medication will be listed for all subjects in the placebo-controlled and DBE 
periods. Start and stop day in the listing will be computed based on the placebo-controlled 
baseline. Please refer to the placebo-controlled SAP for definitions of concomitant therapies 
and PD symptomatic medication use at baseline. 
 
4.2.4 Protocol Deviations 
Protocol deviations identified during site monitoring will be captured in a Protocol Deviation 
log and categorized as major or minor deviations. The major protocol deviations occurred in 


 
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the DBE period will be summarized for subjects enrolled in DBE. The major protocol 
deviations for all ITT subjects in the combined placebo-controlled and DBE periods will also 
be summarized.  Major and minor protocol deviations for all ITT subjects will be listed, 
respectively, across the placebo-controlled period and the DBE period. All summaries for 
protocol deviations will be presented by DBE treatment group.  A separate Covid-19 related 
protocol deviation category will be shown in the protocol deviation listings.  
 
4.2.5 Study Drug Exposure and Study Drug Compliance 
A summary table of study drug exposure and compliance in the DBE period will be provided. 
Number of infusions of BIIB054 received will be summarized as a continuous variable as 
well as a categorical variable (categories as 1-5, 6-10 and 11-15, 16-20, 20-25, >=26) as well 
as a continuous variable. Number of weeks on study treatment, calculated as (date of last 
dose  date of first dose +1)/7, will be summarized as a categorical variable (categories as 
<0.5 years, >=0.5 years, >=1 year, >=2 years, >=3 years) as well as a continuous variable. 
Percentage of study treatment taken up to the last dose, calculated as (the actual number of 
infusions / the number of infusions a subject is expected to take until the date of last 
infusion)*100, will be summarized as a continuous variable. This table will be presented by 
DBE treatment group. A similar table will also be provided on the active treatment (placebo-
controlled and DBE) period in order to summarize the exposure data while subjects are on 
BIIB054.  
A listing of study drug administration records, including infusion start date and time, infusion 
stop date and time, total volume prepared, total volume administered, location of infusion, 
initial infusion rate, dose interruption or rate change or not, time of interruption or rate 
change, infusion rate after interruption or rate change, reason for interruption or rate change 
will be provided for the placebo-controlled and DBE period. A listing of subjects who 
received the wrong treatment compared to what they were randomized to will be provided for 
the placebo-controlled and DBE period. 
4.3 
Efficacy analyses 
4.3.1 General Consideration 
The analysis population for the efficacy analyses are defined in Section 4.2.1. The analysis 
period includes data from both placebo-controlled and DBE period combined.  That is, data 
from both the placebo-controlled and DBE periods will be included in the analysis.  
The following three comparisons will be evaluated for the long-term efficacy analyses of 
BIIB054: 
 The early start 250 mg compared with the pooled delayed start group; 
 The early start 1250 mg compared with the pooled delayed start group; 
 The early start 3500 mg compared with the pooled delayed start group 
The following comparisons may also be evaluated: 
 The early start 250 mg compared with the delayed start 250 mg; 


 
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 The early start 1250 mg compared with the delayed start 1250 mg. 
 The early start 3500 mg compared with the delayed start 3500 mg. 
The pooled delayed start group contains all the subjects who were randomized to placebo 
treatment in the placebo-controlled period including those who did and who did not enter into 
the DBE period.  There will be no multiple comparison adjustments.  Data after subjects start 
PD symptomatic treatment will be included in the analyses, since the majority of subjects are 
expected to take PD medication after Week 52. 
Subjects who were randomized to placebo group but accidentally received one or more doses 
of the active treatment during the placebo-controlled period will be classified as delayed start  
for all the efficacy, pharmacodynamic, and 
 analyses. 
 
Visit Windows for by visit analyses 
For the by visit summaries and MMRM models, the analysis visit should be defined using 
visit windows (see Tables 6-16 in the Appendix).  If there is more than 1 value in the same 
analysis visit window (>1 value for the same analysis visit) for a certain parameter for a 
subject, then the closest record to the target visit day will be used for the by visit analysis.  If 
they are with the same distance from the target visit day, then the record with the later time 
will be used for the by visit analysis.   
 
Handling of missing items for scales 
Please refer to the placebo-controlled SAP for the imputation method.The same method will 
be applied to efficacy endpoints collected in the DBE period. 
 
4.3.2 Primary efficacy endpoint analysis  
The estimand of the primary analysis for MDS-UPDRS Part I+II+III total score at Week 72 is 
the mean difference of the change from baseline at Week 72 between treatment groups in the 
ITT population regardless of whether start of PD medication had occurred or not. 
Specifically, the estimand takes the following into consideration: 
A. Population: ITT population as defined in Section 4.1.1; 
B. Variable: change from baseline to Week 72 in the MDS-UPDRS Part I+II+III total 
score; 
C. Intercurrent events: regardless of whether start of PD medication had occurred or not; 
D. Population-level summary: difference in variable means between each early start 
group and delayed start group 
Change from baseline in the MDS-UPDRS Part I+II+III total score at Week 72 will be 
analyzed using an MMRM model for all the visits in the placebo-controlled and DBE period.  
Data after subjects start PD medication will be included in the primary analyses.   
For details on the model to be used please refer back to the Year 1 SAP, for the analyses of 
MDS-UPDRS including data after PD medication. Adjusted means for each treatment group, 


 
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pairwise adjusted differences for the comparisons, 95% confidence intervals for the 
differences will be presented at each visit, and p-values will be presented for the key visits of 
week 24, 52, and 72.  Dose-response testing will be done using the adjusted mean with the 
pre-specified MCP-MOD procedure with pre-specified candidate models (refer to Year 1 
SAP Sample Size Consideration section).   If the distribution of the outcome is highly 
skewed, p-value will be generated from the MMRM model based on the rank data. Missing 
data are assumed to be missing at random behind the MMRM model.   
 
A multiple comparison adjustment method (graphical procedure) will be applied to control 
the overall type I error at 0.05 in the study, due to the primary endpoint of MDS-UPDRS total 
score being analyzed at Week 52 and Week 72, and superiority against placebo is considered 
reached in study if statistically significant result is achieved at either timepoint. Please refer 
versus delayed-start group(s) will also be conducted, however, no additional multiplicity 
adjustment will be made, and nominal p-values will be reported.   The primary comparison is 
between each of the early-start BIIB054 dose group, with the pooled delayed-start BIIB054 
group.    
The following three comparisons will be evaluated for the long-term efficacy analyses of 
BIIB054: 
 The early start 250 mg compared with the pooled delayed start group; 
 The early start 1250 mg compared with the pooled delayed start group; 
 The early start 3500 mg compared with the pooled delayed start group 
The following comparisons may also be evaluated: 
 The early start 250 mg compared with the delayed start 250 mg; 
 The early start 1250 mg compared with the delayed start 1250 mg. 
 The early start 3500 mg compared with the delayed start 3500 mg. 
  
Per design, a subset of subjects will enter year 3 and 4 for a limited time. There will be some 
visits with too few data in year 3 and 4. If this is the case, the visits with too few data will be 
excluded from the MMRM analyses, Otherwise, the MMRM model will not converge. In 
addition, since most patients will start PD medication by year 1, most data in year 2-4 will be 
after PD medication. Therefore, data after subject start PD medication will be included in the 
MMRM analyses. Otherwise, the MMRM model will not converge. 
Data at the common visits of cohort A and cohort B will be included in the by visit summary 
and MMRM model. Data at all visits will be listed. 
  


 
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4.3.3 Secondary efficacy endpoints and additional endpoints analysis  
Secondary endpoints, e.g., change from baseline in the MDS-UPDRS subscores (e.g., Part I, 
II, or III score, Part II and III total score) will be analyzed in a similar model, but no 
additional multiplicity adjustment will be made or for other secondary endpoints.    
 MDS-UPDRS based endpoints 
 
The analysis approaches and the MMRM model described will be performed for additional 
MDS-UPDRS based endpoints as listed below, except that, 1) the baseline MDS-UPDRS 
total score term in the model will be replaced by the corresponding baseline value of MDS-
UPDRS total or sub-part score being analyzed, 2) MCP-MOD dose-response may be 
performed, 3) no additional multiple comparison adjustment will be applied for secondary 
efficacy and exploratory efficacy endpoints 
 MDS-UPDRS Parts I, II, III (Secondary Efficacy Endpoints), 
 MDS-UPDRS Total Score (I+II+III) at the end of the study  
 MDS-UPDRS Parts II+III, Ib+II+III 
 MDS-UPDRS Part IV 
 Postural Instability -Gait Difficulty (PIGD) score (mean score of MDS-UPDRS items 
2.12+2.13+3.10+3.11+3.12), 
 Lower Extremity (LE) score (mean score of MDS-UPDRS items 
3.10+3.11+3.12+3.13+3.3d+3.3e+3.7a+3.7b +3.8a+3.8b+3.17c+3.17d+2.12+2.13), 
and Tremor score (mean score of MDS-UPDRS items 
2.10+3.15a+3.15b+3.16a+3.16b+3.17a+3.17b+3.17c+3.17d+3.17e+3.18).  
 Other clinical efficacy measures  
 
 
  
  
  
  
  
  
  
  
  
  
  


 
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4.4 
Pharmacodynamics analyses 
There are three types of imaging outcomes in the study: DaT/SPECT imaging, 
 
. Please refer to the placebo-controlled SAP for 
details. 
The analysis population for pharmacodynamic analyses is defined in Section 3.1.1. The 
analysis period is placebo-controlled and DBE period combined.  That is, data from both the 
placebo-controlled and DBE periods will be included in the analyses.  
Similar analyses will be conducted for the pharmacodynamic analyses as for the clinical 
outcome analysis.  The main comparison will be between the early and delayed-start groups. 
The pooled delayed start group contains all the subjects who were randomized to placebo 
treatment in the placebo-controlled period including those who did and who did not enter to 
the DBE period.  There will be no multiple comparison adjustments.  Data after subjects start 
PD symptomatic treatment will be included in the analyses.  
 
Visit Windows for by visit analyses 


 
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For the by visit summaries and MMRM models, the analysis visit should be defined using 
visit windows (see Table 3 in the Appendix).  If there is more than 1 value in the same 
analysis visit window (>1 value for the same analysis visit) for a certain parameter for a 
subject, then the closest record to the target visit day will be used for the by visit analysis.  If 
they are with the same distance from the target visit day, then the record with the later time 
will be used for the by visit analysis.   
A prespecified set of imaging measures as well as the change from baseline will be 
summarized by DBE treatment groups by visit for all the visits in the placebo-controlled and 
DBE period.  
MMRM model analyses: 
Similar MMRM model will be used to conduct the pharmacodynamic analyses as for the 
clinical outcome analysis, with the same terms included in the model.   
 
4.5 
Safety Analyses 
4.5.1 General Considerations 
Analysis population 
Safety population will be used for safety analyses of AEs, clinical laboratory data, vital sign 
data, ECG data, physical and neurological examination findings, Columbia Suicide Severity 
Rating Scale (C-SSRS) data and MRI safety data.  
 
DBE safety treatment groups  
Please refer to Section 3.1 for the safety treatment groups. Subjects who were randomized to 
placebo group but accidentally received one or more doses of BIIB054 during the placebo-
controlled period will be classified as early start  for all the safety analyses that involves 
DBE, and their applicable safety data in the placebo-controlled period will be included in the 
analysis for active treatment (placebo-controlled and DBE) period. 
 
Safety analysis period  
Analysis period will be specified for each output. Analyses periods in this SAP are 
 Long-term extension period  for AE analyses 
 Active treatment (placebo-controlled and DBE) period - for AE analyses and analyses of 
hematology/blood chemistry/urinalysis, hepatotoxicity, vital sign, ECG, MRI. 
Safety data in the specified analysis period will be included in the analysis. Listings will 
include all data in the placebo-controlled and DBE period, unless otherwise specified. 
 
Incidence, incidence proportion and incidence rate 
 Incidence and incidence proportion will be provided in incidence tables. Incidence is 
defined as the number of subjects who experienced an event. Incidence proportion is 


 
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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. 
 Incidence and incidence rate will be provided in incidence rate tables. Incidence rate is 
defined as the number of subjects who experienced an event divided by the total follow-
up time among the subjects in the analysis population (e.g., incidence rate per 100 
subject-years). The total follow-
-up time. The 
follow-up time for a subject is defined as the number of days (inclusive) from the first 
dose of treatment until the last day on study divided by 365.25. For active treatment 
(placebo-controlled and DBE) period analyses, the first dose of treatment is considered as the 
first dose received in the study period (PC or OLE) in which a subject first receives BIIB054. 
Each subject will be counted only once within each category.  
 
4.5.2 Clinical Adverse Events  
Treatment emergent AEs (TEAEs) 
All AEs will be coded using the MedDRA dictionary version 23.0 or higher.   
All AEs will be analyzed based on the principle of treatment emergence.  A treatment 
emergent AE is defined as an AE that started or worsened after the start of first infusion of 
study treatment.  
To define treatment emergence for AEs with missing start or stop date or time the following 
additional criteria will be used: 
 if both the start and stop dates for a particular AE are missing, then that AE is considered 
treatment emergent. 
 if the start date for a particular AE is missing and the stop date/time falls after the first 
dose date/time, then that AE is considered treatment emergent. 
 if the start date for a particular AE was the same as the first dose date, and the start time 
was missing, then that event is considered treatment emergent. 
For AEs with a partial start date, the year/month of the event date will be compared to that of 
the first dosing date to determine whether the event is treatment emergent. 
In addition, SAEs that occurred since a subject was screened in the study and prior to the first 
infusion of study treatment, which by definition are not treatment emergent, will be analyzed 
separately. 
Only TEAEs will be included in the AE tables, unless otherwise specified. Listings of AEs 
will include all events, whether treatment emergent or not.  
 
 Summary and incidence analysis 
Overall summary of AE table will be done for the following periods, by DBE treatment 
groups: 
 DBE period, and, 


 
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 the active treatment (placebo-controlled and DBE) period  
 The following information will be summarized: the number of subjects with any AE, with 
any AE by maximum severity, with any related AE (related to study drug as assessed by 
investigator), with radioligand rated AE, with SAE, with related SAE, with radioligand rated 
SAE, with AE leading to study drug discontinuation, with AE leading to study withdrawal 
and the number of deaths.  
The sorting order of AE incidence tables, unless otherwise specified, will be by decreasing 
DBE treatment group. A subject is counted only once within each category in each table. For 
example, for the table of AEs by system organ class and preferred terms sorted by decreasing 
frequency presented by DBE treatment group, system organ class will be presented in 
decreasing frequency order of BIIB054 total column, and within each system organ class, 
preferred terms will be presented in decreasing frequency order of BIIB054 total column. A 
subject is counted only once within each system organ class and preferred term.  
 
The severity of AEs and SAEs is graded using the  CTCAE grade, version 5.0. The 
categorisation of severity is as follows: grade 1 (mild), 2 (moderate), 3 (severe or medically 
significant), 4 (life-threatening) and 5 (death),  Severe AEs and SAEs are classed as CTCAE 
grade >=3. 
 
The following AE incidence tables will be provided for the DBE period: 
1. AEs by system organ class and preferred term sorted by decreasing frequency  
2. AEs by preferred term  
3. Severe AEs by system organ class and preferred term 
4. Severe AEs by preferred term  
5. Study drug related AEs by system organ class and preferred term  
6. SAEs by system organ class and preferred term sorted by decreasing frequency 
7. SAEs by preferred term  
8. Study drug related SAEs by system organ class and preferred term 
9. AEs that led to discontinuation of study treatment by system organ class and preferred 
term  
10. AEs that led to withdrawal from study by system organ class and preferred term  
 
 Incidence and incidence rate analysis for active treatment (placebo-controlled 
and DBE) period 
Due to the different length of active treatment (placebo-controlled and DBE) period in early 
start versus delayed start subjects, both incidence (proportion) tables and incidence rate tables 
will be used for AE analyses in this period. The entire follow-up time is from the first dose in 


 
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active treatment period (first dose in placebo-controlled period for early start subjects and 
first dose in DBE period for delayed start subjects) until the last day in the study.  
The following incidence (proportion) will be provided for the active treatment (placebo-
controlled and DBE) period. The follow-up adjusted incidence rate table will be provided for 
1, 10, 12, 14, 16 and 17. 
1. AEs by system organ class and preferred term sorted by decreasing frequency  
2. AEs by system organ class and preferred term sorted by alphabetical order analysis  
3. AEs by system organ class  
4. AEs by preferred term  
5. AEs with an incidence of 5% or more in any treatment group by preferred term  
6. Severe AEs by system organ class and preferred term  
7. Severe AEs by preferred term  
8. AEs by maximum severity by system organ class and preferred term (System organ 
class will be presented alphabetically. Preferred term will be presented in decreasing 
frequency order.  
9. AEs by maximum severity by preferred term (Preferred term will be presented in 
decreasing frequency order) 
10. Study drug related AEs by system organ class and preferred term  
11. Radioligand related AEs by system organ class and preferred term 
12. SAEs by system organ class and preferred term  
13. SAEs by preferred term  
14. Study drug related SAEs by system organ class and preferred term  
15. Radioligand related SAEs by system organ class and preferred term 
16. AEs that led to discontinuation of study treatment by system organ class and preferred 
term  
17. AEs that led to withdrawal from study by system organ class and preferred term  
18. AEs that occurred within 2 hours from infusion start by system organ class and 
preferred term  
The following listings will be provided for the placebo-controlled and DBE period: 
1. Listing of AEs 
2. Listing of SAEs  
3. Listing of AEs that led to discontinuation of study treatment 
4. Listing of AEs that led to withdrawal from study 
5. Listing of AEs that occurred within 2 hours from infusion start 
6. Listing of study drug related AEs 
7. Listing of radioligand related AEs 


 
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8. Listing of deaths 
 
 
4.5.3 Clinical Laboratory Data 
The following laboratory assessments will be performed in Year 2-4 to evaluate the safety 
profile of BIIB054: 
 Hematology:  Complete blood count with differential and platelet count, INR, PT, 
and APTT 
 Blood chemistry:  total protein, albumin, creatinine, blood urea nitrogen, uric acid, 
bilirubin (total and direct), alkaline phosphatase, alanine aminotransferase, 
aspartate aminotransferase, gamma-glutamyl transferase, glucose, calcium, 
phosphorus, bicarbonate, chloride, sodium, and potassium 
 Urinalysis:  dipstick for blood, protein, and glucose (microscopic examination 
may also be performed) 
 
  
 
 Quantitative analyses  
For quantitative analyses, analysis period is active treatment (placebo-controlled and DBE) 
period. For numeric laboratory parameters, actual values will be summarized by visit for all 
the common visits in both Cohort A and B in the active treatment (placebo-controlled and 
DBE) period. 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 key numeric laboratory parameters at each visit for all 
the visits in the active treatment (placebo-controlled and DBE) period will be provided.  
Plots of mean actual values (with standard error) for numeric laboratory parameters at each 
visit for all the visits in the active treatment (placebo-controlled and DBE) period may be 
provided. 
Change from baseline and percent change from baseline for numeric laboratory parameters 
will be summarized in the active treatment (placebo-controlled and DBE) period. Placebo-
controlled baseline will be used for early start subjects and DBE baseline will be used for 
delayed start subjects. Change and percent change from baseline will be calculated based on 
the DBE baseline for delayed start subjects. Number of evaluable subjects, mean, standard 
deviation, median, 25% and 75% quartiles, minimum and maximum values will be presented 
at each visit.  
Listings of individual laboratory measurements by patients for all the parameters will be 
provided for placebo-controlled and DBE period.  
 


 
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Visit windows for by visit summaries 
For laboratory by visit summaries, the analysis visit should be defined using visit windows 
(see Table 1 in the Appendix).  Visit windows are generally from mid-points between the 
visit before to the current, and the midpoint from the current visit to the next visit.  If there is 
more than 1 value in the same analysis visit window for a certain parameter for a subject, 
then the closest record to the target 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 subject, 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 subject, then 
the record with the later time will be used for the by visit analysis. 
 
 Qualitative analyses 
For qualitative analyses, all available 
within each visit window in the quantitative analyses). Analysis period is active treatment 
(placebo-controlled and DBE) period.  
 
Shift analyses 
Laboratory data will be summarized using shift tables where appropriate for the active 
treatment (placebo-controlled and DBE) 
 
Shifts from baseline to high/low status will be presented for hematology, blood chemistry and 
urinalysis numeric parameters, and shifts from 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) in order to be included in the analysis. 
For early start subjects, the placebo-controlled baseline will be used and shifts that occurred 
in either placebo-controlled or DBE period will be included. For delayed start subjects, the 
DBE baseline will be used and shifts that occurred in the DBE period based on DBE baseline 
will be included.  
 
Potentially Clinically Significant (PCS) laboratory abnormalities analyses 
Please refer to the placebo-controlled SAP for the parameters and criteria for potentially 
clinically significant laboratory abnormalities analyses.  
The number of subjects with potentially clinically significant laboratory abnormalities post-
baseline will be summarized for the active treatment (placebo-controlled and DBE) period.  


 
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Subjects need to have at least one post-baseline evaluation in the active treatment period in 
order to be included in the analysis. For early start subjects, the placebo-controlled baseline 
will be used and abnormalities that occurred in either placebo-controlled or DBE period will 
be included. For delayed start subjects, the DBE baseline will be used and PCS abnormalities 
that occurred in the DBE period based on DBE baseline will be included. 
A listing of subjects with PCS laboratory abnormalities in the active treatment (placebo-
controlled and DBE) period will also be provided, with all the data in the placebo-controlled 
and DBE period will be listed. 
 
Potential serious hepatotoxicity 
Potential serious hepatotoxicity is defined as ALT or AST > 3x ULN and total bilirubin > 2x 
ULN at any time post-baseline, not necessarily concurrent, in the active treatment (placebo-
controlled and DBE) period. A scatterplot of the maximum post-baseline ALT or AST value 
relative to ULN and maximum post-baseline total bilirubin value relative to ULN (not 
necessarily concurrent) will be provided. In addition, a line plot of ALT, AST, ALP and total 
bilirubin values over time for each subject with potential serious hepatotoxicity will be 
provided. 
A listing of subjects with potential serious hepatotoxicity in the active treatment (placebo-
controlled and DBE) period will be provided with the concurrent records labeled. All the data 
in the placebo-controlled and DBE period will be listed. Concurrent is defined as on the same 
day. Subjects with ALT > 1x ULN, > 3x ULN, > 5x ULN, > 10x ULN or > 20x ULN, 
subjects with AST > 1x ULN, > 3x ULN, > 5x ULN, > 10x ULN or > 20x ULN, subjects 
with total bilirubin > 1x ULN, >1.5x ULN or > 2x ULN, subjects with ALP >1x ULN or 
>1.5x ULN, and subjects with AST or ALT > 3x ULN post-baseline accompanied by 
concurrently elevated total bilirubin > 1.5x ULN or > 2x ULN will be labeled.  
 
4.5.4 Vital Sign Data 
For vital sign data analyses, the analysis period is active treatment (placebo-controlled and 
DBE) period. 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. The 
descriptive statistics for actual values will be summarized at each visit in the active treatment 
(placebo-controlled and DBE) period.  Plot of mean vital sign values in the active treatment 
(placebo-controlled and DBE period) may be provided.  
Summary of change from baseline including number of evaluable subjects, mean, standard 
deviation, median, 25% and 75% quartiles, minimum, and maximum values will be 
summarized at each visit in the active treatment (placebo-controlled and DBE) period. 
Placebo-controlled baseline will be used for early start subjects and DBE baseline will be 
used for delayed start analysis.  
The analysis of vital signs will also focus on the incidence of clinically relevant abnormalities 
at any post-baseline visit in the active treatment (placebo-controlled and DBE) period. Please 
refer to the placebo-controlled SAP for the criteria to assess potential clinically relevant 
abnormalities in vital sign. The incidence and percentage of clinically relevant abnormalities 


 
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determined by each criterion will be summarized in the active treatment (placebo-controlled 
and DBE) period.  
A listing of subjects with clinically relevant abnormalities at any post-baseline visit in the 
active treatment (placebo-controlled and DBE) period will also be provided. All the data in 
the placebo-controlled and DBE period will be listed. 
 
Visit windows for by visit summaries 
For vital sign by visit summaries, the analysis visit should be defined using windows (see 
Table 2 in the Appendix). For the same parameter for a subject, if there is more than 1 record 
in the same analysis visit window, then select the record closest to the target visit day. If there 
are 2 records in the same analysis visit window with the same distance from the target visit 
day, then select the record with the later date. 
 
4.5.5 ECG Data 
For ECG data analyses, the analysis period is active treatment (placebo-controlled and DBE) 
period. The descriptive statistics for actual values will be summarized at each visit in the 
active treatment (placebo-controlled and DBE) period.  Plot of mean ECG values in the 
active treatment (placebo-controlled and DBE) period may be provided. 
Shift from normal or unknown ECG at baseline to abnormal post-baseline ECG, will be 
summarized in the active treatment (placebo-controlled and DBE) group. The number of 
subjects with potential QTcF interval outlier post-baseline will also be summarized in the 
active treatment (placebo-controlled and DBE) period. The criteria of defining QTcF interval 
outliers is specified in the placebo-controlled SAP. For early start subjects, the placebo-
controlled baseline will be used. For delayed start subjects, the DBE baseline will be used.  
A listing of subjects with abnormal ECG status post-baseline in the active treatment (placebo-
controlled and DBE) period will be provided. All data in the placebo-controlled and DBE 
period will be listed. 
 
4.5.6 Physical and Neurological Examination 
Abnormal findings during physical and neurological examinations are captured as adverse 
events and will be reflected in the summary of AEs. 
  
4.5.7 C-SSRS Data 
The Columbia Suicide Severity Rating Scale (C-SSRS) is an assessment that evaluates 
following the increasing severity order: (1) Wish to be dead, (2) Non-specific active suicidal 
thoughts, (3) Active suicidal ideation with any methods (not plan) without intent to act, (4) 
Active suicidal ideation with some intent to act, without specific plan, (5) Active suicidal 
ideation with specific plan and intent, and 


 
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following the increasing severity order: (6) Preparatory acts or behavior, (7) Aborted attempt, 
(8) Interrupted attempt, (9) Actual attempt, (10) Suicidal behavior, (11) Suicide (only at post-
baseline visits).  An
-
suicidal self-injurious behavior is also collected.  
The summary table for C-SSRS will be conducted for the active treatment (placebo-
controlled and DBE) period. Number of subjects who answe
questions post-
subjects who have engaged in non-suicidal self-injurious behavior will be presented.  
A listing of subjects with any suicidal ideation or behavior at baseline or post-baseline will be 
provided for the placebo-controlled and DBE period. 
 
4.5.8 MRI Safety Data 
Brain MRI safety finding are assessed at Screening visit, Week 24, 52, 96, 148 and 4 weeks 
after last dose/ET visits.   
The MRI safety result is classified as normal or abnormal. Shift table from normal or 
unknown MRI at baseline to abnormal post-baseline MRI will be summarized in the active 
treatment (placebo-controlled and DBE) period. The worst post-baseline record of each 
subject is selected. A listing of details for abnormal brain MRI findings will be presented for 
placebo-controlled and DBE period. 
 
4.6 
Pharmacodynamic -Imaging analysis 
4.6.1 General Consideration 
There are three types of imaging outcomes in the study: DaT/SPECT imaging, Neuromelanin 
MRI imaging and Structural MRI imaging. Please refer to the placebo-controlled SAP for 
details. 
The analysis population for pharmacodynamic analysis is defined in Section 3.1.1. The 
analysis period is placebo-controlled and DBE period. That is, data from both the placebo-
controlled and DBE periods will be included in the analysis. All pharmacodynamic analyses 
will be presented by DBE treatment group.  
The following three comparisons will be evaluated for the long-term pharmacodynamic 
analyses of BIIB054: 
 The early start 250 mg compared with the delayed start 250 mg; 
 The early start 1250 mg compared with the delayed start 1250 mg. 
 The early start 3500 mg compared with the delayed start 3500 mg. 
The following comparisons may also be evaluated: 
 The early start 250 mg compared with the pooled delayed start group; 


 
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 The early start 1250 mg compared with the pooled delayed start group; 
 The early start 3500 mg compared with the pooled delayed start group 
The pooled delayed start group contains all the subjects who were randomized to placebo 
treatment in the placebo-controlled period including those who did and who did not enter to 
the DBE period.  There will be no multiple comparison adjustments.  Data after subjects start 
PD symptomatic treatment will be included in the analyses.  
 
Visit Windows for by visit analyses 
For the by visit summaries and MMRM models, the analysis visit should be defined using 
visit windows (see Table 3 in the Appendix).  If there is more than 1 value in the same 
analysis visit window (>1 value for the same analysis visit) for a certain parameter for a 
subject, then the closest record to the target visit day will be used for the by visit analysis.  If 
they are with the same distance from the target visit day, then the record with the later time 
will be used for the by visit analysis.   
 
4.6.2 By Visit Summary and MMRM Model  
A prespecified set of imaging measures as well as the change from baseline will be 
summarized by DBE treatment groups by visit for all the visits in the placebo-controlled and 
DBE period.  
Change or percent change from baseline in the imaging measures will be analyzed using an 
MMRM model for all the visits in the placebo-controlled and DBE period. For details of the 
model to be used please see the 1 year SAP. Adjusted means for each treatment group, 
pairwise adjusted differences for the comparisons, 95% confidence intervals for the 
differences will be presented at each visit, and p-values will be presented for the key visits of 
week 24, 52, 96 and 148. If the distribution of the outcome is highly skewed, p-value will be 
generated from the MMRM model based on the rank data. Missing data are assumed to be 
missing at random behind the MMRM model. 
Per design, a subset of subjects will enter year 3 and 4 for a limited time. There will be some 
visits with too few data in year 3 and 4. If this is the case, the visits with too few data will be 
excluded from the MMRM analyses, Otherwise, the MMRM model will not converge. In 
addition, since most patients will start PD medication by year 1, most data in year 2-4 will be 
after PD medication. Therefore, data after subject start PD medication will be included in the 
MMRM analyses. Otherwise, the MMRM model will not converge. 
Data at the common visits of cohort A and cohort B will be included in the by visit summary 
and MMRM model. Data at all visits will be listed. 
 
4.6.3 Additional analyses of placebo-controlled period due to COVID-19 
Due to COVID-19 public health emergency, considerations were made to allow week 52 
assessments to be delayed up to 4 weeks. If this occurs, some of the data may not be included 
in the all patient week 52 analyses, as they may miss the timeline of the corresponding 


 
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interim database lock. However, these data are still considered in the placebo-controlled 
period because they are before the first dose of DBE period. Depending how much data are 
missing in the all patient week 52 analyses database lock, the MMRM analyses in the 
placebo-controlled period may be repeated by including all the available data in the placebo-
controlled period. 
 
 
 
 
 
 
 
 
 
 
 
 
4.8 
Pharmacokinetics Analysis 
Per protocol, sparse PK data are collected in the DBE period. Therefore, the PK analyses will 
be focused on summarizing the PK concentration over time. The PK analysis population as 
defined in Section 3.1.1 and data from both placebo-controlled and DBE periods will be 
included. All the PK analyses will be presented by DBE treatment group. In addition, an 
exposure-response (ER) analysis from both placebo-controlled and DBE periods will be 
conducted, to detect any ER relationship trend and potential covariate using any primary or 
secondary endpoint and BIIB054 exposure metrics as deemed appropriate.  Other tables and 
figures based on the population PK and ER analyses will be generated by Clinical 
Pharmacology and Pharmacometrics (CPP) team and will be included in a separate report 
from CPP. 
 
 
  
 
4.9 
Immunogenicity Analysis 
4.9.1 Analysis population 
All immunogenicity data will be analyzed based on the immunogenicity population, which is 
same as the safety population as defined in Section 3.1.1. 
 


 
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4.9.2 Method of analysis 
A summary table of subjects with treatment-emergent positive anti-BIIB054 antibody 
responses in the placebo-controlled and DBE active treatment period will be displayed by 
DBE treatment group and by visit. Please refer to the placebo-controlled SAP for the 
definition of treatment-emergent positive anti-BIIB054 antibody responses. In this summary, 
DBE baseline will be used for delayed start subjects who are assigned to receiving BIIB054 
in the DBE period. A listing of immunogenicity data in the placebo-controlled and DBE 
period for subjects with anti-BIIB054 antibody positive responses will be provided. 
 
Visit Windows for by visit analyses 
For immunogenicity by visit summaries, the analysis visit should be defined using visit 
windows (see Table 12 in the Appendix). If there is more than 1 value in the same analysis 
visit window for a subject, then the closest record to the target 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 subject, 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 subject, then the record with the later time will be used for the by visit 
analysis. 
 
4.10 Interim Analyses 
Safety and PK data only will be reviewed by the IDMC after subjects in Cohort A have 
completed Week 12 Visit assessments, and before dosing any subjects in Cohort B.  
After subjects in Cohort A complete the Week 24 Visit, 
, all available serum PK, 
-syn levels and complex formation data, if available) 
from Cohort A will be analyzed by a statistical/PK team independent of the study.  The 
grouped level summary statistics will be reviewed only by a limited number of individuals at 
Biogen who are not involved in the management of the subjects or subject-level data for the 
study.  No changes to the study design are expected based on this review. 
For the purpose of planning for future studies, an administrative interim analysis may be 
performed when approximately 60% of the subjects have completed the Week 52 Visit. A 
small unblinded team from Biogen, separate from the study management team, will have 
access to the unblinded interim analysis results. As of the finalization of protocol Version 8 
and all subjects have completed Week 52 visits, this analyses was not conducted. 
A full analysis of the 1-year data will be performed after all subjects have completed the 
Week 52 Visit.  A small unblinded team from Biogen, separate from the study management 
team, will have access to the unblinded 1-year analysis results. 
An interim analysis when all subjects have completed the Week 72 Visit is planned to be 
conducted.  A small unblinded team from Biogen, separate from the study management team, 
will have access to the unblinded interim analysis results. All efficacy endpoints 
 
 will be analyzed at the Week 72 analyses.  Selected key safety data (e.g. 
summary of AE and SAE, summary of MRI safety findings and incidence of anti-drug 
antibodies) will be summarized, as this is only a snapshort of the safety profile at the time of 


 
Statistical Analysis Plan 
Dose Blinded Extension Period 
V2.0 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
40 
 
the Week 72 interim analysis, and the comprehensive safety profile will be presented at the 
End of Study   
 
A multiple comparison adjustment method will be applied to control the overall type I error 
at 0.05 in the study, due to the primary endpoint of change from baseline in MDS-UPDRS 
total score being analyzed at Week 52 and Week 72, and superiority against placebo is 
considered reached in the study if statistically significant result is achieved at either timepoint 
at the respective adjusted alpha-level.    
A graphical procedure will be used to control the overall type I error at 0.05 level due to 
multiple-testing.  An alpha of 0.04 will be allocated to the Week 52 primary endpoint 
analyses and an alpha of 0.01 will be allocated to the Week 72 primary endpoint analysis.  
 If the Week 52 analysis is statistically significant at the 0.04 level (i.e. p-
0.04), the alpha of 0.04 will be transferred (recycled) to the Week 72 analysis, and 
Week 72 will have alpha=0.05.  
 If the Week 52 analysis is not statistically significant at the 0.04 level, alpha of 0.01 
will be used for the Week 72 analysis.  Statistically significance is considered 
achieved if the p-
 
 If statistical significance is achieved at the Week 72, in either scenarios above, then 
the alpha of 0.01 will be transferred (recycled) back to Week 52, and the Week 52 
primary analysis will be re-evaluated for statistically signifance at the 0.05 level.  This 
will only change the conclusion of the Week 52 results if the initial p-value is greater 
 
 
 No additional multiplicity adjustments will be made for secondary or exploratory endpoint 
analyses.  
A blinded sample size re-estimation may be conducted when approximately 10% of subjects 
have completed the Week 52 Visit or approximately 1 month before enrollment is projected 
to be completed, whichever is earlier.  The study sample size may be increased based on this 
blinded data review.  There may be small adjustments to the percentage depending on actual 
enrollment rate.  As of the finalization of protocol Version 8 and all subjects have completed 
Week 52 visits, this analyses was not conducted.  
 
5 Assessment of the impact of Covid-19 on statistical analyses 
As this study is on-going when the Covid-19 public health emergency (PHE) occurred, 
subject visits and data collection were impacted, including missing visits, delayed visits, 
missed assessments and/or some visits were performed via remote assessments, e.g. 
telephone/video visits.  Every effort was made to document these impacted study activities 
systematically on the eCRF and other electronic source data.   
 


 
Statistical Analysis Plan 
Dose Blinded Extension Period 
V2.0 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of Biogen MA Inc. 
41 
 
A complete listing of all visits impacted (e.g. missed visits, delayed or assessment done via 
remote visits) will be listed in the clinical study report. Missing data due to Covid-19 is 
considered as missing at random. 
   
Impact of COVID-19 on the clinical outcome analyses 
 
In addition, subgroup analyses of the selected key clinical outcome MDS-UPDRS will be 
performed on a subset of subjects who did not have >=3 consecutive missing doses 
throughout the study to further evaluate the impact of Covid-19 on the study. The same 
MMRM model for the primary analyses will be used for the subgroup analyses.  
 
In addition, due to Covid-19, some visits were delayed.  A few subjects will have their Week 
52 imaging done at later visits up to Week 72 and these will still be considered as Week 52 
visit data in the analyses for Week 52.  These data were not included in the Week 52 database 
lock in time, but will be included in the Week 72 database, and the related Week 52 imaging 
analyses will be updated at the time of the Week 72 interim analyses.  
 
Impact of COVID-19 on the safety analyses 
 
During the COVID-19 pandemic period, subjects may be prone to a high risk of getting 
depressed or anxiety. As a result, the analyses below will be performed to evaluate the impact 
of the COVID-19 pandemic on the safety analyses. 
 
1. An overall summary of AE in DBE period based on data after March 7th, 2020, the 
start date when subjects in SPARK get impacted by COVID-19  
2. An overall summary of AE in the active treatment (placebo-controlled and DBE) 
period based on data after March 7th, 2020, the start date when subjects in SPARK get 
impacted by COVID-19 
3. AEs by system organ class and preferred term sorted by decreasing frequency in DBE 
period based on data after March 7th, 2020, the start date when subjects in SPARK get 
impacted by COVID-19 
4. AEs by system organ class and preferred term sorted by decreasing frequency in 
active treatment (placebo-controlled and DBE) period based on data after March 7th, 
2020, the start date when subjects in SPARK get impacted by COVID-19 
5. C-SSRS data summary based on data after March 7th, 2020, the start date when 
subjects in SPARK get impacted by COVID-19