Clinical trial NCT03068468
Conditions: Supranuclear Palsy, Progressive
Sponsor: Biogen
Start date: 2017-06-01; Completion date: 2020-02-07
Enrollment: 490 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The Primary objective of the study is to evaluate the efficacy of BIIB092, compared to placebo, as measured by a change from baseline in the PSP Rating Scale (PSPRS) at Week 52 and to assess the safety and tolerability of BIIB092, relative to placebo, by measuring the frequency of deaths, SAEs, AEs leading to discontinuation, and Grade 3 \& 4 laboratory abnormalities.

The Secondary objective of the study is to evaluate the efficacy of BIIB092, compared to placebo, as measured by a change in baseline in the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II at Week 52, to evaluate the efficacy of BIIB092, compared to placebo, as measured by the Clinical Global Impression of Change (CGI-C) at Week 52, to evaluate the efficacy of BIIB092, compared to placebo, as measured by a change in baseline in the Repeatable Battery for the Assessment of Neuropsychological Disease Severity (RBANS) at Week 52 and to assess the impact of BIIB092 on quality of life, relative to placebo, as measured by change from baseline on the Progressive Supranuclear Palsy Quality of Life scale (PSP-QoL) at Week 52.

Detailed description:
This study, previously posted by Bristol-Myers Squibb, has transitioned to Biogen under a licensing agreement.

Arms: arm 1: Participants will receive BIIB092 50 mg/ml intravenous (IV) infusion once every 4 weeks for 48 weeks in double blind treatment period followed by BIIB092 50 mg/ml IV infusion once every 4 weeks starting at Week 52 up to Week 208. arm 2: Participants will receive BIIB092 matching placebo IV infusion once every 4 weeks for 48 weeks in double blind treatment period followed by BIIB092 50 mg/ml IV infusion once every 4 weeks starting at Week 52 up to Week 208.
Interventions: intervention 1: BIIB092 intervention 2: Placebo
Intervention descriptions: intervention 1: BIIB092 intravenous infusion on specified days intervention 2: Placebo intravenous infusion on specified days

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
1 
Biogen MA Inc. 
225 Binney Street 
Cambridge, MA  02142 
United States 
PROTOCOL NUMBER: 251PP301 / NCT03068468 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
PHASE OF DEVELOPMENT: 2b 
PROTOCOL TITLE: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study to Evaluate the Efficacy and Safety of Intravenously Administered BIIB092 in 
Participants with Progressive Supranuclear Palsy 
EUDRA CT NUMBER:  2016-002554-21 
DATE: 
01 February 2019 
Version 7 
FINAL 
Version 7 supersedes previous Version 6 dated 24 May 2018 




Protocol 251PP301 
Version 7 
Phase 2b Study of BIIB092 in Participants with Progressive Supranuclear Palsy 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
3 
 
SPONSOR INFORMATION 
Biogen is responsible for 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 
Biogen Japan Ltd. 
Nihonbashi 1-chome 
Mitsui Building 14F 
4-1 Nihonbashi 1-chome 
Chuo-ku, Tokyo 
103-0027 Japan 
 
Biogen Australia PTY Ltd. 
Suite 1, Level 3  
123 Epping Road 
North Ryde, NSW 2113 
Australia 
 
For urgent medical issues in which the study Medical Director should be contacted, please refer 
to the Study Reference Guide’s Official Study Contact List for complete contact information. 
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization (CRO) and other third parties; however, Biogen retains overall accountability for 
these activities. 


Protocol 251PP301 
Version 7 
Phase 2b Study of BIIB092 in Participants with Progressive Supranuclear Palsy 
 
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The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
4 
 
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
SPONSOR INFORMATION ..........................................................................................................3 
1. 
SYNOPSIS ...................................................................................................................9 
2. 
SCHEDULE OF ACTIVITIES ..................................................................................14 
3. 
INTRODUCTION ......................................................................................................27 
3.1. 
Study Rationale ...........................................................................................................27 
3.2. 
Background .................................................................................................................28 
3.2.1. 
Research Hypothesis ...................................................................................................28 
3.3. 
Benefit/Risk Assessment ............................................................................................29 
4. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................30 
5. 
STUDY DESIGN .......................................................................................................34 
5.1. 
Overall Design ............................................................................................................34 
5.1.1. 
Overall Study Design ..................................................................................................34 
5.1.2. 
Study Visits .................................................................................................................35 
5.1.3. 
Study Assessments ......................................................................................................35 
5.1.4. 
Home Visits ................................................................................................................35 
5.1.5. 
Discontinuation of Study Treatment and/or Study Withdrawal .................................36 
5.2. 
Substudy Design .........................................................................................................36 
5.3. 
Data Monitoring Committee and Other External Committees ...................................37 
5.4. 
Number of Participants ...............................................................................................37 
5.5. 
End of Study Definition ..............................................................................................37 
5.6. 
Scientific Rationale for Study Design.........................................................................37 
5.6.1. 
Clinical Assessments ..................................................................................................38 
5.6.2. 
Rationale for Inclusion of Key Biomarkers ................................................................38 
5.7. 
Justification for Dose ..................................................................................................38 
6. 
STUDY POPULATION .............................................................................................41 
6.1. 
Inclusion Criteria ........................................................................................................41 
6.1.1. 
Signed Written Informed Consent ..............................................................................41 
6.1.2. 
Type of Participant and Target Disease Characteristics .............................................41 
6.1.3. 
Age and Reproductive Status ......................................................................................43 
6.2. 
Exclusion Criteria .......................................................................................................43 


Protocol 251PP301 
Version 7 
Phase 2b Study of BIIB092 in Participants with Progressive Supranuclear Palsy 
 
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6.2.1. 
Medical Conditions .....................................................................................................43 
6.2.2. 
Prior/Concomitant Therapy ........................................................................................45 
6.2.3. 
Physical and Laboratory Test Findings ......................................................................46 
6.2.4. 
Allergies and Adverse Drug Reaction ........................................................................46 
6.2.5. 
Other Exclusion Criteria .............................................................................................47 
6.3. 
Lifestyle Restrictions ..................................................................................................47 
6.4. 
Screen Failures ............................................................................................................47 
6.4.1. 
Retesting During Screening or Lead-In Period ..........................................................47 
7. 
TREATMENT ............................................................................................................48 
7.1. 
Treatments Administered ............................................................................................50 
7.2. 
Method of Treatment Assignment ..............................................................................50 
7.3. 
Blinding ......................................................................................................................50 
7.4. 
Dosage Modification ..................................................................................................51 
7.5. 
Preparation/Handling/Storage/Accountability ............................................................51 
7.5.1. 
Retained Samples for Bioavailability/Bioequivalence ...............................................52 
7.6. 
Treatment Compliance ................................................................................................52 
7.7. 
Concomitant Therapy .................................................................................................52 
7.7.1. 
Prohibited and/or Restricted Treatments ....................................................................52 
7.7.2. 
Other Restrictions and Precautions .............................................................................53 
7.7.2.1. 
Imaging Restriction and Precautions ..........................................................................53 
7.8. 
Treatment After the End of the Study .........................................................................53 
8. 
DISCONTINUATION CRITERIA ............................................................................54 
8.1. 
Discontinuation From Study Treatment .....................................................................54 
8.2. 
Study Follow-Up ........................................................................................................54 
8.3. 
Withdrawal From the Study ........................................................................................55 
8.4. 
Lost to Follow-Up.......................................................................................................55 
9. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................56 
9.1. 
Efficacy Assessments .................................................................................................56 
9.2. 
Safety Assessments .....................................................................................................60 
9.2.1. 
Physical Examinations ................................................................................................60 
9.2.2. 
Vital signs ...................................................................................................................60 
9.2.3. 
ECGs ...........................................................................................................................60 


Protocol 251PP301 
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Phase 2b Study of BIIB092 in Participants with Progressive Supranuclear Palsy 
 
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9.2.4. 
Clinical Safety Laboratory Assessments ....................................................................60 
9.2.5. 
Suicidal Risk Monitoring ............................................................................................62 
9.2.6. 
Imaging Safety Assessment ........................................................................................62 
9.3. 
Imaging Assessment for the Study .............................................................................62 
9.4. 
Other Assessments ......................................................................................................63 
10. 
ADVERSE EVENTS ..................................................................................................64 
10.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................64 
10.2. 
Method of Detecting AEs and SAEs ..........................................................................64 
10.3. 
Follow-up of AEs and SAEs .......................................................................................65 
10.4. 
Regulatory Reporting Requirements for SAEs ...........................................................65 
10.5. 
Pregnancy ...................................................................................................................65 
10.6. 
Laboratory Test Result Abnormalities ........................................................................66 
10.7. 
Potential Drug Induced Liver Injury ...........................................................................66 
10.8. 
Other Safety Considerations .......................................................................................66 
10.9. 
Expectedness of Events ..............................................................................................66 
10.10. 
Suspected Unexpected Serious Adverse Reactions ....................................................66 
10.11. 
Overdose .....................................................................................................................67 
10.12. 
Medical Emergency ....................................................................................................67 
10.13. 
Unblinding for Medical Emergency ...........................................................................67 
10.14. 
Deaths .........................................................................................................................67 
11. 
PHARMACOKINETICS ...........................................................................................68 
12. 
PHARMACODYNAMICS ........................................................................................70 
 
71 
 
71 
 
71 
14. 
IMMUNOGENICITY ASSESSMENTS....................................................................73 
15. 
OTHER ASSESSMENTS ..........................................................................................74 
15.1. 
PSP phenotypes ..........................................................................................................74 
16. 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ...............75 
17. 
STATISTICAL CONSIDERATIONS .......................................................................76 
17.1. 
Sample Size Determination ........................................................................................76 
17.2. 
Populations for Analyses ............................................................................................76 


Protocol 251PP301 
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Phase 2b Study of BIIB092 in Participants with Progressive Supranuclear Palsy 
 
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17.3. 
Handling of Missing Data ...........................................................................................76 
17.4. 
Statistical Analyses .....................................................................................................77 
17.4.1. 
Efficacy Analyses .......................................................................................................77 
17.4.2. 
Safety Analyses ..........................................................................................................79 
17.4.3. 
Interim Analysis ..........................................................................................................79 
17.5. 
Other Analyses ............................................................................................................79 
17.5.1. 
PK and PD Analyses ...................................................................................................79 
17.5.2. 
Immunogenicity Analyses ..........................................................................................79 
17.5.3. 
Biomarker Analyses ....................................................................................................79 
18. 
REFERENCES ...........................................................................................................80 
19. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................82 
20. 
APPENDICES ............................................................................................................83 
APPENDIX 1. ABBREVIATIONS AND TRADEMARKS ......................................................84 
APPENDIX 2. STUDY GOVERNANCE CONSIDERATIONS...............................................87 
Ethical Requirements .....................................................................................................................87 
Declaration of Helsinki ..................................................................................................................87 
Ethics Committee ...........................................................................................................................87 
Subject Information and Consent...................................................................................................88 
Subject Data Protection..................................................................................................................88 
Compensation for Injury ................................................................................................................88 
Conflict of Interest .........................................................................................................................89 
Registration of Study and Disclosure of Study Results .................................................................89 
Compliance with the Protocol and Protocol Revisions..................................................................89 
Financial Disclosure.......................................................................................................................89 
Source Documents .........................................................................................................................89 
Study Treatment Records ...............................................................................................................90 
Case Report Forms .........................................................................................................................91 
Monitoring. ....................................................................................................................................92 
Records Retention ..........................................................................................................................92 
Return of Study Treatment.............................................................................................................93 
Clinical Study Report and Publications .........................................................................................94 


Protocol 251PP301 
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Phase 2b Study of BIIB092 in Participants with Progressive Supranuclear Palsy 
 
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APPENDIX 3. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING ................................................95 
Adverse Events ..............................................................................................................................95 
Serious Adverse Events .................................................................................................................95 
Evaluating AEs and SAEs .............................................................................................................96 
APPENDIX 4. WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION .........................................................................98 
 
101 
 
LIST OF TABLES 
Table 1: 
Screening Procedural Outline .....................................................................................14 
Table 2: 
Double-Blind Procedural Outline ...............................................................................18 
Table 3: 
Extension Period Procedural Outline ..........................................................................22 
Table 4: 
Quantitative Assessment Procedural Outline for the Extension Period 
Substudy .....................................................................................................................26 
Table 5: 
Summary Statistics of Percent Suppression of Unbound N-terminal Tau 
Relative to Baseline Following 2000 mg Q4W (Simulated) ......................................40 
Table 6: 
Study Treatments for Study 251PP301 .......................................................................49 
Table 7: 
Selection and Timing of Dose ....................................................................................50 
Table 8: 
Laboratory Safety Assessments ..................................................................................61 
Table 9: 
Pharmacokinetic Sampling Schedule .........................................................................68 
 
71 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................34 
 
 
 
 
 
 
 


Protocol 251PP301 
Version 7 
Phase 2b Study of BIIB092 in Participants with Progressive Supranuclear Palsy 
 
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1.
SYNOPSIS
Protocol 
Title: 
Protocol 
Number: 
Version 
Number: 
Name of 
Study 
Treatment: 
Study 
Phase: 
Study 
Indication: 
Study 
Rationale: 
Study 
Objective(s) 
and 
Endpoints: 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Evaluate the Efficacy and Safety of Intravenously Administered BIIB092 in 
Participants with Progressive Supranuclear Palsy 
251PP301
7 
BIIB092 
2b 
Progressive Supranuclear Palsy 
The neuropathological hallmark of Progressive Supranuclear Palsy (PSP) is the 
presence of tau pathology in characteristic subcortical and cortical brain 
regions. N-terminal tau is implicated in mediating the transcellular spreading of 
this tau pathology in PSP. 
Based on the available preclinical and clinical data, BIIB092 (formerly known 
as BMS-986168 and IPN007) is expected to prevent spreading of tau pathology 
by binding and reducing unbound N-terminal tau in brain interstitial fluid, 
thereby delaying the progression of clinical signs and symptoms of PSP. The 
purpose of this study is to demonstrate the efficacy of BIIB092 in the treatment 
of PSP and characterize its safety/tolerability profile. 
The primary objectives of the study are to: 1) Evaluate the efficacy of BIIB092 
and 2) Assess the safety and tolerability of BIIB092. 
The primary endpoints that relate to these objectives are: 1) Change from 
baseline in the total PSP Rating Scale (PSPRS) score at Week 52 in participants 
treated with BIIB092 relative to the change in the total PSPRS score in 
participants treated with placebo and 2) Frequency of deaths, serious adverse 
events (SAEs), adverse events (AEs) leading to discontinuation, and Grade 3 & 
4 laboratory abnormalities. 
Key secondary objectives and endpoints are as follows: 
•
To evaluate the efficacy of BIIB092, compared to placebo, as
measured by a change from baseline in the Movement Disorder


Protocol 251PP301 
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Phase 2b Study of BIIB092 in Participants with Progressive Supranuclear Palsy 
 
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Society-sponsored revision of the Unified Parkinson’s Disease 
Rating Scale (MDS-UPDRS) Part II at Week 52. 
The impact of BIIB092 on the MDS-UPDRS Part II will be 
evaluated relative to the change from baseline at Week 52 of the 
BIIB092-treated participants to that of the placebo-treated 
participants. 
• To evaluate the efficacy of BIIB092, compared to placebo, as 
measured by the Clinical Global Impression of Change (CGI-C) at 
Week 52. 
The impact of BIIB092 on the CGI-C scale score will be evaluated 
at Week 52 in the BIIB092-treated participants and compared to that 
of the placebo-treated participants. 
• To evaluate the efficacy of BIIB092, compared to placebo, as 
measured by a change from baseline in the Repeatable Battery for 
the Assessment of Neuropsychological Disease Severity (RBANS) 
total score at Week 52. 
The impact of BIIB092 on the RBANS scale will be evaluated 
relative to the change from baseline at Week 52 in the BIIB092-
treated participants to that of the placebo-treated participants. 
• To assess the impact of BIIB092 on quality of life, relative to 
placebo, as measured by change from baseline on the Progressive 
Supranuclear Palsy Quality of Life scale (PSP-QoL) at Week 52. 
The impact of BIIB092 on the PSP-QoL scale will be evaluated 
relative to the change from baseline at Week 52 in the BIIB092-
treated participants to that of the placebo-treated participants. 
Other secondary objectives and endpoints are as follows: 
• To assess the efficacy of BIIB092, relative to placebo, as measured 
by a change from baseline at Week 48 (Week 52 for Clinical Global 
Impression of Severity [CGI-S]) on the following instruments: 
− Schwab and England Activities of Daily Living (SEADL) Scale 
− CGI-S 
− Phonemic Fluency Test 
− Letter-Number Sequencing (LNS) Test 
− Color Trails Test 
− Montreal Cognitive Assessment (MoCA) 
The impact of BIIB092 on the instruments mentioned above will be 
evaluated relative to the change from baseline at Week 48 (Week 52 


Protocol 251PP301 
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Phase 2b Study of BIIB092 in Participants with Progressive Supranuclear Palsy 
 
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for CGI-S) in the BIIB092-treated participants to that of the 
placebo-treated participants. 
• To assess the immunogenicity of BIIB092. 
Immunogenicity of BIIB092 will be measured by assessment of the 
presence or absence of anti-BIIB092 antibodies in serum. 
• To assess the efficacy of BIIB092, relative to placebo, as measured 
by absolute and percent change from baseline of brain volumes, as 
determined by magnetic resonance imaging (MRI), at Week 52 in 
the following regions: 
− Ventricles 
− Whole brain 
− Midbrain 
− Pons 
− Superior cerebellar peduncle 
− Third ventricle 
− Frontal lobe 
The impact of BIIB092 on brain volumes, as determined by MRI in 
the regions mentioned above, will be evaluated relative to the 
change from baseline at Week 52 in the BIIB092-treated participants 
to that of the placebo-treated participants. 
Tertiary objectives and endpoints are listed in Section 4. 
Extension 
Objective(s)  
The primary objective of the open-label extension period is to assess the 
long-term safety and tolerability of BIIB092 in participants with PSP based on 
the numbers and percentages of deaths and of participants with SAEs and AEs. 
The secondary objective is to assess the long-term efficacy of BIIB092 in these 
participants based on clinical and health-outcomes measures.  
Study 
Design: 
Randomized, double-blind, placebo-controlled, parallel-group study with an 
open-label extension period. 
This study includes an optional substudy to measure quantitative movement 
assessments (QMAs) using wearable sensors. The QMAs will measure gait, 
postural instability, motor function, and falls in a subset of study participants 
participating in the long-term extension period. 
Study 
Location: 
Approximately 98 sites are planned globally. 


Protocol 251PP301 
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Phase 2b Study of BIIB092 in Participants with Progressive Supranuclear Palsy 
 
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Number of 
Planned 
Participants: 
Approximately 459 participants will be randomly assigned, in a 2:1 ratio, to 
receive BIIB092 or placebo (306 participants in the BIIB092 treatment group 
and 153 in the placebo group). 
Anticipating a dropout rate of approximately 25% (based on previous clinical 
studies in participants with PSP), approximately 345 participants (230 
participants in the BIIB092 treatment group and 115 participants in the placebo 
group) are expected to complete the study through Week 52. Using a two-sided, 
two-sample t-test, with an alpha level set at 0.05, this sample size will provide 
80% power to detect a difference of 3.2 points in the change in PSPRS total 
score from baseline to Week 52 for BIIB092 relative to placebo, assuming a 
common standard deviation of 9.95 in the change in PSPRS total score from 
baseline to Week 52. 
Study 
Population: 
This study will be conducted in male and female participants with probable or 
possible PSP.  
Women of childbearing potential (WOCBP) and sexually active fertile men 
with partners who are WOCBP must use highly effective birth control in Study 
251PP301. 
Detailed criteria are described in Section 6. 
Treatment 
Groups: 
Study treatment includes both Investigational [Medicinal] Products (IP/IMP) 
and Non-investigational [Medicinal] Products (Non-IP/Non-IMP) as listed in 
the following table. 
Study Treatment for 251PP301 
Medication 
Potency 
IP/Non-IP 
BIIB092a 
50 mg/mL 
IP 
Placebob (0.9% Sodium Chloride) 
N/A 
IP 
IP = investigational product 
a Study treatment supplies may be labeled as BIIB092 or BMS-986168. The two study 
treatment names refer to an identical study treatment substance. 
b 5% dextrose injection can be used if sodium chloride is not available. 
 


Protocol 251PP301 
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Phase 2b Study of BIIB092 in Participants with Progressive Supranuclear Palsy 
 
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Study Schematic:  
In the 52-week double-blind treatment period of the study, approximately 
459 participants in total will be randomly assigned, in a 2:1 ratio, to receive 
2000 mg of BIIB092 or placebo (306 participants in the BIIB092 treatment 
group and 153 in the placebo group) administered by intravenous (IV) infusion 
approximately once every 4 weeks (Q4W) up to a total of 13 times, with the 
last dose of the double-blind study treatment administered at Week 48. 
At Week 52, participants completing the double-blind treatment period may 
choose to continue into the open-label extension period of the study. The first 
dose of 2000 mg of BIIB092 of the open-label extension period will be 
administered to all participants by intravenous (IV) infusion at Week 52. All 
participants will be dosed with 2000 mg of BIIB092 by IV infusion 
approximately once Q4W throughout the duration of the open-label extension 
period of the study. The duration of participation in the open-label extension 
period of treatment will vary depending on the date of enrollment of the 
participant in the study. The open-label extension period is expected to continue 
until BIIB092 is commercially available, the development program is 
terminated, or the study is terminated at the discretion of the Sponsor, 
whichever comes first. 
Duration of 
Treatment 
and Follow-
up: 
The study will consist of a 52-week double-blind treatment period followed by 
an open-label extension period for long-term follow-up. 
 
















Protocol 251PP301 
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Phase 2b Study of BIIB092 in Participants with Progressive Supranuclear Palsy 
 
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21 
 
; LP = lumbar puncture; MDS-UPDRS = Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale; 
MoCA = Montreal Cognitive Assessment; NSAE = non-serious adverse event; PK = pharmacokinetic; MRI = magnetic resonance imaging; NE = neurological 
examination; PSP = Progressive Supranuclear Palsy; PSPRS = Progressive Supranuclear Palsy Rating Scale; QoL = quality of life; RBANS = Repeatable Battery 
for the Assessment of Neuropsychological Disease Severity; 
; SAE = serious adverse events; 
SEADL = Schwab and England Activities of Daily Living scale; 
 WOCBP = women of childbearing potential. 
a Efficacy assessments requiring participant involvement should be completed prior to dosing with study treatment unless otherwise specified in the notes; 
specific attention should be paid to conducting the Week 24 MRI within 7 days prior to the Week 24 dosing visit. The study visits at Weeks 0, 12, 24, 36, 48, 
52, and Early Discontinuation, which involve the conduct of efficacy assessments, may be completed over a period of up to 3 consecutive days. 
b Weeks 28, 32, 40, and 44 may qualify for a home visit if appropriate. See Section 5.1.4  for details. 
c Participants who discontinue study treatment during the double-blind period of the study (prior to Week 52) and remain enrolled in the study will be expected 
to complete scheduled safety and efficacy evaluations at Weeks 12, 24, 36, 48, and 52 until the decision is made to withdraw from the study.  
d Early Discontinuation visit procedures should be completed for any participant who discontinues study treatment and also withdraws from the study at any time 
prior to Week 52. Participants who withdraw from the study should be encouraged to return to the clinic at Week 52 to complete the Week 52 procedures. If the 
visit cannot be done in person by the participant, the site should attempt a phone call at approximately Week 52 to collect at a minimum vital status (whether 
the participant is alive or dead) and SAE/AE information on the participant.  
e This 30-day assessment of AEs/SAEs may be done by phone if no visit occurs. 
f CGI interviews collected from Week 36 will be used to review all areas of the functioning section (including complex daily activities and basic functions) and 
will be used to determine whether there have been any changes or additions to the functioning at the Week 48 visit, with both the caregiver and participant 
independently. This will be used to assign the Week 48 SEADL score.  
 












Protocol 251PP301 
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Phase 2b Study of BIIB092 in Participants with Progressive Supranuclear Palsy 
 
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3. 
INTRODUCTION 
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder that leads to death in 
an average of 7 years following symptom onset [Williams 2005]. The National Institute of 
Neurological Disorders and Stroke (NINDS), the National Organization for Rare Disorders 
(NORD), and the European Organisation for Orphan Diseases estimate the prevalence of PSP to 
be between 3 and 6 per 100,000 persons. Both the NINDS and NORD estimate that there are 
approximately 20,000 cases of PSP in the United States and 30,000 in the European Union, while 
there are thought to be approximately 17,000 cases in Japan [Takigawa 2016].  
The disease is characterized by progressive aberrations in gait, eye movements, dysphagia, 
dysarthria, pseudobulbar affect, neuropsychiatric abnormalities, and dementia, as well as 
difficulties with sleep [Boxer 2017; Nath 2003]. Since the syndrome was first characterized in 
1963, it is now recognized that there are a number of different clinical presentations that appear 
to be linked to the regional distribution and severity of pathology in the brain [Williams 2007]. 
There is currently no treatment available to stop or slow the progression of this deadly disease. 
The neuropathological hallmark of PSP is the presence of neurofibrillary tangles in clinically 
correlated regions of the brain, including the basal ganglia, diencephalon, brainstem, and 
cerebellum with restricted involvement of the neocortex [Dickson 2010]. The tangles are 
composed of tau, an intracellular microtubule-associated protein, of which fragments may also 
be released into the cerebrospinal fluid (CSF) and interstitial space as N-terminal tau [Bright 
2015; Guo 2017]. Tau dysfunction is thought to play a key role in the pathophysiology of PSP, 
both by causing neuronal dysfunction via tau aggregation into neurofibrillary tangles and by 
facilitating cell to cell spreading of tau pathology via secreted N-terminal tau.  
BIIB092 is a humanized monoclonal antibody (mAb) that binds to amino acid residues 15 to 22 
of N-terminal tau, removing it from the CSF. It is hypothesized that BIIB092-mediated depletion 
of N-terminal tau will inhibit the spread of tau pathology, potentially slowing the progression of 
PSP. This would be expected to translate into important improvements in function, activities of 
daily living, health outcomes, and overall quality of life for patients living with PSP. 
3.1. 
Study Rationale 
The neuropathological hallmark of PSP is the presence of tau pathology in the form of 
neurofibrillary tangles in characteristic subcortical and cortical brain regions. N-terminal tau is 
implicated in mediating the transcellular spreading of this tau pathology in PSP. 
BIIB092 has been shown to bind N-terminal tau and suppress CSF concentrations of unbound N-
terminal tau (i.e., N-terminal tau that is not bound to BIIB092) in preclinical studies, a single 
ascending dose (SAD) study in normal healthy volunteers (NHVs) (Study CN002001), and a 
multiple ascending dose (MAD) study in participants with PSP (Study CN002003). Based on 
these data, BIIB092 is expected to prevent spreading of tau pathology by binding and reducing 
unbound N-terminal tau in brain interstitial fluid, suggesting that it has potential utility for the 
treatment of human tauopathies, such as PSP. 
The aim of this study is to demonstrate the efficacy of BIIB092 in delaying the progression of 
clinical signs and symptoms of PSP and to characterize its safety/tolerability profile. 


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3.2. 
Background 
BIIB092 (formerly known as BMS-986168 and IPN007) is a humanized mAb of subclass IgG4 
that specifically binds the microtubule-associated protein tau. BIIB092 is derived from the 
murine IgG1 mAb, IPN002, which was produced in response to immunization of mice with 
aggregated, recombinant full-length human tau (tau isoform 2N4R). The affinity, specificity, and 
functional activity of the antibody were maintained following humanization. BIIB092 recognizes 
a linear, amino terminal epitope (including amino acid residues 15 to 22 of full-length human 
tau) of tau. BIIB092 exhibits high affinity for human and cynomolgus monkey tau, with binding 
affinities of 7 × 10-10 M and 6.35 × 10-10 M, respectively. The primary site of action of BIIB092 
is believed to be the interstitial space between neurons where it binds N-terminal tau, thereby 
reducing tau-induced neuronal hyperexcitability and tau-mediated spread of tau pathology. 
BIIB092 is being developed for the treatment of PSP, a rare neurodegenerative disease 
associated with tau pathology that results in a progressive movement disorder. There is a 
significant unmet medical need for safe and effective agents for patients with PSP, as there are 
currently no approved drugs for its treatment. Existing medical management is focused on 
reducing symptoms, using drugs approved for various other indications off-label along with 
dietary supplements. However, it is widely accepted that none of these drugs is particularly 
effective in treating PSP. 
BIIB092 was first introduced into clinical trials in the Phase 1 trials conducted in the United 
States (US), Study CN002001 in healthy adult volunteers and Study CN002003 in participants 
with PSP.  
Results from the first-in-human study, CN002001, indicate that administration of single doses of 
up to 4200 mg of BIIB092 in healthy volunteers is well tolerated. Mean suppression of the CSF-
unbound N-terminal tau in that study ranged from 67% to 97% at doses ranging from 70 to 
4200 mg.  
Study CN002003 was a Phase 1b randomized, double-blind, placebo-controlled, MAD study to 
characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and 
immunogenicity of BIIB092 doses of 150, 700, and 2100 mg in participants with PSP. All 3 
doses were well tolerated based on results from the dose escalation phase of the study. Treatment 
with monthly doses of BIIB092 decreased CSF-unbound N-terminal tau by mean values of 
approximately 90%, 93%, and 96% on Day 29 and 91%, 95%, and 97% on Day 85 at doses of 
150, 700, and 2100 mg, respectively. 
Study 251PP201 is an ongoing open-label extension study to evaluate the long-term safety and 
tolerability of multiple doses of BIIB092 in participants with PSP who participated in 
CN002003.  
A more detailed description of the chemistry, pharmacology, and safety of BIIB092 is provided 
in the Investigator’s Brochure. 
3.2.1. 
Research Hypothesis 
This study will demonstrate that BIIB092 is effective and safe for the treatment of participants 
with PSP. 


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3.3. 
Benefit/Risk Assessment 
The benefit/risk profile of BIIB092 in nonclinical studies, the SAD study in NHVs (Study 
CN002001), and the MAD study and its associated open-label extension study (Studies 
CN002003 and 251PP201, respectively) supports further evaluation of the safety, tolerability, 
immunogenicity, PK, PD response, and clinical efficacy of BIIB092 in participants with PSP. 
BIIB092 is a humanized IgG4 isotype antibody that is considered to have a low potential for 
immunogenicity in humans based on nonclinical studies. There were no adverse effects noted at 
any dose tested in the pivotal toxicity studies in monkeys. Nonclinical findings were limited to 
decreases in CSF unbound N-terminal tau consistent with the intended pharmacology of 
BIIB092. In completed clinical study CN002001, there was no consistent trend showing a 
potential effect of anti-drug antibody (ADA) on the PK of BIIB092. In completed clinical study 
CN002003, there was no apparent dose-related trend in the number of subjects with positive 
immunogenicity results post-treatment. 
Studies evaluating the potential for reproductive and developmental toxicity have not been 
performed for BIIB092. 
As of 25 November 2018, an estimated 486 participants have been exposed to BIIB092 across all 
completed (Studies CN002001 and CN002003) and ongoing clinical studies (Studies 251PP201, 
251PP301, and 251AD201). Based on safety data from a completed Phase 1 study in healthy 
volunteers (Study CN002001) and a completed Phase 1B study in participants with PSP 
(Study CN002003), the benefit/risk profile of BIIB092 was favorable to support further clinical 
development. 
There is no information available about possible interaction of BIIB092 with other drugs, 
although no PK interactions are anticipated. 
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of BIIB092 may be found in the Investigator’s Brochure. However, because 
BIIB092 is an experimental agent, it is possible that unforeseen, unknown, or unanticipated 
reactions may occur.


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4. 
STUDY OBJECTIVES AND ENDPOINTS 
Objective 
Endpoint 
Primary 
To evaluate the efficacy of BIIB092, 
compared to placebo, as measured by a 
change from baseline in the PSP Rating 
Scale (PSPRS) at Week 52. 
The primary efficacy endpoint will be 
evaluated by comparing the change from 
baseline in the total PSPRS score at Week 52 
in participants treated with BIIB092 relative 
to the change in the total PSPRS score in 
participants treated with placebo. 
To assess the safety and tolerability of 
BIIB092, relative to placebo, by measuring 
the frequency of deaths, SAEs, and AEs 
leading to discontinuation, and Grade 3 & 4 
laboratory abnormalities. 
The primary safety endpoint will be 
evaluated by tabulating the numbers and 
percentages of deaths and unique participants 
with SAEs and AEs leading to 
discontinuation, and Grade 3 & 4 laboratory 
abnormalities. 
Key Secondary 
To evaluate the efficacy of BIIB092, 
compared to placebo, as measured by a 
change from baseline in the Movement 
Disorder Society-sponsored revision of the 
Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS) Part II at Week 52. 
The impact of BIIB092 on the MDS-UPDRS 
Part II will be evaluated relative to the 
change from baseline at Week 52 in the 
BIIB092-treated participants and compared to 
that of the placebo-treated participants. 
To evaluate the efficacy of BIIB092, 
compared to placebo, as measured by the 
Clinical Global Impression of Change 
(CGI-C) at Week 52. 
The impact of BIIB092 on the CGI-C scale 
score will be evaluated at Week 52 in the 
BIIB092-treated participants and compared to 
that of the placebo-treated participants. 
To evaluate the efficacy of BIIB092, 
compared to placebo, as measured by a 
change from baseline in the Repeatable 
Battery for the Assessment of 
Neuropsychological Disease Severity 
(RBANS) at Week 52. 
The impact of BIIB092 on the RBANS scale 
will be evaluated relative to the change from 
baseline at Week 52 in the BIIB092-treated 
participants and compared to that of the 
placebo-treated participants. 
To assess the impact of BIIB092 on quality 
of life, relative to placebo, as measured by 
change from baseline on the Progressive 
The impact of BIIB092 on the PSP-QoL will 
be evaluated relative to the change from 
baseline at Week 52 in the BIIB092-treated 


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Supranuclear Palsy Quality of Life scale 
(PSP-QoL) at Week 52. 
participants and compared to that of the 
placebo-treated participants. 
Other Secondary 
To assess the efficacy of BIIB092, relative to 
placebo, as measured by a change from 
baseline at Week 48 (Week 52 for Clinical 
Global Impression of Severity [CGI-S]) on 
the following instruments: 
• Schwab and England Activities of 
Daily Living (SEADL) Scale 
• CGI-S 
• Phonemic Fluency Test 
• Letter-Number Sequencing (LNS) 
Test 
• Color Trails Test (CTT) 
• Montreal Cognitive Assessment 
(MoCA) 
The impact of BIIB092 on the following 
instruments: 
• SEADL Scale 
• CGI-S 
• Phonemic Fluency Test 
• LNS Test 
• CTT 
• MoCA 
will be evaluated relative to the change from 
baseline at Week 48 (Week 52 for CGI-S) in 
the BIIB092-treated participants and 
compared to that of the placebo-treated 
participants. 
To assess the immunogenicity of BIIB092. 
Immunogenicity of BIIB092 will be 
measured by assessment of the presence or 
absence of anti-BIIB092 antibodies in serum. 
To assess the efficacy of BIIB092, relative to 
placebo, as measured by absolute and 
percent change from baseline of brain 
volumes, as determined by magnetic 
resonance imaging (MRI), at Week 52 in the 
following regions: 
• Ventricles 
• Whole brain 
• Midbrain 
• Pons 
• Superior cerebellar peduncle 
• Third ventricle 
• Frontal lobe 
The impact of BIIB092 on brain volumes, as 
determined by MRI in the following regions: 
• Ventricles 
• Whole brain 
• Midbrain 
• Pons 
• Superior cerebellar peduncle 
• Third ventricle 
• Frontal lobe  
will be evaluated relative to the absolute and 
percent changes from baseline at Week 52 in 
the BIIB092-treated participants and 
compared to that of the placebo-treated 
participants. 


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Tertiary/Exploratory 
 
 
 
 
• 
 
 
• 
 
• 
 
 
 
 
 
 
 
• 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
• 
 
• 
 
• 
 
 
 
 
 
 
 
 
• 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• 
 
• 
 
 
 
 
 
 
• 
 
• 
 
 
 
 
 
Open-Label Extension Period 
To assess the long-term safety and 
tolerability of BIIB092 in participants with 
PSP. 
The tertiary endpoint will be incidence of 
AEs, SAEs, and SAEs accompanied by 
death. 
To assess the long-term efficacy of BIIB092 
in participants with PSP. 
The tertiary endpoints will be change from 
baseline over the placebo-controlled period 
and long-term extension period for clinical 
and health-outcomes assessments. 
This study includes an optional substudy to 
measure quantitative movement assessments 
(QMAs) using wearable sensors. The QMAs 
will measure gait, postural instability, motor 
function, and falls in a subset of participants 
participating in the long-term extension 
period. 


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5. 
STUDY DESIGN 
5.1. 
Overall Design 
The study design schematic is presented in Figure 1. 
Figure 1: 
Study Design Schematic 
 
This is a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the 
efficacy and safety of intravenously administered BIIB092 in participants with PSP with an 
open-label extension period. 
5.1.1. 
Overall Study Design 
The study design schematic is presented in Figure 1. The study will consist of a 52-week double-
blind treatment period, which will be followed by a long-term open-label extension period for 
follow up. Participants will be randomized to receive BIIB092 or placebo. Approximately 459 
participants in total will be randomized in a 2:1 ratio to receive BIIB092 or placebo (306 
participants active or 153 placebo). In the double-blind treatment period of the study, participants 
will be dosed approximately once every 4 weeks (Q4W) up to a total of 13 times, with the last 
dose of study treatment of the double-blind period (Dose 13) administered at Week 48. 
At Week 52, participants completing the double-blind treatment period may choose to continue 
into the open-label extension period of the study. Participants who wish to continue in the open-
label extension period will receive the first dose of the open-label study treatment at Week 52. 
Participants will be dosed approximately once Q4W throughout the duration of the open-label 
extension period. The duration of the open-label extension period will vary depending on the 
date of enrollment of the participant in the study. The study is expected to continue until 
BIIB092 is commercially available, the development program is terminated, or the study is 
terminated at the discretion of the Sponsor, whichever comes first. 


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5.1.2. 
Study Visits 
Study visits will be conducted approximately Q4W. Study treatment will be administered and 
safety, efficacy, and other assessments will be performed (Table 1, Table 2, Table 3, and 
Table 4). The study will generally be conducted on an outpatient basis unless some procedures 
would be better performed on an inpatient basis based on the needs of the participant. 
Participants will be observed and monitored by study personnel for approximately 2 hours after 
the end of an infusion. Participants with ongoing AEs or SAEs will remain at the site or be sent 
to an inpatient monitoring facility until the Investigator has determined that these events have 
resolved or do not require inpatient monitoring. 
5.1.3. 
Study Assessments 
• Participants will be closely monitored for safety throughout the study. Physical 
examinations, vital sign measurements, 12-lead electrocardiograms (ECG), and 
clinical laboratory evaluations, including assessments for immunogenicity will be 
performed. AEs will be closely monitored. Suicidality will also be assessed by 
completing the 
 
• PSP-related signs, symptoms, and quality of life will be assessed using the following 
clinical assessments: PSPRS, MDS-UPDRS Part II, SEADL scale, CGI-S, CGI-C, 
MoCA, European Quality of Life (EuroQol) version
 and PSP-QoL 
and neuropsychological testing (RBANS, phonemic fluency, LNS, and CTT). 
• Caregiver burden will also be assessed 
 
• Blood will be collected for immunogenicity, PK, PD, and exploratory biomarker 
analysis from each participant during this study in the double-blind period and in the 
open-label extension period. 
• Structural changes in the brain will be assessed using MRI. It is anticipated that each 
participant will have total of 4 MRIs over the course of the study, including an MRI 
during the screening period (up to Day -14) and at Weeks 24, 52, and 100. 
•  
 
 
 
 
 
 
 
• Participants in the QMA substudy will undergo quantitative assessments of core 
motor features of PSP using wearable sensors to measure gait, postural instability, 
motor function, and falls 
5.1.4. 
Home Visits 
After Week 24, except for those visits when clinical scales, LPs, or MRI assessments are 
performed, visits and procedures may be performed in the home as long as appropriate services 


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are available to perform the required study procedures and adequately monitor for potential 
safety events. In the double-blind period of the study, Weeks 28, 32, 40, and 44 may qualify for 
home visits. 
In the open-label extension period of the study, Week 68, 72, 80, 84, 92, 96, 104, 108, 116, 120, 
128, 132, 140, 144, 152, 156, 164, 168, 176, 180, 188, and 192 visits may qualify for a home 
visit. However, in the event that the participant experienced a clinically significant infusion 
reaction during the first 24 weeks of the protocol, the participant should not be administered 
BIIB092 in the home unless previously approved by the Study Investigator. 
5.1.5. 
Discontinuation of Study Treatment and/or Study Withdrawal 
Participants who discontinue study treatment may belong to 1 of the following groups: 
• Participants who discontinue study treatment but remain enrolled until the end of the 
study  
• Participants who discontinue study treatment and later withdraw from the study  
• Participants who discontinue study treatment and immediately withdraw from the 
study  
Participants who discontinue study treatment during the double-blind period of the study (prior 
to Week 52) and remain enrolled in the study will be expected to complete the scheduled safety 
and efficacy evaluations until the end of the study or until the decision is made to withdraw from 
the study (see Table 2 for schedule of evaluations). SAE collection will be up to 30 days after the 
last dose of study treatment and will continue for as long as the participant remains enrolled in 
the study. 
Early discontinuation visit procedures should be completed for any participant who discontinues 
study treatment and also withdraws from the study at any time prior to end of study. All SAEs 
that occur until 30 days after last dose of study treatment should be monitored and/or recorded. 
In the double-blind period, participants who withdraw from the study should be encouraged to 
return to the clinic at Week 52 to complete the Week 52 procedures.  
5.2. 
Substudy Design 
This study includes an optional substudy to measure QMAs using wearable sensors. The QMAs 
will measure gait, postural instability, motor function, and falls in a subset of participants 
participating in the long-term extension period. 
Study participants included in this substudy will be from selected countries, and participants will 
be required to ambulate independently or with assistive devices. Participants will participate in 
the QMA substudy for 6 months, with in-clinic assessments of gait, postural instability, and 
motor function conducted every 3 months. Falls will be assessed continuously in the home using 
wearable sensors for 6 months to capture and quantify falls. The QMA substudy baseline visit 
will be conducted after participants sign the informed consent form and are eligible to enroll in 
the substudy. Two follow-up visits will be conducted at 3 and 6 months after the baseline visit of 
the QMA substudy. If a participant at a selected site is unwilling to participate in the QMA 
substudy, they can still participate in the open-label extension study. 


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5.3. 
Data Monitoring Committee and Other External Committees 
An independent Data Monitoring Committee (DMC) will be established for this study and its 
activities will be fully described in a DMC Charter. The DMC will be composed of at least 
2 independent physicians and 1 independent statistician with experience in neurological clinical 
trials. In this study, the major tasks of the DMC will be to review unblinded data and monitor the 
benefit/risk of BIIB092, to assess whether there are unacceptable safety findings after 
administration of BIIB092 that require modifying or stopping the study, and potentially to 
adjudicate study treatment-relatedness of SAEs and deaths that are unexpected and/or atypical 
for participants with PSP. 
5.4. 
Number of Participants 
It is anticipated that approximately 459 male and female participants will be dosed in this study. 
Approximately 459 participants will be randomly assigned, in 2:1 ratio, to receive 2000 mg of 
BIIB092 or placebo (306 participants active and 153 placebo) administered by intravenous (IV) 
infusion approximately once Q4W. Randomization will be stratified by country and screening 
CTT Part 2 score of either less than or equal to 170 seconds or greater than 170 seconds. 
Anticipating a dropout rate of approximately 25%, approximately 345 participants 
(230 participants in the BIIB092 treatment group and 115 participants in the placebo group) are 
expected to complete the study through Week 52. 
5.5. 
End of Study Definition 
The date the first participant signs a study-specific informed consent form will be defined as the 
start of the study. A participant is considered enrolled when the study-specific informed consent 
form is signed. The date that the last participant completes the last study visit or scheduled 
procedure shown in Section 2, Schedule of Activities, will be defined as the end of the study. 
5.6. 
Scientific Rationale for Study Design 
The double-blind period of the study is intended to determine the efficacy and safety/tolerability 
of BIIB092. It is anticipated that participants will be randomized in a 2:1 ratio to receive 
2000 mg of BIIB092 or placebo, respectively, administered by IV infusion once Q4W for 
approximately 48 weeks (up to a total of 13 times). The justification for the dose is described in 
Section 5.7 and based on previous studies evaluating the PK of BIIB092 and PD effects on 
unbound N-terminal tau levels in CSF. A duration of treatment of up to 52 weeks and 
comparison with a placebo control are considered adequate and appropriate to evaluate the 
efficacy of BIIB092 on the primary and secondary endpoints, given the natural history of PSP 
and the lack of any approved therapies.  
The open-label extension period of the study is intended to further characterize the long-term 
efficacy and safety/tolerability of BIIB092. It is anticipated that all participants in the study, 
including those randomized to receive placebo in the double-blind period, will receive 2000 mg 
of BIIB092 administered Q4W by IV infusion throughout the open-label extension period of the 
study. 


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The QMA substudy in the open-label extension period is intended to further characterize disease 
progression with wearable sensors. Postural instability, gait disturbances, and falls are prominent 
signs of PSP that impact participant outcomes. At present these signs are assessed in the clinic 
with questionnaires. It is anticipated that advances in wearable sensor technology and analytics 
could improve quantification of these signs and may provide sensitive measures of disease 
progression. 
5.6.1. 
Clinical Assessments 
All participants will have baseline and periodic, on-treatment measures throughout the study to 
evaluate PSP symptoms using the PSPRS, MDS-UPDRS Part II, SEADL scale, CGI-S and CGI-
C; 
MoCA; PSP-QoL, 
, and neuropsychological assessments (RBANS, 
phonemic fluency, LNS, and CTT). The 
will be performed for all participants. Each 
participant will have their respective caregiver assessed for caregiver burden and resource 
utilization using the 
  
5.6.2. 
Rationale for Inclusion of Key Biomarkers 
All participants will have blood collected for assessment of serum concentrations of unbound N-
terminal tau and exploratory biomarkers determined at baseline and at regular intervals during 
the study to confirm target engagement. 
Where local regulations and institutional approvals allow, a deoxyribonucleic acid (DNA) 
sample will be prepared to analyze genetic variation in specific genes associated with PSP, genes 
impacting drug absorption, distribution, metabolism, elimination, and/or neurodegeneration. The 
impact of genetic variation such as H1 and H2 haplotypes on tau protein levels may also be 
examined. 
All participants will have MRI evaluations at baseline and at Weeks 24, 52, and 100 to assess 
structural changes in the brain. 
 
 
 
 
 
 
5.7. 
Justification for Dose 
The dose of BIIB092 selected for this study is 2000 mg, administered once Q4W. 
In the SAD study in NHVs (CN002001), single doses of BIIB092 were well tolerated at all doses 
tested (i.e., 21 to 4200 mg). A maximum tolerated dose was not identified. Robust suppression of 
unbound N-terminal tau in CSF (88% to 97%) was observed for at least 4 weeks after a single 
dose, compared to baseline, in the dose range of 210 to 4200 mg.  
The MAD study in participants with PSP (CN002003) assessed three Q4W doses of BIIB092 of 
150, 700, and 2100 mg during the dose escalation phase of the study. All three doses were well 
tolerated in participants with PSP, based on preliminary results from the dose escalation phase of 


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the study. Treatment with monthly doses of BIIB092 decreased CSF unbound N-terminal tau by 
mean values of approximately 90%, 93%, and 96% on Day 29 and 91%, 95%, and 97% on Day 
85 at doses of 150, 700, and 2100 mg respectively. Additional data on safety, tolerability, PK, 
and PD of all 3 dose levels is accruing with the open-label extension period of this study. 
Emerging PK and unbound N-terminal tau data from Panels 1 and 2 (150 and 700 mg, 
administered Q4W) of CN002003 were modeled using a semi-mechanistic PK-PD model 
developed using the NHV data, and re-estimating the model parameters to describe the observed 
data in participants with PSP. The observed PK-PD profile in participants was well characterized 
by the PK-PD model based on the estimates of the model parameters in participants as well as 
the goodness of fit plots. 
Using the estimated PK-PD model parameters and the variability around these parameters in 
participants with PSP, 1000 profiles were simulated and the time course of PK in serum and CSF 
and PD (unbound N-terminal tau) in CSF were obtained for the 2000 mg dose administered 
Q4W for a period of 1 year. Unbound N-terminal tau concentrations were converted to percent 
suppression, relative to each participant’s baseline value, prior to summarization based on the 
simulations. Table 5 shows summary statistics of percent suppression of unbound N-terminal tau 
relative to baseline levels at 4, 12, 24, and 52 weeks following the 2000 mg Q4W dosing 
regimen. 


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Table 5: 
Summary Statistics of Percent Suppression of Unbound N-terminal Tau 
Relative to Baseline Following 2000 mg Q4W (Simulated) 
 
Statistic 
4 Weeks 
12 Weeks 
24 Weeks 
52 Weeks 
Number of 
simulations 
1000 
1000 
1000 
1000 
Median 
96.46 
97.46 
97.57 
97.58 
Minimum 
93.87 
94.80 
94.82 
94.82 
Maximum 
98.25 
98.92 
99.03 
99.04 
10th percentile 
95.35 
96.34 
96.43 
96.43 
90th percentile 
97.37 
98.25 
98.39 
98.40 
Q4W = once every 4 weeks. 
Based on the results of the simulation, ninety percent of all participants who are dosed the 
2000 mg Q4W dose are expected to have a percentage suppression of unbound N-terminal tau at 
96% or greater at trough. The remaining 10% of participants are expected to have a suppression 
of approximately 95% and greater. 
Whereas the actual level of unbound N-terminal tau suppression in CSF that is associated with 
efficacy in humans is unknown, it is anticipated that higher levels of unbound N-terminal tau 
suppression will be associated with greater efficacy. The high level of suppression of unbound 
N-terminal tau was well tolerated in monkeys and has been well tolerated in both healthy 
volunteers and participants with PSP. 
Overall, a dose of 2000 mg Q4W is expected to be a well tolerated dose in participants with PSP 
that will achieve and maintain greater than 95% suppression of unbound N-terminal tau in CSF 
in the vast majority of participants for the entire study period, which is expected to increase the 
likelihood of demonstrating efficacy with BIIB092. 


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6. 
STUDY POPULATION 
For entry into the study, the following criteria MUST be met. 
6.1. 
Inclusion Criteria 
6.1.1. 
Signed Written Informed Consent 
1. Participants, or a legally authorized representative (where local regulations and 
institutional practices permit), must have signed and dated an Institutional Review Board 
(IRB)-/Independent Ethics Committee (IEC)-approved written informed consent form in 
accordance with regulatory and institutional guidelines. This must be obtained before the 
performance of any protocol-related procedures that are not part of normal participant 
care.  
2. The investigator must obtain consent consistent with the applicable legal, regulatory, and 
institutional policy requirements and specifically, taking into account the participant’s 
state of disease progression and its impact on the participant’s cognitive and motor 
abilities.  
3. In the event that the study participant is unable to sign and date the informed consent 
form, a legally authorized representative, permitted to act on behalf of the participant in 
the context of this study, may provide consent on behalf of the participant.  
4. Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, and other requirements of the study. 
5. Participant’s caregiver must have signed and dated an IRB-/IEC-approved written 
informed consent form in accordance with regulatory and institutional guidelines. This 
must be obtained before the performance of any protocol-related procedures that are not 
part of normal participant care. 
6. Participant’s caregiver must be willing and able to comply with scheduled visits and other 
requirements of the study. Only one caregiver can be designated for the participant at a 
given time. At a minimum, the caregiver should personally attend the following study 
visits: Screening; Baseline; Weeks 12, 24, 36, 48, and 52; and Early Discontinuation. 
Although caregiver assessments cannot be conducted by telephone, the caregiver should 
be available for telephone consultation regarding information on AEs and SAEs when not 
otherwise attending a scheduled visit. 
6.1.2. 
Type of Participant and Target Disease Characteristics 
1. Probable or possible PSP defined 
a. Based on the following: 
− A progressive history of postural instability during the first 3 years that symptoms 
are present 
OR 
− A progressive history of falls during the first 3 years that symptoms are present 


Protocol 251PP301 
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42 
 
b. Based on the following: 
− Vertical supranuclear gaze palsy defined as clear limitation of the range of 
voluntary gaze in the vertical more than in the horizontal plane, more than 
expected with age, which is overcome by activation with the vestibulo-ocular 
reflex (at later stages, the vestibulo-ocular reflex may be lost, or the maneuver 
prevented by nuchal rigidity). 
OR 
− Slow velocity of vertical saccades (i.e., decreased velocity [and gain] of vertical 
greater than horizontal saccadic eye movements). Gaze should be assessed by 
command to a stationary target rather than by pursuit, with the target >20 from 
the position of primary gaze. Typically, saccadic movement is slow enough for 
the examiner to see its progress, rather than just its initial and final positions. 
Deficits are more prominent in the vertical than the horizontal plane. A delay in 
initiation of saccades is not considered slowing. 
c. Age at symptom onset of 40 to 85 years by history, and current age between 41 and 
86 years, inclusive, at the time of screening. 
d. An akinetic-rigid syndrome. 
e. Presence of PSP symptoms for less than or equal to 5 years (determined by the best 
judgement of the Investigator) at screening. 
2. Body weight range of 43 kg/95 lbs. to 120 kg/265 lbs. 
3. Able to ambulate independently or with assistance defined as the ability to take at least 
10 steps with a walker (guarding is allowed provided there is no contact) or the ability to 
take at least 10 steps without a walker or cane with the assistance of another person who 
can only have contact with one upper extremity. 
4. Able to tolerate MRI. 
5. Able to perform all protocol-specified assessments and comply with the study visit 
schedule. 
6. Able to comply with neuropsychological evaluation at screening and throughout the 52-
week double-blind period of the study (determined by the best judgement of the 
Investigator). 
7. Have reliable caregiver to accompany participant to study visits. Caregiver must be able 
to read, understand, and speak local language fluently to ensure comprehension of 
informed consent and informant-based assessments of participant. Caregiver must also 
have frequent contact with participant (at least 3 hours per week at one time or different 
times) and be willing to monitor the participant’s health and concomitant medications 
throughout the study. Caregiver must be willing to sign and date an IRB-/IEC- approved 
written informed consent form in accordance with regulatory and institutional guidelines 
as appropriate. 
8. Score 20 on the Mini Mental State Examination (MMSE) at screening. 


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9. Participant must reside outside a skilled nursing facility or dementia care facility at the 
time of screening and admission to such a facility must not be planned. Residence in an 
assisted living facility is allowed. 
10. If participant is receiving coenzyme Q10, levodopa/carbidopa, levodopa/benserazide, 
fava bean extract, a dopamine agonist, catechol-O-methyltransferase inhibitor, 
amantadine, or other Parkinson’s disease medications, the dose must have been stable for 
at least 60 days prior to baseline and expected to remain stable for the double-blind 
period of the study. 
11. Stable on other chronic medications for at least 30 days prior to baseline. 
6.1.3. 
Age and Reproductive Status 
1. Males and females, ages 41 to 86 years, inclusive. 
2. Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotrophin) within 24 hours prior to the start of study treatment. 
3. Women must not be breastfeeding 
4. WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of treatment with study treatment(s) BIIB092 plus 5 half-lives of study treatment 
BIIB092 plus 30 days (duration of ovulatory cycle) for a total of 155 days post-treatment 
completion. 
5. Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (Appendix 4) for the duration of treatment with study 
treatment(s) BIIB092 plus 5 half-lives of the study treatment plus 90 days (duration of 
sperm turnover) for a total of 215 days post-treatment completion. In addition, male 
participants must be willing to refrain from sperm donation during this time. 
6. Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements 
and still must undergo pregnancy testing as described in this section. 
Investigators shall counsel WOCBP, and male participants who are sexually active with 
WOCBP, on the importance of pregnancy prevention and the implications of an unexpected 
pregnancy. Investigators shall advise on the use of highly effective methods of contraception 
(Appendix 4). 
6.2. 
Exclusion Criteria 
6.2.1. 
Medical Conditions 
1. Presence of other significant neurological or psychiatric disorders including (but not 
limited to) Alzheimer’s disease (AD), dementia with Lewy bodies; prion disease, 
Parkinson's disease (which has not subsequently been revised to a diagnosis of PSP); any 
psychotic disorder; severe bipolar or unipolar depression; seizure; brain tumor or other 
space-occupying lesion; history of clinically significant stroke (e.g., stroke with 


Protocol 251PP301 
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Phase 2b Study of BIIB092 in Participants with Progressive Supranuclear Palsy 
 
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neurological deficit); history of head injury with loss of consciousness for at least 
15 minutes within the past 20 years. 
2. Diagnosis of amyotrophic lateral sclerosis or other motor neuron disease. 
3. Diagnosis of cerebellar ataxia, choreoathetosis, and early symptomatic autonomic 
dysfunction. 
4. History of early, prominent rapid eye movement sleep behavior disorder. 
5. History of or screening brain MRI scan indicative of significant abnormality, including, 
but not limited to, prior hemorrhage or infarct >1 cm3, 3 lacunar infarcts, cerebral 
contusion, aneurysm, vascular malformation >1 cm3, subdural hematoma, hydrocephalus, 
and space-occupying lesion (e.g., abscess or brain tumor). 
6. Known history of serum or plasma progranulin level less than one standard deviation 
below the normal participant mean for the laboratory performing the assay. 
7. Known presence of known disease-associated mutation in C9ORF72, GRN, CHMPB2, 
TBK1, TARBP, or VCP genes or any other frontotemporal lobar degeneration causative 
genes not associated with underlying tau pathology (individuals with MAPT mutations 
may participate if they meet all other eligibility criteria). 
8. Any major surgery within 4 weeks of screening. 
9. History of deep brain stimulator surgery other than sham surgery for deep brain 
stimulation clinical trial. 
10. Inability to be venipunctured and/or tolerate venous access. 
11. Contraindication to the MRI examination for any reason. 
12. 
 
 
 
 
 
 
 
13. History of cancer within 5 years of screening with the exception of fully excised 
non-melanoma skin cancers or non-metastatic prostate cancer that has been stable for at 
least 6 months. 
14. History of clinically significant hematological, endocrine, cardiovascular, renal, hepatic, 
gastrointestinal, or neurological disease. 
15. Autoimmune disease (quiescent rheumatoid arthritis or controlled diabetes are 
acceptable). 
16. Blood transfusion within 4 weeks of screening. 


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17. Any vaccination within 30 days prior to screening. Vaccination may be allowed during 
the study according to guidance issued to study sites by the Sponsor; if necessary, please 
contact the Medical Monitor for that guidance. 
18. Known history of human immunodeficiency virus infection. 
19. Recent (within 6 months of study treatment administration) drug or alcohol abuse as 
defined in Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Diagnostic 
Criteria for Drug and Alcohol Abuse. 
20. Any history of clinically significant suicidal ideation and/or behavior within 1 year of 
screening as determined by the Investigator. 
21. History of a clinically significant medical condition that would interfere with the 
participant’s ability to comply with study instructions, would place the participant at 
increased risk, or might confound the interpretation of the study results. 
22. Any other sound medical, psychiatric, and/or social reason as determined by the 
Investigator. 
23. Current hepatitis C or hepatitis B infection 
• Current hepatitis C virus (HCV) infection (defined as positive HCV antibody and 
detectable HCV ribonucleic acid [RNA]). Participants with positive HCV antibody 
and undetectable HCV RNA are eligible to participate in the study (US Centers for 
Disease Control and Prevention). 
• Current hepatitis B infection (defined as positive for hepatitis B surface antigen 
[HBsAg] and/or hepatitis B core antibody [anti-HBc]). Participants with immunity to 
hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-
HBc, and positive hepatitis B surface antibody [anti-HBs]) or vaccination (defined as 
negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate 
in the study (US Centers for Disease Control and Prevention). 
6.2.2. 
Prior/Concomitant Therapy 
1. Within 4 weeks of screening (first visit) or anticipated during the 52-week double-blind 
period of the study, concurrent treatment with memantine; acetylcholinesterase inhibitors, 
antipsychotic agents, or mood stabilizers (e.g., valproate, lithium); or benzodiazepines, 
with the following exceptions: 
• Low dose lorazepam or other short-acting medications may be used for sedation prior 
to MRI scans for those participants requiring sedation. At the discretion of the 
Investigator, 0.5 to 1 mg may be given orally prior to scan with a single repeat dose 
given if the first dose is ineffective. Neuropsychological testing may not be 
performed on the same day of lorazepam administration. Participants and caregiver 
must be informed of risks of lorazepam use prior to administration. 
• Participants who take short-acting benzodiazepines or other hypnotics (e.g., 
temazepam, zolpidem) for sleep may continue to do so if they have been on a stable 
dose for 30 days prior to screening. 


Protocol 251PP301 
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Phase 2b Study of BIIB092 in Participants with Progressive Supranuclear Palsy 
 
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46 
 
• Clonazepam may be used for treatment of restless legs syndrome, dystonia, or painful 
rigidity associated with PSP if the dose has been stable for 60 days prior to screening. 
• Quetiapine or clozapine may be permitted if at a stable dose for at least 60 days prior 
to screening. 
2. Receipt of systemic corticosteroids within 30 days prior to baseline. 
3. Receipt of an investigational immunomodulator or mAb within 180 days (or 5 half-lives, 
whichever is longer) prior to screening. 
4. Treatment with any other investigational drugs (e.g., salsalate) including placebo or 
devices within 90 days prior to screening. 
6.2.3. 
Physical and Laboratory Test Findings 
1. Evidence of organ dysfunction or any clinically significant deviation from normal in 
physical examination, vital signs, ECG, or clinical laboratory determinations beyond 
what is consistent with the target population. 
2. Clinically significant abnormality on 12-lead ECG prior to study treatment 
administration, confirmed by repeat. 
3. Total bilirubin, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) 
greater than 2 times the upper limit of normal (ULN), confirmed by repeat. Elevated total 
bilirubin suspected to be due to Gilbert syndrome should be discussed with the Medical 
Monitor. 
4. Serum creatinine >168  mol/L (1.9 mg/dL), confirmed by repeat. 
5. Hematocrit <30%, absolute neutrophil cell count of 1500/L (with the exception of a 
documented history of a chronic benign neutropenia), or platelet cell count of 
<120,000/L, or International normalized ratio (INR) >1.4 or other coagulopathy, 
confirmed by repeat. (Note: Participants with INR >1.4 due to antiplatelet/anticoagulant 
medications are eligible.) 
6. A clinically significant abnormal thyroid-stimulating hormone test. 
7. 
 
 
 
 
8. Hemoglobin A1C (HbA1C) >8%, confirmed by repeat. 
6.2.4. 
Allergies and Adverse Drug Reaction 
1. History of allergy, hypersensitivity, or serious adverse reaction to mAbs or related 
compounds. 
2. Allergy to any of the components of the study treatment, such as Polysorbate 80. 
3. History of any significant drug allergy (such as anaphylaxis or hepatotoxicity). 


Protocol 251PP301 
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47 
 
6.2.5. 
Other Exclusion Criteria 
1. Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to 
continue as a participant. Strict conditions apply and Biogen approval is required.) 
2. Participants who are compulsorily detained for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness. 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria. 
6.3. 
Lifestyle Restrictions 
Participants who are active tobacco smokers should not currently be smoking more than 
10 cigarettes per day. 
6.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials publishing requirements, and to respond to queries from regulatory authorities. 
Minimal information includes date of consent, demography, screen failure details, eligibility 
criteria, and any SAEs. 
6.4.1. 
Retesting During Screening or Lead-In Period 
Participant Re-screening: This study permits the re-screening of a participant who screen-failed 
up to 2 times (i.e., participant was not randomized or treated). If re-screened, the participant must 
be re-consented. The assessments to be conducted on re-screening will depend upon how much 
time passed since the previous Screening Visit. Please contact the Medical Monitor for guidance 
regarding the acceptability of any previous assessments completed. 
Retesting of laboratory parameters and/or other assessments within any single screening or lead-
in period will be permitted (in addition to any parameters that require a confirmatory value). 
The most current result prior to Randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state. 
Laboratory parameters and/or assessments that are included in Table 1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant. 


Protocol 251PP301 
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48 
 
7. 
TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation. 
Study treatment includes both Investigational [Medicinal] Product (IP/IMP) and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) as listed in the following table. 
Study Treatment for Study 251PP301 
Medication 
Potency 
IP/Non-IP 
BIIB092a 
50 mg/mL 
IP 
Placebob (0.9% Sodium Chloride) 
N/A 
IP 
IP = investigational product 
a Study treatment supplies may be labeled as BIIB092 or BMS-986168. The 2 study treatment names refer to an 
identical drug substance. 
b The 5% dextrose injection can be used if sodium chloride is not available. 
An IP, also known as IMP in some regions, is defined a pharmaceutical form of an active 
substance or placebo being tested or used as a reference in a clinical study, including products 
already with a marketing authorization but used or assembled (formulated or packaged) 
differently than the authorized form, or used for an unauthorized indication, or when used to gain 
further information about the authorized form. 
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products. 
A rescue medication such as EpiPen or Epi-kit (containing 1 mg/mL of epinephrine) will be 
dispensed for home care visits, for use in the event of an allergic reaction. 
See Table 6 for details regarding study treatments. 
 


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Table 6: 
Study Treatments for Study 251PP301 
Product Descriptiona 
Potency 
IP/Non-IMP 
Study Period 
Packaging/Appearance 
Storage Conditions 
(per label) 
BIIB092 Injection, 
1000 mg/vialb 
50 mg/mL 
IP 
Double-blind  
BIIB092 is supplied as a liquid drug 
product in glass vials containing an 
extractable dose per the DHA 
Store refrigerated 2°C to 
8°C 
Protect from light 
Do not freeze 
BIIB092 Injection, 
1000 mg/vial b 
50 mg/mL 
IP 
Open-label 
extension 
BIIB092 is supplied as a liquid drug 
product in glass vials containing an 
extractable dose per the DHA 
Store refrigerated 2°C to 
8°C 
Protect from light 
Do not freeze 
BIIB092 Injection, 
2000 mg/vial b 
50 mg/mL 
IP 
Open-label 
extension 
BIIB092 is supplied as a liquid drug 
product in glass vials containing an 
extractable dose per the DHA 
Store refrigerated 2°C to 
8°C 
Protect from light 
Do not freeze 
Placebo (0.9% Sodium 
Chloride or 5% Dextrose) c 
0.9% NaCl 
Or 
5% dextrose 
IP 
Double-blind 
Per product label 
Per product label 
DHA = Directions for Handling and Administration; IMP = investigational medicinal product; IP = investigational product; N/A = not applicable 
a BIIB092 dosage form and composition are provided in the DHA 
b BIIB092 is provided open-label to the unblinded pharmacist. After study treatment is prepared by the unblinded pharmacist all other study personnel will 
remain blinded to the identification of study treatment (BIIB092 vs. placebo) through Week 48. 
c Placebo is not provided by Biogen and obtained commercially by the site; storage should be in accordance with the product label. 


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7.1. 
Treatments Administered 
The selection and timing of dose for each participant is as follows (Table 7): 
Table 7: 
Selection and Timing of Dose 
 
Study Treatment Unit Dose Strength(s)/ 
Dosage Level(s) 
Dosage Formulation 
Frequency of 
Administration 
Route of Administration 
BIIB092 
2000 mg 
Q4W 
IV 
Placebo 
Matching dose volume 
at 0.9% NaCl or 5% 
Dextrose 
Q4W 
IV 
IV = intravenous; Q4W = Once every 4 weeks. 
7.2. 
Method of Treatment Assignment 
All participants will be centrally randomized using an Interactive Response Technology (IRT). 
Before the study is initiated, each user will receive log in information and directions on how to 
access the IRT. Randomization will be stratified by country and screening CTT Part 2 stratum of 
a score either less than or equal to 170 seconds or greater than 170 seconds. Randomization will 
only be stratified by screening CTT Part 2 stratum under the IRT system for protocol Version 1. 
To promote treatment balance within each country, randomization will be stratified by both 
country and screening CTT Part 2 when the new IRT system for this protocol is in place.  
Study treatment will be dispensed at the study visits as listed in Schedule of Activities 
(Section 2). 
7.3. 
Blinding 
Blinding of treatment assignment is critical to the integrity of this clinical study. However, in the 
event of a medical emergency or pregnancy in an individual participant in which knowledge of 
the investigational product is critical to the participant's management, the blind for that 
participant may be broken by the Investigator. The participant’s safety takes priority over any 
other considerations in determining if a treatment assignment should be unblinded. 
Before breaking the blind of an individual participant's treatment, the Investigator should 
determine that the unblinded information is necessary, i.e., that it will alter the participant’s 
immediate management. In many cases, particularly when the emergency is clearly not related to 
the IP, the problem may be properly managed by assuming that the participant is receiving active 
product. It is highly desirable that the decision to unblind treatment assignment be discussed with 
the Medical Monitor, but the Investigator always has ultimate authority for the decision to 
unblind. The Principal Investigator should only call in for emergency unblinding AFTER the 
participant has made the decision to discontinue from study treatment. 
For information on how to unblind in an emergency, consult the IRT manual. 


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In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind. The Bioanalytical Sciences section or its designate will be unblinded to the 
randomized treatment assignments in order to minimize unnecessary analysis of samples from 
control group participants. 
Any request to unblind a participant for non-emergency purposes should be discussed with the 
Medical Monitor. 
7.4. 
Dosage Modification 
There will be no dose escalations or reductions of study treatment allowed. 
Participants may be dosed within a ±3-day window for each dosing visit in the double-blind 
portion of the study after the first dose administered on Day 1 of Week 0. For the open-label 
extension period of the study, participants may be dosed within a ±7-day window for each dosing 
visit. 
Participants should be carefully monitored for infusion reactions during administration. If an 
acute infusion reaction is noted, participants should be managed according to Section 14. 
Dosing visits should generally not be skipped, only delayed. In the unusual circumstance where 
an extended delay occurs (e.g., 2 weeks or more), the Investigator should discuss this with the 
Medical Monitor. 
7.5. 
Preparation/Handling/Storage/Accountability 
Study treatment will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice. 
BIIB092 is supplied as a liquid drug product in glass vials containing an extractable dose per the 
Directions for Handling and Administration (DHA). The contents of the BIIB092 label will be in 
accordance with all applicable regulatory requirements. BIIB092 should not be used after the 
expiration date. 
BIIB092 must be stored refrigerated between 2°C and 8°C with protection from light. Study 
treatment not supplied by Biogen will be stored in accordance with the package insert. 
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by the DHA. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment 
should not be dispensed, and Biogen should be contacted immediately. 
The study treatment should be stored in a secure area according to local regulations. It is the 
responsibility of the Investigator to ensure that study treatment is only dispensed to study 
participants. The study treatment must be dispensed only from official study sites by authorized 
personnel according to local regulations. 
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, storage, and disposal of the study treatment. The DHA will also describe the 
masking of the IV bags of study treatment (both BIIB092 and placebo) to maintain the treatment 
blind. The DHA supersedes all other references (e.g., protocol or Investigator’s Brochure). 


Protocol 251PP301 
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Investigational product documentation (whether supplied by Biogen or not) must be maintained 
to ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (e.g., required diluents, administration sets). 
7.5.1. 
Retained Samples for Bioavailability/Bioequivalence 
Not Applicable. 
7.6. 
Treatment Compliance 
Not applicable as treatment is IV infusion. 
7.7. 
Concomitant Therapy 
7.7.1. 
Prohibited and/or Restricted Treatments  
Prohibited and/or restricted medications taken prior to study treatment administration and during 
the study are described below. Medications taken within 4 weeks prior to study treatment 
administration and during study treatment must be recorded on the case report form (CRF). 
1. Prior exposure to BIIB092. 
2. Within 4 weeks of screening or anticipated during the 52-week double-blind portion of 
the study, concurrent treatment with memantine; acetylcholinesterase inhibitors; 
antipsychotic agents or mood stabilizers (e.g., valproate, lithium); or benzodiazepines, 
with the following exceptions: 
a. Low dose lorazepam or other short-acting medications may be used for sedation prior 
to MRI scans for those participants requiring sedation. At the discretion of the 
Investigator, 0.5 to 1 mg may be given orally prior to scan with a single repeat dose 
given if the first dose is ineffective. Neuropsychological testing may not be 
performed on the same day of lorazepam administration. Participants and caregiver 
must be informed of risks of lorazepam use prior to administration. 
b. Participants who take short-acting benzodiazepines or other hypnotics (e.g., 
temazepam, zolpidem) for sleep may continue to do so if they have been on a stable 
dose for 30 days prior to screening. 
c. Clonazepam may be used for treatment of restless legs syndrome, dystonia, or painful 
rigidity associated with PSP if the dose has been stable for 60 days prior to screening. 
d. Quetiapine or clozapine may be permitted if at a stable dose for at least 60 days prior 
to screening. 
3. Receipt of systemic corticosteroids within 30 days prior to screening. 
4. Receipt of an investigational immunomodulator or mAb within 180 days (or 5 half-lives, 
whichever is longer) prior to screening. 
5. Treatment with any other investigational drugs (e.g., salsalate) including placebo or 
devices within 90 days prior to screening. 


Protocol 251PP301 
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No concomitant medications (prescription, over-the-counter, or herbal) should be administered 
during study unless they are prescribed for treatment of specific clinical events. Any concomitant 
therapies must be recorded on the CRF. 
The Investigator should contact and confirm agreement with the Medical Monitor prior to the 
administration of any concomitant medications that may be prohibited and/or restricted. 
7.7.2. 
Other Restrictions and Precautions 
7.7.2.1. 
Imaging Restriction and Precautions 
The imaging specialist at the study site’s MRI facility is responsible for determining if a 
participant is contraindicated from having this procedure. The following is a list of some 
common conditions that may preclude the participant from having MRI scans. However, this 
should not be used as a substitute for local clinical standards of care. The ultimate decision to 
perform the MRI rests with the site radiologist, the Investigator, and the standard set by the local 
IRB/IEC: 
• A history of claustrophobia 
• An MRI-incompatible pacemaker, epicardial pacemaker wires, incompatible cardiac 
valve prostheses, and MRI-incompatible vascular clips less than 2 months old or 
MRI-incompatible aneurysm clips of any age 
• An MRI-incompatible cochlear implant 
• An MRI-incompatible spinal nerve stimulator 
• An MRI-incompatible infusion pump 
• Metallic fragments in the eyes/orbits or in the vicinity of the brain or major 
neurovascular structures of the body 
• An employment history that involves exposure to welding, unless absence of metallic 
fragments is documented by X-ray examination as per institutional practice 
• Shrapnel at any place in the body 
7.8. 
Treatment After the End of the Study 
Sometime after the completion of the double-blind portion of the study, the Investigator may be 
unblinded to participant’s treatment to either BIIB092 or placebo. 
Biogen reserves the right to terminate access to Biogen supplied study treatment if any of the 
following occur: a) the study is terminated due to safety concerns; b) the development of 
BIIB092 is terminated for other reasons, including, but not limited to, lack of efficacy and/or not 
meeting the study objectives; c) the participant can obtain medication from a 
government-sponsored or private health program. In all cases, Biogen will follow local 
regulations. 


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8. 
DISCONTINUATION CRITERIA 
8.1. 
Discontinuation From Study Treatment 
Participants MUST discontinue study treatment (and non-IP at the discretion of the Investigator) 
for any of the following reasons: 
• Participant’s request to stop study treatment. Participants who discontinue study 
treatment and remain enrolled in the study will be expected to complete scheduled 
safety and efficacy evaluations until the decision is made to withdraw from the study.  
• Any clinical AE, laboratory abnormality, or intercurrent illness which, in the opinion 
of the Investigator, indicates that continued participation in the study is not in the best 
interest of the participant 
• Termination of the study by Biogen 
• Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness 
In the case of pregnancy, the Investigator must immediately notify the Medical Monitor of this 
event and study treatment must be discontinued immediately. In most cases, the study treatment 
will be permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for 
participant safety). Please call the Medical Monitor within 24 hours of awareness of the 
pregnancy. If the Investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study treatment, a discussion between the Investigator and the Medical 
Monitor/designee must occur. 
If study treatment is discontinued prior to the participant’s completion of the study, the reason 
for the discontinuation must be documented in the participant’s medical records and entered on 
the appropriate CRF page. 
8.2. 
Study Follow-Up 
In this study, safety is a key endpoint of the study. Study follow-up is of critical importance and 
is essential to preserving participant safety and the integrity of the study.  
Participants who discontinue study treatment and remain in the study will be expected to 
complete scheduled safety and efficacy tests and assessments until the end of study or 
withdrawal of consent (see Table 2 and Table 3). Participants who discontinue study treatment 
and remain in the study should have all AEs collected up to 30 days after the last dose of study 
treatment. AE collection should continue until the end of study or withdrawal from the study.  
At any point after discontinuing study treatment, if the participant makes the decision to 
withdraw from the study (see Section 8.3), the following should be done: 
• Early Discontinuation visit procedures should be completed. 
• Participants and/or caregivers should receive a follow-up phone call approximately 
30 days after discontinuation of study treatment to collect relevant clinical 


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information, including, but not limited to, safety data (i.e., AEs, SAEs) and vital 
status (e.g., ability to ambulate, cognitive disability, speech, dysphagia, dependence 
on wheelchair for mobility, placement in residential care, and death). 
8.3. 
Withdrawal From the Study 
Participants who request to withdraw from the study should complete the Early Discontinuation 
visit procedures (Table 2 and Table 3). The only exception to this is when a participant 
specifically withdraws consent for any further contact with him/her or persons previously 
authorized by participant to provide this information.  
• Participants should notify the Investigator of the decision to withdraw consent from 
future follow-up in writing, whenever possible. 
• The withdrawal of consent should be explained in detail in the medical records by the 
Investigator, as to whether the withdrawal is from further treatment with study 
treatment only or also from study procedures and/or post treatment study follow-up 
and entered on the appropriate CRF page. 
• In the event that vital status (whether the participant is alive or dead) is being 
measured, publicly available information should be used to determine vital status only 
as appropriately directed in accordance with local law. 
• If the participant withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
8.4. 
Lost to Follow-Up 
• All reasonable efforts must be made to locate participants to determine and report 
their ongoing status. This includes follow-up with persons authorized by the 
participant. 
• Lost to follow-up is defined by the inability to reach the participant after a minimum 
of three documented phone calls, faxes, or emails as well as lack of response by 
participant to one registered mail letter. All attempts should be documented in the 
participant’s medical records. 
• If it is determined that the participant has died, the site will use permissible local 
methods to obtain date and cause of death. 
• The site staff and representative will consult publicly available sources, such as 
public health registries and databases, in order to obtain updated contact information. 
• If after all attempts, the participant remains lost to follow-up, then the last known 
alive date as determined by the Investigator should be reported and documented in the 
participant’s medical records. 


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9. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and timing are summarized in the Schedule of Activities 
(Section 2). 
• Protocol waivers or exemptions are not allowed. 
• All immediate safety concerns must be discussed with the Medical Monitor 
immediately upon occurrence or awareness to determine if the participant should 
continue or discontinue treatment. 
• Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The Investigator will 
maintain a screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of informed consent may be utilized for 
screening or baseline purposes provided the procedure meets the protocol-defined 
criteria and has been performed within the timeframe defined in the Schedule of 
Activities. 
9.1. 
Efficacy Assessments 
Each of the clinician-reported outcome measures described below will be performed by an 
appropriately qualified individual, for example a psychometrist or neurologist. The specific 
requirements will be documented in the procedure manual. The PSPRS and RBANS may be 
recorded (either audio or video) in order to allow for central review for standardization of test 
administration where allowable by country and/or local authorities. 
Each of the participant-reported outcome measures described below may be administered as 
clinician-reported outcome measures where allowable by the assessments author/developer 
meaning that the assessments will be completed by a qualified member of the site staff, who will 
be reporting information collected from the participant and/or the caregiver as appropriate in 
order to promote consistent quality, standardization of test, and minimize burden on the study 
participant and/or caregiver. 
These assessments are described below: 
PSPRS 
The PSPRS [Golbe and Ohman-Strickland 2007] is a quantitative measure of disability in 
participants with PSP. The PSPRS comprises 28 items in six areas. The available total score 
ranges from 0 (normal) to 100. Six items are rated on a 3-point scale (0 to 2), and 22 are rated on 
a 5-point scale (0 to 4). The History/Daily Activities area includes seven items with a total 
maximum of 24 points, the mentation area four items with 16 points, the bulbar area two items 
with 8 points, the ocular motor area four items with 16 points, the limb motor area six items with 


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16 points, and the gait area five items with 20 points. The PSPRS should be conducted by a 
neurologist. 
MDS-UPDRS Part II 
The MDS-UPDRS Part II includes 13 items assessing motor aspects of experiences of daily 
living [Goetz 2007]. These include speech, saliva and drooling, chewing and swallowing, 
handwriting, doing hobbies and other activities, eating tasks, tremor, dressing, hygiene, turning 
in bed, getting out of bed, walking and balance, and freezing. 
CGI-S and CGI-C 
The CGI-S measures the symptomatology of the disease using a 7-point scale. The CGI-C [Guy 
1976] scale measures the change in the participant’s clinical status from a specific point in time. 
Using a 7-point scale, ranging from 1 (very much improved) to 7 (very much worse), with a 
score of 4 indicating no change. Whenever possible, for any individual participant, this 
assessment should be done by the same rater throughout the study. The CGI-C should be 
assessed relative to the CGI at the Week 0 (Day 1) visit as the reference. A version of the CGI 
that has been modified for use in Participants with PSP will be used in this study [Boxer 2014]. 
RBANS 
The RBANS [Randolph 1998] was developed for the dual purposes of identifying and 
characterizing abnormal cognitive decline in the older adult. The full battery is composed of 
12 subtests. 
PSP-QoL 
The PSP-QoL [Schrag 2006] is a participant-reported outcome measure developed specifically 
for assessing the health-related quality of life in people living with PSP. It is a validated 45-item 
questionnaire and visual analog scale that is comprised of two subscales: physical health state 
(22 items), which covers mobility, dysarthria, dysphagia, visual disturbances, self-care, and 
activities of daily living, and mental health state (23 items), which covers emotional, cognitive, 
and social functioning. Items are given a 5-response option format (0 = no problem to 
4 = extreme problem). The subscale results are derived by summing the respective items for that 
subscale and transforming the scores into a range of 0 to 100, with higher scores indicating a 
greater impact of the disease on the aspect measured. The scale has high internal consistency in 
both physical health and mental health subscales (Cronbach’s alpha = 0.93 and 0.95, 
respectively). 
SEADL scale 
The SEADL scale [Dal Bello-Haas 2011] is a means of assessing a person’s ability to perform 
daily activities in terms of speed and independence through a percentage figure. The rating will 
be determined by a qualified staff member according to the participant’s self-reported functional 
ability of specific criteria, with 100% indicating total independence and falling to 0% indicating 
a state of complete dependence. 
QMA  
QMA evaluates the effect of BIIB092 on motor function during typical daily activities. 
Participants in the QMA substudy will undergo quantitative assessments of core motor features 


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of PSP using wearable sensors to measure gait, postural instability, motor function, and falls (see 
Table 4). Participants will be asked to perform motor tasks while wearing lightweight 
accelerometers on their neck, feet, lower back, and wrists. Refer to the QMA manual for details 
of each assessment. The following tests will be performed for QMA: 
• Falls: Participants will be asked to wear a necklace-like sensor at home to capture any 
fall data and quantify the number of falls. 
• Sway: A postural sway test will be conducted, where the participant will be asked to 
remain standing still for 30 seconds while staring at a fixed object on a wall 1 to 4 m 
away. A foot block will be placed between the participant’s feet. Sway jerk, velocity, 
and frequency dispersion will be determined. 
• Gait: Gait speed, stride length, foot strike angle, arm swing range of motion, and turn 
velocity will be determined. 
− Usual gait: The participant will be asked to walk back and forth over a 7-m 
distance, at a comfortable speed, for approximately 2 minutes.  
− Dual-task gait: The participant will be asked to walk back and forth over a 7-m 
distance, at a comfortable speed, while doing a cognitive task, for approximately 
1 minute.  
• Timed chair stands (TCS): This performance-based measure will evaluate the amount 
of time it takes for a participant to rise from a chair and sit down.  
• Instrumented push and release test: This evaluation is similar to a retropulsion test but 
with a standardized pull of force. Participants will lean backward into the examiner 
and will be given a small push and release to quantify postural stepping response. 
• Rapid successive movements: Assessment of rapid successive movements consists of 
2 tasks. Each task will be performed separately for the left and right limbs. Change in 
frequency and amplitude of repetitive movements will be determined during each of 
the following tasks:  
− Toe taps: For this task, both feet will be flat on the floor. Participants will be 
asked to tap their toe as high and as fast as they can without lifting their heel. The 
other foot must remain still.  
− Wrist rotations: For this task, the hand is fully extended. Participants will be 
asked to alternate between having the palm fully up and fully down. This pattern 
will be repeated as quickly as possible.  
• Orthostatic vitals: Resting heart rate and blood pressure will be recorded after the 
participant has been seated for a few minutes. The participant will then be asked to 
stand, and blood pressure and heart rate will be recorded within the first 30 seconds 
and after an additional 3 minutes. 
• Visual acuity: A standard printed Snellen eye chart will be used with the participant 
6 m away.  


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• Joint position test: Position sense will be tested by having the participant close their 
eyes and report if their large toe is “up” or “down” when the examiner manually 
moves the participant's toe in the respective direction.  
• Strength test of hip flexion and knee extension: The participant is tested in the 
recumbent position on the back. Hip flexion and knee extension strength are given a 
Medical Research Council (MRC) Grade from 0 to 5 for each side. 
Phonemic Fluency 
Phonemic fluency is a sensitive test for assessing frontal lobe dysfunction. The participants will 
be given a letter of the alphabet and asked to name as many words as they can that start with that 
letter, in 1 minute. 
LNS 
LNS is a test of working memory which involves ordering a series of up to seven letters and 
numbers in which the numbers are repeated back first in order starting with the lowest number, 
then followed by the letters in alphabetical order. For example, 3 - W - 5 should be repeated back 
as 3 - 5 - W. 
CTT 
The CTT is a language-free version of the Trail Making Test and was developed to allow for 
broader cross-cultural assessment. Numbered circles are printed with vivid pink or yellow 
backgrounds that are perceptible to color-blind individuals. For Part 1, the respondent uses a 
pencil to rapidly connect circles numbered 1 to 25, in sequence. For Part 2, the respondent 
rapidly connects numbered circles in sequence, but alternates between pink and yellow. The 
length of time to complete each trial is recorded, along with qualitative features of performance 
indicative of brain dysfunction, such as near-misses, prompts, number sequence errors, and color 
sequence errors. 
MoCA 
The MoCA [Nasreddine 2005] was designed as a rapid screening instrument for mild cognitive 
dysfunction. It assesses different cognitive domains: attention and concentration, executive 
functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and 
orientation. Time to administer the MoCA is approximately 10 minutes. 
EuroQol 
The EuroQol [Brooks 1996; Rabin and de Charro 2001; The EuroQol Group 1990] is a 
standardized instrument for use as a measure of health outcome. It assesses health-related quality 
of life in five dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression). The
 version of the instrument will be used to measure 
health-related quality of life for participants and/or caregivers as appropriate. 
 
 
 
 


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9.2. 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities (Section 2). 
9.2.1. 
Physical Examinations 
Refer to the Schedule of Activities. 
9.2.2. 
Vital signs 
Refer to the Schedule of Activities. 
9.2.3. 
ECGs 
Refer to the Schedule of Activities. 
9.2.4. 
Clinical Safety Laboratory Assessments 
Investigators must document their review of each laboratory safety report.  




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Pregnancy test (women of childbearing potential only: screening, predose, discharge). 
Follicle-stimulating hormone (screening only for women only) 
 
 
 
a Thyroxine and triiodothyronine were tested if thyroid-stimulating hormone result was abnormal.  
b Hepatitis C antibody RNA was tested if the hepatitis C antibody result was abnormal. 
9.2.5. 
Suicidal Risk Monitoring 
BIIB092 is considered to be a central nervous system (CNS)-active study treatment. There has 
been some concern that some CNS-active study treatments may be associated with an increased 
risk of suicidal ideation or behavior when given to some participants with certain conditions. 
Although this study treatment or other similar drugs in this class have not been shown to be 
associated with an increased risk of suicidal thinking or behavior when given to healthy 
volunteers or participants with PSP, Biogen considers it important to monitor for such events 
before and during this clinical study. 
Participants being treated with BIIB092 should be monitored appropriately and observed closely 
for suicidal ideation and behavior or any other unusual changes in behavior. Consideration 
should be given to discontinuing BIIB092 in participants who experience signs of suicidal 
ideation or behavior. 
Families and caregivers of participants being treated with BIIB092 should be instructed to 
monitor participants for the emergence of unusual changes in behavior, as well as the emergence 
of suicidal ideation and behavior, and to report such symptoms immediately to the Study 
Investigator. 
Baseline assessment of suicidal ideation and behavior and treatment-emergent suicidal ideation 
and behavior will be monitored during the study using the 
 Refer to Section 9.4 for more 
information. 
9.2.6. 
Imaging Safety Assessment 
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
 
9.3. 
Imaging Assessment for the Study 
MRI 
A central imaging vendor will perform imaging analyses. Image acquisition guidelines and 
submission processes will be outlined in the Study 251PP301 Imaging Manual to be provided by 
the core central imaging vendor. Sites will be trained prior to scanning the first study participant. 
Brain volumetric measurements will be done using 3D T1-weighted MRI to estimate brain 
volumes (e.g., ventricles, whole brain, midbrain, pons, superior cerebellar peduncle, third 


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ventricle, and frontal lobes). Specifically, a three-dimensional MRI sequence with 1.0 x 1.0 x 1.2 
mm isotropic voxels will be acquired according to the AD Neuroimaging Initiative 
recommendation. 1.5 T and 3.0 T MRI scanners will be employed in this study. The volumes of 
7 brain structures of particular relevance in PSP (ventricles, whole brain, midbrain, pons, 
superior cerebellar peduncle, third ventricle and frontal lobes) will be measured. In addition, 
volumes of additional brain structures will also be measured (e.g., gray/white matter, cerebrum, 
cerebral cortex, frontal/parietal/temporal/occipital lobes, hippocampus, caudate nucleus, 
cerebellum, brainstem, medulla oblongata). In addition, fluid attenuation inversion recovery 
(FLAIR) and T2 sequences will be performed to exclude new pathologies. 
All MRI scans will be locally and centrally read. Local reads should be performed to confirm 
eligibility. 
9.4. 
Other Assessments 
 
 
 
 
 
 
 
 
 


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10. 
ADVERSE EVENTS 
The definitions of an AE or SAE can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver or surrogate). 
The Investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up on AEs 
that are serious, considered related to the study treatment or the study, or that caused the 
participant to withdraw before completing the study. 
Contacts for SAE reporting are specified in Appendix 3. 
10.1. 
Time Period and Frequency for Collecting AE and SAE Information 
The collection of nonserious AE information should begin at initiation of study treatment and 
continue until end of study at the timepoints specified in the Schedule of Activities (Section 2). 
Section 6.6 in the Investigator’s Brochure represents the Reference Safety Information to 
determine expectedness of SAEs for expedited reporting. Following the participant’s written 
consent to participate in the study, all SAEs, whether related or not related to study treatment, 
must be collected, including those thought to be associated with protocol-specified procedures. 
All SAEs must be collected that occur during the screening period, continuously throughout the 
study, and until 30 days following the last dose (see Table 2 and Table 3). 
• Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the appropriate section of the electronic case 
report form (eCRF) section. 
• All SAEs will be recorded and reported to Sponsor within 24 hours, as indicated in 
Appendix 3. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
this being available. 
• Investigators are not obligated to actively seek AEs or SAEs in former study 
participants; however, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study and he/she considers the 
event reasonably related to the study treatment or study participation, the Investigator 
must promptly notify the Sponsor. 
• The method of evaluating and assessing causality of AEs and SAEs and the 
procedures for completing and reporting/transmitting SAE reports are provided in 
Appendix 3. 
10.2. 
Method of Detecting AEs and SAEs 
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a participant. (In order to prevent reporting bias, participants should not be 
questioned regarding the specific occurrence of one or more AEs.) 


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10.3. 
Follow-up of AEs and SAEs 
Nonserious AEs should be followed to resolution or stabilization or reported as SAEs if they 
become serious (see Appendix 3). 
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment, as appropriate. 
All identified nonserious AEs must be recorded and described on the nonserious AE page of the 
CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs and/or 
laboratory abnormalities that are reported/identified during the course of the study. 
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.4). 
Further information on follow-up procedures is given in Appendix 3. 
10.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification from the Investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met. 
An Investigator who receives an Investigator safety report describing SAEs or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
The Sponsor will be reporting AEs to regulatory authorities and ethics committees according to 
local applicable laws, including European Directive 2001/20/EC and Food and Drug 
Administration Code of Federal Regulations (CFR) 21 CFR Parts 312 and 320. A (suspected, 
unexpected serious adverse reaction (SUSAR) is a subset of SAEs and will be reported to the 
appropriate regulatory authorities and Investigators following local and global guidelines and 
requirements. 
10.5. 
Pregnancy 
Participants should not become pregnant or impregnate their partners for the duration of 
treatment with study treatment(s) BIIB092 plus 5 half-lives of study treatment BIIB092 
plus 30 days for females (duration of ovulatory cycle) or 90 days for males (duration of 
sperm turnover) for a total of 155 days or 215 days for females and males, respectively. If a 
female participant becomes pregnant, study treatment must be discontinued immediately. 
The Investigator must report a pregnancy occurring in a female participant by faxing or emailing 
the appropriate form to Biogen within 24 hours of the site staff becoming aware of the 
pregnancy. Refer to the Study Contact List for complete contact information. The Investigator or 
site staff must report the outcome of the pregnancy to Biogen. A pregnancy is not considered an 
AE and should not be recorded on the AE CRF. 
Congenital abnormalities and birth defects in the offspring of male or female participants should 
be reported as an SAE if conception occurred during the study treatment period. 


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10.6. 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning. 
• Any laboratory test result that is clinically significant or meets the definition of an 
SAE 
• Any laboratory test result abnormality that required the participant to have study 
treatment discontinued or interrupted 
• Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy 
It is expected that wherever possible, the clinical rather than laboratory term should be used by 
the reporting Investigator (e.g., anemia versus low hemoglobin value). 
10.7. 
Potential Drug Induced Liver Injury 
Potential drug induced liver injury (DILI) is defined as follows: 
Aminotransaminases (ATs), including ALT or AST elevation >3 times ULN  
AND 
Total bilirubin >2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND 
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
All occurrences of potential DILIs, meeting the defined criteria must be reported as SAEs (see 
Section 10 and Appendix 3 for reporting details). 
10.8. 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, ECG, x-ray 
filming, or any other potential safety assessment required or not required by protocol should also 
be recorded as a nonserious AE or SAE, as appropriate, and reported accordingly. 
10.9. 
Expectedness of Events 
Expectedness of all AEs will be determined by Biogen according to the Investigator’s Brochure. 
10.10. 
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. 


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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. 
10.11. 
Overdose  
An overdose is any dose of study treatment administered to a participant or taken by a participant 
that exceeds the dose assigned to the participant according to the protocol. Overdoses are not 
considered AEs and should not be recorded as an AE on the CRF; however, all overdoses must 
be recorded on an Overdose form and faxed or emailed 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 or 
emailed to Biogen. All study treatment-related dosing information must be recorded on the 
dosing CRF. 
10.12. 
Medical Emergency  
In a medical emergency requiring immediate attention, site staff will apply appropriate medical 
intervention, according to current standards of care. The Investigator (or designee) should 
contact the study’s Medical Director. Refer to the Study Contact List for complete contact 
information. 
10.13. 
Unblinding for Medical Emergency 
In a medical emergency when knowledge of the participant’s treatment assignment may 
influence the participant’s clinical care, the Investigator may access the participant’s treatment 
assignment by IRT. The Investigator must document the reasons for unblinding in the 
participant’s source documents. The Investigator is strongly advised not to divulge the 
participant’s treatment assignment to any individual not directly involved in managing the 
medical emergency, or to personnel involved with the analysis and conduct of the study. The 
Investigator can contact Biogen to discuss such situations. 
10.14. 
Deaths 
Death is an outcome of an event. The event that resulted in death should be recorded on the 
appropriate CRF. All causes of death must be reported as SAEs within 24 hours of the site 
becoming aware of the event. The Investigator should make every effort to obtain and send death 
certificates and autopsy reports to Biogen. The term death should be reported as an SAE only if 
the cause of death is not known and cannot be determined. 


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11. 
PHARMACOKINETICS 
The PK data obtained in this study will be combined with data from other studies in the clinical 
development program to develop a population PK model. This model will be used to evaluate the 
effects of intrinsic and extrinsic covariates on the PK of BIIB092 and to determine measures of 
individual exposure (such as steady-state trough, or time-averaged concentration, or area under 
the concentration-time curve). Model determined exposures will be used for exposure-response 
analyses of selected efficacy and safety end points. Results of population PK and exposure-
response analyses will be reported separately. 
Table 9 lists the sampling schedule to be followed for the assessment of pharmacokinetics in 
serum and CSF. Further details of blood and CSF collection and processing will be provided to 
the site in the procedure manual and laboratory manual. 
Serum samples will be analyzed for BIIB092 using a validated ligand binding assay. 
Pharmacokinetic samples collected from a participant who received placebo will not be 
analyzed. 
Table 9: 
Pharmacokinetic Sampling Schedule 
Study Week of 
Sample Collection 
Event 
Estimated Time 
(Relative to start 
of Infusion of 
BIIB092) 
Hour: Min 
BIIB092 Blood 
Sample for Serum 
BIIB092 CSF 
Samplea 
Week 0 (Day 1) 
Predose 
00:00 
X 
X 
Week 0 (Day 1) 
EOIb 
01:00 
X 
 
Week 4 
Predose 
00:00 
X 
 
Week 4 
EOIb 
01:00 
X 
 
Week 12 
Predose 
00:00 
X 
 
Week 24 
Predose 
00:00 
X 
 
Week 24 
EOIb 
01:00 
X 
 
Week 36 
Predose 
00:00 
X 
 
Week 48 
Predose 
00:00 
X 
 
Week 48 
EOIb 
01:00 
X 
 
Week 52 
Predose 
00:00 
X 
X 
Week 56 
Predosec 
00:00 
X 
 
Weeks 76, 100, 124, 
148, 172, and 196 d 
Predose 
00:00 
X 
Week 100 only 
CSF = cerebrospinal fluid; EOI = end of infusion. 
a Collect at the time of LP (
) 


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b This sample should be taken immediately prior to stopping the infusion (preferably within 2 minutes prior to the 
end of the infusion). If the end of infusion is delayed to more than the nominal infusion duration, the collection of 
this sample should also be delayed accordingly. 
c The scheduled predose sampling at Week 56 is also the Week 52 postdose sampling (672 hours after Week 52 
dosing). 
d Visit intervals of 24 weeks after Week 52 (Weeks 76, 100, 124, 148, 172, and 196). 


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12. 
PHARMACODYNAMICS 
 
 
 
The final disposition of samples will be conducted per local regulations. 
Details on processes for collection and shipment of these samples can be found in the procedure 
manual. 


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. 
 
 
 
 
 
 
 
 
 
  


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14. 
IMMUNOGENICITY ASSESSMENTS 
A validated immunoassay will be used to assay samples for the presence of, and measure titers 
of, anti-BIIB092 antibodies in serum on an ongoing basis in Study 251PP301. Samples will be 
collected during the 52-week double-blind period at Day 1, Week 4, Week 8, Week 12, Week 
24, Week 36, and Week 48 (Table 2). In addition, samples will also be collected during the open-
label extension period approximately every 24 weeks (Table 3). All samples will be collected 
predose. 
Anti-drug antibody (ADA) titers will be monitored throughout the course of Study 251PP301. If 
ADAs are observed, analyses will be conducted to assess impacts on safety, pharmacological, 
and efficacy measures across treated participants with and without ADAs. ADAs may also be 
assessed for neutralizing activity. 
Participants who withdraw from Study 251PP301 with ADA titers that are not stable or are 
increasing in two consecutive samples leading up to discontinuation will be asked to return for 
follow-up assessment approximately every 6 weeks for up to 24 weeks for measurement of 
ADAs and immunological AE assessment until resolved (defined as two sequential samples 
showing no change or declining levels). 
Clinically relevant immune reactions (e.g., hypersensitivity reactions) will be treated according 
to current standard of care medical practice. Additional samples for immunogenicity assessments 
referred to as “event driven” samples may be justified on the basis of Grade 3 hypersensitivity 
reactions. The immunogenicity and corresponding drug exposure (PK) data from these samples 
will be reported as part of a participant’s overall PK and immunogenicity assessment. 


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15. 
OTHER ASSESSMENTS 
15.1. 
PSP phenotypes 
Based on participant’s medical history, Investigators will be asked to provide the participant’s 
clinical phenotype as outlined in the Movement Disorder Society-PSP criteria [Höglinger 2017].  
PSP clinical phenotypes may include the following: 
• PSP with predominant Richardson syndrome  
• PSP with predominant ocular motor dysfunction 
• PSP with predominant postural instability 
• PSP with predominant parkinsonism 
• PSP with progressive gait freezing 
• PSP with predominant frontal presentation 
• PSP with predominant speech/language disorder 
• PSP with predominant corticobasal syndrome 
 


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16. 
MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS 
Medical resource utilization and health economics data that is associated with medical 
encounters may be collected in the CRF by the Investigator and study site personnel for all 
participants throughout the study. Protocol-mandated procedures, tests, and encounters are 
excluded. 
The data collected may be used to conduct exploratory economic analyses and may include: 
• Number and duration of medical care encounters, including surgeries, and other 
selected procedures (inpatient and outpatient), 
• Duration of hospitalization (total days length of stay, including duration by 
wards; e.g., intensive care unit), 
• Number and character of diagnostic and therapeutic tests and procedures, and 
• Outpatient medical encounters and treatments (including physician or emergency 
room visits, tests and procedures, and medications). 


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17. 
STATISTICAL CONSIDERATIONS 
17.1. 
Sample Size Determination 
Approximately 459 participants will be randomly assigned in a 2:1 ratio to receive BIIB092 or 
placebo (306 participants in the BIIB092 treatment group and 153 in the placebo group). 
Anticipating a dropout rate of approximately 25% (based on previous clinical studies in 
participants with PSP), approximately 345 participants (230 participants in the BIIB092 
treatment group and 115 participants in the placebo group) are expected to complete the study 
through Week 52. 
Using a two-sided, two-sample t-test with an alpha level set at 0.05, this sample size will provide 
80% power to detect a difference of 3.2 points in the change in PSPRS total score from baseline 
to Week 52 for BIIB092 relative to placebo, assuming a common standard deviation of 9.95 
[Stamelou 2016] in the change in PSPRS total score from baseline to Week 52. 
17.2. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Enrolled participants 
All participants who signed informed consent and were assigned 
a participant identification number 
Randomized participants 
Enrolled participants who received a randomization treatment 
assignment from the Interactive Response Technology (BIIB092 
or placebo) 
Treated participants 
Enrolled participants who received at least 1 dose of study 
treatment, i.e., blinded therapy (BIIB092 or placebo) or open-
label BIIB092 
Intention-to-treat (ITT) 
participants 
Randomized participants who received at least 1 dose of blinded 
study treatment 
Cumulative BIIB092- 
treated participants 
All randomized participants who received at least 1 dose of 
BIIB092 during the double-blind and/or the open-label period. 
Additional analysis populations will be defined in the statistical analysis plan. 
17.3. 
Handling of Missing Data 
Missing data patterns will be summarized. Percentage of participants who withdrew from the 
study over time through Week 52 will be summarized and graphically presented by (1) as 
randomized treatment group and reason for discontinuation, and (2) as randomized treatment 
group and disease severity (split by the median of baseline PSPRS). Observed mean change from 
baseline in the primary endpoint will be summarized and graphically presented by treatment 
group and dropout pattern over time. 
Main analyses using a likelihood-based mixed model approach will based on the assumption of 
missing at random (MAR). Sensitivity analyses for the primary endpoint will be conducted with 
missing data imputed by multiple imputation. Specifically, the multiple imputation will be 


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performed under the following methods under the framework of missing not at random 
(MNAR): 
• Copy Differences from Control (CDC): This pattern mixture model assumes that 
changes over time in future outcomes in participants who withdraw from all treatment 
groups are similar to those future changes observed among completers in the control 
group. 
• Jump to Reference (J2R): This pattern mixture model assumes that participants 
withdrawn from all treatment groups would have had outcomes similar to those 
that were observed among completers (with similar baseline characteristics) in the 
control group.  
In addition, an analysis of covariance (ANCOVA) sensitivity analysis at Week 52 will be 
conducted for the primary using the last observation carried forward (LOCF) method adjusted by 
historical progression; that is, missing PSPRS data will be imputed by assuming historical 
placebo progression (11.24 points/year) [Stamelou 2016] from the visit of the last observation 
prior to Week 52. 
17.4. 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock and will 
describe the selection of participants to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. Below is a summary of planned statistical 
analyses of the primary and secondary endpoints. 
17.4.1. 
Efficacy Analyses 
Efficacy analyses will be performed using the intent-to-treat participants. Unless stated 
otherwise, all tests of treatment effects will be conducted at a two-sided significance level of 
0.05. The primary efficacy analyses will be for comparative efficacy of BIIB092 to placebo in 
the double-blind treatment period (including all data through Week 52 for participants 
discontinuing study treatment during the double-blind period). Details of the efficacy analyses 
for the open-label extension period will be provided in the statistical analysis plan. 
Endpoint 
Statistical Analysis Methods 
Primary 
Changes from baseline in PSPRS will be analyzed using a restricted 
maximum likelihood (REML)-based Mixed Model with Repeated 
Measures (MMRM) approach. The principal analysis of the primary 
endpoint will be a MMRM model that will include treatment, visit, 
treatment-by-visit interaction, stratification factors as categorical fixed 
effects, baseline value of PSPRS as a continuous covariate, and 
baseline value of PSPRS-by-visit interaction. An unstructured 
covariance matrix will be used to model the within-participant errors. 
If this analysis fails to converge, the following structures will be tested 
in this order: the heterogeneous Toeplitz covariance structure, 
autoregressive model of order 1, and compound symmetric. The first 
covariance structure yielding convergence will be used. 


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Endpoint 
Statistical Analysis Methods 
The treatment comparison of BIIB092 to placebo will be based on the 
difference in least-squares means with a two-sided 95% confidence 
interval and p-value. 
Sensitivity analyses for the primary endpoint will include the 
following analyses: 
• ANCOVA analysis at Week 52 using LOCF adjusted by 
historical placebo progression: The ANCOVA model will 
include treatment, stratification factors as categorical effects, 
and baseline value of PSPRS as continuous covariate. 
• MMRM analysis with missing data imputed by the CDC 
multiple imputation method. The specification of the MMRM 
model based on the imputed data will be the same as the primary 
MMRM model. 
• MMRM analysis with missing data imputed by the J2R multiple 
imputation method. The specification of the MMRM model 
based on the imputed data will be the same the primary MMRM 
model. 
• Responder analysis in which participants with missing data at 
Week 52 will be treated as non-responders. 
• Subscales of the PSPRS will be summarized over time 
descriptively. 
• Additional analysis may be performed with details specified in the 
statistical analysis plan. 
Key Secondary 
• If the primary analysis finds that participants treated with 
BIIB092 performed significantly better than placebo, the key 
secondary endpoints will be analyzed hierarchically in the 
following order: MDS-UPDRS Part II, CGI-C, RBANS, and 
PSP-QoL. 
• The testing procedure will maintain an alpha level of 0.05 at 
each level of the hierarchy and ensures the preservation of the 
overall type I error at 0.05. 
Non-Key 
Secondary 
• Non-key secondary endpoints will be tested at an uncontrolled 
alpha level of 0.05 per endpoint. The p-values resulting from 
these analyses will be considered as nominal and descriptive in 
nature. 
Exploratory 
• Will be described in the statistical analysis plan. 


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17.4.2. 
Safety Analyses 
Safety analyses will be performed by as-treated treatment group for treated participants. Safety 
endpoints include the frequency and proportion of participants with AEs, SAEs, AEs leading to 
discontinuations and deaths, and other significant AEs reported on case report forms. Other 
safety endpoints include laboratory abnormalities, changes in laboratory parameters, changes in 
vital signs, physical findings, and ECGs. 
In general, AE presentations will be by system organ class and preferred term. 
The primary safety analyses will be for comparative safety of BIIB092 to placebo in the 
double-blind treatment period. Safety endpoints will include data up to the start of the open-label 
extension period for participants who completed the double-blind treatment period and continue 
into the open-label extension, or up to last dosing date plus 30 days for participants discontinuing 
study treatment during the double-blind treatment period. 
Additional safety analyses will include all events reported through the time of database lock for 
the cumulative BIIB092-treated participants. Safety endpoints will include data from the first 
dose of BIIB092 in the study up to the last dose of BIIB092 treatment in the study plus 30 days. 
17.4.3. 
Interim Analysis 
An interim analysis for superiority may be performed before the last participant has had the 
opportunity to complete the Week 52 visit. An alpha spending function approach will be used for 
the analysis. In order to maintain the treatment blind in the event of this interim analysis, an 
independent group external to Biogen that will not be involved in the conduct of the study after 
unblinding will perform the interim superiority analysis. The independent group will present the 
unblinded interim analysis to the DMC. The aim of this interim analysis is to allow the 
possibility to demonstrate treatment effect early. The analysis (including the details of the alpha 
spending approach) will be discussed in the statistical analysis plan. 
17.5. 
Other Analyses 
17.5.1. 
PK and PD Analyses 
PK and PD analyses will be described in the statistical analysis plan. The population PK analysis 
and PD analyses will be presented separately from the main clinical study report. 
17.5.2. 
Immunogenicity Analyses 
Immunogenicity analyses will be described in the statistical analysis plan. 
17.5.3. 
Biomarker Analyses 
Biomarker analyses will be described in the statistical analysis plan. 


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18. 
REFERENCES 
Boxer AL, Lang AE, Grossman M, et al. Davunetide in patients with progressive supranuclear 
palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial. Lancet Neurol. 
2014;13(7):676-85. Epub 2014/05/27. 
Boxer AL, Yu JT, Golbe LI, et al. Advances in progressive supranuclear palsy: new diagnostic 
criteria, biomarkers, and therapeutic approaches. Lancet Neurol. 2017;16(7):552-563. Epub 
2017/06/13. 
Bright J, Hussain S, Dang V, et al. Human secreted tau increases amyloid-beta production. 
Neurobiol Aging. 2015;36(2):693-709. Epub 2014/09/16. 
Brooks R. EuroQol: the current state of play. Health Policy. 1996;37(1):53-72. Epub 1996 Jun 
06. 
Dal Bello-Haas V, Klassen L, Sheppard MS, et al. Psychometric Properties of Activity, Self-
Efficacy, and Quality-of-Life Measures in Individuals with Parkinson Disease. Physiother Can. 
2011;63(1):47-57. Epub 2011/01/20. 
Dickson DW, Ahmed Z, Algom AA, et al. Neuropathology of variants of progressive 
supranuclear palsy. Current opinion in neurology. 2010;23(4):394-400. 
Goetz CG, Fahn S, Martinez-Martin P, et al. Movement Disorder Society-sponsored revision of 
the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric 
testing plan. Mov Disord. 2007;22(1):41-7. 
Golbe LI, Ohman-Strickland PA. A clinical rating scale for progressive supranuclear palsy. 
Brain. 2007;130(Pt 6):1552-65. Epub 2007/04/02. 
Guo T, Noble W, Hanger DP. Roles of tau protein in health and disease. Acta Neuropathol. 
2017;133(5):665-704. Epub 2017/04/06. 
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: U.S. 
Department of Health, Education, and Welfare; 1976. 
Höglinger GU, Respondek G, Stamelou M, et al. Clinical diagnosis of progressive supranuclear 
palsy: The movement disorder society criteria. Mov Disord. 2017;32(6):853-864. Epub 
2017/05/03. 
Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment, MoCA: a 
brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-9. 
Nath U, Ben-Shlomo Y, Thomson RG, et al. Clinical features and natural history of progressive 
supranuclear palsy: a clinical cohort study. Neurology. 2003;60(6):910-6. 
Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med. 
2001;33(5):337-43. 


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Randolph C, Tierney MC, Mohr E, et al. The Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol. 
1998;20(3):310-9. 
Schrag A, Selai C, Quinn N, et al. Measuring quality of life in PSP: the PSP-QoL. Neurology. 
2006;67(1):39-44. 
Stamelou M, Schöpe J, Wagenpfeil S, et al. Power calculations and placebo effect for future 
clinical trials in progressive supranuclear palsy. Mov Disord. 2016;31(5):742-7. Epub 
2016/03/07. 
Takigawa H, Kitayama M, Wada-Isoe K, et al. Prevalence of progressive supranuclear palsy in 
Yonago: change throughout a decade. Brain Behav. 2016;6(12):e00557. Epub 2016/10/11. 
The EuroQol Group. EuroQol--a new facility for the measurement of health-related quality of 
life. Health Policy. 1990;16(3):199-208. 
Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual 
framework and item selection. Medical Care. 1992;30(6):473-83. 
Williams DR, de Silva R, Paviour DC, et al. Characteristics of two distinct clinical phenotypes in 
pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-
parkinsonism. Brain. 2005;128(Pt 6):1247-58. Epub 2005/03/23. 
Williams DR, Holton JL, Strand C, et al. Pathological tau burden and distribution distinguishes 
progressive supranuclear palsy-parkinsonism from Richardson's syndrome. Brain. 2007;130(Pt 
6):1566-76. 
 


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19. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “A Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of Intravenously Administered 
BIIB092 in Participants with Progressive Supranuclear Palsy,” and agree to conduct the study 
according to the protocol and the applicable ICH guidelines and GCP regulations and to inform 
all who assist me in the conduct of this study of their responsibilities and obligations. 
 
 
___________________________________  _______________ 
Investigator’s Signature   Date 
 
 
___________________________________ 
 
Investigator’s Name (Print) 
 
 
___________________________________ 
Study Site (Print) 
 
 


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20. 
APPENDICES 


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APPENDIX 1. ABBREVIATIONS AND TRADEMARKS 
 
Term 
Definition 
AD 
Alzheimer’s disease 
ADA 
anti-drug antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
anti-HBc 
hepatitis B core antibody 
ASA 
acetylsalicylic acid 
AST 
aspartate aminotransferase 
AT 
aminotransaminase 
BP 
blood pressure 
CDC 
Copy Differences from Control 
CFR 
Code of Federal Regulations 
CGI 
Clinical Global Impression 
CGI-C 
Clinical Global Impression of Change 
CGI-S 
Clinical Global Impression of Severity 
CNS 
central nervous system 
CRF 
case report form, paper or electronic 
CSF 
cerebrospinal fluid 
 
 
CTA 
clinical trial agreement 
CTT 
Color Trails Test 
DHA 
Directions for Handling and Administration 
DILI 
drug-induced liver injury 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOI 
end of infusion 
 
 
EuroQol 
European Quality of Life 
GCP 
Good Clinical Practice 
HbA1C 
hemoglobin A1C 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 


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HCV 
hepatitis C virus 
HRT 
hormone replacement therapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
Ig 
immunoglobulin 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IV 
intravenous 
J2R 
Jump to Reference 
LAM 
lactation amenorrhea method 
LP 
lumbar puncture 
LNS 
Letter-Number Sequencing 
LOCF 
last observation carried forward method 
mAb 
monoclonal antibody 
MAD 
multiple ascending dose 
MAPT 
microtubule-associated protein tau 
MAR 
missing at random 
MDS-UPDRS 
Movement Disorder Society-sponsored revision of the Unified 
Parkinson’s Disease Rating Scale 
MMRM 
Mixed Model with Repeated Measures 
MMSE 
Mini Mental State Examination 
MNAR 
missing not at random 
MoCA 
Montreal Cognitive Assessment 
MRI 
magnetic resonance imaging 
MRC 
Medical Research Council 
N/A 
not applicable 
NfL 
neurofilament light chain 
NHV 
normal healthy volunteer  
NSAE 
non-serious adverse event 
 
 
PD 
pharmacodynamic(s) 


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PK 
pharmacokinetic(s) 
 
 
PSP 
progressive supranuclear palsy 
PSP-QoL 
Progressive Supranuclear Palsy Quality of Life scale 
PSPRS 
Progressive Supranuclear Palsy Rating Scale 
RNA 
ribonucleic acid 
Q4W 
every 4 weeks 
QMA 
quantitative movement assessment 
RBANS 
Repeatable Battery for the Assessment of Neuropsychological Disease 
Severity 
 
 
SAD 
single ascending dose 
SAE 
serious adverse event 
SEADL 
Schwab and England Activities of Daily Living 
 
 
SOP 
standard operating procedure 
SUSAR 
suspected, unexpected serious adverse reaction 
TCS 
timed chair stands 
ULN 
upper limit of normal 
US 
United States 
WOCBP 
women of childbearing potential 
 


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APPENDIX 2. STUDY GOVERNANCE CONSIDERATIONS 
The term ‘Participant’ is used in the protocol to refer to a person who has consented to 
participate in the clinical research study. The term ‘Subject’ used in the electronic case report 
form (eCRF) is intended to refer to a person (Participant) who has consented to participate in the 
clinical research study. 
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 case report forms (CRFs) 
electronically prior to any Interim lock or Database lock. 
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines. The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated. The Investigator 
is responsible for supervising those individuals and for implementing procedures to ensure the 
integrity of the tasks performed and any data generated. 
Declaration of Helsinki 
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki. 
Ethics Committee 
The Investigator must obtain ethics committee approval of the protocol, informed consent form 
(ICF), and other required study documents prior to starting the study. The contract research 
organization will submit documents on behalf of the investigational sites worldwide in 
compliance with local regulations. 
If the Investigator makes any changes to the ICF, Biogen must approve the changes before the 
ICF is submitted to the ethics committee. A copy of the approved ICF must be provided to 
Biogen. After approval, the ICF must not be altered without the agreement of the relevant ethics 
committee and Biogen. 
It is the responsibility of the Investigators to ensure that all aspects of institutional review are 
conducted in accordance with current applicable regulations. 
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study. Protocol 
amendments will be subject to the same requirements as the original protocol. 
A progress report must be submitted to the ethics committee at required intervals and no less 
than annually. 


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At the completion or termination of the study, the study site must submit a close-out letter to the 
ethics committee and Biogen. 
Subject Information and Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject, 
in accordance with local practice and regulations.  
The Investigator must reassess the subject’s capacity to provide informed consent periodically 
over the course of the study. In the event the subject is cognitively intact and loses capacity to 
provide informed consent, the Investigator must obtain subject assent and consent by the 
subject’s legally authorized representative (in accordance with local laws and regulations) or 
withdraw the subject from the study. 
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 
subject’s legally authorized representative). The subject must be given sufficient time to consider 
whether to participate in the study. 
Subjects will be informed that their race and ethnicity will be collected during the study (unless 
the collection is not permitted by applicable law or not approved by the governing ethics 
committee) and the data will be used during analysis of study results. 
A copy of the signed and dated ICF must be given to the subject or the subject’s legally 
authorized representative. The original signed and dated ICF will be retained with the study 
records. Local regulations must be complied with in respect to the final disposition of the 
original (wet signature) and copies of the signed and dated ICFs. 
Confirmation of informed consent must also be documented in the subject’s medical record. 
Subject Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., Protected Health Information 
authorization in North America). 
During the study, subjects’ race and ethnicity will be collected (unless the collection is not 
permitted by applicable law or not approved by the governing ethics committee). These data will 
be used in the analysis of the safety and/or pharmacokinetic profile of the study treatment. It is 
unknown whether the effects of the study treatment are influenced by race or ethnicity.  
Study reports will be used for research purposes only. The subject will not be identified by name 
in CRFs, study-related forms, study reports, or any related publications. Biogen, its partners and 
designees, ethics committees, and various government health agencies may inspect the records of 
this study. Every effort will be made to keep the subject’s personal medical data confidential. 
Compensation for Injury 
Biogen maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws. 


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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. 
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. 
Compliance with the Protocol and Protocol Revisions 
The Investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the Institutional 
Review Board/Independent Ethics Committee (IRB/IEC) (and if applicable, also by local health 
authority) except where necessary to eliminate an immediate hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining relevant approval/favorable opinion(s) the deviation or change will be submitted as 
soon as possible to the following: 
• IRB/IEC  
• Regulatory Authority(ies), if applicable by local regulations (per national 
requirements) 
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to Biogen. 
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
subjects currently enrolled in the study if they are affected by the amendment; and (3) the new 
form must be used to obtain consent from new subjects prior to enrollment. 
If the revision is done via an administrative letter, Investigators must inform their IRB(s)/IEC(s). 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
Source Documents  
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original, and attributable, whether the data are hand-written on paper or 
entered electronically. If source data are created (first entered), modified, maintained, archived, 
retrieved, or transmitted electronically via computerized systems (and/or any other kind of 


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electronic devices) as part of regulated clinical trial activities, such systems must be compliant 
with all applicable laws and regulations governing use of electronic records and/or electronic 
signatures. Such systems may include, but are not limited to, electronic medical/health records, 
adverse event (AE) tracking/reporting, protocol required assessments, and/or drug accountability 
records). 
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy consists of a 
copy of original information that has been verified, as indicated by a dated signature, as an exact 
copy having all of the same attributes and information as the original. 
Study Treatment Records  
Records for study treatment use of BIIB092 (whether supplied by Biogen, its vendors, or the 
site) must substantiate study treatment integrity and traceability from receipt, preparation, 
administration, and through destruction or return. Records must be made available for review at 
the request of Biogen or a Health Authority. 
If 
Then 
Supplied by Biogen (or its vendors): 
Records or logs must comply with applicable 
regulations and guidelines and should include 
the following: 
• the amount received and placed in 
storage area 
• the amount currently in storage area 
• the label identification number or 
batch number 
• the amount dispensed to and returned 
by each participant, including unique 
participant identifiers 
• the amount transferred to another 
area/site for dispensing or storage 
• nonstudy disposition (e.g., lost, 
wasted) 
• the amount destroyed at study site, if 
applicable 
• the amount returned to Biogen 
• samples retained for 
bioavailability/bioequivalence, if 
applicable 


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If 
Then 
• dates and initials of person 
responsible for Investigational 
Product (IP) 
dispensing/accountability, as per the 
Delegation of Authority form 
Sourced by site, and not supplied by Biogen or 
its vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy) 
The Investigator or designee accepts 
responsibility for documenting traceability and 
study treatment integrity in accordance with 
requirements applicable under law and the 
Standard Operating Procedures 
(SOPs)/standards of the sourcing pharmacy. 
These records should include: 
• label identification number or batch 
number 
• amount dispensed to and returned by 
each participant, including unique 
participant identifiers 
• dates and initials of person 
responsible for IP 
dispensing/accountability, as per the 
Delegation of Authority Form. 
Biogen will provide forms to facilitate inventory control if the investigational site does not 
have an established system that meets these requirements. 
Case Report Forms  
An Investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study. 
For sites using the Sponsor electronic data capture tool, electronic CRFs will be prepared for all 
data collection fields except for fields specific to serious adverse events (SAEs) and pregnancy, 
which will be reported on the electronic SAE form and Pregnancy Notification and Outcome 
form, respectively. If electronic SAE form is not available, a paper SAE form can be used. 
Spaces may be left blank only in those circumstances permitted by study-specific CRF 
completion guidelines provided by Sponsor. 


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The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). 
The Investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by 
the Investigator or qualified physician who is a sub-Investigator and who is delegated this task 
on the Delegation of Authority form. Sub-Investigators in Japan may not be delegated the CRF 
approval task for electronic CRFs, review and approval/signature is completed electronically 
through the Biogen electronic data capture tool. The Investigator must retain a copy of the CRFs 
including records of the changes and corrections. 
Each individual electronically signing electronic CRFs must meet Sponsor training requirements 
and must only access the Biogen electronic data capture tool using the unique user account 
provided by Sponsor. User accounts are not to be shared or reassigned to other individuals. 
Monitoring 
Sponsor representatives will review data centrally to identify potential issues to determine a 
schedule of on-site visits for targeted review of study records. 
Representatives of Biogen must be allowed to visit all study site locations periodically to assess 
the data quality and study integrity. On site they will review study records and directly compare 
them with source documents, discuss the conduct of the study with the Investigator, and verify 
that the facilities remain acceptable. Certain CRF pages and/or electronic files may serve as the 
source documents: 
In addition, the study may be evaluated by Sponsor internal auditors and government inspectors 
who must be allowed access to CRFs, source documents, other study files, and study facilities. 
Biogen audit reports will be kept confidential. 
The Investigator must notify Biogen promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to Sponsor. 
Records Retention  
The Investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by Biogen or designee, whichever is longer. 
The Investigator (or head of the study site in Japan) must contact Biogen prior to destroying any 
records associated with the study. 
Biogen or designee will notify the Investigator (or head of the study site in Japan) when the 
study records are no longer needed. 
If the Investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another Investigator, study site, IRB). Notice 
of such transfer will be given in writing to Biogen or designee. 


Protocol 251PP301 
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Return of Study Treatment  
For this study, study treatments (those supplied by Biogen, a vendor or sourced by the 
Investigator) such as partially used study treatment containers, vials and syringes may be 
destroyed on site. 
If 
Then 
Study treatments supplied by Biogen (including 
its vendors) 
Any unused study treatments supplied by 
Biogen can only be destroyed after being 
inspected and reconciled by the responsible 
Study Monitor unless study treatments 
containers must be immediately destroyed as 
required for safety, or to meet local regulations 
(e.g., cytotoxics or biologics). 
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor. 
Study treatments sourced by site, not supplied 
by Biogen (or its vendors) (examples include 
study treatments sourced from the sites stock or 
commercial supply or a specialty pharmacy) 
It is the Investigator’s responsibility to dispose 
of all containers according to the institutional 
guidelines and procedures. 
It is the Investigator’s responsibility to arrange for disposal, provided that procedures for proper 
disposal have been established according to applicable federal, state, local, and institutional 
guidelines and procedures, and provided that appropriate records of disposal are kept. The 
following minimal standards must be met: 
• On-site disposal practices must not expose humans to risks from the drug. 
• On-site disposal practices and procedures are in agreement with applicable laws 
and regulations, including any special requirements for controlled or hazardous 
substances. 
• Written procedures for on-site disposal are available and followed. The procedures 
must be filed with the site’s SOPs and a copy provided to Biogen upon request. 
• Records are maintained that allow for traceability of each container, including the 
date disposed of, quantity disposed, and identification of the person disposing the 
containers. The method of disposal, i.e., incinerator, licensed sanitary landfill, or 
licensed waste disposal vendor must be documented. 
• Accountability and disposal records are complete, up-to-date, and available for the 
Monitor to review throughout the clinical trial period. 
It is the Investigator’s responsibility to arrange for disposal of all empty containers. 


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If conditions for destruction cannot be met the responsible Study Monitor will make 
arrangements for return of study treatments provided by Biogen (or its vendors). Destruction of 
non-study treatments sourced by the site, not supplied by Biogen, is solely the responsibility of 
the Investigator. 
Clinical Study Report and Publications  
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on one or more 
of the following criteria: 
• Participant recruitment (e.g., among the top quartile of enrollers) 
• Involvement in trial design 
• Regional representation (e.g., among top quartile of enrollers from a specified 
region or country) 
• Other criteria (as determined by the study team) 
The data collected during this study are confidential and proprietary to Sponsor. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing Investigator participation in the study. 
These requirements include, but are not limited to, submitting proposed publications to Sponsor 
at the earliest practicable time prior to submission or presentation and otherwise within the 
time period set forth in the CTA. 


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APPENDIX 3. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING 
Adverse Events 
 
Adverse Event Definition: 
An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment 
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment. 
Serious Adverse Events 
 
Serious adverse event (SAE) is defined as any untoward medical occurrence that, at any 
dose 
Results in death 
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe) 
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below) 
NOTE: 
The following hospitalizations are not considered SAEs in Biogen clinical studies: 
• a visit to the emergency room or other hospital department <24 hours, that does not 
result in admission (unless considered an important medical or life- threatening 
event) 
• elective surgery, planned prior to signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy) 


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• medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases 
• admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason) 
• admission for administration of anticancer therapy in the absence of any other 
SAEs (applies to oncology protocols) 
Results in persistent or significant disability/incapacity 
Is a congenital anomaly/birth defect 
Is an important medical event (defined as a medical event(s) that may not be immediately life 
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.)  Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.)  Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 10.7 for the definition of potential DILI.) 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
treatment is an SAE. 
Although pregnancy, overdose, cancer, and potential DILI are not always serious by regulatory 
definition, these events must be handled as SAEs. (See Section 10.5 for reporting pregnancies). 
Any component of a study endpoint that is considered related to study treatment should be 
reported as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis 
must be reported). 
Evaluating AEs and SAEs 
The causal relationship to study treatment is determined by a physician and should be used to 
assess all AEs. The causal relationship can be one of the following: 
• Related:  An AE will be considered “related” to the use of the IP if there is a 
reasonable possibility that the event may have been caused by the product under 
investigation. Factors that point toward this assessment include but are not limited to 
a positive rechallenge, a reasonable temporal sequence between administration of the 
IP and the AE, a known response pattern of the suspected product, improvement 
following discontinuation or dose reduction, a biologically plausible relationship 
between the product and the AE, or a lack of an alternative explanation for the AE. 
• Not related:  An AE will be considered “not related” to the use of the IP if there is 
not a reasonable possibility that the event has been caused by the product under 


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investigation. Factors pointing toward this assessment include but are not limited to 
the lack of reasonable temporal relationship between administration of the IP and the 
AE, the presence of a biologically implausible relationship between the product and 
the AE, or the presence of a more likely alternative explanation for the AE. 
 
 
 
 
 
Reporting of SAEs to Sponsor 
 
Follow-up of AEs and SAEs 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports must include the same Investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 
24 hours to Biogen using the same procedure used for transmitting the initial SAE report. 
All SAEs must be followed to resolution or stabilization. 
• SAEs, whether related or not related to study treatment, and pregnancies 
must be reported to Biogen within 24 hours of awareness of the event. 
• SAEs must be recorded on the SAE Report Form; pregnancies on a Pregnancy 
Notification and Outcome Form (electronic or paper forms). 
• The preferred method for SAE data reporting collection is through the electronic 
case report form (eCRF). 
• The paper SAE/pregnancy notification and outcome forms are only intended as a 
back-up option when the eCRF system is not functioning. 
o In this case, the paper forms are to be transmitted via email or confirmed 
facsimile (fax) transmission to: 
SAE Email Address: Refer to Contact Information list. 
SAE Facsimile Number: Refer to Contact Information list. 


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APPENDIX 4. WOMEN OF CHILDBEARING POTENTIAL 
DEFINITIONS AND METHODS OF CONTRACEPTION 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered WOCBP 
• Premenarchal 
• Premenopausal female with 1 of the following: 
− Documented hysterectomy 
− Documented bilateral salpingectomy 
− Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
• Postmenopausal female 
− A postmenopausal state is defined as 12 months of amenorrhea in a woman over 
age 45 years in the absence of other biological or physiological causes. In 
addition, females under the age of 55 years must have a serum follicle-
stimulating hormone, (FSH) level >40 mIU/mL to confirm menopause. 
Note:  Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the Investigators should use their 
judgement in checking serum FSH levels. 
• 1 week minimum for vaginal hormonal products (rings, creams, gels) 
• 4 week minimum for transdermal products 
• 8 week minimum for oral products 
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is >40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal. 


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CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD 
BEARING POTENTIAL 
Any one of the approved methods of contraception listed below is required for the duration of 
this study and for 155 days after treatment has been discontinued. 
Local laws and regulations may require use of alternative and/or additional contraception 
methods. 
Contraceptive methods that are approved for use during and for 
155 days after participation in this study are: 
Failure rate of <1% per year when used consistently and correctly.a 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
− oral 
− intravaginal 
− transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
− oral 
− injectable 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb 
• Intrauterine device (IUD)c 
• Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant. 
• It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
• WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 10.5. 
• 
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 


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NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous. In this case, 
alternative methods of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness. 
Unacceptable Methods of Contraception 
• Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• Withdrawal (coitus interruptus) 
• Spermicide only 
• Lactation amenorrhea method (LAM) 
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL. 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure. 
• Inform any and all partner(s) of their participation in a clinical drug study and the 
need to comply with contraception instructions as directed by the Investigator. 
No additional contraceptive measures are required to be used. 
COLLECTION OF PREGNANCY INFORMATION 
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Notification and Outcome Form is provided in Section 10.5 and Appendix 3. 


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Protocol 251PP301 
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Protocol 251PP301 
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Protocol 251PP301, Version 7
CONFIDENTIAL
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Biogen MA Inc.
2
PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 251PP301 was to update the study treatment 
product provided for use in the open-label extension period, to include the 2000 mg/vial.
Section 7, Treatment (Table 6)
New text is shown in bold type; deleted text is shown with a strikethrough.
Now reads:
Table 6:
Study Treatments for Study 251PP301
Product Descriptiona /
Class and Dosage Form
Potency
IP/Non-IMP
Study 
Period
Packaging/Appearance
Storage 
conditions 
(per label)
BIIB092 Injection,
1000 mg/vial b
50 
mg/mL
IP
Double-
blind
BIIB092 is supplied as 
a liquid drug product 
in glass vials containing 
an extractable dose per 
the DHA
Store 
refrigerated 
2°C to 8°C
Protect from 
light
Do not freeze
BIIB092 Injection,
1000 mg/vial b
(50 mg/mL)
The composition of 
the drug product is:
50 mg/mL, BIIB092, 
histidine, histidine 
hydrochloride 
monohydrate, sucrose, 
pentetic acid, polysorbate 
80, and sterile water for 
injection, pH 6.0
50 
mg/mL
IP
Open-
Label 
extension
Clear to very opalescent,
colorless to slightly
yellow liquid, in which 
light (few) particulates 
may be present
BIIB092 is supplied as 
a liquid drug product 
in glass vials containing 
an extractable dose per 
the DHA
Store 
refrigerated 
2°C to 8°C
Protect from 
light
Do not freeze
BIIB092 Injection,
2000 mg/vial b
50 
mg/mL
IP
Open-
Label 
extension
BIIB092 is supplied as 
a liquid drug product 
in glass vials containing 
an extractable dose per 
the DHA
Store 
refrigerated 
2°C to 8°C
Protect from 
light
Do not freeze
Placebo (0.9% Sodium
Chloride or 5% 
Dextrose)c
0.9% 
NaCl
Or
5% 
Dextrose
IP
Double-
blind
Per product label
Per product 
label


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DHA = Directions for Handling and Administration; IMP = investigational medicinal product; IP = investigational product; 
N/A = not applicable.
a BIIB092 dosage form and composition are provided in the DHA.
b BIIB092 is provided open-label to the unblinded pharmacist. After study drug treatment is prepared by the 
unblinded pharmacist all other study personnel will remain blinded to the identification of study drug treatment
(BIIB092 vs. placebo) through Week 48.
c Placebo is not provided by Biogen and obtained commercially by the site; storage should be in accordance with 
the product label.
Rationale: Introduced the larger 2000 mg/vial size of the study treatment. The vial size was 
increased from the 1000mg/vial dose to the 2000mg/vial dose for the study sites to be able to 
administer 1 vial of the 2000 mg dose, instead of 2 vials of the 1000mg/dose.


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4
SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically. New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 1, Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 2, Schedule of Activities (Table 1, Table 2, and Table 3)
Change: Tables were revised to clarify the safety language in the protocol that specifies the 
timelines during which AEs and SAEs are being collected.
Now reads:
Table 1:
Screening Procedural Outline
Procedure
Screening 
Visita
Notes
Safety Assessments
Monitor for Serious Adverse Events (SAEs)
X
Following written consent to participate in the study, all 
SAEs whether related or not related to study 
drugtreatment that occur during the screening period,
until 30 days post discontinuation of dosing or end of 
treatment continuously throughout the study, and 
until 30 days following the last dose should be 
monitored and recorded.
Table 2:
Double-Blind Procedural Outline
Procedurea
Week 0
(Day 1)
Weeks 4, 
8,
16, 20, 
28,
32, 40, 
44b
(±3 days) 
Weeks 
12,
24, 36
(±3 
days)
Week 
48
(±3 
days)
Week 
52
(±3 
days)
Early 
Discontinuationc,d,
Notes
Monitor for Non-
Serious Adverse 
Events (NSAEs)
Collection of NSAEs begins at initiation of study drugtreatment and continues throughout 
the study and until 30 days following the last dose. Participants thatwho discontinue 
earlystudy treatment should receive a follow up phone callhave an assessment of AEs 30
days after last dose. e


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Procedurea
Week 0
(Day 1)
Weeks 4, 
8,
16, 20, 
28,
32, 40, 
44b
(±3 days) 
Weeks 
12,
24, 36
(±3 
days)
Week 
48
(±3 
days)
Week 
52
(±3 
days)
Early 
Discontinuationc,d,
Notes
Monitor for Serious
Adverse Events 
(SAEs)
See notesFollowing written consent to participate in the study, all SAEs whether related
or not related to study treatment that occur during the screening procedures.period , 
continuously throughout the study, and until 30 days following the last dose should be 
monitored and recorded. Participants who discontinue study treatment should have an 
assessment of SAEs 30 days after last dose. e
e This 30-day assessment of AEs/SAEs may be done by phone if no visit occurs.
Table 3:
Extension Period Procedural Outline
Procedure
Week 
52
Weeks 56, 
60, 68, 72, 
80, 84, 92, 
96, 104, 
108, 116, 
120, 128, 
132, 140, 
144, 152, 
156, 164, 
168, 176, 
180, 188, 
and 192a,b
(±7 days)
4, 8, 16, 
20 week 
intervals 
after Week 
52a,b
Weeks 64, 
88, 112, 136, 
160, 184c
(±7 days)
12 week 
intervals 
after Week 
52c
Weeks 76, 
100, 124, 
148, 172, 
196d
(±7 days)
24 week 
intervals 
after Week 
52d
Early 
Discontinuationa
Notes
Adverse Event Reporting
Monitor for Non-
Serious Adverse 
Events (NSAEs)
Collection of NSAEs begins at initiation of study drug.treatment and continues throughout 
the study and until 30 days following the last dose. Participants thatwho discontinue 
earlystudy treatment should receive a follow up phone callhave an assessment of AEs 30 days 
after last dose.e
Monitor for Serious 
Adverse Events 
(SAEs)
See notesFollowing written consent to participate in the study, all SAEs whether related or 
not related to study treatment that occur during the screening proceduresperiod , 
continuously throughout the study, and until 30 days following the last dose should be 
monitored and recorded. Participants who discontinue study treatment should have an 
assessment of SAEs 30 days after last dose. e
e This 30-day assessment of AEs/SAEs may be done by phone if no visit occurs.


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Rationale: Clarified the language in the protocol that specifies the timelines during which AEs 
and SAEs are being collected.
This change also affects Section 5.1.5, Discontinuation of Study treatment and/or Study 
Withdrawal; and Section 10.1, Time Period and Frequency for Collecting AE and SAE 
Information
Section 2, Schedule of Activities (Table 2)
Change: The table was revised to remove the dispensation of study treatment during the 
Week 52 visit in the double-blind period.
Now reads:
Table 2:
Double-Blind Procedural Outline
Procedurea
Week 0
(Day 1)
Weeks 4, 8,
16, 20, 28,
32, 40, 44b
(±3 days) 
Weeks 
12,
24, 36
(±3 
days)
Week 
48
(±3 
days)
Week 52
(±3 days)
Early 
Discontinuationc,d
Notes
Clinical Drug Supplies
Dispense Study 
DrugTreatment
X
X
X
X
X
Duration of 
infusion will be at 
least 1 hour.
Rationale: Corrected table to be consistent with Study Synopsis and protocol which stated that 
participants will receive “last dose of the double-blind study treatment administered at Week48”.
Section 2, Schedule of Activities (Table 3)
Change: The table was revised to include the dispensation of study treatment during the 
Week 52 baseline visit in the open-label extension period.


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Now reads:
Table 3:
Extension Period Procedural Outline
Procedure
Week 
52
Weeks 56, 60, 
68, 72, 80, 84, 
92, 96, 104, 108, 
116, 120, 128, 
132, 140, 144, 
152, 156, 164, 
168, 176, 180, 
188, and 192a
(±7 days)
4, 8, 16, 20 
week intervals 
after Week 52a,b
Weeks 64, 88, 
112, 136, 160, 
184c
(±7 days)
24 week 
intervals after 
Week 52d
Weeks 76, 
100, 124, 148, 
172, 196d
(±7 days)
24 week 
intervals after 
Week 52d
Early 
Discontinuationb
Notes
Clinical Drug Supplies
Dispense Study 
DrugTreatment
X
X
X
X
Duration of 
infusion will be 
at least 1 hour.
Rationale: Clarified that participants who continue in the open-label extension period will 
receive the first dose of the open-label study treatment at Week 52.
This change also affects Section 5.1.1, Overall Study Design.
Section 3, Introduction
Change: Text introducing tau, tau pathology, PSP disease, and BIIB092 function was updated.
Now reads:
BIIB092 (formerly referred to as BMS 986168 and IPN007) is a humanized monoclonal 
antibody (mAb) of subclass Progressive supranuclear palsy (PSP) is a rare 
neurodegenerative disorder that leads to death in an average of 7 years following symptom 
onset [Williams 2005]. The National Institute of Neurological Disorders and Stroke 
(NINDS), the National Organization for Rare Disorders (NORD), and the European 
Organisation for Orphan Diseases estimate the prevalence of PSP to be between 3 and 6 
per 100,000 persons. Both the NINDS and NORD estimate that there are approximately 
20,000 cases of PSP in the United States and 30,000 in the European Union, while there are 
thought to be approximately 17,000 cases in Japan [Takigawa 2016]. 
The disease is characterized by progressive aberrations in gait, eye movements, dysphagia, 
dysarthria, pseudobulbar affect, neuropsychiatric abnormalities, and dementia, as well as 
difficulties with sleep [Boxer 2017, Nath 2003]. Since the syndrome was first characterized 


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8
in 1963, it is now recognized that there are a number of different clinical presentations that 
appear to be linked to the regional distribution and severity of pathology in the brain 
[Williams 2007]. There is currently no treatment available to stop or slow the progression 
of this deadly disease.
The neuropathological hallmark of PSP is the presence of neurofibrillary tangles in 
clinically correlated regions of the brain, including the basal ganglia, diencephalon, 
brainstem, and cerebellum with restricted involvement of the neocortex [Dickson 2010]. 
The tangles are composed of tau, an intracellular microtubule-associated protein, of which 
fragments may also be released into the cerebrospinal fluid (CSF) and interstitial space as 
N-terminal tau [Bright 2015, Guo 2017]. Tau dysfunction is thought to play a key role in 
the pathophysiology of PSP, both by causing neuronal dysfunction via tau aggregation into 
neurofibrillary tangles and by facilitating cell to cell spreading of tau pathology via 
secreted N-terminal tau. 
BIIB092 is a humanized monoclonal antibody (mAb) that binds to amino acid residues 15 
to 22 of N-terminal tau, removing it from the CSF. It is hypothesized that BIIB092-
mediated depletion of N-terminal tau will inhibit the spread of tau pathology, potentially 
slowing the progression of PSP. This would be expected to translate into important 
improvements in function, activities of daily living, health outcomes, and overall quality of 
life for patients living with PSP.
immunoglobulin (Ig) G4 that recognizes human extracellular tau (eTau).  It is currently being 
evaluated as a treatment for Progressive Supranuclear Palsy (PSP).
Although tau is primarily an intracellular protein, a small amount of tau is secreted.  eTau refers 
to the extracellular, soluble fragments of tau that contain an intact amino terminal and are 
truncated prior to the beginning of the first microtubule binding domain of tau.  eTau produces 
disruptions in neuronal activity in vitro.  eTau is believed to play two roles in the 
pathophysiology of PSP.  First, eTau may cause neuronal dysfunction directly, and second, eTau 
may be partially responsible for the spreading of tau pathology that is observed in human 
tauopathies, such as PSP.
PSP is a neurodegenerative disease characterized by atypical Parkinsonism for which there are 
no approved or effective treatments.  At autopsy, insoluble tau aggregates are found throughout 
the brain within neurons and glia, most notably in the brainstem, deep cerebellar nuclei, basal 
ganglia, and neocortex [Dickson 2012; Dickson 2010; Steele 1964].  Symptoms of PSP include 
early and severe gait instability with falls, greater slowing of vertical than horizontal saccadic 
eye movements, slowed movement, rigidity of the axial musculature, dysphagia, dysarthria, 
pseudobulbar affect, neuropsychiatric abnormalities, and dementia [Boxer 2014; Golbe 2014; 
Steele 1964].  Survival time from symptom onset for PSP patients ranges from 5.3 to 9.7 years 
with a typical figure of 7.4 years from symptom onset.  PSP has a prevalence ranging between 
1 to 9 cases per 100,000 individuals.  The mean age of diagnosis is around 63 years [Boxer 2014;
Golbe, 2014; Nath 2001].  No medications have been approved for PSP.  There is a significant 


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unmet medical need to develop therapies that can either alleviate or slow the relentless 
worsening of PSP symptoms.
In a transgenic mouse tauopathy model, the murine analog of BIIB092 slowed the progression of 
locomotor impairment and limited the spreading of tau pathology.  In non human primates, 
BIIB092 reduced cerebrospinal fluid (CSF) concentrations of free eTau.  Administration of 
single doses of BIIB092 is safe and well tolerated in normal healthy volunteers (NHVs).  In 
addition, administration of multiple doses of BIIB092 is safe and well tolerated in participants 
with PSP.  In both NHVs and participants with PSP, BIIB092 reduces CSF concentrations of free 
eTau in a dose dependent fashion.  These findings suggest that BIIB092 may have utility for the 
treatment of human tauopathies, such as PSP.
Rationale: Clarified the terminology, background, and rationale in using BIIB092 as a treatment 
for PSP. Clarified that the amino acid residues involved in BIIB092 were corrected from “15 to 
24” to “15 to 22”.
Section 3.3, Benefit/Risk Assessment
Change: The number of subjects who have been exposed to BIIB092 has been updated.
Now reads:
BIIB092 is a humanized IgG4 isotype antibody that is considered to have a low potential for 
immunogenicity in humans based on nonclinical studies. There were no adverse effects noted at 
any dose tested in the pivotal toxicity studies in monkeys. Nonclinical findings were limited to 
decreases in CSF unbound N-terminal tau consistent with the intended pharmacology of 
BIIB092. In completed clinical study CN002001, there was no consistent trend showing a 
potential effect of anti-drug antibody (ADA) on the PK of BIIB092. In completed clinical 
study CN002003, there was no apparent dose-related trend in the number of subjects with 
positive immunogenicity results post-treatment.
Studies evaluating the potential for reproductive and developmental toxicity have not been 
performed for BIIB092.
As of July 31, 2017, 114 subjects25 November 2018, an estimated 486 participants have been 
exposed to BIIB092 across all completed (Studies CN002001 and CN002003) and ongoing 
clinical studies (Studies CN002001, CN002003, 251PP201, and 251PP301). , and 251AD201).
Based on safety data from a completed Phase 1 study in healthy volunteers (Study CN002001) 
and a completed Phase 1B study in participants with PSP (Study CN002003), the majority of 
adverse events (AEs) reported to date have been mild to moderate in severity and transient in 
nature.  There have been no deaths or discontinuations due to an AE reported in the program.  
There have been 4 serious AEs (SAEs) reported in 3 participants in Study CN002003, all of 
which were considered not related to study drug by the Investigatorbenefit-risk profile of 
BIIB092 was favorable to support further clinical development.
Rationale: Updated the information based on clinical trial exposure and safety data available as 
of 25 November 2018, to provide the most recent information.


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Section 5, Study Design
Change: A substudy was added to assess changes in motor function and related activities of 
daily living in study participants during the open-label extension period, for long-term follow-up.
Now reads:
Section 5.2.
Substudy Design
This study includes an optional substudy to measure QMAs using wearable sensors. The 
QMAs will measure gait, postural instability, motor function, and falls in a subset of 
participants participating in the long-term extension period.
Study participants included in this substudy will be from selected countries, and 
participants will be required to ambulate independently or with assistive devices. 
Participants will participate in the QMA substudy for 6 months, with in-clinic assessments 
of gait, postural instability, and motor function conducted every 3 months. Falls will be 
assessed continuously in the home using wearable sensors for 6 months to capture and 
quantify falls. The QMA substudy baseline visit will be conducted after participants sign 
the informed consent form and are eligible to enroll in the substudy. Two follow-up visits 
will be conducted at 3 and 6 months after the baseline visit of the QMA substudy. If a 
participant at a selected site is unwilling to participate in the QMA substudy, they can still 
participate in the open-label extension study.
Rationale: The QMA substudy in the open-label extension period was added to further 
characterize disease progression with wearable sensors. Postural instability, gait disturbances, 
and falls are prominent signs of PSP that affect participant outcomes. At present, these signs are 
assessed in the clinic with questionnaires. It is anticipated that advances in wearable sensor 
technology and analytics could improve quantification of these signs and may provide sensitive 
measures of disease progression.
This change also affects: Section 2, Schedule of Activities (Table 4); Section 5.1.3, Study 
Assessments; Section 5.6, Scientific Rationale for Study Design; Section 9.1, Efficacy 
Assessments; Appendix 1, Abbreviations and Trademarks
Section 6.1.1, Signed Written Informed Consent
Change: Content was added to detail consent provided by a legally authorized representative 
when the patient is unable to physically sign the consent form.
Now reads:
6.1.1. Signed Written Informed Consent
1. Participants, or a legally authorized representative (where local regulations and 
institutional practices permit), must have signed and dated an Institutional Review Board 


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(IRB)-/Independent Ethics Committee (IEC)-approved written informed consent form in 
accordance with regulatory and institutional guidelines. This must be obtained before the 
performance of any protocol-related procedures that are not part of normal participant 
care. 
2. The investigator must obtain consent consistent with the applicable legal, regulatory, 
and institutional policy requirements and specifically, taking into account the 
participant’s state of disease progression and its impact on the participant’s 
cognitive and motor abilities. 
3. In the event that the study participant is unable to sign and date the informed 
consent form, a legally authorized representative, permitted to act on behalf of the 
participant in the context of this study, may provide consent on behalf of the 
participant. 
Rationale: Clarified the consent procedures for those participants who are able to give consent 
but who are unable to physically sign a consent form due to progression of disease.
Section 7, Treatment (Section 7.5, Preparation/Handling/Storage/Accountability)
Change: Language regarding the composition, preparation, handling, storage, and accountability 
of the BIIB092 study treatment was modified to refer to the Directions for Handling and 
Administration (DHA).
Now reads:
Study treatment will be manufactured, handled, and stored in accordance with applicable 
Good Manufacturing Practice.
BIIB092 is supplied as a liquid drug product in glass vials containing an extractable dose 
per the Directions for Handling and Administration (DHA). The contents of the BIIB092 
label will be in accordance with all applicable regulatory requirements. BIIB092 should not 
be used after the expiration date.
BIIB092 must be stored refrigerated between 2°C and 8°C with protection from light. The 
placebo will be supplied locally and stored according to the packaging specifications. Study 
treatment not supplied by Biogen will be stored in accordance with the package insert.
The investigational product should be stored in a secure area according to local regulations.  It is 
the responsibility of the Investigator to ensure that investigational product is only dispensed to 
study Participants.  The investigational product must be dispensed only from official study sites 
by authorized personnel according to local regulations.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by Biogen. the 


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DHA. If concerns regarding the quality or appearance of the study treatment arise, the study 
treatment should not be dispensed, and Biogen should be contacted immediately.
The study treatment should be stored in a secure area according to local regulations. It is 
the responsibility of the Investigator to ensure that study treatment is only dispensed to 
study participants. The study treatment must be dispensed only from official study sites by 
authorized personnel according to local regulations.
Study site staff should follow the DHA for specific instructions on the handling, 
preparation, administration, storage, and disposal of the study treatment. The DHA will 
also describe the masking of the IV bags of study treatment (both BIIB092 and placebo) to 
maintain the treatment blind. The DHA supersedes all other references (e.g., protocol or 
Investigator’s Brochure).
Investigational product documentation (whether supplied by Biogen or not) must be maintained 
to ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (e.g., required diluents, administration sets).
Please refer to the current version of the Investigator Brochure and pharmacy manual for 
complete storage, handling, dispensing and infusion information for BIIB092.
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2 and the pharmacy manual.
Rationale: Clarified that the DHA manual is to be followed as guidance for study site staff 
regarding handling, preparation, administration, storage, and disposal of the study treatment. 
This change also affects Section 7, Table 6.
Section 8, Discontinuation Criteria
Change: This change identifies the discontinuation criteria for the study participants who 
discontinue study treatment but remain in the study and for the study participants who 
discontinue study treatment and withdraw early from the study. 
Now reads:
8.1
Discontinuation From Study Treatment
Participants MUST discontinue investigational productstudy treatment (and non-investigational 
product IP at the discretion of the Investigator) for any of the following reasons:

Participant’s request to stop study treatment. Participants who request to discontinue 
study treatment willand remain enrolled in the study and must continue to will be 
followed for protocol specified follow up procedures.  The only exception to 


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thisexpected to complete scheduled safety and efficacy evaluations until the 
decision is when a participant specifically withdraws consent for any further contact 
with him/her or persons previously authorized by participant to provide this 
informationmade to withdraw from the study. 

Any clinical adverse event (AE),, laboratory abnormality, or intercurrent illness 
which, in the opinion of the Investigator, indicates that continued participation in the 
study is not in the best interest of the participant

Termination of the study by Biogen

Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (e.g., infectious disease) 
illness
Refer to the Schedule of Activities (Section 2) for data to be collected at the time of treatment 
discontinuation and follow up and for any further evaluations that can be completed.
In the case of pregnancy, the Investigator must immediately notify the Medical Monitor of this 
event.  In the event a normal healthy female participant becomes pregnant during a clinical trial, 
the and study treatment must be discontinued immediately. In most cases, the study treatment 
will be permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for 
participant safety). Please call the Medical Monitor within 24 hours of awareness of the 
pregnancy. If the Investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study treatment, a discussion between the Investigator and the Medical 
Monitor/designee must occur.
All participants who discontinue study treatment should comply with protocol specified 
follow up procedures as outlined in Section 2.  The only exception to this requirement is when a 
participant withdraws consent for all study procedures including post treatment study follow up 
or loses the ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the 
treatment of either a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason 
for the discontinuation must be documented in the participant’s medical records and entered on 
the appropriate case report form (CRF) page.
8.2
Study Follow Up
In this study, safety is a key endpoint of the study. For participants who discontinue study 
treatment during the double blind period of the study (prior to Week 52):
Study follow-up is of critical importance and is essential to preserving participant safety 
and the integrity of the study. 


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Participants who discontinue study treatment and remain in the study will be expected to 
complete scheduled safety and efficacy tests and assessments until the end of study or 
withdrawal of consent (see Table 2 and Table 3). Participants who discontinue study 
treatment and remain in the study should have all AEs collected up to 30 days after the last 
dose of study treatment. AE collection should continue until the end of study or withdrawal 
from the study. 
At any point after discontinuing study treatment, if the participant makes the decision to 
withdraw from the study (Section 8.2), the following should be done:

Early Discontinuation visit procedures (Table 2) should be completed.

Participants and/or caregivers should receive a follow-up phone call approximately 
30 days after last dose discontinuation of study treatment to collect relevant clinical 
information, including, but not limited to safety data (i.e., AEs, SAEs) and vital status 
(e.g., ability to ambulate, cognitive disability, speech, dysphagia, dependence on 
wheelchair for mobility, placement in residential care, and death).

If possible, participants who discontinue study treatment should be encouraged to 
return to the clinic at Week 52 to complete Week 52 visit procedures.  If the visit 
cannot be done in person by the participant, the site should attempt a phone call at 
approximately Week 52 to collect at a minimum vital status and SAE/AE information 
on the participant.
For participants who discontinue study treatment during the open label extension period of the 
study (after Week 52):

Early Discontinuation visit procedures (Table 3) should be completed.

Participants and/or caregivers should receive a follow up phone call approximately 
30 days after last dose to collect relevant clinical information, including but not 
limited to, safety data (i.e., AEs, SAEs) and vital status (e.g., ability to ambulate, 
cognitive disability, speech, dysphagia, dependence on wheelchair for mobility, 
placement in residential care, and death)
Post study follow up is of critical importance and is essential to preserving participant safety and 
the integrity of the study.  Participants who discontinue study treatment must continue to be 
followed for collection of outcome and/or survival follow up data as required and in line with 
Section 2 until death or the conclusion of the study.
8.3
Withdrawal From the Study
Participants who request to discontinue study treatment will remain in the study and must 
continue to be followed for protocol specified follow upwithdraw from the study should 
complete the Early Discontinuation visit procedures (Table 2 and Table 3).


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Rationale: Clarified criteria for participants, to provide clear instructions on clinic visit 
participation, scheduled assessments, and monitoring of AEs as defined by whether the study 
participants discontinue from study treatment and either remain in the study or withdraw from 
the study.
This change also affects Section 2, Schedule of Activities (Table 2, Double-blind Period 
Procedural Outline, Notes; Table 3, Extension Period Procedural Outline, Notes), and 
Section 5.1.5, Discontinuation of Study Treatment and Withdrawal.
Section 15, Other Assessments
Change: Section 15.1 was added to include different PSP clinical phenotypes.
15.1
PSP phenotypes
Based on participant’s medical history, Investigators will be asked to provide the 
participant’s clinical phenotype as outlined in the Movement Disorder Society-PSP criteria 
[Höglinger 2017]. 

PSP with predominant Richardson-syndrome 

PSP with predominant ocular motor dysfunction

PSP with predominant postural instability

PSP with predominant Parkinsonism

PSP with progressive gait freezing

PSP with predominant frontal presentation

PSP with predominant speech/language disorder

PSP with predominant corticobasal syndrome
Rationale: The text was added to outline PSP clinical phenotypes to aid the Investigator in 
selecting the PSP phenotype based on the participant’s medical history. 


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SUMMARY OF CLARIFICATIONS TO THE PROTOCOL
In addition to the major changes described above, the following clarifications were made.  These 
changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 2, Schedule of Activities (Table 2)
Change: The table was revised to clarify that CGI interview collected from Week 36 will be 
used to assign the Week 48 SEADL score. 
Now reads:
Table 2:
Double-Blind Procedural Outline
Procedurea
Week 0
(Day 1)
Weeks 4, 8,
16, 20, 28,
32, 40, 44b
(±3 days) 
Weeks 
12,
24, 36
(±3 days)
Week 48
(±3 
days)
Week 52
(±3 days)
Early 
Discontinuationc,d
Notes
Efficacy Assessments 
SEADL Phonemic 
Fluency, Letter-
Number 
Sequencing, Color 
Trails Test, MoCA
X
X
Xf
f CGI interviews collected from Week 36 will be used to review all areas of the functioning section (including 
complex daily activities and basic functions) and will be used to determine whether there have been any 
changes or additions to the functioning at the Week 48 visit, with both the caregiver and participant 
independently. This will be used to assign the Week 48 SEADL score.
Rationale: Clarified that the Week 48 CGI interview with the participant and caregiver would 
not be collected and that the participants Week 48 SEADL score would be scored based on the 
Week 36 CGI interview. These changes are intended to facilitate the accurate completion of 
study efficacy assessments.
Section 2, Schedule of Activities (Table 3)
Change: The table was clarified to include the schedule for home visits. Scheduled visits were 
clarified to indicate the “week of visit” instead of “visit intervals.”


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Now reads:
Table 3:
Extension Period Procedural Outline
Procedure
Week 
52
Weeks 56, 60, 
68, 72, 80, 84, 
92, 96, 104, 108, 
116, 120, 128, 
132, 140, 144, 
152, 156, 164, 
168, 176, 180, 
188, and 192a,b
(±7 days)
4, 8, 16, 20 
week intervals 
after Week 52a,b
Weeks 64, 88, 
112, 136, 160, 
184c
(±7 days)
12 week 
intervals after 
Week 52c
Weeks 76, 
100, 124, 148, 
172, 196d
(±7 days)
24 week 
intervals after 
Week 52d
Early 
Discontinuationb
Notes
Clinical Drug Supplies
Dispense Study 
DrugTreatment
X
X
X
X
Duration of 
infusion will be 
at least 1 hour.
a Weeks 68, 72, 80, 84, 92, 96, 104, 108, 116, 120, 128, 132, 140, 144, 152, 156, 164, 168, 176, 180, 188, and 192 
may qualify for home visits if appropriate starting at Week 68. See Section 5.1 for details.
b Visit intervals of 4, 8, 16, and 20 after Week 52 (e.g., Weeks 56, 60, 68, 72, 80, 84, 92, 96, 104, 108, 116, 120, 
128, 132, 140, 144, 152, 156, 164, 168, 176, 180, 188, and 192.
c Visit intervals of 12 weeks after Week 52 (e.g., Weeks 64, 88, 112, 136, 160, and 184).
d Visit intervals of 24 weeks after Week 52 (e.g., 76, 100, 124, 148, 172, and 196).
b Participants who discontinue study treatment during the open-label extension period of the study (after 
Week 52) but remain enrolled in the study will be expected to complete scheduled safety and efficacy 
evaluations at Weeks 64, 76, 88, 100, 112, 124, 136, 148, 160, 172, 184, and 196. 
c Sample to be collected predose.
d This 30-day assessment of AEs/SAEs may be done by phone if no visit occurs.
Rationale: Clarified that the home visits started from Week 68 and not from Week 56 in the 
open label extension period. Visit intervals were updated to the week of visit to facilitate the 
accurate completion of study visits and improve conformity in the document.
This change also affects Section 5.1.4.
Section 4, Study Objectives and Endpoints
Change: The pons region of the brain was added in the list of baseline brain volume assessments 
as a secondary objective for the study.


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Now reads:
Objective
Endpoint
Other Secondary
To assess the efficacy of BIIB092, relative to 
placebo, as measured by absolute and 
percent change from baseline of brain 
volumes, as determined by magnetic 
resonance imaging (MRI), at Week 52 in the 
following regions:

Ventricles

Whole brain

Midbrain

Pons

Superior cerebellar peduncle

Third ventricle

Frontal lobe
The impact of BIIB092 on brain volumes, as 
determined by MRI in the following regions:

Ventricles

Whole brain

Midbrain

Pons

Superior cerebellar peduncle

Third ventricle

Frontal lobe 
will be evaluated relative to the absolute and 
percent changes from baseline at Week 52 of
in the drugBIIB092-treated participants and 
compared to that of the placebo-treated 
participants.
Rationale: Updated the comprehensive assessment of the impact of BIIB092 on brain volumes 
as determined by MRI, by including all areas of the brain assessed.
Section 11, Pharmacokinetic (Table 9)
Change:  The table was simplified by presenting the Week 56 predose estimated sample 
collection time in place of the Week 52 postdose estimated sample collection time. Visit 
intervals were presented as corresponding weeks of visit.


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Now reads:
Table 9:
Pharmacokinetic Sampling Schedule
Study Week of
Sample Collection
Event
Estimated Time
(Relative to start of
Infusion of
BIIB092)
Hour: Min
BIIB092 Blood
Sample for Serum
BIIB092 CSF
Sample
a
Week 0 (Day 1)
Predose
00:00
X
X
Week 0 (Day 1)
EOI
b
01:00
X
Week 4
Predose
00:00
X
Week 4
EOI
b
01:00
X
Week 12
Predose
00:00
X
Week 24
Predose
00:00
X
Week 24
EOI
b
01:00
X
Week 36
Predose
00:00
X
Week 48
Predose
00:00
X
Week 48
EOI
b
01:00
X
Week 52
Predose
00:00
X
X
Week 52
Week 56
Postdosec
Predose
672:00
00:00
X
X
24 week intervals
after Week 52
Weeks 76, 100, 124, 
148, 172, and 196d
Predose
00:00
X
Week 100 only
CSF = cerebrospinal fluid; EOI = end of infusion.
a
Collect at the time of LP (
).
b
This sample should be taken immediately prior to stopping the infusion (preferably within 2 minutes prior to the
end of the infusion).  If the end of infusion is delayed to beyond the nominal infusion duration, the collection
of this sample should also be delayed accordingly.  
c
The Week 52 sampling at 672 hr after Week 52 dosing is the scheduled predose sampling at Week 56 is also 
the Week 52 postdose sampling (672 hours after Week 52 dosing).
d Visit intervals of 24 weeks after Week 52 (Weeks 76, 100, 124, 148, 172, and 196).
Rationale: The Week 52 postdose sampling was the same sampling as that for Week 56 predose 
sampling and for clarity in presenting the sampling hours, Week 52 postdose was replaced by 
Week 56 predose in the table. CSF sample was collected at Week 52. Visit intervals were 
updated to the week of visit to facilitate the accurate completion of study visits and improve 
conformity in the document.


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SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

Section 10.15, Safety (in Section 10: Adverse Events) was moved to Section 9.2: 
Safety Assessments (in Section 9: Study Assessments and Procedures)

Section 5.3, Data Monitoring Committee and Other External Committees: updated 
information regarding reviewing unblinded data

Section 5.7, Justification for Dose: deletion of dose and CSF eTau suppression data 
related to Study IPN-T3

Section 7, Treatment: addition of information regarding rescue medication 
(epinephrine) that will be dispensed for home care for use in the event of an allergic 
reaction

Section 6.2, Exclusion Criteria, and Section 7.7.1, Prohibited and/or Restricted 
Treatments: addition of hypnotics for sleep in the list of treatments allowed

Section 14, Immunogenicity Assessments: clarification/revision from “discontinue” 
to “withdraw” in participants with ADA titers that are not stable

Section 17.2, Populations for Analyses: clarification that additional analysis 
populations will be in the SAP and revision of mITT to ITT only (not modified 
intention-to-treat)

Section 17.3, Handling of Missing Data: clarification that percentage of patients who 
withdrew (not discontinued) over time through Week 52 will be summarized.

Section 17.4.1, Efficacy Analyses: clarification that efficacy analyses will be 
performed using the ITT population (not mITT) and revisions on the statistical 
analysis methods to be performed on the primary efficacy endpoints

Section 17.4.1, Efficacy Analyses: clarification that in the MMRM model for the 
primary analysis of primary endpoint, the interaction between baseline value and visit 
is also added in to the MMRM model.

Section 17.4.1, Efficacy Analyses: in the analysis summary table of the primary 
endpoint, the MMRM analysis for participants with complete data is removed.

Section 17.4.1, Efficacy Analyses: the types and order of structures tested if analysis 
fails to converge was updated.

Section 18, References: updates made re: new and deleted literature entries


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
Appendix 1: updates on the list of abbreviations

Appendix 2: updates on Subject Information and Consent

The version number and date were revised throughout the protocol.

The Table of Contents was updated.

The term “subject/patient” was changed to “participant” pursuant to uniformity where 
applicable.

The term “withdrawn from study” was used where applicable for participants who 
were no longer enrolled in the study.

Reference to study “phase” was changed to “period” pursuant to uniformity where 
applicable. 

The term “study drug” was changed to “study treatment” pursuant to uniformity
where applicable.

The term “extracellular tau/eTau” was updated to “N-terminal tau” where applicable.

The term free “N-terminal tau” was updated to unbound “N-terminal tau” where 
applicable.

Minor editorial changes were made.

Typographical and formatting errors were corrected.




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PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 251PP301was to correct an error.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 6.2, Exclusion Criteria
Change:  The definition of 1 criterion (w/i) was revised.
Now reads:
w. Current hepatitis C or hepatitis B infection
i)
Current hepatitis C infection (defined as positive HCV antibody and detectable HCV 
RNA).  Participants with negative positive HCV antibody and undetectable HCV RNA are 
eligible to participate in the study (US Centers for Disease Control and Prevention).
ii) Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] 
and/or hepatitis B core antibody [anti-HBc]).  Participants with immunity to hepatitis B 
from previous natural infection (defined as negative HBsAg, positive anti-HBc, and 
positive hepatitis B surface antibody [anti-HBs]) or vaccination (defined as negative 
HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study 
(US Centers for Disease Control and Prevention).
Rationale:  This change was necessary to correct an error in the decision criteria that would 
allow a participant who no longer has an active hepatitis C infection to enroll in the study.








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SUMMARY OF MINOR CHANGES TO THE PROTOCOL

The version number and date were revised throughout the protocol.

The Table of Contents was updated.

Typographical and formatting errors were corrected.




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PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 251PP301is an increase in the study sample 
size.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 17.1, Sample Size Determination 
Now reads:
Approximately 396459 participants will be randomly assigned, in a 2:1 ratio, to receive BIIB092
or placebo (264306 participants in the BIIB092 treatment group and 132153 in the placebo 
group).  Anticipating a dropout rate of approximately 25% (based on previous clinical studies in 
participants with PSP), approximately 297345 participants (198230 participants in the BIIB092
treatment group and 99115 participants in the placebo group) are expected to complete the study 
through Week 52.
Using a two-sided, two-sample t-test, with an alpha level set at 0.05, this sample size will 
provide 9080% power to detect a difference of 4.03.2 points in the change in PSPRS total score 
from baseline to Week 52 for BIIB092 relative to placebo, assuming a common standard 
deviation of 9.95 [Stamelou 2016] in the change in PSPRS total score from baseline to Week 52.
Rationale:  Preliminary market research conducted with experts in the field indicates that a 
difference of 2.5 to 3.5 points in the primary efficacy endpoint (the Progressive Supranuclear 
Palsy Rating Score [PSPRS]) would represent a clinically meaningful treatment effect at 
52 weeks.  The sample size has been increased by approximately 15% to improve the estimated 
power of the study to detect a between-treatment difference in PSPRS of that magnitude.
This change also affects Section 5.1, Overall Design (including Figure 1); and Section 5.3, 
Number of Participants.


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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 1, Synopsis
The Synopsis was revised to reflect changes made throughout the protocol.
Section 4, Study Objectives and Endpoints
Change:  Efficacy and safety objectives and endpoints for the open-label extension period were
added.
Now reads:
Open-Label Extension Period
To assess the long-term safety and 
tolerability of BIIB092 in participants
with PSP.
The tertiary endpoint will be incidence of 
AEs, SAEs, and SAEs accompanied by 
death.
To assess the long-term efficacy of 
BIIB092 in participants with PSP.
The tertiary endpoints will be change from 
baseline over the placebo-controlled 
period and long-term extension period for 
clinical and health-outcomes assessments.
Rationale:  The objectives and endpoints of the extension period were not previously stated.
Section 6.4.1, Retesting During Screening or Lead-In Period
Change:  Improper reference to “re-enrollment” of participants who failed a previous screening 
was corrected, and the role of the Medical Monitor in determining testing requirements for re-
screening was made clear.
Now reads:
Participant Re-enrollmentscreening: This study permits the re-enrollmentscreening of a 
participant that who has discontinued the study as a pre treatment failure screen-failed up to 
2 times (i.e., participant hwas not been randomized / has not been or treated).  If re-
enrolledscreened, the participant must be re-consented.  The assessments to be conducted on 
re-screening will depend upon how much time passed since the previous Screening Visit.  
Please contact the Medical Monitor for guidance regarding the acceptability of any 
previous assessments completed.








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SUMMARY OF CLARIFICATIONS TO THE PROTOCOL
In addition to the major changes described above, the following clarifications were made.  These 
changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 2, Schedule of Activities (Table 1, Notes)
Change:  The responsibility of the caregiver to accompany the participant to study visits was 
clarified in the Notes to the table.
Now reads:  
Informed Consent for Caregiver
X
Caregiver is defined as theat person thatwho accompanies participant 
to all/most study visits and has frequent contact with participant of at 
least 3 hours per week at one time or at different times.  Only one 
caregiver can be designated for participant at a given time.  At a 
minimum, caregiver should personally attend the following study 
visits: Screening, Baseline, Weeks 12, 24, 36, 48, 52, and Early 
Discontinuation.  Although caregiver assessments cannot be 
conducted by telephone, caregiver should be available for 
telephone consultation regarding information on AEs and SAEs 
when not otherwise attending a scheduled visit.
Rationale:  This revision is intended to make certain that the caregiver is clearly advised of the 
importance of their commitment to proper conduct of the study. 
This change also affects Table 3 (Extension Period Procedural Outline) and Section 6.1 
(Inclusion Criteria, 1d and 2g).
Section 2, Schedule of Activities (Table 1, Footnote a)
Change:  The timeframe during which Screening procedures may be conducted was clarified.
Now reads:  
a Screening procedures may be conducted Wwithin 42 days prior to first dose unless 
otherwise specified.
Rationale:  This revision is intended to make certain that the Investigator is advised of flexibility 
regarding the completion of Screening procedures. 
Section 2, Schedule of Activities (Table 2, Notes)
Change:  The duration of BIIB092 infusion was clarified.
Now reads:  


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Dispense Study Drug
X
X
X
X
X
Duration of infusion will be 
approximately at least 1 hour.
Rationale:  This revision is intended to make certain that the Investigator is advised that the 
infusion is not required to be completed within approximately 60 minutes.
This change also affects Section 2 (Schedule of Activities, Table 3, Notes) and Section 11 
(Pharmacokinetic, Table 7, Pharmacokinetic Sampling Schedule).
Section 2, Schedule of Activities (Table 2, Footnotes a & b)
Change:  The flexibility associated with the conduct of certain study visits was stated more 
explicitly.
Now reads:  
a Efficacy assessments requiring subject participant participation involvement should be 
completed prior to dosing with study treatment unless otherwise specified in the notes.; 
specific attention should be paid to conducting the Week 24 MRI within 7 days prior to 
the Week 24 dosing visit.  The study visits at Weeks 0, 12, 24, 36, 48, 52, and Early 
Discontinuation, which involve the conduct of efficacy assessments, may be completed 
over a period of up to 3 consecutive days. 
b Weeks 28, 32, 40, and 44 Mmay qualify for home visit if appropriate.  See Section 5.1 for 
details.
Rationale:  These changes are intended to facilitate the completion of certain study visits and 
improve procedural conformity regarding those visits involving efficacy assessments. 
Section 5.5.2, Rationale for Inclusion of Key
Change:  The need for compliance with local regulatory and institutional requirements in the 
practice of 
 and pharmacogenetic analysis was explicitly recognized.
Now reads:
All participants will have blood collected for assessment of serum concentrations of 
 
determined at baseline and at regular intervals during the study to 
confirm target engagement.
In additionWhere local regulations and institutional approvals allow, a deoxyribonucleic acid 
(DNA) sample will be collectedprepared to support future studies examining the relationship 
between H1 and H2 haplotypes on tau protein levels.
Rationale:  This change was made to formalize recognition of jurisdictional differences in the 
acceptability of collecting biological samples for exploratory research and the rights of 
participants who may choose to provide those samples.


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Section 6.1, Inclusion Criteria
Change:  Acceptability of consent provided by a legally authorized representative was 
recognized in 1 criterion (1a), and greater allowance was made for dose stabilization of select 
concomitant medications in 2 criteria (2j and k).
Now reads:
a.
Participants, or a legally authorized representative (where local regulations and 
institutional practices permit), must have signed and dated an Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approved written informed consent form in 
accordance with regulatory and institutional guidelines.  This must be obtained before the 
performance of any protocol-related procedures that are not part of normal 
subjectparticipant care.
j.
If participant is receiving coenzyme Q10, levodopa/carbidopa, levodopa/benserazide, fava 
bean extract, a dopamine agonist, catechol-0O-methyltransferase inhibitor, amantadine, or 
other Parkinson’s disease medications, the dose must have been stable for at least 60 days 
prior to screeningbaseline and expected to remain stable for the double-blind period of the 
study.
k. Stable on other chronic medications for at least 30 days prior to screeningbaseline.
Rationale:  The intent of the change in criterion 1a is to allow for the involvement of those 
participants who can no longer consent freely due to progression of disease; the intent of the 
change in criteria 2j and 2k is to avoid unnecessary screening failures by allowing additional 
time to stabilize the dosing of chronic medications.
Section 6.2, Exclusion Criteria
Change:  Under Subsection 1 (Medical Conditions), 4 criteria were revised (a, e, l, and q) and 
1 criterion was added (w); under Subsection 2 (Prior/Concomitant Therapy), 2 criteria were 
revised (a and b); and, under Subsection 3 (Physical and Laboratory Test Findings), 1 criterion 
was deleted (i).
Now reads:
1. Medical Conditions
a.
Presence of other significant neurological or psychiatric disorders including (but not 
limited to) Alzheimer's disease, dementia with Lewy bodies; prion disease, Parkinson's 
disease (which has not subsequently been revised to a diagnosis of PSP); any psychotic 
disorder; severe bipolar or unipolar depression; prior history of suicidal thoughts or 
behavior that are believed to represent a current safety risk; seizure; brain tumor or other 
space-occupying lesion; history of clinically significant stroke (e.g., stroke with 
neurological deficit); history of head injury with loss of consciousness for at least 
15 minutes within the past 20 years.




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day of lorazepam administration.  Participants and caregiver must be informed of risks 
of lorazepam use prior to administration.
b. Receipt of systemic corticosteroids within 30 days prior to screeningbaseline.
3. Physical and Laboratory Test Findings
i.
Positive blood screen for hepatitis C antibody, hepatitis B surface antigen
Rationale:  The changes in subsections 1 and 2 are intended to reduce inappropriate screening 
failures and provide greater flexibility in the clinical management of study participants; the 
deletion in subsection 3 was duplicative of the exclusion criterion under 1w.
Section 11, PHARMACOKINETIC (Table 7)
Change:  The table was revised to include collection of the Week 52 predose sampling, and a 
footnote was added to clarify the nature of the Week 52 postdose sampling. 
Now reads:
Table 7:
Pharmacokinetic Sampling Schedule
Study Week of
Sample Collection
Event
Estimated Time
(Relative to start of
infusion of
BIIB092)
Hour: Min
BIIB092 Blood
Sample for Serum
BIIB092 CSF
Sample
a
Week 0 (Day 1)
Predose
00:00
X
X
Week 0 (Day 1)
EOI
b
01:00
X
Week 4
Predose
00:00
X
Week 4
EOI
b
01:00
X
Week 12
Predose
00:00
X
Week 24
Predose
00:00
X
Week 24
EOI
b
01:00
X
Week 36
Predose
00:00
X
Week 48
Predose
00:00
X
Week 48
EOI
b
01:00
X
Week 52
Predose
00:00
X
Week 52
Postdosec
672:00
X
X
24-week intervals
after Week 52
Predose
00:00
X
Week 100 only
a
Collect at the time of LP (
).


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b
EOI=End of Infusion,; Tthis this sample should be taken immediately prior to stopping the infusion (preferably
within 2 minutes prior to the end of infusion).  If the end of infusion is delayed to beyond the nominal 
infusion duration, the collection of this sample should also be delayed accordingly.  
c
The Week 52 sampling at 672 hr after Week 52 dosing is the scheduled predose sampling at Week 56.
Rationale:  The original table failed to include the scheduled Week 52 predose sampling, and 
the nature of the Week 52 postdose sampling (as originally described) required clarification.
This change also affects Section 2 (Schedule of Activities; Table 3, PK Assessments).


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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 revised throughout the protocol.

The Table of Contents was updated.

The term “subject” was changed to “participant” pursuant to uniformity.

Reference to study “phase” was changed to “period pursuant to uniformity. 

Minor editorial changes were made.

Typographical and formatting errors were corrected.




Protocol 251PP301, Version 4
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PRIMARY REASON FOR AMENDMENT
The primary reason for this amendment to Protocol 251PP301 is to add a missing safety 
assessment, 12-lead electrocardiogram (ECG), and to add instruction to the assess infusion site to 
the double-blind schedule of events.
Additionally, the following changes were made to Table 2: Double-Blind Procedural Outline:

Pregnancy test was added at the Early Discontinuation visit.  

Footnote “a” language was updated.
New text is shown in bold type; deleted text is shown with a strikethrough.
Section 2, Schedule of Activities, Table 2: Double-Blind Procedural Outline
Now reads:Table 2: Double-Blind Procedural Outline




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c Early Discontinuation visit procedures should be completed for any participant who discontinues at any time prior to Week 52.  If possible, participants who 
discontinue should be encouraged to return to the clinic at Week 52 to complete the Week 52 procedures.  If the visit cannot be done in person by the 
participant, the site should attempt a phone call at approximately Week 52 to collect at a minimum vital status and SAE/AE information on the participant.


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Rationale:  These 2 assessments, 12-lead ECG and assessment of the infusion site, were added 
to the Version 4 protocol amendment as per the Version 1 protocol.
The pregnancy test assessment was added at the Early Discontinuation visit.  This was an 
oversight in the BMS Version 1 of the protocol.
The footnote “a” was revised for clarity.


Protocol 251PP301, Version 4
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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 2, Schedule of Activities, Table 1: Screening Procedural Outline
Change: Text regarding the 
 was revised.
Now reads:
Table 1: Screening Procedural Outline


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Procedure
Screening Visita
Notes
Lumbar Puncture (LP)
X
performed at selected sites 
ONLY
The baseline LP may be performed up to Day -1 to allow recovery before 
dosing.  LP should be performed in the morning (between 08:00 and 12:00 
hours) to minimize potential diurnal variation of cerebrospinal fluid (CSF) 
parameters.  Any participant with an AE related to LP should not be dosed 
until the AE has resolved. Use of low dose acetylsalicylic acid (ASA) or other 
antiplatelet/anticoagulant medications may be associated with a higher risk of 
LP complications.  At the discretion of the iInvestigator, if not 
contraindicated, low dose ASA or other antiplatelet/anticoagulant medications 
may be discontinued for a short period of time prior to performing the LP.  
Stop and start dates must be documented on the appropriate Concomitant 
Medication CRF.  CSF may be assessed for BIIB092 concentrations, white 
and red blood cell counts, protein, glucose, levels of free eTau, total tau, 
phosphorylated tau, and neurofilament light chain (NfL).  Participants should 
be observed for approximately 2 hours after the LP for AEs.  LP can be done 
in either the decubitus or sitting position, however it is preferred that all LPs 
for each participant are performed in the same position.  The position of the 
participant during the LP will be recorded.  LP may be performed under 
fluoroscopy or with computed tomography (CT) guidance at the discretion of 
the iInvestigator.


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Rationale:  The statement was revised to clarify that the 
.
This section also affects Section, 2 Schedule of Activities, Table 2: Double-Blind Procedural 
Outline; Section, 2 Schedule of Activities, Table 3:  On Treatment Procedural Outline for 
Long-Term Open-Label Phase; Section 5.1, Overall Design; and Section 11, Pharmacokinetic, 
Table 7:  Pharmacokinetic Sampling Schedule.
Section 2, Schedule of Activities, Table 3:  On Treatment Procedural Outline for Long-Term 
Open-Label Phase
Change: 
The following changes were made:

Physical measurement was added as a part of safety assessments.

Pregnancy test assessment was added at the Early Discontinuation visit.

Monitoring of serious adverse events (AEs) was revised.

Efficacy assessments were revised.
Now reads:
Table 3: On Treatment Procedural Outline for Long-Term Open-Label Phase


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Procedure
4, 8, 16, 20 week 
intervals after 
Week 52ab
(±7 days)
12 week 
intervals after 
Week 52c
(±7 days)
24 week 
intervals after 
Week 52d
(±7 days)
Early Discontinuation
Notes
Safety Assessments
Physical Examination
See Notes
X
X
At Week 64 only.
Targeted Physical Examination
X
X
X
X
Post-dose.
Targeted, problem-focused physical 
examination performed at clinician’s 
discretion (e.g., to evaluate any AEs).
Neurological Exam (NE)
See Notes
Week 100 only.
Besides documenting signs of PSP, the NE 
should focus on any clinical evidence of 
increased intracranial pressure (e.g., 
history of headache, vomiting, or visual 
disturbances, and neurologic signs such as 
pupillary abnormalities and papilledema) 
that might contraindicate a lumbar 
puncture.
Physical Measurements
X
X
X
Weight only.
Vital Signs
X
X
X
X
12-Lead Electrocardiogram (ECG)
X
X
Assess Infusion site
X
X
X
X
Laboratory Tests
See Notes
X
X
At Week 64 only.
Pregnancy Test
X
X
X
X
For WOCBP only (serum or urine -
local/site).
Adverse Event Reporting


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Procedure
4, 8, 16, 20 week 
intervals after 
Week 52ab
(±7 days)
12 week 
intervals after 
Week 52c
(±7 days)
24 week 
intervals after 
Week 52d
(±7 days)
Early Discontinuation
Notes
Monitor for Non-Serious Adverse 
Events (NSAEs)
Collection of NSAEs begins at initiation of study drug. Participants that 
discontinue early should receive a follow-up phone call 30 days after last 
dose.
Monitor for Serious Adverse Events 
(SAEs)
See note in screening procedures.
Efficacy Assessments
Progressive Supranuclear Palsy Rating 
Scale (PSPRS)
X
X
X
MDS-UPDRS Part II, CGI, RBANS, 
PSP-QoL
See Notes
X
X
At Week 64 only.
SEADL, Phonemic Fluency, Letter-
Number Sequencing, Color Trails Test, 
MoCA
X
 
Magnetic Resonance Imaging (MRI)
See Notes
At Week 100 only.
Lumbar Puncture (LP)
See Notes
At Week 100 only. 
(
).








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14
for 5 times the half life or 6 months, whichever is longer, after their last dose of study treatment.
If a female subject becomes pregnant, study treatment must be discontinued immediately.
Rationale:  The text was updated to be consistent with contraception requirements described in 
Section 6.1, Inclusion Criteria.
Appendix 4, Women of Childbearing Potential Definitions and Methods of Contraception
Change:  The contraception requirements described in Appendix 4 of the protocol were updated 
to be consistent with contraception requirements described as part of eligibility requirements.
Now reads:
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING
POTENTIAL
Any one of the approved methods of contraception listed below is required for the duration of 
this study and for 30155 days after treatment has been discontinued.
Local laws and regulations may require use of alternative and/or additional contraception
methods.
Contraceptive methods that are approved for use during and for 30155 
days after participation in this study are:
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb

oral

intravaginal

transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulationb

oral

injectable
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of
ovulationb

Intrauterine device (IUD)c

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used.

Sexual abstinence


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Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study
and the preferred and usual lifestyle of the participant.

It is not necessary to use any other method of contraception when complete abstinence is
elected.

WOCBP participants who choose complete abstinence must continue to have pregnancy
tests, as specified in Section 10.5

Acceptable alternate methods of highly effective contraception must be discussed in the
event that the WOCBP participants chooses to forego complete abstinence
NOTES:
a Typical use failure rates may differ from those when used consistently and correctly.  Use should be consistent
with local regulations regarding the use of contraceptive methods for participants participating in clinical
studies.
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence
that the IMP and other study medications will not alter hormonal exposures such that contraception would be
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative
methods of contraception should be utilized.
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter
contraception effectiveness.
Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus interruptus)

Spermicide only

Lactation amenorrhea method (LAM)
Rationale:  The contraception requirements for women were revised to be consistent with the 
study eligibility requirements described in Section 6.1, Inclusion Criteria.


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16
SUMMARY OF MINOR CHANGES TO THE PROTOCOL
The following minor changes were made to the protocol, as appropriate:

The version number and date were updated throughout the protocol.

Typographical errors and formatting were corrected.

In Section 3.2, minor edits were made to the text regarding monocloncal antibody for 
consistency.

In Section 7, text was added to include cross-reference to Table 5.

In Section 7.5, minor edits were made for clarity.

In Section 8.1, Discontinuation From Study Treatment, and Section 8.1.1, Post-Study 
Treatment Follow-Up, reference to Section 5, Study Design, was updated to reflect 
Section 2, Schedule of Activities, in particular Table 2 or Table 3, as this section was 
more appropriate.

In Section 9.2, Imaging Assessment for the Study, reference to the central core 
laboratory was updated to central imaging vendor for clarity.

In Section 10.1, Time Period and Frequency for Collecting AE and SAE Information, 
the reference to the Investigator’s Brochure section was updated to Section 6.6, 
Reference Safety Information, as per Biogen’s Investigator Brochure.

In Section 14, Immunogenicity Assessments, text was updated to match BMS 
protocol Version 1.

In Appendix 1, List of Abbreviations, was updated.

In Appendix 2, the text regarding legally authorized representative was deleted.  This 
also affects section 10, Adverse Events.

In Appendix 2, minor edits were made to subsection Clinical Study Report and 
Publications for clarity.

In Appendix 3, Adverse Events and Serious Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow Up and Reporting, text was updated to 
match the BMS protocol Version 1.








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SPONSOR INFORMATION
Biogen is responsible for 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
Biogen Japan Ltd.
Nihonbashi 1-chome 
Mitsui Building 14F
4-1 Nihonbashi 1-chome
Chuo-ku, Tokyo
103-0027 Japan
Biogen Australia PTY 
Ltd.
Suite 1, Level 3 
123 Epping Road
North Ryde, NSW 2113
Australia
For urgent medical issues in which the study Medical Director should be contacted, please 
refer to the Study Reference Guide’s Official Study Contact List for complete contact 
information.
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization (CRO) and other third parties; however, Biogen retains overall accountability 
for these activities.
Rationale: Biogen is now the Sponsor of the study.
This change also affects the following sections and applicable subsections:  Section 2, Schedule 
of Activities; Section 3, Introduction; Section 4, Objective and Endpoints; Section 5, Study 
Design; Section 5.1, Study Schematic (including Figure 5.1-1: Study Design Schematic); Section 
6, Study Population; Section 7, Treatment; Section 8, Discontinuation from Study Treatment; 
Section 9, Study Assessments and Procedures; Section 10, Statistical Considerations; and 
Section 12, Appendices.


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SUMMARY OF MAJOR CHANGES TO THE PROTOCOL
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a strikethrough.
Section 1, Synopsis
The synopsis was revised to reflect changes made throughout the protocol.
Section 2, Schedule of Activities
Change:  Table 1 was revised.
Now reads:
Efficacy Assessments
Progressive Supranuclear
Palsy Rating Scale (PSPRS)
X
Repeatable Battery for the 
Assessment of
Neuropsychological Disease
Severity (RBANS)
X
Montreal Cognitive 
Assessment (MoCA)
X
Phonemic Fluency Test
X
Letter-Number Sequencing
Test (LNS)
X
Color Trails Test (CTT)
X
Randomization will be stratified by country and screening CTT Part 2 
score of either less than or equal to 170 seconds, or greater than 170 
seconds.
Magnetic Resonance 
Imaging (MRI)
X
The MRI should be completed at least 14 days prior to first dose to 
allow for central assessment of image.  A repeat MRI may be requested 
prior to randomization if protocol standards are not yet met.  MRI 
image quality must be determined to be adequate and local 
interpretation performed to determine eligibility and also to rule out any 
contraindication to lumbar puncture for participants participating in the 
Rationale: The randomization scheme was amended to include country as an additional 
stratification factor. Country as a stratification factor was added to promote treatment balance 
within each country.
This change also affects Sections 5.3, Number of Participants and Section 7.2, Method of 
Treatment Assignment.
Change: Table 3 footnote was updated.


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Now reads:
May qualify for home visit if appropriate starting at Week 68. See Section 5.1 for details.
b Visit intervals of 4, 8, 16, and 20 after Week 52 (e.g., Weeks 56, 60, 68, 72, 80, 84, 8292, 96, 104, 108, 116, 120, 
128, 132, 140, 144, 152, 156, 164, 168, 176, 180, 188, and 192
c Visit intervals of 12 weeks after Week 52 (e.g., Weeks 64, 88, 112, 136, 160, and 182184).
d Visit intervals of 24 weeks after Week 52 (e.g., 76, 100, 124, 148, 172, and 196).
e Sample to be collected predose.
Rationale: The footnote was corrected since some of the weeks listed were incorrect. The 
current changes reflect the interval as stated.
Section 3.2 Background
Change: More current information on some of the studies was added.
Now reads:
BIIB092 was first introduced into clinical trials in the Phase 1 trials conducted in the United 
States (US), Study CN002001 in healthy adult volunteers and. The Phase 1b PSP study ( Study 
CN002003) in subjects with PSP.
and corresponding roll over study (CN002004) are ongoing in the US. Preliminary data available
Results from the first-in-human study, CN002001, indicate that administration of single doses of 
up to 4200 mg of BIIB092 in healthy subjects is safe and well tolerated. Mean suppression of the 
CSF eTau in that study ranged from 67% to 97% at doses ranging from 70 mg to 4200 mg. 
Study CN002003 was a Phase 1b randomized, double-blind, placebo-controlled, MAD 
study to characterize the safety, tolerability, PK, PD and immunogenicity of BIIB092 doses 
of 150 mg, 700 mg and 2100 mg in subjects with PSP.  All 3 doses were safe and well 
tolerated based on results from the dose escalation phase of the study.  Treatment with 
monthly doses of BIIB092 decreased CSF free eTau by mean values of approximately 90%, 
93% and 96% on Day 29 and 91%, 95% and 97% on Day 85 at doses of 150 mg, 700 mg 
and 2100 mg respectively.
Study 251PP201 is an ongoing open-label extension study to evaluate the long term safety 
and tolerability of multiple doses of BIIB092 in subjects with PSP who participated in 
CN002003.  
Studies CN002003 and CN002004, Phase 1b study in participants with PSP and the associated 
roll over study, are currently ongoing to evaluate the safety, pharmacokinetics (PK) and 
pharmacodynamics (PD) of multiple doses of BIIB092. Preliminary data indicate that multiple 
doses of 150 , 700 , and 2100 mg of BIIB092 are safe and well tolerated, with an apparent dose
proportional increase in exposures, and a robust and persistent lowering of free eTau consistent 
with the observations in healthy participants.
Rationale: Updated status and general results on safety, tolerability and pharmacokinetics (PK) 
of completed clinical trials were available.


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Section 3.3, Benefit/Risk Assessment
Change:  Section 3.3 was updated.
Now reads:
The overall benefit/risk profile of BIIB092 in several nonclinical studies, the single dose study in 
normal healthy volunteers (CN002001), as well as the multiple dose study and associated roll 
over study open label extension study (Studies CN002003 and CN002004 [Study 251PP201])
support further evaluation of the safety, tolerability, immunogenicity, PK, PD response, and 
clinical efficacy of BIIB092 in participants with PSP.
BIIB092 is an IgG4 isotype antibody that is considered to have a low potential for 
immunogenicity in humans based on nonclinical studies. There were no adverse effects noted at 
any dose tested in the pivotal toxicity studies in monkeys. Nonclinical findings were limited to 
decreases in CSF free eTau consistent with the intended pharmacology of BIIB092.
Studies evaluating the potential for reproductive and developmental toxicity have not been 
performed for BIIB092.
As of July 31, 2017, 114 subjects have been exposed to BIIB092 across all completed and 
ongoing clinical studies (Studies CN002001, CN002003, 251PP201 and 251PP301).  Based 
on safety data from a completed Phase 1 studies in healthy volunteers (CN002001) and a 
completed Phase 1B study in subjects with PSP (Study CN002003), the majority of AEs 
reported to date have been mild to moderate in severity and transient in nature.  There 
have been no deaths or discontinuations due to an AE reported in the program.  There 
have been 4 SAEs reported in 3 subjects in the CN002003 study, all of which were 
considered not related to study drug by the Investigator.
Based on preliminary data from the CN002001 study and still ongoing studies CN002003 and 
CN002004, observed AEs to date have mostly been mild to moderate in severity and transient in 
nature. AEs considered related to the study drug by the investigator were belching, nausea, 
headache, and flushing. One AE of headache and one AE of diverticulitis were considered 
moderate; all other AEs were considered mild. Four (4) SAEs considered not related to study 
drug by the investigator have been reported to date in three (3) participants; one SAE was a 
urinary tract infection requiring hospitalization, one SAE was an aspiration pneumonia requiring 
hospitalization; the other two SAEs were aspiration pneumonia and a related metabolic 
encephalopathy in the same participant requiring hospitalization. Overall, there were no apparent 
BIIB092 treatment related trends observed in the occurrences of AEs.
There is no information available about possible interaction of BIIB092 with other drugs, 
although no PK interactions are anticipated.
More detailed information about the known and expected benefits and risks and reasonably 
anticipated AEs of BIIB092 may be found in the Investigator’s Brochure.  However, as BIIB092
is an experimental agent, it is possible that unforeseen, unknown, or unanticipated reactions may 
occur.


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Rationale:  Clinical experience text was updated to include results from Study CN002003 and 
align with the Investigator’s Brochure.
Section 5.1 Overall Design
Change: The responsibility of approving in-home administration of the study treatment was 
changed.
Now reads: In the open-label portion of the study, visits occurring at 4, 8, 16 and 20 week 
intervals after Week 52, may qualify for a home visit starting with the Week 68 visit. However, 
in the event that the participant experienced a clinically significant infusion reaction during the 
first 24 weeks of the protocol, the participant should not be administered BIIB092 in the home 
unless previously approved by the study Medical MonitorInvestigator.
Rationale: The Investigator, and not the Medical Monitor, is the person who approves in-home 
administration of BIIB092.
Section 5.6 Justification for Dose
Change: Update for which dose data will be accrued.
Now reads: In the SAD study in normal healthy volunteers (CN002001), single doses of 
BIIB092 were safe and well tolerated at all doses tested (i.e., 21 mg to 4200 mg). A maximum 
tolerated dose was not identified. Robust suppression of free eTau in CSF (88% to 97%) was 
observed for at least 4 weeks after a single dose, compared to baseline, in the dose range of 210 
mg to 4200 mg.  The MAD study in participants with PSP (CN002003) assessed Q4W doses of 
BIIB092 of 150 mg, 700 mg and 2100 mg during the dose escalation phase of the study. All 
three doses were safe and well tolerated in participants with PSP, based on preliminary results 
from the dose escalation phase of the study. Preliminary results also showed robust suppression 
of free eTau in CSF at the end of the first 4 week dosing interval, with 89%, 93%, and 97% 
suppression relative to baseline for 150 mg, 700 mg, and 2100 mg, respectively. Treatment with 
monthly doses of BIIB092 decreased CSF free eTau by mean values of approximately 90%, 
93% and 96% on Day 29 and 91%, 95% and 97% on Day 85 at doses of 150 mg, 700 mg
and 2100 mg respectively. Based on the near maximal suppression of eTau and the lack of any 
noteworthy findings on safety and tolerability of BIIB092, at the maximum dose of 2100 mg 
Q4W studied during the escalation phase of the study, the dose for the expansion panel in Study 
CN002003 was chosen to be continued at 2100 mg Q4W. Additional data on safety, tolerability, 
PK, and PD ofthe 2100 mg all 3 dose levels are accruing with the expansion panelopen label 
extension of this study.
Rationale: Additional data on safety, tolerability, PK, and PD are accruing for all 3 doses of 
study treatment, not just in the 2100-mg dose group in the open-label extension panel.
Section 7, Treatment


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Change:  Table was revised to reflect updated study drug constituents and study drug 
information (based on the Investigator’s Brochure) and language was added about how study 
drug will be labeled when provided to sites.
Now reads:
Study treatment includes both Investigational [Medicinal] Product (IP/IMP) and Non-
investigational [Medicinal] Product (Non-IP/Non-IMP) as listed:
Study Drug for Study 251PP301
Medication
Potency
IP/Non-IP
BIIB092*
50 mg/mL
IP
Placebo** (0.9% Sodium 
Chloride)
N/A
IP
* Drug supplies may be labeled as BIIB092 or BMS-986168. The two drug names refer to an 
identical drug substance.
** 5% dextrose injection can be used if sodium chloride is not available.


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Table 7.-1:
Study treatments for 251PP301
Product Description /
Class and Dosage
Form
Potency
IP/Non-IMP
Blinded or 
Open-Label
a
Packaging /
Appearance
Storage
Conditions
(per label)
BIIB092 Injection,
1000 mg/vial
(50 mg/mL)
The composition of the
drug product is:
50 mg/mL,
010 mM
Sodium Phosphate,
140 mM Sodium
Chloride, 0.02% (w/v)
Polysorbate 80, pH 6.1
BIIB092, histidine, 
histidine 
hydrochloride 
monohydrate, 
sucrose, pentetic acid, 
polysorbate 80, and 
sterile water for 
injection, pH 6.0
50 mg/mL
IP
Open-label
Clear to very
opalescent,
colorless to
slightly yellow
liquid, in which 
light (few) 
particulates may 
be present
Store
Refrigerated 
2C to 8C,
protect from
light. Do not
freeze
Placebo (0.9% Sodium
Chloride or 5%
Dextrose)b
0.9% NaCl
Or
5% Dextrose
IP
N/A
Per Product Label
Per Product
Label
a BIIB092 is provided Open-label to the unblinded pharmacist. After study drug is prepared by the
unblinded pharmacist all other study personnel will remain blinded to the identification of study drug 
(BIIB092 vs. placebo) up to Week 52.
b Placebo is not provided by Biogen and obtained commercially by the site, storage should in accordance with the
product label
Rationale:  Until the end of 2017, study supplies will continue to be labeled BMS-986168. Early 
in 2018, drug labels will switch from the BMS compound name to the Biogen compound name.  
This text was added to address drug supply transition from BMS-labeled drug product to Biogen-
labeled drug product and convey in the protocol that the two drug names are synonymous with 
one another.
Section 7.2, Method of Treatment Assignment 
Change: Section 7.2 was updated to clarify when stratification by country will be implemented.
Now reads: 


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All participants will be centrally randomized using an Interactive Response Technology (IRT). 
Before the study is initiated, each user will receive log in information and directions on how to 
access the IRT. Randomization will be stratified by country and screening Color Trails Test Part 
2 stratum of a score either less than or equal to 170 seconds or greater than 170 seconds. 
Randomization will only be stratified by screening Color Trails Test Part 2 stratum under 
the IRT system for protocol Version 1. To promote treatment balance within each country, 
randomization will be stratified by both country and screening Color Trails Test Part 2 
when the new IRT system for this protocol is in place.
Rationale: The randomization scheme was amended to include country as an additional 
stratification factor. Text was added to clarify that stratification by country will not occur until 
the programming in IRT is updated to V1.3.
Section 8.3, Lost to Follow-Up
Change:  Section 8.3 was revised to reflect alignment with processes at Biogen for patients lost 
to follow-up.
Now reads:

All reasonable efforts must be made to locate participants to determine and report 
their ongoing status. This includes follow-up with persons authorized by the 
participant.

Lost to follow-up is defined by the inability to reach the participant after a minimum 
of three documented phone calls, faxes, or emails as well as lack of response by 
participant to one registered mail letter. All attempts should be documented in the 
participant’s medical records.

If it is determined that the participant has died, the site will use permissible local 
methods to obtain date and cause of death.

If investigator’s use of a third party representative to assist in the follow up portion of 
the study has been included in the participant’s informed consent, then the 
investigator may use a sponsor retained third party representative to assist site staff 
with obtaining participant’s contact information or other public vital status data 
necessary to complete the follow up portion of the study.

The site staff and representative will consult publicly available sources, such as 
public health registries and databases, in order to obtain updated contact information.

If after all attempts, the participant remains lost to follow-up, then the last known 
alive date as determined by the investigator should be reported and documented in the 
participant’s medical records.


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Rationale:  The site Principal Investigator or designee will make every reasonable effort to 
contact any patient lost to follow up, a third party vendor will not be required to manage these 
activities. To date, the third party vendor services have not been required to assist site staff with 
obtaining participant’s contact information or other public vital status data necessary to complete 
the follow-up portion of the study.
Section 10, Adverse Events
Change:  Section 10 text was revised.
Now reads:
Pregnancy
Subjects should not become pregnant or impregnate their partners during the study and 
for 5 times the half-life or 6 months, whichever is longer, 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 by faxing or 
emailing the appropriate form to Biogen within 24 hours of the site staff becoming aware of 
the pregnancy.  Refer to the Study Contact List for complete contact information.  The 
Investigator or site staff must report the outcome of the pregnancy to Biogen.  A pregnancy 
is not considered an AE and should not be recorded on the AE CRF.
Congenital abnormalities and birth defects in the offspring of male or female subjects 
should be reported as an SAE if conception occurred during the study treatment period.
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5 
half lives after product administration, the investigator must immediately notify the Medical 
Monitor of this event and complete and forward a Pregnancy Surveillance Form to the Medical 
Monitor or their designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Appendix 3
In most cases, the study treatment will be permanently discontinued in an appropriate manner 
(e.g., dose tapering if necessary for participant safety). Please call the Medical Monitor within 24 
hours of awareness of the pregnancy.
Protocol required procedures for study discontinuation and follow up must be performed on the 
participant.
Follow up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 


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disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
Potential Drug Induced Liver Injury (DILI)
Potential drug induced liver injury (DILI) is defined as:
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) AND
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline
phosphatase),
AND
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia,
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the
administration of other drug(s) known to be hepatotoxic.
All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs (see 
Section 9 10 Appendix 3 for reporting details).
Expectedness of Events
Expectedness of all AEs will be determined by Biogen according to the Investigator’s 
Brochure.
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.
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 CRF; however, all overdoses 
must be recorded on an Overdose form and faxed or emailed 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 or emailed to Biogen.  All study treatment-related dosing information 
must be recorded on the dosing CRF.
Medical Emergency
In a medical emergency requiring immediate attention, site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator (or 


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designee) should contact the study’s Medical Director.  Refer to the Study Contact List for 
complete contact information.
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 may access the subject’s treatment 
assignment by IRT.  The Investigator must document the reasons for unblinding in the 
subject’s source documents.  The Investigator is strongly advised not to divulge the 
subject’s treatment assignment to any individual not directly involved in managing the 
medical emergency, or to personnel involved with the analysis and conduct of the study.  
The Investigator can contact Biogen to discuss such situations.
Deaths
Death is an outcome of an event.  The event that resulted in death should be recorded on 
the appropriate CRF.  All causes of death must be reported as SAEs within 24 hours of the 
site becoming aware of the event.  The Investigator should make every effort to obtain and 
send death certificates and autopsy reports to Biogen.  The term death should be reported 
as an SAE only if the cause of death is not known and cannot be determined.
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities.
Rationale:  The changes to Section 10 were made to reflect compatibility and alignment with 
safety processes at Biogen.
Section 19, Signed Agreement of the Study Protocol
Change: This section was inserted into the protocol.
Now reads:
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of Intravenously Administered 
BIIB092 in Participants with Progressive Supranuclear Palsy,” 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


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____________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)
Rationale: The signature page was inserted in accordance with the process at Biogen
Appendix 2, Study Goverance Considerations, Informed Consent Process
Change:  The text in Appendix 2 was revised.
Now reads:  
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 CRFs electronically, 
prior to any Interim lock or Database lock.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the 
appropriately qualified persons to whom significant study-related duties have been 
delegated.  The Investigator is responsible f or supervising those individuals and for 
implementing procedures to ensure the integrity of the tasks performed and any data 
generated.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the 
Declaration of Helsinki.
Ethics Committee
The Investigator must obtain ethics committee approval of the protocol, ICF, and other 
required study documents prior to starting the study.  The Contract Research 
Organization will submit documents on behalf of the investigational sites worldwide in 
compliance with the local regulations.


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If the Investigator makes any changes to the ICF, Biogen must approve the changes before 
the ICF is submitted to the ethics committee.  A copy of the approved ICF must be 
provided to Biogen.  After approval, the ICF must not be altered without the agreement of 
the relevant ethics committee and Biogen.
It is the responsibility of the Investigators to ensure that all aspects of institutional review 
are conducted in accordance with current applicable regulations.
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  
Protocol amendments will be subject to the same requirements as the original protocol.
A progress report must be submitted to the ethics committee at required intervals and not 
less than annually.
At the completion or termination of the study, the study site must submit a close-out letter 
to the ethics committee and Biogen.
Subject Information and Consent
Prior to performing any study-related activities under this protocol, including screening 
tests and assessments, written informed consent with the approved ICF must be obtained 
from the subject or subject’s legally authorized representative (e.g., parent or legal 
guardian), as applicable, in accordance with local practice and regulations.  
If informed consent is initially given by a participant’s legally acceptable representative or 
legal guardian, and the participant subsequently becomes capable of making and 
communicating his or her informed consent during the study, consent must additionally be 
obtained from the participant.
The Investigator must reassess the patient’s capacity to provide informed consent 
periodically over the course of the study.  In the event the patient loses capacity to provide 
informed consent, the Investigator must obtain subject assent and consent by the legal 
representative (in accordance with local laws and regulations).
The background of the proposed study, the procedures, the benefits and risks of the study, 
and that study participation is voluntary for the subject must be explained to the subject 
(or the subject’s legally authorized representative).  The subject must be given sufficient 
time to consider whether to participate in the study.
Subjects will be informed that their race and ethnicity will be collected during the study 
(unless the collection is not permitted by applicable law or not approved by the governing 
ethics committee) and the data will be used during analysis of study results. 
A copy of the signed and dated ICF must be given to the subject or the subject’s legally 
authorized representative.  The original signed and dated ICF will be retained with the 
study records.  Local regulations must be complied with in respect to the final disposition 
of the original (wet signature) and copies of the signed and dated ICFs.
Confirmation of informed consent must also be documented in the subject’s medical 
record.


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Subject Data Protection
Prior to any testing under this protocol, including screening tests and assessments, 
candidates must also provide all authorizations required by local law (e.g., Protected 
Health Information authorization in North America).
During the study, subjects’ race and ethnicity will be collected (unless the collection is not 
permitted by applicable law or not approved by the governing ethics committee).  These 
data will be used in the analysis of the safety and/or pharmacokinetic profile of the study 
treatment.  It is unknown whether the effects of the study treatment are influenced by race 
or ethnicity.  
Study reports will be used for research purposes only.  The subject will not be identified by 
name in CRFs, study-related forms, study reports, or any related publications.  Biogen, its 
partners and designees, ethics committees, and various government health agencies may 
inspect the records of this study.  Every effort will be made to keep the subject’s personal 
medical data confidential.
Compensation for Injury
Biogen maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws.
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.
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.
REGULATORY AND ETHICAL CONSIDERATIONS GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Good Clinical Practice (GCP),
•
as defined by the International Council on Harmonisation (ICH)
•
in accordance with the ethical principles underlying European Union Directive 
2001/20/EC
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50)
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 


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Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental 
integrity of the subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment).
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials (e.g., 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates.
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and 
other information (e.g., expedited safety reports, amendments, and administrative letters) 
according to regulatory requirements or institution procedures.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects and their caregiver are clearly and fully informed about 
the purpose, potential risks, and other critical issues regarding clinical studies in which they 
volunteer to participate.
In situations where consent cannot be given to subjects, their legally acceptable representatives 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the participant volunteers to participate.
Sponsor or designee will provide the investigator with an appropriate (i.e., Global or Local) 
sample informed consent form which will include all elements required by ICH, GCP and 
applicable regulatory requirements. The sample informed consent form will adhere to the ethical 
principles that have their origin in the Declaration of Helsinki.
Investigators must:

Provide a copy of the consent form and written information about the study in the
language in which the participant is most proficient prior to clinical study participation.
The language must be non technical and easily understood.

Allow time necessary for participant and participant's caregiver, their legally
acceptable representative to inquire about the details of the study.

Obtain an informed consent signed and personally dated by the participant or the
participant's legally acceptable representative and by the person who conducted the


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informed consent discussion.

Obtain an informed consent signed and personally dated by the participant’s caregiver 
and by the person who conducted the informed consent discussion.

Obtain the IRB/IEC’s written approval/favorable opinion of the written informed 
consent form and any other information to be provided to the subjects, prior to the
beginning of the study, and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or
legal
guardian,
and the
participant
subsequently
becomes
capable of making and
communicating his or her informed consent during the study, consent must additionally be
obtained from the participant.
Revise the informed consent whenever important new information becomes available that
is relevant to the participant's consent. The investigator, or a person designated by the
investigator,
should fully inform the participant or the participant's legally acceptable
representative or legal guardian, of all pertinent aspects of the study and of any new
information relevant to the participant's willingness to continue participation in the study.
This communication should be documented.
The confidentiality of records that could identify subjects must be protected, respecting the
privacy and confidentialityrules applicable to regulatory requirements, the subjects' signed ICF
and, in the US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have
direct access to participant records.
The rights, safety, and well being of the study subjects are the most important considerations
and should prevail over interests of science and society.
Rationale:  Text regarding ethical considerations was updated to conform to Biogen template 
language.  Additionally, text was added to outline course of action in the event of cognitive 
worsening of study participants over the study in the protocol. Also, clarification was needed to 
appropriately outline the responsibilities of the Investigator in situations where a study 
participant loses capacity to provide informed consent over the course of the study.  This 
additional language is based on a Protocol Clarification Letter for Study 251PP301, dated 21 
June 2017.
Appendix 3, Adverse Events and Serious Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow Up and Reporting
Change: The text in Appendix 3 was revised.
Now reads:


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The causal relationship to study drug is determined by a physician and should be used to
assess all AEs. The causal relationship can be one of the following:
Related: An AE will be considered “related” to the use of the investigational 
product if there is a reasonable possibility that the event may have been caused by 
the product under investigation.  Factors that point toward this assessment 
include but are not limited to a positive rechallenge, a reasonable temporal 
sequence between administration of the investigational product and the AE, a 
known response pattern of the suspected product, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between 
the product and the AE, or a lack of an alternative explanation for the AE.
Not related:
An AE will be considered “not related” to the use of the 
investigational product if there is not a reasonable possibility that the event has 
been caused by the product under investigation.  Factors pointing toward this 
assessment include but are not limited to the lack of reasonable temporal 
relationship between administration of the investigational product and the AE, 
the presence of a biologically implausible relationship between the product and 
the AE, or the presence of a more likely alternative explanation for the AE.
REPORTING OF SAES TO SPONSOR
Assessment of Causality
The causal relationship to study drug is determined by a physician and should be used to
assess all adverse events (AE). The causal relationship can be one of the following:
Related:  There
is  a
reasonable
causal  relationship
between
study  drug
administration and the AE.
Not related: There is not a reasonable causal relationship between study drug
administration and the AE.
The term "reasonable causal relationship" means there is evidence to suggest a causal
relationship.


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Rationale: Appendix 3 was updated to reflect compatibility and alignment with safety processes 
at Biogen.
Appendix 4, Women of Childbearing Potential Definitions and Methods of Contraception
Change:  Appendix 4 was revised.
Now reads:
Contraceptive methods that are approved for use during and for 30 
days after participation in this study are:
Failure rate of <1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb

oral

intravaginal

transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulationb

oral

injectable
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of

SAEs, whether related or not related to study drug, and pregnancies must be
reported to Biogen within 24 hours of awareness of the event.

SAEs must be recorded on the SAE Report Form; pregnancies on a Pregnancy
Notification and OutcomeSurveillance Form (electronic or paper forms).

The preferred method for SAE data reporting collection is through the eCRF.

The paper SAE/pregnancy surveillance forms are only intended as a back-up option
when the eCRF system is not functioning.
o
In this case, the paper forms are to be transmitted via email or confirmed
facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list. SAE
Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission
is the required method for reporting. In the event the electronic system is unavailable for
transmission, paper forms must be used and submitted immediately. When paper forms are
used, the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact
Information list


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ovulation b

Intrauterine device (IUD)c

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used.

Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study
and the preferred and usual lifestyle of the participant.

It is not necessary to use any other method of contraception when complete abstinence is
elected.

WOCBP participants who choose complete abstinence must continue to have pregnancy
tests, as specified in Section 10.5.

Acceptable alternate methods of highly effective contraception must be discussed in the
event that the WOCBP participants chooses to forego complete abstinence
NOTES:
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent
with local regulations regarding the use of contraceptive methods for participants participating in clinical
studies.
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy
of the contraceptive method. Hormonal contraception is permissible only when there is sufficient evidence
that the IMP and other study medications will not alter hormonal exposures such that contraception would be
ineffective or result in increased exposures that could be potentially hazardous. In this case, alternative
methods of contraception should be utilized.
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter
contraception effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of >1% per year when used consistently and correctly.

Male or female condom with or without spermicide. Male and female condoms cannot
be used simultaneously

Diaphragm with spermicide

Cervical cap with spermicide

Vaginal Sponge with spermicide

Progestogen only  oral  hormonal  contraception, where inhibition of ovulation is not 
the primary mechanism of action

Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, post-ovulation methods)


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
Withdrawal(coitus interruptus).

Spermicide only

Lactation amenorrhea method (LAM)
Rationale:  Based on feedback from the Medicines and Healthcare products Regulatory Agency 
(MHRA), Appendix 4 was revised to align with the body of the protocol, which describes the 
need for highly effective contraceptive use.


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24
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.

Table of Contents was updated.

List of Abbreviations was updated.


CONFIDENTIAL 
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Biogen MA Inc. 
1 
Biogen MA Inc. 
225 Binney Street 
Cambridge, MA  02142 
United States 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
______________________________________________________________________ 
AMENDMENT SUMMARY 
Biogen Protocol 251PP301 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the 
Efficacy and Safety of Intravenously Administered BIIB092 in Participants with Progressive 
Supranuclear Palsy  
Version 2 
Date:  25 August 2017 
Version 2 of the protocol has been prepared for this amendment, which supersedes Version 1. 






Protocol 251PP301, Version 2 
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4 
SPONSOR INFORMATION 
Biogen is responsible for 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 
Biogen Japan Ltd. 
Nihonbashi 1-chome 
Mitsui Building 14F 
4-1 Nihonbashi 1-chome 
Chuo-ku, Tokyo 
103-0027 Japan 
 
Biogen Australia PTY 
Ltd. 
Suite 1, Level 3  
123 Epping Road 
North Ryde, NSW 2113 
Australia 
 
For urgent medical issues in which the study Medical Director should be contacted, please 
refer to the Study Reference Guide’s Official Study Contact List for complete contact 
information. 
 
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization (CRO) and other third parties; however, Biogen retains overall accountability 
for these activities. 
 
Rationale:  Biogen is now the Sponsor of the study. 
This change also affects the following sections and applicable subsections:  Section 2, Schedule 
of Activities; Section 3, Introduction; Section 4, Objective and Endpoints; Section 5, Study 
Design; Section 5.1, Study Schematic (including Figure 5.1-1: Study Design Schematic); Section 
6, Study Population; Section 7, Treatment; Section 8, Discontinuation from Study Treatment; 
Section 9, Study Assessments and Procedures; Section 10, Statistical Considerations; and 
Section 12, Appendices.


Protocol 251PP301, Version 2 
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5 
 
SUMMARY OF MAJOR CHANGES TO THE PROTOCOL 
Changes to the protocol are presented chronologically.  New text is shown in bold type; deleted 
text is shown with a strikethrough. 
 
Section 1, Synopsis 
 
The synopsis was revised to reflect changes made throughout the protocol. 
 
Section 3.3, Benefit/Risk Assessment 
 
Change:  Section 3.3 was updated. 
 
Now reads: 
The overall benefit/risk profile of BIIB092 in several nonclinical studies, the single dose study in 
normal healthy volunteers (CN002001), as well as the multiple dose study and associated roll 
over study (Studies CN002003 and CN002004 [Study 251PP201]) support further evaluation of 
the safety, tolerability, immunogenicity, PK, PD response, and clinical efficacy of BIIB092 in 
participants with PSP. 
BIIB092 is an IgG4 isotype antibody that is considered to have a low potential for 
immunogenicity in humans based on nonclinical studies. There were no adverse effects noted at 
any dose tested in the pivotal toxicity studies in monkeys. Nonclinical findings were limited to 
decreases in CSF free eTau consistent with the intended pharmacology of BIIB092. 
Studies evaluating the potential for reproductive and developmental toxicity have not been 
performed for BIIB092. 
As of July 31, 2017, 114 subjects have been exposed to BIIB092 across all completed and 
ongoing clinical studies (Studies CN002001, CN002003, 251PP201 and 251PP301).  Based 
on safety data from a completed Phase 1 studies in healthy volunteers (CN002001) and a 
completed Phase 1B study in subjects with PSP (Study CN002003), the majority of AEs 
reported to date have been mild to moderate in severity and transient in nature.  There 
have been no deaths or discontinuations due to an AE reported in the program.  There 
have been 4 SAEs reported in 3 subjects in the CN002003 study, all of which were 
considered not related to study drug by the Investigator. 
Based on preliminary data from the CN002001 study and still ongoing studies CN002003 and 
CN002004, observed AEs to date have mostly been mild to moderate in severity and transient in 
nature. AEs considered related to the study drug by the investigator were belching, nausea, 
headache, and flushing. One AE of headache and one AE of diverticulitis were considered 
moderate; all other AEs were considered mild. Four (4) SAEs considered not related to study 
drug by the investigator have been reported to date in three (3) participants; one SAE was a 
urinary tract infection requiring hospitalization, one SAE was an aspiration pneumonia requiring 




Protocol 251PP301, Version 2 
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7 
 
This change also affects Sections 5.3, Number of Participants and Section 7.2, Method of 
Treatment Assignment. 
 
Section 7, Treatment 
 
Change:  Table was revised to reflect updated study drug information (based on the 
Investigator’s Brochure) and language was added about how study drug will be labeled when 
provided to sites. 
 
Now reads: 
Study treatment includes both Investigational [Medicinal] Product (IP/IMP) and Non-
investigational [Medicinal] Product (Non-IP/Non-IMP) as listed: 
 
Study Drug for 251PP301 
Medication 
Potency 
IP/Non-IP 
BIIB092* 
50 mg/mL 
IP 
Placebo** (0.9% Sodium 
Chloride) 
N/A 
IP 
* Drug supplies may be labeled as BIIB092 or BMS-986168. The two drug names refer to an 
identical drug substance. 
** 5% dextrose injection can be used if sodium chloride is not available. 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 251PP301, Version 2 
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8 
 
Table 7.-1: 
Study treatments for 251PP301 
Product Description / 
Class and Dosage 
Form 
Potency 
IP/Non-IMP 
Blinded or 
Open-Label
a 
Packaging / 
Appearance 
Storage 
Conditions 
(per label) 
BIIB092 Injection, 
1000 mg/vial 
(50 mg/mL) 
The composition of the 
drug product is: 
50 mg/mL, 
010 mM 
Sodium Phosphate, 
140 mM Sodium 
Chloride, 0.02% (w/v) 
Polysorbate 80, pH 6.1 
BIIB092, histidine, 
histidine 
hydrochloride 
monohydrate, 
sucrose, pentetic acid, 
polysorbate 80, and 
sterile water for 
injection, pH 6.0 
50 mg/mL 
IP 
Open-label 
Clear to very 
opalescent, 
colorless to 
slightly yellow 
liquid, in which 
light (few) 
particulates may 
be present 
Store 
Refrigerated 
2°C to 8°C, 
protect from 
light. Do not 
freeze 
Placebo (0.9% Sodium 
Chloride or 5% 
Dextrose)b 
0.9% NaCl 
Or 
5% Dextrose 
IP 
N/A 
Per Product Label 
Per Product 
Label 
a BIIB092 is provided Open-label to the unblinded pharmacist. After study drug is prepared by the 
unblinded pharmacist all other study personnel will remain blinded to the identification of study drug 
(BIIB092 vs. placebo) up to Week 52. 
b Placebo is not provided by Biogen and obtained commercially by the site, storage should in accordance with the 
product label 
 
Rationale:  Until the end of 2017, study supplies will continue to be labeled BMS-986168. Early 
in 2018, drug labels will switch from the BMS compound name to the Biogen compound name.  
This text was added to address drug supply transition from BMS-labeled drug product to Biogen-
labeled drug product and convey in the protocol that the two drug names are synonymous with 
one another. 
 
Section 8.3, Lost to Follow-Up 
 
Change:  Section 8.3 was revised to reflect alignment with processes at Biogen for patients lost 
to follow-up. 
 
Now reads: 


Protocol 251PP301, Version 2 
 CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
9 
 
1.1. 
Lost to Follow-Up 
• All reasonable efforts must be made to locate participants to determine and report 
their ongoing status. This includes follow-up with persons authorized by the 
participant. 
• Lost to follow-up is defined by the inability to reach the participant after a minimum 
of three documented phone calls, faxes, or emails as well as lack of response by 
participant to one registered mail letter. All attempts should be documented in the 
participant’s medical records. 
• If it is determined that the participant has died, the site will use permissible local 
methods to obtain date and cause of death. 
• If investigator’s use of a third party representative to assist in the follow up portion of 
the study has been included in the participant’s informed consent, then the 
investigator may use a sponsor retained third party representative to assist site staff 
with obtaining participant’s contact information or other public vital status data 
necessary to complete the follow up portion of the study. 
• The site staff and representative will consult publicly available sources, such as 
public health registries and databases, in order to obtain updated contact information. 
If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records. 
 
Rationale:  The site Principal Investigator or designee will make every reasonable effort to 
contact any patient lost to follow up, a third party vendor will not be required to manage these 
activities. To date, the third party vendor services have not been required to assist site staff with 
obtaining participant’s contact information or other public vital status data necessary to complete 
the follow-up portion of the study. 
 
Section 10, Adverse Events 
 
Change:  Section 10 was revised to reflect compatibility with safety processes at Biogen. 
 
Now reads: 
1.2. 
Pregnancy 
Subjects should not become pregnant or impregnate their partners during the study and 
for 5 times the half-life or 6 months, whichever is longer, after their last dose of study 
treatment. If a female subject becomes pregnant, study treatment must be discontinued 
immediately. 


Protocol 251PP301, Version 2 
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Biogen MA Inc. 
10 
 
The Investigator must report a pregnancy occurring in a female subject by faxing or 
emailing the appropriate form to Biogen within 24 hours of the site staff becoming aware of 
the pregnancy.  Refer to the Study Contact List for complete contact information.  The 
Investigator or site staff must report the outcome of the pregnancy to Biogen.  A pregnancy 
is not considered an AE and should not be recorded on the AE CRF. 
Congenital abnormalities and birth defects in the offspring of male or female subjects 
should be reported as an SAE if conception occurred during the study treatment period. 
1.3. 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning. 
• Any laboratory test result that is clinically significant or meets the definition of an 
SAE 
• Any laboratory test result abnormality that required the participant to have study 
treatment discontinued or interrupted 
• Any  laboratory  test  result  abnormality  that  required  the  participant  to  receive  
specific corrective therapy 
It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (e.g., anemia versus low hemoglobin value). 
1.4. 
Potential Drug Induced Liver Injury (DILI) 
Potential drug induced liver injury (DILI) is defined as: 
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) AND 
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND 
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs (see 
Section 10 and Appendix 3 for reporting details). 


Protocol 251PP301, Version 2 
 CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
11 
 
1.5. 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiogram, x-ray filming, any other potential safety assessment required or not required 
by protocol should also be recorded as a nonserious or serious AE, as appropriate, and reported 
accordingly. 
1.6. 
Expectedness of Events 
Expectedness of all AEs will be determined by Biogen according to the Investigator’s 
Brochure. 
1.7. 
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. 
1.8. 
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 CRF; however, all overdoses 
must be recorded on an Overdose form and faxed or emailed 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 or emailed to Biogen.  All study treatment-related dosing information 
must be recorded on the dosing CRF. 
1.9. 
Medical Emergency  
In a medical emergency requiring immediate attention, site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator (or 
designee) should contact the study’s Medical Director.  Refer to the Study Contact List for 
complete contact information. 
1.10. 
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 may access the subject’s treatment 


Protocol 251PP301, Version 2 
 CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
12 
 
assignment by IRT.  The Investigator must document the reasons for unblinding in the 
subject’s source documents.  The Investigator is strongly advised not to divulge the 
subject’s treatment assignment to any individual not directly involved in managing the 
medical emergency, or to personnel involved with the analysis and conduct of the study.  
The Investigator can contact Biogen to discuss such situations. 
1.11. 
Deaths 
Death is an outcome of an event.  The event that resulted in death should be recorded on 
the appropriate CRF.  All causes of death must be reported as SAEs within 24 hours of the 
site becoming aware of the event.  The Investigator should make every effort to obtain and 
send death certificates and autopsy reports to Biogen.  The term death should be reported 
as an SAE only if the cause of death is not known and cannot be determined. 
1.12. 
Safety 
Planned time points for all safety assessments are listed in the Schedule of Activities. 
 
Rationale:  Section 6 was updated to reflect compatibility and alignment with safety processes at 
Biogen. 
 
Appendix 2, Study Goverance Considerations, Informed Consent Process 
 
Change:  Appendix 2 was revised to reflect replacing BMS language regarding ethical 
considerations to Biogen template language.  Additionally, text was added to outline course of 
action in the event of cognitive worsening of study participants over the study in the protocol.   
 
Now reads:   
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 CRFs electronically, 
prior to any Interim lock or Database lock. 
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines.  The Investigator should maintain a list of the 
appropriately qualified persons to whom significant study-related duties have been 
delegated.  The Investigator is responsible f or supervising those individuals and for 
implementing procedures to ensure the integrity of the tasks performed and any data 
generated. 


Protocol 251PP301, Version 2 
 CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
13 
 
Declaration of Helsinki 
This study will be performed in alignment with the ethical principles outlined in the 
Declaration of Helsinki. 
Ethics Committee 
The Investigator must obtain ethics committee approval of the protocol, ICF, and other 
required study documents prior to starting the study.  ICON plc will submit documents on 
behalf of the study sites in countries other than the US. 
If the Investigator makes any changes to the ICF, Biogen must approve the changes before 
the ICF is submitted to the ethics committee.  A copy of the approved ICF must be 
provided to Biogen.  After approval, the ICF must not be altered without the agreement of 
the relevant ethics committee and Biogen. 
It is the responsibility of the Investigators to ensure that all aspects of institutional review 
are conducted in accordance with current applicable regulations. 
Biogen must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, protocol number, and ICF, prior to the initiation of the study.  
Protocol amendments will be subject to the same requirements as the original protocol. 
A progress report must be submitted to the ethics committee at required intervals and not 
less than annually. 
At the completion or termination of the study, the study site must submit a close-out letter 
to the ethics committee and Biogen. 
Subject Information and Consent 
Prior to performing any study-related activities under this protocol, including screening 
tests and assessments, written informed consent with the approved ICF must be obtained 
from the subject or subject’s legally authorized representative (e.g., parent or legal 
guardian), as applicable, in accordance with local practice and regulations.   
If informed consent is initially given by a participant’s legally acceptable representative or 
legal guardian, and the participant subsequently becomes capable of making and 
communicating his or her informed consent during the study, consent must additionally be 
obtained from the participant. 
The Investigator must reassess the patient’s capacity to provide informed consent 
periodically over the course of the study.  In the event the patient loses capacity to provide 
informed consent, the Investigator must obtain subject assent and consent by the legal 
representative (in accordance with local laws and regulations). 


Protocol 251PP301, Version 2 
 CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
14 
 
The background of the proposed study, the procedures, the benefits and risks of the study, 
and that study participation is voluntary for the subject must be explained to the subject 
(or the subject’s legally authorized representative).  The subject must be given sufficient 
time to consider whether to participate in the study. 
Subjects will be informed that their race and ethnicity will be collected during the study 
(unless the collection is not permitted by applicable law or not approved by the governing 
ethics committee) and the data will be used during analysis of study results.  
A copy of the signed and dated ICF must be given to the subject or the subject’s legally 
authorized representative.  The original signed and dated ICF will be retained with the 
study records.  Local regulations must be complied with in respect to the final disposition 
of the original (wet signature) and copies of the signed and dated ICFs. 
Confirmation of informed consent must also be documented in the subject’s medical 
record. 
Subject Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, 
candidates must also provide all authorizations required by local law (e.g., Protected 
Health Information authorization in North America). 
During the study, subjects’ race and ethnicity will be collected (unless the collection is not 
permitted by applicable law or not approved by the governing ethics committee).  These 
data will be used in the analysis of the safety and/or pharmacokinetic profile of the study 
treatment.  It is unknown whether the effects of the study treatment are influenced by race 
or ethnicity.   
Study reports will be used for research purposes only.  The subject will not be identified by 
name in CRFs, study-related forms, study reports, or any related publications.  Biogen, its 
partners and designees, ethics committees, and various government health agencies may 
inspect the records of this study.  Every effort will be made to keep the subject’s personal 
medical data confidential. 
Compensation for Injury 
Biogen maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws. 
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. 


Protocol 251PP301, Version 2 
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Biogen MA Inc. 
15 
 
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. 
REGULATORY AND ETHICAL CONSIDERATIONS GOOD CLINICAL PRACTICE 
This study will be conducted in accordance with: 
• 
Good Clinical Practice (GCP), 
• 
as defined by the International Council on Harmonisation (ICH) 
• 
in accordance with the ethical principles underlying European Union Directive 
2001/20/EC 
• 
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
• 
applicable local requirements. 
 
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study. 
All potential serious breaches must be reported to Sponsor or designee immediately. A serious 
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental 
integrity of the subjects of the study or the scientific value of the study. 
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. 
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials (e.g., 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 


Protocol 251PP301, Version 2 
 CONFIDENTIAL 
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Biogen MA Inc. 
16 
 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and 
other information (e.g., expedited safety reports, amendments, and administrative letters) 
according to regulatory requirements or institution procedures. 
 
Rationale:  Text regarding ethical considerations was updated to conform to Biogen template 
language.  Also, clarification was needed to appropriately outline the responsibilities of the 
Investigator in situations where a study participant loses capacity to provide informed consent 
over the course of the study.  This additional language is based on a Protocol Clarification Letter 
for Study 251PP301, dated 21 June 2017.  
 
Appendix 3, Adverse Events and Serious Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow Up and Reporting 
 
Change: Appendix 3 was revised to reflect compatibility with safety processes at Biogen. 
 
Now reads: 
The causal relationship to study drug is determined by a physician and should be used to 
assess all AEs. The causal relationship can be one of the following: 
Related:  An AE will be considered “related” to the use of the investigational 
product if there is a reasonable possibility that the event may have been caused by 
the product under investigation.  Factors that point toward this assessment 
include but are not limited to a positive rechallenge, a reasonable temporal 
sequence between administration of the investigational product and the AE, a 
known response pattern of the suspected product, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between 
the product and the AE, or a lack of an alternative explanation for the AE. 
Not related:   An AE will be considered “not related” to the use of the 
investigational product if there is not a reasonable possibility that the event has 
been caused by the product under investigation.  Factors pointing toward this 
assessment include but are not limited to the lack of reasonable temporal 
relationship between administration of the investigational product and the AE, 
the presence of a biologically implausible relationship between the product and 
the AE, or the presence of a more likely alternative explanation for the AE. 
 
Rationale: Appendix 3 was updated to reflect compatibility and alignment with safety processes 
at Biogen. 
 
Appendix 4, Women of Childbearing Potential Definitions and Methods of Contraception 
 
Change:  Appendix 4 was revised to clarify contraceptive requirements. 
Now reads: 
Contraceptive methods that are approved for use during and for 30 


Protocol 251PP301, Version 2 
 CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
17 
 
days after participation in this study are: 
Failure rate of <1% per year when used consistently and correctly.a 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
− oral 
− intravaginal 
− transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulationb 
− oral 
− injectable 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b 
• Intrauterine device (IUD)c 
• Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant. 
• It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
• WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 10.5. 
• 
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. Hormonal contraception is permissible only when there is sufficient evidence that the 
IMP and other study medications will not alter hormonal exposures such that contraception would be ineffective 
or result in increased exposures that could be potentially hazardous. In this case, alternative methods of 
contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 


Protocol 251PP301, Version 2 
 CONFIDENTIAL 
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Biogen MA Inc. 
18 
 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness 
Less Than Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of >1% per year when used consistently and correctly. 
• 
Male or female condom with or without spermicide.  Male and female condoms cannot 
be used simultaneously 
• 
Diaphragm with spermicide 
• 
Cervical cap with spermicide 
• 
Vaginal Sponge with spermicide 
• 
Progestogen only  oral  hormonal  contraception,  where  inhibition  of  ovulation  is  not  
the primary mechanism of action 
• 
Unacceptable Methods of Contraception 
• Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• Withdrawal(coitus interruptus). 
• Spermicide only 
• Lactation amenorrhea method (LAM) 
 
Rationale:  Based on feedback from the Medicines and Healthcare products Regulatory Agency 
(MHRA), Appendix 4 was revised to align with the body of the protocol, which describes the 
need for highly effective contraceptive use.


Protocol 251PP301, Version 2 
 CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
19 
 
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. 
• Table of Contents was updated. 
• List of Abbreviations was updated. 
 

SAP_001.pdf: 
1  
 2 5 1 P P 3 0 1 O L E S A P  
Versi o n 1. 0  
St atistic al A n al ysis Pl a n  
– O p e n l a bel e xte nsi o n peri o d
Versi o n N o.:  1 .0  
 St u d y Title: A R a n d o mi ze d, D o u ble -Bli n d, Pl ac e b o -C o nt rolle d, P a rallel -G r o u p St u d y t o E v al u ate 
t he Effic ac y a n d S afet y of I nt r a ve n o usl y A d mi niste re d BII B 0 9 2 i n P a rtici p a nts wit h P ro g ressi ve 
S u p r a n ucle a r P als y  
Na me of St u d y Tre at me nt: BII B 0 9 2  
Pr ot oc ol N o.: 2 5 1 P P 3 0 1 / N C T 0 3 0 6 8 4 6 8  
St u d y P hase: P hase 2 b  
C o nfi de nti al I nf o r m ati o n  
T h e i nf or m ati o n c o nt ai n e d i n t his St atistic al A n al ysis Pl a n ( S A P) is c o nfi d e nti al a n d m a y n ot b e 
re pr o d u ce d or ot h er wise disse mi n at e d wit h o ut t h e a p pr o v al of Bi o g e n, I nc.   




 
3  
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T A B L E  O F  C O N T E N T S  
 
 
1  
O V E R VI E W  O F T H E S T U D Y  ....................................................................................................... 7  
1. 1 St u d y D esi g n  ................................................................................................................................... 7  
1. 2 N u m b er of Partici pa nts  .................................................................................................................. 9  
1. 3 Start of St u d y a n d E n d of St u d y D efi niti o ns  ................................................................................ 9  
1. 4 Treat m e nt  ........................................................................................................................................ 9  
2  
D E S C RI P TI O N O F O BJ E C TI V E S A N D E N D P OI N T S  ............................................................ 1 0  
3  
G E N E R A L  C O N SI D E R A TI O N S  ................................................................................................. 1 3  
3. 1 Ge neral M et h o ds ........................................................................................................................... 1 3  
3. 2 P o p ulati o n  ..................................................................................................................................... 1 4  
3. 2 A nal ysis Peri o d  ............................................................................................................................. 1 5  
3. 3 Baseli n e  ......................................................................................................................................... 1 6  
4  
S T U D Y S U BJ E C T S  ...................................................................................................................... 1 6  
4. 1 Ac c o u nti n g of s u bj e cts  ................................................................................................................. 1 6  
4. 2 De m o gra p h i c a n d  Baseli n e  Disease  C hara ct eristi cs  ................................................................... 1 6  
4. 3 St u d y Dr u g E x p os ur e a n d St u d y Dr u g C o m plia n c e ................................................................... 1 7  
4. 4 Me di cati o ns a n d N o n -dr u g t h era pi es  .......................................................................................... 1 7  
4. 5 Pr ot o c ol  D e viati o ns  ...................................................................................................................... 1 7  
5  
E F FI C A C Y  D A T A ......................................................................................................................... 1 8  
5. 1 Ge neral C o nsi d erati o ns  ................................................................................................................ 1 8  
5. 2 Visit wi n d o ws f or ma p pi n g effi ca c y e n d p oi nt ............................................................................ 1 8  
5. 3 C o nsi d erati o ns f or i nteri m a nal ysis  ............................................................................................. 2 1  
5. 4 B y Visit S u m mar y a n d Mi x e d M o d el Re p eat e d M eas ur es ( M M R M) M o del  .......................... 2 1  
6  
S A F E T Y  D A T A  ............................................................................................................................. 2 2  
6. 1 Ge neral C o nsi d er ati o ns  ................................................................................................................ 2 2  
 
A nal ysis p o p ulati o n  ......................................................................................................... 2 2  
 
A nal ysis peri o d a n d a nal ysis dis pla ys  ............................................................................ 2 2  
 
Visit wi n d o ws ................................................................................................................... 2 2  
 
I n ci d e n c e, i n ci d e n c e pr o p orti o n a n d i nci d e n ce rat e....................................................... 2 2  
6. 2 Cli nical A d v erse E v e nts  ............................................................................................................... 2 3  
 
Treat m e nt -e m er g e nt A Es ( T E A Es) ................................................................................. 2 3  
 
S u m mar y a n d i n ci d e n c e a nal ysis  .................................................................................... 2 4  


 
4  
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Versi o n 1. 0  
 
 
I n ci d e n c e rat e a nal ysis ..................................................................................................... 2 5  
 
A d v erse e v e nt of s pe cial i nt er est  .................................................................................... 2 5  
 
I nf usi o n rea cti o ns ............................................................................................................. 2 6  
6. 3 Cli nical  La b orat or y  Data  .............................................................................................................. 2 7  
 
Q u a ntitati v e a nal yses  ....................................................................................................... 2 8  
 
Q u alitati v e a nal yses  ......................................................................................................... 2 9  
6. 4 E C Gs  ............................................................................................................................................. 3 1  
 
A nal ysis of C e ntral T e n d e n c y  ......................................................................................... 3 3  
 
Cate g ori cal A nal ysis  ........................................................................................................ 3 3  
6. 5 Vi tal Si g ns  ..................................................................................................................................... 3 3  
6. 6 P h ysi cal E xa mi nati o n  ................................................................................................................... 3 6  
6. 7 Ne ur ol o gi cal E xa mi nati o n  ........................................................................................................... 3 7  
 3 7  
6. 9 M RI Res ults  .................................................................................................................................. 3 7  
7  
P H A R M A C O KI N E TI C D A T A  .................................................................................................... 3 7  
7. 1 0 C S F  C o n c e ntrati o n  D a ta............................................................................................................. 3 8  
7. 1 1 Ser u m  P har ma c o ki n eti cs  ............................................................................................................ 3 8  
8  
A N TI -D R U G A N TI B O D Y  D A T A  ............................................................................................... 3 9  
9  
S A M P L E  SI Z E  C O N SI D E R A TI O N S  .......................................................................................... 4 0  
1 0  
Refer e n c es  .................................................................................................................................... 4 0  
1 1  
A p p e n di x  ...................................................................................................................................... 4 1  
1 1. 1  A d v erse e v e nt of s p e cial i nterest searc h  ................................................................................... 4 1  
1 1. 2  I nf usi o n r ea cti o ns c ust o m sear c h............................................................................................... 4 2  
 
 
A B B R E V IA TI O N S  
 
Te r m  
Defi niti o n  
A D A  
A nti -dr u g a nti b o d y  
A E  
a d verse e v e nt  
A L T  
ala ni n e a mi n otra nsferase  
A S T  
as partate a mi n otra nsferase  
B U N  
bl o o d ur ea nitr o g e n  
C GI -C  
Cli nical Gl o bal I m pr essi o n C ha n g e  
C GI -S  
Cli nical Gl o bal I m pr essi o n S e v erit y  
Ci nf  
e n d -of -i nf usi o n ser u m c o n c e ntrati o n 


 
5  
 2 5 1 P P 3 0 1 O L E S A P  
Versi o n 1. 0  
 
Te r m  
Defi niti o n  
C S F  
cer e br os pi nal fl ui d  
 
 
C T C A E  
C o m m o n T o xicit y Criteria f or A d v erse E v e nts 
Ctr o u g h  
tr o u g h ser u m c o n c e ntrati o n 
C T T  
C ol or Trails T est  
E C G  
ele ctr ocar di o gra m  
e T a u 
e xtra cell ular ta u  
E ur o Q ol  
E ur o pea n Q u alit y  of  Life  
I C H 
I nt er nati o nal C o nfer e nc e o n Har m o nisati o n 
I N R 
i nt er nati o nal n or mali z e d  rati o 
I P 
i n v esti gati o nal pr o d u ct 
I T T 
int e nt -t o-tr eat 
I V 
i ntra v e n o us 
L L O Q  
lo wer  lim it of  q u a nti fica tio n  
L N S  
Lett er n u m b er se q u e nc e  
L P  
l u m bar p u n ct ure 
M D S -U P D R S  
M o v e me nt Dis or d er S o ci et y -s p o ns or e d r e visi o n of t h e U nifi e d 
  
  
  
  
M M R M  
mi x e d m o d el r e p eate d m eas ures  
M o C A  
M o ntr eal  C o g niti v e  Assess me nt  
M R I 
ma g n eti c res o na n c e i ma gi n g  
Nf L  
ne ur ofila me nt li g ht c hai n  
O L E  
o p e n -la b el e xte nsi o n  
P C S  
p ot e ntiall y cli nicall y si g nifi ca nt  
P D  
p har ma c o d y na mi c(s)  
P E  
p h ysical  e xa mi nati o n  
P K  
p har ma c o ki n eti c(s)  
 
 
P S P  
pr o gressi v e s u pra n u cl ear pals y 
P S P -Q o L  
Pr o gr essi v e S u pra n u cl ear Pals y Q u alit y of life scale 
P S P R S  
Pr o gr essi v e S u pra n u cl ear Pals y  Rati n g Scal e  
Q 4 W  
e v er y  4 wee ks  
Q M A  
q u a ntitati ve m o v e me nt assess m e nts  


 
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Te r m  
Defi niti o n  
 
R B A N S  
Re peata bl e Batt er y  f or t h e Assess m e nt of N e ur o ps y c h ol o gi cal  Disease  
Se v erit y  
 
 
S A E  
seri o us a d v erse e ve nt 
S E A D L  
Sc h wa b a n d E n gla n d  Acti viti es of Dail y  Li vi n g  
 
 
U L N  
u p per li mit of n or mal  
U S  
U nit e d  Stat es  
W O C B P  
w o me n of c hil d b eari n g p ot e ntial  
 
 
 


 
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1  
O V E R VI E W  O F T H E S T U D Y  
 
1. 1  St u d y Desi g n  
T he  st u d y d esi g n sc h e matic  is pr ese nt e d  i n Fi g ure  1 . 
Fi g ur e  1 : 
St u d y Desi g n Sc he m atic  
 
T his is a ra n d o mi z e d, d o u bl e -bli n d, pla c e b o -c o ntr olle d, parallel -gr o u p st u d y t o e val u at e t h e 
effi ca c y a n d safet y of i ntra v e n o usl y (I V) a d mi nist er e d BII B 0 9 2 i n parti ci pa nts wit h pr o gr essi ve 
s u pra n u clear pals y ( P S P) wit h a n o p e n -la b el e xt e nsi o n. 
O v erall st u d y d esi g n:   T h e st u d y d esi g n sc h e mati c is pr ese nt e d i n Fi g ure  1 .  T he st u d y will c o nsist 
of a 5 2 -wee k d o u bl e -bli n d tr eat m e nt p eri o d, w hi c h will be f oll o we d b y a l o n g -t er m o p e n la b el 
e xt e nsi o n p eri o d f or f oll o w u p.  Parti ci pa nts will b e ra n d o mi z e d t o r e cei v e BII B 0 9 2 o r pla c e b o.  
A p pr o xi mat el y 4 5 9 partici pa nts i n t otal will b e ra n d o mi z e d i n a 2: 1 rati o t o r e cei v e BII B 0 9 2 or 
pla ce b o ( 3 0 6 parti ci pa nts a cti v e or 1 5 3 pla c e b o).  I n t h e d o u bl e -bli n d tr eat m e nt p eri o d of t he st u d y, 
parti ci pa nts will be d ose d a p pr o xi matel y o n c e e v er y 4 we e ks ( Q 4 W) f or a p pr o xi matel y 4 8 we e ks 
( u p t o a t otal of 1 3 ti m es).  At W ee k 5 2, partici pa nts c o m pleti n g t h e d o u ble-bli n d tr eat m e nt peri o d 
ma y c h o ose t o c o nti n u e i nt o t h e o p e n -la b el e xt e nsi o n p eri o d of t his st u d y, i n w hi c h, all parti ci pa nts 
will r e c ei ve BII B 0 9 2.  Parti ci pa nts will b e d ose d a p pr o xi mat el y o n c e - e v er y 4 we e ks t hr o u g h o ut 
t h e d urati o n of t h e o p e n-la b el e xt e nsi o n p eri o d.  T h e d urati o n of t h e o p e n-la bel e xt e nsi o n will var y 
de p e n di n g o n t h e date of e nr oll m e nt of t he parti ci pa nt i n t he st u d y .  T h e st u d y is e x pe cte d t o 
c o nti n u e u ntil BII B 0 9 2 is c o m m er ciall y a vaila bl e, t h e d e v el o p m e nt pr o gra m is t er mi nat e d, or t h e 
st u d y is t er mi nat e d at t h e discr eti o n of t h e s p o ns or, w hic h e ver c o m es first.  
St u d y visits:   St u d y visits will b e c o n d u ct e d a p pr o xi ma t el y e v er y 4 wee ks.  St u d y dr u g will b e 
a d mi nist ere d a n d safet y, effi ca c y, a n d ot h er assess m e nts will be p erf or m e d.  T he st u d y will 
ge n erall y b e c o n d u cte d o n a n o ut pati e nt basis u nl ess s o me pr o c e d ur es w o ul d be b ett er perf or m e d 
o n a n i n pati e nt basis base d o n t h e n e e ds of t he parti ci pa nt.  Parti ci pa nts will be o bser ve d a n d 
m o nit ore d b y st u d y p ers o n n el f or a p pr o xi mat el y 2 h o urs aft er t h e e n d of a n i nf usi o n.  Parti ci pa nts 
wit h o n g oi n g A Es or seri o us A Es ( S A Es) will r e mai n at t h e sit e or b e se nt t o a n i n pati e nt 
m o nit ori n g fa cilit y u ntil t he I n v esti gat or has deter mi n e d t hat t h ese e v e nts ha ve r es ol v e d or d o n ot 
re q uire i n patie nt m o nit ori n g. 
St u d y  assess me nts:  


 
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•  Parti ci pa nts will be cl osel y m o nit or e d f or safet y t hr o u g h o ut t h e st u d y.  P h ysical 
e xa mi nati o ns, vital si g n m eas ur e m e nts, 1 2 -l ea d el e ctr o car di o gra ms ( E C G), a n d cli nical 
la b orat or y e val u ati o ns, i ncl u di n g assess m e nts f or a nt i-dr u g a nti b o d y  ( A D A) will b e 
perf or m e d.  A Es  will b e cl osel y m o nit or e d.  
 
 
•  P S P r elat e d si g ns, s y m pt o ms a n d q u alit y of life will be assesse d usi n g cli nic al 
assess m e nts: P S P Rati n g S cal e ( P S P R S), M o ve m e nt Dis or d er S o ci et y -s p o ns or e d 
re visi o n of t h e U nifi e d Par ki ns o n’s Disease Rati n g S cal e ( M D S-U P D R S Part II), 
Sc h wa b a n d E n gla n d Acti vities of Dail y Li vi n g ( S E A D L) scal e, Cli ni cal Gl o bal 
I m pr essi o n of S e verit y ( C GI-S), Cli ni cal Gl o bal I m pr essi o n of C ha n g e ( C GI -C), 
M o ntr eal C o g niti v e Assess m e nt ( M o C A), 
 
 a n d P S P Q u alit y of Life scale ( P S P-Q o L) a n d 
ne ur o ps y c h ol o gi cal testi n g ( R B A N S, p h o n e mi c fl u e nc y, l ett er -n u m b er se q u e n ci n g, a n d 
c ol or trails t est ).  
•  Care gi ver b ur d e n will als o b e assesse d 
 
. 
•  Bl o o d will be c oll ecte d f or A D A  (as part of t h e assess m e nt f or i m m u n o g e ni cit y) P K, 
P D, a n d e x pl orat or y bi o mar k er a nal ysis fr o m ea c h parti ci pa nt d uri n g t his st u d y i n t h e 
d o u bl e -bli n d p eri o d a n d i n t h e o p e n -la b el e xte nsi o n peri o d. 
•  Str u ct ural c ha n g es i n brai n re gi o ns ass o ciat e d wit h P S P disease pr o gressi o n  will b e 
assesse d usi n g M RI.  It is a nti ci pat e d t hat ea c h parti ci pa nt will ha v e t otal of 4 M RIs 
o v er t h e c o urse of t h e st u d y, i n cl u di n g a n M RI d uri n g t he scre e ni n g p eri o d ( u p t o Da y -
1 4) a n d at W e e ks 2 4, 5 2, a n d 1 0 0.  
•   
 
 
 
 
 
 
•  Parti ci pa nts i n t h e  Q M A s u bst u d y will u n d er g o q u a ntitati v e assess m e nts of c ore m ot or 
feat ures of P S P usi n g weara bl e se ns ors t o meas ur e gait , p ost ural i nsta bilit y, m ot or 
f u n cti o n, a n d falls. 
H o me visits:   After W e e k 2 4, e x c e pt f or t h ose visits w h e n cli ni cal scal es, L Ps, or M R I assess m e nts 
are perf or m e d, visits a n d pr o c e d ur es ma y be p erf or m e d i n t h e h o m e as l o n g as a p pr o priat e ser vi c es 
are a vaila ble t o perf or m t h e re q uir e d st u d y pr o c e d ur es a n d a d e q u at el y m o nit or f or p ot e ntial safet y 
e v e nts.  I n t h e d o u bl e -bli n d peri o d of t h e st u d y, W ee ks 2 8, 3 2, 4 0, a n d 4 4 m a y q u alif y f or h o m e 
visits.  
I n t h e o p e n-la b el e xt e nsi o n p eri o d of t he st u d y, W e e k 6 8, 7 2, 8 0, 8 4, 9 2, 9 6, 1 0 4, 1 0 8, 1 1 6, 1 2 0, 
1 2 8, 1 3 2, 1 4 0, 1 4 4, 1 5 2, 1 5 6, 1 6 4, 1 6 8, 1 7 6, 1 8 0, 1 8 8, a n d 1 9 2  visits ma y q u alif y f or a h o me visit.   
H o we v er, i n t h e e ve nt t hat t h e parti ci pa nt e x p eri e nc es a cli ni call y si g nifi ca nt i nf usi o n r ea cti o n as 
de t er mi n e d b y i n v estigat or s d uri n g t h e first 2 4 we e ks of t h e pr ot o c ol, t h e partici pa nt s h o ul d n ot b e 
a d mi nist ere d BII B 0 9 2 i n t he h o m e u nl ess pre vi o usl y a p pr o v e d b y t h e St u d y I n v esti gat or.  


 
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Disc o nti n u ati o n of St u d y tr eat me nt a n d/ or St u d y Wit h dra wal:   Parti ci pa nts w h o disc o nti n u e st u d y 
treat m e nt ma y bel o n g t o 1  of t h e f oll o wi n g gr o u ps:   
•  Parti ci pa nts w h o disc o nti n u e st u d y tr eat m e nt b ut r e mai n e nr olle d u ntil  t he e n d of t he  
st u d y  
•  Parti ci pa nts w h o disc o nti n u e st u d y tr eat m e nt a n d lat er  wit h dra w fr o m t h e st u d y   
•  Parti ci pa nts w h o disc o nti n u e st u d y tr eat m e nt a n d i m me diat el y wit h dra w fr o m t h e st u d y  
Parti ci pa nts w h o disc o nti n u e st u d y tr eat m e nt d uri n g t h e d o u bl e -bli n d p eri o d of t h e st u d y ( pri or t o 
We e k 5 2) a n d r e mai n e nr oll e d i n t h e st u d y will b e e x pe ct e d t o c o m pl et e t h e sc h e d ul e d safet y a n d 
effi ca c y e val u ati o ns u ntil t h e e n d of t he st u d y or u ntil t h e de cisi o n is ma d e t o wit h dra w fr o m t h e 
st u d y (se e Er r o r! Refe r e nc e s o ur c e n ot f o u n d.  f or sc h e d ule of e val u ati o ns i n t h e Pr ot oc ol). 
A Es/ S A E c oll e cti o n will be u p t o 3 0 da ys aft er t h e last d ose of st u d y tr eat m e nt a n d will c o nti n u e 
f or as l o n g as t h e parti ci pa nt r e mai n s e nr oll e d i n t h e st u d y.  
Earl y disc o nti n u ati o n visit pr oc e d ures s h o ul d b e  c o m pl et e d f or a n y parti ci pa nt w h o disc o nti n u es 
st u d y tr eat me nt a n d als o wit h dra ws fr o m t h e st u d y at a n y ti m e pri or t o e n d of st u d y. A ll S A Es t hat 
oc c ur u ntil 3 0 da ys aft er last d ose of st u d y tr eat m e nt s h o ul d b e m o nit ore d a n d/ or r e c or d e d. I n t h e 
d o u bl e -bli n d p eri o d, partici pa nts w h o wit h dra w fr o m t h e st u d y  s h o ul d b e e n c o ura ge d t o r et ur n t o 
t h e cli ni c at W e e k 5 2 t o c o m pl et e t h e W ee k 5 2 pr o c e d ures. F urt h er d etails o n t h e sc h e d ul e of 
assess m e nt is c o ntai n e d i n Se cti o n 2 of t h e pr ot o c ol . 
 
1. 2  N u m be r of P artici p a nts  
It is a nti ci pat e d t hat a p pr o xi mat el y 4 5 9 mal e a n d fe male parti ci pa nts will b e d ose d i n t his st u d y.  
A p pr o xi mat el y 4 5 9 partici pa nts will b e ra n d o ml y assi g ne d, i n 2: 1 rati o, t o r e c ei ve 2 0 0 0 m g of 
BII B 0 9 2 or pla ce b o ( 3 0 6 partici pa nts a cti v e a n d 1 5 3 pla c e b o) a d mi nist ere d b y I V a p pr o xi mat el y 
o n c e Q 4 W.  Ra n d o mizati o n is stratifi e d b y c o u ntr y a n d scr ee ni n g C ol or Trails T est ( C T T) Part 2 
c o m pl eti o n ti m e of eit h er ≤ 1 7 0 or > 1 7 0 se c o n ds.  A nti ci pati n g a dr o p o ut rate of a p pr o xi mat el y 
2 5 %, a p pr o xi matel y 3 4 5 parti ci pa nts ( 2 3 0  parti ci pa nts i n t h e BII B 0 9 2 treat m e nt gr o u p a n d 1 1 5 
parti ci pa nts i n t h e pla ce b o gr o u p) ar e e x p e ct e d t o c o m plete t he st u d y t hr o u g h W e e k 5 2.  
 
1. 3  St art of St u d y a n d E n d of St u d y Defi niti o ns  
T he dat e t h e first parti ci pa nt si g ns a st u d y -s p ecifi c i nf or m e d c o nse nt f or m will b e defi n e d as t h e 
start of t h e st u d y.  A partici pa nt is c o nsi d er e d e nr oll e d w h e n t he st u d y -s pe cifi c i nf or m e d c o nse nt 
f or m is si g n e d.  T h e date t hat t h e last parti ci pa nt c o m plet es t h e last st u d y visit or sc h e d ul e d 
pr o c e d ure will b e d efi n e d as t h e e n d of t h e st u d y.  
 
1. 4  Tr e at me nt  
St u d y tr eat m e nt is defi n e d as a n y i n v esti gati o nal treat m e nt(s), mar k et e d pr o d u ct(s), pla c e b o or 
m e dical d e vi c e i nt e n d e d t o b e a d mi nist er e d t o a st u d y parti ci pa nt a c c or di n g t o t h e st u d y 
ra n d o mi zati o n or tr eat m e nt all o cati o n 
 


 
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Versi o n 1. 0  
 
St u d y T re at me nt  
U nit d ose  
st re n gt h(s)/ D os a g e 
le vel(s) 
D os a g e  f or m ul ati o n 
Fre q ue nc y of  
A d mi nist rati o n  
R o ute  of  A d mi nist r ati o n  
BII B 0 9 2  
2 0 0 0  m g  
O nce  e ver y 4  we e ks  
( Q 4 W) 
I V 
Pl ace b o  
Matc hi n g  d ose  v ol u me   
0. 9 % Na Cl or  5 % 
De xtr ose  
O nce  e ver y 4  we e ks  
( Q 4 W) 
I V 
All parti ci pa nts are ce ntrall y ra n d o mi ze d usi n g a n I ntera cti v e Res p o nse T ec h n ol o g y (I R T). B ef or e 
t h e st u d y is i nitiat e d, ea c h user r e c ei ves l o g i n i nf or mati o n a n d dir e cti o ns o n h o w t o a c cess t he I R T. 
Ra n d o mi zati o n is stratifie d b y c o u ntr y a n d scr e e ni n g C T T Part 2 c o m pl eti o n ti m e of eit h er ≤ 1 7 0 or 
> 1 7 0 se c o n ds.  
 
 
2  
D E S C RI P TI O N O F O B J E C TI V E S A N D E N D P OI N T S  
 
T he o bj ecti ves a n d e n d p oi nts fr o m t h e pr ot oc ol S e cti o n 4  ar e descri b e d bel o w.  
O bje cti v e  
E n d p oi nt  
Pri m ar y  
T o e val u ate t he effi ca c y of BII B 0 9 2, c o m par e d 
t o pla c e b o, as meas ur e d b y a c ha n g e fr o m 
baseli n e i n t he P S P Rati n g Scal e ( P S P R S) at 
We e k 5 2.  
T he pri mar y effi ca c y e n d p oi nt will b e e val u at e d 
b y c o m pari n g t h e c ha n g e fr o m baseli n e i n t h e 
t otal P S P R S sc or e at W ee k 5 2 i n parti ci pa nts 
treat e d wit h BII B 0 9 2 relati ve t o t h e c ha n ge fr o m 
baseli n e i n t he t otal P S P R S sc ore i n parti ci pa nts 
treat e d wit h pla c e b o. 
T o assess t h e safet y a n d t ol era bilit y of 
BII B 0 9 2, relati v e t o pla c e b o, b y meas uri n g t h e 
fr e q u e n c y of d eat hs, S A Es, a n d A Es lea di n g t o 
disc o nti n u ati o n , a n d Gra d e 3 & 4 la b orat or y 
a b n or malities.  
T he pri mar y safet y e n d p oi nt will be e val u at e d b y 
ta b ulati n g t he n u m bers a n d p er ce nta g es of deat hs 
a n d u ni q u e partici pa nts wit h S A Es a n d A Es 
lea di n g t o disc o nti n u ati o n, a n d Gra d e 3 & 4 
la b orat or y a b n or maliti es. 
K e y Se c o n d ar y  
T o e val u ate t he effi ca c y of BII B 0 9 2, c o m par e d 
t o pla c e b o, as meas ur e d b y a c ha n g e fr o m 
baseli n e i n t he M o v e me nt Dis or d er S oci et y -
s p o ns ore d re visi o n of t h e U nifie d Par ki ns o n’s 
Disease Rati n g S cale ( M D S -U P D R S) Part II at 
We e k 5 2.  
T he i m pa ct of BII B 0 9 2 o n t h e M D S-U P D R S 
Part II will b e e val u at e d relati ve t o t h e c ha n ge 
fr o m baseli ne at W e e k 5 2 i n t h e BII B 0 9 2-tr eat e d 
parti ci pa nts a n d c o m par e d t o t hat of t he pla c e b o -
treat e d parti ci pa nts. 
T o e val u ate t he effi ca c y of BII B 0 9 2, c o m par e d 
t o plac e b o, as meas ur e d b y t h e Cli ni cal Gl o bal 
I m pr essi o n of C ha n ge ( C GI-C) at W ee k 5 2.  
T he i m pa ct of BII B 0 9 2 o n t h e C GI -C scal e sc or e 
will b e e val u at e d at W ee k 5 2 i n t h e BII B 0 9 2 -
treat e d parti ci pa nts a n d c o m par e d t o t hat of t he 
pla ce b o -tr eat e d parti ci pa nts. 


 
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T o e val u ate t he effi ca c y of BII B 0 9 2, c o m par e d 
t o pla c e b o, as meas ur e d b y a c ha n g e fr o m 
baseli n e i n t he R e peata bl e Batt er y f or t h e 
Assess me nt of N e ur o ps y c h ol o gi cal Disease 
Se v erit y ( R B A N S) at W ee k 5 2.  
T he i m pa ct of BII B 0 9 2 o n t h e R B A N S scal e will 
be e val u at e d r elati v e t o t h e c ha n g e fr o m baseli ne 
at W ee k 5 2 i n t h e BII B 0 9 2 -tr eat e d parti ci pa nts 
a n d c o m par e d t o t hat of t h e pla c e b o -tr eat e d 
parti ci pa nts.  
T o assess t h e i m pa ct of BII B 0 9 2 o n q u alit y of 
life, r elati v e t o pla c e b o, as m eas ur e d b y c ha n g e 
fr o m baseli ne o n th e Pr o gr essi v e S u pra n u cl ear 
Pals y Q u alit y of Life scale ( P S P -Q o L) at W ee k 
5 2.  
T he i m pa ct of BII B 0 9 2 o n t h e P S P -Q o L will b e 
e val u ate d r elati v e t o t h e c ha n g e fr o m baseli n e at 
We e k 5 2 i n t h e BII B 0 9 2 -tr eat e d parti ci pa nts a n d 
c o m par e d t o t hat of t h e pla c e b o -treat e d 
parti ci pa nts.  
Ot he r  Se c o n d ar y  
T o assess t h e effi ca c y of BII B 0 9 2, relati v e t o 
pla ce b o, as m eas ure d b y a c ha n g e fr o m baseli n e 
at W ee k 4 8 ( We e k 5 2 f or Cli ni cal Gl o bal 
I m pr essi o n of S e verit y [ C GI-S]) o n t h e 
f oll o wi n g i nstr u m e nts: 
•  Sc h wa b a n d E n gla n d Acti vities of 
Dail y Li vi n g ( S E A D L) S cal e  
•  C GI -S  
•  P h o ne mic Fl u e nc y T est  
•  Letter -N u m b er S e q u e n ci n g T est 
( L N S) 
•  C ol or Trails T est  
•  M o ntr eal C o g niti v e Assess m e nt 
( M o C A) 
T he i m pa ct of BII B 0 9 2 o n t h e f oll o wi n g 
i nstr u m e nts: 
•  S E A D L S cal e  
•  C GI -S  
•  P h o ne mic Fl u e nc y T est  
•  L N S T est  
•  C T T  
•  M o C A  
will b e e val u at e d r elati v e t o t h e c ha n g e fr o m 
baseli n e at W e e k 4 8 ( W e e k 5 2 f or C GI -S) i n t h e 
BII B 0 9 2 -tr eat e d parti ci pa nts a n d c o m par e d t o 
t hat of t h e pla c e b o-treat e d parti ci pa nts. 
T o assess t h e i m m u n o g e nicit y of BII B 0 9 2.  
I m m u n o ge ni cit y of BII B 0 9 2 will be meas ur e d 
b y assess m e nt of t h e pr ese n c e or a bse n c e of a nti -
BII B 0 9 2 a nti b o di es (a nti -BII B 0 9 2) i n ser u m.  
T o assess t h e effi ca c y of BII B 0 9 2, relati v e t o 
pla ce b o, as m eas ure d b y a bs ol ut e a n d per c e nt 
c ha n ge fr o m baseli n e of brai n v ol u m es, as 
det er mi n e d b y ma g n eti c r es o na n c e i ma gi n g  
( M RI), at We e k 5 2 i n t h e f oll o wi n g r e gi o ns: 
•  Ve ntri cl es  
•  W h ol e brai n  
•  Mi d brai n  
•  S u p eri or c er e b ellar p e d u n cl e  
•  T hir d v e ntri cl e  
T he i m pa ct of BII B 0 9 2 o n brai n v ol u m es, as 
det er mi n e d b y M RI i n t h e f oll o wi n g re gi o ns:  
•  Ve ntri cl es  
•  W h ol e bra i n 
•  Mi d brai n  
•  S u p eri or c er e b ellar p e d u n cl e  
•  T hir d v e ntri cl e  
•  Fr o ntal l o b e  
•  P o ns  


 
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•  Fr o ntal l o b e  
•  P o ns  
will b e e val u at e d r elati v e t o t h e a bs ol ut e a n d 
perc e nt c ha n g es fr o m baseli ne at We e k 5 2 i n t h e 
BII B 0 9 2 -tr eat e d parti ci pa nts a n d c o m par e d t o 
t hat of t h e pla c e b o -treat e d parti ci pa nts. 
Te rti ar y/ E x pl o r at o r y  
 
 
 
 
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O pe n -L a bel E xte nsi o n P h as e  
T o assess t h e l o n g -t er m safet y a n d t olera bilit y of 
BII B 0 9 2 i n parti ci pa nts wit h P S P.  
T he t ertiar y e n d p oi nt will be i nci d e n ce of A Es, 
S A Es, a n d d eat h.  
T o assess t h e l o n g -t er m effi ca c y of BII B 0 9 2 i n 
parti ci pa nts wit h P S P.  
T he t ertiar y e n d p oi nts will b e c ha n g e fr o m 
baseli n e o v er t h e pla ce b o -c o ntr olle d p eri o d a n d 
l o n g-ter m e xt e nsi o n p eri o d f or cli ni cal a n d 
healt h -o ut c o m es assess m e nts.  
T his st u d y i n cl u d es a n o pti o nal s u bst u d y t o 
m eas ur e q u a ntitati v e m o v e m e nt assess m e nts 
( Q M As) usi n g weara bl e se ns ors. T h e Q M As will 
m eas ur e gait, p ost ural  i nsta bilit y, m ot or 
f u n cti o n, a n d falls i n a s u bset of parti ci pa nts 
parti ci pati n g i n t h e l o n g -ter m e xte nsi o n peri o d. 
 
 
 
 
3  
G E N E R A L  C O N SI D E R A TI O N S  
 
3. 1  Ge ne r al M et h o ds  
 
T his statistical a nal ysis pla n ( S A P) is f or t he p ur p ose of t he i nt eri m a nal ysis w hi c h will use data 
c oll e ct e d i n t h e pla c e b o-c o ntr oll e d ( P C) a n d o p e n la bel e xt e nsi o n ( O L E ) p eri o d s o n c e  all s u bj e cts 
ha v e c o m plete d t h e P C p eri o d . It c o v ers t h e a nal yses f or t h e O L E p orti o n of t h e st u d y a n d a nal yses 
a cr oss b ot h t h e P C a n d  t h e O L E peri o ds. T h e a nal ysis f or  t h e P C peri o d is d oc u m e nt e d i n a 
se parat e 2 5 1 P P 3 0 1 pla c e b o -c o ntr oll e d S A P . T h e a nal yses of sel e ct e d e x pl or at or y e n d p oi nts ma y b e 
d o c u m e nt e d se paratel y. Si n c e t h e o bj e cti v es a n d e n d p oi nts gi v e n i n S e cti o n 2 are ta k e n dire ctl y 
fr o m t h e pr ot oc ol w hic h c o v ers b ot h P C a n d O L E peri o ds, o nl y a nal yses  rel e va nt t o t he O L E 


 
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peri o d w hi c h wil l ha ve s uffi ci e nt data at t h e ti me of t h e i nt eri m a nal ysis will b e pr ese nt e d i n t his 
S A P .  
S u m mar y ta bl es will b e pr ese nt e d usi n g d escri pti v e s u m mar y statistics. F or c o nti n u o us varia bl es, 
s u m mar y statisti cs will g e n erall y i n cl u d e: n u m ber of s u bj e cts wit h d ata, m ea n, sta n dar d d e viati o n, 
m e dia n, 2 5 % p er ce ntil e, 7 5 % p er c e ntil e, mi ni m u m a n d ma xi m u m. F or cat e g ori cal varia bl es, t his 
will g e n erall y i n cl u d e : n u m b er of s u bj e cts ra n d o mi z e d or d ose d, n u m b er wit h data, a n d t he p er c e nt 
of t h ose wit h data i n ea c h cate g or y.  
U nl ess ot her wise s pe cifi e d, c ha n g e fr o m baseli n e will b e d efi n e d as p ost -baseli n e val u e mi n us 
baseli n e val u e.   Se e S e cti o n 3. 3 f or t h e defi niti o n of baseli n e.  
U nl ess stat e d ot h er wise, all statisti cal t ests will be 2 -si d e d wit h statisti cal si g nifi ca nc e l e v el of 0. 0 5.  
T he statisti cal s oft war e, S A S ®  will b e use d f or all s u m mari es a n d a nal yses.  
T he h ealt h care r e gi o n use d i n t h e a nal ysis (r eferre d as re gi o n i n t his S A P) is d efi n e d as:  
•  U S: U nit e d Stat es  
•  N o n -U S: A ustralia, A ustria, Ca na da, Fra n c e, G er ma n y, Gr e ec e, Ital y, R ussi a n, S pai n, 
U nit e d Ki n g d o m, Ja pa n a n d K or ea  
T he t er m “s u bj ect” is t h e e q ui vale nt t o “ parti ci pa nt” use d i n t h e p r ot o c ol. 
T h is O L E peri o d a nal ysis  pla n d o es  n ot i n cl u d e  listi n gs si n ce t h e y are pr o vi d e d i n t he pla c e b o-
c o ntr olle d p eri o d a nal ysis ( pl ease r efer t o  t h e 2 5 1 P P 3 0 1 pla ce b o -c o ntr olle d S A P) . T h ese listi n gs will 
i n cl u d e all data i n t he pla c e b o-c o ntr oll e d a n d O L E peri o ds (all data i n t he st u d y), wit h a n i n dicat or 
of t h e st u d y peri o d ( scr e e ni n g, pla c e b o-c o ntr oll e d, or O L E) f or e a c h re c or d t o i n dicate w h e n t he 
e v e nt o c c urre d.  
 
3. 2 P o p ul ati o n  
•  D ose d s u bje cts : e nr oll e d s u bje cts w h o  r ec ei ve d at  least o n e  d ose  of  st u d y t h era p y, i. e., bli n d e d  
t h era p y (BII B 0 9 2  or  pla ce b o)  or  o p e n -la bel BII B 0 9 2 . T his is t h e sa m e as t h e “ Treate d 
parti ci pa nts” i n S e cti o n 1 7. 2 of t h e pr ot o c ol.  
 
•  I nt e nt-t o-tr eat (I T T) p o p ulati o n:  
T he i nt e nt -t o-treat p o p ulati o n is d efi ne d as all ra n d o mi z e d s u bj e cts w h o r e c ei v e d at l east o n e 
d ose of bli n d e d st u d y tr eat m e nt ( BII B 0 9 2 or pla c e b o).  
 
•  Safet y p o p ulati o n : all ra n d o mi z e d s u bj e cts w h o r e c ei v e d at l east o ne d ose of st u d y tr eat m e nt 
( BII B 0 9 2 or pla ce b o).    
 
•  Effi ca c y M RI p o p ulati o n : t he s u bset of t h e I T T p o p ulati o n w h o ha d a l east o ne m eas ura bl e 
b rai n v ol u m etri c m eas ur e m e nt. 
 
•  Safet y M RI p o p ulati o n : t h e s u bset of t he safet y p o p ulati o n w h o ha d a l east o ne p ost -baseli n e 
safet y M RI. 
 
•  Ser u m P K a nal ysis  p o p ulati o n : t h e s u bset of t h e safet y p o p ulati o n w h o ha d at least o n e 
m eas ura bl e p ost -baseli n e BII B 0 9 2 c o n c e ntrati o n i n ser u m.  


 
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•  C S F P K a nal ysis p o p ulati o n : t h e s u bset of t h e safet y p o p ulati o n w h o ha d at l east o n e 
m eas ura bl e p ost -baseli n e BII B 0 9 2 c o n c e ntrat i o n i n C S F. 
 
•  C S F P D a nal ysis p o p ulati o n : t h e s u bset of t h e safet y p o p ulati o n w h o  ha d b ot h baseli ne a n d at 
least o n e m eas ura bl e p ost-baseli n e N -t er mi nal ta u  C S F sa m pl e. 
 
•  A nti -dr u g a nti b o d y  ( A D A) a nal ysis p o p ulati o n : t h e s u bset of t h e safet y p o p ulati o n w h o ha d at 
least o n e p ost-d ose sa m ple e val u a ble f or  A D A .   
 
O L E t re at me nt gr o u ps  f or a n alyses 
A nal yses  f or effi ca c y data  will b e dis pla y e d b y t h e f oll o wi n g tr eat m e nt gr o u ps a cc or di n g t o 
ra n d o mi zati o n assi g n m e nt at t h e start of t h e pla c e b o -c o ntr oll e d p eri o d : 
•  BII B 0 9 2 earl y start : s u bj e cts w h o ar e assi g ne d t o  ( 1) r e cei ve BII B 0 9 2 i n t he pla ce b o -
c o ntr olle d p eri o d a n d ( 2) c o nti n u e r ec ei vi n g BII B 0 9 2 i n t h e O L E p eri o d  
•  BII B 0 9 2 late s tart: s u bj e cts w h o ar e assi g n e d t o ( 1) r e c ei ve pla c e b o i n t h e pl a ce b o -
c o ntr olle d p eri o d a n d ( 2) s wit c h t o  BII B 0 9 2 i n t h e O L E  p eri o d   
U nl ess ot her wise s pe cifi e d, a nal yses f or safet y, P K, a n d A D A data  will be dis pla ye d b y t h e 
f oll o wi n g tr eat m e nt gr o u ps a c c or di n g t o d ose re c ei v e d : 
•  BII B 0 9 2 earl y start : s u bj e cts w h o r e c ei ve BII B 0 9 2 i n t h e pla ce b o -c o ntr olle d p eri o d 
(re gar dl ess of ra n d o mizati o n assi g n me nt)  
•  BII B 0 9 2 late start : s u bj e cts w h o r e cei ve o nl y pla c e b o i n t h e pla ce b o -c o ntr olle d p eri o d 
(re gar dl ess of ra n d o mizati o n assi g n me nt) a n d s wit c h t o r e cei v e BII B 0 9 2 i n t he O L E  peri o d   
•  BII B 0 9 2 t otal : s u bj e cts i n eit h er BII B 0 9 2 earl y or lat e start tr eat m e nt gr o u ps  
If all s u bj ects r e cei v e d st u d y tr eat m e nt a c c or di n g t o t heir ra n d o mi zati o n assi g n m e nts d uri n g t he 
pla ce b o -c o ntr oll e d p eri o d (i. e. n o s u bj e ct assi g ne d t o pla c e b o re c ei v e d BII B 0 9 2, a n d  n o s u bj e ct 
assi g n e d t o BII B 0 9 2 re c ei v e d o nl y pla ce b o ) t h e n t h e assi g n m e nt of s u bj ec ts t o treat m e nt gr o u ps 
will b e t h e sa me  as t h ose  f or effi ca c y. 
 
3. 2  A n al ysis Pe ri o d  
 
De pe n di n g o n t h e p ur p ose, differ e nt a nal yses will be c o n d u ct e d o n t he f oll o wi n g st u d y p eri o ds:  
1. O L E  pe ri o d . O nl y data i n t h e O L E  p eri o d will b e i n cl u d e d i n t h ese a nal yses.  T his  O L E  
a nal ysis  p eri o d will b e a p pli e d t o  all t h e A E a nal yses , a n d t h e a nal yses will i ncl u d e all 
s u bje cts w h o wer e d ose d i n t h e O L E  peri o d.  
2. Pl ac e b o -c o ntr olle d a n d O L E  pe ri o d . All t h e data i n t h e pla c e b o-c o ntr olle d a n d O L E  
peri o ds will b e i n cl u d e d i n t hese a nal yses. T his a nal ysis p eri o d will b e a p pli e d t o all 
effi ca c y a nal yses. T h e a nal yses will i ncl u d e all s u bj e cts w h o wer e d ose d i n t he st u d y  
i n cl u di n g t h ose w h o di d n ot  e nr oll i nt o t he O L E peri o d .  
3. A cti v e tr e at me nt (pl ac e b o -c o ntr olle d a n d O L E) pe ri o d . T he a cti ve tr e at m e nt peri o d is 
defi n e d as t h e st u d y peri o d(s) i n w hi c h a s u bj e ct re c ei v ed  BII B 0 9 2 . F or earl y start s u bj e cts, 
all data fr o m pla c e b o -c o ntr oll e d a n d O L E  p eri o ds will be i ncl u d e d. F or lat e start s u bj e cts , 


 
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o nl y data i n t he O L E  peri o d will b e i n cl u de d. T his a nal ysis peri o d  will b e a p pli e d t o all 
safet y a nal yses, a n d t h e a nal yses will i n cl u de all s u bj e cts w h o wer e d ose d i n t h e st u d y 
e x c e pt f or s u bj e cts w h o r ecei v e d o nl y pla c e b o i n t h e pla c e b o -c o ntr oll e d p eri o d a n d di d n ot 
get d ose d i n t h e  O L E  p eri o d.   
F or a gi v e n o ut p ut , b ot h t h e a nal ysis p o p ulati o n a n d t he a nal ysis p eri o d  will det er mi n e w hic h 
s u bje cts will be i ncl u d e d. F or e xa m pl e, t h e i n ci d e n c e ta bl e of a d verse e v e nts i n t he O L E  p eri o d will 
i n cl u d e s u bj e cts i n t h e safet y p o p ulati o n f or t h e O L E  p eri o d, i. e., all ra n d o miz e d s u bj e cts w h o 
re cei v e d at l east o n e d ose of st u d y tr eat me nt i n t h e O L E  p eri o d. T h e i n ci de n c e rat e ta bl e of a d verse 
e v e nts i n t he a cti ve tr eat m e nt ( pla c e b o -c o ntr oll e d a n d O L E) p eri o d  will i n cl u de s u bj e cts i n t h e 
safet y p o p ulati o n f or t h e a cti v e tr eat m e nt p eri o d, i.e., all ra n d o mi z e d s u bj e cts w h o r e c ei v e d at  l east 
o n e d ose of  treat m e nt i n t he a cti ve tr eat m e nt peri o d. I n t his S A P we d o n ot se parat el y d efi n e t h e 
a nal ysis p o p ulati o n i n ea c h a nal ysis peri o d.  
3. 3  B aseli ne  
Pla c e b o -c o ntr oll e d a n d O L E p eri o d : U nl ess ot h er wise s p e cifi e d, baseli ne f or t h e Pla c e b o -c o ntr olle d 
a n d O L E p eri o d  r efers t o t h e baseli n e val u e f or t he P C  d osi n g  p eri o d a n d is defi n e d as t h e m ost 
re ce nt n o n-missi n g m eas ur e m e nt c oll ecte d pri or t o t h e first d ose  of st u d y dr u g .  
Acti v e treat m e nt p eri o d baseli n e is defi n e d  as t h e last n o n -missi n g m eas ure m e nt c oll e ct e d pri or t o 
t h e first d ose of st u d y dr u g re c ei v e d i n t h e d osi n g  p eri o d ( P C or O L E) i n w hic h a s u bj ect first 
re cei v es BII B 0 9 2. A cti v e tr eat m e nt p eri o d  baseli n e will b e use d f or t he Acti ve tr eat m e nt ( pla ce b o -
c o ntr olle d a n d O L E) p eri o d  a n d O L E p eri o d a nal yses , u nl ess ot h er wise s p e cifie d.  
T he s u m mari es i n t his se cti o n will b e base d o n t h e I T T p o p ulati o n. A nal ysis p eri o d will be 
s pe cifi e d f or ea c h ta bl e or fi g ur e. U nless ot h er wise s p e cifi e d, s u m mar y ta bl es will b e pr ese nte d b y 
O L E  tr eat m e nt gr o u p.  
 
4  
S T U D Y S U B J E C T S  
 
4. 1  Ac c o u nti n g of s u bje cts  
N u m b er of s u bj e cts w h o c o m pl et e d t h e P C  p eri o d, a n d n u m ber of s u bj e cts w h o e nr oll e d i n t h e O L E  
peri o d will b e s u m mari z e d. Dis p ositi o n i n t h e O L E  p eri o d will b e s u m mariz e d f or s u bje cts e nr oll e d 
i n O L E . T h e s u m mar y data will i n cl u de n u m ber ( %) of s u bj ects d ose d i n t h e O L E  p eri o d, n u m b er 
( %) of s u bj e cts o n g oi n g i n t h e O L E,  n u m b er ( %) of s u bje cts w h o c o m plet e d t h e tr eat me nt/st u d y i n 
O L E , a n d n u m b er ( %) of s u bj e cts w h o disc o nti n u e d tr eat me nt a n d/ or wit h dr e w fr o m st u d y i n O L E . 
Dis p ositi o n i n t h e e ntir e st u d y p eri o d ( P C a n d O L E p eri o d ) will als o b e s u m mari z e d . T h e s u m mar y 
will i n cl u d e n u m ber ( %) of s u bje cts ra n d o mi ze d, n u m b er ( %) of s u bj ects d ose d  i n ea c h p eri o d, a n d 
n u m b er ( %) of s u bj e cts  w h o disc o nti n u e d tr eat m e nt a n d/ or wit h dr e w fr o m st u d y  i n eit her P C or 
O L E p e ri o d.  
 
4. 2  De m o g r a p h ic a n d  B aseli ne  Dise ase  C h ar acte ristics  
 
De m o gra p hics, baseli n e c hara ct eristi cs , a n d m e di cal hist or y will b e s u m mariz e d f or s u bje cts 
e nr oll e d i n t he O L E  peri o d  a n d f or s u bje cts n ot e nr oll e d i n t h e O L E  p eri o d, res pe cti v el y .   
 


 
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4. 3  St u d y Dr u g E x p os ur e a n d St u d y Dr u g C o m pli a nc e  
 
A s u m mar y ta bl e of st u d y dr u g e x p os ure a n d c o m plia n c e i n t h e O L E  p eri o d will b e pr o vi d e d. 
N u m b er of d ose s ( BII B 0 9 2) re c ei ve d will b e s u m mari z e d as a cate g ori cal varia bl e ( cat e g ories 
o f 1-5, 6 -1 0, 1 1 -1 5, 1 6 -2 0, 2 1 -2 6, 2 7 -3 9, 4 0 -5 2 a n d 5 3 -6 5) as well as a c o nti n u o us varia bl e. 
T he n u m b er of d ose s ( BII B 0 9 2) re cei v e d via h o m e i nf usi o n will b e s u m mari z e d.  N u m ber of 
we e ks o n st u d y tr eat m e nt ( BII B 0 9 2), cal c ulat e d as ( dat e of last d ose –  dat e of first d ose 
+ 2 8 )/ 7, will be s u m mari z e d as a cat e g orical varia bl e ( e v er y 6 m o nt hs f or t h e first 2 y ears of 
O L E , a n d t h e n e v er y year) as well as a c o nti n u o us varia bl e. P er ce nta g e of st u d y treat m e nt 
ta k e n u p t o t h e last d ose, calc ulat e d as (t h e a ct u al n u m b er of d ose s di vi de d b y t h e n u m b er of 
d ose s a s u bj e ct is e x p e ct e d t o ta k e u ntil t h e dat e of last d ose ) * 1 0 0, will b e s u m mari z e d as a 
c o nti n u o us varia bl e. T his ta bl e will b e pr ese nt e d b y O L E  tr eat m e nt gr o u p. A si milar ta bl e will 
als o be pr o vi d e d o n t h e a cti v e treat m e nt (P C  a n d O L E) p eri o d  i n or d er t o s u m mari z e t h e 
e x p os ure data w hil e s u bj e cts are o n BII B 0 9 2.  
 
 
4. 4  M e dic ati o ns a n d N o n -dr u g t he r a pies  
 
T he n u m b er ( %) of s u bj e cts ta ki n g c o n c o mita nt m e di cati o n a n d n o n -dr u g t h era pies  ( d efi n e d as 
dia g n osti c pr o ce d ur es or m e dical tr eat m e nt pr o c e d ures)  i n t h e O L E  peri o d will b e s u m mariz e d. I n 
a d diti o n, n u m b er of s u bje cts i n t h e I T T p o p ulati o n t hat ha ve ta k e n a n y c o n c o mita nt m e di cati o ns 
a n d n o n -dr u g t h era pi es i n t h e a cti ve tr eat m e nt ( pla c e b o -c o ntr oll e d a n d O L E) p eri o d  will be 
s u m mariz e d.   
Par ki ns o n’s disease  m e di cati o ns ta k e n c o n c o mita ntl y at  baseli n e  of t h e pla c e b o -c o ntr oll e d p eri o d  
are defi n e d as Par ki ns o n’s disease  me di cati o ns t hat wer e b ei n g ta k e n at t he ti m e of t h e first d ose, 
i.e., start e d pri or t o t h e first d ose a n d c o nti n u e d u ntil aft er t h e first d ose. F or s u bje cts e nr oll e d i n t h e 
O L E  p eri o d , th e n u m b er ( %) of s u bj e cts ta ki n g Par ki ns o n’s disease m e di cati o ns c o n c o mita ntl y at 
t h e baseli n e  of t he pla c e b o -c o ntr oll e d peri o d  will b e s u m m ari z e d. A si milar s u m mar y will b e 
pr o vi d e d f or s u bje cts ta ki n g Par ki ns o n’s disease  me di cati o n c o n c o mita ntl y at t he baseli n e of t h e 
O L E  p eri o d. I n a d diti o n, n u m b er of s u bje cts usi n g Par ki ns o n’s disease me di cati o ns c o n c o mita ntl y 
at baseli n e of t h e O L E  p eri o d  will b e s u m mari z e d b y i n di vi d u al m e dicati o n . S u bj e cts w h o ha v e a n y 
c ha n ge i n Par ki ns o n’s disease m e di cati o ns d uri n g t h e O L E  p eri o d  will b e s u m mari z e d o v erall a n d 
b y t he ti mi n g of c ha n g e, i. e., t he n u m ber of s u bj e cts c ha n gi n g b et wee n W ee k 5 2  a n d We e k 6 4 , t h e 
n u m b er of s u bj ects c ha n gi n g b et we e n W e e k 6 4  a n d W e e k 7 6 , et c.  
 
4. 5  Pr ot o c ol  De vi ati o ns  
 
Pr ot o c ol d e viati o ns i de ntifi e d d uri n g sit e m o nit ori n g will b e ca pt ure d i n a Pr ot oc ol De viati o n l o g 
a n d cat e g ori ze d as k e y  or n o n -k e y  d e viati o ns base d o n Pr ot o c ol D e viati o n Classificati o n (se e 
A p p e n di x of t h e pla c e b o -c o ntr oll e d S A P). Ke y pr ot o c ol d e viati o ns  t hat oc c urre d i n t h e O L E  p eri o d 
will b e s u m mariz e d f or s u bj e cts e nr oll e d i n t h e O L E . Ke y  pr ot oc ol d e viati o ns f or all I T T s u bje cts 
i n t h e c o m bi n e d pla ce b o-c o ntr oll e d a n d O L E  p eri o ds will als o b e s u m mari z e d.   
 
 


 
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Versi o n 1. 0  
 
5  
   E F FI C A C Y  D A T A  
 
5. 1  Ge ne r al C o nsi de r ati o ns   
T he a nal ysis p o p ulati o n f or effi ca c y a nal ysis is t h e I T T p o p ulati o n a n d data fr o m b ot h t he pla c e b o -
c o ntr olle d a n d O L E  peri o ds will b e i n cl u d e d. All effi ca c y a nal yses will b e prese nte d b y BII B 0 9 2 
late start a n d BII B 0 9 2 earl y start  gr o u ps , a nd al o n g wit h t h e b y -visit c o m paris o n bet we e n t h e t w o 
gr o u ps .  
T her e will b e n o m ulti pl e c o m paris o n a dj ust m e nts.  
 
5. 2  Visit wi n d o ws f o r m a p pi n g effic ac y e n d p oi nt  
F or effi ca c y data t hat ar e s u m mari z e d or a nal y ze d b y visit, data c oll e ct e d o n all sc h e d ul e d visits 
a n d all u nsc h e d ul e d visits will be ma p p e d t o a n a p pr o priate a nal ysis visit usi n g t he wi n d o wi n g 
sc h e m e s h o w n i n T a bl e 1. If t h er e ar e 2 or m ore assess m e nts a v aila ble i n t h e sa m e a nal ysis wi n d o w 
f or a s u bj ect, t h e assess m e nt t hat is cl osest t o t h e tar g et visit da y will b e use d f or a nal ysis. If t here 
are 2 or m or e assess m e nts i n t he sa m e a nal ysis wi n d o w wit h t h e sa m e dista n c e fr o m t h e tar g et visit 
da y, t h e lat er assess m e nt will be use d.  
 
T a ble 1  
 Visit Wi n d o ws f o r Pri m ar y E n d p oi nt : P S P R S  
A n al ysis visit  
T ar g et visit d a y  A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e ce nt n o n -missi n g val u e  o n or pri or t o 
t h e first d ose dat e 
We e k 1 2  
8 5  
[ 4 3, 1 2 6]  
We e k 2 4  
1 6 9  
[ 1 2 7, 2 1 0] 
We e k 3 6  
2 5 3  
[ 2 1 1, 2 9 4] 
We e k 4 8  
3 3 7  
[ 2 9 5, 3 5 0] 
We e k 5 2  
3 6 5  
[ 3 5 1, 3 7 8 ] 
We e k 6 4  
4 4 9  
[ 4 0 7, 4 9 0 ] 
We e k 7 6  
5 3 3  
[ 4 9 1, 5 7 4 ] 
We e k 8 8  
6 1 7  
[5 7 5, 6 5 8 ] 
We e k 1 0 0  
7 0 1  
[6 5 9 , 7 4 2 ] 
We e k 1 1 2  
7 8 5  
[ 7 4 3, 8 2 6 ] 
We e k 1 2 4  
8 6 9  
[ 8 2 7, 9 1 0]  
We e k 1 3 6  
9 5 3  
[ 9 1 1, 9 9 4]  
We e k 1 4 8  
1 0 3 7  
[ 9 9 5, 1 0 7 8]  
We e k 1 6 0  
1 1 2 1  
[1 0 7 9 , 1 1 6 2]  
We e k 1 7 2  
1 2 0 5  
[1 1 6 3 , 1 2 4 6]  
We e k 1 8 4  
1 2 8 9  
[ 1 2 4 7, 1 3 3 0]  
We e k 1 9 6  
1 3 7 3  
> = 1 3 3 1  


 
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Versi o n 1. 0  
 
 
 
 
T a ble 2  ( a) 
Visit Wi n d o ws f o r K e y Se c o n d ar y Effic ac y E n d p oi nts  (M D S -U P D R S, C GI, 
P S P c o g niti v e c o m p osite b atte r y   a n d P S P -Q o L ) a n d R B A N S 
A n al ysis visit  
T ar g et visit d a y  
A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e ce nt n o n -missi n g val u e  o n or pri or t o 
t h e first d ose dat e 
We e k 1 2  
8 5  
[ 4 3, 1 2 6] 
We e k 2 4  
1 6 9  
[ 1 2 7, 2 1 0] 
We e k 3 6  
2 5 3  
[ 2 1 1, 3 0 8] 
We e k 5 2  
3 6 5  
[ 3 0 9, 3 7 8 ] 
We e k 6 4  
4 4 9  
[ 4 0 7, 4 9 0] 
We e k 7 6  
5 3 3  
[ 4 9 1, 6 1 6 ] 
We e k 1 0 0  
7 0 1  
[ 61 7 , 7 8 4]  
We e k 1 2 4  
8 6 9  
[7 8 5 , 9 5 2]  
We e k 1 4 8  
1 0 3 7  
[9 5 3 , 1 1 2 0] 
We e k 1 7 2  
1 2 0 5  
[ 1 1 2 1, 1 2 8 8] 
We e k 1 9 6  
1 3 7 3  
> = 1 2 8 9  
 
 
T a ble 3  ( b) 
Visit Wi n d o ws f o r K e y Se c o n d ar y Effic ac y E n d p oi nt  P S P c o g niti v e 
c o m p osite b atte r y  ( 1 3 i n di vi d u al s u btests) 
A n al ysis visit  
T ar g et visit d a y  
A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e ce nt n o n -missi n g val u e  o n or pri or t o 
t h e first d ose dat e 
We e k 1 2  
8 5  
[ 4 3, 1 2 6] 
We e k 2 4  
1 6 9  
[ 1 2 7, 2 1 0] 
We e k 3 6  
2 5 3  
[ 2 1 1, 3 0 8] 
We e k 5 2  
3 6 5  
[ 3 0 9, 3 7 8 ] 
We e k 7 6  
5 3 3  
[ 4 4 9, 6 1 6] 
We e k 1 0 0  
7 0 1  
[ 6 1 7, 7 8 4] 
We e k 1 2 4  
8 6 9  
[ 7 8 5, 9 5 2] 
We e k 1 4 8  
1 0 3 7  
[ 9 5 3, 1 1 2 0] 
We e k 1 7 2  
1 2 0 5  
[ 1 1 2 1, 1 2 8 8] 
We e k 1 9 6  
1 3 7 3  
> = 1 2 8 9  
 


 
2 0  
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Versi o n 1. 0  
 
T a ble 4  
Visit Wi n d o ws f o r Ot he r Se c o n d ar y Effic ac y E n d p oi nts : S E AD L,  P h o n e mic 
Fl ue nc y Test, W AI S -I V Lette r N u m be r Se q ue nc i n g T as k, C ol o r Tr ails t est, 
a n d M o C A    
 
                 
 
 
 
 
 
 
 
A n al ysis visit  
T ar g et visit d a y  A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e ce nt n o n -missi n g val u e  o n or pri or t o 
t h e first d ose dat e 
We e k 1 2  
8 5  
[ 4 3, 1 2 6] 
We e k 2 4  
1 6 9  
[ 1 2 7, 2 1 0] 
We e k 3 6  
2 5 3  
[ 2 1 1, 2 9 4] 
We e k 4 8  
3 3 7  
[ 2 9 5, 4 3 4 ] 
We e k 7 6  
5 3 3  
[ 43 5 , 6 1 6 ] 
We e k 1 0 0  
7 0 1  
[ 6 1 7, 7 8 4] 
We e k 1 2 4  
8 6 9  
[ 7 8 5, 9 5 2] 
We e k 1 4 8  
1 0 3 7  
[ 9 5 3, 1 1 2 0] 
We e k 1 7 2  
1 2 0 5  
[ 1 1 2 1, 1 2 8 8] 
We e k 1 9 6  
1 3 7 3  
> = 1 2 8 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
2 1  
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Versi o n 1. 0  
 
T a ble 5  
Visit Wi n d o ws f o r V ol u metric M RI  
 
 
 
 
 
 
T a ble 6 : Visit Wi n d o ws f o r C S F P D a n al ysis  d at a  
A n al ysis visit  
T ar g et visit d a y  A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e ce nt n o n-missi n g pr e -d ose val u e  
We e k 5 2  
3 6 5  
[ 2 7 4, 5 3 2 ] 
We e k 1 0 0  
7 0 1  
> = 5 3 3  
 
H a n dli n g of missi n g ite ms f or sc ales  
Pl ease refer t o t h e pla ce b o -c o ntr oll e d S A P f or t h e i m p utati o n met h o d. T h e s a m e m et h o d will b e 
a p plie d t o effi ca c y e n d p oi nts c oll e ct e d i n t h e O L E  p eri o d.  
 
5. 3  C o nsi de r ati o ns  f o r i nte ri m a n al ysis 
F or t he i nt eri m a nal ysis, t h e effica c y a nal ysis i n t h e O L E p eri o d will o n l y f o c us o n t h e pri mar y a n d 
k e y se c o n dar y effi ca c y e n d p oi nts:  
•  2 8 -it e m P S P R S t otal sc or e  a n d 1 5 -it e m P S P R S t otal sc or e ,  
•  M D S -U P D R S Part II, C GI -C, P S P c o g niti ve c o m p osit e batt er y , a n d P S P-Q o L.  
F or t he pri mar y e n d p oi nt P S P R S, t h e f oll o wi n g a nal yses will als o be c o n d u cte d:  
•  B y -visit s hift fr o m baseli n e a nal ysis a n d t h e b y -visit cat e g orical s u m mar y f or ea c h 
i n di vi d u al it e m i n t h e 2 8-it e m P S P R S will b e pr ese nt e d. T h e sa m e a nal yses will b e 
perf or m e d f or  ea c h it e m of t h e 1 5 -it e m P S P R S.  
•  T he c ha n g e fr o m baseli n e i n ea c h of t h e 6 s u bscal es of 2 8 -ite m P S P R S will be s u m mari z e d 
b y visit, a nal y ze d b y M M R M a n d pl ott e d o v er ti m e. T h e sa m e a nal ysis will be a p pli e d t o 
t h e 3  s u bscal es of 1 5 -it e m P S P R S (gait/li m b,  o c ular m ot or, a n d b ul bar ). 
Be ca use t o o fe w patie nts will ha v e r ea c he d W e e k 1 0 0 at t he ti m e of i nteri m a nal ysis data base l oc k, 
t h e C S F P D a nal ysis a n d t he effi ca c y M RI a nal ysis will n ot b e c o n d u ct e d. 
 
5. 4  B y Visit S u m m ar y a n d M i xe d M o del R e pe ate d M e as ur es (M M R M ) M o del  
C ha n g e fr o m baseli ne a nal yses will b e perf or m e d usi n g s u m mar y statisti cs  a n d M M R M. Visits 
wit h t o o fe w data ma y b e e xcl u d e d fr o m t h e M M R M a nal ysis. Li n e pl ots f or a dj ust e d mea n c ha n g e 
fr o m baseli ne o v er ti me will be pr o vi d e d. 
 
A n al ysis visit  
T ar g et visit d a y  A n al ysis visit wi n d o w  
Baseli n e  
1  
< = 8 4  
We e k 2 4  
1 6 9  
[8 5 , 2 5 2 ] 
We e k 5 2  
3 6 5  
[ 28 1 , 4 4 8 ] 
We e k 1 0 0  
7 0 1  
[ 6 1 7, 7 8 4] 


 
2 2  
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Versi o n 1. 0  
 
C o nsi d er ati o ns f or b ase M M R M m o d el f or c h a n g e fr o m b aseli n e a n alyses  
T he baseli ne a n d c ha n ge fr o m baseli n e f or a para m et er of i nterest will be s u m mari z e d b y O L E  
treat m e nt gr o u p at ea c h p ost-baseli n e visit. A M M R M m o d el will be use d as t h e pri mar y a nal ysis 
t o a nal y z e c ha n g e fr o m baseli ne usi n g fi xe d effe cts of O L E  tr eat me nt gr o u p, ti m e ( cat e gori cal), 
O L E  tr eat m e nt gr o u p-b y -ti m e i nt era cti o n, baseli n e f or t h e para m et er of i nt er est, ( baseli n e f or t h e 
para m et er of i nt er est) b y ti m e i ntera cti o n, baseli n e C ol or Trails 2 test ( ≤ 1 7 0 or > 1 7 0 sec o n ds ) a n d 
re gi o n. A n u nstr u ct ur e d c o varia nc e matri x will be use d t o m o del t h e wit hi n -pati e nt varia n c e -
c o varia n ce err ors.  If t h e u nstr u ct ur e d c o varia nc e str u ct ure matri x r es ults i n a la c k of c o n v er g e n ce, 
t h e h et er o g e n e o us T o e plit z c o varia n c e str u ct ure f oll o we d b y t he h et er o g e n e o us first -or d er 
a ut ore gr essi ve c o varia nc e str u ct ure will b e use d.  T h e Ke n war d-R o g er a p pr o xi mati o n will b e use d 
t o esti mate t he d e n o mi nat or d e gre es of fr ee d o m.  
 
6  
S A F E T Y  D A T A  
 
6. 1  Ge ne r al C o nsi de r ati o ns  
 
 A n al ysis p o p ul ati o n  
Safet y p o p ulati o n will b e use d f or safet y a nal yses of A Es, cli ni cal la b orat or y data, 
 
 data, E C G data, a n d vital si g n s data.   T h e safet y M RI p o p ulati o n 
will b e use d f or t he a nal ysis of safet y M RI data.  
 A n al ysis  pe ri o d a n d a n al ysis dis pl a ys  
T he a nal ysis peri o d will b e s p e cifi e d f or ea c h o ut p ut. A nal ysis p eri o ds i n t his S A P  are:  
•  O L E  p eri o d  –  f or A E a nal yses 
•  a cti v e tr eat m e nt ( pla ce b o -c o ntr olle d a n d O L E) peri o d  - f or all safet y a nal yses 
S afet y data will b e s u m mari z e d b y O L E  treat m e nt gr o u p (BII B 0 9 2 earl y start , BII B 0 9 2 late start, 
a n d i n a d diti o n BII B 0 9 2 t otal).  
 Visit wi n d o ws  
 
Visit wi n d o ws will be m ut u all y e x cl usi ve, c o ntai n n o ga ps, a n d e n d at t h e mi d p oi nt b et we e n  
sc h e d ul e d p ost-baseli ne visits, wit h t h e mi d p oi nt itself assi g n e d t o t h e s u bse q u e nt visit wi n d o w. If 
t w o or m or e e val u ati o ns o c c ur i n t h e sa me visit wi n d o w, t he e val u ati o n cl osest t o t he tar g et visit 
da y will b e sel e ct e d f or i n cl usi o n i n t h e a nal ysis. If m ulti pl e e val u ati o ns o n differ e nt da ys ar e 
e q u all y cl ose t o t h e tar g et visit da y, t h e n t h e lat est e val u ati o n will be sel ecte d f or i n cl usi o n i n t h e 
a nal ysis. If m ulti pl e e val u ati o ns o cc ur o n t h e sa m e da y, t he earli est val u e will be c h ose n f or 
a nal ysis if ti m e of c oll e cti o n is a vaila bl e; a sc h e d ul e d val u e will b e c h ose n b ef ore a n u nsc h e d ule d 
or earl y disc o nti n u ati o n r e c or d.  
 
 I nci de nc e, i nci de nc e pr o p o rti o n a n d i nci de nc e r ate  
•  I n ci d e n c e a n d i n ci d e n c e pr o p orti o n will b e pr o vi d e d i n i n ci d e n c e pr o p orti o n ta bl es. I nci d e nc e is 
defi n e d as t h e n u m b er of s u bj e cts w h o e x p eri e n ce d a n e ve nt. I n ci d e n c e pr o p orti o n is d efi n e d as 
t h e n u m b er of s u bj ects w h o e x p eri e n c e d a n e v e nt di vi d e d b y t otal n u m b er of s u bj ects i n t h e 
a nal ysis p o p ulati o n, i.e., p er ce nta g e. Ea c h s u bj ect will b e  c o u nt e d o nl y o nc e wit hi n ea c h 
cat e g or y.  
  


 
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Versi o n 1. 0  
 
•  I n ci d e n c e a n d i n ci d e n c e rat e will b e pr o vi de d i n i nci d e n ce rat e ta bl es. T w o differ e nt ki n ds of 
i n ci de n c e rat e ta bl es will b e pr o vi d e d as a p pr o priat e f or differe nt a nal yses. Defi niti o ns ar e 
pr o vi d e d b el o w.  
 
• 
F oll o w -u p a dj ust e d i nci d e nc e rat e ( F AI R) –  d efi n e d as t he n u m ber of s u bje cts wit h a n 
e v e nt di vi d e d b y t h e t otal f oll o w -u p ti m e a m o n g t h e s u bj e cts i n t h e a nal ysis p o p ulati o n  
(e. g., i n ci de n c e rat e p er 1 0 0 s u bj e ct-years). T h e t otal f oll o w -u p ti m e (s u bje ct -y ea rs) is t he 
s u m of all s u bj e cts’ f oll o w-u p ti me, w h er e a s u bje ct’s f oll o w -u p ti m e is calc ulate d as t h e 
n u m b er of da ys (i ncl usi v e) fr o m first d ose of treat m e nt u ntil t he last da y o n st u d y di vi d e d 
b y 3 6 5. 2 5. F or a cti v e tr eat me nt p eri o d a nal yses, t he first d os e of treat m e nt is  c o nsi d er e d 
t h e first d ose re c ei v e d i n t h e st u d y p er i o d ( P C or O L E) i n w hi c h a s u bj e ct first re c ei v es 
BII B 0 9 2.  Ea c h s u bj ect will b e c o u nt e d o nl y o nc e wit hi n ea c h cat e g or y.  
 
• 
E x p os ur e -a dj uste d i n ci d e n c e rate ( E AI R) –  defi n e d as t h e n u m b er o f s u bj e cts wit h a n 
e v e nt di vi d e d b y t h e t otal e x p os ure a dj ust e d f oll o w-u p ti m e (i. e. t otal ti me at ris k f or t h e 
e v e nt) a m o n g t he s u bj e cts i n t he a nal ysis p o p ulati o n  ( e. g., i n ci d e n c e rat e p er 1 0 0 s u bj e ct-
years) . T h e e x p os ur e a dj ust e d f oll o w -u p ti m e  (ti m e at ris k f or t h e e ve nt) f or a s u bje ct is t h e 
ti m e fr o m t he first d ose of  st u d y dr u g i n t h e first BII B 0 9 2  d osi n g p eri o d  ( P C or O L E) t o 
t h e i nitial o cc urr e nc e of t he e v e nt f or s u bj e cts w h o e x p eri e nc e d t h e e v e nt, a n d is t h e ti m e 
fr o m first d ose of st u d y  dr u g  i n t h e first BII B 0 9 2  d osi n g p eri o d  t o t h e e n d of f oll o w-u p 
(t h e last da y o n st u d y) f or s u bj e cts w h o di d n ot e x p eri e n ce t he e v e nt. T he t ot al ti m e at ris k 
is t h e s u m of all s u bj ects’ ti m e at ris k. Ea c h s u bj e ct will b e c o u nt e d o nl y o n c e wit hi n ea c h 
cat eg or y.  
  
6. 2  Cli nic al A d v e rse E v e nts  
 
 Tr e at me nt -e me r g e nt A Es ( T E A Es)  
All A Es will b e a nal y ze d base d o n t h e pri n ci pl e of treat m e nt e m er ge n c e.  A treat m e nt -e mer g e nt A E 
is d efi n e d as a n A E t hat start e d or w orse n e d aft er t h e start of first d ose  of st u d y tr eat m e nt.  
T o d efi n e tr eat m e nt e m er g e n ce f or A Es wit h missi n g start or st o p dat e or ti m e t h e f oll o wi n g 
a d diti o nal crit eria will b e use d:  
•  if b ot h t h e start a n d st o p dat es f or a partic ular A E ar e missi n g, t he n t hat A E is c o nsi d er e d 
treat m e nt e m er g e nt; 
•  if t he start dat e f or a partic ular A E is missi n g a n d t h e st o p dat e/ti me falls aft er t h e first d ose 
dat e/ti m e, t he n t hat A E is c o nsi d er e d tr eat m e nt e mer g e nt;  
•  if t he start dat e f or a partic ular A E was t h e sa m e as t h e first d ose date, a n d t he start ti m e was 
missi n g,  t h e n t hat e v e nt is c o nsi d er e d treat m e nt e m er ge nt. 
F or A Es wit h a partial start dat e, t h e y ear/ m o nt h of t he e v e nt dat e will b e c o m pare d t o t hat of t h e 
first d osi n g dat e t o d et er mi n e w het h er t he e v e nt is tr eat m e nt e mer g e nt. 
I n a d diti o n, S A Es t hat o c c urre d si n c e a s u bj e ct was scr e e n e d i n t h e st u d y a n d pri or t o t h e first d ose  
of st u d y tr eat m e nt, w hi c h b y d efi niti o n are n ot tr eat me nt -e m er ge nt, will b e i ncl u d e d i n r el e va nt 
listi n gs b ut will n ot b e s u m mari z e d. 
O nl y T E A Es will b e i n cl u de d i n t he A E ta bles, u nless ot h er wise s p e cifi e d.  
 


 
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 S u m m ar y a n d i nci de nc e a n al ysis  
 
O v erall s u m mar y of A E ta bl e will b e d o ne f or t h e O L E  peri o d, as well as f or t h e a cti v e tr eat m e nt 
( pla ce b o-c o ntr oll e d a n d O L E)  p eri o d pr ese nte d b y O L E  treat m e nt gr o u p. T h e f oll o wi n g 
i nf or mati o n will be s u m mari z ed : t h e n u m b er of s u bj e cts wit h a n y A E, wit h a n y A E b y ma xi m u m 
se v erit y (as assesse d b y t h e i n vesti gat or), t h e n u m b er of s u bj e cts wit h a n y r elate d A E (r elat e d t o 
st u d y dr u g as assesse d b y i n vesti gat or), t h e n u m b er of s u bj e cts wit h S A E, t h e n u m b er of s u bj e cts 
wit h relat e d S A E, t h e n u m b er of s u bj e cts wit h A E l ea di n g t o st u d y dr u g disc o nti n u ati o n, t h e 
n u m b er of s u bj ects wit h a n A E t hat le d t o wit h dra wal fr o m t h e st u d y a n d t h e n u m b er of s u bj e cts 
wit h a fatal e ve nt .  
T he s orti n g or d er f or A E i nci d e n ce ta bles,  u nless ot h er wise s p e cifi e d, will b e b y d e cr easi n g 
fr e q u e n c y or d er of “ BII B 09 2  t otal” c ol u m n  wit hi n ea c h cat e g or y i n t h e ta bl es pr ese nte d b y O L E  
treat m e nt gr o u p. A s u bje ct is c o u nt e d o nl y o n c e wit hi n ea c h cate g or y i n ea c h ta bl e. F or e xa m pl e, 
f or t h e ta bl e of A Es b y s yste m or ga n class a n d pr eferr e d t er ms s ort e d b y d e creasi n g fr e q u e n c y 
pr ese nt e d b y tr eat m e nt gr o u p , s yst e m or ga n class will b e pr ese nt e d i n d e cr easi n g fr e q u e nc y or d er 
of BII B 0 9 2  t otal c ol u m n, a n d wit hi n ea c h s yst e m or ga n class, pr eferr e d t er ms will b e pr ese nte d i n 
de cr easi n g fr e q u e nc y or d er of BII B 0 9 2  t otal c ol u m n. A s u bj e ct is c o u nt e d o nl y o n c e wit hi n  ea c h 
s yst e m or ga n class a n d pr eferr e d t er m.  
T he f oll o wi n g A E i n ci d e n c e  pr o p orti o n  ta bl es will b e pr o vi d e d f or t h e O L E  peri o d ( pr ese nt e d b y 
t h e O L E  treat m e nt gr o u p u nl ess ot her wise s pe cifi e d): 
1.  A Es b y s yst e m or ga n class a n d pr eferr e d t er m s ort e d b y d e cr eas i n g fr e q u e n c y  
2.  A Es b y s yst e m or ga n class a n d pr eferr e d t er m s ort e d b y al p ha b etical or d er   
3.  A Es b y s yst e m or ga n class, hi g h l e v el gr o u p t er m a n d pr eferr e d t er m  
4.  A Es b y s yst e m or ga n class  
5.  A Es b y pr eferr e d t er m  
6.  A Es wit h a n i n ci d e n c e of 2 % or m or e i n a n y tr ea t m e nt gr o u p b y pr eferr e d t er m  
7.  A Es wit h a n i n ci d e n c e of 5 % or m or e i n a n y tr eat m e nt gr o u p b y pr eferr e d t er m  
8.  Se v er e or v er y se v er e A Es b y s yst e m or ga n class a n d pr eferr e d t er m  
9.  Se v er e  or v er y se v er e A Es b y pr eferr e d t er m  
1 0.  A Es b y ma xi m u m se v erit y b y s yst e m or ga n class a n d pr eferre d t er m. ( S yst e m or ga n class 
will b e pr ese nt e d al p ha b eti call y. Pr eferr e d t er ms will b e pr ese nt e d i n d e cr easi n g fr e q u e nc y 
or d er. Ma xi m u m se verit y will b e pr ese nt e d wit hi n ea c h preferre d ter m i n t h e or d er of mil d, 
m o d erat e, se v e r e, v er y se v er e, u n k n o w n a n d t otal. A s u bj e ct will b e c o u nte d o nl y o n c e at 
t h e ma xi m u m se v erit y wit hi n ea c h s yst e m or ga n class a n d preferre d ter m.)  
1 1.  A Es b y ma xi m u m se v erit y b y pr eferr e d t er m . ( Pr eferr e d t er ms will b e pr ese nt e d i n 
de cr easi n g fr e q u e nc y or d er . Ma xi m u m se v erit y will b e pr ese nte d wit hi n ea c h pr eferre d ter m 
i n t h e or d er of mil d, m o d erat e, se v er e, v er y se v er e, u n k n o w n a n d t otal. A s u bj e ct will b e 
c o u nt e d o nl y o n ce at t h e ma xi m u m se v erit y wit hi n ea c h pr eferr e d t er m.)  
1 2.  Relat e d A Es b y s yst e m or ga n cla ss a n d pr eferr e d t er m  
1 3.  S A Es b y s yst e m or ga n class a n d pr eferr e d t er m  
1 4.  S A Es b y preferre d ter m  


 
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1 5.  Relat e d S A Es b y s yst e m or ga n class a n d preferr e d t er m  
1 6.  A Es t hat l e d t o disc o nti n u ati o n of st u d y tr eat m e nt b y s yste m or ga n class a n d pr eferr e d t er m  
1 7.  A Es t hat l e d t o  wit h dra wal fr o m st u d y b y s yst e m or ga n class a n d pr eferr e d t er m  
1 8.  S A Es wit h fatal o ut c o m e b y s yst e m or ga n class a n d preferr e d ter m  
1 9.  A Es b y  1 2 -wee k i nter vals b y s yst e m or ga n class a n d preferre d ter m  
2 0.  S A Es b y  1 2 -we e k i nt er vals b y s yste m or ga n class a n d pr eferr e d t er m  
 
I n a d diti o n t o listi n gs pr o vi de d as part of t he a nal ysis d escri be d i n t he pla c e b o -c o ntr oll e d S A P, a 
listi n g of A Es t hat l e d t o wit h dra wal fr o m st u d y will b e pr o vi d e d.  
 
 I nci de nc e r ate a n al ysis  
D u e t o t h e differ e nt l e n gt h of a cti v e tr eat m e nt ( pla ce b o -c o ntr olle d a n d O L E) p eri o d  i n earl y start 
vers us lat e start s u bj e cts, F AI R ( defi ne d i n S e cti o n 6. 1) ta bl es will b e use d f or f oll o wi n g A E 
a nal yses f or t h e a cti v e tr eat m e nt ( pla c e b o -c o ntr oll e d a n d O L E)  p eri o d  ( pr ese nt e d b y O L E  treat m e nt 
gr o u p):  
1.  A Es b y s yst e m or ga n class a n d pr eferr e d t er m s ort e d b y d e cr easi n g fr e q u e n c y  
2.  A Es b y s yst e m or ga n class, hi g h l e v el gr o u p t er m a n d pr eferr e d t er m  
3.  A Es b y pr eferr e d t er m  
4.  Se v er e  or v er y se v er e  A Es b y s yst e m or ga n clas s a n d pr eferr e d t er m 
5.  Se v er e or v er y se v er e A Es b y pr eferr e d t er m  
6.  Relat e d A Es b y s yst e m or ga n class a n d pr eferr e d t er m  
7.  S A Es b y s yst e m or ga n class a n d pr eferr e d t er m  
8.  S A Es b y preferre d ter m  
9.  Relat e d S A Es b y s yst e m or ga n class a n d preferr e d t er m  
 
 A d v e rse e v e nt of s pe ci al i nte r est  
 
I mm u n o ge ni cit y  is a n A E SI i n t he BII B 0 9 2 cli ni cal d e v el o p m e nt pr o gra m. A d v erse e v e nts  
re prese nti n g p ote ntial i m m u n e/ h y p erse nsiti vit y r ea cti o ns will b e i d e ntifie d usi n g c ust o mi z e d 
Me d D R A searc h criteria: A na p h yla cti c r ea cti o n, A n gi o e d e ma, a n d S e ver e c uta ne o us a d v erse 
rea cti o ns via S M Q ( narr o w a n d br oa d) searc h; E osi n o p hilia, a n d Misc ella ne o us t er ms. F urt her 
details ar e gi v e n i n A p p e n di x 1 1. 1.  
 
A n i n ci de n c e pr o p orti o n ta bl e f or p ot e ntial i m m u n e / h y p erse nsiti vit y r ea cti o ns or ga ni z ed  b y  
S M Q/ Misc ella n e o us cat e g ories a n d b y P T (f or b ot h A Es a n d S A Es),  a n d si milarl y f or  
p ote ntial i m m u n e/ h y p erse nsiti vit y r ea cti o ns f or s u bj e cts wit h a n d wit h o ut tr eat m e nt  
e m er g e nt p ositi v e a nti -dr u g a nti b o d y ( A D A) r es ults will be pr ese nt e d  f or b ot h A Es a n d  S A Es  f or 
t h e O L E Peri o d. P ositi v e tr eat m e nt e m er g e nt A D A will b e base d o n t h e d efi niti o n i n S ecti o n 8 
usi n g t h e i nt e grat e d pla ce b o -c o ntr olle d a n d o p e n la bel e xt e nsi o n data.  
 


 
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A n e x p os ure a dj ust e d i n ci d e nt rat e ta bl e will b e pr o vi d e d f or t h e  a cti v e tr eat m e nt ( pla ce b o-
c o ntr olle d a n d O L E) p eri o d.  
 
T he f oll o wi n g a nal yses (i n ci d e nc e pr o p orti o n o nl y) will b e p erf or m e d f or t h e O L E p eri o d t o 
e x pl or e t h e r elati o ns hi p bet wee n A D As a n d t h e safet y of BII B 0 9 2 : 
•  A Es f or s u bj e cts wit h a n d wit h o ut p ositi ve tr eat m e nt e mer g e nt A D As 
•  S A Es f or s u bj e cts wit h a n d wit h o ut p ositi v e treat m e nt e m er ge nt A D As  
 
 I nf usi o n r e acti o ns 
 
Inf usi o n rea cti o ns will b e i d e ntifi e d t hr o u g h 1)  t e m p oral ass o ciati o n, d efi n e d as t h ose e v e nts w hi c h 
oc c ur o n t h e da y of a n i nf usi o n or t h e s u bse q u e nt t w o cal e n dar da ys after a n  i nf usi o n; a n d 2) 
t hr o u g h a c ust o m M e d D R A sear c h of pr eferr e d t er ms . T h e list of c ust o m M e d D R A sear c h t er ms 
ca n b e f o u n d i n A p p e n di x 1 1. 2. A seri o us i nf usi o n r ea cti o n is a seri o us a d v erse e ve nt w hic h is 
i d e ntifi e d b y o n e or b ot h m et h o ds.  
 
F or t he O L E p eri o d, a n o v erall s u m mar y of i nf usi o n r ea cti o ns will b e pr o vi d e d wit h t h e n u m b er of 
s u bje cts ( n, %) wit h a n y i nf usi o n r ea cti o n; wit h a n y i nf usi o n rea cti o n i d e ntifie d b y t e m p oral 
ass o ciati o n o nl y; wit h a n y i nf usi o n r ea cti o n i d e ntifi e d t hr o u g h t he c ust o m se arc h o nl y; a n d a n y 
i nf usi o n rea cti o n i d e ntifi e d t hr o u g h b ot h m et h o ds. A d diti o nall y, t he f oll o wi n g i nci d e n ce pr o p orti o n 
ta bl es will b e pr o vi d e d f or t h e O L E p eri o d: 
 
1.  I nf usi o n rea cti o ns (t e m p oral ass o ciati o n or c ust o m searc h) b y S O C a n d P T  
2.  Seri o us i nf usi o n r ea cti o ns (t e m p oral ass o ciati o n or c ust o m sear c h) b y S O C a n d P T  
3.  I nf usi o n rea cti o ns (t e m p oral ass o ciati o n or c ust o m searc h) f or s u bje cts wit h a n d wit h o ut 
p ositi v e tr e at m e nt e m er g e nt A D As  b y P T  
4.  Seri o us i nf usi o n r ea cti o ns (t e m p oral ass o ciati o n or c ust o m searc h) f or s u bj e cts wit h a n d 
wit h o ut p ositi v e tr eat m e nt e m er g e nt A D As  b y P T   
5.  I nf usi o n rea cti o ns t hat o c c urre d i n t e m p oral ass ociati o n t o a n i nf usi o n b y p h ysi cal l o cati o n 
of i nf usi o n (i n -cli ni c vs. h o me) b y S O C a n d P T  
6.  Seri o us i nf usi o n r ea cti o ns t hat o c c urr e d i n t e m p oral ass o ciati o n t o a n i nf usi o n  b y p h ysi cal 
l o cati o n of  i nf usi o n (i n-cli ni c vs. h o m e ) b y S O C  a n d P T  
7.  I nf usi o n rea cti o ns i d e ntifi e d t hr o u g h c ust o m sear c h criteria b y P T  
8.  I nf usi o n rea cti o ns (t e m p oral ass o ciati o n or c ust o m searc h) b y 1 2 -wee k i nter vals b y P T  
 
P ositi ve tr eat m e nt e mer g e nt A D A will be base d o n t he d efi n iti o n i n S e cti o n 8 usi n g t h e i nt e grat e d 
pla ce b o -c o ntr oll e d a n d o p e n la b el e xte nsi o n data.  
 
A n e x p os ure a dj ust e d i n ci d e nt rat e ta bl e  f or i nf usi o n r ea cti o ns will b e pr o vi de d f or t he a cti v e 
treat m e nt ( pla c e b o-c o ntr olle d a n d O L E) p eri o d.  
 
A d diti o nall y, t h e f oll o wi n g i n ci d e n c e pr o p orti o n ta bl es will b e pr o vi d e d f or t h e a cti v e 
treat m e nt ( pla c e b o-c o ntr olle d a n d O L E) p eri o d :  
 




 
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H e m o g lo bi n A 1 C ( H b A 1 C )- scree ni n g o nl y 
Pre g na nc y  test ( W O C BP o nl y : scree ni n g, pre d ose, disc har ge).  
F ollicl e  sti m ulati ng  h or m o n e  ( F S H) (scre e ni n g o nl y f or w o me n ) 
 
 
  
 
S u m mari es of cli nical la b orat or y data will be p erf or m e d f or sc h e d ule d la b orat or y para m et ers, 
e x cl u di n g C S F para m et ers . Listi n gs of i n di vi d u al la b orat or y m eas ure m e nts b y s u bje cts f or all t he 
para m et ers , b ot h sc h e d ul e d a n d u nsc h e d ule d, will be pr o vi d e d  as p er t h e pla c e b o-c o ntr olle d S A P .  
 
A n alysis p eri o d a n d a n alysis dis pl a ys  
T he a nal ysis peri o d a n d a nal ysis dis pla ys ar e d efi ne d i n S e cti o n 6. 1 .2 . 
 
 Q u a ntit ati v e a n al yses  
Act u al val u es, c ha n ge fr o m baseli n e a n d p er c e nt c ha n g e fr o m baseli n e will be s u m mari z e d b y visit 
f or h e mat ol o g y, bl o o d c h e mistr y, c oa g ulati o n (I N R a n d pr ot hr o m bi n ti m e), a n d t h e uri nal ysis 
para m et ers s p e cifi c gra vit y a n d p H  (a ct u al val u es o ver ti m e o nl y), f or all t h e visits i n t h e a cti v e 
treat m e nt ( pla c e b o-c o ntr olle d a n d O L E) p eri o d . N u m b er of e val u a bl e s u bj e cts, m ea n, sta n dar d 
de viati o n, 2 5 % a n d 7 5 % q u artil es, mi n a n d ma x val u es will b e pr e se nt e d at ea c h visit.  
Pl ots of m ea n val u es ( wit h sta n dar d err or) f or n u m eri c la b orat or y para m et ers at ea c h visit f or all t h e 
visits i n t h e a cti v e tr eat m e nt ( pla c e b o -c o ntr oll e d a n d O L E) p eri o d  will be pr o vi d e d.  M ea n val u es at 
ti m e p oi nts w h ere n < 2 0 will n ot b e pl ott e d.  
 
Visit wi n d o ws f or b y visit s u m m aries  
F or la b orat or y b y visit s u m mari es, t h e a nal ysis visit s h o ul d b e defi n e d usi n g visit wi n d o ws (see 
T a ble s 7  a n d 8  b el o w).   
 
T a ble 7  
Visit Wi n d o ws f o r L a b o r at o r y b y Visit S u m m aries  f o r BII B 0 9 2 E arl y St art 
S u bje cts  
A n al ysis visit  
T ar g et visit d a y  A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e ce nt n o n -missi n g val u e pri or t o t he 
first d ose of st u d y dr u g i n t he P C d osi n g 
peri o d  
We e k 4  
2 9  
[1 ( p ost-d ose o nl y) , 4 2] 
We e k 8  
5 7  
[4 3 , 7 0 ] 
We e k 1 2  
8 5  
[7 1 , 1 2 6 ] 
We e k 2 4  
1 6 9  
[1 2 7 , 2 1 0 ] 
We e k 3 6  
2 5 3  
[2 1 1 , 2 9 4 ] 


 
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A n al ysis visit  
T ar g et visit d a y  A n al ysis visit wi n d o w  
We e k 4 8  
3 3 7  
[2 9 5 , 3 5 0] 
We e k 5 2  
3 6 5  
[ 3 5 1, 4 0 6 ] 
We e k 6 4  
4 4 9  
[4 0 7 , 4 90 ] 
We e k 7 6  
5 3 3  
[ 4 91 , 6 1 6]  
We e k 1 0 0  
7 0 1  
[ 6 1 7, 7 8 4] 
We e k 1 2 4  
8 6 9  
[ 7 8 5, 9 5 2] 
We e k 1 4 8  
1 0 3 7  
[ 9 5 3, 1 1 2 0] 
We e k 1 7 2  
1 2 0 5  
[ 1 1 2 1, 1 2 8 8] 
We e k 1 9 6  
1 3 7 3  
> = 1 2 8 9  
A nal ysis Visit, T ar g et visit da y a n d A nal ysis visit wi n d o w ar e cal c ulate d r el ati v e t o 
t h e da y of first d ose of st u d y dr u g ( BII B 0 9 2 or pla c e b o) i n t he P C d osi n g  peri o d.  
 
T a ble 8  
Visit Wi n d o ws f o r L a b o r at o r y b y Visit S u m m aries f o r BII B 0 9 2  L ate St art 
S u bje cts  
A n al ysis visit  
T ar g et visit d a y  
A n al ysis visit wi n d o w  
O L E  Baseli n e  
1  
M ost r e ce nt n o n -missi n g val u e pri or t o t he 
first d ose of st u d y dr u g i n t he O L E d osi n g 
peri o d  
We e k 1 2  
8 5  
[1 ( p ost-d ose o nl y) , 1 2 6 ] 
We e k 2 4  
1 6 9  
[1 2 7  2 5 2 ] 
We e k 4 8  
3 3 7  
[2 5 3 , 4 2 0 ] 
We e k 7 2  
5 0 5  
[4 2 1 , 5 8 8 ] 
We e k 9 6  
6 7 3  
[5 8 9 , 7 5 6 ] 
We e k 1 2 0  
8 4 1  
[7 5 7 , 9 2 4 ] 
We e k 1 4 4  
1 0 0 9  
> = 9 2 5  
A nal ysis Visit, T ar g et visit da y a n d A nal ysis visit wi n d o w ar e cal c ulate d r el ati v e t o 
t h e da y of first d ose of st u d y dr u g i n t h e O L E d osi n g p eri o d.. 
 
 
 Q u alit ati v e a n al yses  
F or all q u alitati v e a nal yses, all val u es will b e i n cl u d e d ( n ot j ust t h e “ a nal yz e d r e c or d” wit hi n ea c h 
visit wi n d o w i n t he q u a ntitati v e a nal yses).  
 
S hift a n alyses  
La b orat or y data will b e s u m mari ze d usi n g s hift ta bles w h er e a p pr o priat e  f or t h e a cti v e tr eat m e nt 
( pla ce b o-c o ntr oll e d a n d O L E) peri o d .  Ea c h s u bje ct’s h e mat ol o g y, bl o o d c h e mistr y , c oa g ulati o n 
a n d uri nal ysis ( e x cl u di n g mi cr osc o pi c e xa mi nati o n) n u m er i c val u es will b e fla g g e d as “l o w”, 


 
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“ n or mal”, or “ hi g h” r elati v e t o t h e n or mal ra n g es of t he c e ntral la b orat or y or as “ u n k n o w n” if n o 
res ult is a vaila bl e.  Ea c h s u bj ect’s uri nal ysis cat e g orical val u es (para m et ers of pr ot ei n, gl u c ose, 
bl o o d,  a n d l e u k o c yt e est erase) will be fla g g e d as “ a b n or mal” if p ositi v e, “ n or mal” if  ne gati v e, or 
“ u n k n o w n” if n o val u e is a vaila bl e.  
F or ea c h para m et er, t h e a nal ysis will b e base d o n s u bj e cts wit h at l east o n e p ost -baseli n e val u e. 
S hifts fr o m baseli ne t o hi g h/l o w stat us will b e pr ese nt e d f or h e mat ol o g y, bl o o d c h e mistr y a n d 
uri nal ysis (s pe cifi c gra vit y a n d p H) n u meri c para m et ers, a n d s hifts fr o m baseli n e t o a b n or mal 
( p ositi v e) will b e pr ese nt e d f or uri nal ysis cat e g orical para m et ers (pr ot ei n, gl u c ose, bl o o d,  a n d  
le u ko c yt e est erase ).  S hift t o l o w i n cl u d es n or mal t o l o w, hi g h t o l o w, a n d u n k n o w n t o l o w; shift t o 
hi g h i ncl u d es n or mal t o hi g h, l o w t o hi g h, a n d u n k n o w n t o hi g h. S u bje cts n e e d t o ha v e at l east o n e 
p os t-baseli n e e val u ati o n a n d a baseli n e val u e eit h er u n k n o w n or n ot l o w /hi g h /a b n or mal (i n cl u di n g 
missi n g) i n or d er t o b e i n cl u d e d i n t h e a nal ysis.  
F or earl y start s u bj ects, t h e pla c e b o -c o ntr oll e d baseli n e will b e use d a n d s hifts t hat oc c urr e d i n 
eit h er pla c e b o -c o ntr olle d or O L E  p eri o d will b e i n cl u d e d . F or lat e start s u bj e cts, t h e a cti v e 
treat m e nt p eri o d baseli n e will b e use d a n d s hifts t hat oc c urr e d i n t h e O L E  p eri o d base d o n t h e 
a cti v e tr eat m e nt p eri o d  baseli n e will b e i n cl u d e d.  
 
P ote nti ally Cli nic ally Si g nific a nt l a b or at ory a b n or m alities a n alyses  
F o r h e mat ol o g y, bl o o d c h e mistr y a n d uri nal ysis, t h e n u m b er of s u bj e cts wit h p ote ntiall y cli ni call y 
si g nifi ca nt ( P C S) la b orat or y a b n or maliti es p ost-baseli n e will b e s u m mariz e d f or t h e para m et ers 
pr o vi d e d i n T a bl e 9  f or t h e a cti v e tr eat me nt ( pla c e b o-c o ntr oll e d a n d O L E) p eri o d .  
S u bj e cts n e e d t o ha v e at least o n e p ost -baseli n e e val u ati o n  i n t h e a cti ve tr eat m e nt peri o d a n d a 
baseli n e val u e n ot p ote ntiall y cli ni call y si g nifi ca nt (i n cl u di n g missi n g) i n or der t o b e i n cl u d e d i n 
t h e a nal ysis.  
Sa m e as t h e s hift a nal ysis, f or earl y start s u bje cts, t h e pla ce b o -c o ntr oll e d baseli n e will b e use d a n d 
a b n or malities t hat oc c urr e d i n eit h er pla c e b o -c o ntr oll e d or O L E  p eri o d will be i n cl u d e d. F or lat e 
start s u bj e cts, t he a cti ve tr eat m e nt peri o d  baseli n e will b e  use d a n d t he P C S a b n or malities t hat 
oc c urr e d i n t h e O L E  p eri o d base d o n t he a cti v e tr eat m e nt p eri o d  baseli ne  will be i ncl u d e d.  
 
T a ble 9 : Crite ri a t o Dete r mi ne P ote nti all y Cli nic all y Si g nific a nt ( P C S) L a b o r at o r y 
A b n o r m alities  
Cli nic al L a b or at or y O utlier Criteri a  
P ar a meter n a me  
P C S L o w  
P C S Hi g h  
H E M A T O L O G Y  
W hit e bl o o d cells  
< 3. 0 x 1 0 9/ L  
> 1 6 x 1 0 9/ L  
L y mp h oc yt es  
< 0. 8 x 1 0 9/ L  
> 1 2 x 1 0 9/ L  
Ne utr o p hils  
< 1. 5 x 1 0 9/ L  
> 1 3. 5 x 1 0 9/ L  
M o n oc yt es  
N/ A  
> 2. 5 x 1 0 9/ L  
E osi n o p hils  
N/ A  
> 1. 6 x 1 0 9/ L  
B as o p hils  
N/ A  
> 1. 6 x 1 0 9/ L  
R e d bl o o d cells  
≤3. 5 x 1 0 1 2/ L 
≥6. 4 x 1 0 1 2/ L 
He m o gl o bi n - F e mal es  
≤9 5 g/ L  
≥1 7 5 g/ L  
He m o gl o bi n - Males  
≤1 1 5 g/ L  
≥1 9 0 g/ L  
He mat ocrit - F e males  
≤0. 3 2 L/ L  
≥0. 5 4 L/ L  
He mat ocrit - Males  
≤0. 3 7 L/ L   
≥0. 6 0 L/ L  


 
3 1  
 2 5 1 P P 3 0 1 O L E S A P  
Versi o n 1. 0  
 
Cli nic al L a b or at or y O utlier Criteri a  
P ar a meter n a me  
P C S L o w  
P C S Hi g h  
Pl at el et c o u nt  
≤7 5 x 1 0 9/ L 
≥7 0 0 x 1 0 9/ L 
B L O O D C H E MI S T R Y  
Al a ni ne a mi n otra nsferas e ( A L T)  
N/ A  
> 3 x U L N  
As part at e a mi n otra nsferase ( A S T)  
N/ A  
> 3 x U L N  
Al kali ne p h os p hatase ( A L P)  
N/ A  
> 3 x U L N  
T ot al bilir u bi n  
N/ A  
> 1. 5 x U L N  
Bl o o d urea nitr o ge n ( B U N)  
N/ A  
≥1 0. 7 m m ol/ L  
Creati ni ne  
N/ A  
≥1 7 6. 8 u mol/ L  
S o di u m  
≤1 2 6 m m ol/ L  
≥1 5 6 m m ol/ L  
P ot assi u m  
≤3 m mol/ L  
≥6 m mol/ L  
C hl ori de  
≤9 0 m mol/ L  
≥1 1 8 m m ol/ L  
Gl uc ose  
≤2. 2 m mol/ L  
≥9. 7 m mol/ L  
C al ci u m  
≤2 m mol/ L  
≥3 m mol/ L  
P h os p h or us  
≤0. 6 m mol/ L  
≥1. 7 m mol/ L  
Al b u mi n  
≤2 5 g/ L  
≥6 2 5 g/ L  
T ot al pr ot ei n  
≤4 5 g/ L  
≥1 0 0 g/ L  
U RI N A L Y SI S  
Gl uc ose  
N/ A  
≥1 0 0 0 m g/ d L   
Pr ot ei n  
N/ A  
≥ 1 0 0 m g/ d L  
U L N = u p per li mit of n or mal  
 
P ote nti al seri o us h e p at ot o xicity  
 
P ot e ntial seri o us h e pat ot o xi cit y is d efi ne d as A L T or A S T > 3 x U L N a n d t ot al bilir u bi n > 2 x U L N 
at a n y ti m e p ost -baseli n e  i n t h e a cti ve tr eat m e nt ( pla ce b o -c o ntr oll e d a n d O L E) p eri o d , n ot 
ne c essaril y c o nc urr e nt. A scatt er pl ot of t h e ma xi m u m p ost -baseli n e A L T or A S T val u e r elati v e t o 
U L N a n d ma xi m u m p ost -baseli n e t otal bilir u bi n val u e r elati v e t o U L N ( n ot ne c essaril y c o nc urr e nt)  
f or ea c h s u bj e ct will b e pr o vi d e d. A li n e pl ot of A L T, A S T, A LP  a n d t otal bilir u bi n val u es o v er 
ti m e f or s u bj e cts wit h p ote ntial seri o us h e pat ot o xi cit y will be pr o vi d e d. I n a d diti o n, s u bje cts wit h 
A L T > 1 x U L N, > 3 x U L N, > 5 x U L N, > 1 0 x U L N or > 2 0 x U L N, s u bj e cts wit h A S T > 1 x U L N, > 3 x 
U L N, > 5 x U L N, > 1 0 x U L N or > 2 0 x U L N, s u bje cts wit h t otal bilir u bi n > 1 x U L N or > 2 x U L N, 
s u bje cts wit h A L P > 1 x U L N or > 1. 5 x U L N, a n d s u bje cts wit h A S T or A L T > 3 x U L N p ost -
baseli n e a c c o m pa ni e d b y c o n c urr e ntl y el e vate d t otal bilir u bi n > 1. 5 x U L N or > 2 x U L N will b e 
pr ese nt e d. C o n c urre nt is d efi ne d as o n t h e sa m e da y. A listi n g of s u bje cts w it h p ot e ntial seri o us 
he pat ot o xicit y will b e pr o vi d e d  as part of t h e a nal ysis s p e cifie d b y t h e pla ce b o -c o ntr oll e d S A P .  
 
6. 4   
E C Gs  
 
F or a nal yses of  t h e a cti v e tr eat m e nt ( pla ce b o -c o ntr olle d a n d O L E) peri o d , a cti v e tr eat m e nt p eri o d 
baseli n e will b e use d . 
All of t h e a vaila ble E C G para m et er val u es fr o m ea c h s u bj ect will b e i n cl u d e d i n t h e E C G data set. 
Alt h o u g h all r e c or d e d E C G para m et er val u es will be i ncl u d e d i n t h e data listi n gs  (as part of t h e 
a nal ysis s p e cifie d b y t h e pla ce b o -c o ntr oll e d S A P) , o nl y val u es r e c ord e d at or n ear sc he d ul e d ti m e 
p oi nts will be i ncl u d e d i n t h e s u m mar y statistics  (see T a bl e 8 ). T h e s u m mar y of E C Gs at sc h e d ul e d 
visits will be pr ese nt e d b y t h e O L E  tr eat me nt gr o u p t hr o u g h t h e c o m bi n e d a cti v e tr eat m e nt 
( pla ce b o-c o ntr oll e d a n d O L E) peri o d . T h e E C G wi n d o wi n g s h o ul d f oll o w t he r e q uir e m e nts 
s pe cifi e d i n t h e fi nal pr ot oc ol. All i n di vi d u al val u es f or Q T i nt er val, Q T i nt er val c orr ecte d f or h eart 


 
3 2  
 2 5 1 P P 3 0 1 O L E S A P  
Versi o n 1. 0  
 
rate b y Ba z ett's f or m ula ( Q T c B), a n d Q T i nt er val c orre ct e d f or h eart rat e b y Fri deri cia's f or m u la 
( Q T c F) will b e pr ese nt e d i n t h e data listi n gs (as part of t h e a nal ysis s p ecifi e d b y t he pla c e b o -
c o ntr olle d S A P) . Q T, Q T c B, a n d Q T c F will als o b e i n cl u d e d i n t h e s u m mar y statisti cs, b ut o nl y 
Q T c F will b e a nal y z e d a n d disc usse d i n t he r e p ort.  
All a vaila bl e n o n -missi n g val u es of E C G para m et ers s h o ul d b e use d i n t h e s u m mari e s, a n d a nal yses 
f or t h e d o u ble-bli n d a n d o p e n -la bel tr eat m e nt p eri o d . H o we v er, if Q T c F is missi n g a n d R R i nter val 
i n se c o n ds is a vaila bl e, t he n Q T c F will b e cal c ulat e d as  
3
/1
R R
Q T
Q Tc F
=
 
If b ot h Q T c F a n d R R i n se c o n ds are missi n g, t h e n Q T c F will be calc ulat e d as 
(
)
3
/1
60
R A T E
H E A R T
Q T
Q Tc F =
 
 
T a ble 1 0  
Visit Wi n d o ws f o r E C G  Visit S u m m aries f o r BII B 0 9 2 E arl y St art s u bje cts 
 
 
 
 
 
 
 
 
 
 
 
T a ble 1 1  
Visit Wi n d o ws f o r E C G b y Visit S u m m aries f o r BII B 0 9 2 L ate St art 
s u bje cts 
A n al ysis visit  
T ar g et visit d a y  
A n al ysis visit wi n d o w  
 Baseli n e  
1  
M ost r e ce nt n o n -missi n g val u e pri or t o 
t h e first d ose of st u d y dr u g i n t h e O L E 
d osi n g p eri o d  
We e k 2 4  
1 6 9  
[1 ( p ost-d ose o nl y),  2 5 2 ] 
We e k 4 8  
3 3 7  
[ 25 3 , 4 2 0] 
A n al ysis visit  
T ar g et visit d a y  A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e ce nt n o n -missi n g val u e pri or t o t he  
first d ose of st u d y dr u g i n t he P C d osi n g 
peri o d  
We e k 2 4  
1 6 9  
[1 ( p ost-d ose o nl y) , 2 6 6] 
We e k 5 2  
3 6 5  
[ 2 6 7, 4 48 ] 
We e k 7 6  
5 3 3  
[4 4 9, 6 1 6 ] 
We e k 1 0 0  
7 0 1  
[ 6 1 7, 7 8 4] 
We e k 1 2 4  
8 6 9  
[ 7 8 5, 9 5 2] 
We e k 1 4 8  
1 0 3 7  
[ 9 5 3, 1 1 2 0] 
We e k 1 7 2  
1 2 0 5  
[ 1 1 2 1, 1 2 8 8] 
We e k 1 9 6  
1 3 7 3  
> = 1 2 8 9  
T ar get visit da y a n d A nal ysis visit wi n d o w ar e cal c ulat e d r elati v e t o t h e da y of first 
d ose of st u d y dr u g ( BII B 0 9 2 or pla c e b o) i n t h e P C d osi n g p eri o d.  
 


 
3 3  
 2 5 1 P P 3 0 1 O L E S A P  
Versi o n 1. 0  
 
A n al ysis visit  
T ar g et visit d a y  
A n al ysis visit wi n d o w  
We e k 7 2  
5 0 5  
[ 4 2 1, 5 8 8] 
We e k 9 6  
6 7 3  
[ 5 8 9, 7 5 6] 
We e k 1 2 0  
8 4 1  
[ 7 5 7, 9 2 4] 
We e k 1 4 4  
1 0 0 9  
> = 9 2 5  
A nal ysis Visit, T ar g et visit da y a n d A nal ysis visit wi n d o w ar e cal c ulate d r el ati v e t o 
t h e da y of first d ose of st u d y dr u g i n t h e O L E d osi n g p eri o d. 
 
 A n al ysis of Ce ntr al Te n de nc y  
 
S u m mar y statisti cs ( n, m ea n, S D, me dia n, mi ni m u m, a n d ma xi m u m) will be pr ese nte d f or ea c h 
E C G para m et er a n d t h e c orres p o n di n g c ha n ges fr o m baseli n e b y t h e O L E  tr eat m e nt gr o u p t hr o u g h 
t h e c o m bi n e d pla c e b o-c o ntr oll e d a n d O L E  p eri o d .  Fr e q u e n c y distri b uti o n of ma xi m u m p ost d ose 
E C G i nt er vals ta bl es will als o b e g e n erat e d .    
 C ate g o ric al A n al ysis  
 
T he fr e q u e n c y distri b uti o n of s u bj ects ma xi m u m re c or d e d p ost -d ose Q T c F, P R, Q R S, a n d Q T c F 
will b e ta b ulate d b y tr eat m e nt a n d s u m mari z e d wit hi n t h e C S R f or t h e f oll o wi n g ra n g es: 
•  F or Q T c F: Q T c F ≤ 4 5 0 mse c, 4 5 0 msec < Q T c F ≤ 4 8 0 mse c, 4 8 0 mse c < Q T c F ≤ 5 0 0  mse c, 
Q T c F > 5 0 0 mse c  
•  F or P R: P R ≤ 2 0 0 mse c, P R > 2 0 0 mse c  
•  F or Q R S: Q R S ≤ 1 2 0 mse c, Q R S > 1 2 0 msec  
•  F or Q T c F: Q T c F ≤ 3 0 mse c, 3 0 msec < Q T c F ≤ 6 0 mse c, Q T c F >  6 0 msec  
I n di vi d u al Q T c F, P R, Q R S, or Q T c F val u es m eeti n g t hese crit eria will b e fl a g g e d i n t h e data listi n g  
as part of t h e a nal ysis s p ecifi e d i n t h e pla ce b o -c o ntr oll e d S A P .  
 
 
6. 5   
Vit al  Si g ns  
 
A cti v e treat m e nt p eri o d baseli n e will b e use d  f or t h e vital si g n s u m mari es. 
Vital si g n para m et ers i n cl u de b o d y t e m p erat ur e, s yst olic bl o o d pr ess ure, diast oli c bl o o d press ur e, 
heart rat e, res pirati o n rate a n d wei g ht. T he d escri pti v e statisti cs f or a ct u al  val u es  will b e 
s u m mariz e d b y all t h e visit s i n t h e c o m bi ne d a cti v e treat m e nt ( pla c e b o -c o ntr oll e d a n d O L E) p eri o d . 
T he n u m b er of s u bj e cts, m ea n, sta n dar d d e viati o n, m e dia n, mi ni m u m a n d m a xi m u m will b e 
pr ese nt e d at ea c h visit. Li n e pl ots  of m ea n vital si g n o v er ti m e b y O L E  tr eat m e nt gr o u p will b e 
pr o vi d e d  f or t h e c o m bi n e d pla c e b o-c o ntr oll e d a n d O L E  p eri o d.  
S u m mar y of c ha n ge fr o m baseli n e i n cl u di n g n u m ber of s u bj e cts, m ea n, sta n dar d d e viati o n, m e dia n, 
mi ni m u m a n d ma xi m u m val u es will b e s u m mari z e d i n t h e a cti ve tr eat m e nt ( pla ce b o -c o ntr oll e d a n d 
O L E) p eri o d . Pla c e b o-c o ntr oll e d baseli n e will b e use d f or earl y start s u bj e cts a n d a cti ve tr eat m e nt 
peri o d  baseli n e will b e use d f or lat e start s u bj e cts.  


 
3 4  
 2 5 1 P P 3 0 1 O L E S A P  
Versi o n 1. 0  
 
T he a nal ysis of vital si g ns will als o f o c us o n t he i n ci d e n ce of cli ni call y r el e v a nt o utli ers base d o n 
t h e f oll o wi n g crit eria. T h e i n ci d e n c e a n d p er c e nta g e of cli nicall y r el e va nt o utli ers deter mi n e d b y 
ea c h crit eri o n will b e s u m mari z e d  i n t h e a cti v e tr eat m e nt ( pla c e b o -c o ntr olle d a n d O L E) p eri o d  b y 
treat m e nt gr o u p. A listi n g of s u bj e cts wit h cli ni call y r ele va nt vital si g ns will b e pr o vi d e d as part of 
t h e a nal ysis s p e cifie d i n t he pla c e b o-c o ntr oll e d S A P . 
 
 
T a ble 1 2 : Crite ri a Use d t o Assess P ote nti al Cli nic all y Rele v a nt O utlie rs i n Vit al Si g ns  
V ari a bl e  
L o w  
Hi g h  
S yst oli c Bl o o d Press ure  
< 9 0 m m H g or > 2 0 m m H g 
decreas e fr o m B aseli ne ( B L)  
> 1 8 0 m m H g or > 2 0 m m H g 
i ncrease fr o m B L 
Di ast oli c Bl o o d Press ure  
< 5 0 m m H g or > 1 5 m m H g 
decreas e fr o m B L  
> 1 0 5 m g H g or > 1 5 m m H g 
i ncrease fr o m B L 
He art R at e  
< 5 0 b p m or >  1 5 b p m d ecr ease fr o m 
B L  
> 1 2 0 b p m or >  1 5 b p m i ncr ease 
fr o m B L 
Te m per at ure  
> 2 de gree C decrease fr o m B L  
> 3 8. 5 C or > 2 de grees C  i ncrease 
fr o m B L 
R es pirati o n R ate  
< 1 0 breat hs per mi n ute or >  5 0 % 
decreas e fr o m B L  
> 2 5 breat hs per mi n ute or > 5 0 % 
i ncrease fro m B L  
Wei g ht  
> 7 % decrease fr o m B L  
> 7 % i ncrease fr o m B L  
B L = baseli ne; b p m = beats per mi n ute  
 
 
Visit wi n d o ws f or b y visit s u m m aries  
F or vital si g n b y visit s u m mari es, t h e a nal ysis visit s h o ul d b e d efi ne d usi n g wi n d o ws (see T a bl e s 1 3  
a n d 1 4 b el o w). If t h ere is m or e t ha n 1 val u e i n t he sa m e a nal ysis visit wi n d o w f or a certai n 
para m et er f or a s u bj e ct, t h e n t he cl osest r ec or d t o t h e tar g et  visit da y will b e use d f or t he b y visit 
a nal ysis.  If t h er e ar e 2 val u es i n t he sa m e a nal ysis visit wi n d o w wit h t h e sa m e dista nc e fr o m t he 
tar g et visit da y f or a certai n para m et er f or a s u bj e ct, t he n t h e r e c or d wit h t h e later dat e will b e use d 
f or t h e b y visit a nal ysis.   
 
T a bl e 1 3 : Vi sit Wi n d o w s f or Vit al Si g n b y Vi sit S u m m ari e s f or BII B 0 9 2 E arl y St art S u bj e ct s 
A n al ysis visit  
T ar g et visit d a y  A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e ce nt n o n -missi n g val u e pri or t o t he 
first d ose of st u d y dr u g i n t he P C d osi n g 
peri o d  
We e k 4  
2 9            
[1 ( p ost-d ose o nl y) , 4 2] 
We e k 8  
5 7  
[ 4 3, 7 0] 
We e k 1 2  
8 5  
[ 7 1, 9 8] 
We e k 1 6  
1 1 3  
[ 9 9, 1 2 6] 
We e k 2 0  
1 4 1  
[ 1 2 7, 1 5 4] 
We e k 2 4  
1 6 9  
[ 1 5 5, 1 8 2] 
We e k 2 8  
1 9 7  
[ 1 8 3, 2 1 0] 
We e k 3 2  
2 2 5  
[ 2 1 1, 2 3 8] 
We e k 3 6  
2 5 3  
[ 2 3 9, 2 6 6] 
We e k 4 0  
2 8 1  
[ 2 6 7, 2 9 4] 


 
3 5  
 2 5 1 P P 3 0 1 O L E S A P  
Versi o n 1. 0  
 
A n al ysis visit  
T ar g et visit d a y  A n al ysis visit wi n d o w  
We e k 4 4  
3 0 9  
[ 2 9 5, 3 2 2] 
We e k 4 8  
3 3 7  
[ 3 2 3, 3 5 0] 
We e k 5 2  
3 6 5  
[ 3 5 1, 3 7 8 ] 
We e k 5 6  
3 9 3  
[3 7 9,  4 0 6 ] 
We e k 6 0  
4 2 1  
[ 4 0 7, 4 3 4] 
We e k 6 4  
4 4 9  
[4 3 5, 4 6 2]  
We e k 6 8  
4 7 7  
[ 4 6 3, 49 0]  
We e k 7 2  
5 0 5  
[ 49 1, 5 1 8 ] 
We e k 7 6  
5 3 3  
[ 5 19 , 5 4 6]  
We e k 8 0  
5 6 1  
[ 5 4 7, 5 7 4]  
We e k 8 4  
5 8 9  
[ 5 7 5, 6 0 2] 
We e k 8 8  
6 1 7  
[ 6 0 3, 6 3 0] 
We e k 9 2  
6 4 5  
[ 6 3 1, 6 5 8] 
We e k 9 6  
6 7 3  
[ 6 5 9, 6 8 6] 
We e k 1 0 0  
7 0 1  
[ 6 8 7, 7 1 4] 
We e k 1 0 4  
7 2 9  
[ 7 1 5, 7 4 2] 
We e k 1 0 8  
7 5 7  
[ 7 4 3, 7 7 0] 
We e k 1 1 2  
7 8 5  
[ 7 7 1, 7 9 8] 
We e k 1 1 6  
8 1 3  
[ 7 9 9, 8 2 6] 
We e k 1 2 0  
8 4 1  
[ 8 2 7, 8 5 4] 
We e k 1 2 4  
8 6 9  
[ 8 5 5, 8 8 2] 
We e k 1 2 8  
8 9 7  
[ 8 8 3, 9 1 0] 
We e k 1 3 2  
9 2 5  
[ 9 1 1, 9 3 8] 
We e k 1 3 6  
9 5 3  
[ 9 3 9, 9 6 6] 
We e k 1 4 0  
9 8 1  
[ 9 6 7, 9 9 4] 
We e k 1 4 4  
1 0 0 9  
[ 9 9 5, 1 0 2 2] 
We e k 1 4 8  
1 0 3 7  
[ 1 0 2 3, 1 0 5 0] 
We e k 1 5 2  
1 0 6 5  
[ 1 0 5 1, 1 0 7 8] 
We e k 1 5 6  
1 0 9 3  
[ 1 0 7 9, 1 1 0 6] 
We e k 1 6 0  
1 1 2 1  
[ 1 1 0 7, 1 1 3 4] 
We e k 1 6 4  
1 1 4 9  
[ 1 1 3 5, 1 1 6 2] 
We e k 1 6 8  
1 1 7 7  
[ 1 1 6 3, 1 1 9 0] 
We e k 1 7 2  
1 2 0 5  
[ 1 1 9 1, 1 2 1 8] 
We e k 1 7 6  
1 2 3 3  
[ 1 2 1 9, 1 2 4 6] 
We e k 1 8 0  
1 2 6 1  
[ 1 2 4 7, 1 2 7 4] 
We e k 1 8 4  
1 2 8 9  
[ 1 2 7 5, 1 3 0 2] 
We e k 1 8 8  
1 3 1 7  
[ 1 3 0 3, 1 3 3 0] 
We e k 1 9 2  
1 3 4 5  
[ 1 3 3 1, 1 3 5 8] 
We e k 1 9 6  
1 3 7 3  
> = 1 3 5 9  
T ar get visit da y a n d A nal ysis visit wi n d o w ar e cal c ulat e d r elati v e t o t h e da y of first 
d ose of st u d y dr u g ( BII B 0 9 2 or pla c e b o) i n t h e P C d osi n g p eri o d.  
 
 
 


 
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T a bl e 1 4 : Vi sit Wi n d o w s f or Vit al Si g n b y Vi sit S u m m ari e s f or BII B 0 9 2 L at e St art s u bj e ct s 
A n al ysis visit  
T ar g et visit d a y  A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e ce nt n o n -missi n g val u e pri or t o t he 
first d ose of st u d y dr u g i n t he O L E d osi n g 
peri o d  
We e k 4  
2 9            
[1 ( p ost-d ose o nl y) , 4 2] 
We e k 8  
5 7  
[ 4 3, 7 0] 
We e k 1 2  
8 5  
[ 7 1, 9 8] 
We e k 1 6  
1 1 3  
[ 9 9, 1 2 6] 
We e k 2 0  
1 4 1  
[ 1 2 7, 1 5 4] 
We e k 2 4  
1 6 9  
[ 1 5 5, 1 8 2] 
We e k 2 8  
1 9 7  
[ 1 8 3, 2 1 0] 
We e k 3 2  
2 2 5  
[ 2 1 1, 2 3 8] 
We e k 3 6  
2 5 3  
[ 2 3 9, 2 6 6] 
We e k 4 0  
2 8 1  
[ 2 6 7, 2 9 4] 
We e k 4 4  
3 0 9  
[ 2 9 5, 3 2 2] 
We e k 4 8  
3 3 7  
[ 3 2 3, 3 5 0] 
We e k 5 2  
3 6 5  
[ 3 5 1, 3 7 8] 
We e k 5 6  
3 9 3  
[ 3 7 9, 4 0 6] 
We e k 6 0  
4 2 1  
[ 4 0 7, 4 3 4] 
We e k 6 4  
4 4 9  
[4 3 5, 4 6 2]  
We e k 6 8  
4 7 7  
[ 4 6 3, 49 0]  
We e k 7 2  
5 0 5  
[ 49 1, 5 1 8 ] 
We e k 7 6  
5 3 3  
[ 5 19 , 5 4 6]  
We e k 8 0  
5 6 1  
[ 5 4 7, 5 7 4] 
We e k 8 4  
5 8 9  
[ 5 7 5, 6 0 2] 
We e k 8 8  
6 1 7  
[ 6 0 3, 6 3 0] 
We e k 9 2  
6 4 5  
[ 6 3 1, 6 5 8] 
We e k 9 6  
6 7 3  
[ 6 5 9, 6 8 6] 
We e k 1 0 0  
7 0 1  
[ 6 8 7, 7 1 4] 
We e k 1 0 4  
7 2 9  
[ 7 1 5, 7 4 2] 
We e k 1 0 8  
7 5 7  
[ 7 4 3, 7 7 0] 
We e k 1 1 2  
7 8 5  
[ 7 7 1, 7 9 8] 
We e k 1 1 6  
8 1 3  
[ 7 9 9, 8 2 6] 
We e k 1 2 0  
8 4 1  
[ 8 2 7, 8 5 4] 
We e k 1 2 4  
8 6 9  
[ 8 5 5, 8 8 2] 
We e k 1 2 8  
8 9 7  
[ 8 8 3, 9 1 0] 
We e k 1 3 2  
9 2 5  
[ 9 1 1, 9 3 8] 
We e k 1 3 6  
9 5 3  
[ 9 3 9, 9 6 6] 
We e k 1 4 0  
9 8 1  
[ 9 6 7, 9 9 4] 
We e k 1 4 4  
1 0 0 9  
> = 9 9 5  
A nal ysis Visit, T ar g et visit da y a n d A nal ysis visit wi n d o w ar e cal c ulate d r el ati v e t o 
t h e da y of first d ose of st u d y dr u g i n t h e O L E d osi n g  p eri o d. . 
 
6. 6   
P h ysic al E x a mi n ati o n  
 
P h ysi cal e xa mi nati o n data will b e list e d .  


 
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6. 7   
Ne ur ol o gic al E x a mi n ati o n  
 
Ne ur ol o gi cal e xa mi nati o n  data will b e list e d .  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
6. 9   M RI Res ults  
 
Ne w 
p ost -baseli n e 
M RI fi n di n gs 
will 
b e s u m mariz e d f or  ( 1) 
mi cr o h e m orr ha g es, ( 2) 
ma cr o h e m orr ha ges, ( 3) s u perfi cial si d er osis a n d ( 4) vas o g e nic e d e ma .   N e w fi n di n gs ar e defi ne d as 
fi n di n gs t hat wer e n ot pr ese nt i n t h e pr e vi o us sca n, or t hat ha ve i n crease d i n siz e c o m par e d t o t h e 
pr e vi o us sca n . 
A b y -s u bj e ct listi n g of M RI r es ults is pro vi d e d f or e nr oll e d s u bj ects  wit h n e w safet y fi n di n gs (i. e., 
t h ose wit h a “ Yes” r es p o nse t o t he n e w safet y fi n di n gs q u esti o n at a n y ti m e d uri n g t h e st u d y)  as part 
of t h e a nal ysis s p e cifie d i n t he pla c e b o -c o ntr oll e d S A P . 
7  
 
P H A R M A C O KI N E TI C D A T A  
 
Ser u m  sam ples  will  b e  co ll ecte d a t pr ot o c ol  d e si g na t e d tim es for BII B 0 9 2  p h ar m a c o ki n etic  
assess m e nts fr o m s u bj ects i n t h e ser u m P K a nal ysis p o p ulati o n.  C S F sa m pl es  will  be  c o ll e ct e d 
a t pr ot o c ol  d e si g na t e d tim es for BII B 0 9 2  C S F  p har m a c o ki n etic assess m e nts  fr o m s u bje cts i n 
t h e C S F P K a nal ysis p o p ulati o n . 


 
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7. 1 0   
C S F  C o nc e ntr ati o n  D a t a 
 
T he C S F P K a nal ysis p o p ulati o n will b e use d f or t h e a nal ysis of C S F c o n c e ntrati o n data.  
 
C S F  c o n ce ntrati o ns fr o m 2 5 1 P P 3 0 1 will be liste d a n d s u m mari z e d b y tr eat m e nt gr o u p a n d visit.  
S u m mar y statisti cs of C S F N -t er mi nal ta u at W e e k s 0, 5 2 a n d 1 0 0  will b e s u m mari z e d b y 
treat m e nt i n t h e a cti v e tr eat m e nt ( pla c e b o -c o ntr oll e d a n d O L E ) p eri o d . T h e r elati o ns hi p b et we e n 
C S F BII B 0 9 2  c o n ce ntrati o ns a n d C S F N -t er mi nal ta u c ha n ges at W e e ks 0, 5 2  a n d 1 0 0  will be 
e x pl or e d gra p hi call y.   
 
C S F c o n ce ntrati o ns  al o n g wit h  th e sc h e d ul e d ( n om i nal) a n d a ct u al  sa m pli n g tim es (i. e.,  tim e  fro m  
d osi n g) will  b e list e d ( w h e n a p pli cab l e) fo r ea c h s ub ject,  gr o u p , a n d da y. Di ffer e n c es b et we e n  
sc h e d ul e d a n d a ct u a l sa m pli n g  ti m es will  als o  b e  list e d for all  s u bjects. P e rc e nta g e di ffer e n c e s 
bet wee n  a ct u a l a d m i nist ere d  d ose a n d  n o m i nal d ose will  a ls o b e liste d.  
 
C S F c o n ce ntr a ti o ns b elo w  t h e l o wer lim it of  q u a n tifi ca ti o n (L L O Q) will  b e  i n dicat e d b y “ B L Q”. 
F or t he  p ur p ose of cal c ulati n g  t y pi cal d escri p tiv e  statisti cs ( n, m ea n,  S D, % C V, g e o m etri c  m ea n, 
ge o m etri c % C V,  m e dia n, m ini m u m,  a n d m a xi m u m ) for C S F c o n c e ntrati o ns,  all B L Q val u es will b e  
set t o half t h e L L O Q val u e . Mea n  C S F c o n c e nt rati o ns  t ha t a re  B L Q will  b e  pr ese n t e d as B L Q, a n d 
t h e S D a n d  % C V will  be  re p ort e d as  n ot  a p pli ca bl e.  S u m m ar y sta tistic s of  t h e C S F c o n c e ntrati o ns  
will  b e  ta b ulate d  b y d a y a n d sc he d ule d  tim e  p oi nt.  At t h e discr eti o n of  t he p harm a c o ki n eti cist  
a n d/ or  bi ostatisti cia n,  sam pl es  ma y  b e  e xcl u d e d  fr o m descri p tiv e  statistics  if t h er e ar e lar ge 
de viati o n s bet w e e n sc h e d ul e d a n d a ct u al sam pl in g  da ys or ti m es, or lar g e d e viati o ns  b et we e n  a ct u al 
d ose a n d  n o m inal  d ose.  
 
Be ca use t o o fe w patie nts will ha v e r ea c he d W e e k 1 0 0 at t he ti m e of i nteri m a nal ysis data base l oc k, 
t h e C S F PK a nal ysis will n ot b e c o n d u ct e d  f or t he p ur p oses of t his i nt eri m a nal ysis. 
 
7. 1 1   
Se r u m  P h ar m ac o ki netics  
 
 
T he P K P o p ulati o n will be use d f or all listi n gs, s u m maries, a n d statistical a n al yses. A nal ysis will 
i n cl u d e all vali d data i n t h e P K dataset f or BII B 0 9 2  i n t h e a cti v e tr eat m e nt ( pla ce b o -c o ntr oll e d a n d 
O L E ) p eri o d . 
I n t his st u d y, a d diti o nal sa m ples f or ser um P K , r eferr e d t o as “ e v e nt dri v e n” sa m ples, ma y b e 
c oll e ct e d f or s u bj e cts wit h h y p erse nsiti vit y e v e nts. Data fr o m t h ese sa m pl es will b e c o nsi d er e d part 
of a s u bj ect’s o v erall  ser u m P K assess m e nt.  
S u bj e ct  ser u m BII B 0 9 2  c o n c e ntrati o ns will be list e d a n d s u m mari z e d b y tr e at m e nt gr o u p a n d visit .  
T he i n di vi d u al ser u m P K para meter C tr o u g h will b e list e d f or BII B 0 9 2  i n cl u di n g a n y e xcl usi o ns a n d 
reas o ns f or e x cl usi o ns. S u m mar y statisti cs will b e ta b ulate d b y tr eat m e nt gr o u p a n d visit. Pl ots of 
i n di vi d u al Ctr o u g h o v er ti m e ma y  be pr o vi de d. O verla ys of i n di vi d u al C tr o u g h o ver ti m e ma y  b e 
pr o vi d e d b y tr eat me nt. Pl ots of m ea n ( + S E ) Ctr o u g h v ers us ti me will be prese nt e d b y tr eat m e nt 
gr o u p. G e o m etri c m ea ns a n d c o effi ci e nts of variati o n will als o b e pr ese nt e d  f or Ctr o u g h. 
 
 
 


 
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ge o m etri c % C V, me dia n,  m ini m u m , a n d ma xi m u m ) f or ser u m c o nc e ntrati o ns, B L Q val u e pr e da y 
1 of st u d y tr eat m e nt will be set t o 0, all  p ost first d ose of st u d y treat me nt B L Q val u es  will  b e set t o 
half t h e L L O Q val u e . M ea n  ser u m c o n ce ntra ti o ns t ha t a re  B L Q will  be  pr es e n t e d as B L Q, a n d t h e 
S D a n d  % C V will  be  re p ort e d as  n ot  a p pli ca bl e.  S u m m ar y sta tistic s of  t he ser u m c o n c e ntrati o ns 
will b e ta b ulate d b y gr o u p , da y, a n d sc h e d ule d ti m e p oi nt. At t he discreti o n of t h e 
p har ma c o ki n eti cist a n d/ or bi ostatisti cia n, sa m pl es ma y b e e x cl u d e d fr o m d escri pti v e statisti cs if 
t h er e ar e lar g e de viati o ns b et we e n sc h e d ul e d a n d a ct u al sa mpli n g ti m es, or l ar ge d e viati o ns 
bet wee n a ct u al d ose a n d n o mi nal d ose.  
 
M ea n ( ± S E) ser u m c o n ce ntrati o n  vs. ti m e  (sc h e d ule d) pr ofil es  f or t h e treat m e nt gr o u p will  b e  
p rese nt e d gr a p hi call y  o n li n ear  a n d sem il o garit h mi c scal es. S er u m  c o n ce ntrati o n vs.  tim e  (a ct u al) 
pr ofil es  fro m  Da y 1 t o  W e e k 1 0 0,  f or ea c h s u bj e ct, ma y b e pr o vi d e d. Sa m pl es  m a y  be  e x cl u de d 
fr o m t h e m ea n pl ots  if t h er e are lar g e d e viati o ns bet wee n  sc h e d ul e d a n d a ct u al sam pli n g  tim es, 
or lar g e  d e viati o ns  b et we e n  a ct u al  d ose a n d  n o m i nal d ose.  
 
 
 
8  
 
A N TI -D R U G A N TI B O D Y  D A T A  
 
A nal yses  f or a nti -dr u g a nti b o di es ( A D As)  will  b e base d  o n  s u bje cts i n th e A D A p o p ulati o n, 
defi n e d as s u bj e cts i n t h e safet y p o p ulati o n  w h o  ha d  at  l east o n e p ost -d ose  e val u ati o n f or 
A D A s.  
 
A cti v e treat m e nt p eri o d baseli n e will b e use d  f or A D A. If baseli n e is missi n g t h e n it will  b e  
im p ut e d  as  n e gati v e.  
 
T he f oll o wi n g d efi niti o ns will b e use d i n t he a nal ysis of A D A data:  
 
•  Treat m e nt e m er ge nt p ositi v e : 
− A p ost -baseli n e s u bj e ct sa m pl e t hat is p ositi ve w he n t h e baseli n e sa m pl e is n e gati v e ; or 
− A p ost - baseli n e s u bj e ct sa m pl e t hat has a tit er gr eater t ha n or e q u al t o 4 ti m es  t h e baseli n e 
sa m ple tit er w h e n t he baseli ne sa m pl e is p ositi v e. If t h e tit er val u e is n ot a vaila bl e f or a 
p ositi v e baseli n e r es ult, t h e n t h e baseli n e titer val u e will b e i m p ute d as t h e mi ni m u m r e q uir e d 
dil uti o n ( M R D) ; or 
− A p ositi v e p ost -baseli n e res ult w her e  n o tit er  is a vaila bl e, r e gar dl ess of baseli n e val u e 
•  Persist e ntl y p ositi v e : T w o or m or e tr eat m e nt e m er g e nt p ositi v e A D A r es ults, w h er e t h e ti m e 
bet wee n t h e first a n d last p ositi v e res ults is 1 6 wee ks or m or e ; or if t h er e are n o f urt her sa m pl es 
a vaila bl e  1 6 we e ks or m or e f oll o wi n g a tr eat me nt e m er g e nt p ositi ve r es ult (i n cl u di n g t h e O L E 
peri o d) . 
•  Tra nsi e ntl y p ositi v e : m or e t ha n o n e treat m e nt-e m er g e nt p ositi v e e val u ati o n, l ess t ha n 1 6 we e ks 
a part, or a si n gl e treat m e nt e m er g e nt p ositi v e ( n ot i n cl u di n g pr etreat m e nt) w h e n t h er e ar e sa m pl es 
a vaila bl e 1 6 we e ks or m ore f oll o wi n g t he p ositi ve r es ult.  
 
T he  n u m ber  a n d p er c e nta g e  of  s u bje cts wit h  a n y sa m ple t hat t este d p ositi v e i n t h e A D A  assa y 
(i n cl u di n g at baseli n e), a n d t h e n u m b er a n d p er c e nta g e of s u bj e cts wit h o ut a n y p ositi v e p ost -
treat m e nt r es ult (r e gar dl ess of baseli ne) will be prese nt e d . Th e n u m b er of s u bj e cts wit h tr eat m e nt  
e m er g e nt p ositi v e  at ea c h  vi sit a n d  at a n y ti me p ost -baseli n e  will  b e  pr ese nte d; t h e  n u m ber  a n d 
perc e nta ge  of  s u bje cts wit h  p er sist e ntl y p ositi v e r es p o nse a n d s u bj e cts wit h  tra nsi e ntl y p ositi v e 
res p o nses will  b e pr ese nt e d  sim ilarl y. 


 
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I n t his st u d y, a d diti o nal sa m ples f or A D A, r eferr e d t o as “ e v e nt dri v e n” sa m pl es, ma y b e  c oll ecte d 
f or s u bj ects wit h h y p erse nsiti vit y e v e nts. Data fr o m t h ese sa m pl es will b e c o nsi der e d part of a 
s u bje ct’s o v erall A D A assess me nt.  
 
Ass ociati o ns of A D A  wit h P K a n d/ or sel e ct A Es ma y be e x pl or e d . 
 
 
9  
S A M P L E  SI Z E  C O N SI D E R A TI O N S  
All s u bj e cts w h o parti ci pat e d i n t h e pla c e b o -c o ntr oll e d p eri o d a n d m et t h e crit eria f or O L E  p eri o d 
will b e eli gi bl e t o e nt er i nt o t he O L E  p eri o d.  
 
1 0   Refe r e nc es  
 
B o xer A L, La n g A E, Gr oss ma n M, et al. Da v u neti d e i n pati e nts wit h pr o gressi v e s u pra n u clear 
pals y: a ra n d o mise d, d o u bl e -bli n d, pla c e b o -c o ntr olle d p hase 2/ 3 trial. La nc et Ne ur ol. 
2 0 1 4; 1 3( 7): 6 7 6 -8 5. E p u b 2 0 1 4/ 0 5/ 2 7.  
 
Car p e nter J R, R o g er J H, Ke n war d M G. A nal ysis of l o n git u di nal trials wit h pr ot o c ol d e viati o n: a 
fra m e w or k f or r el e va nt, a c c essi bl e ass u m pti o ns, a n d i nfer e n c e via m ulti ple i m p utati o n. J Bi o p har m 
Stat. 2 0 1 3; 2 3( 6): 1 3 5 2 -7 1.  
 
D ola n P. M o d eli n g val u ati o ns f or E ur o Q ol h ealt h states. Me di cal Care 1 9 9 7: 3 5: 1 0 9 5 -1 1 0 8.  
I C H E 9 ( R 1): A d d e n d u m t o statisti cal pri n ci pl es f or cli ni cal trials o n c h o osi n g a p pr o priate 
esti ma n ds a n d d efi ni n g se nsiti vit y a nal yses i n cli nical trials . E n d orse d b y t h e I C H Ste eri n g 
C o m mitte e. 2 0 1 4.  
 
I C H E 9 ( R 1): A d d e n d u m o n Esti ma n ds a n d S e nsiti vit y A nal ysis i n Cli ni cal Trials t o t h e G ui d eli n e 
o n Statisti cal Pri n ci pl es f or Cli ni cal Trials. E ur o p ea n M e di ci nes A g e n c y. 2 0 1 7.  
 
Li, K. H. ( 1 9 8 8), "I m p utati o n Usi n g Mar k o v C hai ns,"  J o ur n al of St atistic al C o m p ut ati o n a n d 
Si m ul ati o n , 3 0, 5 7– 7 9.  
 
Lit tl e, R.J. A. ( 1 9 9 3). Patt er n‑ mi xt ur e m o d els f or m ulti variat e i n c o m pl et e data. J o ur n al of t h e  
A meric a n St atistic al Ass o ci ati o n, 8 8 , 1 2 5-1 3 4.  
 
Littl e, R.J. A. ( 1 9 9 4). A class of patter n ‑ mi xt ure m o d els f or n or mal missi n g data. Bi o metrik a,  
8 1 , 4 7 1-4 8 3 . 
 
R u bi n, D. B. ( 1 9 7 6) “I nfere n c e a n d missi n g data.” Bi o m etri k a, 6 3( 3), 5 8 1 -5 9 2.  
 
R u bi n D. B. M ulti pl e I m p utati o n f or N o nres p o nse i n S ur ve ys. J o h n Wil e y & S o ns. 1 9 8 7.  
 
Sc hafer J. L. A nal ysis of I n c o m plete M ulti variate Data. C ha p ma n a n d Hall, Ne w Y or k. 1 9 9 7.  
 
S ha w J W, J o h ns o n J A, C o o ns SJ. U. S. Val u ati o n of t h e E Q -5 D Healt h St ates:  D e v el o p m e nt a n d 
T esti n g of t h e D 1 Val u ati o n M o d el. Me di cal Care. 2 0 0 4.  


 
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Versi o n 1. 0  
 
 
T he S h ort -F or m -3 6 Healt h S ur ve y. Ra n d C or p orati o n a n d J o h n E. War e Jr., 1 9 9 0, re vise d 1 9 9 6.  
 
va n Gi n k el, J. R., Sijts ma, K., va n der Ar k, L. A., & Ver m u nt, J. K. ( 2 0 1 0). I n ci d e n c e of missi n g 
ite m sc or es i n p ers o nalit y m eas ur e m e nt, a n d si m pl e it e m-sc or e i m p utati o n. Met h o d ol o g y: 
E ur o p e a n J o ur n al of Rese arc h Met h o ds f or t h e Be h a vi or al a n d S o ci al S cie nc es, 6 ( 1), 1 7-3 0.  
 
Ya n, X., Le e, S., a n d Li, N. ( 2 0 0 9), “ Missi n g data ha n dli n g met h o ds i n m e di cal d e vic e cli ni cal 
trials,” J o ur nal of Bi o p har ma ce uti cal Statisti cs, 1 9( 6), 1 0 8 5-1 0 9 8.  
 
Z u c k er, D. M., Wittes, J. T., Sc ha b e n ber g er, O. a n d Brittai n, E. I nt er nal pil ot st u di es II:  c o m paris o n 
of vari o us pr o c e d ur es. Statisti cs i n M e dici n e. 1 9 9 9; 1 8: 3 4 9 3 – 3 5 0 9.  
 
 
 
1 1  A p pe n di x  
 
1 1. 1  A d v e rse e v e nt of s pe ci al i nte r est  se ar c h 
 
T he f oll o wi n g sear c h will b e p erf or m e d  usi n g M e d D R A 2 2. 0.  
 
•  A na p h yla cti c r ea cti o n S M Q narr o w  a n d br oa d  
•  A n gi o e d e ma S M Q narr o w a n d br oa d  
•  Se v er e c uta n e o us a d v erse r ea cti o ns S M Q narr o w a n d br oa d  
•  E osi n o p hilia ( P T t er ms: E osi n o p hilia; E osi n o p hil c o u nt i n cr ease d;  All er gi c e osi n o p hilia ; 
P ul m o nar y e osi n o p hilia ) 
•  Miscella n e o us t er ms  
o  C yt o ki n e release s y n dr o m e P T  
o  I nf usi o n relate d rea cti o n P T 
o  I nf usi o n sit e r ea cti o n P T 
o  Aller gi c c o n diti o ns N E C H L T  
o  Dr u g h y p erse nsiti vit y P T  
o  D o c u m e nt e d h y perse nsiti vit y t o a d mi nist er e d pr o d u ct P T  
o  Vasc ulitis P T  
o  S yst e mi c L u p us er yt he mat os us P T  
o  R h e u mat oi d art hritis P T  
o  A nti b o d y t est p ositi ve P T  
o  A nti b o d y t est a b n or mal P T  
o  A nti b o d y t est P T  
o  Dr u g s p e cific a nti b o d y prese nt P T  
o  Ne utrali si n g a nti b o di es P T 
o  Ne utralisi n g a nti b o di es p ositi v e P T  
o  N o n -n e utralisi n g a nti b o di es p ositi v e P T  
 
 
 
 


 
4 2  
 2 5 1 P P 3 0 1 O L E S A P  
Versi o n 1. 0  
 
1 1. 2  I nf usi o n r e acti o ns c ust o m se ar c h  
 
T he f oll o wi n g pr eferr e d t er ms ar e c o nsi d er e d  as part of t h e c ust o m M e d D R A sear c h ( versi o n 2 2. 0) 
f or i nf usi o n r ea cti o ns: 
 
•  I nf usi o n sit e r ea cti o n 
•  I nf usi o n sit e ras h 
•  I nf usi o n sit e der matitis 
•  I nf usi o n sit e h y p erse nsiti vit y 
•  I nf usi o n sit e p h ot ose nsiti vit y r ea cti o n 
•  I nf usi o n sit e urti caria 
•  I nf usi o n sit e e cz e ma  
•  I nf usi o n sit e vasc ulitis 
•  I nf usi o n sit e r e call r ea cti o n 
•  I nf usi o n relate d rea cti o n 
•  A d mi nistrati o n site ras h  
•  A d mi nistrati o n site d er matitis  
•  A d mi nistrati o n site ec z e ma  
•  A d mi nistrati o n site h y p erse nsiti vit y  
•  A d mi nistrati o n site urti caria  
•  A d mi nistrati o n site p h ot ose nsiti vit y r ea cti o n  
•  A d mi nistrati o n site r ecall r ea cti o n  
•  A d mi nistrati o n site vasc ulitis  
•  A d mi nistrati o n r elat e d r ea cti o n  
•  I nj e cti o n sit e d er matitis 
•  I nj e cti o n sit e h y p erse nsiti vit y 
•  I nj e cti o n sit e ras h 
•  I nj e cti o n sit e urticaria  
•  I nj e cti o n sit e p h ot ose nsiti vit y r ea cti o n 
•  I nj e cti o n sit e e c z e ma 
•  I nj e cti o n sit e r e call r ea cti o n 
•  I nj e cti o n sit e vasc ulitis 
•  I nj e cti o n r elat e d r ea cti o n 
•  I m m e diat e p ost-i nje cti o n rea cti o n 
•  aller gi c r ea cti o n t o e xci pie nt  
•  rea cti o n t o e x ci pi e nt 
•  c yt o ki n e st or m  
•  c yt o ki n e r el ease s y n dr o me  
•  i m m u n e-m e diat e d a d v erse r ea cti o n  
 
 
 
 
 
 
 


2 5 1 P P 3 0 1 
Statistic al A nal ysis Pla n Versi o n 2. 0 
 
1 
St atistic al A n al ysis Pl a n- 
Pl a ce b o- C o nt r olle d Pe ri o d
Versi o n N o.:  2. 0 
St u d y Titl e: A R a n d o mi ze d, D o u ble- Bli n d, Pl ac e b o- C o nt r olle d, P arallel- G ro u p St u d y t o E v al u ate 
t he Effic ac y a n d S afet y of I nt r a ve n o usl y A d mi niste re d BII B 0 9 2 i n P a rtici p a nts w it h P ro g ressi ve 
S u p r a n ucle a r P als y  
Na me of St u d y Tre at me nt: BII B 0 9 2 
Pr ot oc ol N o.:  2 5 1 P P 3 0 1  
St u d y P hase: P hase 2 b 
C o nfi de nti al I nf o r m ati o n 
T h e i nf or m ati o n c o nt ai n e d i n t his St atistic al A n al ysis Pl a n ( S A P) is c o nfi d e nti al a n d m a y n ot b e 
re pr o d u ce d or ot h er wise disse mi n at e d wit h o ut t h e a p pr o v al of Bi o g e n, I nc. 






2 5 1 P P 3 0 1  
 
Statistic al  A n a ly sis Pla n  Versi o n 2 . 0 
 
3  
 
 
T A B L E  O F  C O N T E N T S  
 
 
1  
O V E R VI E W  O F T H E S T U D Y  ................................................................................................ 9  
1. 1 St u d y D e si g n  ........................................................................................................................ 9  
1. 2 N u m b er of P arti ci p a nt s  ...................................................................................................... 1 1  
1. 3 St art of St u d y a n d E n d of St u d y D efi niti o n s  ...................................................................... 1 1  
1. 4 Tr e at m e nt  ........................................................................................................................... 1 1  
2  
D E S C RI P TI O N O F O B J E C TI V E S A N D E N D P OI N T S ........................................................ 1 3  
3  
G E N E R A L  C O N SI D E R A TI O N S  .......................................................................................... 1 6  
3. 1 G e n er al M et h o d s  ................................................................................................................ 1 6  
3. 2 P o p ul ati o n s  ......................................................................................................................... 1 7  
3. 3 Tr e at m e nt gr o u p s f or a n al y si s  ........................................................................................... 1 9  
4  
S T U D Y S U B J E C T S  .............................................................................................................. 1 9  
4. 1 A c c o u nti n g of s u bj e ct s  ....................................................................................................... 1 9  
4. 2 D e m o gr a p h i c a n d  B a s eli n e  Di s e a s e  C h ar a ct eri sti c s  ........................................................ 2 0  
4. 3 St u d y Dr u g E x p o s ur e a n d St u d y Dr u g C o m pli a n c e  .......................................................... 2 1  
4. 4 M e di c ati o n s a n d N o n -dr u g t h er a pi e s  ................................................................................ 2 2  
 
C o n c o mit a nt m e di c ati o n  .......................................................................................... 2 2  
 
Di s all o w e d t h er a pi e s  ............................................................................................... 2 3  
4. 5 Pr ot o c ol  D e vi ati o n s  ............................................................................................................ 2 4  
5  
E F FI C A C Y  D A T A  ................................................................................................................. 2 4  
5. 1 G e n er al C o n si d er ati o n s  ..................................................................................................... 2 4  
 
Vi sit wi n d o w s f or m a p pi n g effi c a c y e n d p oi nt  .......................................................... 2 5  
 
H a n dli n g of mi s si n g it e m s f or s c al e s ....................................................................... 2 7  
 
C o n si d er ati o n s f or m ulti pl e c o m p ari s o n a dj u st m e nt s  ............................................. 2 8  
 
C o n si d er ati o n s f or b a s e M M R M m o d el f or c h a n g e fr o m b a s eli n e a n al y s e s  ......... 2 8  
5. 2 Pri m ar y Effi c a c y E n d p oi nt  .................................................................................................. 2 8  
 
Pri m ar y e n d p oi nt f or U nit e d St at e s ( U S)  ................................................................ 2 9  
 
Pri m ar y e n d p oi nt f or E ur o p e a n d J a p a n  ................................................................. 2 9  
 
Pri m a r y a n al y si s....................................................................................................... 3 0  
 
S e n siti vit y a n al y si s ................................................................................................... 3 0  
 
S u p pl e m e nt ar y a n al y si s  .......................................................................................... 3 2  
5. 3 S e c o n d ar y Effi c a c y E n d p oi nt s  ........................................................................................... 3 5  




2 5 1 P P 3 0 1  
 
Statistic al  A n a ly sis Pla n  Versi o n 2 . 0 
 
5  
7. 1 C S F  C o n c e ntr ati o n  D a t a .................................................................................................... 5 7  
7. 2 S er u m  P h ar m a c o ki n eti c s  ................................................................................................... 5 8  
8  
A N TI -D R U G A N TI B O D Y D A T A  ........................................................................................... 5 8  
9  
S A M P L E  SI Z E  C O N SI D E R A TI O N S  .................................................................................... 6 0  
1 0  
C H A N G E S C O M P A R E D T O V E R SI O N 1  ........................................................................ 6 0  
1 1  
A P P E N DI X  ......................................................................................................................... 6 1  
1 1. 1 S c ori n g m a n u al f or 1 5 -it e m P S P R S ................................................................................ 6 1  
1 1. 2 I m pl e m e nt ati o n of t h e C o p y I n cr e m e nt fr o m R ef er e n c e, J u m p t o R ef er e n c e a n d P att er n 
Mi xt ur e M o d el  ........................................................................................................................... 6 3  
 
C o p y I n cr e m e nt fr o m R ef er e n c e ( CI R)  ................................................................ 6 3  
 
J u m p t o R ef er e n c e ( J 2 R)  ..................................................................................... 6 3  
 
P att er n Mi xt ur e M o d el  .......................................................................................... 6 4  
1 1. 3 A d v er s e e v e nt of s p e ci al i nt er e st c u st o m s e ar c h crit eri a  ............................................... 6 4  
1 1. 4 I nf u si o n r e a cti o n s c u st o m s e ar c h  .................................................................................... 6 5  
1 2  
R E F E R E N C E S  .................................................................................................................. 6 6  
 
 
 
 


2 5 1 P P 3 0 1  
 
Statistic al  A n a ly sis Pla n  Versi o n 2 . 0 
 
6  
A B B R E V IA TI O N S  
 
Te r m  
Defi niti o n  
A D  
Al z h ei mer’s disease  
A E  
a d verse e v e nt  
A E SI  
A d v erse e v e nt of s p ecial i nt erest  
A L T  
ala ni n e  a mi n otra nsferase  
A N C O V A  
a nal ysis of c o varia nc e  
A S T  
as pa rtate a mi n otra nsferase 
B MI  
b o d y mass i n de x  
B U N  
b l o o d ur ea nitr o g e n 
C GI -C  
Cl i nical Gl o bal I m pr essi o n C ha n g e  
C GI -S  
Cli nical Gl o bal I m pr essi o n S e v erit y  
Ci nf  
e n d -of -i nf usi o n ser u m c o n c e ntrati o n 
CI R  
co p y i n cre m e nt fr o m r efer e n c e 
C R F  
case r e p ort f or m,  pa p er or el e ctr o nic  
C S F  
cer e br os pi nal fl ui d  
 
 
C T A  
cli nical trial a gre e me nt  
C T C A E  
C o m m o n T o xi c it y Criteria f or A d v erse E v e nts 
Ctr o u g h  
Tr o u g h ser u m c o n c e ntrati o n 
C T T  
C ol or Trails T est  
E C G  
ele ctr ocar di o gra m  
e C R F  
ele ctr o ni c case r e p ort f or m  
e T a u 
e xtra cell ular ta u  
E ur o Q ol  
E ur o pea n  Q u alit y  of  Life  
 
 
G C P  
G o o d Cli nical Pra cti c e  
I C F 
i nf or m e d c o nse nt f or m 
I C H 
I nt er nati o nal C o nfer e nc e o n Har m o nisati o n 
I E C 
I n d e p e n d e nt Et hics C o m mitt e e  
I N R 
i nt er nati o nal n or mali z e d  rati o 
I P 
i n v esti gati o nal pr o du ct  
I RB  
I nstit uti o nal Re vi e w B oar d 


2 5 1 P P 3 0 1  
 
Statistic al  A n a ly sis Pla n  Versi o n 2 . 0 
 
7  
Te r m  
Defi niti o n  
I R T 
I nt era cti ve R es p o nse T e c h n ol o g y 
I T T 
int e nt -t o-tr eat 
I V 
i ntra v e n o us 
J 2 R 
J u m p t o refer e n ce 
L N S  
Lett er n u m b er se q u e nc e  
L P  
l u m bar p u n ct ure 
Me d D R A  
Me di cal Di cti o nar y f or R e g ulat or y Acti viti es  
M A P T  
mi cr ot u b ul e -ass o ciat e d pr ot ei n ta u  
M C S  
me ntal c o m p o ne nt s u m mar y  
M C M C  
Mar k o v c hai n M o nte Carl o  
M D S -U P D R S  
M o v e me nt Dis or d er S o ci et y -s p o ns or e d r e visi o n of t he U nifi e d Par ki ns o n’s  
 Disease Rati n g S cal e  
M M R M  
mi x e d m o d el r e p eate d m eas ures  
M M S E  
Mi ni -Me ntal Stat e E xa m  
M o C A  
M o ntr e al C o g niti v e  Assess m e nt  
M R I 
ma g n eti c res o na n c e i ma gi n g  
Nf L  
ne ur ofila m e nt li g ht  
O L E  
o p e n la b el e xt e nsi o n  
 
 
P C S  
p ot e ntiall y cli nicall y si g nifi ca nt, p h ysi cal  c o m p o n e nt s u m mar y  
P D  
p har ma c o d y na mi c(s)  
P E  
p h ysical  e xa mi nati o n  
P K  
p har ma c o ki n eti c(s)  
P M M  
patter n mi xt ure m o d el  
 
 
P S P  
pr o gressi v e s u pra n u cl ear pals y 
P S P R S  
Pr o gr essi v e S u pra n u cl ear Pals y  Rati n g S cal e  
P S P -Q o L  
P r o gr essi v e S u pra n u cl ear Pals y Q u alit y of Life scale 
P T  
Preferre d T er m  
Q 4 W  
e v er y 4 we e ks  
Q M A  
q u a ntitati ve m o v e me nt assess m e nts  
 
 


2 5 1 P P 3 0 1  
 
Statistic al  A n a ly sis Pla n  Versi o n 2 . 0 
 
8  
Te r m  
Defi niti o n  
 
R B A N S  
Re peata bl e Batt er y  f or t h e Assess me nt of Ne ur o ps y c h ol o gi cal  Disease  
Se v erit y  
S A E  
seri o us a d v erse e ve nt 
S A P  
statisti cal a nal ysis pla n 
S E A D L  
Sc h wa b a n d E n gla n d Acti viti es of Dail y  Li vi n g  
 
 
S O C  
S yst e m Or ga n Class  
U L N  
u p per li mit of n or mal  
U S  
U nit e d  Stat es  
W AI S -I V 
We c hsl er A d ult I nt elli ge n c e Scal e  - I V 
W H O Dr u g  
W orl d Healt h Or ga nizati o n Dr u g  
W O C B P  
w o me n of c hil d b ea ri n g p ot e ntial 
 
 
 


2 5 1 P P 3 0 1  
 
Statistic al  A n a ly sis Pla n  Versi o n 2 . 0 
 
9  
 
1  
O V E R VI E W  O F T H E S T U D Y  
 
1. 1  St u d y Desi g n  
T he  st u d y d esi g n sc h e matic  is pr ese nt e d  i n Fi g ure  1 . 
Fi g ur e  1 : 
St u d y Desi g n Sc he m atic  
 
T his is a ra n d o miz e d, d o u ble -bli n d, pla c e b o -c o ntr oll e d, parall el -gr o u p st u d y t o e val u at e t h e effi ca c y a n d 
safet y of i ntra ve n o usl y (I V) a d mi nist er e d BII B 0 9 2 i n parti ci pa nts wit h pr o gr essi v e s u p ra n u cl ear pals y 
(P S P ) wit h a n o p e n -la b el e xt e nsi o n. 
O v erall st u d y d esi g n:   T h e  st u d y d esi g n sc he mati c is pr ese nt e d i n Fi g ure  1 .  T h e st u d y will c o nsist of a 
5 2 -we e k d o u bl e -bli n d treat m e nt p eri o d, w hi c h will be f oll o we d b y a l o n g -t er m o p e n la b el e xt e nsi o n 
peri o d f or f oll o w u p.  Parti ci pa nts will b e ra n d o mi z e d t o r e c ei v e BII B 0 9 2 or pla ce b o.  A p pr o xi mat el y 4 5 9 
parti ci pa nts i n t otal will be ra n d o mi ze d i n a 2: 1 rati o t o re c ei v e BII B 0 9 2 or pla ce b o ( 3 0 6 part ici pa nts 
a cti v e or 1 5 3 pla c e b o).  I n t h e d o u ble -bli n d t r eat me nt p eri o d of t h e st u d y, parti ci pa nts will be d ose d 
a p pr o xi mat el y o n c e e v er y 4 wee ks ( Q 4 W) f or a p pr o xi mat el y 4 8 we e ks ( u p t o a t otal of 1 3 ti mes).  At 
We e k 5 2, parti ci pa nts c o m pl eti n g t h e d o u bl e -b li n d tr eat m e nt peri o d ma y c h o ose t o c o nti n u e i nt o t h e ope n -
la b el e xt e nsi o n p eri o d of t his st u d y, i n w hi ch, all parti ci pa nts will r e c ei v e BII B 0 9 2.  Partici pa nts will b e 
d ose d a p pr o xi mat el y o n c e - e v er y 4 wee ks t hr o u g h o ut t h e d urati o n of t he o p e n -la bel e xt e nsi o n p eri o d.  
T he d urati o n of t h e o pe n -la b el e xt e nsi o n will var y d e p e n di n g o n th e dat e of e nr oll me nt of t he partici pa nt 
i n t h e st u d y.  T h e st u d y is e x p ecte d t o c o nti n u e u ntil BII B 0 9 2 is c o m m er ciall y a vaila bl e, t h e de v el o p m e nt 
pr o gra m is t er mi nat e d, or t h e s t u d y is t er mi nat e d at t h e discr eti o n of t h e s p o ns or, w hi c he v er c o mes first. 
St u d y visits:   St u d y visits will b e c o n d u ct e d a p pr o xi mat el y e v er y 4 we e ks.  St u d y dr u g will b e  
a d mi nist ere d a n d safet y, effica c y, a n d ot h e r assess m e nts will b e p erf or m e d.  T h e st u d y will g e n erall y b e 
c o n d u cte d o n a n o ut pati e nt basis u nless s o me pr oc e d ures w o ul d be b ett er p erf or m e d o n  a n i n pati e nt basis 
base d o n t h e n e e ds of t h e parti ci pa nt.  Parti ci pa nts will b e o bser v e d a n d m o nit or e d b y st u d y p ers o n n el f or 
a p pr o xi mat el y 2 h o urs aft er t h e e n d of a n i nf usi o n.  Parti ci p a nts wit h o n g oi n g A Es or seri o us A Es ( S A Es ) 
will r e mai n at t he sit e or b e se nt t o a n i n pati e nt m o nit ori n g fa cilit y u ntil t h e I n v esti gat or has d et er mi n e d 
t hat t h ese e ve nts ha v e r es ol v e d or d o n ot r e q uir e i n pati e nt m o nit ori n g. 
St u d y  assess me nts:  
•  Parti ci pa nts  will b e cl osel y m o nit ore d f or safet y t hr o u g h o ut t h e st u d y.  P h ysi ca l e xa mi nati o ns, 
vital si g n 
m eas ur e m e nts, 1 2 -lea d el e ctr o car di o gra ms ( E C G), a n d cli ni cal la b orat or y 


2 5 1 P P 3 0 1  
 
Statistic al  A n a ly sis Pla n  Versi o n 2 . 0 
 
1 0  
e val u ati o ns, i n cl u di n g assess m e nts f or i m m u n o g e ni cit y  will b e p erf or m e d.  A Es  will b e 
cl o sel y m o nit or e d.  
 
 
•  P S P r elat e d si g ns, s y m pt o ms a n d q u alit y of life will be assesse d usi n g cli nical assess m e nts: 
P S P Rati n g S cal e ( P S P R S), M o v e me nt Dis or der S o ci et y -s p o ns or e d r e visi o n of t he U nifi e d 
P ar ki ns o n’s Disease Rati n g Scal e ( M D S -U P D R S Part II), S c h wa b a n d E n gl a n d Acti viti es of 
Dail y Li vi n g ( S E A D L) scal e, Cli ni cal Gl o bal I m pr essi o n of S e verit y ( C GI -S), Cli ni cal Gl o bal 
I m pr essi o n of C ha n g e ( C GI-C), M o ntr eal C o g niti v e Assess m e nt ( M o C A), 
 
 a n d P S P Q u alit y of Life scale ( P S P-
Q o L) a n d n e ur o ps yc h ol o gical testi n g ( R B A N S, p h o ne mi c fl u e n c y, l ett er -n u m ber se q u e n c i n g, 
a n d c ol or trails t est  ). 
•  Care gi ver b ur d e n will als o b e assesse d 
 
. 
•  Bl o o d will b e c oll e ct e d f or i m m u n o g e ni cit y, P K, P D, a n d e x pl orat or y bi o mar k er a nal ysis fr o m 
ea c h parti ci pa nt d uri n g t his st u d y i n t h e d o u bl e -bli n d p er i o d a n d i n t h e o p e n-la b el e xt e nsi o n 
peri o d.  
•  Str u ct ur al c ha n g es i n brai n r e gi o n s ass o ciat e d wit h P S P disease pr o gr essi on  will b e assesse d 
usi n g M RI.  It is a ntici pat e d t hat ea c h parti ci pa nt will ha v e t otal of 4 M RIs o ver t h e c o urse  of 
t h e st u d y, i n cl u di n g an M RI d uri n g t h e scre e ni n g p eri o d ( u p t o Da y -1 4) a n d at We e ks 2 4, 5 2, 
a n d 1 0 0 . 
•  
 
 
 
 
 
 
•  Parti ci pa nts i n t h e Q M A s u bst u d y will u n d er g o q u a ntitati v e assess m e nts of c or e m ot or 
feat ures of P S P usi n g weara bl e se ns ors t o m eas ure gait , p ost ural i nsta bilit y, m ot or f u ncti o n, 
a n d falls. 
H o me visits:   Aft er  W e e k 2 4, e x ce pt f or t h ose  visits w h e n cli ni cal scales, L Ps, or M RI assess m e nts are 
perf or m e d, visits a n d pr o c e d ur es ma y b e p erf or m e d i n t h e h o m e as l o n g as a p pr o priat e ser vi c es ar e 
a vaila bl e t o p erf or m t h e r e q uir e d st u d y pr o c e d ures a n d a d e q u atel y m o nit or f or p ot e ntial safet y e ve nts.  I n 
t h e d o u bl e-bli n d p eri o d  of t h e st u d y , We e k s 2 8, 3 2, 4 0, a n d 4 4 ma y q u alif y f or h o m e visit s. 
I n t h e o p e n-la bel e xte nsi o n peri o d of t h e st u d y, W ee k  6 8, 7 2, 8 0, 8 4, 9 2, 9 6, 1 0 4, 1 0 8, 1 1 6, 1 2 0, 1 2 8, 1 3 2, 
1 4 0, 1 4 4, 1 5 2, 1 5 6, 1 6 4 , 1 6 8, 1 7 6, 1 8 0, 1 8 8, a n d 1 9 2  visits ma y q u alif y f or a h o m e visit.  H o we ver, i n t h e 
e v e nt t hat t h e partici pa nt e x p eri e n c e d a cli ni call y si g nifi ca nt i nf usi o n r ea cti o n d uri n g t h e f irst 2 4 we e ks 
of t h e pr ot o c ol, t h e parti ci pa nt s h o ul d n ot be a d mi nist er e d BII B 0 9 2 i n t he h o m e u nless pr e vi o usl y 
a p pr o ve d b y t h e S t u d y I n vesti gat or. 
Disc o nti n u ati o n of St u d y  tr eat me nt a n d/ or St u d y 
Wit h dra wal:  Partici pa nts w h o disc o nti n u e st u d y 
treat m e nt may bel o n g t o 1  of t h e f oll o wi n g gr o u ps:   
•  Parti ci pa nts w h o disc o nti n u e st u d y tr e at m e nt b ut r e mai n e nr olle d  u ntil  t h e e n d of t he  st u d y  
•  Parti ci pa nts w h o disc o nti n u e st u d y tr eat m e nt a n d lat er  wit h dra w fr o m t h e st u d y   


2 5 1 P P 3 0 1  
 
Statistic al  A n a ly sis Pla n  Versi o n 2 . 0 
 
1 1  
•  Parti ci pa nts w h o disc o nti n u e st u d y tr eat m e n t a n d i m me diat el y wit h dra w fr o m t h e st u d y  
Parti ci pa nts w h o disc o nti n u e st u d y treat m e nt d uri n g t he d o u ble -bli n d p eri o d of t h e st u d y ( pri or t o W e e k 
5 2) a n d r e mai n e nr oll e d i n t h e st u d y will b e e x p e ct e d t o c o m pl et e t he sc he d ul e d safet y a n d effi ca c y 
e val u ati o ns u ntil t h e e n d of t he st u d y or u ntil t he d e cisi o n is ma d e t o wit h dra w fr o m th e st u d y  (se e S e cti o n 
2  f or sc h e d ul e of e val u ati o ns i n t h e Pr ot o c ol). S A E c olle cti o n will b e u p t o 3 0 da ys aft er t he last d ose of 
st u d y tr eat me nt a n d will c o nti n u e f or as l o n g as t h e partici pa nt r e mai n s e nr olle d i n t h e st u d y .  
Earl y disc o nti n u ati o n visit p r oc e d ures s h o ul d b e c o m pl et e d f or a n y partici pa nt w h o disc o nti n u es st u d y 
treat m e nt a n d als o wit h dra ws fr o m t h e st u d y at a n y ti m e pri or t o e n d of st u d y. A ll S A Es t hat o c c ur u ntil 
3 0 da ys aft er last d ose of st u d y treat m e nt s h o ul d b e m o nit or e d a n d/ or re c or de d . I n t h e d o u bl e-bli n d p eri o d, 
parti ci pa nts w h o wit h dra w fr o m t h e st u d y  s h o ul d b e e n c o ura g e d t o r et ur n t o t h e cli ni c at W e e k 5 2 t o 
c o m pl et e t h e W e e k 5 2 pr o c e d ures.  F urt h er d etails  o n t h e sc h e d ule of assess m e nt is c o ntai n e d i n  S e cti o n 
2  of t h e pr ot o c ol . 
 
1. 2  N u m be r of P artici p a nts  
It is a nti ci pat e d t hat a p pr o xi mat el y 4 5 9 male a n d fe mal e parti ci pa nts will b e d ose d i n t his st u d y.  
A p pr o xi mat el y 4 5 9 parti ci pa nts will b e ra n d o ml y assi g n e d, i n 2: 1 rati o, t o r e cei v e 2 0 0 0 m g of BII B 0 9 2 
or pla c e b o ( 3 0 6 parti ci pa nts a cti v e a n d 1 5 3 pla ce b o) a d mi nis t er e d b y I V a p pr o xi mat el y o n c e Q 4 W.  
Ra n d o mi zati o n is stratifi e d b y c o u ntr y a n d scre e ni n g C ol or Trails T est ( C T T) Part 2 c o m pl eti o n ti m e of  
eit h er ≤ 1 7 0  or > 1 7 0 se c o n ds .  A nti ci pati n g a dr o p o ut rat e of a p pr o xi mat el y 2 5 %, a p pr o xi mat el y 3 4 5 
parti ci pa n ts ( 2 30  parti ci pa nts i n t he BII B 0 9 2 tr eat m e nt gr o u p a n d 1 1 5 partici pa nts i n t h e pla c e b o gr o u p) 
are e x p e ct e d t o c o m pl et e t h e st u d y t hr o u g h We e k 5 2 . 
 
1. 3  St art of St u d y a n d E n d of St u d y Defi niti o n s 
T he date t h e first parti ci pa nt si g ns a st u d y -s p e cifi c i nf or m e d co nse nt  f or m will be d efi n e d as t h e start of 
t h e st u d y.  A partici pa nt is c o nsi d er e d e nr oll e d w h e n t h e st u d y-s p e cific i nf or m e d c o nse nt f or m is si g n e d.  
T he dat e t hat t h e last partici pa nt c o m pl et es t h e last st u d y visit or sc h e d ul e d pr o c e d ure will b e d efi ne d as 
t h e e n d of t he st u d y.  
 
1. 4  Tr e at me nt  
St u d y tr eat m e nt is d efi ne d as a n y i n vesti gati o nal tr eat me nt(s), mar k et e d pr o d u ct(s), pla c e b o or m e di cal 
de vi c e i nte n d e d t o b e a d mi nist er e d t o a st u d y parti ci pa nt a c c or di n g t o t h e st u d y ra n d o mi zati o n or 
treat m e nt all o cati o n  
 
St u d y T re at me nt  
U nit d ose  
st re n gt h(s)/ D os a g e 
le vel(s) 
D os a g e  f or m ul ati o n 
Fre q ue nc y of  
A d mi nist rati o n  
R o ute  of  A d mi nist r ati o n  
BII B 0 9 2  
2 0 0 0  m g  
O nce  e ver y 4  we e ks  
( Q 4 W) 
I V 
Pl ace b o  
Matc hi n g  d ose  v ol u me  
at 0. 9 % Na Cl or  5 % 
De xtr ose  
O nce  e ver y 4  we e ks  
( Q 4 W) 
I V 


2 5 1 P P 3 0 1  
 
Statistic al  A n a ly sis Pla n  Versi o n 2 . 0 
 
1 2  
 
All parti ci pa nts ar e c e ntrall y ra n d o miz e d usi n g a n I nt era cti ve Res p o nse T e c h n ol o g y (I R T). Bef or e t h e 
st u d y is i nitiat e d, ea c h user r ec ei v es l o g i n i nf or mati o n a n d dir ecti o ns o n h o w t o a c c ess t h e I R T. 
Ra n d o mi zati o n is stratifi e d b y c o u ntr y a n d scr e e ni n g C T T Part 2 c o m pleti o n ti m e of eit h er ≤ 1 7 0 or > 
1 7 0 se c o n ds.  
 
 


 
 
1 3  
 
2  
D E S C RI P TI O N O F O B J E C TI V E S A N D E N D P OI N T S  
 
T he o bj ecti ves a n d e n d p oi nts fr o m  t he pr ot oc ol S e cti o n 4  ar e descri b e d bel o w.  
O bje cti v e  
E n d p oi nt  
Pri m ar y  
T o e val u ate t he effi ca c y of BII B 0 9 2, 
c o m par e d t o pla c e b o, as m eas ure d b y a c ha n g e 
fr o m baseli ne i n t h e P S P Rati n g Scal e 
( P S P R S) at W ee k 5 2. 
T he pri mar y effi ca c y e n d p oi nt will b e 
e val u ate d b y c o m pari n g t h e c ha n g e fr o m 
baseli n e i n t he t otal P S P R S sc ore at We e k 5 2 i n 
parti ci pa nts tr eat e d wit h BII B 0 9 2 rel ati v e t o t h e 
c ha n ge fr o m baseli n e i n t he t otal P S P R S sc or e 
i n parti ci pa nts tr eat e d wit h pla c e b o. 
T o assess t h e safet y a n d t ol era bilit y of 
BII B 0 9 2, relati v e t o pla c e b o, b y meas uri n g t h e 
fr e q u e n c y of d eat hs, S A Es, a n d A Es lea di n g t o 
disc o nti n u ati o n, a n d Gra d e 3 & 4 la b orat or y 
a b n or malities.  
T he pri mar y safet y e n d p oi nt will be e val u at e d 
b y ta b ulati n g t h e n u m b ers a n d per c e nta g es of 
deat hs a n d u n i q u e parti ci pa nts wit h S A Es a n d 
A Es l ea di n g t o disc o nti n u ati o n, a n d Gra de 3 & 
4 la b orat or y a b n or maliti es.  
K e y Se c o n d ar y  
T o e val u ate t he effi ca c y of BII B 0 9 2, 
c o m par e d t o pla c e b o, as m eas ure d b y a c ha n g e 
fr o m baseli ne i n t h e M o v e me nt Dis or d er 
S o ci et y -s p o nsor e d re visi o n of t h e U nifi e d 
Par ki ns o n’s Disease Rati n g S cal e ( M D S -
U P D R S) Part II at W e e k 5 2.  
T he i m pa ct of BII B 0 9 2 o n t h e M D S -U P D R S 
Part II will b e e val u at e d relati ve t o t h e c ha n ge 
fr o m baseli ne at W e e k 5 2 i n t h e BII B 0 9 2 -
treat e d parti ci pa nts a n d c o m par e d t o t hat of t he 
pla ce b o -tr eat e d parti ci pa nts. 
T o e val u ate t he effi ca c y of BII B 0 9 2, 
c o m par e d t o pla c e b o, as m eas ure d b y t h e 
Cli nical Gl o bal I m pressi o n of C ha n g e 
( C GI-C) at W e e k 5 2.  
T he i m pa ct of BII B 0 9 2 o n t h e C GI -C scal e 
sc ore will b e e val u at e d at W e e k 5 2 i n t h e 
BII B 0 9 2 -tr eat e d parti ci pa nts a n d c o m par e d t o 
t hat of t he pla c e b o -treat e d parti ci pa nts. 
T o e val u ate t he effi ca c y of BII B 0 9 2, 
c o m par e d t o pla c e b o, as m eas ure d b y a c ha n g e 
fr o m baseli ne i n t h e R e peata bl e Batt er y f or t h e 
Assess me nt of N e ur o ps y c h ol o gi ca l Disease 
Se v erit y ( R B A N S) at W ee k 5 2.  
T he i m pa ct of BII B 0 9 2 o n t h e R B A N S scal e 
will b e e val u at e d r elati v e t o t h e c ha n g e fr o m 
baseli n e at W e e k 5 2 i n t h e BII B 0 9 2 -tr eat e d 
parti ci pa nts  a n d c o m par e d t o t hat of t he 
pla ce b o -tr eat e d parti ci pa nts. 
T o assess t h e i m pa ct of BII B 0 9 2 o n q u alit y of 
life, r elati v e t o pla c e b o, as meas ur e d b y 
c ha n ge fr o m baseli n e o n t h e Pr o gr essi v e 
S u pr a n u cl ear Pals y Q u alit y of Life scal e ( P S P -
Q o L) at W e e k 5 2.  
T he i m pa ct of BII B 0 9 2 o n t h e P S P -Q o L will b e 
e val u ate d r elati v e t o t h e c ha n g e fr o m baseli n e 
at W ee k 5 2 i n t h e BII B 0 9 2 -tr eat e d parti ci pa nts 
a n d c o m par e d t o t hat of t h e pla c e b o-tr eat e d 
parti ci pa nts.  


 
 
1 4  
 
Ot he r  Se c o n d ar y  
T o assess t h e effi ca c y of BII B 0 9 2, relati v e t o 
pla ce b o, as m eas ure d b y a c ha n g e fr o m 
baseli n e at W e e k 4 8 ( W e e k 5 2 f or Cli ni cal 
Gl o bal I m pr essi o n of S e verit y  [C GI -S ]) o n t h e 
f oll o wi n g i nstr u m e nts: 
•  Sc h wa b a n d E n gla n d Acti vities of 
Dail y Li v i n g ( S E A D L) S cal e  
•  C GI -S  
•  P h o ne mic Fl u e nc y T est  
•  Letter -N u m b er S e q u e n ci n g T est  
( L N S) 
•  C ol or Trails T est  ( C T T) 
•  M o ntr eal C o g niti v e Assess m e nt 
( M oC A)  
T he i m pa ct of BII B 0 9 2 o n t h e f oll o wi n g 
i nstr u m e nts: 
•  S E A D L S cal e  
•  C GI -S  
•  P h o ne mic Fl u e nc y T est  
•  L N S  T est  
•  C T T  
•  M o C A  
wil l b e e val u ate d r elati v e t o t h e c ha n g e fr o m 
baseli n e at W e e k 4 8 ( W e e k 5 2 f or C GI -S) i n 
t h e BII B 0 9 2 -tr eat e d parti ci pa nts a n d c o m par e d 
t o t hat of t he pla c e b o -tr eate d partici pa nts. 
T o assess t h e i m m u n o g e nicit y of BII B 0 9 2.  
I m m u n o ge ni cit y of BII B 0 9 2 will be meas ur e d 
b y assess m e nt of t h e pr ese n c e or a bse n c e of 
a nti -BII B 0 9 2  a nti b o di es (a nti -BII B 0 9 2) i n 
ser u m. 
T o assess t h e effi ca c y of BII B 0 9 2, rela ti v e t o 
pla ce b o, as m eas ure d b y a bs ol ut e a n d per c e nt 
c ha n ge fr o m baseli n e of bra i n v ol u m es, as 
det er mi n e d b y ma g n eti c  r es o na n c e i ma gi n g 
(M RI ), at We e k 5 2 i n t h e f oll o wi n g r e gi o ns: 
•  Ve ntri cl es  
•  W h ol e brai n  
•  Mi d brai n  
•  S u p eri or c er e b ellar p e d u n cl e  
•  T hir d v e ntri cl e  
•  Fr o ntal l o b e  
•  P o ns  
T he i m pa ct of BII B 0 9 2 o n brai n v ol u m es, as 
det er mi n e d b y M RI i n t h e f oll o wi n g re gi o ns: 
•  Ve ntri cl es  
•  W h ol e brai n  
•  Mi d brai n  
•  S u p eri or c er e b ellar p e d u n cl e  
•  T hir d v e ntri cl e  
•  Fr o ntal l o b e  
•  P o ns  
will b e e val u at e d r elati v e t o t h e a bs ol ut e a n d 
perc e nt c ha n g es fr o m baseli ne at We e k 5 2 i n 
t h e BII B 0 9 2 -tr eat e d parti ci pa nts a n d c o m par e d 
t o t hat of t he pla c e b o-tr eate d partici pa nts. 
Te rti ar y/ E x pl o r at o r y  


 
 
1 5  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•  
 
 
•  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•  
 
•  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
•  
 


 
 
1 6  
 
 
 
•  
 
 
 
 
 
•  
 
•  
 
 
 
 
 
O pe n -L a bel E xte nsi o n P h as e  
T o assess t h e l o n g -t er m safet y a n d t olera bilit y 
of BII B 0 9 2 i n parti ci pa nts wit h P S P.  
T he t ertiar y e n d p oi nt w ill be i nci d e n ce of A Es, 
S A Es, a n d d eat h.  
T o assess t h e l o n g -t er m effi ca c y of BII B 0 9 2 i n 
parti ci pa nts wit h P S P.  
T he t ertiar y e n d p oi nts wil l b e c ha n g e fr o m 
baseli n e o v er t h e pla ce b o -c o ntr olle d p eri o d a n d 
l o n g-ter m e xt e nsi o n p eri o d f or cli ni cal a n d 
healt h -o ut c o m es assess m e nts.  
T his st u d y i n cl u d es a n o pti o nal s u bst u d y t o 
m eas ur e q u a ntitati v e m o v e m e nt assess m e nts 
( Q M As) usi n g weara bl e se ns ors. Th e Q M As 
will m eas ure gait, p ost ural i nsta bilit y, m ot or 
f u n cti o n, a n d falls i n a s u bset of parti ci pa nts 
parti ci pati n g i n t h e lo n g -ter m e xte nsi o n peri o d. 
 
 
 
 
3  
G E N E R A L  C O N SI D E R A TI O N S  
 
3. 1  Ge ne r al M et h o ds  
T his statisti cal a nal ysis pla n ( S A P) o nl y c o vers t h e a nal ys es f or t h e d o u bl e -bli n d  pla c e b o -
c o ntr olle d p orti o n of t h e st u d y. H er eaft er, t h e d o u bl e -bli n d , pla c e b o -c o ntr oll e d p ort i o n of t h e st u d y 
will b e r eferre d t o as “t h e st u d y” i n t h e rest of t his S A P (e. g., c o m pl eti o n of t h e st u d y m ea ns 
c o m pl eti o n of t h e pla c e b o -c o ntr olle d p orti o n). A se parat e S A P will b e pr e p are d f or t h e a nal yses 
of t h e  o p e n la b el e xt e ns i o n (O L E ) p eri o d a n d i n t e grat e d a nal yses a cr oss b ot h p orti o ns of t h e st u d y. 
T he a nal yses of sele cte d e x pl orat or y e n d p oi nts ma y be d oc u m e nt e d se paratel y. T h e t er m “ s u bj e ct” 
use d i n t his S A P a n d i n t h e a nal yses is e q ui val e nt t o t he t er m “ parti ci pa nt” use d i n  t h e Pr ot o c ol. 
S u m mar y ta bl es will be pr ese nt e d usi n g d escri pti ve s u m mar y statistics. F or c o nti n u o us varia bl es, 
s u m mar y statisti cs will g e n erall y i n cl u de: n u m b er of s u bj ects wit h data, mea n, sta n dar d d e viati o n, 
m e dia n, 2 5 % per c e ntile, 7 5 % p er ce ntil e, mi ni m u m a n d ma xi m u m.  F or cat e g orical varia bl es, t his 


 
 
1 7  
 
will g e n era ll y i ncl u d e: n u m b er of s u bj ects ra n d o miz e d or d ose d, n u m b er wit h data, a n d t he p er ce nt 
of t h ose wit h da ta i n ea c h cate g or y.  
I n g e n eral, listi n gs will i n cl u d e all data i n t h e pla c e b o-c o ntr oll e d a n d O L E  p eri o ds (all data i n t h e 
st u d y), wit h a n i n di cat or of t he st u d y peri o d ( scr ee ni n g, pla c e b o-c o ntr oll e d, or O L E ) f or ea c h 
re c or d t o i n dicat e w h e n t h e e ve nt o c curre d.  
U nl ess ot h er wise s p e cifi e d, baseli n e val u e is d efi n e d as t h e m ost r e ce nt n o n -missi n g m eas ure m e nt 
c oll e ct e d pri or t o t he first d ose. C ha n g e fr o m baseli n e will be d efi n e d as p ost -baseli n e val u e mi n us 
baseli n e val u e.  
U nl ess stat e d ot h er wise, all stati sti cal t ests will b e 2-si d e d wit h statistical sig nifi ca n c e l e vel of 
0. 0 5.  
T he statisti cal s oft war e S A S ®  will be use d  f or all s u m maries a n d a nal yses.  
T he h ealt h care r e gi o n use d i n t h e a nal ysis  (r eferre d as re gi o n i n t his S A P) is d efi n e d as: 
•  U S : Unit e d St at es  
•  N o n -U S : A ustralia, A ustria, Ca na da, Fra n c e, Ger ma n y, Gr e e ce, Ital y, R ussi a n, S pai n, 
U nit e d Ki n g d o m , Ja pa n a n d K or ea 
 
3. 2  P o p ul ati o ns  
•  E nr oll e d s u bje cts: a ll s u bj e cts w h o si g n e d i nf or m e d c o nse nt a n d wer e assi g ne d a s u bj e ct 
i d e ntifi cati o n n u m b er. 
 
•  Ra n d o mi z e d  s u bje cts: e nr oll e d s u bj e cts w h o r ec ei v e d a ra n d o mizati o n tr eat m e nt assi g n m e nt 
fr o m t h e I nt era cti v e R es p o nse T e c h n ol og y  ( BII B 0 9 2 or pla ce b o). 
 
•  D ose d s u bje cts : e nr olle d s u bj e cts w h o  r ec ei ve d at l east o n e  d ose  of  st u d y t hera p y, i. e., bli n d e d  
t h era p y (BII B 0 9 2  or  pla ce b o)  or  o p e n -la bel BII B 0 9 2 . T his is t h e sa m e as t h e “ Treate d 
parti ci pa nt s” i n S e cti o n 1 7. 2 of t h e pr ot o c ol. 
 
•  I nt e nt-t o-tr eat (I T T) p o p ulati o n: all ra n d o mi ze d s u bj e cts w h o r e cei v e d at least o n e d ose of 
bli n de d st u d y tr eat m e nt (BII B 0 9 2  or pla c e b o).  
 
•  Per -pr ot o c ol p o p ulati o n : all s u bj e cts i n t he I T T p o p ulati o n w h o als o  
o  ha d n o vi olati o ns of t h e f oll o wi n g i n cl usi o n cr it eria: 
▪ Pr o ba bl e  or p ossi bl e P S P  as d efi n e d i n Se cti o n 6. 1. 2 of t h e pr ot o c ol ; 
a. Base d o n t h e f oll o wi n g  
- 
A pr o gr essi v e hist or y of p ost ural i nst a bilit y d uri n g t he first 3 
years t hat  s y m pt o ms ar e pr ese nt 
O R  
- 
A pr o gr essi ve hist or y of falls d uri n g t h e first 3 years  t hat 
s y m pt o ms ar e pr ese nt  
b.  Base d o n t h e f oll o wi n g  
- 
Verti cal s u pra n u cl ear ga ze pals y d efi n e d as cl ear li mitati o n of 
t h e ra n g e of v ol u ntar y ga z e i n t h e v ertical m ore t ha n i n t h e 


 
 
1 8  
 
h oriz o ntal pla n e, 
m or e t ha n  e x p ecte d 
wit h a g e, 
w hic h is 
o v er c o me b y a cti vati o n wi t h t h e v esti b ul o-o c ular  refl e x (at lat er 
sta ges, t he v esti b ul o-o c ular r efl e x ma y b e l ost, or t h e ma n e u v er  
pr e v e nt e d b y n u c hal ri gi dit y). 
O R  
- 
Sl o w v el o cit y of v ertical sa c ca d es (i.e., de cr ease d v el o cit y (a n d 
gai n) 
of  v erti cal 
gr eater t ha n 
h ori z o ntal sa c ca di c  e y e 
m o v e m e nts);  Ga z e s h o ul d b e assesse d b y c o m ma n d t o a 
stati o nar y tar g et rat her t ha n b y p urs uit, wit h t h e tar g et > 2 0 ° fr o m 
th e p ositi o n o f pri mar y ga z e. T y pi call y, sa c ca di c m o v e m e nt is 
sl o w e n o u g h f or t h e e xa mi n er t o se e its pr o gress, rat h er t ha n j ust 
its i nitial a n d fi nal p ositi o ns. D eficits ar e m or e pr o mi ne nt i n t h e 
verti cal t ha n t h e h ori z o ntal pla n e. A d ela y i n i nitiati o n of  
sa cca d es is n ot  c o nsi d er e d sl o wi n g . 
 
c.  A g e at s y m pt o m o nset of 4 0 t o 8 5 y ears b y hist or y a n d c urre nt a g e 
bet wee n 4 1  a n d 8 6 y ears, i n cl usi ve, at t h e ti m e of scr e e ni n g  
 
d.  A n a ki n eti c -ri gi d s y n dr o me 
 
e.  Prese n ce of P S P s y m pt o ms f or l ess t ha n or e q u al t o 5 y ears 
( d et er mi ne d b y th e  b est j u d g e m e nt of t h e I n vesti gat or) at scr e e ni n g  
 
▪ A bl e t o a m b ulat e i n d e p e n d e ntl y or wit h assista n c e d efi n e d as t h e  a bilit y t o 
ta k e at l east 1 0 st e ps wit h a wal k er ( g u ar di n g is all o we d pr o vi de d t h er e is 
n o c o nta ct) or t h e a bilit y t o ta k e at l east 1 0 ste p s wit h o ut a wal k er or ca n e 
wit h t h e assista n ce of a n ot h er p ers o n w h o ca n o nl y ha v e c o nta ct wit h o n e 
u p p er e xtr e mit y.  
o  ha d at l east 1 0  i nf usi o ns. 
 
•  Effi ca c y M RI p o p ulati o n : t he s u bset of t h e I T T p o p ulati o n w h o ha d a l east o ne meas ura bl e 
b rai n v ol u m etri c m eas ur e m e nt. 
 
•  Safet y p o p ulati o n : all ra n d o mi z e d s u bj e cts w h o r ec ei v e d at l east o n e d ose of st u d y tr eat me nt 
(BII B 0 9 2  or pla ce b o).    
 
•  Safet y M RI p o p ulati o n : t he s u bset of t h e safet y p o p ulati o n w h o ha d at l east o n e p ost-baseli n e  
safet y M R I. 
 
•  Se r um P K a nal ysis p o p ulati o n : th e s u bset of t h e safet y p o p ulati o n w h o  ha d at l east o n e 
m eas ura bl e p ost -baseli n e BII B 0 9 2  c o n c e ntrati o n i n s er u m.  
 
•  C S F P K a nal ysis p o p ulati o n : t h e s u bset of t h e safet y p o p ulati o n  w h o ha d at l east o n e 
m eas ura bl e p ost -basel i n e BII B 0 9 2 c o n c e ntrati o n i n C S F . 
 
 


 
 
1 9  
 
 
•  A nti -dr u g  a nti b o d y  ( A D A) a nal ysis p o p ulati o n : t he s u bset of t h e safet y p o p ulati o n w h o  h a d at 
least o n e p ost-d ose sa m p le e val u a ble f or a nti -dr u g a nti b o d y .   
 
3. 3  T r e at me nt g r o u ps f o r a n al ysis 
A nal yses usi n g  t h e I T T p o p ulati o n , P er Pr ot o c ol p o p ulati o n, a n d Effi ca c y M RI p o p ulati o n  will b e 
perf or m e d a c c or di n g t o t h e tr eat m e nt gr o u ps t o w hi c h s u bj ects were ra n d o miz e d u nl ess ot her wise 
s pe cifi e d. 
F or t h e safet y p o p ulati o n a n d p o p ulati o ns d efi n e d a b o v e w hi c h ar e base d o n t he safet y p o p ulati o n, 
safet y tr eat m e nt gr o u ps will b e use d f or a nal ysis u nl ess ot h er wise s p e cifi e d. If a s u bj ect r ec ei v e d 
o n e o r m or e d oses of BII B 0 9 2 t he n h e/s h e will b e i ncl u d e d i n t h e BII B 0 9 2 safet y tr eat me nt gr o u p. 
If a s u bj e ct o nl y re c ei v e d d oses of pla c e b o, h e/s h e will b e i ncl u d e d i n t h e pla c e b o safet y tr eat m e nt 
gr o u p.   
A listi n g of s u bj ects  w h ose safet y treat m e nt gr o u p is d iffer e nt fr o m t h eir r a n d o mi z e d treat m e nt 
gr o u p  will b e pr o vi d e d.  
F or ser u m P K a n d C S F P K p o p ulati o ns, a s u bj e ct ma y b e e x cl u de d fr o m a nal ysis d u e t o k e y 
pr ot o c ol d e viati o ns.  
 
4  
S T U D Y S U B J E C T S  
 
A nal yses i n t he secti o n will b e base d o n I T T p o p ulati o n  u nl ess ot her wise i n di cat e d .  
 
4. 1  Ac c o u nti n g of s u bje cts  
Dis p ositi o n will be s u m mariz e d  f or t h e ra n d o miz e d s u bj e cts p o p ulati o n  b y tr eat m e nt gr o u p  a n d 
th e s u m mar y data will i n cl u d e n u m b er ( %) of s u bj e cts ra n d o miz e d a n d d ose d, n u m ber ( %) of 
s u bje cts w h o c o m pl et e d t h e tr eat m e nt/st u d y, a n d n u m ber ( %) of s u bj e cts w h o disc o nti n u e d 
treat m e nt a n d/ or wit h dr e w fr o m st u d y.  T h e n u m b er  of s u bj e cts disc o nti n u e d  fr o m st u d y 
treat m e nt/wit h dr e w fr o m st u d y will als o b e s u m mariz e d b y treat m e nt gr o u p a n d b y baseli ne 2 8 -
ite m a n d 1 5 -ite m P S P R S t otal sc ore ( ≤ m e dia n, > m e dia n). F or s u bj e cts w h o disc o nti n u e d 
treat m e nt a n d/ or wit h dr e w fr o m st u d y, t h e r eas o ns f or disc o nti n u ati o n an d/ or wit h dra wal, a n d da ys 
o n tr eat m e nt a n d da ys o n st u d y will be s u m mari ze d a n d list e d. T h e n u m ber of s u bj e cts 
disc o nti n ui n g tr eat m e n t will be s u m mariz e d i n ti m e i nt er vals, i. e., 0 t o <  1 2 we e ks, > = 1 2 t o < 2 4 
we e ks , > = 2 4 t o < 3 6 we e ks, > = 3 6 t o < 4 8 we e ks , a n d  > =  4 8 we e ks . A si milar s u m mar y will b e d o ne 
f or su bj e cts w h o wit h dr e w fr o m st u d y . N u m b er of s u bj e cts e x cl u de d fr o m t h e per -pr ot o c ol 
p o p ulati o n will als o b e s u m mari z e d. Ti m e t o tr eat m e nt disc o nti n u ati o n a n d ti me t o st u d y 
wit h dra wal will b e dis pla ye d b y Ka pla n -M ei er pl ot  b y  tr eat m e nt gr o u p. 
T he n u m b er of s u bj e cts i n ea c h a nal ysis p o p ulati o n will be s u m mari ze d.   T h e n u m b er of s u bj e cts 
d os e d will be s u m mari z e d b y  r e gi o n as d efi n e d i n S e cti o n 3. 1 , c o u ntr y a n d site. I n a d diti o n, t he 
n u m b er of s u bj ects w h o c o m pl et e d t h e tr eat m e nt/st u d y will be s u m mari z e d b y r e gi o n, c o u ntr y a n d 
sit e.  
A ra n d o mi zati o n listi n g i n cl u d i n g c o u ntr y, C T T  2 , ra n d o mi zati o n n u m b er, ra n d o mi zati o n date,  
a n d t h e pr ot oc ol v ersi o n , as well as a listi n g of ra n d o mi ze d s u bj ects e x cl u d e d fr o m t h e IT T 


 
 
2 0  
 
p o p ulati o n, a n d a listi n g of d ose d s u bj ects e xcl u d e d fr o m t h e P P p o p ulati o n  will b e pr o vi d e d.  
S u bj e cts wit h a mis mat c h b et we e n ra n d o mizati o n C T T  2 cate g ori zati o n a n d a ct u al C T T  2 
cat e g ori zati o n will b e list e d.   
 
4. 2  De m o g r a p h ic a n d  B aseli ne  Dise ase  C h ar acte ristics  
T he d e m o gra p hi c data i n cl u di n g a ge, se x, et h nicit y,  ra c e, hei g ht, wei g ht, a n d b o d y mass i n d e x 
( B MI) will b e s u m mari z e d. Ra c e a n d et h ni cit y will b e pr ese nt e d as U n k n o w n  f or s u bj ects w h ere  
c oll e cti o n of t h ese data is n ot p er mitt e d p er l o cal re g ulati o ns. A ge will als o b e prese nt e d usi n g t h e 
f oll o wi n g gr o u pi n gs: <4 1 , 4 1 -5 0 , 5 1 -6 0 , 6 1 -7 0 , 7 1 -8 0 , 8 1 -8 6, > 8 6  years ; ≤6 4, 6 5 -7 4 a n d ≥7 5 ; 
a n d ≤me dia n, > m e dia n  w h er e m e dia n is t h e m e dia n a g e base d o n t h e o v erall I T T p o p ulati o n .  
S u m mar y of t h e baseli n e c hara ct eristi cs of P S P will i n cl u d e t h e f oll o wi n g baseli n e cli ni cal 
assess m e nt s:  
•  2 8 -it e m P S P R S t otal sc or e*  a n d 2 8 -it e m P S P R S ( ≤m e dia n, > m e dia n)  w h er e m e dia n is base d 
o n t he o v erall I T T p o p ulati o n ;  
•  1 5 -it e m P S P R S t otal sc or e * a n d 1 5 -it e m P S P R S ( ≤m e dia n, > m e dia n)  w h er e m e dia n is base d 
o n t he o v erall I T T p o p ulati o n ; 
•  M D S -U P D R S Part II * ; 
•  P S P c o g niti v e c o m p osit e batter y * ; 
•  C GI -S * ;  
•  
 
   
•  C T T  2 *  a n d t w o  cate g ori zati o ns : ≤1 7 0 a n d > 1 7 0 se cs * , a n d < 2 4 0 a n d ≥2 4 0 se cs; 
•  Mi ni -Me ntal Stat e E xa m (M M S E ) a n d M M S E (< 2 0 a n d ≥2 0 ); 
•  n u m b er of y ears si n ce first P S P si g ns a n d s y m pt o ms* ;  
•  n u m b er of y ears si n ce dia g n osis of P S P * ; 
•  ta u ha pl ot y pe ( H 1/ H1 , H 1/ H 2, or H 2/ H 2)* ;  
•  Par ki ns o n’s Disease m e di cati o n use at baseli n e ( y es or n o; se e S ecti o n 4. 4  f or d efi niti o n of 
Par ki ns o n’s Disease me di cati o n use at baseli ne )* ; 
•  S E A D L ; 
•  P h o n e mic Fl u e nc y T est;  
•  Letter N u m b er S e q u e nci n g T est  t otal sc or e a n d l o n g est lett er n u m b er se q u e n c e sc or e;  
•  C T T 1 ;  
•  M o C A ; 
•  R B A N S ; 
•  P ossi bl e or pr o ba bl e P S P ; 


 
 
2 1  
 
•  2 8 -it e m P S P R S Gait it e m 2 6 at baseli n e ( < 3, > = 3) .   
A se parat e ta bl e w hi c h s u m mari z es k e y baseli n e c har a ct eristi cs of P S P (t h ose mar k e d wit h  * 
a b o v e) will be pr o vi de d. S u bj ect listi n gs will b e g e n erat e d f or d e m o gr a p hi cs a n d baseli n e 
c hara ct eristi cs of P S P . 
Me di cal hist or y will b e c o d e d usi n g t h e M e di cal Di cti o nar y f or R e g ulat or y Acti viti es ( Me d D R A  
versi o n 2 2. 0  or hi g h er ). T h e n u m b er ( %) of s u bj e cts wit h hist or y (i n cl u di n g b ot h o n g oi n g a n d n ot 
o n g oi n g ) me di cal c o n diti o ns will be s u m mari z e d b y S O C  a n d P T . A listi n g of m e di cal hist or y will 
be g e n erat e d.  
T he n u m b er ( %) of s u bj ects f or ea c h P S P  p h e n ot y p e  retr os p e cti v el y r e p ort e d at s y m pt o m o nset 
will b e s u m mariz e d .  S hift  fr o m b aseli ne t o W e e k 5 2 of P S P p h e n ot y pe will als o be ta b ulate d. 
 
 
4. 3  St u d y Dr u g E x p os ur e a n d St u d y Dr u g C o m pli a nc e  
T he  a nal ysis i n this se cti o n will b e base d o n safet y p o p ulati o n. N u m ber of  d oses  (i.e. i nf usi o ns of  
BII B 0 9 2 or pla c e b o) r e cei v e d will b e s u m mari z e d as a cat e g ori cal varia ble ( as i nt e g ers fr o m 1 t o 
1 3 ; as ≥1 0;  a n d as 1 -5, 6 -9 , 1 0-1 3 , ≥1 4 ) as well as a c o nti n u o us varia bl e. D u e t o t he o n ce m o nt hl y 
d osi n g sc h e d ule, o n e d ose of st u d y dr u g is c o nsi d er e d 2 8 da ys of st u d y tr e at m e nt e x p os ur e. T h e 
n u m b er of we e ks o n st u d y treat m e nt ( BII B 0 9 2 or pla c e b o), calc ulat e d a s ( d ate of last d ose –  dat e 
of fi rst d ose +2 8 )/ 7, will b e s u m mariz e d as a cate g ori cal varia bl e (> 0 -4, > 4 -1 4, > 1 4 -2 2, > 2 2 -3 0, 
> 3 0 -3 8, > 3 8 -4 6, a n d > 4 6 we e ks ) as well as a c o nti n u o us varia ble. P er ce nta g e of st u d y dr u g  ta k e n 
u p t o t h e last d ose, cal c ulat e d a s (t h e a ct u al n u m b er of d oses di vi d e d b y t he n u m b er of d oses a 
s u bje ct is e x p e ct e d t o ta k e u p t o a n d i n cl u di n g t h e dat e of t h e last d oses) * 1 0 0, will b e s u m mariz e d 
as a c o nti n u o us varia bl e. T he n u m b er of y ears o n st u d y treat m e nt ( BII B 0 9 2 or pla ce b o), cal c ul at e d 
as ( dat e of last d ose –  date of first d ose + 2 8)/ 3 6 5. 2 5 , will be s u m mari ze d as a c o nti n u o us varia bl e. 
D urati o n of F oll o w -u p ( y ears) , cal c ulat e d as [( dat e of last da y of pla c e b o -c o ntr olle d p eri o d) - ( dat e 
of first  d ose of pla c e b o or  BII B 0 9 2) + 1]/ 3 6 5. 2 5  will b e s u m mari z e d as a c o nti n u o us varia bl e, 
i n cl u di n g t he s u m a cr oss s u bj e cts pr ese nt e d as  total d urati o n of f oll o w -u p ( y ears) . 
T he ti me o n st u d y aft er treat m e nt disc o nti n u ati o n will  b e cal c ulat e d as f oll o ws:  
•  P ositi ve ti m e o n st u d y aft er  treat m e nt disc o nti n u ati o n: F or s u bj e cts w h ose d ate of last da y 
o n st u d y is 
m or e t ha n 2 8 da ys af t er t h e last d ose, ti m e o n st u d y after tr eat m e nt 
disc o nti n u ati o n (i n we e ks) will b e cal c ulat e d as (( Dat e of last da y o n st u d y) –  ( Date of last 
d ose of pla c e b o or BII B 0 9 2 + 2 8 ))/ 7; 
•  N o ti m e o n st u d y aft er tr eat me nt disc o nti n u ati o n:  F or s u bje cts w h ose dat e of last da y o n 
st u d y is l ess t ha n or e q u al t o 2 8 da ys aft er t h e dat e of last d ose ( pla c e b o or BII B 0 9 2), ti m e 
o n st u d y ( we e ks) aft er tr eat me nt disc o nti n u ati o n is c o nsi d er e d 0.  
F or t h is a nal ysis, s u bj e cts are c o nsi d er e d t o ha v e disc o nti n u e d tr eat m e nt if t he y eit h er disc o nti n u e d 
treat m e nt earl y i n t h e P C p eri o d or if t he y c o m pl et e d tr eat m e nt i n t h e P C p eri o d a n d are n ot d ose d 
i n t he O L E. T h e n u m b er ( %) of s u bje cts wit h n o ti me o n st u d y aft er  tr eat m e nt disc o nti n u ati o n a n d 
wit h p ositi v e ti m e o n st u d y aft er tr eat m e nt disc o nti n u ati o n will be s u m mariz e d . Ti m e o n st u d y  
( we e ks) after tr eat m e nt disc o nti n u at i o n will be s u m mari z e d as a c o nti n u o us v aria bl e , i ncl u di n g t h e 
s u m a cr oss  s u bj e cts pr ese nte d as t otal ti m e o n st u d y ( wee ks) after tr eat m e nt disc o nti n u ati o n.  


 
 
2 2  
 
A listi n g of st u d y dr u g a d mi nistrati o n r e c or ds, i n cl u di n g t otal v ol u m e pr e pare d a n d  t otal v ol u me 
inf use d  at ea c h i nf usi o n, a n d c u m ulati v e n u m b er of d oses  will b e pr o vi de d.  
A l isti n g of dr u g  s u p pl y i nf or mati o n (e. g. l ot n u m b er ) will als o be pr o vi d e d.  
 
A listi n g wit h i nf or mati o n o n i nf usi o n i nt err u pti o ns a n d i nf usi o n rat e r e d u cti o ns will b e pr o vi d e d.  
 
 
4. 4  M e dic ati o ns a n d N o n -dr u g t he r a pies  
 
C o nc o mit a nt me dic ati o n  
T he pr e vi o us a n d c o nc o mita nt m e di cati o n e C R F c o ntai ns m e di cati o ns a d mi nist er e d u p t o 4 we e ks 
pri or t o st u d y dr u g a d mi nistrati o n.  T h e f oc us of t h e a nal yses 
will b e o n c o nc o mita nt 
m e dicati o ns/t h er a pi es.  
All me di cati o ns will b e c o d e d usi n g t he W orl d Healt h Or ga ni zati o n Dr u g ( W H O Dr u g  Mar c h 2 0 1 9  
or hi g h er ) di cti o nar y. All n o n -dr u g t h era pi es ( d efi n e d as dia g n osti c pr oc e d ures or m e di cal 
treat m e nt pr oc e d ures) will be c o d e d usi n g t h e M e d D R A di cti o nar y v e rsi o n 2 2. 0 or hi g h er.  A 
c o n c o mita nt me di cati o n  (t h era p y) will b e defi ne d as a n y t hat was ta k e n o n or aft er t he da y of t h e 
first d ose of st u d y dr u g. T his i n cl u d es t hera pi es t hat start pri or t o t h e i nitiati o n of t h e first d ose if 
t h eir use c o nti n u es o n or aft er t h e dat e of first d ose. T o defi n e c o n c o mita nt use f or t h era pi e s wit h 
missi n g start or st o p dat es, t h e f oll o wi n g a d diti o nal crit eria will b e use d:  
•  if b ot h t he start a n d st o p dates of a t h era p y ar e missi n g, t hat t h era p y will be c o nsi der e d 
c o n c o mita nt.  
•  if t h e start dat e of a t h era p y is missi n g a n d t h e st o p dat e of t hat t h era p y fall o n or aft er t he 
dat e of t h e first d ose, t hat t h era p y will b e c o nsi d er e d c o n c o mita nt.  
•  if t h e start date of a t h era p y is pri or t o t h e date of t h e first d ose a n d t he st o p date of t hat 
t h era p y is missi n g a n d t h e t hera p y is list e d as c o nti n ui n g, t hat t h era p y will be c o nsi d er e d 
c o n c o mita nt, or  
•  if t h e start date of a t h era p y is pri or t o t h e date of t h e first d ose a n d t he st o p date of t hat 
t h era p y is missi n g a n d t h e t h era p y is n ot list e d as c o nti n ui n g, t hat t h era p y will b e 
c o nsi d er e d c o n c o mita nt.  
F or a t h era p y wit h a partial st art dat e, t he y ear/ m o nt h of t h e t h era p y dat e will b e c o m pare d t o t hat 
of t h e first d osi n g dat e t o d et er mi n e w h et her t he t hera p y is c o n c o mita nt.  
T he n u m ber ( %) o f s u bje cts ta ki n g c o nc o mita nt m e di cati o n a n d n o n-dr u g t h era pi es will b e 
s u m mariz e d.   M e di cati o n s a n d n o n-dr u g t h era pies will b e list e d , i n cl u di n g m e dicati o ns t hat were 
st o p p e d d uri n g t h e 4 we e ks pri or t o t h e dat e of first d ose.    
Par ki ns o n’s disease  m e di cati o ns ta k e n c o n c o mita ntl y at baseli n e ar e d efi n e d as Par ki ns o n’s 
disease  m e di cati o ns t hat wer e  b ei n g ta k e n at t h e ti m e of t h e first d ose, i.e., st arte d pri or t o t h e first 
d ose a n d c o nti n u e d u ntil aft er t h e first d ose. T he n u m b er ( %) of s u bje cts ta ki n g Pa r ki ns o n’s disease 
m e dicati o ns c o n c o mita ntl y at baseli ne will be s u m mari ze d. I n a d diti o n, n u m ber of s u bje cts usi n g 
Par ki ns o n’s disease m e dicati o ns c o n c o mita ntl y at baseli n e will be s u m m ariz e d b y i n di vi d u al 
m e dicati o n . S u bj e cts w h o ha v e a n y c ha n g e i n Par ki ns o n’s disease m e di cati o ns after t h e i nitiati o n 
of st u d y tr eat m e nt will b e s u m mari z e d o v erall a n d b y t he ti mi n g of c ha n g e  e v er y 3 m o nt hs , i. e., 
t h e n u m b er of s u bj e cts c ha n gi n g i n 0 - 1 2 we e ks , t he n u m b er of s u bj e cts c ha n gi n g b et wee n 1 2 - 2 4 


 
 
2 3  
 
we e ks , et c.   S u bj e cts w h o ha v e c ha n g es i n m ulti ple i nt er vals will be c o u nt e d i n ea c h i nter val.  A 
listi n g of  s u bjects wit h a n y c ha n g e i n Par ki ns o n’s disease m e di cati o ns i n t h e st u d y will b e 
pr o vi d e d.  
 
 
Dis all o we d t he r a pies  
Per S e cti o n 7. 7. 1  of t h e Pr ot o c ol , p r o hi bite d a n d/ or r estri ct e d m e di cati o ns ta k e n pri or t o st u d y 
treat m e nt a d mi nistrati o n a n d d uri n g t h e st u d y are descri b e d b el o w. Me di c ati o ns ta k e n wit hi n 4 
we e ks pri or t o st u d y tr eat m e nt a d mi nis trati o n a n d d uri n g st u d y tr eat m e nt m ust b e r e c or d e d o n t h e 
case r e p ort f or m ( C R F).  
1.  Pri or e x p os ure t o BII B 0 9 2.  
2.  W it hi n 4 wee ks of scr e e ni n g or a nti ci pat e d d uri n g t he 5 2-we e k d o u ble -bli n d p orti o n of t h e 
st u d y, c o n c urre nt tr eat m e nt wit h m e ma nti n e; a cet ylc h oli n est erase i n hi bit ors; a nti ps y c h oti c 
a ge nts or m o o d sta biliz ers ( e. g., val pr oate,  lit hi u m); or b e nz o dia ze pi n es are disall o we d, 
wit h t he f oll o wi n g e x c e pti o ns:  
a.   L o w d ose l ora z e pa m or ot h er s h ort -a cti n g m e di cati o ns ma y b e use d f or se dati o n pri or  
t o M RI sca ns f or t h ose parti ci pa nts r e q uiri n g se dati o n.  At t he discreti o n of t h e I n v esti gat or, 
0. 5 t o 1 m g ma y b e gi ve n orall y pri or t o sca n wit h a si n gl e re p eat d ose gi v e n if t he first  
d ose is i n effe cti v e.  N e ur o ps y c h ol o gi cal testi n g ma y n ot b e p erf or m e d o n t h e sa m e da y of 
l ora ze pa m a d mi nistrati o n.  Parti ci pa nts a n d car e gi v er m ust b e i nf or m e d of ris ks of 
l ora ze pa m use pri or t o a d mi nistrati o n. 
b.   Parti ci pa nts 
w h o ta k e s h ort -a cti n g be n zo dia z e pi n es  or ot her h y p n otics  ( e. g., 
te ma ze pa m, z ol pi d e m) f or sle e p ma y c o nti n u e t o d o s o if t h e y ha ve b e e n o n a sta bl e d ose 
f or 3 0 da ys pri or t o scre e ni n g. 
c.   Cl o na z e pa m ma y b e use d f or treat m e nt of restl ess l e gs s y n dr o m e, d yst o nia, or pai nf ul 
ri gi dit y ass o ciat e d wit h P S P if t h e d ose has b ee n sta bl e f or 6 0 da ys pri or t o  scr ee ni n g. 
d.   Q u etia pi n e or cl o za pi n e ma y b e p er mitte d if at a sta bl e d ose f or at l east 6 0 da ys pri or 
t o scr e e ni n g. 
 
3.  Re c ei pt of s yst e mi c c orti c ost er oi ds wit hi n 3 0 da ys pri or t o scre e ni n g.  
4.  Re c ei pt of a n i n v esti gati o nal i m m u n o m o d ulat or or m A b wit hi n 1 8 0 da ys ( or 5 half -li v es, 
w hi c h e v er is l o n g er) pri or t o scr e e ni n g.  
5.  Treat m e nt wit h a n y ot h er i n vesti gati o nal dr u gs ( e. g., salsalat e) i n cl u di n g pla c e b o or 
de vi c es wit hi n 9 0 da ys pri or t o scr e e ni n g.  
T he i nci d e n ce of disall o we d m e di cati o ns will b e s u m mari z e d.  A  listi n g of  s u bje cts w h o t o o k a n y 
dis all o we d  me di cati o ns  will b e pr o vi d e d.  
 


 
 
2 4  
 
4. 5  Pr ot o c ol  De vi at i o ns 
Pr ot o c ol d e viati o ns i de ntifi e d d uri n g site m o nit ori n g will be ca pt ure d i n a Pr ot oc ol D e viat i o n l o g 
a n d cat e g ori z e d as k e y or n o n -k e y  de viati o ns base d o n Pr ot o c ol D e viati o n Classifi cati o n  F or m . 
T he k e y pr ot o c ol d e viati o ns will be s u m mari z e d b y tr eat me n t gr ou p. Listi n gs will b e ge n erat e d f or 
t h e k e y or n o n -k e y pr ot o c ol d e viati o ns, r es p ecti v el y.   
 
5  
   E F FI C A C Y  D A T A  
 
5. 1  Ge ne r al C o nsi de r ati o ns  
All effi ca c y a nal yses will b e p erf or m e d o n t h e I T T p o p ulati o n . I n a d diti o n, t h e pri mar y a n d t h e 
k e y se c o n dar y e n d p oi nt s will als o be p erf or m e d o n t he P P  p o p ulati o n.  
T he pri mar y, se nsiti vit y a n d s u p pl e m e ntar y a nal y ses f or t h e pri mar y a n d k e y sec o n dar y e n d p oi nts 
are list e d i n t h e bel o w ta ble. 
 
T a ble 1               A n al ysis f o r Pri m ar y a n d K e y Se c o n d ar y E n d p oi nts  
E n d p oi nt  
A n al ysis  
A n al ysis 
P o p ul ati o n  
S A P 
Se cti o n  
2 8 -ite m 
P S P R S  
t ot al sc o r e, 
1 5 -ite m 
P S P R S 
t ot al sc o r e 
Pri mar y: A nal ysis of c ha n ge fr o m baseli n e at 
W e e k 5 2 
( M M R M) 
I T T 
5. 2. 3  
Se nsiti vit y: 
C o p y i ncre m e nt fr o m refer e n ce 
m et h o d 
(M M R M ) 
I T T 
5. 2. 4. 1  
Se nsiti vit y: J u m p t o r efer e n c e m et h o d (M M R M ) 
IT T  
5. 2. 4. 2  
Se nsiti vit y: I m p utati o n b y nat ural disease pr o gr essi o n 
( A N C O V A) 
I T T 
5. 2. 4. 3  
Se nsiti vit y: Ti p pi n g p oi nt a nal ysis ( A N C O V A)  
I T T 
5. 2. 4. 4  
Se nsiti vit y: Patt er n mi xt ur e m o d el ( M M R M ) 
I T T 
5. 2. 4. 5  
S u p pl e me ntar y:  P S P R S s u bscal e a nal ysis  (M M R M ) 
I T T 
5. 2 . 5. 1 
S u p pl e me ntar y:  T i me t o cli nical o ut c o me a nal ysis ( Ka pla n 
Meier a nal ysis a n d C o x pr o p orti o nal ha zar d m o d el)  
I T T 
5. 2. 5. 2  
S u p pl e me n tar y: 
Ce ns ori n g 
aft er 
i nt er c urr e nt 
e v e nts 
( M M R M) * 
I T T 
5. 2. 5. 3  
S u p pl e me ntar y: P er -pr ot o c ol a nal ysis ( M M R M)  
Per -pr ot o c ol  5. 2. 5. 4  
S u p pl e me ntar y: Res p o n d er a nal ysis ( L o gisti c re gr essi o n)  
I T T 
5. 2. 5. 5  


 
 
2 5  
 
S u p pl e me ntar y: S l o p e a nal ysis ( M M R M) 
I T T 
5. 2. 5. 6  
S u p p l e me ntar y: Di v er g e n c e effe ct a nal ysis ( M M R M)  
I T T 
5. 2. 5. 7  
M D S -
U P D R S 
P art II,  
P S P 
c o g niti v e 
c o m p osite 
b atte r y , 
P S P -Q o L  
Pri mar y: A nal ysis of c ha n ge fr o m baseli n e at 
W e e k 5 2 
( M M R M) 
I T T 
5. 3. 1. 1  
5. 3. 1. 3  
5. 3. 1. 4  
Se nsiti vit y: Patt er n mi xt ur e m o d el ( M M R M ) 
I T T 
5. 3. 1. 5  
S u p pl e me ntar y: 
Ce ns ori n g 
aft er 
i nt er c urr e nt 
e v e nts 
( M M R M) * 
I TT  
5. 3. 1. 5  
S u p pl e me ntar y: P er -pr ot o c ol a nal ysis ( M M R M)  
Per -pr ot o c ol  5. 3. 1. 5  
S u p pl e me ntar y: S l o p e a nal ysis ( M M R M) 
I T T 
5. 3. 1. 5  
S u p pl e me ntar y: Di v er g e n c e effe ct a na l ysis ( M M R M)  
I T T 
5. 3. 1. 5  
S u p pl e me ntar y:  S u bscale a nal ysis f or 
P S P c o g niti v e 
c o m p osit e batt er y  ( M M R M) 
I T T 
5. 3. 1. 5  
C GI -C  
Pri mar y: A nal ysis at W ee k 5 2 ( M M R M)  
I T T 
5. 3. 1. 2  
S e nsiti vit y: Patt er n mi xt ur e m o d el (M M R M ) 
I T T 
5. 3. 1. 5  
S u p pl e me ntar y: 
Ce ns ori n g 
aft er 
i nt er c urr e nt 
e v e nts 
( M M R M) * 
I T T 
5. 3. 1. 5  
S u p pl e me ntar y: P er -pr ot o c ol a nal ysis ( M M R M)  
Per -pr ot o c ol  5. 3. 1. 5  
S u p pl e me ntar y: S l o p e a nal ysis ( M M R M) 
I T T 
5. 3. 1. 5  
S u p pl e me ntar y: Di v er g e n c e effe ct a nal ysis ( M M R M)   
I T T 
5. 3. 1. 5  
* A nal ysis  e x cl u d es data c olle ct e d aft er t h e i nt erc urr e nt e v e nt  of pre mat ur e disc o nti n u ati o n of t h e 
st u d y tr eat m e nt. All ot h er a nal yses will i n cl u de data c oll ecte d aft er i nt er c urre nt e v e nts  [I C H E 9 
( R 1) A d d e n d u m 2 0 1 7]. 
 
 
 
Visit wi n d o ws f o r m a p pi n g effic ac y e n d p oi nt  
F or effi ca c y data t hat ar e s u m mari z e d or a nal yz e d b y visit, data c oll e ct e d o n all sc h e d ul e d visits 
a n d all u nsc h e d ul e d visits w ill be ma ppe d t o a n a p pr o priate a nal ysis visit usi n g t h e wi n d o wi n g 
sc h e m e s h o w n i n T a ble s 2 -6 .  If t h er e are 2 or m or e assess me nts a vaila bl e i n t h e sa m e a nal ysis 
wi n d o w f or a s u bj e ct, t h e assess m e nt t hat is cl osest t o t he tar g et vis it da y will b e use d f or a nal ysis. 
If t h ere ar e 2 or m ore assess m e nts i n t h e sa m e a nal ysis wi n d o w wit h t h e sa m e dista n c e fr o m t h e 
tar g et visit da y, t he later assess me nt will be use d.  
 


 
 
2 6  
 
T a ble 2  
 Visit Wi n d o ws f o r Pri m ar y E n d p oi nt : P S P R S 
A n al ysis visit  
T ar g et  visit d a y  A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e c e nt n o n -missi n g val u e  o n or pri or t o 
t h e first d ose dat e 
We e k 1 2  
8 5  
[ 4 3, 12 6]  
We e k 2 4  
1 6 9  
[ 1 2 7, 2 1 0]  
We e k 3 6  
2 5 3  
[ 2 1 1, 2 9 4] 
We e k 4 8  
3 3 7  
[ 2 9 5, 3 5 0] 
We e k 5 2  
3 6 5  
[ 3 5 1, 3 7 8 ] 
 
T a ble 3  
Visit 
Wi n d o ws f o r K e y Se c o n d ar y Effic ac y E n d p oi nts  (M D S -U P D R S, 
C GI, P S P c o g niti v e c o m p osite b atte r y, a n d P S P -Q o L ) a n d R B A N S  
A n al ysis visit  
T ar g et visit d a y  
A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e c e nt n o n -missi n g val u e  o n or pri or t o 
t h e first d ose dat e  
We e k 1 2  
8 5  
[ 4 3, 1 2 6] 
We e k 2 4  
1 6 9  
[ 1 2 7, 2 1 0]  
We e k 3 6  
2 5 3  
[ 2 1 1, 3 0 8] 
We e k 5 2  
3 6 5  
[ 3 0 9, 3 7 8 ] 
 
T a ble 4  
Visit 
Wi n d o ws f o r 
Ot he r  Se c o n d ar y 
Effic ac y 
E n d p oi nts : S E A D L, 
P h o ne mic Fl ue nc y Test, W AI S -I V Lette r N u m be r Se q ue nci n g T as k, C ol o r 
Tr ails test, a n d M o C A  
A n al ysis visit  
T ar g et visit d a y  A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e c e nt n o n -missi n g val u e  o n or pri or t o 
t h e first d ose dat e 
We e k 1 2  
8 5  
[ 4 3, 1 2 6] 
We e k 2 4  
1 6 9  
[ 1 2 7, 2 1 0]  
We e k 3 6  
2 5 3  
[ 2 1 1, 2 9 4] 
We e k 4 8  
3 3 7  
[ 2 9 5, 4 3 4 ] 


 
 
2 7  
 
 
T a ble 5  
Visit 
Wi n d o ws f o r Te rti ar y/ E x pl o r at o r y  e n d p oi nts: 
 
 a n d 
 
 
T a ble 6  
Visit Wi n d o ws f o r v o lu metric M RI  
 
 
H a n d li n g of missi n g ite ms f o r sc ales 
 
If a n y of t h e i n di vi d u al it e ms f or t h e M D S -U P D R S Part II  a n d M o C A  is missi n g, t h e tot al sc or e 
of t h e c orr es p o n di n g e n d p oi nt will b e i m p ut e d b y pr orati n g t h e o bser ve d sc ores [ va n Gi n k el 
2 0 1 0].  
•  F or M D S -U P D R S Part II , if 3 or fe wer of 1 3 ite ms (< 2 5 %) ar e missi n g, t h e t otal sc or e will 
be i m p ut e d b y t he pr orati n g  al g orit h m. If m or e t ha n 3 it e ms ar e missi n g, t h e t otal sc or e of 
M D S -U P D R S Part II  at t hat visit will b e c o nsi d er e d missi n g.   
•  F or  M o C A , if 1 d o mai n (< 2 5 %)  of t h e 7 d o mai ns  is missi n g, t h e t otal sc ore will b e i m p ut e d 
usi n g t h e sa me pr orati n g al g orit h m; if m or e t ha n 1  d o mai ns  ar e missi n g , t he t otal sc ore at 
t hat visit will b e c o nsi d er e d as missi n g. 
F or C T T  1 a n d 2, if a n y test sc or es ar e missi n g d u e t o p arti ci pa nt t o o i m pai re d, parti ci pa nt r ef use d , 
ref usa l (s u bj e ct or i nf or ma nt), ph ysi cal r eas o n , or t o o i m pair e d (c o g niti v el y or ps y c hiatricall y) , th e 
missi n g val u es  will be i m p ut e d t o 2 4 0 se c o n ds. If s u bj ects fail e d t he C T T pret e st (h e n c e n o C T T  
was assesse d ), or  di d  n ot  c o m pl et e C T T wit hi n t h e ti m e li mit of  2 4 0 se c o n ds, t h e missi n g val u es 
will b e i m p ut e d t o 2 4 0 se c o n ds as well.  
F or L ett er n u m b er se q u e nc e t est, if partial  it e m sc or es are missi n g d u e t o p artici pa nt t o o i m pair e d , 
p arti ci pa nt r ef use d , ref usal (s u bj e ct or i nf or ma nt), ph ysi cal r eas o n  or t o o i m pair e d ( c o g niti v el y or 
ps y c hiatri call y) , th e missi n g L N S t otal ra w sc or e  will b e i m p ute d wit h t h e s u m  of c o m pl et e d ite m 
sc ores, a n d the l o n g est L N S t otal ra w sc or e  will b e i m p ut e d wit h t h e c o u nt of l o n g est se q u e n c e 
(stri n g)  n u mbers a n d lett ers c orr ectl y r e pr o d u c e d b y parti ci pa nt.  
A n al ysis visit  
T ar g et visit d a y  A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e c e nt n o n -missi n g val u e  o n or pri or t o 
t h e first d ose dat e, e x ce pt f or  
 
 
We e k 2 4  
1 6 9  
[ 8 5, 2 5 2] 
We e k 4 8  
3 3 7  
[ 2 5 3, 4 3 4 ] 
A n al ysis visit  
T ar g et visit d a y  A n al ysis visit wi n d o w  
Baseli n e  
1  
< = 8 4  
We e k 2 4  
1 6 9  
[8 5 , 2 5 2 ] 
We e k 5 2  
3 6 5  
[ 28 1 , 4 4 8 ] 


 
 
2 8  
 
F or ea c h of t he i n di vi d u al c o m p o ne nt  t ests i n t h e P S P c o g niti v e c o m p osit e batt er y , if partial it e m 
sc ores wit hi n a t est are missi n g d u e t o p arti ci pa nt t o o i m pair e d , parti cipa nt r ef use d , ref usal (s u bj e ct  
or i nf or ma nt) , ph ysical r eas o n , or to o i m pair e d ( c o g niti v el y or ps y c hiatri call y) , t h e missi n g t est 
sc ore will b e i m p ut e d usi n g t he s u m of c o m pl et e d it e m sc or es.  
 
 
C o nsi de r ati o ns f o r m ulti ple c o m p aris o n a dj ust me nts  
Ke y se c o n dar y e n d p oi nts ha ve b ee n ra n k pri oriti z e d, i n t h e or d er s h o w n i n Se cti o n 2 .  I n or d er t o 
c o ntr ol f or a T y p e I err or  f or t h e k e y sec o n dar y e n d p oi nts, a se q u e ntial cl ose d t esti n g pr o ce d ur e 
will b e use d .  If statisti cal si g nifi ca nc e is n ot a c hi e ved f or a k e y se c o n d ar y e n d p oi n t, all k e y 
se c o n dar y e n d p oi nt(s) of a l o wer ra n k will n ot b e c o nsi d er e d  statisti call y si g nifi ca nt.  
T her e will b e n o m ulti ple  c o m paris o n a dj ust me nts f or t h e se nsiti vit y or  s u p ple m e ntar y a nal yses 
f or t h e pri mar y a n d k e y se c o n dary effi ca c y e n d p oi nts, t h e n o n -k e y se c o n dar y e n d p oi nts, t h e 
tertiar y effi ca c y e n d p oi nts, t h e s u b gr o u p a nal yses or t h e a d diti o nal anal yses.  
 
 
C o nsi de r ati o ns f o r b ase 
M M R M 
m o del f o r c h a n g e fr o m b aseli ne 
a n al yses  
T he o bser v e d val u e a n d c ha n g e fr o m baseli ne f or a para m et er of i nt er est will b e s u m mari z e d b y 
treat m e nt gr o u p at eac h p ost -baseli ne visit. A mi x e d m o d el r e peat e d m eas ures ( M M R M)  m o d el 
will b e use d as t h e pri mar y a nal ysis t o a nal yz e c ha n g e fr o m baseli n e usi n g fi x e d effe cts of 
treat m e nt gr o u p, ti m e ( cat e gori cal), tr eat m e nt gr o u p -b y -ti m e i nt era cti o n, baseli n e f or t he 
para m et e r of i nt erest, ( baseli n e f or t h e para m et er of i nt erest) b y ti m e i nt era cti o n, baseline C ol or 
Trails 2 t est ( ≤ 1 7 0 or  > 1 7 0 sec o n ds ) a n d r e gi o n (se e h ealt h care r e gi o n d efi niti o ns i n Se ctio n 3. 1 ). 
A n u nstr u ct ure d c o varia nc e matri x will b e use d t o m o del t h e wit hi n -s u bj ect varia n c e -c o varia n c e 
err or s.  If t h e u nstr u ct ure d c o varia nc e str u ct ur e matri x r es ults i n a la c k of c o n v er g e n c e, t h e 
het er o g e n e o us 
T o e plitz c o va ria n c e str u ct ure f oll o we d b y the h et er o g e n e o us first -or d er 
a ut ore gr essi ve c o varia nc e str u ct ure will b e use d.  T h e  Ke n war d -R o ger a p pr o xi mati o n will b e use d 
t o esti mat e t h e d e n o mi nat or de gr e es of fr e e d o m.  If t h e u nstr u ct ur e d varia n c e -c o varia n ce str u ct ure 
d o es n ot c o n ver g e  i n t h e M M R M m o del a n d a str u ct ure d m o d el is use d, t h e sa n d wi c h esti mat or 
will be use d t o g et t h e varia n c e of t he tr eat me nt effe ct esti mat or . T h e  a dj ust e d mea n of ea c h 
treat m e nt gr o u p, as well as t h e tr eat m e nt gr o u p differ e nc es will b e dis pla y e d wit h 9 5 % CI a n d p -
val u e.  In t he pri mar y a nal ysis  of ea c h e n d p oi nt , missi n g data ar e ass u m e d t o be missi n g at ra n d o m 
[ R u bi n 1 9 7 6].  
 
5. 2  Pri m ar y Effic ac y E n d p oi nt  
 
T w o pri mar y e n d p oi nts  me eti n g e vi d e ntiar y r e q uire m e nts of t he 
U S , a n d E ur o pe/Ja pa n , 
res pe cti v el y wer e sel e ct e d: c ha n ge fr o m  baseli n e i n 1 5 -it e m P S P R S at W e e k 5 2 ( U S ); a n d c ha n ge 
fr o m baseli ne i n 2 8-it e m P S P R S at W e e k 5 2 ( E ur o p e a n d Ja pa n ).  F or e a c h re gi o n, o nl y t h e 
e n d p oi nt w hi c h met e vi de ntiar y  r e q uire m e nts of t h e r e gi o n is c o nsi dere d pri mar y  a n d  t h e ot h er is 
c o nsi d er e d a n o n -k e y se c o n dar y e n d p oi nt.  
 


 
 
2 9  
 
T he ori gi nal P S P R S c o m prises 2 8 it e ms i n 6 ar eas. Si x it e ms ( 1, 2, 2 0 -2 3) are rat e d o n a 3 -p oi nt 
scal e ( 0-2) a n d 2 2 r e mai ni n g i t e ms ar e rat e d o n 5-p oi nt s cal e ( 0 -4). Si x s u bscal e sc or es are a ut o -
cal c ulate d as f oll o ws:  
•  Hist or y: s u m of 7 ite m sc or es wit h t otal m a xi m u m sc or e of 2 4 p oi nts: it e m 1 wit h dra wal, 
ite m 2 irrita bilit y, it e m 3 d ys p ha gia f or s oli ds, it e m 4 k nife a n d f or k, ite m 5 falls, it e m 6 
uri nar y i n c o nti n e n c e, it e m 7 sl e e p diffi c ult y;  
•  Me ntati o n: s u m of 4 it e m sc ores wit h t otal 
ma xi m u m sc ore of 1 6 p oi nts : it e m 8 
dis ori e ntati o n, it e m 9 bra d y p hr e nia, ite m 1 0 e m oti o nal i n c o nti n e nc e, it e m 1 1 gras pi n g;  
•  B ul bar: s u m of 2 ite m sc ore s wit h t otal ma xi m u m sc ore of 8 p oi nts: it e m 1 2 d ysart hria a n d 
ite m 1 3 d ys p ha gia f or li q ui ds; 
•  Oc ular: s u m of 4 it e m sc or es wit h t otal ma xi m u m sc or e of 1 6 p oi nts: it e m 1 4 u p war d e y e 
m o v e m e nt, it e m 1 5 d o w n war d e y e m o v e m e nt, it e m 1 6 left -ri g ht e ye m o v e m e nt, it e m 1 7 
e y eli d d ysf u n cti o n;  
•  Li m b: s u m of 6 it e m sc or es wit h t otal ma xi m u m sc or e of 1 6 p oi nts: it e m 1 8 l i m b ri gi dit y, 
ite m 1 9 li m b d ysto nia. it e m 2 0 fi n g er ta p pi n g, it e m 2 1 t oe ta p pi n g, it e m 2 2 a pra xia of ha n d 
m o v e m e nt, it e m 2 3 tr e m or;  
•  Gait: s u m of 5 it e m sc or es wit h t otal ma xi m u m sc or e of 2 0 p oi nts: it e m 2 4 ne c k ri gi dit y, 
ite m 2 5 arisi n g fr o m c hair, it e m 2 6 gait, it e m 2 7 p ost ural sta bili t y, it e m 2 8 sitti n g d o w n. 
 
 
Pri m ar y e n d p oi nt f o r U nite d St ates ( U S ) 
 
Fift e e n  ite ms wer e  sel e ct e d fr o m t h e ori gi nal 2 8-ite m P S P R S t o f or m a 1 5 -ite m P S P R S: it e ms 3, 
4, 5, 1 2, 1 3, 1 4, 1 5, 1 6, 1 7, 1 9, 2 4, 2 5, 2 6 , 2 7, a n d 2 8 . A m o ng  t h ese 1 5  it e ms, r es p o nse o pti o ns  of 
1 3 ite ms will be  c olla pse d  a n d r esc or e d (d etails ar e pr o vi d e d i n S e cti o n 1 1 .1 )
 
 
 
  
 
Base d  o n fa ct or a nal ysis  of p o ol e d  hist ori cal data , t hr e e d o mai n s were i d entifi e d: gait/li m b 
f u n cti o n (8 it e ms, i n cl u di n g it e ms 4, 5, 1 9, 2 4-2 8), o c ular m ot or ( 4  ite ms, i n cl u di n g a v era ge of 
ite ms 1 4-1 6 a n d  it e m 1 7 ), a n d b ul bar (3 ite ms, i n cl u di n g it e ms 3, 1 2, 1 3).  T h e c ha n ge fr o m baseli ne 
at W e e k 5 2 i n t his 1 5 -it e m P S P R S t otal s c or e is use d as t h e pri mar y e n d p oi nt f or U S . T h e t er ms 
“ 1 5 -it e m P S P R S” a n d “1 5 -it e m P S P R S t otal sc or e” will b e use d i nterc ha n g ea bl y. T he 2 8 -it e m 
P S P R S will be i ncl u d e d i n t h e d ossier as s u p p orti v e i nf or mati o n f or t h e U S.   
 
 
Pri m ar y e n d p oi nt f o r E ur o pe a n d J a p a n  
 
T he ori gi nal 2 8 -P S P R S t otal sc or e is  a ut o -cal c ulat e d as t h e s u m of all 2 8 ite m sc or es, a n d ra n g es 
fr o m 0 ( n or mal) t o 1 0 0 p oi nts. T he c ha n g e fr o m baseli n e at W e e k 5 2 i n t his 2 8 -it e m P S P R S is t h e 
pri mar y e n d p oi nt f or  E ur o p e a n d Ja pa n . T h e t er ms “ 2 8 -it em P S P R S” a n d “ 2 8 -it e m P S P R S t otal 
sc ore” will be use d i nt erc ha n g ea bl y. T h e 1 5 -ite m P S P R S will b e i n cl u d e d i n t h e d ossi er as 
s u p p orti v e i nf or mati o n f or E ur o p e a n d Ja pa n.  
 


 
 
3 0  
 
 
Pri m ar y a n al ysis  
T he pri mar y a nal ysis of t h e pri mar y e n d p oi nt s, c ha n ge fr o m baseli n e i n 1 5 -it e m a n d 2 8 -it e m 
P S P R S at W e e k 5 2 , is t h e tr eat m e nt p oli c y a p pr oa c h [I C H E 9 ( R 1) A d de n d u m 2 0 1 4, 2 0 1 7]. T he 
e sti ma n d of t he pri mar y a nal ysis  is defi n e d as: 
•  P o p ulati o n : a ll s u bj e cts i n t he I T T p o p ulati o n 
•  Varia bl e : c ha n g e fr o m baseli n e i n P S P R S at W e e k 5 2  
•  Ha n dli n g of i nt er c urr e nt e ve nts : re gar dl ess of i nt er c urr e nt e v e nts ( e xa m pl e, tr eat m e nt 
disc o nti n u ati o n ) 
•  S u m mar y statisti cs: d iffer e n ce i n varia bl e mea ns b et wee n tr eat me nt gr o u ps 
T he pri mar y a nal ysis will be base d o n t h e M M R M m o d el d es cri b e d i n Se cti o n 5. 1 . A li n e pl ot of 
a dj uste d m ea n c ha n g e fr o m baseli n e  o v er ti m e  a n d a  bar pl ot of r es ults at We e k 5 2 will als o b e 
pr o vi d e d.  
I n a d diti o n t o t his pri mar y a nal ysis, s o m e se nsiti vit y a nal yses ( S ec ti o n 5. 2. 4 ) a n d s u p pl e m e ntar y 
a nal yses ( S e cti o n 5. 2. 5 ) will b e perf or m e d. F or est pl ots of a dj uste d m ea n c ha n ge fr o m baseli n e 
vers us  pla c e b o at W ee k 5 2 fr o m pri mar y, s e nsiti vit y a n d s u p p l e m e ntar y a nal yses will b e pr o vi d e d. 
A listi n g of pri mar y e n d p oi nts will b e pr o vi d e d.  
 
 
Se nsiti vi t y a n al ysis 
T he f oll o wi n g se nsiti vit y a nal yses will b e p erf or me d t o assess t h e r o b ust n ess of t he pri mar y 
a nal ysis t o d e viati o n fr o m t h e missi n g -at -ra n d o m ass u m pti o n. All t he se nsiti vit y a nal yses will be 
c o n d u cte d f or t h e  I T T p o p ulati o n f or b ot h 1 5 -it e m a n d 2 8-it e m P S P R S . 
 C o p y i nc r e me nt fr o m r efe r e nc e ( CI R) met h o d  
T he CI R met h o d ( w hi c h is t h e sa me as t h e c o p y differ e n ce fr o m c o ntr ol m et h o d d escr i be d i n t h e 
st u d y pr ot o c ol) will b e a p pli e d t o i m p ute t he p ost -wit h dra wal data f or a n y s u bj e ct assi g n e d t o  
BII B 0 9 2 treat m e nt w h o wit h dra ws fr o m st u d y earl y base d o n data fr o m t h e pla ce b o gr o u p rat her 
t ha n t he s u bj e ct’s o w n ra n d o mi ze d treat m e nt gr o u p [ Car p ent er et al. 2 0 1 3]. S p ecifi ca ll y, f or a 
s u bje ct assi g n e d t o BII B 0 9 2 tr eat me nt w h o wit h dra ws earl y, his or her m ea n traje ct or y aft er earl y 
wit h dra wal is ass u m e d t o b e parallel t o t h e m ea n traje ct or y of t h e pla c e b o gr o u p, a n d t h e differe n c e 
bet wee n t h e t w o m e a ns is t h e sa m e as t h e differ e nc e at t h e ti me of wit h dra wal. T his m et h o d 
ass u m es t hat a n y b e n efit gai n e d f r o m pr e vi o us treat m e nt will b e r etai n e d, b ut s u bj e cts pr o gr ess as 
if t h e y were o n pla c e b o aft er wit h dra wal fr o m st u d y. F or a n y s u bj ect o n pla c e b o w h o wit h dra ws 
earl y, hi s or her p ost-wit h dra wal pr ofile will be i m p u t e d f oll o wi n g t h e missi n g-at -ra n d o m 
pri nci ple. I m pl e m e ntati o n d etails ca n b e f o u n d i n S e cti o n  1 1 . 2. 1.  
Aft er all missi n g data ha ve b e e n i m p ute d, M M R M m o d el d escri b e d i n Se cti o n 5. 1  will b e a p plie d 
f or a nal ysis. 
 J u m p t o r efe r e nc e  met h o d ( J 2 R)  
T he J 2 R m et h o d will b e a p pli e d t o i m p ut e t he p ost -wit h dra wal data f or a n y s u bj e ct assi g n e d t o 
BII B 0 9 2 treat m e nt w h o wit h dra ws fr o m st u d y earl y base d o n data fr o m t h e pla ce b o gr o u p rat her 
t ha n t he s u bj e ct’s o w n ra n d o mi ze d treat m e nt gr o u p [ Car p e nt er et al. 2 0 1 3]. Sp ecifi call y, f or a 
s u bje ct assi g n e d t o BII B 0 9 2 tr eat me nt w h o wit h dra ws earl y, his or h er m ea n traje ct or y aft er earl y 


 
 
3 1  
 
wit h dra wal is ass u m e d t o b e t he sa m e m ea n traj e ct or y as t he pla c e b o gr o u p. T his m et h o d ass u m es 
t hat a n y b e n efit gai n e d fr o m pre vi o us tr eat me nt will b e i m m e diat el y l ost. F or a n y s u bj e ct o n 
pla ce b o w h o wit h dra ws earl y, his or h er p ost -wit h dra wal pr ofil e will b e i m p ute d f oll o wi n g t h e 
missi n g -at -ra n d o m pri n ci pl e. Im pl e m e ntati o n d etails ca n b e f o u n d i n S e cti o n 1 1 .2 .2 .  
 
Aft er all missi n g data ha ve b e e n i m p ute d, M M R M m o d el d escri b e d i n Se cti o n 5. 1 will b e a p plie d 
f or a nal ysis. 
 
 I m p ute d b y  n at ur al  dise ase pr o g r essi o n  
A ft er earl y wit h dra wal fr o m t he st ud y, s u bj ects ar e ass u m e d t o e x hi bit a n e v ol uti o n of t he disease 
si milar as t h e nat ural disease pr o gr essi o n (f or all tr eat me nt gr o u ps)  i n t his i m p utati o n met h o d. T he 
missi n g data at W e e k 5 2 f or t his st u d y will b e i m p ut e d usi n g t h e li near e xtra p olati o n a p pr oa c h. 
Missi n g data  ar e i m p ut e d b y ass u mi n g hist ori cal pla ce b o pr o gr essi o n ( 1 1. 3 9  p oi nts/ y ear )) i n t h e 
2 8 -it e m P S P R S t otal sc or e fr o m t h e visit of t he last o bser vati o n pri or t o W e e k 5 2 . F or e xa m pl e, if 
a partici pa nt disc o nti n u es at W ee k 2 4 wit h 2 8 -it em P S P R S t otal sc or e of 4 1  p oi nts, t he n t h e W ee k 
5 2 val u e is i m p ute d wit h 4 1  + 1 1. 3 9 *( 1 -( 2 4/ 5 2)). T he nat ural disease pr o gr essi o n , 1 1.3 9  
p oi nts/ y ear i n 2 8 -it e m P S P R S a n d 9.3 4 p oi nts/ y ear i n 1 5 -it e m P S P R S, w er e det er mi n e d base d o n 
a n  a nal ysis of s u bje cts wit h P S P disease o nset < 5 y ears fr o m t h e Da v u n eti d e st u d y.  Aft er all 
missi n g data ha ve b e e n i m p u t e d, a n A N C O V A m o d el a dj usti n g f or tr eat m e nt gr o u p, baseli n e 
P S P R S, baseli ne C ol or Trails 2 t est ( ≤ 1 7 0 or > 1 7 0 se c o n ds ) a n d r e gi o n will be a p plie d t o a nal y z e 
t h e c ha n ge fr o m baseli n e i n P S P R S  t otal sc or e at W e e k 5 2. 
 Ti p pi n g p oi nt a n al ysis  
T he  ti p pi n g-p oi nt a nal ysis is a pr o gr essi v e str es s-testi n g t o assess h o w se vere d e part ur es fr o m 
missi n g -at -ra n d o m m ust b e i n or d er t o o v ert ur n t h e c o n cl usi o n of t he pri mar y a nal ysis [ Ya n et al. 
2 0 0 9].  F or o ur st u d y, s u bj e cts are ass u m e d t o ha ve w orse sc ores a ft er earl y wit h dra wal fr o m st u d y 
c o m par e d t o su bje cts w h o re mai n o n st u d y.  
T he missi n g data ar e first i m p ute d b y t he sta n dar d m ulti pl e i m p utati o n ( ass u mi n g missi n g at 
ra n d o m). T o r efl e ct t h e w orse p erf or ma n c e aft er earl y wit h dra wal, pre -s p e cifie d s hift para m et ers 
𝛿𝑐 a n d 𝛿𝑡 (e. g.,  t h e differ e n c e b et we e n 𝛿𝑐 a n d 𝛿𝑡 is t h e o bser v e d tr eat m e nt effe ct r o u n d e d  u p  t o t he 
ne xt i nt e g er ) ar e a d d e d t o t h e i m p ut e d val u es f or s u bj e cts o n pla c e b o a n d BII B 0 9 2, res pe cti v el y. 
T he a dj ust e d m ulti pl e i m p ute d datasets will t h e n b e a nal y z e d b y a n A N C O V A m o d el a n d t he 
res ults will b e c o mbi n e d usi n g t he R u bi n’s r ule f or i nfer e n c e.  
A ra n g e of s hift para m et ers 𝛿𝑐 a n d 𝛿𝑡 will b e a p plie d a n d p -val u e  will b e pr ese nt e d f or ea c h 
c o m bi nati o n of 𝛿𝑐 a n d 𝛿𝑡. T he ti p pi n g re gi o n is d efi n e d as t h e c o m bi nati o ns of 𝛿𝑐 a n d 𝛿𝑡 s u c h t hat 
t h e treat m e nt effe ct is n o l o n g er si g nifica nt ( p-val u e gr eat er t ha n t h e si g nifica nc e l e v el).  Pl ot of 
ti p pi n g r e gi o n f or c ha n g e fr o m baseli ne i n P S P R S  at We e k 5 2  will be prese nte d . 
T he scie ntifi c pla usi bilit y of t h e ti p pi n g re gi o n will b e e val u ate d. If i m pla usi bl e d e part ur es fr o m 
t h e missi n g-at -ra n d o m ass u m pti o n (lar g e δ) are ne e d e d i n or der t o c ha n g e t h e r es ults fr o m 
statisti call y si g nifi ca nt t o i nsi g nifi ca nt, t h e r es ults of t h e p rimar y a nal ysis are c o nsi dere d t o b e 
r o b ust t o de part ur e fr o m t h e missi n g-at -ra n d o m ass u m pti o n. 


 
 
3 2  
 
 P atte r n mi xt ur e m o del  
T he patt er n mi xt ur e m o del ( P M M) re pr ese nts a g e n eral a n d fle xi bl e fra m e w or k t o m o d el t he 
pr e di cti v e distri b uti o n of missi n g data c o n diti o n al o n t h e o bser v e d data [ Littl e 1 9 9 3, 1 9 9 4]. It 
all o ws f or m ulati n g ass u m pti o ns re gar di n g missi n g data i n a tra ns par e nt  a n d cli ni call y i nt er pr eta ble 
ma n n er.  
I n t h e P M M fra m e w or k, s u bje cts ar e gr o u p e d i nt o missi n g patt er ns s o t hat s u bj e cts i n t h e sa m e 
patt e r n s hare si milar missi n g n ess c hara ct eristi cs. I n t his a nal ysis, missi n g patter ns will b e d efi n e d 
a cc or di n g t o t h e r eas o ns f or earl y wit h dra wal fr o m st u d y as r e p ort e d o n t h e el e ctr o nic cas e r e p ort 
f or m ( e C R F). T h e f oll o wi n g t w o patt er ns will b e c o nsi d er e d: 
•  S u bj e cts w h o wit h dra w d u e t o reas o ns t hat ma y b e r elat e d t o effica c y, i ncl u di n g la c k of 
effi ca c y, s u bj ect r e q u est t o disc o nti n u e st u d y tr eat me nt, s u bj ect wit h dr e w c o nse nt, p o or/ n o n -
c o m plia n c e, d eat h a n d wit h dra wal b y car e gi v er;  
•  S u bj e cts w h o wit h dra w d u e t o  reas o ns t hat are u nli k el y r elat e d t o effi ca c y, i ncl u di n g a d v erse 
e v e nt , l ost t o f oll o w-u p, pr e g na n c y, s u bj e ct n o l o n g er m e ets st u d y crit eri a, a d mi nistrati v e 
reas o n b y s p o ns or, a n d ot h er. 
S u bj e cts w h o wit h dra w d u e t o r eas o ns t hat ma y be relat e d t o effi ca c y  w ill b e pe nali z e d a n d t h eir 
missi n g data will b e i m p ut e d usi n g t h e c o p y i n cr e m e nt fr o m r efer e n c e ( CI R) m et h o d [ Car p e nter 
et al. 2 0 1 3] (se e S e cti o n 5. 2. 4. 1  f or d escri pti o n of t h e CI R m et h o d). S u bj e cts w h o wit h dra w d u e 
t o r eas o ns t hat ar e u nli k el y r elate d t o effi ca c y will b e ha n dl e d usi n g t h e missi n g-at -ra n d o m 
ass u m pti o n a n d t h eir missi n g data wi ll be i m p ut e d usi n g t h e sta n dar d m ulti ple i m p utati on met h o d 
[ R u bi n 1 9 8 7]. S u bj e cts wit h missi n g data d u e t o r eas o ns ot h er t ha n earl y wit h dra wal (s u c h as ite m 
missi n g, o ut of wi n d o w, et c.) will  b e ha n dle d usi n g t h e missi n g -at -ra n d o m ass u m pti o n. F or b ot h 
i m putati o n m et h o ds, t h e f oll o wi n g c o variat es will b e i n cl u d e d i n t h e i m p utati o n m o d el: tr eat m e nt 
gr o u p, baseli n e P S P R S, bas eli n e C ol or Trails 2 t est ( ≤ 1 7 0 or > 1 7 0 sec o n ds ), r e gi o n a n d o bser v e d 
p ost baseli n e P S P R S t otal sc or e ( data fr o m ea c h visit as a c o var iat e). I m pl e m e ntati o n d etails ca n 
be f o u n d i n Se cti o n  1 1 . 2. 3. 
T he i m p ut e d datasets will be a nal y z e d b y M M R M m o d el descr i b e d i n S e cti o n 5. 1 .  T h e a nal y z e d 
res ults fr o m t h e i m p ut e d datasets will b e c o m bi ne d base d o n R u bi n’s r ul es [ R u bi n 1 9 8 7] ass u mi n g 
t hat t h e statisti cs esti mat e d fr o m ea c h i m p ut e d dataset ar e n or mall y distri b ut e d. 
If i nt er m e diat e missi n g va l u es ar e e n c o u nt er e d (s u c h as data missi n g at W e e k 1 2 b ut are a vaila bl e 
at s u bse q u e nt visits), a Mar k o v c hai n M o nt e Carl o ( M C M C) met h o d t hat ass u m es m ulti variate 
n or malit y will b e use d t o i m p ut e t h e i nt er m e diat e missi n g val u es a n d pr o d u c e a m o n ot o n e missi n g 
patt er n ( data wit h o nl y t er mi nal missi n g a n d n o i nter me diat e missi n g) [ Li 1 9 8 8; Sc hafer 1 9 9 7].  
 
 
S u p ple me nt ar y a n al ysis  
 P S P R S  s u bsc ales a n d ite m le v el sc o r es 
T he 2 8 -ite m P S P R S is c o m prise d of 6 s u bscal es: Hist or y, M e ntati o n, B u l bar, O c ular, Li m b, a n d 
Gai t. 2 8 -ite m P S P R S is t he s u m of t h e sc or es f or t h ese 6 s u bscal es. F or ea c h of t h e 6 s u bscal es, 
t h e baseli n e val u e a n d t h e c ha n g e fr o m baseli n e at ea c h p ost-base li n e visit will be s u m mari z e d b y 
treat m e nt gr o u p. T he sa m e M M R M m o d el as t h e pri mar y a nal ysis wil l als o b e a p pli e d t o t h e 6 


 
 
3 3  
 
s u bscal es. A f or est pl ot of a dj ust e d mea n c ha n g e fr o m baseli n e v erse pla ce b o at W ee k 5 2 fr o m of 
ea c h s u bscal e will be pr o vi d e d.  A cat e g orical s u m mar y of ea c h of t h e 2 8 ite ms will b e p erf or me d.  
T he sa m e s u m mar y a n d M M R M a nal yses will b e a p pli e d t o t h e 3 s u bscales of 1 5-ite m P S P R S, 
gait/li m b f u ncti o n, o c ular m ot or a n d b ul bar . A cate g ori cal s u m mar y of ea c h of t h e 1 5  it e ms will 
als o be p erf or m e d.  
 
 P S P R S  ti me t o cli nic al o utc o me a n d s hift a n al ysis  
 
Ti me t o cli nical outc o m e  a nal ysis will  i ncl u d e t h e f oll o wi n g cli ni cal o ut c o m e d efi niti o ns base d o n 
sel e ct e d it e ms i n t h e 2 8 -it e m P S P R S: 
•  L oss of i n d e p e n d e nt wal ki n g: c ha n ge fr o m 0, 1, 2 or 3 at baseli ne t o 4 at a n y p ost -baseli n e 
visits u p t o W e e k 5 2 i n It e m 2 6 Gait; 
•  U ni nt elli gi bl e s pe e c h : c ha n ge fr o m 0, 1, 2, or 3 at baseli n e t o 4 a t a n y p ost-baseli n e visits 
u p t o W e e k 5 2 i n It e m 1 2 D ysart hria ; 
•  U na bl e t o d o a cti viti es of d ail y Li vi n g: c ha n g e fr o m 0, 1, 2 or 3 at baseli n e t o 4 at a n y p ost-
ba seli n e visits u p t o We e k 5 2 i n It e m 4 Usi n g k nife & f or k, b utt o ni n g cl ot h es, was hi n g; 
•  Re q uir e u se of fe e di n g t u b e: c ha n ge fr o m 0, 1, 2 or 3 at baseli ne t o 4 at a n y  p ost -baseli n e 
visits u p t o W e e k 5 2 i n It e m 3  d ys p ha gia s oli ds  or It e m 1 3 d ys p ha gia li q ui ds; 
•  A n y  cli ni cal o ut c o m e : m e et a n y of t h e a b o v e f o ur cli ni ca l o ut c o m es.  
Ti me t o cli ni cal o ut c o m e is d efi ne d as t h e ti m e fr o m t h e first d ose t o t he first cli ni cal o ut c o m e i n 
t h e pla c e b o-c o ntr oll e d peri o d. S u bj ects w h o d o n’t r ea c h t h e cli nical  o ut c o m e s will be c e ns ore d 
a n d t he ce ns ori n g date is t h e last dat e i n t h e pla ce b o -c o ntr oll e d p eri o d. Ti m e t o cli ni cal o ut c o m e  
will b e dis pla y e d b y Ka pla n -M ei er pl ot b y tr eat m e nt gr o u p a n d als o be a nal y z e d usi n g a C o x 
pr o p orti o nal ha zar ds m o d el a dj usti n g f or tr eat m e nt gr o u p, baseli ne C ol or Tr ails 2 t est ( ≤ 1 7 0 or > 
1 7 0 se c o n ds) a n d r e gi o n.   
W it h t h e re c o g niti o n t hat d eat h ca n oft e n b e dir e ctl y r elat e d t o t h e pr o gr essi o n of P S P a n d t h e 
de v el o p m e nt  of t he cli ni cal o utc o m e u n der c o nsi d erati o n, we will rea nal yz e t he data usi n g t he ti m e 
t o cli ni cal o ut c o me  or deat h as  a c o m p osit e o utc o m e  f or ea c h cli ni cal o utc o m e d efi n e d a b o v e.  
S hifts fr o m baseli n e t o ea c h sc or e val u e at p ost baseli n e visits f or i n di vi d u al it e m f or all t h e 2 8 
ite ms i n P S P R S will  b e prese nt e d. T he sa m e s hift fr o m baseli ne a nal ysis will b e a p pli e d t o ea c h 
ite m i n t h e 1 5-it e m P S P R S. 
 Ce ns o ri n g afte r i nte r c ur r e nt e v e nts  
T he pri mar y a nal ysis ( S ecti o n 5. 2. 3 ) will b e r e p eat e d wit h t h e data c ens ore d after t h e i nt er c urr e nt 
e v e nt of pr e mat ur e disc o nti n u ati o n of t h e st u d y tr eat m e nt . T he  esti mate of t his a nal ysis r efl e cts 
t h e tr eat m e nt effe ct of BII B 0 9 2 if t h e dr u g is ta k e n as dir ecte d.  
 Pe r -pr ot o c ol a n al ysis  
T he p er -pr ot oc ol a nal ysis will b e d o ne u si n g t h e sa me m o d el as t h e pri mar y a nal ysis ( S ecti o n 5. 1 ) 
a n d a p pli e d i n t h e p er-pr ot o c ol p o p ulati o n ( S ecti o n 3. 2 ).  


 
 
3 4  
 
 Res p o n de r a n al ysis  
T o f urt h er assess w h et her s u bj e cts o n BII B 0 9 2 pr o gr ess differ e ntl y fr o m t h ose o n pla c e b o, 
res p o n der a nal ysis will b e c o n d uct e d. T h e r es p o n d ers will b e d et er mi n e d b y a t hr es h ol d of t h e 
pri mar y e n d p oi nt, i. e., s u bje cts w h ose c ha n g e fr o m baseli n e P S P R S at W e e k 5 2 is s mall er t ha n or 
e q u a l t o t h e thr es h ol d will be classifi e d as r es p o n d ers ( n ot w orse ni n g) a n d ot her wise will b e 
clas sifi e d as n o n-r es p o n ders ( w orse ni n g). All s u bje cts wit h missi n g data at 
W ee k 5 2 will be 
classifi e d as n o n -r es p o n d ers. 
T he r es p o n d er a nal ysis will b e  c o n d u ct e d f or  t w o t hr esh ol d val u es  i.e., s u bj e cts w h ose c ha n g e 
fr o m baseli n e i n 2 8-it e m P S P R S at W e e k 5 2 ar e less t ha n or e q u al t o t h e t hr es h ol d val u es . T he 
n u m b er of res p o n d ers a n d t h e r es p o nse rat e will be s u m mariz e d b y tr eat m e nt gr o u p. T he 
di c h ot o mi z e d r es p o nse, r es p o n der vs.  n o n -r es p o n d er, will b e m o del e d usi n g a l o gisti c r e gressi o n 
a dj usti n g f or t h e f oll o wi n g varia bl es : tr eat me nt gr o u p, baseli n e P S P R S, baseli n e C ol or Trails 2 
test ( ≤ 1 7 0 or > 1 7 0 se c o n ds) a n d r e gi o n.  I n a d diti o n t o t h e t w o sel ect e d t hr es h ol d val u es, t he 
c o nti n u o us r es p o n d er c ur v e t hat dis pla ys t h e p er ce nta ge of r es p o n ders u n der a wi d e ra n ge of 
t hr es h ol d val u es will be pr ese nte d b y treat m e nt gr o u p. T h e sa me a nal yses will b e a p pli e d t o 1 5 -
ite m P S P R S t otal sc or e usi n g t w o ot h er t hr es h ol d val u es. T h e t hr es h ol d val u es deter mi n e d usi n g 
a nc h or - a n d distri b ut e d -base d m et h o ds o n Da v u neti de st u d y data are: 6 p oi nts a n d 1 1 p oi nts f or 
2 8 -it e m P S P R S c ha n g e sc or e; 4 p oi nts a n d 9 p oi nts f or 1 5 -ite m P S P R S c ha n ge sc or e. 
Si n c e all missi n g data will b e c o nsi d ere d as n o n -r es p o nse, whi c h is a s p e cial f or m of  missi n g -n ot -
at-ra n d o m, t his a nal ysis ca n pr o vi de a d diti o nal i nsi g hts f or t h e r o b ust n ess of t he pri mar y a nal ysis 
res ults.  
 Sl o pe a n al ysis   
Sl o p e a nal ysis will b e c o n d u cte d t o assess t h e differ e n c e b et we e n t h e BII B 0 9 2 treat me nt gr o u p 
a n d pla ce b o gr o u p i n t h e sl o p e of c ha n g e fr o m baseli n e i n P S P R S  u p t o W e e k 5 2. A r e d u cti o n i n 
t h e sl o p e of t h e BII B 0 9 2 tr eat m e nt gr o u p c o m pare d wit h pla c e b o gr o u p  w o ul d i n di cat e a sl o wer 
rate of disease pr o gr essi o n, t h us r efl e cti n g a disease m o dif yi n g effe ct of BII B 0 92. A M M R M  
m o d el will b e use d, wit h d e p e n d e nt varia bl e as t h e c ha n ge fr o m baseli n e sc or e i n P S P R S at ea c h 
visit a n d wit h fi x e d ef fe cts of tr eat m e nt gr o u p, ti m e (c o nti n u o us), tr eat m e nt gr o u p-b y -ti m e 
i nt era cti o n, baseli n e P S P R S sc ore , ( baseli n e P S P R S sc ore ) by ti m e i nt era cti o n, baseli n e C ol or 
Trails 2 t est ( ≤ 1 7 0 or > 1 7 0 se c o n ds ) a n d r e gi o n.  T he c o nti n u o us ti me varia bl e is cal c ulat ed as 
n u m b er of years si n ce t h e 1 st i nf usi o n, s o t h e sl o p e esti mate r efl e cts t he a n n u al rat e of c ha n g e. T h e 
sa me met h o ds as i n t he pri mar y a nal ysis of ea c h e n d p oi nt will be c o nsi d er e d f or t h e c o varia nc e 
str u ct ur e a n d t h e d e gre es of fr ee d o m.  
 
 Di v e r g e nc e effe ct a n al ysis  
A di v er ge n c e effe ct a nal ysis will b e p erf or m e d t o assess w h et h er t h e tr eat m e nt differ e n ce bet we e n 
t h e BII B 0 9 2 treat e d s u bj e cts a n d t he pla c e b o s u bj e cts i n cr eases o v er ti me [ Li 2 0 1 7]. A li n ear tr e n d 
test will b e c o n d u ct e d o n treat m e nt differ e n c e at  We e k 1 2, 2 4, 3 6, 4 8 a n d 5 2 esti mate d fr o m t h e 
M M R M m o d el of S e cti o n 5. 2. 3 , t o assess if t h e sl o p e of t h e tr eat m e nt differ e nc e is p ositi v e or n ot.  
Let t h e esti mat e of tr eat m e nt differ e n c e b e 𝛿𝑐 at ti m e p oi nt 𝛿𝑡, w here 𝛿𝑐=  1 2, 2 4, 3 6, 4 8, a n d 5 2  
( we e k). T h e least-s q u are esti mat e of t h e sl o p e is 


 
 
3 5  
 
𝛿𝑐𝛿𝑡=
∑(𝛿𝑐−𝛿̅)𝑡𝛿
∑(𝑐𝛿−𝑡̅) 2 , 
w h ere  𝛿̅ is t h e m ea n of 𝑐𝛿’s. T h e h y p ot h esis t o b e t est e d is 
𝑡0 : 𝛿𝑐𝛿𝑡≤0   v ers us   
𝐻𝑎: 𝛽𝐷𝐼𝐹> 0 . 
Gi v e n 𝛽𝐷𝐼𝐹 is a li n ear c o m bi nati o n of t h e tr eat m e nt differ e n c e 𝛿𝑖, t his a nal ysis ca n b e i m pl e me nt e d 
b y t he “ esti mat e” stat e me nt i n t h e S A S pr o c mi x e d pr o c e d ur e.  
 
5. 3  Se c o n d ar y Effic ac y E n d p oi nts  
 
K e y Se c o n d ar y Eff ic ac y E n d p oi nts 
 
T he k e y se c o n dar y e n d p oi n ts i n cl u d e M D S-U P D R S Part II, C GI -C, P S P c o g niti ve c o m p osit e 
batt er y a n d P S P -Q o L. T h e se q u e ntial t est descri b e d i n S ecti o n 5. 1  will b e use d t o t est t h e k e y 
se c o n dar y e n dp oi nts i n t he f oll o wi n g or d er : M D S -U P D R S Part II, C GI -C, P S P c o g niti v e 
c o m p osit e batter y, P S P -Q o L p h ysical sc al e, P S P -Q o L m e ntal sc al e a n d P S P -Q o L V A S . An o v erall  
s u m mar y of all k e y se c o n dar y e n d p oi nts will b e pr ovi d e d. A li n e pl ot of a dj ust e d m ea n c ha n g e 
fr o m baseli ne o v er ti m e a n d a bar pl ot of a dj ust e d m ea n c ha n g e fr o m baseli ne at W ee k 5 2  will b e 
pr o vi d e d f or all k e y se c o n dar y e n d p oi nts  wit h t h e e xc e pti o n f or C GI -C w h er e o nl y a dj ust e d m ea n 
will b e use d . Listi n gs will b e pr o vi d e d f or all se c o n dar y effi ca c y e n d p oi nts.  
 Pri m ar y a n al ysis of M D S -U P D R S P art II  
T he M D S -U P D R S Part II i n cl u d es 1 3 it e ms assessi n g m ot or as p e cts of e x p erie n ces of dail y li vi n g. 
T hese i n cl u d e s p e e c h,  sali va a n d dr o oli n g, c h e wi n g a n d s wall o wi n g, ha n d writi n g, d oi n g h o b bi e s 
a n d ot h er a cti viti es, eati n g tas ks, tre m or, dr essi n g, h y gi e n e, t ur ni n g i n b e d, g etti n g o ut of b e d, 
wal ki n g a n d bala n c e, a n d fr e e zi n g. Ea c h i n di vi d u al ite m has a 5 -p oi n t scal e, ra n gi n g fr o m 0 t o 4: 
0 f or “ N or mal”; 1 f or “ Sli g ht”; 2 f or “ Mil d”; 3 f or “ M o derate”; a n d 4 f or “ S e vere”.  T he t otal sc or e 
is cal c ulat e d b y a d di n g all r e q uir e d it e m sc or es, a n d ra n g es fr o m 0 t o 5 2. 
T he pri mar y a nal ysis of c ha n ge fr o m baseli n e M D S -U P D R S Part II  sc or es will b e base d o n t h e 
base M M R M m o d el d escri b e d i n Se cti o n 5. 1 . A li n e pl ot of a dj ust e d m ea n c ha n ge fr o m baseli n e 
o v er ti m e  a n d a bar pl ot of a dj ust e d m ea n c ha n g e fr o m baseli n e at W e e k 5 2 will b e pr o vi d e d.  
 Pr i m ar y a n al ysis of C GI-C  
T he C GI -C f or m is t h e se c o n d part of a t w o-part str u ct ur e C GI i n t er vi e w. It is i nte n d e d t o 
det er mi n e t h e c ha n ge i n t h e parti ci pa nt’s c urre nt cli ni cal stat us, r elati v e t o t he baseli n e visit, w h ere 
C GI -S is use d. T h e C GI -S meas ur e s t he o v erall cli nical gl o bal i m pr essi o n of d isease se v erit y usi n g 
a 7 -p oi nt scale. T he C GI -C scal e m eas ures t h e c ha n g e i n t h e partici pa nt’s c h a n g e i n cli ni cal stat us 
fro m t h e baseli n e visit at a s p ecifi c ti m e p oi nt usi n g a 7 -p oi nt scal e: 1 f or “ M ar k e d I m pr o ve m e nt”; 
2 f or “ M o derate I m pr o v e m e nt”; 3 f or  “ Mi ni mal I m pr o ve m e nt”; 4 f or “ N o C ha n g e”; 5 f or 
“ Mi ni mal W orse ni n g”; 6 f or “ M o derat e W orse ni n g”; 7 f or “ Mar k e d W orse ni n g”. O nl y o ne a ns wer 
ca n b e c h ose n.  
T he C GI -C  sc or es will b e s u m mari ze d b y tr eat me nt gr o u p at ea c h p ost -baseli n e visit. A n M M R M 
m o d el will b e use d as t he pri mar y a nal ysis t o a nal y z e C GI -C usi n g fi x e d effe cts of tr eat m e nt gr o u p, 
ti m e ( cat e g ori cal), treat m e nt gr o u p-b y -ti m e i nt era cti o n, baseli n e C GI-S, b aseli n e C GI -S b y ti m e 




 
 
3 7  
 
 
  
T he z -sc or e f or ea c h d o mai n is cal c ulat e d as t h e s u m of z -sc or es of t h e c o m plet e d t ests di vi d e d b y 
t h e n u m b er of t ests c o m plet e d . A fi nal t otal c o m p osit e z -sc ore of t h e P S P c o g niti ve c o m p osit e 
batt er y is calc ulat e d as t he a v era g e of t hr e e d o mai n z -sc or es. If t h er e ar e a n y missi n g  val u es f or  
d o mai n z -sc or es, t h e n n o fi nal c o m p osit e z -sc ore will be calc ulat e d. 
T he R B A N S is c oll e ct e d at W e e k s 0, 1 2 , 2 4, 3 6, a n d 5 2 , w hil e t h e lett er n u m ber se q u e n ce t est a n d 
p h o ne mic fl u e n ce t est ar e c oll ecte d at W e e ks  0, 1 2, 2 4, 3 6, a n d 4 8. T h e wi n d o w i n g r ule of R B A N S 
(Se cti o n 5. 1. 1  T a bl e 3 ) will be a p pli e d t o all s u b-tests.  
T he c o m p osite z -sc ore will b e use d f or t h e pri mar y a nal ysis of t h e P S P  c o g niti v e c o m p osite batt er y  
usi n g  t h e base M M R M m o d el d escri be d i n S e cti o n 5. 1 . A li n e pl ot of a dj ust e d m ea n c ha n g e fr o m 
baseli n e o v er ti me  will als o be pr o vi de d . 
 
 Pri m ar y a n al ysi s of P S P -Q o L  
T he P S P -Q o L is a partici pa nt -r e p orte d o utc o m e meas ur e d e v el o p e d s p e cific all y for assessi n g t he 
healt h -relat e d q u alit y of life i n p e o ple li vi n g wit h P S P. It is a vali dat e d 4 5-it e m q u esti o n nair e a n d 
vis u al a nal o g scale t hat is c o m prise d o f t wo s u b scal es: p h ysi cal h ealt h state ( 2 2 it e ms), w hi c h 
c o v ers m o bilit y, d ysart hria, d ys p ha gia, v is u al dist ur ba n c es, self-car e, a n d a cti vities of dail y li vi n g, 
a nd me ntal h ealt h stat e ( 2 3 ite ms), w hi c h c o vers e m oti o nal, c o g niti ve a n d s o cial f u n cti o ni n g. It e ms 
are gi v e n a 6 -r e p o nse o pti o n f or mat ( N o Pr o ble m, Sli g ht Pr o ble m, M o d er ate Pr o ble m, Mar k e d 
Pr o bl e m, E xtre m e Pr o bl e m a n d N ot A p plica bl e). T h e s u bscal e res ults are cal c ulat e d fr o m 
s u m mi n g t he r es pe cti v e it e ms f or t hat s u bscal e a n d tra nsf or mi n g t h e sc or es i nt o a  ra n g e of 0 t o 
1 0 0, wit h hi g h er sc ores i n di cati n g a great er i m pa ct of t h e disease o n t h e as pe ct m eas ure d.  T h e 
tra nsf or mati o n al g orit h m f or p h ysical a n d m e ntal scal es is 1 0 0 *( o bser v e d  sc or e -mi n i mal p ossi bl e  
sc ore)/( ma x p ossi bl e sc ore - mi n i mal p ossi bl e  scor e ) w here t he mi ni mal p ossi bl e sc or e is 0.  
T he P S P -Q o L als o c o m prises of a Life Satisfa cti o n rati n g ga u g e, w hi c h is a vis u al a nal o g scal e 
wit h a ra n g e of 0 ( w orst) t o 1 0 0 ( b est).  
T he p ri mar y a nal ysis of c ha n g e fr o m baseli n e P S P-Q o L p h ysi cal scal e, m e ntal scal e a n d life 
satisfa cti o n rati n g scale sc ores will b e base d o n t h e base M M R M m o del d escri b e d i n S e cti o n 5. 1 . 
A li ne pl ot of a dj uste d m ea n c ha n g e fr o m baseli n e o ver ti m e  will b e pr o vi d e d.   
 Se nsiti vit y a n d S u p pl e me nt ar y a n al ysis  
T he f oll o wi n g se nsiti vit y a n d s u p pl e me ntar y a nal yses t hat are pla n n e d f or t h e pri mar y effi ca c y 
e n d p oi n t will als o b e c o n d u ct e d f or t h e k e y sec o n dar y effica c y e n d p oi nts:  
•  Patt er n mi xt ure m o d el  
•  Ce ns ori n g aft er i nt er c urre nt e v e nts  
•  Per -p r ot o col  a nal ysis  
•  Sl o p e a nal ysis  
•  Di v er ge n c e effect a nal ysis  
F or t h e 3 d o mai n  z -sc or es of t he P S P c o g niti ve c o m p osit e batter y , t h e baseli n e val u e a n d t h e 
c ha n ge fr o m baseli n e at ea c h p ost -base li ne visit will b e s u m mari ze d b y tr eat m e nt gr o u p. T h e sa m e 


 
 
3 8  
 
M M R M m o d el as t h e pri mar y a nal ysis will als o b e a p pli e d t o t h e d o mai n  z -sc ores. A f or est pl ot 
of a dj ust e d m ea n c ha n g e fr o m baseli n e v ers us pla ce b o at W e e k 5 2 fr o m ea c h d o mai n will b e 
pr o vi d e d.    
F or t h e t otal sc or e of t he 1 1 R B A N S t est s, t h e baseli n e val u e a n d t h e c ha n ge fr o m baseli n e at ea c h 
p ost -baseli n e visit will b e s u m mari z e d b y treat m e n t gr o u p. T h e sa m e M M R M m o del as t h e 
pri mar y a nal ysis will als o b e a p pli e d t o t his t otal sc or e of 1 1 R B A N S t ests . 
F or C GI -C , t h e cat e g ori cal s u m mar y of t h e pr o p orti o ns ( 1) i n ea c h sc o r e c ate g or y ( 1-7) a n d ( 2) 
i m pr o v e m e nt, n o c ha n ge a n d w orse ni n g will  b e p erf or me d.    
 
 
N o n -K e y Se c o n d ar y Effic ac y E n d p oi nts  
N o n -k e y se c o n dar y e n d p oi nts ar e t est e d at a n u n c o ntr oll e d al p ha l e vel of 0. 0 5 per e n d p oi nt. T he 
P val u es r es ulti n g fr o m t h ese a nal yse s ar e c o nsi der e d as n o mi nal a n d d escri pti v e i n nat ure.  
Se cti o ns 5. 3. 2. 1  t hr o u g h 5. 3. 2. 6  pr o vi d e  a d diti o nal details a b o ut t he effi ca c y assess m e nts.  
 S E A D L Sc ale  
T he S E A D L scal e is a mea ns of assessi n g a p ers o n’s a bilit y t o perf or m dail y a cti viti es i n t er ms of 
s pe e d a n d i n d e p e n de n c e t hr o u g h a p er c e nta g e fi g ur e. T h e rati n g is d et er mi n e d b y a q u alifi e d staff 
m e m b er a cc or di n g t o t h e parti ci pa nt’s self -r e p ort e d f u n cti o nal a bilit y of s pe cifi c crit eria, wit h 
1 0 0 % i n dicati n g t otal i n d e pe n de n c e ( healt h y), falli n g t o 0 % ( b e dri d d e n), w hi c h i n di cat es a stat e 
of c o m pl et e d e p e n de n c e. T h e S E A D L c o m prises o f o ne q u esti o n t o be rate d b y sel e cti n g a val u e 
ra n gi n g fr o m 1 0 0 % t o 0 %, i n 1 1 a nswer o pti o ns: 1 0 0 %, 9 0 %, 8 0 %, 7 0 %, 6 0 %, 5 0 %, 4 0 %, 3 0 %, 
2 0 %, 1 0 %, a n d 0 %. Ea c h a ns wer o pti o n has s p ecifi c cli ni cal d escri pt ors a n d o nl y o n e a ns wer ca n 
be c h ose n.  
T he pri mar y a n al ysis of c ha n ge fr o m baseli n e S E A D L will be ba se d o n t h e base M M R M m o del 
descri b e d  i n S ecti o n 5. 1 .  
Cate g ori cal s u m mar y of t h e pr o p orti o ns i n ea c h sc or e cat eg or y ( 0 % -1 0 0 %) will  als o b e  p erf or me d.  
 C GI -S  
T he C GI -S m eas ures t he o v erall gl o bal cli ni cal i m pressi o n of disease se v erit y usi n g a 7 -p o i nt scal e. 
T he C GI -S as ks t h e cli ni cia n o n e q u esti o n: “ C o nsi d eri n g y o ur t otal cli ni cal e x p eri e n ce wit h t his 
parti c ular p o p ulati o n, h o w m e ntall y ill is t h e s u bj e ct at t his ti m e? ” w hi c h is r ate d o n t he f oll o wi n g 
7 -p oi nt sca l e: 1 f or “ N or mal, n ot at all ill”; 2 f or “ B or d erli n e m e ntall y ill; 3 f or “ Mil dl y ill; 4 f or 
“ M o d eratel y ill; 5 f or “ Mar k e dl y ill; 6 f or “ Se v er el y ill; 7 f or “ A m o n g t h e m ost e xtr e m el y ill 
s u bje cts”. O nl y o n e a ns wer ca n b e c h ose n. 
T he pri mar y a nal ysis of c h a n g e fr o m baseli n e C GI -S sc or es wil l be base d o n t h e base M M R M 
m o d el d escri b e d i n S e cti o n 5. 1 .  
Cate g ori cal s u m mar y of t h e pr o p orti o ns i n ea c h sc ore cate g or y ( 1 -7) will als o  be p erf or m e d.  


 
 
3 9  
 
 P h o ne mic Fl ue nc y Test  
P h o ne mic fl u e n c y is a se nsiti v e t est  f or assessi n g fr o ntal l o b e d ysf u n cti o n. Parti ci pa nts are gi v e n 
a lett er of t h e al p ha b et a n d as k e d t o n a m e as ma n y w or ds as t h e y ca n t hat start wit h t hat l etter i n 1 
mi n ut e.  
T he sc ore f or ea c h trial is a ut o -cal c ulat e d as f oll o ws: 
•  Trial 1: T otal n u m b er of c orr ect r es p o nses f or t h e first lett er (ra n g e 1 t o 4 0); 
•  Trial 2: T otal n u m b er of c orr ect r es p o nses f or t h e se c o n d l etter (ra n g e 1 t o 4 0). 
T he t otal sc or e fr o m t h e t w o trial s will be use d f or a nal ysis. 
T he visit assi g n m e nt f or ea c h f or m wit h ass o ciat e d l ett ers is s h o w n b el o w. 
 
F o r m  
Lette rs  
Visits  
A  
F, L  
Scr e e ni n g, W e e k 2 4  
B  
T, S  
Visit 1, W e e k 4 8  
C  
R, M  
We e k 1 2, W e e k 3 6  
 
T he pri mar y a nal ysis of c ha n ge fr o m baseli n e p h o n e mi c fl u e n c y t est sc ores will b e base d o n t h e 
base M M R M m o d el d escri b e d i n S e cti o n 5. 1 .  
 W AI S -I V Lette r N u m be r Se q ue nci n g T as k 
T he W AI S -I V (W e c hsl er A d ult I ntelli g e n c e S cal e --I V) L N S T as k c o ntai ns 1 0 it e ms. Ea c h it e m 
has 3 trials, a n d all 3 trials n e e d t o b e rat e d  as I nc orr e ct ( 0) or C orr e ct ( 1) b e f ore t he rat er is all o we d 
t o m o ve t o t h e f oll owi n g it e m.  
T he L N S t otal ra w sc or e ( 0 t o 3 0 ra n g e) is a ut o -calc ulat e d b y s u m mi n g t h e 1 0 i n di vi d u al it e m 
sc ores (ra n g e 0 t o 3 f or ea c h it e m).  
 
T he l o n g est L N S t otal ra w sc or e ( 2 t o 8 ra n g e) is a ut o-cal c ulat e d f r o m t h e c o u nt of t h e l o n g est 
se q u e nc e (stri n g) of n u m b ers a n d l ett ers c orr e ctl y r e pr o d u ce d b y parti ci pa nt.  
T he pri mar y a nal ysis of c ha n g e fr o m baseli ne L N S  t otal ra w sc or es a n d c ha n g e fr o m baseli ne 
l o n g est L N S t otal ra w sc or e will b e base d o n t h e base M M R M  m o del descri be d i n S e cti o n 5. 1 .  
 C ol o r Tr ails Test  
T he C T T is a la n g u a g e -fre e v ersi o n of t h e Trail Ma ki n g T est a n d was d e vel o p e d t o all o w f or 
br oa d er cr oss -c ult ural assess m e n t. T he f or m c o nsists of t w o parts, C T T 1 a n d C T T 2.   
 
F or C T T 1, t h e parti ci pa nt si m pl y has t o c o n n e ct t h e n u m b er e d cir cl es, i n or der, fr o m 1 t o 2 5, b y 
dra wi n g a c o nti n u o us li n e fr o m cir cl e t o cir cl e.  
 
F or C T T 2 , t h e t est d e ma n d is t h e sa m e, e x cept t he pa rti ci pa nt must alt er nate bet wee n c o l ors w hil e 
c o n n ecti n g t h e cir cl es.  


 
 
4 0  
 
 
T he sc or e f or ea c h part of t he t est is t h e t otal ti m e r e q uir e d f or c o m pleti o n i n sec o n ds. T he 
ma xi m u m ti m e all o we d f or ea c h t est trial is 2 4 0  se c o n ds. 
T he pri mar y a nal ysis of c ha n g e fr o m baseli ne C T T 1 will b e base d o n t h e base M M R M m o d el 
descri b e d i n S ecti o n 5. 1 . 
T he pri mar y a nal ysis of c ha n g e fr o m baseli ne C T T 2 will b e base d o n t h e base M M R M m o d el 
descri b e d i n S ecti o n 5. 1  al o n g wi t h re m o vi n g t he C T T 2 fa ct or i n t h e m o del. 
 M o C A  
T he M o C A is a  o n e -pa g e 3 0 -p oi nt t est d esi g ne d  as a ra pi d scr e e ni n g i nstr u m e nt f or mil d c o g niti ve 
d ysf u n cti o n. S c ores f or 8  c o g niti v e d o mai ns are cal c ulate d: vis u os patial/e x e c uti v e ( ma xi m u m of 
5 p oi nts); na mi n g ( ma xi m u m of 3 p oi nts); m e m or y (t otal n u m b er of w or ds r e m e m b er e d c orre ctl y 
a cr oss 2 trials; n o p oi nts);  att e nti o n (s u m of sc ores f or 3 q u esti o ns; ma xi m u m of 6 p oi nts); la n g u a g e 
(s u m of sc or es f or 2 q u esti o ns; ma xi m u m of 3 p oi nts); a bstra cti o n ( ma xi m u m of  2 p oi nts); dela y e d 
re call ( ma xi m u m of 5 p oi nts); ori e ntati o n ( ma xi m u m of 6 p oi nts). T h e t otal sc ore is cal c ulat e d b y 
s u m mi n g all d o mai n sc or es (e x cl u di n g m e m or y) a n d a d di n g a p oi nt f or p artici pa nt’s e d u cati o n 
le v el ≤ 1 2 y ears. T h e ma xi m u m t otal sc or e is 3 0 p oi nts; a sc or e of 2 6 or a b o v e is c o nsi d ere d 
n or mal.  
T he pri mar y a nal ysis of c ha n g e fr o m baseli ne M o C A  t otal sc ores will b e base d o n t h e base M M R M 
m o d el d escri b e d i n S e cti o n 5. 1 .  
 R B A N S  
T he R B A N S was d e v el o p e d f or t h e d u al p ur p oses of i d e ntif yi n g a n d c hara ct eri zi n g a b n or mal 
c o g niti v e de cli n e i n t h e ol d er a d ult. T h e f ull batt er y is c o m p ose d of 1 2 s u bt ests: List L ear ni n g; 
St or y M e m or y; Fi g ur e C o p y; Li ne Ori e ntati o n; Pi ct ur e Na mi n g; S e ma nti c Fl u e n c y; Di gi t S pa n; 
C o di n g; List R ecall; List R e c o g niti o n; St or y R e call; a n d Fi g ur e  R e call. Fi v e S u m of I n de x S c or es 
are cal c ulate d fr o m t h e 1 2 s u bt ests:  
• 
List Lear ni n g a n d St or y M e m or y  
• 
Fi g ur e C o p y a n d Li ne Ori e ntati o n  
• 
Pi ct ure Na mi n g a n d S e ma nti c Fl u e n c y  
• 
Di g it S pa n a n d C o di n g 
• 
List R e call, List R e c o g niti o n, St or y Re call a n d Fi g ure R ecall  
T he t otal scal e sc or e is cal c ulate d fr o m t h e 5 I n d e x Sc or es w hi c h will be use d f or t h e pri mar y 
a nal ysis of R B A N S . T he pri mar y a nal ysis of c ha n g e fr o m baseli ne R B A N S sc or es will b e base d 
o n t h e base M M R M m o d el d escri b e d i n S e cti o n 5. 1. A li n e p l ot of a dj uste d m ea n c ha n g e fr o m 
baseli n e o v er ti me will b e pr o vi de d.  A listi n g will als o be g e n erat e d . 
F or t h e 5 R B A N S i n d e x sc or es, t h e baseli n e val u e a n d t h e c ha n g e fr o m b aseli n e at ea c h p ost -
baseli n e visit will b e s u m mari z e d b y tr eat m e nt gr o u p. T he sa m e M M R M m o d el as t h e pri mar y 
a nal ysis will als o be a p pli e d t o t h e 5 s u m of i n d e x sc or es.  


 
 
4 1  
 
 V ol u metric M RI  A n al ysis  
 
Brai n v ol u m etri c m eas ur e m e nts will b e carri e d o ut t o esti mat e brai n v ol u m es of 7 pri mar y brai n 
re gi o ns of parti c ular r el e va n c e i n P S P: v e ntri cles, w h ol e brai n, mi d brai n, p o ns,  s u p eri or c er e b ellar 
pe d u n cle, t hir d v e ntri cl e a n d fr o ntal l o b es. I n a d diti o n, v ol u m es of se c o n dar y brai n str u ct ur es ( e. g., 
brai nst e m, c er e br al c ort e x, c ere br u m, lat eral v e ntri cl es, left ca u dat e n u cl e us , ri g ht ca u date n u cle u s, 
m e d ulla o bl o n gata , t otal gra y  matter a n d t otal w hite matt er ) a n d ot h er brai n str u ctu res (e. g. 
c ere b ell u m, f ourt h v e nt ri cl es, l eft/ri g ht hi p p o ca m p us, left/ri g ht i nferi or v e ntricles, l eft/ri g ht 
oc ci pital  l o be, l eft/ri g ht pari etal  l o b e, left/ri g ht te m p oral l o be) will b e m eas ure d . 
T he c ha n ge fr o m baseli n e i n a bs ol ut e v ol u m es w hi c h pass e n d p oi nt Q C  a n d are m eas ur e d o n t h e 
sa me M RI sca n n er as use d at scr e e ni n g will b e t h e pri mar y M RI effica c y e n d p oi nt f or a nal ysis. 
T he effi ca c y M RI a nal ysis p o p ulati o n will b e use d f or t he a nal ysis of v ol u m etri c M RI data.  T h e  
a bs ol ut e val u es , cha n g e a n d p er c e nt c ha n g e fr o m bas eli n e i n v ol u m es of all brai n re gi o ns  will b e 
s u m mariz e d b y treat m e nt gr o u p a n d b y visit .  T h e c ha n g e fr o m baseli n e i n v ol u mes of t h e pri mar y 
re gi o ns a n d th e se c o n dar y re gi o ns will b e a nal y z e d  usi n g  t h e M M R M m o d el d escri be d i n S e cti o n 
5. 1 . F or t he pri mar y  brai n r e gi o ns, t he a dj ust e d mea n c ha n ge fr o m baseli n e i n  v ol u m es will b e 
pr ese nt e d gra p hicall y b y li n e pl ot. A  f or est pl ot f or a dj uste d mea n %  c ha n ge fr o m baseli n e at W e e k 
5 2 f or t h e pri mar y  brai n r e gi o ns  will al s o b e pr o vi de d. A listi n g of t h e pri mar y  brai n r e gi o n 
v ol u m etric M RI data will be pr o vi d e d.   
 
5. 4  Te rti ar y Effic ac y E n d p oi nts  
 
 
 
 
 
 
 
 
 
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5. 5  S u b g r o u p  A n al ysis  
S u b gr o u p a nal yses will b e p erf or m e d f or t h e pri mar y a n d  t h e ke y se c o n dar y e n d p oi nts. T h e 
f oll o wi n g pre-d efi n e d s u b gr o u ps will b e c o nsi d er e d:  
De m o gra p hics:  
•  Se x  (fe mal e, mal e)  
•  A g e ( ≤ me dia n, > m e dia n) ; 
•  Ra c e ( W hite, N o n -W hit e ); 
•  R e gi o n ( U S, N o n -U S) ; 
Baseli n e  c hara ct eristi cs:  
•  Baseli n e c ol or trails 2 t est cat e g ori zati o n  (≤ 1 7 0 or > 1 7 0 se c o n ds);  
•  Ti me si nc e first o nset of P S P  s y m pt o m (≤ m e dia n , > m e dia n) 
•  Baseli n e 2 8 -it e m P S P R S t otal sc or e ( ≤ me dia n, >  me dia n)  
•  Baseli n e 1 5 -it e m P S P R S t otal sc or e ( ≤ me dia n, >  me dia n)  
•  Baseli n e use of Par ki ns o n ’s disease me di cati o n  ( y es, n o; se e S ecti o n 4. 4 f or d efi niti o n of 
Par ki ns o n’s Disease me di cati o n use at baseli ne ); 
•  P ossi bl e or p r o ba bl e P S P   
•  2 8 -it e m P S P R S Gait it e m 2 6 at baseli n e ( < 3 , > = 3)  
•  ta u ha pl ot y pe ( H 1/H 1 , H 1/ H 2, or H 2/ H 2) 
S u bj e ct s i n ea c h s u b gr o u p cat e g or y will be a nal y z e d se parat el y usi n g t h e sa m e  M M R M a nal ysis 
of t h e pri mar y a n d k e y se c o n dar y e n d p oi nts . F or est pl ots of a dj ust e d mea n c ha n ge fr o m baseli n e 
vers us  pla c e b o at W e e k 5 2 fr o m all s u b gr o u p a nal yses will als o b e pr o vi d e d . S u b gr o u p a nal yses 
w ill n ot b e p erf or m e d if o ne of t h e s ub gr o u p s is b el o w 1 0 % of t h e t otal n u m ber of s u bj e cts 
a nal y z e d. S u b gr o u p a nal yses will n ot b e p erf or me d if t h e a nal ysis m o d el  ca n n ot c o n v er g e. 
 
 
 
 
 
  


 
 
4 6  
 
 
 
 
 
 
 
6  
S A F E T Y  D A T A  
 
6. 1  Ge ne r al C o nsi de r ati o ns  
 
 
A n al ysis p o p ul ati o n  
T he s afet y p o p ulati o n will b e use d f or safet y a nal yses of A Es,  S A Es,  cli ni cal la b orat or y data, 
data, E C G data a n d vital si g n data.   T h e safet y 
M RI p o p ulati o n will b e use d f or t he a nal ysis  of safet y M RI data.  
 
 
Vis it wi n d o ws 
 
Visit wi n d o ws will  b e  m ut u all y  e x cl u siv e, c o ntai n n o  g a ps, a n d e n d at t he m id p oi nt  b et we e n 
sc h e d ul e d p ost -baseli n e  visits,  wit h  t h e m id p oi nt  itself assi g n e d t o t h e s u bse q u e nt visit  w i n d o w. If 
t w o or  m or e  e valu a ti o ns o c cur  i n t h e sa m e visit  wi n d o w,  t h e e val ua ti o n c losest  t o th e tar get vi sit 
d a y  will  b e  sel e ct e d for  in cl usi o n i n th e a nal y sis.  If m ulti pl e e va lu ati o ns  o n different da ys a re e q u all y  
cl o se  t o t h e targ et vi sit da y,  t h e n t h e lat e st e va lu ati o n will  b e  sel ec te d for  i nclu si o n i n th e a nal ysis.  
If m ulti pl e e val u ati o ns o c c ur o n t h e sa m e da y, t h e earli est val u e will b e c h ose n f or a nal ysis if ti me 
of c oll e cti o n is a vaila bl e; a sc h e d ul e d val u e will be c h ose n b ef or e a n u nsc h e d ul e d or ea rl y 
disc o nti n u ati o n r e c or d.  
 
 
Inci de nc e , i nci de nc e pr o p o rti o n, a n d i nci de nc e r ate  
•  I n ci d e n c e a n d i n ci d e n c e pr o p orti o n will b e pr o vi de d i n i nci d e n ce pr o p orti o n  ta bl es. I nci d e n ce 
is d efi n e d as t h e n u m b er of s u bj e cts w h o e x p eri e nc e d a n e v e nt. I n ci de n c e pr o p orti o n is d efi n e d 
as t he n u m b er of s u bj e ct s w h o e x p eri e n ce d a n e v e nt di vi d e d b y t otal n u m ber of s u bj e cts i n t he 
a nal ysis p o p ulati o n, i. e., p er ce nta g e. Ea c h s u bje ct will be c o u nt e d o nl y o n c e wit hi n ea c h 
cat e g or y.  
  
•  I n ci d e n c e a n d i n ci d e n c e rat e will be pr o vi d e d i n i n ci d e n c e rate ta bl es. F oll o w -u p a d j ust e d 
i n ci de n c e rat e will be use d a n d is  d efi n e d as t he n u m b er of s u bj e cts wit h a n e ve nt di vi d e d b y 
t h e t otal f oll o w-u p ti m e a m o n g t h e s u bj e cts i n t he a nal ysis p o p ulati o n ( e. g., i nci d e n ce rat e per 
1 0 0 s u bj ect -years).  T h e t otal f oll o w -u p ti m e (s u bj ect -y ear s) is t h e s u m of all s u bj e cts’ f oll o w-
u p ti m e, w her e a s u bje ct’s f oll o w -u p ti m e is cal c ulat e d as t h e n u m b er of da ys (i n cl usi ve) fr o m 
first d ose of st u d y dr u g u ntil t h e last da y o n st u d y, di vi d e d b y 3 6 5. 2 5. F or a nal yse s of e v e nts 
aft er treat m e nt disc o nti n u a tio n, ti m e aft er tr eat m e nt disc o nti n u ati o n will be use d t o c o m p ute 
t otal f oll o w-u p ti m e. Ea c h s u bj ect will b e c o u nt e d o nl y o nc e wit hi n ea c h cat e g or y.  
 


 
 
4 7  
 
6. 2  Cli nic al A d v e rse E v e nts  
 
 
Tr e at me nt -e me r g e nt A Es ( T E A Es)  
 
All A Es will b e a nal y z e d base d o n t h e pri n ci pl e  of tr eat m e nt e m er g e n c e.  A tr eat m e nt -e mer g e nt 
A E was defi n e d as a n A E t hat starte d or w orse ne d after t h e start of first d ose  of st u d y dr u g .  
T o d efi ne tr eat me nt e m er g e n c e f or A Es wit h missi n g start or st o p dat e or ti me t h e f oll o wi n g 
a d diti o nal crit eria will b e use d: 
•  if b ot h t h e start a n d st o p dat es f or a parti c ular A E ar e missi n g, t he n t hat A E is c o nsi der e d 
treat m e nt e m er g e nt; 
•  if t h e start dat e f or a parti c ular A E is missi n g a n d t h e st o p dat e/ti me falls aft er t h e first d ose 
dat e/ti m e, t he n t hat A E is c o nsi d er e d tr eat m e nt e mer g e nt;  
•  if t he start dat e f or a parti c ular A E was t he sa m e as t h e first d ose dat e, a n d t he start ti m e was 
missi n g, t h e n t hat  e v e nt is c o nsi d er e d treat m e nt e m er ge nt.  
F or A Es wit h a partial start dat e,  t he y ear/ m o nt h of t he e v e nt dat e will b e c o m pare d t o t hat of  t h e 
first d osi n g dat e t o d et er mi n e w het h er t he e v e nt is tr eat m e nt e mer g e nt. 
I n a d diti o n, S A Es t hat oc c urr e d si nc e a s u bj e ct was scr ee n e d i n t h e st u d y a n d pri or t o t h e first 
i nf usi o n of st u d y dr u g , w hi c h b y d efi niti o n ar e n ot tr eat m e nt-e mer g e nt, will b e i n cl u d e d i n r ele va nt 
listi n gs b ut will n ot b e s u m mari z e d. 
O nl y T E A Es will b e i n cl u d e d i n t h e A E ta bl es, u nl ess ot h er wis e s pe cifi e d. All S A Es (i n cl u di n g 
pr e -d osi n g S A Es) will b e i n cl u d e d i n t he lis ti n g of S A Es, wit h a n i n di cat or f or pre-d osi n g S A Es . 
O nl y T E A Es will b e i n cl u de d i n ot h er A E listi n gs, if n ot ot h er wise s p e cifie d.  
 
 
S u m m ar y a n d i nci de nc e a n al ysis  
 
O v erall s u m mar y  of A E ta bl e will s u m mari z e t h e n u m b er of s u bj e cts wit h a n y A E, wit h a n y A E 
b y ma xi m u m se v erit y  (as assesse d b y t h e in v esti gat or) , t h e n u m b er of s u bj e cts wit h a n y r elat e d 
A E (relate d t o st u d y dr u g as assesse d b y i n v esti gat or), t h e n u m ber of s u bj e cts wit h S A E, t h e 
n u m b er of s u bj e cts wit h r elate d S A E, t h e n u m ber of s u bj ects wit h A E l ea di n g t o st u d y dr u g 
disc o nti n u ati o n, a n d t he n u m ber  of fatal A Es.  
T he s orti n g or der f or A E i n ci d e n c e ta bl es,  u nl ess ot h er wise s p e cifi e d, will b e b y d e cr easi n g 
fr e q u e n c y or d er of “ BII B 09 2 ” c ol u m n. A s u bj e ct is c o u nt e d o nl y o n c e wit hi n ea c h cat e g or y i n 
ea c h ta bl e. F or e xa m pl e, f or t he ta bl e of A Es b y S O C  a n d P Ts  s orte d b y de cr easi n g fr e q u e nc y 
pr ese nt e d b y tr eat m e nt gr o u p, S O C  will b e pr ese nt e d i n de cr easi n g fr e q u e n c y or d er of BII B 0 9 2  
c ol u m n, a n d wit hi n ea c h S O C , P T s will be pr ese nt e d i n de cr easi n g fr eq u e n c y or d er of BII B 0 9 2  
c ol u m n. A s u bje ct is c o u nt e d o nl y o n c e wit hi n ea c h S O C  a n d P T .  
T he f oll o wi n g A E i n ci d e n c e ta bl es will b e pr o vi d e d : 
1.  A Es b y S O C  a n d P T   
2.  A Es b y S O C  a n d P T  s ort e d b y al p ha beti cal or d er   
3.  A Es b y S O C , hi g h l e v el gr o u p t er m a n d P T   


 
 
4 8  
 
4.  A Es b y  S O C  
5.  A Es b y P T   
6.  A Es wit h at l east 2 % hi g h er i n ci d e n c e f or BII B 0 9 2  c o m pare d t o pla c e b o b y S O C  a n d P T   
7.  A Es wit h at least 2 % hi g h er i nci d e n ce f or BII B 0 9 2  c o m pare d t o pla ce b o b y  1 2 -we e k 
i nt er vals b y S O C  a n d P T   
8.  A Es wit h a n i nci d e nc e of 2 % or m ore i n a n y treat m e nt gr o u p b y 1 2 -we e k i nt er vals  b y P T  
9.  A Es wit h a n i nci de n ce of 2 % or m ore i n a n y treat me nt gr o u p b y P T  
 
1 0.  A Es wit h a n i n ci d e n c e of 5 % or m or e i n a n y tr ea t m e nt gr o u p b y P T   
1 1.  Se v er e or v er y se v er e A Es b y S O C  a n d P T  
1 2.  Se v er e  or v er y se v er e A Es b y P T   
1 3.  A Es b y ma xi m u m  se v erit y b y S O C  a n d P T . (S O C  will be pr ese nte d al p ha beti call y. P T s 
will b e pr ese nt e d i n d e cr easi n g fr e q u e n c y or der. Ma xi m u m se v erit y will be pr ese nte d 
wit hi n ea c h P T  i n t h e or d er of mil d, m o d erat e, se v er e, v er y se v er e, u n k n o w n a n d t otal. A 
s u bje ct will be c o u nt e d o nl y o n c e at t he ma xi m u m se v erit y wit hi n ea c h S O C  a n d P T .)  
1 4.  A Es b y ma xi m u m se v erit y b y P T . (P T s will be pr ese nt e d i n de cr easi n g fr e q u e n c y or d er. 
Ma xi m u m se v erit y will b e pr ese nt e d wit hi n ea c h P T  i n t h e or der of mil d, m o derate, se v er e, 
ver y se v er e , u n k n o w n a n d t otal. A s u bj e ct will b e c o u nte d o nl y o n c e at t he ma x i m u m 
se v erit y wit hi n ea c h P T .) 
1 5.  Relat e d A Es b y S O C  a n d P T   
1 6.  S A Es b y S O C  a n d P T   
1 7.  S A Es b y P T   
1 8.  Relat e d S A Es b y S O C  a n d  P T   
1 9.  A Es t hat l e d t o disc o nti n u ati o n of st u d y tr eat m e nt b y S O C  a n d P T  
2 0.  S A Es wi t h fatal o ut c o m e b y S O C  a n d  P T  
2 1.  A Es b y 1 2 -wee k i nter vals b y S O C  a n d P T   
2 2.  S A Es b y 1 2 -we e k  i nt er vals b y S O C  a n d P T   
   
T he f oll o wi n g listi n gs will be pr o vi de d.  
1.  Listi n g of A Es  
2.  Listi n g of S A Es (i n cl u di n g pr e -d osi n g S A Es)  
3.  Listi n g of A Es t hat l e d t o disc o nti n u ati o n of st u d y tr eat m e nt  
4.  Listi n g of S A Es wit h fat al o ut c o m e  
 
 
A d v e rse e v e nt of s pe ci al i nte r est  
 


 
 
4 9  
 
I mm u n o ge ni cit y  is a n A E SI i n t h e BII B 0 9 2 cli nical de v el o p m e nt pr o gra m. A d v erse e v e nts 
re prese nti n g p ot e ntial i m m u ne/ h y perse nsiti vit y rea cti o ns will b e i d e ntifi e d usi n g 
c ust o miz e d 
Me d D R A sear c h crit eria : A na p h yla cti c r ea cti o n, A n gi o e d e m a, a n d S e v er e  
c uta n e o us  a d v erse r ea cti o ns via S M Q ( narr o w a n d br oa d) sear c h ; E osi n o p hilia, a n d  
Miscella n e o us t er ms . F urt h er details ar e gi v e n i n  A p p e n di x  1 1 . 3. 
  
A n i n ci de n c e pr o p orti o n ta bl e f or p ot e ntial i m m u n e / h y p erse nsiti vit y r ea cti o ns or ga ni z e d b y 
S M Q / Misc ella n e o us cat e g ori es a n d b y P T  (f or b ot h A Es a n d S A Es) , a n d si milarl y f or 
p ote ntial  i m m u n e/ h y p erse nsiti vit y rea cti o ns f or s u bj ects 
wit h a n d 
wit h o ut tr eat m e nt 
e m er g e nt p ositi v e a nti -dr u g a nti b o d y ( A D A) r es ults (as d efi n e d i n S e cti on 8 ) will b e 
pr ese nt e d  f or b ot h A Es a n d S A Es. A listi n g of p ot e ntial  i m m u n e/ h y perse nsiti vit y  rea cti o ns 
will b e pr o vi d e d.   
 
T he f oll o wi n g a nal yses (i n ci d e n c e pr o p orti o n o nl y) will be p erf or m e d t o e x pl or e t h e 
relati o ns hi p b et we e n A D As a n d t h e safet y of BII B 0 9 2 : 
•  A Es f or s u bj e cts wit h a n d wit h o ut tr eat m e nt e m er g e nt p ositi v e A D As  
•  S A Es f or s u bj e cts wit h a n d wit h o ut tr eat m e nt e m er g e nt p ositi ve A D As  
 
I n t his st u d y, ad diti o nal sa m ples f or A D A , r eferr e d t o as “ e v e nt dri v e n” sa m pl es , ma y b e 
c oll e ct e d  f or s u bj e cts wit h  h y p erse nsiti vit y e v e nts . A listi n g of A Es f or s u bj e cts wit h a n y e ve nt 
dri ve n A D A sa m ples will be pr o vi de d.  
 
 
 
I nf usi o n r e acti o ns 
 
Inf usi o n rea cti o ns will b e i d e ntifi e d t hr o u g h 1)  t e m p oral ass o ciati o n, d efi n e d as t h ose a d v erse 
e v e nts w hi c h o c c ur o n t h e da y of a n  i nf usi o n or t h e s u bse q u e nt t w o cal e n dar da ys aft er a n 
i nf usi o n; a n d 2) t hr o u g h a c ust o m M e d D R A searc h of pr e ferr e d t er ms ( A p p e n di x 1 1. 4). A 
seri o us i nf usi o n r ea cti o n is a seri o us a d verse e v e nt w hi c h is i d e ntifie d b y o n e or b ot h m et h o ds.  
A n o v er all s u m mar y of i nf usi o n r ea cti o ns will b e pr o vi de d wit h t h e n u m b er of s u bje cts ( n, %) 
wit h a n y i nf usi o n r ea cti o n; wit h a n y i nf usio n r e a cti o n i d e ntifi e d b y t em p oral  ass o ciati o n  o nl y; 
wit h a n y i nf usi o n r ea cti o n i d e ntifie d t hr o u g h t h e c ust o m searc h o nl y; a n d a n y i nf usi o n rea cti o n 
i d e ntifi e d t hr o u g h b ot h met h o ds. A list i n g of i nf usi o n r ea cti o ns will b e pr o vi de d. A d diti o nall y , 
t h e foll o wi n g i n ci de n c e pr o p orti o n ta bl es will b e pr o vi d e d:  
 
1.  I nf usi o n rea cti o ns t hat o c c urre d i n t e m p oral ass ociati o n t o a n i nf usi o n b y S O C  a n d P T   
2.  Seri o us inf usi o n r ea cti o ns  t hat o c c urr e d i n te m p oral ass o ciati o n t o a n i nf usi o n b y S O C  a n d 
P T   
3.  I nf usi o n rea cti o ns i d e ntifi e d t hr o u g h c ust o m sear c h criteria b y P T  
4.  Seri o us inf usi o n r ea cti o ns i d e ntifi e d t hr o u g h c ust o m sear c h crit eria b y P T  
5.  I nf usi o n rea cti o ns (t e m p oral ass o ciati o n or c ust o m searc h) b y 1 2 -wee k i nter vals b y P T  
 
 




 
 
5 1  
 
I N R 
Pr ot hr o m bi n Ti me  
H e m o g lo bi n A 1 C ( H b A 1 C )- scree ni n g o nl y 
Pre g na nc y  test ( W O C BP o nl y : scree ni n g, pre d ose, disc har ge).  
F ollicl e  sti m ulati ng  h or m o n e  ( F S H) (scre e ni n g o nl y f or w o me n  o nl y)  
 
S u m mari es of cli ni cal la b orat or y data will b e p erf o r m e d f or sc he d ul e d la b orat or y para m et ers o nl y. 
Listi n gs of i n di vi d u al la b orat or y m eas ure m e nts b y s u bj e cts f or all t he para m et ers, b ot h sc h e d ul e d 
a n d u nsc h e d ule d,  will be pr o vi de d.  
 
 
Q u a ntit ati v e a n al yses  
A ct u al val u es, c ha n g e fr o m baseli n e a n d p er c e nt c h a n g e fr o m baseli n e  will b e s u m mari z e d b y visit  
f or he mat ol o g y, bl o o d c h e mistr y, c oa g ulati o n  (I N R a n d pr ot hr o m bi n ti m e ), a n d t he uri nal ysis 
para m et ers s pe cifi c gra vit y a n d p H (a ct u al  val u es o v er ti m e o nl y) . N u m ber of e val u a bl e s u bj e cts, 
m ea n, sta n dar d d e v iati o n, m e dia n, 2 5 % a n d 7 5 % q u artil es, mini m u m a n d ma xi m u m val u es will 
be pr ese nte d at ea c h visit. Pl ots of m ea n val u es ( wit h sta n dar d err or ) f or a ct u al val u es at ea c h visit 
will b e pr o vi d e d ; m ea n val u es at t i m e p oi nts w h er e n <  2 0 will n ot b e pl otte d .  
 
V isit wi n d o ws f or b y visit s u m m aries 
F or la b orat or y b y visit s u m mari es, t h e a nal ysis visit s h o ul d b e defi n e d usi n g visit wi n d o ws (see 
T a ble 8 ).   
 
 
T a ble 8  
Visit Wi n d o ws f o r L a b o r at o r y b y Visit S u m m aries  
A n al ysi s visit 
T ar g et visit d a y  A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e ce nt n o n -missi n g pr e -d ose val u e  
We e k 4  
2 9  
[1 ( p ost -d ose o nl y) , 4 2] 
We e k 8  
5 7  
[ 4 3, 7 0] 
We e k 1 2  
8 5  
[ 7 1, 1 2 6] 
We e k 2 4  
1 6 9  
[ 1 2 7, 2 1 0] 
We e k 3 6  
2 5 3  
[ 2 1 1, 2 9 4] 
We e k 4 8  
3 3 7  
[ 2 9 5, 3 5 0] 
We e k 5 2  
3 6 5  
[ 3 5 1, t he e n d da y of t h e pla c e b o-c o ntr oll e d 
peri o d *]  
* T h e e n d da y of t h e pla c e b o -c o ntr oll e d peri o d is t he last da y b ef or e t h e first d ose  i n 
O L E  f or s u bj e cts w h o e nt er O L E , a n d is t h e last da y i n st u d y f or s u bj e cts w h o d o n ot 
e nt er O L E . 


 
 
5 2  
 
 
 
Q u alit ati v e a n al yses  
F or all q u alitati v e a nal yses, all val u es will b e i n cl u de d ( n ot j ust t he “ a nal y z e d r ec or d” wit hi n ea c h 
visit wi n d o w i n t he q u a ntitati v e a nal yses).  
 
S hift a n alyses  
La b orat or y data will be s u m mari z e d usi n g s hift ta bl es w her e a p pr o pri ate.  Ea c h s u b j ect’s 
he mat ol o g y, b l o o d c h e mistr y, c oa g ulati o n a n d  uri nal ysis  (e x cl u di n g mi cr osc o pi c e xa mi nati o n) 
val u es will be fla g g e d as “l o w”, “ n or mal”, or “ hi g h” r elati v e t o t he n or mal ra n g es of t he c e ntral 
la b orat or y or as “u n k n o w n” if n o r es u lt is a vaila bl e.  Ea ch s u bj ect’s uri nal ysis v al u es f or pr otei n, 
gl u c ose, bl o o d,  a n d le u k o c yt e esterase will b e fla g g e d as “ a b n or mal”  if p ositi v e, “ n or mal ”  if 
ne gati v e , or “ u n k n o w n” if n o val u e is a vaila ble.   
F or  ea c h para m e ter, t h e a nal y sis will  b e  base d  o n  s u bj ects wit h  at least o n e  p ost -baseli ne val u e.  
S hifts fr o m baseli n e t o hi g h/l o w stat us will b e pr ese nte d f or h e mat ol o g y, bl o o d c h e mistr y,  
c oa g ulati o n  a n d uri nal ysis (s p ecifi c gra vit y a n d p H) , a n d s hifts fr o m baseli n e t o a b n or ma l ( or 
u n k n o w n t o a b n o r mal) will b e prese nt e d  for  uri nal ysis para m et ers  (pr otei n, gl u c ose, bl o o d,  a n d  
le u k o c yt e esterase).  S hift t o l o w i n cl u d es n or mal t o l o w, hi g h t o l o w, a n d u n k n o w n t o l o w; shift 
t o hi g h i ncl u d es n or mal t o hi g h, l o w t o hi g h, a n d u n k n o w n t o hi g h. S u bje cts n e e d t o ha v e at least 
o n e p ost -baseli n e e val u ati o n a n d a baseli ne val u e eit h er u n k n o w n or n ot l o w /hi g h /a b n or mal i n 
or d er t o be i ncl u d e d i n t h e a nal ysis.  
 
Gr a d e a n alyses  
Ea c h sc h e d ule d la b orat or y para meter will b e s u m mari ze d b ot h b y w orst p ost -b aseli n e gra d e a n d 
b y w orst c u m ulati v e p ost -baseli n e gra d e ; t his a nal ysis i ncl u d es t h e pri mar y e n d p oi nts of Gra d e 3 
a n d 4 la b orat or y a b n or maliti es . S u bj ects ne e d t o ha v e at l east o ne p ost -baseli ne e val u ati o n i n or der 
t o b e i nclu d e d i n t he a nal ysis. C o m m o n T er mi n ol o g y Criteria f o r A d v erse E v e nts v 4. 0. 3 ( C T C A E) 
p u blis h e d o n 1 4 J u ne 2 0 1 0 will b e use d f or gra d e deter mi nati o n. Gra de d et er mi nati o n is base d 
s ol el y o n la b orat or y val u es a n d d o es n ot  tak e ot h er  cli ni cal i nf or mati o n  i nt o a c c o u nt; t h er ef ore, a 
l o wer grad e ma y b e assi g n e d t o a la b orat or y para m eter r es ult si n ce cli ni cal i nf or mati o n d o es n ot 
c o ntri b ut e t o t h e gra di n g assess m e nt. T h us, t h e i nci d e n ce of hi g her gra d es m a y be u n d er esti mat e d.  
 
F or cal ci u m ( m m ol/ L), t h e la b orat or y r es ult will b e c orre ct e d b y t h e  c o n c urre nt al b u mi n ( g / L) 
res ult f or C TC A E gra d e d et er mi nati o n. T h e d eri vati o n of t h e c orr e ct e d cal ci u m ( m m ol/ L) will b e 
deri v e d as f oll o ws:  
 
C orr e ct e d calci u m ( m m ol/ L) = ¼ * [cal ci u m( m m ol / L) - 0. 8 *( 0. 1 * a l b u mi n( g/ L) -4)]  
 
P ote nti ally Cli nic ally Si g nific a nt l a b or at ory a b n or m alities a n al yses 
F or  he mat ol o g y, bl o o d c h e mistr y a n d uri nal ysis, t h e n u m b er of s u bj e cts wit h p ot e ntiall y cli ni call y 
si g nifi ca nt ( P C S) la b orat or y a b n or maliti es p ost-baseli n e will b e s u m mari z e d f or t he para m et ers 
pr o vi d e d i n T a bl e 9 , w h i c h als o s h o ws t h e t hr es h ol ds use d t o d et er mi n e  P C S res ults . S u bje cts n e e d 


 
 
5 3  
 
t o ha v e at l east o n e p ost-baseli ne e val u ati o n a n d a baseli ne val u e n ot P C S  (i n cl u di n g missi n g) i n 
or d er t o b e i n cl u de d i n t h e a nal ysis. A listi n g will b e pr o vi d e d f or s u bj e cts wit h a n y P C S r es ult 
p ost -baseli n e.  
 
T a ble 9       Crite ri a  t o Dete r mi ne P ote nti all y Cli nic all y Si g nific a nt ( P C S) L a b o r at o r y 
A b n o r m alities  
Cli nic al L a b o rat o r y O utlie r C rite ri a  
P ar a mete r n a me  
P C S L o w  
P C S Hi g h  
H E M A T O L O G Y  
W hit e bl o o d cells  
< 3. 0 x 1 0 9/ L  
> 1 6 x 1 0 9/ L  
L y m p h oc yt es  
< 0. 8 x 1 0 9/ L  
> 1 2 x 1 0 9/ L  
Ne utr o p hils  
< 1. 5 x 1 0 9/ L  
> 1 3. 5 x 1 0 9/ L  
M o n oc yt es  
N/ A  
> 2. 5 x 1 0 9/ L  
E osi n o p hils  
N/ A  
> 1. 6 x 1 0 9/ L  
B as o p hils  
N/ A  
> 1. 6 x 1 0 9/ L  
R e d bl o o d cells  
≤3. 5 x 1 0 1 2/ L 
≥6. 4 x 1 0 1 2/ L 
He m o gl o bi n - Fe mal es  
≤9 5 g/ L  
≥1 7 5 g/ L  
He m o gl o bi n - M al es  
≤1 1 5 g/ L  
≥1 9 0 g/ L  
He mat ocrit - Fe mal es  
≤0. 3 2  L/ L   
≥0 .5 4  L/ L  
He mat ocrit - M al es  
≤0 .3 7  L/ L  
≥0 .6 0  L/ L  
Pl atelet c o u nt  
≤7 5 x 1 0 9/ L 
≥7 0 0 x 1 0 9/ L 
B L O O D C H E MI S T R Y  
Al a ni ne a mi n otra nsferase ( A L T)  
N/ A  
> 3 x U L N  
As part at e a mi n otra nsferase ( A S T)  
N/ A  
> 3 x U L N  
Al kali ne p h os p hat ase ( A L P)  
N/ A  
> 3 x U L N  
T ot al bilir u bi n  
N/ A  
> 1. 5 x U L N  
Bl o o d urea nitr o ge n ( B U N)  
N/ A  
≥1 0. 7 m m ol/ L  
Cre ati ni ne  
N/ A  
≥1 7 6. 8 u m ol/ L  
S o di u m  
≤1 2 6 m m ol/ L  
≥1 5 6 m m ol/ L  
P otassi u m  
≤3 m m ol/ L  
≥6 m m ol/ L  
C hl ori d e  
≤9 0 m m ol/ L  
≥1 1 8 m m ol/ L  
Gl uc ose  
≤2. 2 m m ol/ L  
≥9. 7 m m ol/ L  
C al ci u m  
≤2 m m ol/ L  
≥3 m m ol/ L  
P h os p h or us  
≤0. 6 m m ol/ L  
≥1. 7 m m ol/ L  
Al b u mi n  
≤2 5 g/ L  
≥6 2 5 g/ L  
T ot al pr ot ei n  
≤4 5 g/ L  
≥1 0 0 g/ L  
U RI N A L Y SI S  
Gl uc ose  
N/ A  
≥ 1 0 0 0  m g/ d L  
Pr otei n  
N/ A  
≥ 1 0 0 m g/ d L  
U L N = u p per li mit of n or mal  
 
P ote nti al seri o us h e p at ot o xicity  
 


 
 
5 4  
 
P ot e ntial seri o us h e pat ot o xicit y is d efi n e d as A L T or A S T > 3 x U L N a n d t ot al bilir u bi n >  2 x U L N 
at a n y ti m e p ost -baseli ne, n ot ne c essaril y c o nc urr e nt. A sc att er pl ot of t h e ma xi m u m p ost -baseli n e 
A L T or A S T val u e relati ve t o U L N a n d ma xi m u m p ost -baseli ne t otal bilir u bi n val u e  r elati v e t o 
U L N ( n ot ne c essaril y c o n c urr e nt) f or ea c h s u bj ect will b e  pr o vi de d. A li n e  pl ot of A L T, A S T, A L P  
a n d t otal bilir u bi n val u es o v er ti me f or s u bj e cts wit h p ot e ntial seri o us h e pat ot o xi cit y will b e 
pr o vi d e d. I n a d diti o n, s u bje cts wit h A L T > 1 x U L N, > 3 x U L N, > 5 x U L N, > 1 0 x U L N or > 2 0 x 
U L N, s u bj e cts wit h A S T > 1 x U L N, > 3 x U L N, > 5 x U L N, > 1 0 x U L N or > 2 0 x U L N, s u bj e cts wit h 
t otal bilir u bi n > 1 x U L N or > 2 x U L N, s u bj e cts wit h A L P > 1 x U L N or > 1. 5 x U L N, a n d s u bj e cts 
wit h A S T or A L T > 3 x U L N p ost -baseli n e a c c o m p a ni e d b y c o n c urr e ntl y el e vate d t otal bilir u bi n 
> 1. 5 x U L N or > 2 x U L N will be pr ese nt e d . C o n c urr e nt is d efi n ed as o n t h e sa m e da y. A listi n g of 
s u bje cts wit h p ot e ntial seri o us he pat ot o xicit y will b e pr o vi d e d.   
 
6. 4  E C Gs  
 
A ll i n di vi d u al val u es f or Q T i nt er val, QT i nt er val c orr e ct e d f or h eart rate b y Ba z ett's f or m ula 
( Q T c B), a n d Q T i nter val c orr e ct e d f or h eart rat e b y Fri d eri cia's f or m ula ( Q T c F) will b e pr ese nt e d 
i n t h e data listi n gs. Q T, Q T c B, a n d Q T c F will als o b e i n cl u d e d i n t h e s u m m ar y statisti cs. 
All a vaila bl e n o n -missi n g val u es of E C G para meters s h o ul d be use d i n t h e listi n gs, s u m mari es, 
a n d a nal yses f or t h e d o u bl e -bli n d a n d o pe n -la b el tr eat m e nt p eri o ds. H o we ver, if Q T c F is missi n g 
a n d R R i nt er val i n se c o n ds is a vaila ble, t h e n Q T c F will be calc ulat e d as  
3
/1
R R
Q T
Q T c F
=
 
If b ot h Q T c F a n d R R i n se c o n ds are missi n g, t h e n Q T c F will be calc ulat e d as 
(
)
3
/1
6 0
R A T E
H E A R T
Q T
Q Tc F =
 
Alt h o u g h a ll r e c or d e d E C G para m et er val u es , i n cl u di n g a b n or mal E C G fi n di n gs, will b e i n cl u d e d 
i n t h e data listi n gs, onl y q u a ntitati v e val u es r e c or d e d at or n ear sc h e d ul e d ti me p o i nts will b e 
i n cl u d e d i n t h e s u m mar y statisti cs (se e T a bl e 1 0).  
T a ble  1 0   
Visit Wi n d o ws  f o r E C G  
 
A n al ysis visit  
T ar g et visit d a y  A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e ce nt n o n -missi n g pr e -d ose val u e  
We e k 2 4  
1 6 9  
[1 ( p ost -d ose o nl y) , 2 6 6] 
We e k 5 2  
3 6 5  
[ 2 6 7, t he e n d da y of t h e pla c e b o-c o ntr oll e d 
peri o d *]  
* T h e e n d da y of t h e pla c e b o -c o ntr oll e d peri o d is t he last da y b ef or e t h e first d ose  i n 
O L E  f or s u bj e cts w h o e nt er O L E , a n d is t h e last da y i n st u d y f or s u bj e cts w h o d o n ot 
e nt er O L E . 
 


 
 
5 5  
 
 
A n al ysi s of Ce ntr al Te n de nc y 
 
S u m mar y statisti cs ( n, m ea n, S D, m e dia n, mi ni m u m, a n d ma xi m u m) will be pr ese nt e d f or ea c h 
E C G para m et er a n d t h e c orres p o n di n g c ha n ges fr o m baseli n e b y tr eat m e nt a n d ti m e p oi nt.  
Fre q u e n c y distri b uti o n of ma xi m u m p ost d ose E C G i nt er val s ta bles will als o be g e n erat e d.    
 
C ate g o ric al A n al ysis  
 
T he fre q u e n c y distri b uti o n of s u bje cts ma xi m u m r e c or d e d p ost -d ose Q T c F, P R, Q R S, a n d Q T c F 
(c ha n ge fr o m baseli n e i n Q T c F)  will b e ta b ulat e d b y tr eat m e nt a n d s u m mariz e d wit hi n t h e C S R 
f or t h e f oll o win g ra n g es:  
•  F or Q T c F: Q T c F ≤ 4 5 0 mse c, 4 5 0 msec < Q T c F ≤ 4 8 0 mse c, 4 8 0 mse c < Q T c F ≤ 5 0 0  msec, 
Q T c F > 5 0 0 mse c  
•  F or P R: P R ≤ 2 0 0 mse c, P R > 2 0 0 mse c  
•  F or Q R S: Q R S ≤ 1 2 0 mse c, Q R S > 1 2 0 msec  
•  F or Q T c F: Q T c F ≤ 3 0 mse c, 3 0 msec < Q T c F ≤ 6 0 mse c, Q T c F > 6 0 mse c  
I n di vi d u al Q T c F, P R, Q R S, or Q T c F val u es me eti n g t h ese crit eria will b e fla g g e d i n t h e data 
listi n g.  
 
6. 5   Vit al  Si g ns  
 
Vital si g n para meters i n cl u d e b o d y t e m p erat ur e, s yst oli c bl o o d pr ess ur e, diast oli c bl o o d pr ess ure, 
heart rat e, r es pirati o n rat e a n d wei g ht . T h e d escri pti ve statisti cs f or a ct u al val u es a n d c ha n g e fr o m 
baseli n e will b e s u m mari z e d at ea c h visit. Pl ot of m ea n vital si g n val u es at ea c h visit will b e 
pr o vi d e d.  
T he a nal ysis of vital si g ns will als o f o c us o n t h e i n ci d e n c e of cli ni call y rele va nt o ut li ers base d o n 
t h e f oll o wi n g crit eria. T h e i n ci d e n c e a n d per c e nta g e of cli ni call y r el e va nt o utliers d et er mi n e d b y 
ea c h  crit eri o n will b e s u m mari ze d. A listi n g of s u bj e cts wit h cli ni call y rele v a nt vital si g ns will b e 
pr o vi d e d.  
 
T a ble 1 1         Crite ri a Us e d t o Assess P ote nti al Cli nic all y Rele v a nt O utli e rs i n Vit al Si g ns  
V ari a ble  
L o w  
Hi g h  
S yst olic B l o o d Pr ess ure 
< 9 0 m m H g or > 2 0 m m H g 
de cr ease fr o m Baseli n e ( B L)  
> 1 8 0 m m H g or > 2 0 m m H g 
i n cr ease fr o m B L 
Diast olic Bl o o d Pr ess ure  < 5 0 m m H g or > 1 5 m m H g 
de cr ease fr o m B L  
> 1 0 5 m g H g or > 1 5 m m H g 
i n cr ease fr o m B L 
Heart Rate  
< 5 0 b p m or >  1 5 b p m d e cr ease 
fr o m B L 
> 1 2 0 b p m or >  1 5 b p m 
i n cr ease fr o m B L 
T e m p erat ure  
> 2 d e gr e e C d e cr ease fr o m B L  > 3 8. 5 
C 
or 
> 2 
d e gr e es 
C  i n cr ease fr o m B L 


 
 
5 6  
 
Res pirati o n Rat e  
< 1 0 breat hs p er mi n ut e or >  
5 0 % d e cr ease fr o m B L  
> 2 5 breat hs p er 
mi n ute or 
> 5 0 % i n cr ease fr o m B L  
Wei g ht  
> 7 % d e cr ease fr o m B L  
> 7 % i n crease fr o m B L  
B L = baseli n e; b p m = b eats per mi n ute  
 
Visit wi n d o ws f or b y visit s u m m aries  
F or vital si g n b y visit s u m maries, t h e a nal y sis visit s h o ul d b e d efi ne d usi n g wi n d o ws (se e Ta bl e  
bel o w).  
 
T a ble 1 2                  Visit Wi n d o ws f o r Vit al Si g n b y Visit S u m m aries  
A n al ysis visit  
T ar g et visit d a y  A n al ysis visit wi n d o w  
Baseli n e  
1  
M ost r e ce nt n o n -missi n g pr e -d ose val u e  
We e k 4  
2 9            
[1 ( p ost-d ose o nl y) , 4 2] 
We e k 8  
5 7  
[ 4 3, 7 0] 
We e k 1 2  
8 5  
[ 7 1, 9 8] 
We e k 1 6  
1 1 3  
[ 9 9, 1 2 6] 
We e k 2 0  
1 4 1  
[ 1 2 7, 1 5 4] 
We e k 2 4  
1 6 9  
[ 1 5 5, 1 8 2] 
We e k 2 8  
1 9 7  
[ 1 8 3, 2 1 0] 
We e k 3 2  
2 2 5  
[ 2 1 1, 2 3 8] 
We e k 3 6  
2 5 3  
[ 2 3 9, 2 6 6] 
We e k 4 0  
2 8 1  
[ 2 6 7, 2 9 4] 
We e k 4 4  
3 0 9  
[ 2 9 5, 3 2 2] 
We e k 4 8  
3 3 7  
[ 3 2 3, 3 5 0] 
We e k 5 2  
3 6 5  
[ 3 5 1, the e n d da y of t h e pla c e b o -c o ntr oll e d 
peri o d *]  
* T he e n d da y of t h e pla c e b o -c o ntr oll e d p eri o d is t he last da y b ef or e t he first d ose i n 
O L E  f or s u bj e cts w h o e nter O L E , a n d is t he last da y i n st u d y f or s u bje cts w h o d o n ot 
e nt er O L E . 
 
6. 6   P h ysic al E x a mi n ati o n  
 
P h ysi cal e xa mi nati o n data will b e list e d .  
 
6. 7   Ne ur ol o gic al E x a mi n ati o n  
 
Ne ur ol o gi cal e xa mi nati o n  data will b e list e d .  
 
  
 
 
 
  
 


 
 
5 7  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
6. 9   M RI Res ults  
 
Ne w p ost -baseli n e 
M RI fi n di n gs 
will b e s u m mariz e d f or  ( 1) 
mi cr o h e m orr ha g es, ( 2) 
ma cr o h e m orr ha ges, ( 3) s u perfi cial si d er osis a n d ( 4) vas o ge n i c e d e ma.  
A b y -s u bj ect listi n g of M RI res ults is pro vi d e d f or e nr oll e d s u bje cts  wit h  n e w safet y fi n di n gs (i. e., 
t h ose wit h a “ Y es” r es p o nse t o t h e n e w safet y fi n di n gs q u esti o n at a n y ti m e d uri n g t h e st u d y). 
 
7  
 
P H A R M A C O KI N E TI C D A T A  
 
C S F sa m pl es  will  b e  co ll e ct e d a t pr ot oc ol  d e si g na t e d tim es for BII B 0 9 2 p har m a c o ki neti c  
assess m e nt s fr o m s u bj ects 
. S er u m  sam pl es  will  b e  co ll e ct e d a t pr ot oc ol  
de si g na t e d tim es for BII B 0 9 2  p har m a c o ki n eti c assess m e nts fr o m s u bj e cts.  
 
7. 1   C S F  C o nc e ntr ati o n  D a t a 
 
T he C S F P K a nal ysis  p o p ulati o n will b e use d f or t h e a nal ysis of C S F c o n c e ntr ati o n data.   
 
C S F c o n ce ntrati o ns  al o n g  wit h  th e sc h e d ul e d ( n om i nal) a n d a ct u al sa m pli n g tim es (i.e.,  tim e  fro m  
d osi n g) will  b e  list e d ( w h e n a p plicab l e) fo r ea c h s ub je ct,  gr o u p , a n d da y. Di ffer e nc es b et we en  
sc h e d ul e d a n d  a ct u a l sa m pli n g  ti m es will  als o  b e  list e d for al l s u bj ec ts. P e rc e nta g e di ffer e n c e s 
bet wee n  a ct u a l a d m i nist ere d  d ose a n d  n o m i nal d ose will  a ls o b e liste d.   
 


 
 
5 8  
 
C S F c o nc e ntr a ti o ns b elo w  t h e l o wer lim it of  q u a n tifi ca ti o n (L L O Q) will  b e  i n dicat e d b y “ B L Q”. 
F or t h e  p ur p ose of cal c ulati n g  t y pical d es cri p tiv e  statistics ( n, m ea n, S D, % C V, g e o m etri c  m ea n, 
ge o m etri c % C V,  m e dia n, m ini m u m,  a n d m a xi m u m ) for C S F c o n ce ntrati o ns,  all B L Q val u es will 
be  set t o half t he L L O Q val u e . M ea n  C S F c o n ce ntrati o ns t ha t a re B L Q will  b e  pr ese n t e d as B L Q, 
a n d t h e S D a n d  % C V  will  be  r e po rt e d as n ot  a p pli ca ble.  S u m m ar y sta tistic s of  t h e C S F 
c o n c e ntrati o ns  will  b e  ta b ulat e d  b y d a y a n d sc he d ul e d  tim e  p oi nt.  At t h e discr eti o n of  t he 
p har m a c o ki neti cist  a n d/ or  bi ostatisti cia n,  sam pl es  ma y  b e  e x cl u d e d fr o m d escri p tiv e  statistics if 
t h er e are  lar g e d e viati o n s b et w e e n  sc he d ul e d a n d a ct u al  sam pl in g  da ys or ti m es,  or lar ge de viati o ns  
bet wee n  a ct u al d ose a n d  n o m inal  d ose.  
 
7. 2   Se r u m  P h ar m ac o ki netics  
 
T he P K a nal ysis p o p ulati o n will be use d f or all listi n gs, s u m mari es, a n d statisti cal a nal yse s. 
A nal ysis will i n cl u d e all vali d data i n t h e P K dataset f or BII B 0 9 2 . T he listi n gs will als o i n cl u d e 
data fr o m t h e O L E p eri o d.  
S u bj e ct  ser u m BII B 0 9 2  c o n c e ntrati o ns will be list e d o nl y.  
I n di vi d u al ser u m P K para m et ers Ctr o u g h a n d C i nf will b e list e d f or BI I B 0 9 2 i ncl u di n g a n y 
e x cl usi o ns. S u m mar y statisti cs (i ncl u di n g g e o m etri c m ea ns a n d c o efficie nts of variati o n) will be 
ta b ulate d f or ea c h P K para m et er b y visit. Pl ots of i n di vi d u al C tr o u g h a n d C i nf o ver ti m e will b e 
pr o vi d e d.  
 
Ser u m  c o n c e ntr a ti o ns b el o w t h e lo wer  lim it of  q u a nti fi ca tio n  ( L L O Q) will b e  i n di cat e d b y 
“ B L Q”.  F or t h e  p ur p ose of cal c ulati n g  t y pi ca l d escrip tiv e statistic s ( n, m ea n,  S D, 
% C V, 
ge o m etri c m ea n,  g e o m etri c % C V, m e dia n,  m ini m u m , a n d ma xi m u m ) f or plasm a  c o n c e ntrat i o ns, 
B L Q val u e pre da y 1 of st u d y tr ea t m e nt will b e set t o 0, all p ost first d ose of st u d y treat me nt B L Q 
val u es  will  b e set t o half t h e L L O Q val u e . M ea n  ser u m c o nc e ntrati o ns t ha t a re B L Q will  b e  
pr es e n t e d as B L Q, a n d  t h e S D a n d  % C V will  be  r e p ort e d as n ot  a p pli ca bl e.  At t h e discreti o n of 
t h e phar ma c o ki n eti cist a n d/ or bi ostatisti cia n, sa m pl es ma y b e e x cl u d e d fr o m descri pti v e statistics 
if t h er e ar e lar g e de viati o ns bet we e n sc h e d ule d a n d a ct u al sa m pli n g ti m es, or lar g e d e viati o ns 
bet wee n a ct u al d ose a n d n o mi nal d ose.  
 
Ser u m  c o n c e ntrati o n vs.  tim e  (a ct u al) pr ofil es  fro m  Da y 1 t o  We e k 4 8 , f or ea c h s u bj ect, as well  
as t h e m ea n  ( ± S E) ser u m c o nc e ntrati o n  vs. ti m e  (sc h e d ul e d) pr ofiles  f or t h e tr eat me nt gr o u p, 
will  b e  p r ese nt e d gr a p hi call y  o n li n ear  a n d sem il o garith mi c  scal es. Sam pl es  m a y  b e  e x cl u d e d  
fro m  t h e m ea n  pl ots  if t h ere ar e lar ge de viati o ns bet wee n  sc he d ul e d a n d a ct u al sam pli n g  tim es,  
or lar g e  d e viati o ns  b et we e n  a ct u al  d ose a n d  n o m i nal d ose.  
 
 
 
8  
A N TI -D R U G A N TI B O D Y D A T A  
 
T he a nti -dr u g a nti b o d y  ( A D A) p o p ulati o n will b e use d f or t h e a nal ysis of A D A  data . All a vaila bl e 
A D A  data will b e liste d.  A D A  data will b e list e d f or s u bj e cts wit h a n y p ositi v e A D A r es ult.  
Ass ociati o ns of A D A  m eas ures wit h P K a n d/ or sele ct A Es ma y b e e x pl or e d  as n ee d e d .  
 


 
 
5 9  
 
T he baseli n e val u e is d efi ne d as t h e last a vaila bl e val u e pri or t o first d ose of pla c e b o or BII B 0 9 2. 
F or s u bj e cts wit h missi n g baseli n e assess m e nt, t h e m ost c o nser vati v e  a p pr oa c h will b e ta k e n, a n d 
t h e y will be c o nsi dere d n e gati v e f or A D A at baseli n e.  
 
T he f oll o wi n g d efi niti o ns will b e use d i n t he a nal ysis of A D A d ata:  
 
•  Treat m e nt e m er ge nt p ositi v e : 
− A p ost -baseli n e s u bj e ct sa m pl e t hat is p ositi ve w he n t h e baseli n e s a m pl e is n e gati v e; or 
− A p ost - baseli n e s u bj e ct sa m pl e t hat has a titer gr eat er t ha n or e q u al t o 4 ti m es  t h e baseli n e 
sa m ple tit er w h e n t h e baseli n e sa m pl e is p ositi ve . If t h e titer val u e  is n ot a vaila ble f or a 
p ositi v e baseli ne  r es ult, t h e n t h e baseli n e tit er val u e will be i m p ut e d as t h e mi ni m u m 
re q uire d dil uti o n ( M R D); or 
− A p ositi v e  p ost -baseli n e res ult w her e  n o tit er  is a vaila bl e, r e gar dl ess of baseli n e val u e  
•  Persist e ntl y p ositi v e : T w o or m or e tr eat m ent e m er ge nt p ositi v e A D A r es ults, w h er e t h e ti m e 
bet wee n t h e first a n d last p ositi ve res ults is 1 6 we e ks or m or e ; or if t h er e are n o f urt h er sa m pl es 
a vaila bl e  1 6 we e ks  or m or e f oll o wi n g  a tr eat me nt e m er g e nt  p ositi ve r es ult  (i ncl u di n g t h e O L E 
peri o d) . 
•  Tra n si e ntl y p ositi v e: m or e t ha n o n e tr eat m e nt-e m er g e nt p ositi v e e val u ati o n , l ess t ha n 1 6 we e ks 
a part; or a si n gle tr eat m e nt e m er g e nt p ositi ve ( n ot i n cl u di n g pr etr eat m e nt) w h e n  t her e ar e 
sa m ples a vaila bl e 1 6 we e ks  or m or e  f oll o wi n g t h e p ositi v e r es ult. 
 
T he  f oll o wi n g will b e ta b ulat e d b y tr eat m e nt gr o u p: t h e n u m b er  a n d p er ce nta g e  of  s u bje cts 
wit h  a n y baseli n e sa m pl e t hat teste d p ositiv e i n t he A D A assa y ; t h e n u m b er  a n d p erc e nta ge  of  
s u bje cts wit h  a n y sa m pl e t hat t est e d p ositi v e i n t he A D A assa y (i ncl u di n g at baseli n e) ; t h e  
n u m b er a n d perc e nta g e of s u bje cts wit h tr eat m e nt e m er g e nt p ositi v e  at  ea c h vi sit a n d  at a n y  
ti m e p ost -base li n e; t h e n u m ber  a n d p erc e nta ge of  s u bj ects wit h p ersiste ntl y p ositi v e  sa m pl es 
a n d si milar l y f or tra nsi e ntl y p ositi v e sa m pl es; t h e n u m b er a n d p er ce nta g e of s u bje cts wit h n o 
treat m e nt e m er g e nt p ositi v e A D A sa m ple.    
 
I n t his st u d y, ad diti o nal sa m ples f or A D A , r eferr e d t o as “ e v e nt dri v e n” sa m ples, ma y b e 
c oll e ct e d f or s u bje cts wit h h y p erse nsiti vit y e v e nts. A D A data will be list e d f or s u bj e cts wit h 
a n y e ve nt dri v e n sa m pl e.  D ata fr o m t h ese sa m pl es will b e c o nsi d er e d part of a s u bj e ct’s o vera ll 
A D A assess m e nt.  
 
T he  a nal ysis wi n d o ws  are d efi n e d  base d  o n  t h e sc he d ul e d p ost -baseli n e visits  f or A D A  i n Ta bl e 
1 3.  T he sa m e visit wi n d o wi n g a p pr oa c h d escri b e d i n S e cti o n 6. 1. 2 will b e use d.  
 
 
 
T a ble  1 3                Visit  Wi n d o ws  f o r A nti -dr u g A nti b o d y   
 
A n al ysis  visit  
T arg et visit d a y  
A n al ysis  visit  wi n d o w  
B aseli n e 
1  
Last  a v ail a b le v al u e  pri o r t o th e first d o se of st u d y dr u g  
We e k  4  
2 9  
[1  (p ost -d ose o nl y) , 4 2] 
W e e k  8  
5 7  
[4 3,  7 0]  


 
 
6 0  
 
W e e k  1 2  
8 5  
[7 1,  1 2 6]  
W e e k  2 4  
1 6 9  
[ 1 2 7, 2 1 0]  
We e k 3 6  
2 5 3  
[ 2 1 1, 2 9 4] 
We e k 4 8  
3 3 7  
[2 9 5, th e e n d  d a y  of t h e p la ce b o -c o n tro ll e d pe ri o d*]  
* T he e n d da y of t he pl ace b o -c o ntr olle d peri o d is t he last d a y bef ore t he first d ose i n O L E 
f or s u bj ects w h o e nt er O L E, a n d is t he last d a y i n st u d y f or s u bj e cts w h o d o n ot e nt er O L E . 
 
 
 
 
9  
S A M P L E  SI Z E  C O N SI D E R A TI O N S  
A p pr o xi mat el y 4 5 9 mal e a n d fe male parti ci pa nts will b e e nr oll e d i n t his st u d y.  A p pro xi mat el y 
4 5 9 partici pa nts will be ra n d o ml y assi g n e d, i n 2: 1 rati o, t o r e c ei v e 2 0 0 0 m g of BII B 0 9 2 or pla ce b o 
( 3 0 6 partici pa nts a cti v e a n d 1 5 3 pla c e b o) a d mi nistere d b y I V a p pr o xi mat el y o n ce Q 4 W.  
Ra n d o mi zati o n will b e stratifie d b y c o u nt r y a n d scre e ni n g C olor Trails T est Part  2  sc ore of eit h er 
≤ t o 1 7 0 se c o n ds, or ≥ 1 7 0  se c o n ds.  A nti ci pati n g a dr o p o ut rat e of a p pr o xi mat el y 2 5 %, 
a p pr o xi mat el y 3 4 5 parti ci pa nts ( 2 3 0  parti ci pa nts i n t he BII B 0 9 2 tr eat m e nt gr o u p a n d 1 1 5 
parti ci pa nts i n t h e pla ce b o gr o u p) ar e e x p e ct e d t o c o m plete t he st u d y t hr o u g h W e e k 5 2.  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
6 1  
 
1 1  A P P E N DI X  


 
 
6 2  
 


 
 
6 3  
 
1 1. 2  I m ple me nt ati o n of t he C o p y I nc r e me nt fr o m Refe r e nc e, J u m p t o R efe r e nc e a n d 
P atte r n Mi xt ur e M o del  
 
C o p y I nc r e me nt fr o m Refe r e nc e  ( CI R) 
T he dataset will first b e i m p ut e d t o m o n ot o n e missi n g usi n g P R O C MI wit h t h e M C M C a n d 
i m p ut e = m o n ot o n e o pti o n. I m p utati o n will b e carri e d o ut 1 0 0 0 ti m es a n d a ny i nt er nal missi n g 
o bser vati o ns, i n cl u di n g mi ssi n g baseli n e c o variat es a n d i nt er m e diat e missi n g i n  t h e res p o nse 
varia ble will b e r e pla c e d wit h t h e a v era g e a cr oss all i m p utati o ns.  
F or t h e r es ult e d data wit h m o n ot o n e missi n g, t h e f oll o wi n g st e ps will b e use d  t o cr eat e i m p ut e d 
datasets:  
( 1) Data fr o m all s ubj ect s will b e use d t o fit a 
m ulti variat e n or mal dist ri b uti o n wit h 
u nstr u ct ur e d 
m ea n a n d u nstr u ct ure d varia n c e usi n g a Ba y esia n a p pr oa c h 
wit h a 
n o ni nf or mati ve pri or f or t h e m ea n a n d a c o nj u gat e pri or f or t h e var ia n c e c o varia n ce matri x. 
( 2) Dra w a pse u d o -i n d e p en d e nt sa m pl e f or t h e li n ear pr e di ct or para m et ers a n d t he c o varia nc e 
para m et ers fr o m t h e j oi nt p ost eri or distri b uti o n o btai n e d i n st e p ( 1). B ot h ste ps ( 1) a n d ( 2) 
will b e d o n e usi n g P R O C M C M C i n S A S.  
( 3) Use t h e li n e ar pr e di ct or para m et ers a n d t h e c o varia nc e pa ra m et ers o btai n e d i n ste p ( 2) t o 
c o nstr u ct n e w m ea n v e ct ors se parat el y f or ea c h tr eat m e nt gr o u p ( pla c e b o  a n d BII B 0 9 2 ). 
S p e cifi call y, t h e n e wl y c o nstr u ct e d m ea n v e ct or f or s o m e o n e o n treat m e nt gr o u p 𝛿 w h ose 
last o bser v e d visit was visit 𝑐 is calc ulat e d as 
𝛿𝑡
(𝛿) = {
𝑐𝛿,𝑡,
𝛿𝑐 𝛿≤𝑡
𝛿𝑐,𝛿−𝑡𝛿,𝑐+ 𝛿𝑡,𝐻,𝑎𝛽 𝐷> 𝐼 
Her e 𝐹 r e pr ese nts t h e pla c e b o gr o u p. F or s u bje cts wit h n o p ost-baseli ne r ec or ds, or s u bje cts 
o n t h e pla ce b o gr o u p, t h e n e wl y c o nstr u ct e d m ea n v ect or is t he sa m e as t h e p la ce b o mea n. 
( 4) Usi n g 𝛽𝐷
(𝐼) fr o m st e p ( 3) a n d c o varia n c e para m et ers fr o m st e p ( 2), fi n d t h e c o n diti o nal 
n or mal distri b uti o n of t h e visit wit h missi n g data, a n d use t his c o n diti o nal distri b uti o n t o 
i m p ut e t h e missi n g data.  
 
 
J u m p t o  Refe r e nc e  ( J 2 R) 
T he dataset will first b e i m p ut e d t o m o n ot o n e missi n g usi n g P R O C MI wit h t h e M C M C a n d 
i m p ut e = m o n ot o n e o pti o n. I m p utati o n will b e carri e d o ut 1 0 0 0 ti m es a n d a n y i nt er nal missi n g 
o bser vati o ns, i n cl u di n g m issi n g baseli n e c o variat es a n d i nt er m e diat e missi n g i n t h e  res p o nse 
varia ble will b e r e pla c e d wit h t h e a v era g e a cr oss all i m p utati o ns.  
F or t h e r es ult e d data wit h m o n ot o n e missi n g, t h e f oll o wi n g st e ps will b e use d t o cr eat e i m p ut e d 
datasets:  
( 1) Data fr o m all su bj ect s will b e use d t o fit a 
m ulti variat e n or mal distri b u ti o n wit h 
u nstr u ct ur e d 
m ea n a n d u nstr u ct ure d varia n c e usi n g a Ba y esia n a p pr oa c h 
wit h a 
n o ni nf or mati ve pri or f or t h e m ea n a n d a c o nj u gat e pri or f or t h e varia n c e c o varia n ce matri x.  


6 4  
( 2) Dra w a pse u d o -i n d e pe n d e nt  sa m pl e f or t h e li n ear pr e di ct or para m et ers a n d t he c o varia nc e
para m et ers fr o m t h e j oi nt p ost eri or distri b uti o n o b tai n e d i n st e p ( 1). B ot h ste ps ( 1) a n d ( 2)
will b e d o n e usi n g P R O C M C M C i n S A S.
( 3) Use t h e li n ear pr e di ct or para m et ers a n d t h e c o varia nc e p ara m et ers o btai n e d i n ste p ( 2) t o
c o nstr u ct n e w m ea n v e ct ors se parat el y f or ea c h tr eat m e nt gr o u p ( pla c e b o  a n d BII B 0 9 2 ).
S p e cifi call y, t h e n e wl y c o nstr u ct e d m ea n v e ct or f or s o m e o n e o n treat m e nt gr o u p 𝛿 w h ose
last o bser v e d visit was visit 𝑐 is calc ulat e d as
𝛿𝑡
(𝛿) = {𝑐𝛿,𝑡,
𝛿𝑐 𝛿≤𝑡
𝛿𝑐,𝛿,
𝑡𝛿 𝑐> 𝛿
Her e 𝑡 r e pr ese nts t h e pla c e b o gr o u p. F or s u bje cts wit h n o p ost-bas eli ne r ec or ds, or s u bje cts 
o n t h e pla ce b o gr o u p, t h e n e wl y c o nstr u ct e d m ea n v ect or is t he sa m e as t h e pla ce b o mea n.  
Usi n g 𝐻𝑎
(𝛽) fr o m st e p ( 3) a n d c o varia n c e para m et ers fr o m st e p ( 2), fi n d t h e c o n diti o nal
n or mal distri b uti o n of t h e visit wit h missi n g data, a n d use t his c o n diti o nal distri b uti o n t o 
i m p ut e t h e missi n g data. 
 
P atte r n Mi xt ur e M o del  
S u bj e cts will b e assi g ne d o ne of t h e fol l o wi n g t hr ee patt er ns: 
1.
C o m pl et er: s u bj e cts wit h n o missi n g data at W e e k 1 2, 2 4, 2 6, 4 8 a n d 5 2 f or pri mar y
e n d p oi nts a n d at W e e k 1 2, 2 4, 3 6 a n d 5 2  f or k e y se c o n dar y e n d p oi nts;
2.
S u bj e cts w h o wit h dre w d u e t o r eas o ns t hat ma y be r elat e d t o effi ca c y , i ncl u di n g la c k of
effi ca c y, s u bj ect r e q u est t o disc o nti n u e st u d y treat m e nt, s u bje ct wit h dre w c o nse nt,
p o or/ n o n -c o m plia n c e, d eat h, a n d wit h dra wal b y care gi v er;
3.
All t h e ot her s u bj e cts wit h missi n g data.
T he dataset will first b e i m p ut e d t o m o n ot o n e  missi n g  usi n g P R O C MI wit h t h e M C M C a n d 
i m p ut e = m o n ot o n e o pti o n. I m p utati o n will b e carri e d o ut 1 0 0 0 ti m es a n d a n y i nt er nal missi n g 
o bser vati o ns, i n cl u di n g missi n g baseli n e c o variat es a n d i nt er m e diat e missi n g i n t h e res p o nse 
varia ble will b e r e pla c e d wit h t h e a v era g e a cr oss all i m p utati o ns.  
F or t h e r es ult e d data wit h m o n ot o n e missi n g, t h e f oll o wi n g st e ps will b e use d t o cr eat e i m p ut e d 
datasets:  
( 1) S u bset s u bj ects i n patt er n 1 a n d patt er n 2, a n d i m p ute t he missi n g data usi n g t h e c o p y
i n cr e me nt fr o m r efere n c e m et h o d d escri b e d i n S e cti o n 1 0. 2. 1 .
( 2) S u bset s u bj e cts i n patter n 1 a n d patt er n 3, a n d i m p ut e t h e missi n g data usi n g P R O C MI
wit h t he M O N O T O N E R E G o pti o n.
( 3) C o m bi n e d datasets o btai n e d i n ste ps ( 1) a n d ( 2).
1 1. 3  A d v e rse e v e nt of s pe ci al i nte r est c ust o m se ar c h c rite ria 
I mm u n o ge ni cit y  is a n A E SI i n t h e BII B 0 9 2 cli nical de v el o p m e nt pr o gr a m. A d v erse e v e nts 
re prese nti n g p ot e ntial i m m u n e/ h y p erse nsiti vit y rea cti o ns will b e i d e ntifi e d usi n g t h e f oll o wi n g 
c ust o miz e d M e d D R A searc h crit eria : 
•
A na p h yla cti c r ea cti o n S M Q narr o w  a n d br oa d
•
A n g i o e d e ma S M Q narr o w a n d br oa d


6 5  
•
Se v er e c uta n e o us a d v erse r ea cti o ns S M Q narr o w a n d br oa d
•
E osi n o p hilia  ( P T ter ms: E osi n o p hilia; E osi n o p hil c o u nt i n cr ease d;  All er gi c e osi n o p hilia ;
P ul m o nar y e osi n o p hilia )
•
Miscella n e o us t er ms
o
C yt o ki n e release s y n dr o m e P T
o
I nf usio n relate d rea cti o n P T
o
I nf usi o n sit e r ea cti o n P T
o
Aller gi c c o n diti o ns N E C H L T
o
Dr u g h y p erse nsiti vit y P T
o
D o c u m e nt e d h y perse nsiti vit y t o a d mi nist er e d pr o d u ct P T
o
Vasc ulitis P T
o
S yst e mi c L u p us er yt he mat os us P T
o
R h e u mat oi d art hrit is P T
o
A nti b o d y t est p ositi ve P T
o
A nt i b o d y t est a b n or mal P T
o
A nti b o d y t est P T
o
Dr u g s p e cific a nti b o d y prese nt P T
o
Ne utrali si n g a nti b o di es P T
o
Ne utralisi n g a nti b o di es p ositi v e P T
o
N o n -n e utralisi n g a nti b o di es p ositi v e P T
o
Res pirat or y d ys ki n esia P T
1 1. 4  I nf usi o n r e acti o ns c ust o m se ar c h  
•
I nf usi o n sit e r ea cti o n
•
I nf usi o n sit e ras h
•
I nf usi o n sit e der matitis
•
I nf usi o n sit e h y p erse nsiti vit y
•
I nf usi o n sit e p h ot ose nsiti vit y r ea cti o n
•
I nf usi o n sit e urti caria
•
I nf usi o n sit e ecz e ma
•
I nf usi o n sit e vasc ulitis
•
I nf usi o n sit e r e call r ea cti o n
•
I nf usi o n relate d rea ctio n
•
A d mi nistr ati o n site ras h
•
A d mi nistrati o n site d er matitis
•
A d mi nistrati o n site ec z e ma
•
A d mi nistrati o n site h y p erse nsiti vit y
•
A d mi nistrati o n site urti caria
•
A d mi nistrati o n site p h ot ose nsiti vit y  r ea cti o n
•
A d mi nistrati o n site r ecall r ea cti o n
•
A d mi nistrati o n site vasc ulitis
•
A d m i nistrati o n r elat e d r ea cti o n


6 6  
•
I nj e cti o n sit e d er matitis
•
I nj e cti o n sit e h y p erse nsiti vit y
•
I nj e cti o n sit e ras h
•
I nj e cti o n sit e urticaria
•
I nj e cti o n sit e p h ot ose nsiti vit y r ea cti o n
•
I nj e cti o n sit e e c z e ma
•
Inj e cti o n sit e r e call r ea cti o n
•
I nj e cti o n sit e vasc ulitis
•
I nj e cti o n r elat e d r ea cti o n
•
I m m e diat e p ost-i nje cti o n rea cti o n
•
aller gi c r ea cti o n t o e xci pie nt
•
rea cti o n t o e x ci pi e nt
•
c yt o ki n e st or m
•
c yt o ki n e r el ease s y n dr o me
•
i m m u n e-m e diat e d a d v erse r ea cti o n
1 2  R E F E R E N C E S  
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pals y: a ra n d o mise d, d o u bl e -bli n d, pla ce b o -c o ntr oll e d p hase 2/ 3 tri al. 
La n c et 
Ne ur ol. 
2 0 1 4; 1 3( 7): 6 7 6 -8 5. E p u b 2 0 1 4/ 0 5/ 2 7.  
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m ulti pl e i m p utati o n. J 
Bi o p har m Stat. 2 0 1 3; 2 3( 6): 1 3 5 2 -7 1.  
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C o m mitte e. 2 0 1 4.  
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Bi o p har ma c e uti cal R esear c h. 2 0 1 7; 9: 3 9 0 -3 9 8.  
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Si m ul ati o n , 3 0, 5 7– 7 9.  
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A meric a n St atistic al Ass o ci ati o n, 8 8 , 1 2 5-1 3 4.  


6 7  
Littl e, R.J. A. ( 1 9 9 4). A class of patter n ‑ mi xt ure m o d els f or n or mal missi n g data. Bi o metrik a,  
8 1 , 4 7 1-4 8 3 . 
 
 
 
R u bi n, D. B. ( 1 9 7 6) “I nfere n c e a n d missi n g data.” Bi o m etri k a, 6 3( 3), 5 8 1 -5 9 2.  
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