Clinical trial NCT04374253
Conditions: Alzheimer Disease
Sponsor: Hoffmann-La Roche
Start date: 2021-01-26; Completion date: 2023-03-06
Enrollment: 1382 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, multicenter, rollover study to evaluate the safety, tolerability, and efficacy of long-term administration of open-label gantenerumab in participants with AD who completed Study WN29922 or WN39658, either the double-blind or open-label extension (OLE) part.

Detailed description:
Participants who were in the active arm in the double blind part and those who have completed OLE part in the parent study, will continue receive open-label gantenerumab 510 mg sub-cutaneously (SC) every 2 weeks (Q2W). Participants who are naive to gantenerumab treatment will be required to undergo the 3 step uptitration scheme as in the parent study before receiving target dose of open label gantenerumab.

Arms: arm 1: Participants, who completed the double-blind part and did not enter the OLE part of Study WN29922 or WN39658, will be enrolled and receive open-label gantenerumab approximately 2 weeks after the Week 116 visit of Study WN29922 or WN39658. This will be considered the OLE baseline visit (OLE Day 1). arm 2: Participants, who completed the double-blind part and the OLE part of Study WN29922 or WN39658, will be enrolled and receive open-label gantenerumab approximately 2 weeks after the OLE Week 34 visit or the final dose visit in the Study WN29922 or WN39658 OLE.
Interventions: intervention 1: Gantenerumab intervention 2: Gantenerumab
Intervention descriptions: intervention 1: Group 1 participants who were in the active arm in the double blind part in the parent study (WN29922 or WN39658), will continue to receive open-label gantenerumab 510 mg SC, Q2W. Participants who are naive to gantenerumab treatment will be required to undergo the 3 step uptitration scheme before receiving target dose of open label gantenerumab, 510 mg SC, Q2W. intervention 2: Group 2 participants who have completed OLE part in the parent study (WN29922 or WN39658), will continue to receive open-label gantenerumab 510 mg SC, Q2W

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
An Open-Label, Multicenter, Rollover Study to Evaluate the Safety, 
Tolerability, and Efficacy of Long-Term Gantenerumab Administration 
in Participants With Alzheimer's Disease 
NCT Number: 
NCT04374253 
Document Date: 
Protocol Amendment 4: 11-May-2022 
 
 
 


CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, 
especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its 
control) and therefore is provided to you in confidence as an investigator, potential investigator, or 
consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional 
Review Board.  It is understood that this information will not be disclosed to others without written 
authorization from Roche except to the extent necessary to obtain informed consent from persons 
to whom the drug may be administered. 
 
Gantenerumab—F. Hoffmann-La Roche Ltd 
Protocol WN42171, Version 4 
PROTOCOL 
TITLE: 
AN OPEN-LABEL, MULTICENTER, ROLLOVER 
STUDY TO EVALUATE THE SAFETY, 
TOLERABILITY, AND EFFICACY OF 
LONG-TERM GANTENERUMAB 
ADMINISTRATION IN PARTICIPANTS WITH 
ALZHEIMER'S DISEASE 
PROTOCOL NUMBER: 
WN42171 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2020-000766-42 
IND NUMBER: 
102,266 
NCT NUMBER: 
NCT04374253 
TEST PRODUCT: 
Gantenerumab (RO4909832) 
MEDICAL MONITOR: 
, MBBS, Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
APPROVAL DATE: 
See electronic signature and stamp on the final 
page of this document. 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
2/Protocol WN42171, Version 4 
PROTOCOL HISTORY 
Protocol 
Associated Country-Specific Protocols 
Version 
Date Final 
Country 
Version 
Date Final 
4 
See electronic date 
stamp on the final 
page of this document. 
 
 
 
3 a 
10 May 2022 
 
 
 
2 
7 December 2021 
China 
2 
17 December 2021 
1 
7 March 2020 
Taiwan 
Addendum 1 
15 November 2021 
United Kingdom 
Addendum 1 
7 April 2021 
France 
Addendum 2 
7 April 2021 
France 
Addendum 1 
18 February 2021 
a Version 3 was demoted incorrectly in anticipation of refinalization, but the final decision is to 
issue new version to avoid confusion.  
 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
3/Protocol WN42171, Version 4 
PROTOCOL AMENDMENT, VERSION 4: 
RATIONALE 
Protocol WN42171 has been amended primarily to extend the open-label treatment 
(OLE) period from 2 to 4 years.  The changes to the protocol, along with a rationale for 
each change, are summarized below.  Note that as Version 3 of the protocol was either 
withdrawn or not submitted, Version 4 will reflect all changes from Version 2 in italics.  
 
Section 1.3.1 has been updated to reflect that with the 2-year extension participants 
will receive open-label gantenerumab for up to 4 years. 
 
Sections 1.2.1 and 1.3.2.3 have been updated to reflect that Studies WN25203 and 
WN28745 are completed. 
 
Section 1.3.2.3 has been updated to clarify that no interactions between positron 
emission tomography (PET) tracers and the coronavirus disease 2019 (COVID-19) 
vaccines are expected to occur based on the available information. 
 
The secondary efficacy objective included change over time in cognition and/or 
function. The reference to “change over time of other outcomes” has been removed 
since the other outcomes are exploratory efficacy endpoints. 
 
Section 3.1.1 has been updated to include that the participants will be treated for 4 
years with the last visit in the study at OLE-Week 208 and the follow-up visit at OLE-
Week 220. The study period extension will allow the collection of more information 
on the long-term safety and tolerability of gantenerumab in Alzheimer’s Disease 
(AD) and its efficacy in the context of long-term exposure, thus increasing 
understanding of gantenerumab’s long term safety and efficacy profile.  In addition, 
it will allow to better understand the long-term effect of gantenerumab on the 
pathophysiology of AD as well as changes on Study biomarkers. 
 
Section 3.2 has been updated to reflect that with the 2-year extension, the total 
duration of the study from baseline visit is expected to be approximately 4 years with 
the end of the study expected to occur by the end of 2026. 
 
Section 3.3.3.2 has been added to include the rationale for the additional 2 years. 
The extension of the study treatment duration from 2 to 4 years will allow the 
collection of more longitudinal safety and efficacy information of gantenerumab in 
AD. 
 
Sections 4.4.1 and 4.4.2 have been updated to reflect less stringent requirements 
regarding permitted medication that do not have an impact on participant safety and 
to clarify that study drug should be temporarily interrupted whilst anticoagulation 
therapy is ongoing. 
 
Section 4.4.1 has been updated to clarify that the administration of COVID-19 
vaccines will be considered, just as with other vaccinations, as a concomitant 
medication and that it is recommended to avoid vaccination in the 48 hours around 
the study dug injection to facilitate the correct attribution of adverse events (AEs). 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
4/Protocol WN42171, Version 4 
 
Section 4.5.3 has been amended to clarify that collecting ethnicity data facilitates  
evaluation of whether gantenerumab is metabolized or eliminated differently or if the 
treatment effect will be different in participants of different ethnic origins. 
 
Sections 4.5.4, 4.5.6.1, 4.5.7.3, 4.5.12, 4.5.13, 4.6.1 and Appendix 1 have been 
amended to reflect that OLE-W104 is a dosing visit and not the final efficacy and 
safety visit, to include additional visits during the study extension with the last visit in 
the study at OLE-Week 208 and to reflect that the follow-up visit will be at OLE-
Week 220 and not at OLE-W116. 
 
Section 4.5.6.13 has been updated to reflect that the Zarit Caregiver Interview for 
Alzheimer’s Disease (ZCI-AD) scale is also captured electronically. This was 
omitted in error. 
 
Section 5.3.5.4 has been amended to clarify reporting of serious or severe 
secondary events.  
 
The reporting of adverse events and serious adverse events related to preexisting 
conditions prior to the parent study baseline has been clarified to ensure the correct 
collection of data in view of the combined analysis with the data from the parent 
studies (Sections 5.3.5.12 and 5.3.5.13). 
 
The Medical Monitor and applicable contact information have been aligned 
throughout the protocol and deleted from Section 5.4.1.  To avoid the inclusion of 
outdated phone numbers in the protocol, the protocol refers to the Emergency 
Medical Call Center Help Desk, which will always have an up-to-date list of Medical 
Monitor and Medical Responsible contact information. 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12 
PROTOCOL SYNOPSIS .................................................................................... 13 
1. 
BACKGROUND ............................................................................ 23 
1.1 
Background on Alzheimer’s Disease ....................................... 23 
1.2 
Background on Gantenerumab ................................................ 23 
1.2.1 
Nonclinical and Clinical Studies ............................................... 24 
1.3 
Study Rationale and BenefitRisk Assessment ....................... 25 
1.3.1 
Study Rationale ....................................................................... 25 
1.3.2 
Safety Overview ....................................................................... 29 
1.3.2.1 
Amyloid-Related Imaging Abnormalities .................................. 29 
1.3.2.2 
Injection-Site Reactions ........................................................... 30 
1.3.2.3 
Overall BenefitRisk Summary ................................................ 31 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 32 
2.1 
Safety Objective ....................................................................... 32 
2.1.1 
Primary Objective:  Safety ....................................................... 32 
2.2 
Efficacy Objective .................................................................... 33 
2.2.1 
Secondary Objective:  Efficacy ................................................ 33 
2.2.2 
Exploratory Objective:  Efficacy ............................................... 33 
2.3 
Pharmacokinetic Objective ...................................................... 34 
2.4 
Immunogenicity Objective ........................................................ 34 
2.5 
Biomarker Objective ................................................................ 34 
2.6 
Health Status Utility Objective .................................................. 34 
3. 
STUDY DESIGN ........................................................................... 34 
3.1 
Description of the Study ........................................................... 34 
3.1.1 
Overview of Study Design........................................................ 34 
3.1.2 
Substudies ............................................................................... 36 
3.1.3 
Independent Data Monitoring Committee ................................ 37 
3.2 
End of Study and Length of Study ........................................... 38 
3.3 
Rationale for Study Design ...................................................... 38 
3.3.1 
Rationale for Gantenerumab Dose and Titration Schedule ..... 38 


 
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3.3.2 
Rationale for Participant Population ......................................... 38 
3.3.3 
Rationale for Study Treatment Duration .................................. 38 
3.3.3.1 
Rationale for the First 2-Year Duration .................................. 38 
3.3.3.2 
Rationale for the Subsequent 2-Year Duration ........................ 39 
3.3.4 
Rationale for ARIA Management Rules ................................... 39 
3.3.5 
Rationale for Biomarker Assessments ..................................... 39 
3.3.5.1 
Cerebral Spinal Fluid Biomarkers ............................................ 40 
3.3.5.2 
Brain Volumetry, Connectivity, and Fiber Tract Integrity .......... 40 
3.3.6 
Rationale for Pharmacokinetic Sampling ................................. 42 
4. 
MATERIALS AND METHODS ...................................................... 42 
4.1 
Participants .............................................................................. 42 
4.1.1 
Inclusion Criteria ...................................................................... 42 
4.1.2 
Exclusion Criteria ..................................................................... 44 
4.2 
Method of Treatment Assignment and Blinding ....................... 44 
4.2.1 
Treatment Assignment ............................................................. 44 
4.2.2 
Blinding .................................................................................... 45 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 45 
4.3.1 
Gantenerumab and Placebo .................................................... 46 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 46 
4.3.3 
PET Tracers ............................................................................. 49 
4.3.4 
Investigational Medicinal Product Accountability ..................... 49 
4.3.5 
Continued Access to Gantenerumab ....................................... 49 
4.4 
Concomitant Therapy .............................................................. 50 
4.4.1 
Permitted Therapy ................................................................... 50 
4.4.2 
Prohibited Therapy .................................................................. 52 
4.5 
Study Assessments ................................................................. 52 
4.5.1 
Informed Consent Forms and Screening Log .......................... 53 
4.5.2 
Baseline Definition and Assessments ...................................... 53 
4.5.3 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 54 
4.5.4 
Physical Examinations ............................................................. 54 
4.5.5 
Vital Signs ................................................................................ 55 


 
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4.5.6 
Cognitive, Functional, and Health Economics Assessments ... 55 
4.5.6.1 
Clinical Dementia Rating Scale ................................................ 56 
4.5.6.2 
Alzheimer’s Disease Assessment Scale-Cognitive 
Subscale .................................................................................. 56 
4.5.6.3 
Mini-Mental State Examination ................................................ 57 
4.5.6.4 
Verbal Fluency Task ................................................................ 57 
4.5.6.5 
Coding ..................................................................................... 57 
4.5.6.6 
Functional Activities Questionnaire .......................................... 57 
4.5.6.7 
Alzheimer’s Disease Cooperative Study-Activities of 
Daily Living Inventory ............................................................... 57 
4.5.6.8 
Zarit Caregiver Interview for Alzheimer’s Disease ................... 57 
4.5.6.9 
Quality of Life–Alzheimer’s Disease ........................................ 58 
4.5.6.10 
EQ-5D ...................................................................................... 58 
4.5.6.11 
Resource Utilization in Dementia Scale ................................... 58 
4.5.6.12 
Neuropsychiatric Inventory Questionnaire ............................... 59 
4.5.6.13 
Electronic Assessment of Rating Scales ................................. 59 
4.5.6.14 
Treatment Period Assessments ............................................... 59 
4.5.7 
Laboratory, Biomarker, and Other Biological Samples ............ 62 
4.5.7.1 
Pharmacokinetic Samples ....................................................... 62 
4.5.7.2 
Plasma Samples for Immunogenicity Analysis ........................ 63 
4.5.7.3 
Biomarker Samples ................................................................. 63 
4.5.8 
Electrocardiograms .................................................................. 65 
4.5.9 
ColumbiaSuicide Severity Rating Scale ................................. 66 
4.5.10 
Brain Magnetic Resonance Imaging ........................................ 66 
4.5.11 
Positron Emission Tomography Scan ...................................... 68 
4.5.12 
Final Safety and Efficacy Visit Assessments ........................... 69 
4.5.13 
Study Completion or Early Termination Visit Assessments ..... 69 
4.5.14 
Optional Samples for Research Biosample Repository ........... 69 
4.5.14.1 
Overview of the Research Biosample Repository .................... 69 
4.5.14.2 
Approval by the Institutional Review Board or 
Ethics Committee ..................................................................... 70 
4.5.14.3 
Sample Collection .................................................................... 70 
4.5.14.4 
Confidentiality .......................................................................... 71 


 
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4.5.14.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 71 
4.5.14.6 
Withdrawal from the Research Biosample Repository ............. 71 
4.5.14.7 
Monitoring and Oversight ......................................................... 72 
4.6 
Treatment, Participant, Study, and Site Discontinuation .......... 72 
4.6.1 
Study Treatment Discontinuation ............................................. 72 
4.6.2 
Participant Discontinuation from the Study .............................. 73 
4.6.3 
Study Discontinuation .............................................................. 73 
4.6.4 
Site Discontinuation ................................................................. 74 
5. 
ASSESSMENT OF SAFETY ......................................................... 74 
5.1 
Safety Plan .............................................................................. 74 
5.1.1 
Risks Associated with Gantenerumab ..................................... 74 
5.1.1.1 
Amyloid-Related Imaging Abnormalities .................................. 74 
5.1.1.2 
Injection-Site Reactions ........................................................... 75 
5.1.1.3 
Immunogenicity ........................................................................ 75 
5.1.2 
Management of Participants Who Experience Adverse 
Events ...................................................................................... 75 
5.1.2.1 
Dose Modifications and Treatment Interruptions ..................... 75 
5.2 
Safety Parameters and Definitions .......................................... 77 
5.2.1 
Adverse Events ........................................................................ 77 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 77 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 78 
5.2.4 
Selected Adverse Events ......................................................... 78 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 79 
5.3.1 
Adverse Event Reporting Period .............................................. 79 
5.3.2 
Eliciting Adverse Event Information ......................................... 79 
5.3.3 
Assessment of Severity of Adverse Events ............................. 80 
5.3.4 
Assessment of Causality of Adverse Events............................ 80 
5.3.5 
Procedures for Recording Adverse Events .............................. 80 
5.3.5.1 
Injection Reactions .................................................................. 80 
5.3.5.2 
ARIA Findings .......................................................................... 81 


 
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5.3.5.3 
Diagnosis versus Signs and Symptoms ................................... 81 
5.3.5.4 
Adverse Events That Are Secondary to Other Events ............. 81 
5.3.5.5 
Persistent or Recurrent Adverse Events .................................. 82 
5.3.5.6 
Abnormal Laboratory Values ................................................... 82 
5.3.5.7 
Abnormal Vital Sign Values ..................................................... 83 
5.3.5.8 
Abnormal Liver Function Tests ................................................ 83 
5.3.5.9 
Deaths ..................................................................................... 84 
5.3.5.10 
Preexisting Medical Conditions ................................................ 84 
5.3.5.11 
Lack of Efficacy or Worsening of Alzheimer’s Disease ............ 85 
5.3.5.12 
Hospitalization or Prolonged Hospitalization ............................ 85 
5.3.5.13 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse ............................................................................. 85 
5.3.5.14 
Clinical Outcome Assessment Data ......................................... 87 
5.3.5.15 
Safety Biomarker Data ............................................................. 87 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 87 
5.4.1 
Emergency Medical Contacts .................................................. 88 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 88 
5.4.3 
Reporting Requirements for Pregnancies ................................ 89 
5.4.3.1 
Pregnancies in Female Participants ........................................ 89 
5.4.3.2 
Abortions.................................................................................. 89 
5.4.3.3 
Congenital Anomalies/Birth Defects ........................................ 90 
5.4.4 
Reporting Requirements for Medical Device Complaints ......... 90 
5.5 
Follow-Up of Participants after Adverse Events ....................... 90 
5.5.1 
Investigator Follow-Up ............................................................. 90 
5.5.2 
Sponsor Follow-Up .................................................................. 90 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 91 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 91 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 91 
6.1 
Determination of Sample Size ................................................. 92 
6.2 
Summaries of Conduct of Study .............................................. 92 


 
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6.3 
Summaries of Demographic and Baseline Characteristics ...... 92 
6.4 
Safety Analyses ....................................................................... 92 
6.5 
Efficacy Analyses ..................................................................... 93 
6.6 
Pharmacokinetic Analyses ....................................................... 93 
6.7 
Immunogenicity Analyses ........................................................ 93 
6.8 
Biomarker Analyses ................................................................. 93 
6.9 
Health Status Utility Analyses .................................................. 94 
6.10 
Interim Analyses ...................................................................... 94 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 94 
7.1 
Data Quality Assurance ........................................................... 94 
7.2 
Electronic Case Report Forms ................................................. 95 
7.3 
Electronic Reported Outcome Data ......................................... 95 
7.4 
Source Data Documentation .................................................... 95 
7.5 
Use of Computerized Systems ................................................ 96 
7.6 
Retention of Records ............................................................... 96 
8. 
ETHICAL CONSIDERATIONS ...................................................... 97 
8.1 
Compliance with Laws and Regulations .................................. 97 
8.2 
Informed Consent .................................................................... 97 
8.3 
Institutional Review Board or Ethics Committee ...................... 98 
8.4 
Confidentiality .......................................................................... 99 
8.5 
Financial Disclosure ................................................................. 99 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 100 
9.1 
Study Documentation ............................................................ 100 
9.2 
Protocol Deviations ................................................................ 100 
9.3 
Management of Study Quality ................................................ 100 
9.4 
Site Inspections ..................................................................... 100 
9.5 
Administrative Structure ......................................................... 100 
9.6 
Dissemination of Data and Protection of Trade Secrets ........ 101 
9.7 
Protocol Amendments ........................................................... 102 
10. 
REFERENCES............................................................................ 103 
 


 
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LIST OF TABLES 
Table 1 
Gantenerumab Dosing Design for Participants Who Did Not 
Participate in the OLE Part of the Parent Study (WN29922 or 
WN39658) ................................................................................... 48 
Table 2 
Bioclinica 5-Point Scale Definition ............................................... 76 
Table 3 
Adverse Event Severity Grading Scale ....................................... 80 
 
 
LIST OF FIGURES 
Figure 1 
Mean (SE) PET Amyloid Reductions in the OLE PET 
Substudies .................................................................................. 27 
Figure 2 
Patient-Level Amyloid Reductions over 3 Years of Treatment 
in the OLE PET Substudies ........................................................ 28 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities ................................................................ 108 
Appendix 2 
Management Rules for Amyloid-Related Imaging 
Abnormalities ............................................................................ 139 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
AN OPEN-LABEL, MULTICENTER, ROLLOVER 
STUDY TO EVALUATE THE SAFETY, 
TOLERABILITY, AND EFFICACY OF LONG-TERM 
GANTENERUMAB ADMINISTRATION IN 
PARTICIPANTS WITH ALZHEIMER'S DISEASE 
PROTOCOL NUMBER: WN42171 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2020-000766-42 
IND NUMBER: 
102,266 
NCT NUMBER: 
NCT04374253 
TEST PRODUCT: 
Gantenerumab (RO4909832) 
MEDICAL MONITOR: 
, MBBS, Ph.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor. 
 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
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PROTOCOL SYNOPSIS 
TITLE: 
AN OPEN-LABEL, MULTICENTER, ROLLOVER STUDY TO 
EVALUATE THE SAFETY, TOLERABILITY, AND EFFICACY OF 
LONG-TERM GANTENERUMAB ADMINISTRATION IN 
PARTICIPANTS WITH ALZHEIMER'S DISEASE 
PROTOCOL NUMBER: 
WN42171 
VERSION NUMBER: 
4 
EUDRACT NUMBER: 
2020-000766-42 
IND NUMBER: 
102,266 
NCT NUMBER: 
NCT04374253 
TEST PRODUCT: 
Gantenerumab (RO4909832) 
PHASE: 
Phase IIIb 
INDICATION: 
Alzheimer’s disease 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
This study will evaluate the safety, tolerability, and efficacy of long-term administration of 
openlabel gantenerumab in participants with Alzheimer’s disease (AD) who completed 
Study WN29922 or WN39658.  Specific objectives and corresponding endpoints for the study 
are outlined below. 
Primary Objective: Safety 
Corresponding Endpoint 
● To evaluate the safety and 
tolerability of long-term 
gantenerumab administered by SC 
injection 
● Nature, frequency, severity, timing, and outcomes 
of adverse events and serious adverse events 
● Physical examinations (including neurologic 
systems), vital signs, ECG, laboratory tests, and 
C-SSRS 
● Nature, frequency, severity, and timing of ARIA-E 
and ARIA-H 
● Nature, frequency, severity, timing, and outcomes 
of injection-site reactions 
● Incidence of treatment discontinuations for adverse 
events 
● Incidence of adverse events of special interest 
 
 


 
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Secondary Objective: Efficacy 
Corresponding Endpoints 
● To evaluate the efficacy of 
long-term gantenerumab 
administered by SC injection  
● The change over time in cognition and/or function 
as measured by the following: 
− 
CDR 
− 
MMSE 
− 
ADAS-Cog11 and ADAS-Cog13 
− 
Verbal Fluency Task 
− 
Coding 
− 
FAQ 
− 
ADCS-ADL 
Exploratory Objective: Efficacy 
Corresponding Endpoints 
● To evaluate the efficacy of 
long-term gantenerumab 
administered by SC injection 
● The change over time in: 
− 
Health-related quality of life, as assessed by 
the QoL-AD scale 
− 
Behavioral and neuropsychiatric symptoms of 
AD, as measured by the NPI-Q 
− 
Caregiver burden, as assessed by the ZCI-AD 
scale 
− 
Elements of resource utilization, as assessed 
by the RUD-Lite 
Exploratory Pharmacokinetic Objective 
Corresponding Endpoint 
● To characterize the PK profile of 
gantenerumab administered by SC 
injection 
● Plasma concentration of gantenerumab 
administered subcutaneously at 
specified timepoints 
Immunogenicity Objective 
Corresponding Endpoint 
● To evaluate the immune response 
to gantenerumab administered by 
SC injection 
● Prevalence of ADAs at baseline and incidence of 
ADAs during the study 
Exploratory Biomarker Objective 
Corresponding Endpoints 
● To evaluate the long-term effects 
of gantenerumab administered by 
SC injection 
● Brain amyloid load over time, as measured by 
amyloid PET scan in a subset of participants 
● Brain tau load over time, as measured by tau PET 
scan in a subset of participants 
● CSF markers of disease over time in a subset of 
participants, including, but not limited to, A1−42, 
ttau, and p-tau 
● MRI-derived measurements over time, such as 
volumetric changes in whole brain, ventricles, 
hippocampus, or other structures; changes in 
functional brain connectivity; or changes in the 
integrity of white matter, in all participants. 
● Blood and plasma markers over time 
 
 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
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Exploratory Health Status Utility 
Objective 
Corresponding Endpoint 
● To evaluate the health status utility 
scores of participants treated with 
gantenerumab 
● Health outcome in participant and caregiver, as 
measured by EQ-5D 
ADAlzheimer’s disease; ADAS-Cog11Alzheimer’s Disease Assessment Scale-Cognition 
Subscale 11; ADAS-Cog13 Alzheimer’s Disease Assessment Scale-Cognition Subscale 13; 
ADCS-ADLAlzheimer’s Disease Cooperative Study Group-Activities of Daily Living; ARIA-
Eamyloid-related imaging abnormality-edema/effusion; ARIA-Hamyloid-related imaging 
abnormality-microhemorrhage/hemosiderin deposition; CDRClinical Dementia Rate; 
CSFCerebrospinal fluid; C-SSRSColumbia-Suicide Severity Rating Scale; EQ-5DEuroQoL 
5Dimension Questionnaire; FAQFunctional Activities Questionnaire; MRImagnetic resonance 
imaging; NPI-QNeuropsychiatric Inventory Questionnaire; PETpositron emission tomography; 
PKpharmacokinetic; ptauphosphorylated-tau; SCsubcutaneous; RUD-LiteResource 
Utilization in DementiaLite; t-tautotal tau; ZCI-ADZarit Caregiver Interview for Alzheimer’s 
Disease. 
 
Study Design 
Description of Study 
This is an open-label, multicenter, rollover study to evaluate the safety, tolerability, and efficacy 
of long-term administration of open-label gantenerumab in participants with AD who completed 
study WN29922 or WN39658, either the double-blind or open-label extension (OLE) part, as 
applicable (parent study).  The blind to the study treatment allocation during the parent study 
will be maintained to protect study integrity. 
Participants who have completed study WN29922 or WN39658, either the double-blind or OLE 
part as applicable, will be eligible to participate in this study.  Participants who discontinued 
early from study treatment during Study WN29922 or WN39658, regardless of the reason, will 
not be eligible for this study.  
Informed consent should be obtained from participants while they are in the parent study 
(WN29922 or WN39658) including in the safety follow-up, until a day before the first dose in the 
study WN42171.  In special situations, informed consent can be obtained at a later timepoint 
upon providing an appropriate rationale to the Sponsor, and it must be obtained before any 
study procedures in this study are performed. 
The first administration of gantenerumab in this study will be as follows: 
 
For participants who completed the double-blind part and did not enter the OLE part of 
study WN29922 or WN39658:  The first administration of open-label gantenerumab should 
take place approximately 2 weeks after the last efficacy and safety visit of the double-blind 
part of the parent study (WN29922 or WN39658) and will be considered the OLE baseline 
visit (OLE Day 1). 
 
For participants who completed the double-blind part and the OLE part of study WN29922 
or WN39658, the first administration of gantenerumab in this study should take place 
approximately 2 weeks after the OLE Week 34 visit or the final dose visit in the 
study WN29922 or WN39658 OLE.  Participants who have a gap in their transition between 
the OLE part of the parent study (WN29922 or WN39658) and this study, for unforeseen 
reasons, will roll over to this study continuing the schedule of activities as per their last visit 
in the OLE part of the parent study (WN29922 or WN39658.  Discussion with the Sponsor is 
recommended. 
 
Participants with evidence of amyloid-related imaging abnormalityedema/effusion (ARIA-E) on 
the last per-protocol study magnetic resonance imaging (MRI) scan report in Study WN29922 or 
WN39658, either its double-blind or OLE part, as applicable, will be retained in the WN29922 or 
WN39658 study until the ARIA-E finding is resolved.  They may then enroll in Study WN42171.  


 
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For those enrolling from the OLE part, the first visit of the participants in study WN42171 will 
be adapted according to the schedule of the visits of each participant in the parent study. 
The data from the last visit in the studies WN29922 or WN39658 (e.g., final efficacy and safety 
visit of the double-blind part, or last visit in the WN29922 or WN39658 OLE part) will be used as 
the data for the first visit in this study if the two visits take place within 4 weeks of each other.  
All cognitive scales, and the C-SSRS do not need to be repeated if they were performed within 
6 months in the previous parent study.  The MRI scan does not need to be repeated if 
performed within 6 months in the previous parent study (WN29922 or WN39658) and following 
the final study drug dose in the parent study.  Vital signs and urine pregnancy test will have to 
be performed at the first visit in this study before dosing.  MRI and urine pregnancy test results 
must be available before dosing. 
In this study, participants who were in the active double-blind arm in the parent study (WN29922 
or WN39658) will continue receiving open-label gantenerumab 510 mg SC Q2W, and those 
participants who were in the placebo double-blind arm will go through a full uptitration scheme 
while retaining the blinding to the previous treatment allocation.  If there is a delay in a 
participant’s transition between the OLE part of the parent study (WN29922 or WN39658) and 
this study (for instance, due to delays in the approval of this study at a site) that goes beyond a 
reasonable time frame as determined by the Sponsor, the participant may be asked to start at 
the dose they were at previously when they completed the parent study and to perform a safety 
MRI before receiving the target dose.  In this case, such decisions will be made after discussion 
with the Sponsor. 
The dosing schedule and the schedule of activities will be different for participants, depending 
on whether they completed the OLE part of the study WN29922 or WN39658, which covers the 
uptitration phase for the participants in the placebo arm, or if they completed only the 
doubleblind part. 
Following baseline assessments (i.e., OLE Day 1 either in this protocol or in the parent 
protocol), each participant will be treated for 4 years.  The study duration has been extended 
from 2 to 4 years in order to collect more information on the long-term safety and tolerability 
of gantenerumab in AD and its efficacy in the context of long-term exposure and to increase 
the overall number of participant-years of exposure, thus increasing understanding of 
gantenerumab’s long-term safety and efficacy profiles.  Unless participants are eligible and 
choose to enroll in an alternative gantenerumab OLE study that becomes available, the final 
dose of study drug will be administered at OLE Week 206.  At the end of the treatment period, 
all participants will undergo an OLE Week 208 visit.  Participants will be asked to come back for 
a follow-up visit at OLE Week 220 unless they are transitioning to an alternative 
gantenerumab OLE study that becomes available. 
Participants who discontinue study drug at any time during this study will be asked to complete 
an early termination visit 2 weeks after their final dose and also return for collection of safety 
data (except safety MRI) and limited efficacy data (i.e., secondary endpoints).  
Participants who do not meet the criteria for participation in this study (screening failure) may be 
re-screened.  The investigator will record reasons for screening failure in the screening log. 
Substudies 
The substudies associated with study WN42171 will be described in separate protocols, and 
participants consenting to enroll in these substudies will be asked to sign the associated 
Informed Consent Forms.  To date, two optional substudies are associated with Study 
WN42171:  a longitudinal amyloid positron emission tomography (PET) substudy and a 
longitudinal tau PET substudy.   
The amyloid and tau PET assessments will enable a longitudinal evaluation of the effect of 
gantenerumab on brain amyloid deposition as measured by florbetaben or flutemetamol PET 
radioligands and tau burden as measured by [18F]GTP1 (Genentech Tau Probe 1; an 
investigational radioligand for in vivo imaging of tau protein aggregates) in participants with AD.  
The collected PET data are expected to help in understanding the effects of gantenerumab on 
amyloid and tau pathology over time as well as the relationship between changes in 
florbetaben/flutemetamol/[18F]GTP1-PET and changes in other endpoints in study WN42171. 
Two optional substudies associated with this protocol may be introduced.  


 
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In one of them, post-mortem brain tissue may be obtained from participants for evaluation of the 
effect of long-term gantenerumab therapy on the brain.  The opportunity to donate post-mortem 
brain tissue may be discussed with participants. 
In the other one, digital tools that assess the disease progression of the participants may be 
tested for validation and for other exploratory purposes. 
Interested participants would be provided with additional details.  Any further procedures, with 
respect to the optional substudies, will be governed by a separate consent form and separate 
substudy protocol document. 
Independent Data Monitoring Committee 
The independent Data Monitoring Committee (iDMC) will evaluate participant safety on a 
regular basis.  In addition to the data defined in the iDMC Charter (e.g., the incidence and 
nature of adverse events, serious adverse events, adverse events of special interest, ARIA-E, 
amyloid-related imaging abnormality microhemorrhage/hemosiderin deposition (ARIA-H), and 
injection site reactions [ISRs]), the iDMC will review all necessary cumulative data, including 
efficacy data if necessary, at regular intervals during the study.  It is anticipated that these 
assessments will occur approximately every 3 months or as detailed in the iDMC charter.  At 
the time of each review, the iDMC will make appropriate recommendations (e.g., the study 
should continue as planned, the safety risk management should be modified, the protocol 
should otherwise be amended, and enrollment should be held pending further safety 
evaluations).  
Decisions will be made after considering the totality of the available data.  Ad-hoc meetings may 
be called in addition to scheduled meetings, as necessary, to provide recommendations on 
management of any new safety issues.  Specific operational details, such as the committee's 
composition, frequency and timing of meetings, and members' roles and responsibilities are 
detailed in the iDMC Charter.  
Final decisions will rest with the Sponsor. 
In the event, the iDMC which reviews safety in both the parent studies (WN29922 and 
WN39658), and study WN42171 is no longer required (for instance after the unblinding of the 
parent studies) evaluation of participant safety may be taken over by the Sponsor’s Internal 
Monitoring Committee (IMC), with details documented in an IMC charter. 
Number of Participants 
The planned enrollment is expected to be no more than approximately 2032 participants with 
AD but will be determined by the number of participants who complete the parent studies 
WN29922 and WN39658 and enroll in this study. 
Target Population 
Inclusion Criteria 
Participants must meet the following criteria for study entry: 
 
Signed Informed Consent Form by the participant with AD and/or the legal authorized 
representative as per local requirements 
 
Completed study WN29922 or WN39658, either its double-blind part (participants have 
reached the 510 mg every 2 weeks [Q2W] dose schedule by the time of completion) or OLE 
part (participants have received at least 3 doses of 510 mg every 4 weeks [Q4W]), and did 
not discontinue study drug early  
 
Ability to comply with the study protocol 
 
Willingness and ability to complete all aspects of the study (including MRI) 
 
The participant should be capable of completing assessments either alone or with the help 
of the caregiver. 
 
Availability of a person (referred to as the “caregiver” throughout the protocol) who: 
– 
In the investigator’s judgement, has frequent and sufficient contact (e.g., 5 times per 
week or approximately 10 hours per week) with the participant; 
– 
In the investigator’s judgement, is able to provide accurate information regarding the 
participant’s cognitive and functional abilities, including knowledge about domestic 
activities, hobbies, routines, social skills, and basic activities of daily life; work and 
educational history; cognitive performance including memory abilities, language 


 
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abilities, temporal and spatial orientation, judgement, and problem solving; emotional 
and psychological state; and can report any changes in the general health status. 
– 
Agrees to provide information and to complete all aspects of the study at clinic visits 
(which require partner input for scale completion) 
– 
Signs the necessary Informed Consent Form(s), and has sufficient cognitive capacity to 
accurately report on the participant’s behavior as well as cognitive and functional 
abilities 
– 
Is fluent in the language used at the site and has sufficiently good general health to 
have a high likelihood of maintaining the same level of interaction with the participant 
and participation in study procedures throughout the duration of the study 
Every effort should be made to have same caregiver participate throughout the 
duration of the study. 
  
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception as defined below: 
- 
Women must remain abstinent or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for at least 16 weeks after the final dose of 
gantenerumab. 
- 
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined 
by the investigator (e.g., Müllerian agenesis).  The definition of childbearing potential 
may be adapted for alignment with local guidelines or regulations. 
- 
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. 
- 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the participant.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not adequate methods of contraception.  If required per local guidelines or regulations, 
locally recognized adequate methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
 
Agreement not to donate blood or blood products for transfusion for the duration of the study 
and for 1 year after final dose of study drug. 
 
Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from study entry: 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or within at 
least 16 weeks after the final dose of study drug  
Women of childbearing potential must have a negative urine pregnancy test at the final 
visit of the parent study. 
 
Prematurely discontinued from study WN29922 or WN39658, either its double-blind or OLE 
part, as applicable, or from study drug, for any reason  
 
Any medical condition that the investigator or Sponsor determines may jeopardize the 
participant’s safety if he or she continues to receive study treatment 
 
Received any investigational treatment other than gantenerumab during or since completion 
of study WN29922 or WN39658, either its double-blind or OLE part, as applicable 
 
Evidence of disseminated leptomeningeal hemosiderosis (i.e., more than three focal 
leptomeningeal hemosiderosis) 
 
Evidence of intracerebral macrohemorrhage 
 
Use of prohibited medication  


 
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 
Evidence of ARIA-E on the last MRI scan report in Study WN29922 or WN39658, either its 
double-blind or OLE part, as applicable 
Participants should remain in the parent study, as governed by that protocol, and may enroll in 
this study once the ARIA-E is resolved. 
End of Study 
The end of this study is defined as the date when the last participant, last visit, occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is received 
from the last participant, whichever occurs later.  The end of the study is expected to occur by 
the end of 2026. 
In addition, the Sponsor may decide to terminate the study at any time. 
Length of Study 
The total length of this study from baseline visit (OLE Day 1 in either the Study WN42171 
protocol or in the parent protocol) to the end of the study (including the follow-up visit) is 
expected to be approximately 4 years and 3 months.  Following uptitration, participants will 
receive up to 86 doses of gantenerumab 510 mg Q2W.  Participants who did not participate in 
the OLE part of the parent study (WN29922 or WN39658) will also go through an uptitration 
scheme in the WN42171 study with a duration of at least 34 weeks. 
Investigational Medicinal Products 
The investigational medicinal product for this study is gantenerumab. 
Test Product (Investigational Drug) 
Gantenerumab or placebo will be administered by SC injection to all patients. 
Statistical Methods 
Primary Analysis 
The safety analysis population will include all enrolled participants who received at least one 
dose of study drug in this protocol. 
The following safety outcome measures will be summarized using descriptive statistics: 
 
Nature, frequency, severity, timing, and outcomes of adverse events and serious adverse 
events 
 
Physical examinations (including neurological systems), vital signs, ECG, laboratory tests, 
and Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Nature, frequency, severity, and timing of ARIA-E and ARIA-H 
 
Nature, frequency, severity, timing, and outcomes of injection-site reactions 
 
Incidence of treatment discontinuations for adverse events 
 
Incidence of adverse events of special interest 
Statistical methods, endpoint definitions, and analyses of the safety endpoints will be described 
in a Statistical Analysis Plan (SAP).  
Determination of Sample Size 
The sample size will include all eligible participants who consent to this study.  The sample size 
is expected to be no more than approximately 2032 participants but will be determined by the 
number of participants who complete the parent studies (WN29922 and WN39658) and enroll in 
this study. 
Interim Analyses 
To adapt to information that may emerge during the course of this study, the Sponsor may 
choose to conduct one or more interim analysis(es), which may include efficacy, safety, and 
biomarker outcomes.  An interim analysis may be considered when the parent pivotal studies 
WN29922 and WN39658 are completed and the submission folder is under preparation.  Details 
will be pre-specified in a SAP. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
[18F]GTP1 
Genentech Tau Probe 1 
A 
amyloid beta 
AChEI 
acetylcholinesterase inhibitor 
AD 
Alzheimer’s disease 
ADA 
anti-drug antibody 
ADAS-Cog11 
Alzheimer's Disease Assessment ScaleCognition, 
Subscale 11 
ADAS-Cog13 
Alzheimer's Disease Assessment ScaleCognition, 
Subscale 13 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study 
GroupActivities of Daily Living 
ADL 
activities of daily living 
APOE 
Apolipoprotein E 
APOE 4- 
apolipoprotein E gene allele 4- 
ARIA 
amyloid-related imaging abnormality  
ARIA-E 
amyloid-related imaging abnormalityedema/effusion  
ARIA-H 
amyloid-related imaging abnormality 
microhemorrhage/hemosiderin deposition 
BOLD 
blood oxygenation level-dependent  
CDR 
Clinical Dementia Rating 
CDR-GS 
Clinical Dementia RatingGlobal Score 
CDR-SOB 
Clinical Dementia RatingSum of Boxes 
COA 
clinical outcome assessment 
COVID-19 
coronavirus disease 2019 
CSF 
cerebrospinal fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DTI 
diffuse tensor imaging   
DSST 
Digit Symbol Substitution Test 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EQ-5D 
EuroQoL 5-Dimension Questionnaire 
E.U. 
European Union 
FA 
fractional anisotropy 
FAQ 
Functional Activities Questionnaire 
FDA 
(U.S.) Food and Drug Administration 


 
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Abbreviation 
Definition 
GRE 
gradient recalled echo 
GTP1 
Genentech Tau Probe 1 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Council for Harmonisation 
iDMC 
independent Data Monitoring Committee 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
ISR 
injection-site reaction 
IxRS 
interactive voice or web-based response system 
MAD 
multiple ascending dose 
MMSE 
Mini-Mental State Examination 
MN 
mobile nursing 
MRI 
magnetic resonance imaging 
MR-NP 
Marguerite RoAD (Study WN28745) double-blind 
placebo (non-pretreated patients in the placebo arm of 
Study WN28745 during the double-blind phase) 
MR-P 
Marguerite RoAD (Study WN28745) double-blind 
active (pretreated patients in the active treatment arm 
of Study WN28745 during the double-blind phase) 
NMDA 
N-methyl-D-aspartate 
NPI-Q 
Neuropsychiatric Inventory Questionnaire 
OLE 
open-label extension 
PD 
pharmacodynamics 
PET 
positron emission tomography 
PK 
pharmacokinetic 
p-tau 
phosphorylated tau 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
QoL 
quality of life 
QoL-AD 
Quality of LifeAlzheimer's Disease 
RBR 
Research Biosample Repository 
rs-fMRI 
resting-state functional magnetic resonance imaging 
RUD-Lite 
Resource Utilization in DementiaLite 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SR 
Scarlet RoAD (Study WN25203) 
T4 
thyroxine 


 
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Abbreviation 
Definition 
t-tau 
total tau 
ULN 
upper limit of normal 
WAIS-IV 
Wechsler Adult Intelligence Scale-Fourth Edition 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
ZCI-AD 
Zarit Caregiver Interview for Alzheimer’s Disease 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON ALZHEIMER’S DISEASE 
The World Health Organization estimates that around 50 million people worldwide are 
diagnosed with dementia and that there are 10 million new cases every year.  The total 
number of people with dementia is estimated to reach 82 million in 2030 and will more 
than triple to 152 million by 2050.  Alzheimer’s disease (AD) is the most common form of 
dementia, accounting for 60%70% of cases (World Health Organization 2019).  
The prevalence of AD increases with age, with a global prevalence of 5%8% in people 
60 years and older.  Because of its increasing prevalence, long duration, and high cost 
of care, AD is expected to continue to represent a major public health problem for 
decades to come. 
The median survival time following a diagnosis of AD strongly depends on the 
patient’s age at diagnosis and ranges from 8.3 years for persons diagnosed with AD at 
65 years old to 3.4 years for those 90 years old (Brookmeyer et al. 2002; 
Zanetti et al 2009), but some individuals survive as long as 20 years. 
It is well recognized that in comparison to other therapeutic domains, there is a real 
unmet medical need in AD therapy (Gauthier et al. 2016).  To date, only five medications 
have received marketing approval in the European Union and United States to treat the 
symptoms of AD, including acetylcholinesterase inhibitors (AChEIs) and 
N-methyl-D-aspartate (NMDA) receptor antagonists.  These approved drugs are 
recognized to temporarily improve some clinical symptoms of AD in some patients but 
do not modify progression of the disease (Cummings et al. 2018). 
Currently, one compelling therapeutic target (Graham et al. 2017) is amyloid beta (A), 
and A-targeting therapies remain the major trend in AD drug development 
(Bachurin et al. 2017).  These therapies are based on the amyloid hypothesis that posits 
A accumulation as the primary factor driving AD pathogenesis (Selkoe 1991; 
Hardy and Selkoe 2002; Selkoe and Hardy 2016).  This A accumulation in the brain 
begins well before the development of clinical dementia in AD and causes a series of 
downstream events leading to synaptic dysfunction, inflammation, neurodegeneration, 
and clinical symptoms.  For these reasons, treatments that prevent, slow, or decrease 
the accumulation of brain A are being tested as therapeutic agents in AD. 
1.2 
BACKGROUND ON GANTENERUMAB 
Gantenerumab (RO4909832) is a recombinant, human monoclonal antibody of the IgG1 
subclass directed against the Apeptide.  Gantenerumab recognizes a conformational 
epitope of Aand has demonstrated activity for both major types of A(A140, 
A142).  In vitro, gantenerumab recognizes synthetic aggregated Aβ fibrils and Aβ 
oligomers with high nanomolar affinity (KD, ~0.61.2 nM).  The mechanism of action of 
gantenerumab is primarily clearance of Aβ plaques by antibody-dependent cell-mediated 


 
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phagocytosis.  Gantenerumab also works via dissociation of A peptide aggregates by 
direct resolution and by blockade of toxic A oligomers. 
Gantenerumab is manufactured by cell culture of a recombinant Chinese hamster ovary 
K1 mammalian cell line and subsequent purification of the antibody.  Gantenerumab 
drug substance manufacturing was optimized during development to improve process 
robustness and increase overall process yield, leading to several generations of 
manufacturing process (G1, G2, G3, and G4).  Drug material manufactured by the 
G4 process is used in pivotal Phase III clinical trials (Studies WN29922 and WN39658).  
G4 drug material will be used in this study. 
1.2.1 
Nonclinical and Clinical Studies 
Nonclinical evidence has suggested that monoclonal anti-A antibodies may be able to 
remove and reduce deposition of A aggregates from the brain.  In transgenic animal 
models of AD, vaccination with A or passive immunization with anti-A antibodies 
resulted in decreased amyloidosis and in improvement of memory function in some 
transgenic models of cognitive function (Janus et al. 2000).  Accumulating clinical 
evidence also supports that monoclonal A antibodies can bind A and promote its 
clearance (Salloway et al. 2009; Ostrowitzki et al. 2012; Klein et al. 2019b), reduce 
deposition of A aggregates, and reduce markers of neurodegeneration in the 
cerebrospinal fluid (CSF;Roche Research Report No. 1066251).  In a Phase I study with 
the anti-A monoclonal antibody aducanumab, reduction of deposited amyloid as shown 
on brain amyloid positron emission tomography (PET) imaging was associated with a 
time- and dose-related slowing of cognitive decline (Sevigny et al. 2016).  Because the 
pathological changes associated with AD develop decades before clinical symptoms 
emerge, it is thought that earlier intervention may be more effective in arresting or 
delaying disease progression (Sevigny et al. 2016).  Consequently, therapies targeting 
this process have the potential to significantly alter the progression of the disease.  
Gantenerumab, a fully human monoclonal antibody targeting aggregated forms of A, 
such as A oligomers, fibrils, and plaques, is expected to address this need (Bohrmann 
et al. 2012). 
Gantenerumab has been investigated in 10 completed Phase I clinical studies:  3 single 
ascending dose studies in healthy volunteers and patients with mild to moderate AD 
(Studies BN18726, JP22474, and BP30042); 2 multiple ascending dose (MAD) studies 
of patients with mild to moderate AD (Studies NN19866 and JP22431); and 
4 bioavailability studies in healthy subjects1 study comparing the IV and SC 
formulations of gantenerumab (Study WP22461), 2 studies comparing lyophilized and 
high-concentration liquid formulations of gantenerumab (Studies WP27951 and 
BP29113), and 1 study comparing drug substance manufactured through the third and 
fourth generation (G3 and G4) processes (Study WP40052).  A tolerability study that 
compared injection-site pain between faster and slower SC administration of 
gantenerumab was also conducted (Study WP39322).  Overall, a total of 543 subjects 


 
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have participated in the Phase I studies; of these participants, 406 healthy volunteers 
and 101 patients with mild to moderate AD have received gantenerumab. 
Based on results of the MAD Study NN19866 and of the relative bioavailability study 
(WP27951), the doses of 105 mg SC every 4 weeks (Q4W; equivalent to 60 mg IV 
Q4W) and 225 mg SC Q4W (equivalent to 130 mg IV Q4W) were initially selected for the 
Phase III studies WN25203 and WN28745.  Following the results of the Study WN25203 
futility analysis, these studies were converted into open-label extensions (OLEs) to 
examine the safety and tolerability of a higher dose of gantenerumab (1200 mg 
SC  Q4W). 
Overall, 383 patients enrolled in the OLEs of Studies WN25203 and WN28745.  As of 
1 May 2019, 363 patients had been exposed to G3 gantenerumab doses higher than 
225 mg, and 309 patients reached the target 1200 mg dose.  Continuous monitoring of 
safety data and magnetic resonance imaging (MRI) findings by the Sponsor has not 
identified any new safety signals in these ongoing studies.  Injection-site reactions 
(ISRs) and amyloid-related imaging abnormalities (ARIAs) remain the only identified 
risks for gantenerumab.  These OLE studies were completed respectively in 2020 and in 
2021, and patients who did not discontinue study treatment at the end of the prescribed 
study period were provided an option to enroll in an open-label rollover study to evaluate 
the safety and tolerability of long-term administration of gantenerumab 
(Study WN41874). 
Based on safety results from OLE Studies WN25203 and WN28745, and on data from 
the PET substudies that confirmed the pharmacodynamic (PD) effects of gantenerumab 
treatment (1200 mg SC Q4W) on A plaque reduction (Klein et al. 2019b), two pivotal 
multicenter, Phase III studies in patients with early (prodromal to mild) AD were initiated:  
WN29922 (Graduate 1) and WN39658 (Graduate 2).  These studies are examining the 
efficacy, safety, and tolerability of gantenerumab uptitrated to 510 mg every 2 weeks 
(Q2W) dosing; they are currently ongoing and are expected to be completed in 2023.  
Refer to the Gantenerumab Investigator's Brochure for more details on nonclinical and 
clinical studies. 
1.3 
STUDY RATIONALE AND BENEFITRISK ASSESSMENT 
1.3.1 
Study Rationale 
Study WN42171 allows participants previously treated with gantenerumab or placebo for 
approximately 2 years in the parent Studies WN22992 or WN39658 to continue 
receiving open-label gantenerumab. 
Currently, approved therapies for AD focus on symptomatic approaches that target 
synaptic function and cognitive enhancement (Cummings 2004).  However, the amyloid 
hypothesis suggests that overproduction of A or failure to effectively clear this peptide 
contributes to AD (Selkoe and Hardy 2016) and that accumulation of A peptides is a 
factor contributing to AD progression (Sun et al. 2015).  Thus, the targeting of A and 


 
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subsequent displacement of A from the brain is a rational approach to modify 
AD progression. 
Accumulating clinical evidence supports that monoclonal A antibodies can bind A and 
promote its clearance (Salloway et al. 2009; Ostrowitzki et al. 2012; Sevigny et al. 2016; 
Klein et al. 2019b), reduce deposition of A aggregates, and reduce markers of 
neurodegeneration in CSF (Ostrowitzki et al. 2017).  A Phase I study of aducanumab 
(Sevigny et al. 2016) and a Phase II study of BAN2401 (Swanson et al. 2018) suggested 
that reduction of deposited amyloid, as seen on brain amyloid PET imaging, was 
associated with a dose-related slowing of cognitive decline. 
Gantenerumab data from the PET substudies of the WN25203 and WN28745 OLEs 
confirmed that gantenerumab treatment at a dose of 1200 mg SC Q4W reduced 
A plaques in patients with AD (Klein et al. 2019b).  Overall, 89 patients from the OLEs 
of Studies WN25203 and WN28745 were included in amyloid PET substudies using 
florbetapir F18.  As of 31 August 2019, of these 89 patients, 67 patients received 
follow-up scans at Week 52, 42 patients at Week 104, and 30 patients at Week 156 of 
the OLE. 
Results of the PET substudies showed a marked and consistent reduction of amyloid 
load in patients receiving higher-dose gantenerumab in all three patient groups that were 
analyzed (Figure 1):  1) MR-NP (non-pretreated patients in the placebo arm of Study 
WN28745); 2) MR-P (pretreated patients in the active treatment arm of 
Study WN28745); and 3) SR (patients from Study WN25203).  Indeed, amyloid 
reductions were seen consistently in nearly all patients in the three analyzed subgroups 
(Figure 2). 


 
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Figure 1 Mean (SE) PET Amyloid Reductions in the OLE PET Substudies 
 
MR-PMarguerite RoAD (Study WN28745) double-blind active (pretreated patients in the active 
treatment arm of Study WN28745 during the double-blind phase); MR-NPMarguerite RoAD 
(Study WN28745) double-blind placebo (non-pretreated patients in the placebo arm of Study 
WN28745 during the double-blind phase); OLE = open-label extension; PET = positron emission 
tomography; SE = standard error; SR = Scarlet RoAD (Study WN25203); SUVR = standardized 
uptake value ratio. 
a Analyzed using a mixed-model for repeated measures. 
Source:  Klein et al. 2019a. 
 
The threshold for amyloid positivity is an important anchor for interpreting the 
PET substudy results.  It is defined as the quantitative threshold that best discriminates 
pathologically-verified absence of plaques or sparse plaques from moderate to frequent 
plaques.  A centiloid value of 24 is generally recognized as the amyloid positivity 
threshold (Landau and Jagust 2015; Navitsky et al. 2018; Klein et al. 2019b).  Results in 
the ongoing substudies WN25203 and WN28745 confirm the amyloid plaque removal 
component of the gantenerumab mechanism of action.  The results further show that 
following 3 years of gantenerumab treatment, 80% of subjects were below the positivity 
threshold, and 43% of subjects were below a centiloid value of 0, which represents the 
mean amyloid load of a healthy normal population (Figure 2). 


 
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Figure 2 Patient-Level Amyloid Reductions over 3 Years of Treatment in 
the OLE PET Substudies 
 
OLE = open-label extension; PET = positron emission tomography; SUVR  standardized uptake 
value ratio. 
Source:  Klein et al. 2019a. 
 
In summary, the PET substudy results demonstrate continued amyloid removal beyond 
2 years of gantenerumab treatment.  Thus, this study, which provides open-label 
gantenerumab for 4 additional years to patients already receiving gantenerumab in the 
parent Study (WN22992 or WN39658), will provide valuable information on how 
continued amyloid removal may translate into continued clinical effect. 
Study WN42171 will also provide the opportunity for participants previously treated with 
placebo in the double-blind phase of parent Study WN22992 or WN39658 to receive 
gantenerumab treatment for up to 4 years.  To protect study data integrity and to aid the 
assessment of the long-term effects of gantenerumab, treatment assignment information 
from the double-blind phase of parent Study WN22992 or WN39658 will remain blinded 
to the Sponsor, investigator, and participant at least until database lock of the parent 
studies, which will happen while this study is ongoing. 


 
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1.3.2 
Safety Overview 
Nonclinical characterization of gantenerumab did not show relevant safety findings.  
No differences between gantenerumab and placebo groups have been observed in 
laboratory parameters, physical and neurologic examinations, vital signs, or 
ECG parameters. 
The identified risks of gantenerumab treatment are ARIAs and ISRs.  Safety data and 
MRI findings are continuously monitored in all ongoing studies, and no new safety 
signals have been identified. 
The Gantenerumab Investigator’s Brochure includes a summary of safety data with 
gantenerumab SC in participants with AD from Studies WN25203 and WN28745 as well 
as from Phase I studies with gantenerumab SC and IV. 
Providing participants who complete study treatment in the pivotal Studies WN22992 
and WN39658 with an opportunity to extend or initiate treatment with open-label 
gantenerumab in Study WN42171 will allow the collection of more information on the 
long-term safety and tolerability of gantenerumab in AD.  It will also provide more 
information on its efficacy in the context of long-term exposure.  Furthermore, the OLE 
will increase the overall number of participants exposed to gantenerumab and 
participant-years of exposure, thus increasing understanding of the safety and efficacy 
profiles. 
1.3.2.1 
Amyloid-Related Imaging Abnormalities 
ARIAs are one of the most significant adverse events reported in therapies against 
aggregated forms of A.  These findings appear to be dependent on dose-, time-, and 
apolipoprotein E gene allele 4- (APOE 4-) (Piazza and Winblad 2016). 
The mechanism underlying the development of amyloid-related imaging 
abnormalityedema/effusion (ARIA-E) and amyloid-related imaging 
abnormalitymicrohemorrhage/hemosiderin deposition (ARIA-H) during 
anti-amyloid treatment is not yet fully understood.  Because antibodies remove Afrom 
both the parenchyma and cerebral vasculature, vessels with preexisting amyloid 
vascular pathology might become transiently more susceptible to leakage of vascular 
contents.  This pathology results in ARIA-E if the leakage consists of proteinaceous fluid 
and in ARIA-H if the leakage consists of blood products (Sperling et al. 2012).  
An anti-Atherapy that effectively maintains vascular Aclearance would allow vascular 
remodeling and might, over time, decrease the risk of such extravasation events 
(Sperling et al. 2012).  This is consistent with experiences in previous and ongoing 
studies and with reported data from the long-term extension study of aducanumab 
treatment (Viglietta et al. 2016). 
Understanding of the clinical significance of ARIA by study sponsors, investigators, and 
regulators has substantially evolved since ARIA events were first seen on MRI scans in 


 
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a Phase I clinical trial with bapineuzumab (Black et al. 2010).  The accrued clinical 
evidence with gantenerumab and other N-terminus anti-amyloid antibodies has shown 
that ARIA events tend to occur early in treatment, are dose- and APOE 4-dependent, 
and can be monitored by MRI and managed with dose intervention algorithms. 
The Sponsor’s experience with managing patients with ARIA findings and increasing 
understanding of the impact of such findings on patient clinical outcomes has resulted in 
the introduction of revised ARIA risk mitigation measures in studies with gantenerumab 
over time.  Accordingly, ARIA management has shifted from more cautious 
management, where an ARIA-E finding resulted in treatment interruption regardless of 
intensity (Study WN25203 [double-blind]), to less restrictive management, where only 
moderate-severe intensity ARIA-E and symptomatic ARIA-E findings result in treatment 
interruption (Studies WN25203 and WN28745:  OLE; Studies WN29922 and WN39658).  
Similarly, the cumulative number of ARIA-H findings that trigger treatment 
discontinuation was changed from 5 (Studies WN25203 and WN28745 [double-blind]) to 
10 (Studies WN25203 and WN28745 [OLE]), to 15 (Studies WN29922 and WN39658).  
The revised management led to similar and acceptable safety profiles.  
In Studies WN29922 and WN39658, safety reviews of unblinded data by an independent 
Data Monitoring Committee (iDMC) have not identified any new safety signal. 
Taking into account the evolving experience with managing ARIA findings, including the 
finding that continued gantenerumab treatment during episodes of asymptomatic mild 
ARIA-E was not associated with clinically unfavorable outcomes, the Sponsor intends to 
examine the safety of continuing gantenerumab treatment through mild to moderate 
asymptomatic ARIA-E findings and to examine the safety of gantenerumab therapy in 
the presence of an increased number of ARIA-H microhemorrhages. 
Study WN42171 will require an MRI scan documenting the absence of ARIA-E or 
evidence of disseminated leptomeningeal hemosiderosis prior to the first gantenerumab 
dose.  If ARIA findings occur during the study, MRI monitoring, temporary dose holding, 
or permanent study drug discontinuation will be implemented according to an 
ARIA management plan, as described in Appendix 2. 
Safety findings, including individual participant and aggregate data, will be reviewed on a 
regular basis by the Sponsor and by an iDMC.  In the event the iDMC which reviews 
safety in both the parent Studies (WN29922 and WN39658) and Study WN42171 is no 
longer required (for instance after the unblinding of the parent studies) evaluation of 
participant safety may be taken over by the Sponsor's Internal Monitoring Committee 
(IMC), with details documented in an IMC charter. 
1.3.2.2 
Injection-Site Reactions 
The incidence of ISRs in gantenerumab-treated patients with up to the target 
gantenerumab dose (1200 mg SC Q4W) ranged from 36% (Study WN25203 OLE) to 
38% (Study WN28745 OLE) as of 1 May 2019.  All ISRs were non-serious, mostly mild 


 
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to moderate in intensity, and the majority resolved without treatment.  The most common 
signs and symptoms of ISRs included injection-site erythema, redness, swelling, and 
itching.  No patients discontinued study treatment due to ISRs. 
1.3.2.3 
Overall BenefitRisk Summary 
The benefitrisk assessment of gantenerumab treatment in Study WN42171 is based on 
the following: 
 
Gantenerumab has shown evidence of continuous reduction of the amyloid plaque 
component in up to 3 years of treatment and thus shows potential benefit in slowing 
the progression of AD. 
 
Findings from Study WN25203 (Klein et al. 2019), the PRIME study with 
aducanumab (Sevigny et al. 2016), and from the Phase II study with BAN2401 
(Swanson et al. 2018) suggest that reduction in deposited amyloid is associated 
with a dose-related slowing of cognitive decline, providing additional support for the 
hypothesis that anti-amyloid treatment may be associated with a beneficial clinical 
effect. 
 
Results from the double-blind part of Studies WN25203 and WN28745, as well as 
from the completed OLEs Studies WN25203 and WN28745, showed that 
ARIA-E findings are mostly asymptomatic, non-serious, of mild severity, and do not 
require permanent cessation of treatment. 
 
No new safety signals have been identified from the ongoing Phase III studies with 
gantenerumab with doses of up to 510 mg Q2W or equivalent, which supports the 
safety of continued administration of gantenerumab uptitrated to the target dose in 
the current and planned studies, including Study WN42171. 
 
Study WN42171 will provide participants with the opportunity to extend treatment 
with gantenerumab beyond 2 years, thereby providing more information on the 
long-term safety, tolerability, and efficacy of gantenerumab in AD.  Furthermore, the 
study will increase the overall number of participants exposed to gantenerumab and 
the patient-years of exposure and increase the understanding of the safety:efficacy 
profile.  Analyzing the long-term safety, tolerability, and efficacy of gantenerumab is 
of critical importance to help clinicians make informed therapeutic decisions for 
participants. 
 
The design of Study WN42171 will allow participants with moderate asymptomatic 
ARIA-E and with any number of ARIA-H microhemorrhages to continue 
gantenerumab treatment.  This is in line with the evolving understanding of the 
clinical significance of ARIA by the clinical trial Sponsors and medical community 
(see Section 3.3.4). 
 
An iDMC will evaluate safety data on a regular basis, including the incidence and 
nature of adverse events, serious adverse events, adverse events of special 
interest, ARIA-E, ARIA-H, and ISRs and will make appropriate recommendations 
(see Section 3.1.3).  In the event the iDMC which reviews safety in both the parent 
studies (WN29922 and WN39658) and Study WN42171 is no longer required (for 
instance after the unblinding of the parent studies), evaluation of participant safety 


 
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may be taken over by the Sponsor's IMC, with details documented in an IMC 
charter. 
 
The benefitrisk ratio of conducting Study WN42171 during the Coronavirus 
Disease 2019 (COVID-19) pandemic remains unchanged.  This is supported by the 
nonclinical and clinical data collected through the development program of 
gantenerumab where there has been no indication that gantenerumab 
administration compromised the immune system or made individuals more 
susceptible to infections.  Thus, there are no data or biological rationale suggesting 
that gantenerumab administration could increase the risk of infection by severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or more severe 
COVID19 outcomes. 
 
Participating in study visits at the investigational sites may however increase the risk 
of exposure to SARS-COV-2, therefore, whenever appropriate, the Sponsor allows 
the possibility to perform home visits by adequately trained health care 
professionals.  All necessary precautions will be taken to protect the health of the 
study participants and minimize the risk of exposure.  As such the 
Principal Investigator, in addition to all appropriate study staff that come into contact 
with the study participants, will wear personal protective equipment during the visit 
as per local requirements. 
 
Based on the available information, no interactions between gantenerumab or PET 
tracers and the COVID-19 vaccines are expected to occur, and no other safety 
concerns have been identified that would prohibit the vaccination of participants 
enrolled in the studies where gantenerumab is being investigated for the treatment 
of AD.  Just as with other vaccinations (e.g., influenza), the administration of 
COVID-19 vaccines will be considered as a concomitant medication in this study. 
 
Overall, the anticipated benefitrisk profile of gantenerumab supports open-label 
gantenerumab treatment in Study WN42171 for participants who completed either the 
double-blind or OLE part of parent Study WN29922 or WN39658. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the safety, tolerability, and efficacy of long-term administration of 
open-label gantenerumab in participants with AD who completed Study WN29922 or 
WN39658.  Specific objectives and corresponding endpoints for the study are outlined 
below. 
2.1 
SAFETY OBJECTIVE 
2.1.1 
Primary Objective:  Safety 
The primary objective for this study is to evaluate the safety and tolerability of long-term 
gantenerumab administered by SC injection on the basis of the following endpoints: 
 
Nature, frequency, severity, timing, and outcomes of adverse events and serious 
adverse events 


 
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 
Physical examinations (including neurologic systems), vital signs, ECG, laboratory 
tests, and Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Nature, frequency, severity, and timing of ARIA-E and ARIA-H 
 
Nature, frequency, severity, timing, and outcomes of ISRs 
 
Incidence of treatment discontinuations for adverse events 
 
Incidence of adverse events of special interest 
 
2.2 
EFFICACY OBJECTIVE 
2.2.1 
Secondary Objective:  Efficacy 
The secondary objective for this study is to evaluate the efficacy of long-term 
gantenerumab administered by SC injection on the basis of the following endpoints: 
 
Change over time in cognition and/or function as measured by the following: 
– 
Clinical Dementia Rating (CDR) 
– 
Mini-Mental State Examination (MMSE) 
– 
Alzheimer Disease Assessment ScaleCognition, Subscale 11 (ADAS-Cog11) 
and Alzheimer Disease Assessment ScaleCognition, Subscale 13 
(ADAS-Cog13) 
– 
Verbal Fluency Task 
– 
Coding 
– 
Functional Activities Questionnaire (FAQ) 
– 
Alzheimer Disease Cooperative Study GroupActivities of Daily Living 
(ADCS-ADL) 
 
2.2.2 
Exploratory Objective:  Efficacy 
The exploratory objective for this study is to evaluate the efficacy of 
long-term gantenerumab administered by SC injection on the basis of the following 
endpoints: 
 
Change over time in: 
– 
Health-related quality of life, as assessed by the Quality of 
LifeAlzheimer's Disease (QoL-AD) scale 
– 
Behavioral and neuropsychiatric symptoms of AD, as measured by the 
Neuropsychiatric Inventory Questionnaire (NPI-Q) 
– 
Caregiver burden, as assessed by the Zarit Caregiver Interview for 
Alzheimer's Disease (ZCI-AD) scale 
– 
Elements of resource utilization, as assessed by the Resource Utilization in 
DementiaLite (RUD-Lite) 


 
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2.3 
PHARMACOKINETIC OBJECTIVE 
The exploratory pharmacokinetic (PK) objective for this study is to characterize the 
PK profile of gantenerumab administered by SC injection on the basis of the following 
endpoint: 
 
Plasma concentration of gantenerumab administered SC at specified timepoints 
 
2.4 
IMMUNOGENICITY OBJECTIVE 
The immunogenicity objective for this study is to evaluate the immune response to 
gantenerumab administered by SC injection on the basis of the following endpoint: 
 
Prevalence of anti-drug antibodies (ADAs) at baseline and incidence of ADAs during 
the study 
 
2.5 
BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to evaluate the long-term effects of 
gantenerumab administered by SC injection based on the following endpoints: 
 
Brain amyloid load over time, as measured by amyloid PET scan in a subset of 
participants 
 
Brain tau load over time, as measured by tau PET scan in a subset of participants 
 
CSF markers of disease over time in a subset of participants, including, but not 
limited to, A1−42, total tau (t-tau), and phosphorylated tau (p-tau) 
 
MRI-derived measurements over time, such as volumetric changes in whole brain, 
ventricles, hippocampus, or other structures; changes in functional brain 
connectivity; or changes in the integrity of white matter in all participants 
 
Blood and plasma markers over time 
 
2.6 
HEALTH STATUS UTILITY OBJECTIVE 
The exploratory health status utility objective for this study is to evaluate the health 
status utility scores of participants treated with gantenerumab on the basis of the 
following endpoint: 
 
Health outcomes in participant and caregiver, as measured by EuroQol 5-Dimension 
Questionnaire (EQ-5D)  
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
Study WN42171 is an open-label, multicenter, rollover study to evaluate the safety, 
tolerability, and efficacy of long-term administration of open-label gantenerumab in 
participants with AD who completed Study WN29922 or WN39658, either the 
doubleblind or OLE part, as applicable (parent study).  The blind to the study treatment 
allocation during the parent study will be maintained to protect study integrity. 


 
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Participants who have completed Study WN29922 or WN39658, either the double-blind 
or OLE part as applicable, will be eligible to participate in this study.  Participants who 
discontinued early from study treatment during Study WN29922 or WN39658, regardless 
of the reason, will not be eligible for this study. 
Informed consent should be obtained from participants while they are in the parent study 
(WN29922 or WN39658) including in the safety follow-up, until a day before the first 
dose in the Study WN42171.  In special situations, informed consent can be obtained at 
a later timepoint upon providing an appropriate rationale to the Sponsor, and it must be 
obtained before any study procedures in this study are performed. 
The first administration of gantenerumab in this study will be as follows: 
 
For participants who completed the double-blind part and did not enter the OLE part 
of Study WN29922 or WN39658:  The first administration of open-label 
gantenerumab should take place approximately 2 weeks after the last efficacy and 
safety visit of the double-blind part of the parent study (WN29922 or WN39658) and 
will be considered the OLE baseline visit (OLE Day 1). 
 
For participants who completed the double-blind part and the OLE part of 
Study WN29922 or WN39658, the first administration of gantenerumab in this study 
should take place approximately 2 weeks after the OLE Week 34 visit or the final 
dose visit in the Study WN29922 or WN39658 OLE.  Participants who have a gap in 
their transition between the OLE part of the parent study (WN29922 or WN39658) 
and this study, for unforeseen reasons, will roll over to this study continuing the 
schedule of activities as per their last visit in the OLE part of the parent study 
(WN29922 or WN39658).  Discussion with the Sponsor is recommended. 
 
Participants with evidence of ARIA-E on the last per-protocol study MRI scan report in 
Study WN29922 or WN39658, either its double-blind or OLE part, as applicable, will be 
retained in the WN29922 or WN39658 study until the ARIA-E finding is resolved.  
They may then enroll in Study WN42171.  For those enrolling from the OLE part, the 
first visit of the participants in Study WN42171 will be adapted according to the schedule 
of the visits of each participant in the parent study. 
The data from the last visit in study WN29922 or WN39658 (e.g., final efficacy and 
safety visit of the double-blind part or last visit in the WN29922 or WN39658 OLE part) 
will be used as the data for the first visit in this study if the two visits take place within 4 
weeks of each other.  All cognitive scales, and the C-SSRS do not need to be repeated if 
they were performed within 6 months in the previous parent study.  The MRI scan does 
not need to be repeated if performed within 6 months in the previous parent 
study (WN29922 or WN39658) and following the final study drug dose in the parent 
study.  Vital signs and urine pregnancy test will have to be performed at the first visit in 
this study before dosing.  MRI and urine pregnancy test results must be available before 
dosing. 


 
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In this study, participants who were in the active double-blind arm in the parent 
study (WN29922 or WN39658) will continue receiving open-label gantenerumab 510 mg 
SC Q2W, and those participants who were in the placebo double-blind arm will go 
through a full uptitration scheme while retaining the blinding to the previous treatment 
allocation.  Details of the dosing scheme are described in Section 4.3.2.  If there is a 
delay in a participant’s transition between the OLE part of the parent Study (WN29922 or 
WN39658) and this study (for instance, due to delays in the approval of this study at a 
site) that goes beyond a reasonable time frame as determined by the Sponsor, the 
participant may be asked to start at the dose they were at previously when they 
completed the parent study and to perform a safety MRI before receiving the target 
dose.  In this case, such decisions will be made after discussion with the Sponsor. 
The dosing schedule and the schedule of activities will be different for participants, 
depending on whether they completed the OLE part of Study WN29922 or WN39658, 
which covers the uptitration phase for the participants in the placebo arm, or if they 
completed only the double-blind part.  Details are described in Appendix 1. 
Following baseline assessments (i.e., OLE Day 1 either in this protocol or in the parent 
protocol), each participant will be treated for 4 years.  The study duration has been 
extended from 2 to 4 years in order to collect more information on the long-term safety 
and tolerability of gantenerumab in AD and its efficacy in the context of long-term 
exposure and to increase the overall number of participant-years of exposure, thus 
increasing understanding of gantenerumab’s long-term safety and efficacy profiles.  
Unless participants are eligible and choose to enroll in an alternative gantenerumab 
OLE study that becomes available, the final dose of study drug will be administered at 
OLE Week 206.  At the end of the treatment period, all participants will undergo an OLE 
Week 208 visit.  Participants will be asked to come back for a follow-up visit at OLE 
Week 220 unless they are transitioning to an alternative gantenerumab OLE study that 
becomes available. 
Participants who discontinue study drug at any time during this study will be asked to 
complete an early termination visit 2 weeks after their final dose and also return for 
collection of safety data (except safety MRI) and limited efficacy data (i.e., secondary 
endpoints) (see Section 4.6.1). 
Participants who do not meet the criteria for participation in this study (screening failure) 
may be re-screened.  The investigator will record reasons for screening failure in the 
screening log (Section 4.5.1). 
3.1.2 
Substudies 
The substudies associated with Study WN42171 will be described in separate protocols, 
and participants consenting to enroll in these substudies will be asked to sign the 
associated Informed Consent Forms.  To date, two optional substudies are associated 


 
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with Study WN42171:  a longitudinal amyloid PET substudy and a longitudinal tau 
PET substudy. 
The amyloid and tau PET assessments will enable a longitudinal evaluation of the effect 
of gantenerumab on brain amyloid deposition as measured by florbetaben or 
flutemetamol PET radioligands and tau burden as measured by [18F]GTP1 (Genentech 
Tau Probe 1; an investigational radioligand for in vivo imaging of tau protein aggregates) 
in participants with AD. 
The collected PET data are expected to help in understanding the effects of 
gantenerumab on amyloid and tau pathology over time as well as the relationship 
between changes in florbetaben/flutemetamol/[18F]GTP1-PET and changes in other 
endpoints in Study WN42171. 
Two optional substudies associated with this protocol may be introduced. 
In one of them, post-mortem brain tissue may be obtained from participants for 
evaluation of the effect of long-term gantenerumab therapy on the brain.  
The opportunity to donate post-mortem brain tissue may be discussed with participants. 
In the other one, digital tools that assess the disease progression of the participants may 
be tested for validation and for other exploratory purposes. 
Interested participants would be provided with additional details.  Any further 
procedures, with respect to the optional substudies, will be governed by a separate 
consent form and separate substudy protocol document. 
3.1.3 
Independent Data Monitoring Committee 
The iDMC will evaluate participant safety on a regular basis.  In addition to the data 
defined in the iDMC Charter (e.g., the incidence and nature of adverse events, serious 
adverse events, adverse events of special interest, ARIA-E, ARIA-H, and ISRs), the 
iDMC will review all necessary cumulative data, including efficacy data if necessary, at 
regular intervals during the study.  It is anticipated that these assessments will occur 
approximately every 3 months or as detailed in the iDMC charter.  At the time of each 
review, the iDMC will make appropriate recommendations (e.g., the study should 
continue as planned, the safety risk management should be modified, the protocol 
should otherwise be amended, and enrollment should be held pending further safety 
evaluations). 
Decisions will be made after considering the totality of the available data.  
Ad-hoc meetings may be called in addition to scheduled meetings, as necessary, to 
provide recommendations on management of any new safety issues.  Specific 
operational details, such as the committee's composition, frequency and timing of 
meetings, and members' roles and responsibilities are detailed in the iDMC Charter. 


 
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Final decisions will rest with the Sponsor. 
In the event the iDMC which reviews safety in both the parent studies (WN29922 and 
WN39658) and Study WN42171 is no longer required (for instance after the unblinding 
of the parent studies) evaluation of participant safety may be taken over by the 
Sponsor's IMC, with details documented in an IMC charter. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last participant, last visit, occurs or 
the date at which the last data point required for statistical analysis or safety follow-up is 
received from the last participant, whichever occurs later.  The end of the study is 
expected to occur by the end of 2026. 
In addition, the Sponsor may decide to terminate the study at any time. 
The total length of this study from baseline visit (OLE Day 1 in either the 
Study WN42171 protocol or in the parent protocol) to the end of the study (including the 
follow-up visit) is expected to be approximately 4 years and 3 months.  Following 
uptitration, participants will receive up to 86 doses of gantenerumab 510 mg Q2W.  
Participants who did not participate in the OLE part of the parent study (WN29922 or 
WN39658) will also go through an uptitration scheme in the WN42171 study with a 
duration of at least 34 weeks. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Gantenerumab Dose and Titration Schedule 
All participants will receive a target dose of 510 mg gantenerumab SC Q2W, which is the 
same as the target dose received in the parent Study (WN29922 or WN39658).  
Participants who will be receiving gantenerumab for the first time in the WN42171 study 
will follow a titration schedule with a low starting dose and gradual increase in dosing 
that is expected to reduce the risk of ARIA-E for both apolipoprotein E (APOE) carriers 
and non-carriers, which was also followed in the WN29922 and WN39658 studies. 
3.3.2 
Rationale for Participant Population 
Participants with AD who completed Study WN29922 or WN39658, either the 
double-blind or OLE part, as applicable, will be eligible to participate in this study in 
order to evaluate the safety, tolerability, and efficacy of long-term gantenerumab 
administration.  Additionally, participants in the placebo double-blind arm in the parent 
studies will get exposure to potentially active treatment. 
3.3.3 
Rationale for Study Treatment Duration 
3.3.3.1 
Rationale for the First 2-Year Duration 
In order to collect safety, tolerability, and efficacy data for long-term gantenerumab 
administration, this study will provide open-label gantenerumab to participants who 


 
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completed study WN29922 or WN39658, either its double-blind or OLE part, as 
applicable, for 2 years starting from baseline (OLE Day 1 in either this protocol or the 
parent protocol).  With the 2-year duration, participants in the placebo double-blind arm 
in the parent studies (WN29922 or WN39658) will receive the full 2 years of therapy, like 
their co-participants who were in the active double-blind arm. 
3.3.3.2 
Rationale for the Subsequent 2-Year Duration 
The extension of the study treatment duration from 2 to 4 years will allow the 
collection of more information on the long-term safety and tolerability of gantenerumab 
in AD and its efficacy in the context of long-term exposure.  In addition, this will 
increase the overall number of participants exposed to gantenerumab and participant-
years of exposure, thus increasing understanding of gantenerumab’s long term safety 
and efficacy profiles. 
3.3.4 
Rationale for ARIA Management Rules 
In previous studies with gantenerumab, the Sponsor used the Barkhof scale 
(Barkhof et al. 2013) to assess the radiological severity of ARIA-E.  In this study, the 
Sponsor plans to use the Bioclinica 5-point scale (Bracoud et al. 2017), which is a 
simpler scale for assessing ARIA-E severity that is based on a single overall assessment 
of ARIA-E extent.  The Bioclinica 5-point scale is easier for clinicians to use than the 
Barkhof scale.  The Bioclinica scale is commonly used in other clinical trials that are 
testing anti-amyloid antibodies (Ferrero et al. 2016). 
Most cases of ARIA-E occur as an imaging finding alone, without any detectable 
clinical symptoms (see Gantenerumab Investigator’s Brochure safety summary section).  
As detailed in Appendix 2, ongoing dosing of gantenerumab will occur in cases where 
ARIA-E is asymptomatic with a low or moderate imaging severity; in such cases, more 
frequent MRI surveillance (Q4W) will be mandatory.  Any ARIA-E associated with 
symptoms (see definition of symptomatic ARIA-E in Section 5.3.5.2 and Appendix 2), 
regardless of radiographic severity, will require temporary withholding of study drug 
administration, until symptoms and ARIA-E findings resolve.  The goal, in the context of 
this carefully controlled study with strict safety monitoring, is to minimize unnecessary 
study drug interruption, which could itself have a negative impact upon participants.  
Because of the safety monitoring and the regular review of safety data by the iDMC or 
IMC (in the event that the iDMC is no longer required), this ARIA management 
strategy has a neutral impact upon participant risk. 
3.3.5 
Rationale for Biomarker Assessments 
The following biomarker assessments will be used to investigate the effects of 
gantenerumab on the underlying pathology of AD in the participant population:  CSF, 
plasma, and RNA (Section 4.5.7.3); PET imaging (Section 4.5.11); and brain volumetry, 
connectivity, and fiber tract integrity (Section 4.5.10). 


 
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Exploratory research on potential safety biomarkers may be conducted to support future 
drug development, including guidance for safety risk management. 
3.3.5.1 
Cerebral Spinal Fluid Biomarkers 
Amyloid plaque deposition, neurofibrillary tangle formation, and neuronal degeneration 
are known pathologic features of AD.  Decreased CSF A1−42 and elevated CSF t-tau 
and p-tau are considered a biochemical signature of AD.  Accumulating evidence 
suggests that low CSF A1−42 reflects underlying amyloid plaque pathology, whereas 
increased t-tau and p-tau levels may be reflective of neurodegeneration and/or tau 
pathology.  Amyloid deposition may be the initiating event in the cascade of pathologic 
processes underlying AD, whereas tau pathology appears to be a subsequent event and 
more associated with neurodegeneration.  Therefore, t-tau and p-tau may be studied as 
downstream biomarkers of the primary target of anti-amyloid therapies such as 
gantenerumab. 
Although biomarkers indicative of certain neuropathologies have not yet been validated 
as surrogate markers for clinical efficacy, there is some evidence that anti-A treatments 
may cause changes in these biomarkers.  A neuropathologic study of patients with AD 
(Study AN1792) suggests that active amyloid immunotherapy ameliorates neurite 
abnormalities and tau pathology through decreased tau phosphorylation 
(Serrano-Pozo et al. 2010).  In a pooled analysis of CSF data from two Phase II trials 
with bapineuzumab in patients with mild to moderate AD, a decrease in both p-tau and 
t-tau levels relative to baseline was observed in the bapineuzumab group after 
12 months of therapy (Blennow et al. 2010).  These findings were confirmed in 
two Phase III studies with bapineuzumab (Sperling et al. 2012) as well as in 
Study WN25203 with gantenerumab.  In Study WN25203, CSF biomarkers were 
analyzed over the 2-year period for changes in multiple proteins, including A1-42, t-tau, 
p-tau, and neurogranin.  Markers of neurodegeneration were significantly reduced in the 
225-mg gantenerumab group compared with placebo over 2 years, with greater relative 
reduction in p-tau relative to t-tau.  The greatest effect was reduction in p-tau in the 
225-mg gantenerumab arm at 2 years relative to the change in the placebo arm.  There 
was no treatment effect on CSF A1−42 (Nikolcheva et al. 2015).  Because no evidence of 
efficacy has been demonstrated with these therapies in clinical trials yet, changes in 
these biomarkers provide meaningful information about the PD effects of gantenerumab 
and the effect on pathologic processes underlying AD. 
Based on these data and on the proposed mechanism of action of gantenerumab, levels 
of CSF t-tau and p-tau and additional exploratory biomarkers reflecting 
neurodegeneration will be assessed in this study.  Because gantenerumab is expected 
to clear amyloid from the brain, levels of CSF A1−42 will also be measured. 
3.3.5.2 
Brain Volumetry, Connectivity, and Fiber Tract Integrity 
A characteristic feature of AD is neuronal destruction.  Such neuronal loss is 
demonstrated at a macroscopic level by progressive cerebral atrophy, which can be 


 
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tracked on MRI (Fox and Kennedy 2009).  Multiple changes in brain anatomy beyond 
those associated with normal aging have been reported in patients with AD 
(e.g., enlarged ventricles, decreased cortical thickness, decreased total brain volume, 
and hippocampal atrophy), and there is evidence for strong correlations between these 
imaging biomarkers and functional cognitive measures (Li and Wahlund 2011).  Based 
on volumetric MRI measurements, the two most established markers of disease 
progression in longitudinal observational studies are hippocampal and whole brain 
atrophy (Fox et al. 2000, 2005; Jack et al. 2010), with ventricular expansion a related 
quantitative marker. 
Therefore, to quantify the effects of gantenerumab on neurodegeneration, whole brain 
volume, ventricular enlargement, and regional brain volume changes will be assessed in 
this study.  All MRI reads and volume measures will be conducted by the central reader. 
In addition to the structural brain volume changes, changes in brain functioning of 
participants will be assessed using a blood oxygenation level-dependent (BOLD) 
resting-state functional MRI (rs-fMRI) procedure (at sites where this procedure is 
available) with a paradigm-free procedure (Grecius et al. 2004; Filippi and Agosta 2011).  
Increased concentrations of A in the brains of patients with AD contribute to neuronal 
degeneration in the brain over time and have been associated with reduced functional 
connectivity of various brain networks using rs-fMRI (Sheline et al. 2010; 
Binnewijzend et al. 2012; Brier et al. 2012; Sheline and Raichle 2013).  Resting-state 
functional connectivity has been found to be decreased in brain regions such as the 
hippocampus, the default mode network (regions such as precuneus, anterior cingulate, 
and parietal and temporal cortices), and cortical regions in which the functional 
connectivity is continuously decreased as disease progresses.  It has also been found to 
be decreased in cognitively normal elderly patients with brain amyloid deposition 
(Pittsburgh Compound-B  PET scans).  Alteration of the decreased brain functional 
connectivity has been shown using therapeutic interventions such as memantine 
(Lorenzi et al. 2011) or donepezil in patients with AD (Goveas et al. 2011; 
Solé-Padullés et al. 2013).  Increased brain functional connectivity was found after just 
3 months of treatment with donepezil, which correlated with changes in cognitive 
measures such as the ADAS-Cog (Goveas et al. 2011; Solé-Padullés et al. 2013).  
Therefore, therapeutic interventions, which act to remove A from the brains of patients 
with AD, may help to reverse the altered functional connectivity presumably caused by 
the accumulation of A in the brain. 
The integrity of white matter tracts will be assessed prior to and after treatment with 
gantenerumab using diffuse tensor imaging (DTI)-MRI techniques.   DTI-MRI is based 
on the measurement of diffusion properties of water molecules in the axonal fiber tracts 
in white matter.  Whereas water molecules can diffuse isotropically in CSF, they are 
restricted axially in white matter bundles.  Widespread group differences in the degree of 
anisotropic diffusion, or fractional anisotropy (FA), has been seen between patients with 
AD and healthy subjects (Jack et al. 2015).  Greater FA values are thought to indicate 


 
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greater white matter integrity.  Likewise, mean diffusivity, which measures the average 
rate of diffusion in all directions, has been shown to be higher in groups with AD 
compared with healthy controls, presumably owing to increased white matter injury in 
patients with AD (Nir et al. 2013). 
At sites having the required software and hardware, rs-fMRI (BOLD rs-fMRI) and 
DTI-MRI will be performed when feasible during the same scanning session as the 
structural MRI to assess functional brain connectivity and fiber tract integrity. 
3.3.6 
Rationale for Pharmacokinetic Sampling 
A sparse sampling schedule is being utilized to minimize participant burden while 
providing an adequate characterization of the population PK profile of gantenerumab.  
The PK data may be combined with available data from other gantenerumab studies and 
may be used to assess exposureresponse relationships for relevant imaging, CSF, 
plasma PD biomarkers, ECGs, and efficacy and safety outcomes in participants with AD, 
as appropriate. 
4. 
MATERIALS AND METHODS 
4.1 
PARTICIPANTS 
Any participant who has completed Study WN29922 or WN39658, either the 
double-blind or OLE part, as applicable, can be enrolled in this study if they meet the 
inclusion/exclusion criteria set out below.  This should lead to no more than 
2032 participants with AD enrolled in Study WN42171, dependent on the number of 
eligible participants completing the parent Studies (WN29922 and WN39658) and who 
consent to Study WN42171. 
4.1.1 
Inclusion Criteria 
Participants must meet the following criteria for study entry: 
 
Signed Informed Consent Form by the participant with AD and/or the legal 
authorized representative as per local requirements 
 
Completed Study WN29922 or WN39658, either its double-blind part (participants 
have reached the 510 mg Q2W dose schedule by the time of completion) or 
OLE part (participants have received at least 3 doses of 510 mg Q4W), and did not 
discontinue study drug early 
 
Ability to comply with the study protocol 
 
Willingness and ability to complete all aspects of the study (including MRI). 
 
The participant should be capable of completing assessments either alone or with 
the help of the caregiver. 
 
Availability of a person (referred to as the “caregiver” throughout this protocol) who: 
– 
In the investigator’s judgment, has frequent and sufficient contact (e.g., 5 times 
per week or approximately 10 hours per week) with the participant 


 
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– 
In the investigator’s judgment, is able to provide accurate information regarding 
the participant’s cognitive and functional abilities, including knowledge about 
domestic activities, hobbies, routines, social skills, and basic activities of daily 
life; work and educational history; cognitive performance including memory 
abilities, language abilities, temporal and spatial orientation, judgment and 
problem solving; emotional and psychological state; and can report any 
changes in the general health status 
– 
Agrees to provide information and to complete all aspects of the study at clinic 
visits (which require partner input for scale completion) 
– 
Signs the necessary Informed Consent Form(s), and has sufficient cognitive 
capacity to accurately report on the participant’s behavior as well as cognitive 
and functional abilities 
– 
Is fluent in the language used at the site and has sufficiently good general 
health to have a high likelihood of maintaining the same level of interaction with 
the participant and participation in study procedures throughout the duration of 
the study 
Every effort should be made to have same caregiver participate throughout 
the duration of the study. 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception as defined below: 
– 
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period and for at least 16 weeks after the 
final dose of gantenerumab. 
– 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
– 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
– 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
participant.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not adequate methods of 
contraception.  If required per local guidelines or regulations, locally recognized 
adequate methods of contraception and information about the reliability of 
abstinence will be described in the local Informed Consent Form. 
 
Agreement not to donate blood or blood products for transfusion for the duration of 
the study and for 1 year after final dose of study drug. 
 


 
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4.1.2 
Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from study entry: 
 
Pregnant or breastfeeding, or intending to become pregnant during the study or 
within at least 16 weeks after the final dose of study drug 
Women of childbearing potential must have a negative urine pregnancy test at 
the final visit of the parent study. 
 
Prematurely discontinued from Study WN29922 or WN39658, either its double-blind 
or OLE part, as applicable, or from study drug, for any reason 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the participant’s safety if he or she continues to receive study treatment 
 
Received any investigational treatment other than gantenerumab during or since 
completion of Study WN29922 or WN39658, either its double-blind or OLE part, as 
applicable 
 
Evidence of disseminated leptomeningeal hemosiderosis (i.e., more than three focal 
leptomeningeal hemosiderosis) 
 
Evidence of intracerebral macrohemorrhage 
 
Use of prohibited medication (see Section 4.4.2) 
 
Evidence of ARIA-E on the last MRI scan report in Study WN29922 or WN39658, 
either its double-blind or OLE part, as applicable 
Participants should remain in the parent study, as governed by that protocol, and 
may enroll in this study once the ARIA-E is resolved. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
4.2.1 
Treatment Assignment 
This is a non-randomized, open-label study.  An interactive voice or web-based 
response system (IxRS) will be used to manage participant enrollment and drug supply.  
After initial written informed consent has been obtained the study site may obtain the 
participant’s identification number.  After all screening procedures and assessments 
have been completed, and eligibility has been established for a participant, the study site 
will obtain the participant's treatment assignment from the IxRS. 
Participants randomized to the active treatment arm in the parent study (WN29922 or 
WN39658) will continue to be administered the study drug every 2 weeks (Q2W 
administration of 510 mg SC gantenerumab).  Participants randomized to the placebo 
arm in the parent study (WN29922 or WN39658) will have to go through at least 
34 weeks of uptitration.  Participants, sites, and Sponsor will remain blinded to previous 
treatment allocation in the parent study (WN29922 or WN39658) to protect study 
integrity. 


 
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4.2.2 
Blinding 
To protect study data integrity and to aid the assessment of the long-term effects of 
gantenerumab, study site personnel and participants will be blinded to previous 
treatment assignment in the parent studies (WN29922 or WN39658).  The Sponsor and 
its agents will also be blinded to previous treatment assignment, at least until unblinding 
of the parent studies (WN29922 and WN39658), which will happen while this study is 
ongoing, with the exception of individuals who require access to participant’s treatment 
assignments to fulfill their job roles during a clinical trial.  These roles include the 
unblinding group responsible, clinical supply chain managers, operational assay group 
personnel, IxRS service provider, and iDMC members. 
Pharmacokinetics and immunogenicity samples will be collected from all participants, 
regardless of the treatment assignment.  Laboratories responsible for performing study 
drug PK and ADA assays will be unblinded to participants’ treatment assignments.  
Baseline immunogenicity samples will be analyzed for all participants. 
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which participant management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations. 
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  
The investigator should document and provide an explanation for any non-emergency 
unblinding.  If the Medical Monitor agrees to participant unblinding, the investigator will 
be able to break the treatment codes by contacting the IxRS. 
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment assignment code for all serious, unexpected suspected adverse 
reactions (see Section 5.7) that are considered by the investigator or Sponsor to be 
related to study drug.  The participant may continue to receive treatment, and the 
investigator, participant, and Sponsor personnel, with the exception of the Drug Safety 
representative and personnel who must have access to participant treatment 
assignments to fulfill their roles (as defined above), will remain blinded to treatment 
assignment. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal product (IMP) for this study is gantenerumab. 


4.3.1 
Gantenerumab and Placebo 
The Sponsor will supply gantenerumab and placebo, as required for the uptitration 
period, as liquid formulation ready for SC administration.  Packaging of the study drug 
will be overseen by the Roche Clinical Trial Supplies Department and will bear a label 
with the identification required by local law, the protocol number, study drug 
identification, and dose.  The packaging and labeling will be in accordance with Roche 
standard and local regulations.  Upon receipt of the investigational products at the site, 
site personnel should check the product for damage and verify the proper identity, 
quantity, and integrity of the study drug.  Site personnel should report any deviations or 
product complaints to the monitor upon discovery.  For further details, please refer to the 
Gantenerumab Investigator’s Brochure. 
For information on the formulation and handling of gantenerumab, see the pharmacy 
manual and the Gantenerumab Investigator’s Brochure. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
During the WN42171 study, participants previously randomized to the active treatment 
arm and those who were previously randomized to placebo and have completed 
OLE uptitration in the parent study (WN29922 or WN39658) will continue to be 
administered the study drug every 2 weeks (Q2W administration of 510 mg SC 
gantenerumab).  Participants previously randomized to the placebo arm who did not 
participate in the OLE part of the parent study (WN29922 or WN39658) will be required 
to undergo the uptitration scheme of 34 weeks.  Participants who completed the OLE 
part of the parent study (WN29922 or WN39658), will continue the schedule of activities 
as per their OLE Day 1 visit in the parent study (WN29922 or WN39658). 
In order to maintain the previous study treatment blinding (the Sponsor, investigator, and 
participant), all participants will be dosed every 2 weeks as illustrated in Table1 .  A 
safety MRI should be performed before each uptitration to ensure the participant can be 
safely uptitrated to the next dose. 
To ensure blinding to previous treatment, IMP will be administered as one 0.8-mL and 
two 1.7-mL injections for the 120-mg dose or as two 1.7-mL injections for the 
255-mg dose and 510-mg dose, respectively, SC to the abdomen.  Injections may
contain active gantenerumab or placebo to ensure the correct total dose of active
gantenerumab at each visit (see Table 1).  Refer to the pharmacy manual for detailed
instructions on drug preparation, storage, and administration.
Note:  A minimum of 3 doses during each dosing step must be administered before the 
participant is eligible for uptitration, subject to the results of a pre-uptitration safety MRI.  
A dose is defined as two consecutive dosing visits (one with an odd dose number 
and one with an even dose number, see Table 1).  A participant may still be eligible 
for uptitration even if these requirements are not met, provided that they have been 
administered IMP at 3 odd dosing visits at a given dose level (see Table 1). 
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After OLE Week 34 (i.e., beyond the time frame considered in Table 1), all participants 
who have completed the uptitration will receive two 1.7-mL injections of active 
gantenerumab for the 510-mg dose at each subsequent 2-week visit. 
At applicable sites, study treatment may be administered by a trained nursing 
professional at the participant's home or another suitable location, if the participant has 
given written informed consent to participate in home nursing visits. 
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of accidental 
overdose or medication error along with any associated adverse events should be 
reported as described in Section 5.3.5.13. 
Guidelines for treatment interruption or discontinuation for participants who experience 
selected adverse events are provided in Section 5. 
 


 
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Table 1 
Gantenerumab Dosing Design for Participants Who Did Not Participate in the OLE Part of the 
Parent Study (WN29922 or WN39658) 
Visit 
OLE 
Day 1 
OLE 
Wk 
2 
OLE 
Wk 
4 
OLE 
Wk 
6 
OLE 
Wk 
8 
OLE 
Wk 
10 
OLE 
Wk 
12 
OLE 
Wk 
14 
OLE 
Wk 
16 
OLE 
Wk 
18 
OLE 
Wk 
20 
OLE 
Wk 
22 
OLE 
Wk 
24 
OLE 
Wk 
26 
OLE 
Wk 
28 
OLE 
Wk 
30 
OLE 
Wk 
32 
OLE 
Wk 
34 
Dose Number Within 
Study WN42171 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Participants 
previously on 
placebo 
Dose 
120 mg Q4W 
255 mg Q4W 
510 mg Q4W 
Injections 
(mL) 
1   
0.8A 
   
2   
1.7P 
1   
0.8P 
   
2   
1.7P 
1   
0.8A
   
2   
1.7P 
1   
0.8P
   
2  
1.7P 
1   
0.8A
   
2   
1.7P 
1   
0.8P
   
2   
1.7P 
1   
1.7A
   
1   
1.7P 
2   
1.7P 
1   
1.7A
   
1   
1.7P 
2   
1.7P 
1   
1.7A
   
1   
1.7P 
2   
1.7P 
2   
1.7A 
2   
1.7P 
2   
1.7A 
2   
1.7P 
2   
1.7A 
2   
1.7P 
Participants 
previously on 
active 
Dose 
510 mg Q2W 
Injections 
(mL) 
2   
1.7A 
   
1   
0.8P 
2   
1.7A 
   
1   
0.8P 
2   
1.7A
   
1   
0.8P 
2   
1.7A
   
1   
0.8P 
2   
1.7A
   
1   
0.8P 
2   
1.7A 
   
1   
0.8P 
2   
1.7A 
2   
1.7A 
2   
1.7A 
2   
1.7A 
2   
1.7A 
2   
1.7A 
2   
1.7A 
2   
1.7A 
2   
1.7A 
2   
1.7A 
2   
1.7A 
2   
1.7A 
A  active treatment; OLE  open-label extension; P  placebo; Q2W  every 2 weeks; Q4W  every 4 weeks; Wk  week. 


 
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4.3.3 
PET Tracers 
All participants who are enrolled in the PET substudies will be assessed by PET imaging 
using the same PET ligand as per the parent study (florbetaben or flutemetamol for the 
amyloid PET and [18F]GTP1 for the tau PET substudy).  According to European Union 
(E.U.) guidance, the PET tracers, as used in the context of this study, are designated as 
non-IMP.  In some regions, according to local regulations, these PET tracers may be 
considered to be IMP. 
In countries where the PET radioligands are approved for marketing, the approved local 
product information will be provided, and in countries where they are not approved for 
marketing, the Investigator’s Brochures will be provided. 
For the safety reporting requirements dealing with the PET tracers used in this study 
please refer to Section 5.7. 
4.3.4 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site will acknowledge receipt of IMPs supplied by the Sponsor, using the IxRS to confirm 
the shipment condition and content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 
4.3.5 
Continued Access to Gantenerumab 
The Sponsor will offer continued access to Roche IMP gantenerumab free of charge to 
eligible participants in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A participant will be eligible to receive Roche IMP gantenerumab after completing the 
study if all of the following conditions are met: 
 
The participant has a life-threatening or severe medical condition and requires 
continued Roche IMP treatment for his or her well-being. 
 
There are no appropriate alternative treatments available to the participant. 
 
The participant and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them. 
 


 
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A participant will not be eligible to receive Roche IMP gantenerumab after completing 
the study if any of the following conditions are met: 
 
The Roche IMP is commercially marketed in the participant's country and is 
reasonably accessible to the participant (e.g., is covered by the participant's 
insurance or wouldn't otherwise create a financial hardship for the participant). 
 
The Sponsor has discontinued development of the IMP or data suggest that the IMP 
is not effective for AD. 
 
The Sponsor has reasonable safety concerns regarding the IMP as treatment for AD 
 
Provision of the Roche IMP is not permitted under the laws and regulations of the 
participant's country. 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a participant in addition to protocol-mandated treatment from 
3 months prior to first administration of study drug in Study WN42171 to the OLE final 
follow-up visit.  All such medications (including name, dose, administration schedule, 
start and end dates) used by the patient during Study WN42171 should be reported to 
the investigator and recorded on the Concomitant Medications eCRF. 
4.4.1 
Permitted Therapy 
Participants are eligible for study participation whether or not they are receiving 
approved medication for AD (i.e., AChEIs, memantine, and/or medical 
food supplements, where approved) with the exception of GV-971.  Participants who 
have received GV-971, are currently receiving GV-971 or who are planning to receive 
GV-971 during the study are not eligible.  Information about background AD medication 
(e.g., drug name, dose, and start and stop dates, reason for interruption or modification) 
should be captured on the eCRF. 
Adding a new medication or changing the dose of a medication during the study should 
occur only for the treatment of an adverse event or in case of AD progression.  
Whenever possible, a medication listed below should be used if appropriate. 
The following medications are permitted.  Doses are expected to remain stable after 
baseline: 
 
Anticonvulsant medications 
 
Selective serotonin reuptake inhibitors for the treatment of depressive symptoms 


 
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 
Over-the-counter and/or herbal medications, food additives, or any other agent or 
supplement intended to improve cognition or reduce cognitive decline 
 
Medications used to treat a mood or anxiety disorder given as 
maintenance treatment (with the exception of benzodiazepine) 
 
Use of short-acting (non-extended release) opioid medications for pain  
 
Use of benzodiazepines, including alprazolam, lorazepam, oxazepam, triazolam, or 
temazepam, or short-acting hypnotic medication (e.g., zolpidem)  
 
A dose of benzodiazepine for pre-surgical and pre-imaging sedation at appropriate 
visits if allowed by the Ethics Committee (EC) or Institutional Review Board (IRB) 
 
Use of centrally acting antihistamine medications  
 
Under certain circumstances, initiation of anti-hemostasis medications during the 
study conduct 
 
Anticoagulation therapy lasting no longer than 3 weeks (e.g., temporary usage during 
surgery) is permitted.  However, for any such use it is recommended to prospectively 
seek advice from the Medical Monitor, and study drug should be temporarily interrupted 
whilst anticoagulation therapy is ongoing. 
Participants who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
The administration of COVID-19 vaccines, just as with other vaccinations 
(e.g., influenza) will be considered as a concomitant medication.  Based on the available 
information, no interactions between gantenerumab or PET tracers and the COVID-19 
vaccines are expected to occur, and no other safety concerns have been identified that 
would prohibit the vaccination of participants enrolled in the studies where 
gantenerumab is being investigated for the treatment of AD.  However, the published 
safety data for COVID-19 vaccines show that overlapping adverse events between 
medicines such as gantenerumab and the vaccine can occur:  the timing and the nature 
of local injection reactions (occurring within 24 hours) as well as of systemic injection 
reactions may be similar for both products.  To facilitate the correct clinical assessment 
of any adverse events and to continue correct attribution of adverse events related to 
study drugs (gantenerumab and PET tracers) or to the vaccination, namely of local and 
systemic reactions following the injections, the Sponsor recommends to vaccinate study 
participants at least 2448 hours after an injection of study drug.  Similarly, 
vaccination in the 48 hours preceding a study drug administration should also 
preferably be avoided.  However, the timing of the study visits and study drug 
administration should not be unduly postponed because of a vaccination. 


 
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4.4.2 
Prohibited Therapy 
The following medications are prohibited at study start and during the entire period of 
study participation.  Participants who start these medications during the study may be 
withdrawn from study treatment: 
 
Any active immunotherapy (vaccine) that is being evaluated to prevent or postpone 
cognitive decline 
 
Any passive immunotherapy (immunoglobulin) or other long-acting biologic agent 
that is under evaluation or approved to prevent or postpone cognitive decline within 
1 year of screening, except for gantenerumab 
 
Any other investigational treatment or any other treatment with an investigational 
monoclonal antibody within 5 half-lives or 4 months prior to screening, whichever is 
longer 
 
Any previous administration of GV-971 
 
Anti-coagulation medications 
– 
Anti-platelet treatments (e.g., aspirin, clopidogrel, and dipyridamol) are 
permitted. 
– 
Short-term, perioperative use of anticoagulant medications will not result in 
permanent discontinuation from the study; however, for any such use, it is 
recommended to prospectively seek advice from the Medical Monitor and study 
drug should be temporarily interrupted whilst anticoagulation therapy is 
ongoing. 
 
The following medications should preferably be avoided in this study although they are 
not strictly prohibited: 
 
Stimulant medications (amphetamine, methylphenidate preparations, or modafinil) 
throughout the study 
 
Typical antipsychotic or neuroleptic medication 
 
Atypical antipsychotic medications 
 
Chronic use of opiates or opioids (including long-acting opioid medication) 
 
Chronic use of benzodiazepines, barbiturates, or hypnotics 
 
If possible, use should be limited to intermittent short-term use.  Consideration should 
be made as to whether clinically appropriate to interrupt the medication 2 days or at 
least 5 half-lives (whichever is longer) prior to any neurocognitive assessment due to 
their psychoactive effects. 
4.5 
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each participant. 


 
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At applicable sites, certain study assessments may be performed by a mobile nursing 
(MN) professional at the participant's home or another suitable location, such as a 
nursing center, to improve access and convenience for participants participating in the 
study.  The Sponsor will select a healthcare company that will be responsible for 
providing MN services for participating sites (the MN vendor).  The MN vendor is 
responsible for ensuring that all MN professionals are licensed, qualified, and in good 
standing, as per applicable regulations, and that appropriate background checks have 
been performed.  If the investigator at a participating site determines that MN services 
are appropriate for a participant and the participant gives written informed consent to 
participate in MN visits, the MN network will communicate with the participant and the 
participant's site.  MN visits will be scheduled on specified visit days, to allow for relevant 
assessments to be performed by the MN professional.  The schedule of activities 
(see Appendix 1) specifies the assessments that may be performed by an 
MN professional. 
4.5.1 
Informed Consent Forms and Screening Log 
Informed consent should be obtained from participants while they are in the parent study 
(WN29922 or WN39658) including in the safety follow up, until a day before the first 
dose in the study WN42171.  In special situations, informed consent can be obtained at 
a later timepoint upon providing an appropriate rationale to the Sponsor.  Written 
informed consent for participation in the study must be obtained before performing 
any study-related procedures.  Informed Consent Forms for enrolled participants and for 
participants who are not subsequently enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that participants 
meet all eligibility criteria before enrollment.  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. 
4.5.2 
Baseline Definition and Assessments 
For participants who completed the double-blind part and did not enter the OLE part of 
study WN29922 or WN39658:  The first dosing visit in this study will be considered as 
baseline (OLE Day 1), and the final efficacy and safety visit assessment of the parent 
Study (WN29922 or WN39658) will be considered as baseline assessment if occurring 
within a specific timeframe. 
For participants who completed the double-blind part and the OLE part of 
study WN29922 or WN39658:  the baseline visit will be the OLE Day 1 visit of the parent 
study (WN29922 or WN39658).  This group of participants will roll over to 
study WN42171 upon the completion of their uptitration.  The first visit in this study 
should take place approximately 2 weeks after the OLE Week 34 visit or the last dose 
visit in the parent study (WN29922 or WN39658) OLE. 


 
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On the day of the first dose of gantenerumab in study WN42171, if results of 
standard-of-care tests or examinations (coagulation, ECG, serum chemistry, and 
hematology; complete physical examination) performed within 4 weeks are available, 
they do not have to be repeated.  For C-SSRS, and cognitive scale results, the time 
interval is 6 months.  MRI scan does not need to be repeated if performed within 
6 months in the parent study and following the final study drug dose in the parent study.  
Vital signs, urine pregnancy test for women of childbearing potential, collection of 
adverse events, and review of concomitant medications have to take place before each 
dose administration.  The MRI can only be used if it was the last prescribed per-protocol 
MRI in the parent study, including those required for ARIA-E follow up. 
4.5.3 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
 
Medical history and demographic data as collected in the parent Study WN29922 or 
WN39658 will be used in this study and should include clinically significant diseases, 
surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, smoking history, and use of alcohol and drugs of abuse.  Medical history and 
demographic data will be automatically transferred into the study WN42171 eCRF.  
In addition, ongoing concomitant medications will automatically be transferred from the 
parent study (WN29922 or WN39658) to study WN42171.  All changes to medications 
during the study (e.g., prescription drugs, over the counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) should be recorded in the eCRF.  
Changes in medical history will be collected once after completion of the double-blind 
part in the parent study (WN29922 or WN39658) and before OLE Day 1 either in the 
parent study or in study WN42171. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
Because this study is being conducted in multiple geographic regions, it is likely that 
participants of different ethnic origins will be enrolled in the study.  Although there is 
currently no indication that gantenerumab is metabolized or eliminated differently or 
that the treatment effect would be different in participants of different ethnic origins, 
collecting this information is essential to adequately evaluate the results of this study 
(e.g., possible differences in PK exposure [concentration of the drug in the blood] or 
treatment effect). 
4.5.4 
Physical Examinations 
A complete physical examination, performed at specified visits as per the schedule of 
activities (Appendix 1), should include an evaluation of the head, eyes, ears, nose, and 
throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, and neurologic systems; genitourinary examinations may be performed 
if clinically indicated.  Conditions reported as part of the medical history or adverse 
events in the parent study do not need to be re-entered. 


 
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Limited, symptom-directed physical examinations should be performed at specified visits 
and as clinically indicated.  Changes from baseline abnormalities should be recorded in 
participant notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
In addition, weight will be obtained at OLE Day 1, at OLE Week 104, at OLE Week 208, 
or at the OLE early termination visit, at every visit at which creatinine clearance is tested, 
and at any other visit as deemed necessary by the investigator.  Height will be obtained 
at the first dosing visit only. 
The physical examination does not have to be repeated at OLE Day 1 or at the first 
dosing visit in the WN42171 study if the last examination performed in the parent study 
(WN29922 or WN39658) occurred within the previous 4 weeks. 
4.5.5 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure while the participant is in a seated position, and temperature.  
Any abnormalities recorded in the parent studies do not need to be re-entered on the 
Study WN42171 eCRF.  At subsequent visits, record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF. 
Blood pressure and pulse rate should be taken when the participant is at rest and should 
not be measured unless at least 15 minutes have elapsed since the last blood draw.  
The same arm should be used for all blood pressure measurements. 
Pulse rate will be determined and will be recorded as beats per minute.  If obtained 
manually, the pulse rate should be counted for a minimum of 20 seconds at each 
assessment. 
Vital sign measurements may be performed by an MN professional. 
4.5.6 
Cognitive, Functional, and Health Economics Assessments 
The assessments described in this section will be performed as outlined in the schedule 
of activities (see Appendix 1) and in the order specified in Section 4.5.6.14. 
Whenever possible, there should be consistency in the rater and caregiver who 
complete the scales for each participant throughout the duration of this study and also 
between this study and the parent study.  Potential raters will receive training and be 
approved by the rating scale contract research organization prior to being allowed to 
administer any cognitive assessments or rating scales in the study. 
Whenever possible, cognitive and functional assessments should be performed at the 
visit timepoints indicated in the schedule of activities (see Appendix 1).  However, in 
exceptional circumstances, if the caregiver, the primary rater, or even the participant 


 
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cannot perform these assessments as per the schedule of activities, they may be 
performed up to 4 weeks out of window. 
Given that the CDR, a secondary efficacy outcome measure in this trial, involves 
subjective judgment, the adequacy of participant and caregiver interviews and ratings 
will be monitored by an endpoint reliability program administered by the rating scale 
vendor.  This is considered an essential part of good research methodology.  
For CDR as well as for some other scales, audio recordings may be used for quality 
assurance purposes.  Prior studies have clearly demonstrated that the failure to 
adequately monitor such ratings can substantially increase the risks of failed trials 
(Becker and Greig 2008; Kobak 2010). 
During OLE Day 1 or the visit of the first study drug administration in Study WN42171, 
scale assessments do not have to be repeated if the last assessments performed in the 
parent study WN29922 or WN39658 occurred within 6 months. 
4.5.6.1 
Clinical Dementia Rating Scale 
The CDRGlobal Score (CDR-GS) characterizes a participant’s level of impairment 
according to the following categories:  0 (normal), 0.5 (very mild dementia), 
1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia).  The CDRSum of 
Boxes (CDR-SOB) score is a detailed quantitative general index that provides more 
information than the CDR-GS in participants with mild dementia (Berg 1988; 
Morris et al. 2001, O'Bryant et al. 2010) and is scored from 018 with higher scores 
indicating greater impairment.  The CDR characterizes six domains:  memory, 
orientation, judgment and problem solving, community affairs, home and hobbies, and 
personal care.  The necessary information to make each rating is obtained through a 
semi-structured interview with the participant and a reliable informant or collateral source 
(e.g., a caregiver). 
As much as is feasible, the CDR should be administered to an individual participant by 
the same assessor throughout the study, preferably the same assessor as in the parent 
study, and that assessor should not perform the MMSE, ADAS-Cog, Verbal Fluency 
Task, Coding, FAQ, or ADCS-ADL.  However, if in exceptional circumstances only this 
assessor is available to perform these other scales, then the CDR participant interview 
must be completed after the caregiver interview but before ADAS-Cog, MMSE, 
Verbal Fluency Task, Coding, and other scales are completed.  Nevertheless, on 
OLE Day 1, on OLE Week 52, on OLE Week 104, on OLE Week 156, and on OLE 
Week 208, the CDR rater cannot perform other scales than the CDR.  In addition, the 
CDR rater should not be involved in safety assessments and especially should not 
receive information about any ARIA findings. 
4.5.6.2 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 
The ADAS-Cog is the most frequently used scale to assess cognition in clinical trials for 
mild to moderate AD dementia (Rozzini et al. 2007; Connor and Sabbagh 2008; 


 
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Ihl et al. 2012).  More specifically, the ADAS-Cog is a participant-based assessment that 
measures learning and memory, language production, language comprehension, 
constructional praxis, ideational praxis, and orientation.  The modified version will be 
used; it has 13 items and includes the addition of delayed word recall and a number of 
cancellation subtests, as well as use of only one trial for word recognition 
(Mohs et al. 1997).  Equivalent alternate forms of the word recall, word recognition, and 
number cancellation subtests will be used in successive test administrations. 
4.5.6.3 
Mini-Mental State Examination 
The MMSE is a set of standardized questions used to evaluate possible cognitive 
impairment and help stage the severity level of this impairment (Folstein et al. 1975).  
The questions target six areas:  orientation, registration, attention, short-term recall, 
language, and constructional praxis/visuospatial abilities.  The MMSE is a 
participant-based assessment. 
4.5.6.4 
Verbal Fluency Task 
The category verbal fluency (e.g., animals) is a participant-based assessment that 
measures speed and flexibility of verbal thought.  Verbal fluency tests are sensitive tools 
for detecting dementia (Pasquier et al. 1995; Lezak et al. 2004) and for monitoring 
decline over time (Clark et al. 2009). 
4.5.6.5 
Coding 
The Coding, also called Digit Symbol Substitution Test (or DSST), is a subtest from the 
Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV; Wechsler 2008).  
The Coding is a participant-based assessment that measures speed of processing and 
associative memory.  The test is known to be sensitive to disease progression 
(Lezak et al. 2004).  The 120-second version of the test will be used in this study. 
4.5.6.6 
Functional Activities Questionnaire 
The FAQ (Pfeffer et al. 1982) is an informant-based measure of functional abilities.  
Informants provide performance ratings of the target person on ten complex higher-order 
activities. 
4.5.6.7 
Alzheimer’s Disease Cooperative Study-Activities of 
Daily Living Inventory 
The ADCS-ADL (Galasko et al. 1997) is the scale most widely used to assess functional 
outcome in participants with AD (Vellas et al. 2008).  The ADCS-ADL is a 
23-item informant-based questionnaire that covers both basic activities of daily living 
(ADL) (e.g., eating and toileting) and more complex ADL or instrumental ADL (e.g., using 
the telephone, managing finances, preparing a meal).  It has a 4-week recall period.  
Total scores range from 078, with higher scores indicating better functioning. 
4.5.6.8 
Zarit Caregiver Interview for Alzheimer’s Disease 
ZCI-AD is a modified version of the Zarit Burden Interview, which was originally 
designed to reflect the stresses experienced by caregivers for people with dementia 


 
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(Zarit and Zarit 1990).  The modified version includes slight modifications in item and title 
wording (e.g., removal of “your relative” to refer directly to the participant, removal of 
“burden” from title) and the use of 11-point numerical rating scales.  The ZCI-AD scale 
consists of 30 items and is completed by the caregiver without involvement from the site 
staff.  It has a 4-week recall period. 
4.5.6.9 
Quality of Life–Alzheimer’s Disease 
The QoL-AD was developed to assess quality of life (QoL) in participants who have 
dementia (Logsdon et al. 1999, 2002).  The QoL-AD consists of 13 items covering 
aspects of participants’ relationships with friends and family, physical condition, mood, 
concerns about finances, and overall assessment of QoL.  The total score is the sum of 
the 13 items and ranges from 1352, with higher scores indicating better 
health-related QoL.  In this study, the QoL-AD will be administered in a standardized, 
structured interview format to participants by investigative staff in order to gather 
participant responses about QoL.  The caregiver will also complete the caregiver version 
of the questionnaire to enable proxy responses from the caregiver. 
4.5.6.10 
EQ-5D 
The EQ-5D is a standardized measure of health status designed to provide a simple 
generic measure of health for clinical and economic appraisal.  It is broadly applicable 
across a wide range of health conditions and treatment. 
The EQ-5D assesses five domains to provide a health state index.  These are 
anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. 
The following two versions will be used in this study: 
 
EQ-5D-5L Proxy, Version 1:  The caregiver (the proxy) is asked to rate the 
participant’s health-related QoL in his or her (the proxy’s) opinion. 
 
EQ-5D-5L, Self-Complete Version:  The caregiver is asked to rate his or her own 
health-related QoL. 
 
4.5.6.11 
Resource Utilization in Dementia Scale 
The RUD scale (Wimo et al. 2003) aims to document formal and informal resource use 
in a clinical trial setting.  The RUD-Lite captures the most important elements in 
dementia care:  accommodation, informal care, hospitalizations, and community care 
services.  Information on caregiver sociodemographics in addition to working status and 
effect on productivity will be collected.  The amount of informal care will be collected 
according to three types of care:  personal ADL, instrumental ADL, and supervision.  
Data on accommodation and temporary changes in accommodation during the last 
month and the duration of these will be collected according to four levels of 
accommodation:  own home, intermediate forms of accommodation, dementia-specific 
residential accommodation, and nursing home.  Resource utilization will be recorded as 
the number of nights spent in different types of hospital wards, the number of visits to the 


 
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most common types of outpatient care, and the number of visits in community care 
services. 
4.5.6.12 
Neuropsychiatric Inventory Questionnaire 
The NPI-Q (Kaufer et al. 2000) was developed to assess a wide range of behaviors 
encountered in patients with dementia, to provide a means of distinguishing severity of 
behavioral changes, and to facilitate rapid behavioral assessment through the use of 
screening questions.  It is an informant-based instrument in which 12 behavioral 
domains are evaluated.  The recall period is the past month, and severity scores range 
from 036, with higher scores indicating greater severity.  The caregiver's distress 
portion of the scale will not be used in this study. 
4.5.6.13 
Electronic Assessment of Rating Scales 
The following rating scales will be captured electronically and transferred to the 
database directly from the core laboratory:  ADAS-Cog, Verbal Fluency Task, 
ADCS-ADL, CDR, MMSE, FAQ, QoL-AD, EQ-5D, RUD-Lite, NPI-Q, ZCI-AD, 
and CSSR-S. 
4.5.6.14 
Treatment Period Assessments 
The recommended order of assessments and rating scales is as follows: 
 
Clinical assessments (e.g., CDR, MMSE, and ADAS-Cog), including all those that 
require caregiver input, should be completed before any invasive safety 
assessments. 
 
Vital sign measurements, physical examination, ECGs, blood draws for clinical 
laboratory assessments, PK, ADA, plasma biomarker sampling, and urine samples 
are recommended to be conducted following scale assessments and must be 
performed prior to study drug administration. 
 


 
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The recommended order of clinical assessments/rating scales at baseline is as follows: 
Participant Assessments 
Caregiver Assessments 
1. ADAS-Cog13 
2. CDR (participant interview) 10-min 
break (optional) 
3. MMSE 
4. Coding 
5. Verbal Fluency Task 10-min break 
(optional) 
6. QoL-AD 
7. C-SSRS 
1. CDR (caregiver input) 
2. FAQ 
3. ADCS-ADL 
4. ZCI-AD 
5. QoL-AD 
6. EQ-5D 
7. RUD-Lite 
8. NPI-Q 
ADAS-Cog13  Alzheimer’s Disease Assessment ScaleCognition, Subscale 13; 
ADCS-ADL  Alzheimer’s Disease Cooperative StudyActivities of Daily Living; CDR  Clinical 
Dementia Rating; C-SSRS  ColumbiaSuicide Severity Rating Scale; EQ-5DEuroQol-5-
Dimension Questionnaire; FAQ  Functional Activities Questionnaire; MMSE  Mini-Mental 
State Examination; NPI-Q  Neuropsychiatric InventoryQuestionnaire; QoL-AD  Quality of 
LifeAlzheimer’s Disease; RUD-Lite  Resource Utilization in DementiaLite; ZCI-AD  Zarit 
Caregiver Interview for Alzheimer’s Disease. 
 
If assessments are split over 2 days, all safety assessments must be performed on the 
same day as the study drug administration. 
On each dosing day, after all assessments prior to dosing have been completed (see the 
schedule of activities in Appendix 1), gantenerumab and matching placebo where 
applicable during uptitration will be administered SC at room temperature. 
For participants who completed the double-blind part and did not enter the OLE part of 
parent Study (WN29922 or WN39658):  Participants should be observed for a minimum 
of 2 hours for the first eight administrations.  Starting at the ninth administration, 
participants should be observed for a minimum of 1 hour. 
For participants who completed the double-blind part and the OLE part of parent 
Study (WN29922 or WN39658):  Participants should be observed for a minimum of 
1 hour. 
Participants should leave the study center after injections only if they appear to be 
tolerating the injections.  When doses are to be administered remotely from the clinical 
sites, study drug administration may be performed only by qualified health care 
providers, as defined by local regulations, who must remain with the participants for a 
minimum of 1 hour after each injection and be equipped with rescue medications. 
Rescue medications to treat anaphylactic and anaphylactoid reactions must be available 
at the site or at the dosing location for HN visits.  Participants and their caregivers will be 


 
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alerted to watch for signs of anaphylactic and anaphylactoid reactions and to contact the 
study center as soon as possible if any such signs are noted. 
Visits at which the participant receives study drug may take place within  3 days of the 
protocol-specified date in the schedule of activities (Appendix 1).  It is recommended not 
to administer more than 2 dosing visits (e.g., 2  510 mg Q2W) within 28 days.  At every 
visit, participants should return to the initial planned visit schedule defined as per the 
baseline visit (OLE Day 1). 
All visits should be scheduled as close as possible to the exact day.  It is preferred that 
all assessments for a visit be performed on the same day, but, if necessary, 
assessments may be performed over more than one day.  Preferably, all clinical scales 
and assessments should be performed on the same day.  Study drug administration 
should be performed only after all assessments and rating scales for the participant have 
been completed. 


 
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4.5.7 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent for analysis:  
 
Serum chemistry panel:  AST, ALT, ALP, total protein, total bilirubin, serum albumin, 
creatine phosphokinase, sodium, potassium, calcium, BUN, serum creatinine 
(and creatinine clearance calculated by the central laboratory).  Hemoglobin A1c 
(HbA1C), glucose, insulin, C-reactive protein, folic acid, and vitamin B-12 will also be 
assessed according to the schedule of activities (Appendix 1). 
 
Coagulation:  prothrombin time 
 
Thyroid function testing:  thyroid-stimulating hormone, thyroxine (T4), and free T4  
 
Lipids:  cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides 
 
Hematology:  WBC count, RBC count (with morphology), hemoglobin, hematocrit, 
platelet count, and differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells) 
 
Urinalysis 
At the OLE Day1 visit or at the visit of the first study drug administration in 
Study WN42171, if deemed necessary by the investigator, urinalysis may be 
performed at the site by dipstick for blood, protein, glucose, and pH.  
Microscopic examination will be performed by the central laboratory if blood 
and/or protein results are positive or strongly positive. 
 
Urine pregnancy test 
Urine pregnancy tests will be performed at each dosing visit (prior to dose 
administration) and at the safety follow up visit for women of childbearing 
potential (including those who have had a tubal ligation) and at the site for any 
other female participants if required by local regulations.  If a urine pregnancy 
test is positive, it must be confirmed by a serum pregnancy test at the central 
laboratory. 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
Sample Handling and Logistics Manual. 
During the OLE Day 1 visit or at the visit of the first study drug administration in 
Study WN42171, the above laboratory assessments (excluding urine pregnancy test) do 
not have to be repeated if the last assessments performed in the parent studies 
WN29922 or WN39658 occurred within 4 weeks. 
4.5.7.1 
Pharmacokinetic Samples 
Plasma Samples 
Blood samples will be collected to evaluate the pharmacokinetics of gantenerumab in 
plasma as noted in the schedule of activities (see Appendix 1). 
An additional PK sample for the assessment of plasma concentrations of gantenerumab 
will be obtained as soon as practicable (e.g., at an unscheduled visit or the next study 


 
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visit) once the site becomes aware of the occurrence or worsening of ARIA-E or ARIA-H 
that meets the discontinuation criteria. 
Samples will not be analyzed in real time but will be batched for analysis throughout the 
study. 
Unused sample material may be used for the purpose of current gantenerumab assay 
improvement and for the quantification of specific gantenerumab glycan species. 
Cerebrospinal Fluid Samples 
For participants who were randomized in parent study (WN29922 or WN39658) based 
on CSF A and tau level results who undergo lumbar puncture in the schedule of 
activities, an aliquot of CSF obtained by lumbar puncture, described in Section 4.5.7.3, 
will be allocated for the measurement of gantenerumab concentration.  Unused sample 
material may also be used for the purposes of current assay improvement. 
4.5.7.2 
Plasma Samples for Immunogenicity Analysis 
Blood samples will be collected to assess the possible development of ADAs in all 
participants as noted in the schedule of activities (see Appendix 1).  Plasma samples will 
be analyzed for antibodies to gantenerumab. 
Unused sample material may also be used for the purposes of current ADA assay 
improvement. 
4.5.7.3 
Biomarker Samples 
Samples will be obtained from all participants and will be used for research purposes to 
identify dynamic biomarkers that may be predictive of response to treatment with 
gantenerumab (in terms of dose, safety, and tolerability) and will help to better 
understand the pathogenesis, course, and outcome of AD and related diseases. 
For participants who consent to the optional Roche Research Biosample Repository 
(RBR), residual biomarker samples will be kept for future biomarker research 
(see Section 4.5.14). 
Cerebrospinal Fluid and Serum Biomarkers 
CSF samples and matching serum samples will be obtained from participants who were 
randomized in the parent Study (WN29922 or WN39658) based on CSF A and tau 
level results.  CSF samples will be collected during the study at different timepoints for 
monitoring the levels of A and tau as well as other CSF biomarkers. 
The serum samples collected at every timepoint at which a CSF sample is collected may 
be used to determine parameters that allow the assessment of blood-brain barrier status 
and/or inflammatory processes in the brain, such as the CSF/serum albumin ratio, 
CSF/serum IgG and IgM indices, and oligoclonal bands.  CSF and serum samples will 
be collected according to the schedule of activities (see Appendix 1). 


 
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Lumbar puncture will be performed by an individual who meets all local requirements 
and is proficient in the procedure.  Lumbar puncture procedures and post-lumbar 
puncture care will be performed in accordance with local practice.  CSF sampling should 
be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal 
variation of CSF parameters.  Procedures for processing the CSF samples can be found 
in the Sample Handling and Logistics Manual. 
Approximately 12 mL of CSF will be collected at each timepoint.  The sample will be 
divided into aliquots onsite and used for the following: 
 
Central measurement of CSF gantenerumab levels 
 
Analysis of biomarkers in CSF, including A1−42, t-tau, p-tau, and other exploratory 
CSF biomarkers 
 
Samples may also be used to support the development of biomarker assays for 
diagnostic use. 
Plasma Biomarkers 
Plasma samples will be collected at different timepoints (see Appendix 1) from every 
participant who has consented to participate in the study.  Samples will be used to 
evaluate exploratory plasma biomarkers in peripheral blood, which may include, but will 
not be limited to A, tau, neurofilament, and neurogranin. 
An additional plasma sample for the assessment of exploratory biomarkers will be 
obtained as soon as practicable (e.g., at an unscheduled visit or the next study visit) 
following each MRI scan showing ARIA-E until and including ARIA-E resolution 
(i.e., new, worsened, stable, improved, resolved ARIA-E). 
RNA Biomarkers 
Blood samples at different timepoints (see Appendix 1) will be obtained for 
RNA extraction from every participant who has consented to participate in the study, at 
OLE Day 1 (only if an RNA sample has not been collected at the final efficacy and safety 
visit of the parent study [WN29922 or WN39658]), at OLE Week 104 visit, and OLE 
Week 208 visit or OLE early termination visit of this study. 
The sample may be used to evaluate clusterin messenger RNA and other exploratory 
genetic markers in peripheral blood. 
Additionally, an RNA blood sample for the assessment of exploratory biomarkers will be 
obtained as soon as practicable (e.g., at an unscheduled visit or the next study visit) 
following each MRI scan showing ARIA-E until and including ARIA-E resolution 
(i.e., new, worsened, stable, improved, resolved ARIA-E). 


 
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SAMPLING PROCEDURES AND STORAGE 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Roche may keep information about test results, medical history, and demographic 
information for all participants also from the parent studies for future development of 
diagnostic tests related to A, APOE genotype, and AD, as well as additional analyses. 
Unless the participant gives specific consent for his or her leftover samples to be stored 
for optional exploratory research (Section 4.5.14), biological samples will be destroyed 
no later than the time of completion of the final Clinical Study Report, with the following 
exceptions: 
 
Plasma samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and for PK or immunogenicity assay 
development and validation, therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed. 
 
Blood, plasma, serum, and CSF samples collected for biomarker research and 
biomarker assay development will be destroyed no later than 5 years after the final 
Clinical Study Report has been completed.  However, the storage period will be in 
accordance with the IRB/EC-approved Informed Consent Form and applicable laws 
(e.g., health authority requirements) 
 
When a participant withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the participant specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, 
if samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication. 
4.5.8 
Electrocardiograms 
Single 12-lead ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled timepoints 
as indicated. 


 
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The centrally provided electrocardiograph machine should record the following:  
heart rate, QRS duration, and RR, PR, and QT intervals and transferred to the Sponsor 
database from the core laboratory. 
At the OLE Day 1 visit or at the visit of the first study drug administration in 
Study WN42171, ECG does not have to be repeated if the last ECG performed in the 
parent studies WN29922 or WN39658 occurred within 4 weeks. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the participant has been resting in a supine position for at least 
5 minutes.  All ECGs are to be obtained prior to other procedures scheduled at that 
same time (e.g., vital sign measurements, blood draws, brain MRI scans, and lumbar 
puncture).  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation), should be avoided 
during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all 
ECG tracings.  Paper copies of ECG tracings will be kept as part of the participant's 
permanent study file at the site. 
4.5.9 
ColumbiaSuicide Severity Rating Scale 
The C-SSRS (http://www.cssrs.columbia.edu) is an assessment tool used to assess the 
lifetime suicidality of a participant (C-SSRS at baseline) as well as any new instances of 
suicidality (C-SSRS since last visit).  The structured interview prompts recollection of 
suicidal ideation, including the intensity of the ideation, behavior, and attempts with 
actual or potential lethality.  The C-SSRS baseline from the parent study will be used, 
and the C-SSRS since the last visit will be collected at subsequent visits as indicated in 
the schedule of activities (see Appendix 1). 
The assessment will be completed by a certified C-SSRS rater after he or she interviews 
the participant and the participant’s caregiver during the study visit. 
4.5.10 
Brain Magnetic Resonance Imaging 
MRI should be performed using 1.5-T or 3.0-T scanners.  Whenever possible, the same 
scanner should be used for an individual participant for the full duration of the study.  
The MRI obtained at baseline and/or at the final efficacy and safety visit in the parent 
study may be used as a baseline measure of structural brain volumes and as baseline 
information for the PET substudies (see the schedule of activities in Appendix 1). 
Where available, exploratory MRI techniques including rs-fMRI and DTI, will also be 
used. 


 
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The MRI from the final efficacy and safety visit of the parent study (WN29922 or 
WN39658) will be used to determine whether there are any significant findings (e.g., 
presence of mass lesions, etc.) that may preclude the participant's safe participation in 
and completion of this study.  Similarly, the MRI obtained at the end of the titration in 
participants who completed the parent study OLE will be used to determine if any 
significant findings preclude participation in Study WN42171.  In case of an 
ARIA-E finding, the participant should undergo Q4W MRI monitoring until the ARIA-E is 
resolved.  Participants may enroll in study WN42171 once the ARIA-E is resolved using 
their last MRI in the parent study (WN29922 or WN39658) for eligibility purposes. 
MRI will be used during the study to help assess safety, such as the occurrence of ARIA.  
Additional unscheduled MRI scans may be performed to better understand if relevant 
CNS adverse events (such as increased confusion) are occurring in the context of ARIA 
or to follow up a sign that emerges at a scheduled scan; contrast agent may be used in 
such a case of follow-up MRI scans if administration of contrast agent is considered safe 
for the participant according to local standards.  In addition, structural MRI (to assess 
whole brain and regional brain atrophy), fMRI, and DTI-MRI will be performed at multiple 
timepoints to determine potential treatment effects on MRI outcome measures 
(according to the schedule of activities). 
MRI scans will include the following sequences: 
 
3D T1-weighted gradient recalled echo (GRE) scans 
 
T2*-weighted GRE scans 
 
T2-weighted fluid-attenuated inversion recovery scans 
 
BOLD rs-fMRI, if available (to assess resting-state functional connectivity at 
investigative sites having the required software and sequences) 
 
DTI-MRI, if available (to assess fiber tract integrity) 
 
For details on the specific imaging sequences and acquisition times required, refer to the 
MRI manual. 
Magnetic resonance imaging should not be performed unless at least 3 days have 
passed since a lumbar puncture.  If an MRI and lumbar puncture are both scheduled for 
the same day, the MRI should be performed first. 
MRI scans will be reviewed by a central MRI core laboratory, which will perform the 
diagnostic reads and assessments of MRI outcome measures.  MRI scans should 
preferably be transferred to the central MRI core laboratory electronically.  Data transfer 
from individual study sites to the central MRI core laboratory may take up to 7−10 days, 
if not done electronically.  Upon receipt of the MRI scans from the study sites, the central 
MRI core laboratory will provide the diagnostic reads.  MRI results must be made 
available to investigators prior to the dosing visit that the MRI corresponds to (refer to 
Section 5.1.2 for additional details on MRI safety management). 


 
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MRI facility qualification and scan quality control will be performed by the central 
MRI core laboratory. 
In addition to any local reading according to local procedures and requirements, all 
MRI scans will be reviewed by an expert central reader within approximately 1 week of 
receipt and a report provided to the site.  For the purposes of overall study relevant 
decisions and recommendations results from the expert central reader will be used.  
Any time the central reader identifies a new MRI finding, the study center medical staff 
and the Sponsor will be rapidly notified (see Section 5.1.2). 
Refer to Section 5.1.2 for instructions in the event of new MRI findings (ARIA-E and 
ARIA-H). 
At the OLE Day 1 visit or at the visit of the first study drug administration in the 
Study WN42171, MRI does not have to be repeated if the last MRI performed in the 
parent studies WN29922 or WN39658 is within 6 months.  The MRI can only be used if it 
was the last prescribed per-protocol MRI in the parent study. 
Additional instructions regarding the procedures for MRI scan acquisition and transmittal 
to the central reading facility can be found in the MRI manual. 
Healthy Volunteer Magnetic Resonance Imaging Scans for 
Site Qualification 
In case of a major upgrade to the site’s scanner, any other event deemed significant 
enough to affect image quality, or per central reader guidance, the two volunteers will be 
asked to complete additional scans that will be reviewed for suitable image quality and 
used for qualitative comparison.  The volunteer must provide written consent to take part 
in the scanning calibration.  Volunteers must not have any contraindications for 
MRI scanning (evaluation per local procedures at the imaging site), and they will not be 
enrolled in the study or undergo any other assessments as part of the trial.  
This procedure will help ensure consistency in scanning quality over the duration of the 
study.  Two volunteers are ideal in case one volunteer is no longer readily available for 
test scanning. 
Additional instructions regarding the procedures for MRI facility qualification can be 
found in the MRI manual. 
4.5.11 
Positron Emission Tomography Scan 
A PET scan will be performed in the context of the two associated PET substudies 
(a longitudinal amyloid PET substudy and a longitudinal tau PET substudy 
(see Section 3.1.2). 
Detailed instructions regarding the procedures for PET scan methodology, including 
scanning procedures, can be found in the PET Technical Operations Manual. 


 
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4.5.12 
Final Safety and Efficacy Visit Assessments 
Participants who complete the treatment period (defined as completion of 
OLE Week 206 dosing visit) have to complete the final safety and efficacy assessment 
period 2 weeks following the final dose (Week 208). 
4.5.13 
Study Completion or Early Termination Visit Assessments 
All participants who withdraw from treatment or discontinue from the study early will be 
asked to return 2 weeks after the final dose of study drug in order to complete the early 
termination visit. 
In addition, participants who withdraw from treatment will be asked to return for 
collection of safety (except MRI) and limited efficacy data (i.e., secondary endpoints) at 
visits that have efficacy assessments (e.g., OLE Week 52, OLE Week 76, 
OLE Week 104, OLE Week 130, OLE Week 156, OLE Week 182, OLE Week 208, and 
OLE Week 220). 
Autopsy reports, including cause of death, for all participants who die during the study 
(i.e., prior to the OLE Week 220 follow-up visit) should be requested. 
Refer to the schedule of activities to be performed at the study completion 
(OLE Week 208 or OLE early termination visit) in Appendix 1. 
When participants complete the treatment period or discontinue early, every effort 
should be made to ensure that the safety follow-up period and all related assessments 
are completed. 
4.5.14 
Optional Samples for Research Biosample Repository 
4.5.14.1 
Overview of the Research Biosample Repository 
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biological specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection, storage, and analysis of 
RBR samples will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
participants in the future. 
Samples for the RBR will be collected from participants who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
 
To study the association of biomarkers with efficacy or disease progression 
 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
 
To increase knowledge and understanding of disease biology and drug safety 


 
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 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.14.2 
Approval by the Institutional Review Board or 
Ethics Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.14) 
will not be applicable at that site. 
4.5.14.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to gantenerumab, AD, or 
drug safety: 
 
Leftover blood, serum, plasma, CSF samples collected for biomarker analysis, and 
any derivatives thereof (e.g., DNA, RNA, proteins, peptides) 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods.  Genomics is increasingly informing 
researchers’ understanding of disease pathobiology.  Whole genome sequencing and 
WES provide a comprehensive characterization of the genome and exome, respectively, 
and, along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches or new methods for monitoring efficacy and 
safety or predicting which participants are more likely to respond to a drug or develop 
adverse events. 
Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 


 
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4.5.14.4 
Confidentiality 
RBR samples and associated data will be labeled with a unique patient identification 
number. 
Participant medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
participant, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.14.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each participant the 
objectives, methods, and potential hazards of participation in the RBR.  Participants will 
be told that they are free to refuse to participate and may withdraw their consent at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a participant's agreement to provide optional RBR samples.  
Participants who decline to participate will not provide a separate signature. 
The investigator should document whether or not the participant has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
4.5.14.6 
Withdrawal from the Research Biosample Repository 
Participants who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the participant.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a participant wishes to withdraw consent to the 


 
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testing of his or her RBR samples during the study, the investigator must inform the 
Medical Monitor in writing of the participant's wishes through use of the appropriate 
RBR Subject Withdrawal Form and must enter the date of withdrawal on the 
RBR Research Sample Withdrawal of Informed Consent eCRF.  If a participant wishes 
to withdraw consent to the testing of his or her RBR samples after closure of the site, the 
investigator must inform the Sponsor by emailing the study number and participant 
number to the following email address: 
global.rcr-withdrawal@roche.com 
A participant's withdrawal from this study does not, by itself, constitute withdrawal of 
consent for testing of RBR samples.  Likewise, a participant's withdrawal of consent for 
testing of RBR samples does not constitute withdrawal from this study. 
4.5.14.7 
Monitoring and Oversight 
 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to participant participation in the RBR for the purposes of 
verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples. 
4.6 
TREATMENT, PARTICIPANT, STUDY, AND SITE 
DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Participants must permanently discontinue study treatment if they experience any of the 
following: 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the participant's safety if he or she continues to receive study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the participant 
 
Pregnancy 
 
Evidence of an intracerebral macrohemorrhage 
 
Evidence of disseminated leptomeningeal hemosiderosis 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Participants who discontinue study treatment prematurely will not be 
replaced. 


 
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All participants who withdraw from treatment will be asked to return 2 weeks after their 
final dose in order to complete the early termination visit assessments. 
In addition, participants who withdraw from treatment will be asked to return for 
collection of safety data (except MRI) and limited efficacy data (i.e., secondary 
endpoints) at visits that have efficacy assessments (e.g., OLE Week 52, OLE Week 76, 
OLE Week 104, OLE Week 130, OLE Week 156, OLE Week 182, OLE Week 208, and 
OLE Week 220) according to the schedule of activities.  
4.6.2 
Participant Discontinuation from the Study 
Participants will return to the clinic for an early termination visit 2 weeks after last dose. 
Participants have the right to voluntarily withdraw from the study at any time for any 
reason.  In addition, the investigator has the right to withdraw a participant from the 
study at any time. 
Reasons for participant discontinuation from the study may include, but are not limited 
to, the following: 
 
Participant withdrawal of consent 
 
Study termination or site closure 
 
Adverse event or any medical condition that the investigator or Sponsor determines 
may jeopardize the participant’s safety if he or she continues in the study 
 
Loss to follow-up 
 
Investigator or Sponsor determines it is in the best interest of the participant 
 
Participant non-compliance with the study and/or study procedures, defined as 
missing more than six consecutive dosing visits because of nonsafety-related 
reasons or more than half of the dosing visits in a calendar year 
 
When participants discontinue early, every effort should be made to ensure that the 
safety follow-up period and all related assessments are completed and to obtain a reason 
for participant discontinuation from the study.  The primary reason for discontinuation 
from the study should be documented on the appropriate eCRF.  If a participant requests 
to be withdrawn from the study, this request must be documented in the source 
documents and signed by the investigator.  Participants who withdraw from the study will 
not be replaced. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to participants. 
 
Participant enrollment is unsatisfactory. 


 
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 
Data from other studies suggest that treatment with gantenerumab is likely not 
effective. 
 
Sponsor determines it is the best interest of the participants. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all participants have completed the study and all obligations 
have been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
Gantenerumab is not yet approved, and clinical development is ongoing.  The safety 
plan for participants in this study is based on clinical experience with gantenerumab in 
completed and ongoing studies.  The identified risks for gantenerumab are outlined 
below.  Please refer to the Gantenerumab Investigator’s Brochure for a complete 
summary of safety information. 
Several measures will be taken to ensure the safety of participants participating in this 
study.  Eligibility and discontinuation criteria both in the parent studies (WN29922 and 
WN39658) and in study WN42171 have been designed to exclude participants at higher 
risk for imaging-related abnormalities.  Participants will undergo safety monitoring during 
the study, including assessment of the nature, frequency, severity, and timing of 
adverse events.  In addition, guidelines for managing selected adverse events, including 
criteria for dosage modification and treatment interruption or discontinuation, are 
provided below. 
5.1.1 
Risks Associated with Gantenerumab 
5.1.1.1 
Amyloid-Related Imaging Abnormalities 
To date, clinical experience with gantenerumab has shown that ARIA events are 
dose- and APOE 4-dependent.  These events are manageable with MRI monitoring and 
dose intervention algorithms.  In addition, in case of clinical symptoms, the use of 
IV glucocorticosteroids may be considered. 


 
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Rules for management of participants who develop ARIA-E or ARIA-H are provided in 
Appendix 2. 
5.1.1.2 
Injection-Site Reactions 
Gantenerumab may cause a reaction when given as an SC injection.  In studies with 
gantenerumab, the most common events occurring more frequently with gantenerumab 
than with placebo were local ISRs, such as injection-site erythema.  The majority of 
events were of mild intensity and resolved without treatment (see Section 1.3.2.2 for 
details). 
Detailed information on the characteristic signs and symptoms of ISRs (e.g., erythema, 
pruritus) will be recorded on the dedicated eCRF page (see Section 5.3.5.1 for details on 
recording of ISRs). 
5.1.1.3 
Immunogenicity 
As with administration of any exogenous protein, there is the potential for the 
development of ADAs, which can be neutralizing and/or sensitizing and which can 
potentially lead to febrile or allergic reactions, including anaphylaxis.  The immunogenic 
risk of gantenerumab is considered low since it is a fully human antibody. 
There are no clinical findings indicative of an immunogenic response to gantenerumab.  
Investigators should explain to participants how to recognize the signs and symptoms of 
hypersensitivity reactions, and participants should be monitored. 
5.1.2 
Management of Participants Who Experience Adverse Events 
5.1.2.1 
Dose Modifications and Treatment Interruptions 
Participants who completed the double-blind part and did not enter the OLE part of the 
parent Study (WN29922 or WN39658) will undergo uptitration in this study, which will 
last at least 34 weeks.  During the uptitration phase, participants will undergo brain 
MRI examinations prior to every dose increase (pre-uptitration MRI scans).  
The pre-uptitration MRI scans will determine eligibility for the next uptitration dose, as 
described in Appendix 2. 
In order to determine the radiological severity of an ARIA-E event, the Bioclinica 
5-point scale (Bracoud et al. 2017) will be used; refer to Table 2. 


 
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Table 2 
Bioclinica 5-Point Scale Definition 
ARIA-E Extent 
ARIA-E Focality 
5-Point Scale 
No ARIA-E 
N/A 
0 
 5 cm 
Monofocal 
1 (Mild) 
Multifocal 
2 (Mild ) 
510 cm 
Monofocal 
3 (Moderate) 
Multifocal 
4 (Moderate ) 
 10 cm 
Monofocal 
5 (Severe) 
Multifocal 
ARIA-E  amyloid-related imaging abnormalityedema/effusion; N/A  not applicable. 
 
The participants’ eligibility for uptitration will be determined according to the 
ARIA management rules outlined in Appendix 2.  In the Study WN42171, there must be 
a minimum of 3 complete administrations of each dosing level for the participants to be 
eligible for a pre-uptitration MRI scan.  A complete IMP administration is defined as two 
consecutive dosing visits (one with an odd dose number and one with an even dose 
number (see Appendix 1 and Table 1).  A participant may still be eligible for a 
preuptitration MRI scan and uptitration even if these requirements are not met provided 
that they have been administered IMP at 3 odd dosing visits at a given dose level 
(see Table 1). 
All participants, regardless of where they completed their gantenerumab dose uptitration 
(i.e., WN22992 or WN39658 OLE or this study), will undergo regular MRI scans 
according to the schedule of activities while they are on the target gantenerumab dose. 
In addition, the dose adjustment and discontinuation rules for MRI findings as described 
in Appendix 2 will apply. 
The investigator may choose to perform additional MRI monitoring for ARIA at any time.  
MRI monitoring of ARIA findings should be conducted at approximately 4-week intervals.  
Any other new significant findings will be reviewed by the Medical Monitor, and 
appropriate dose action will be proposed. 
The iDMC will review the incidence of ARIA in an unblinded manner and may 
recommend adjustment of dosing regimen and/or ARIA management rules for the 
overall study population or for a specific APOE 4 genotype.  In the event the iDMC 
which reviews safety in both the parent studies (WN29922 and WN39658) and study 
WN42171 is no longer required (for instance after the unblinding of the parent studies) 
evaluation of participant safety may be taken over by the Sponsor's Internal 
Monitoring Committee (IMC), with details documented in an IMC charter. 


 
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5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified 
vital signs, and conducting other protocol-specified tests that are deemed critical to the 
safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.10 and 
5.3.5.11 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
participant at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.12) 


 
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 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the participant's ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
participant or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events; see Section 5.3.3); 
the event itself may be of relatively minor medical significance (such as severe 
headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2 for reporting instructions).  Adverse events of special interest for this 
study are as follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.8). 
 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a participant exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 
5.2.4 
Selected Adverse Events 
Additional data and safety MRI scans will be collected for the following selected 
adverse events: 
 
ARIA-E:  ARIAs suggestive of vasogenic edema and sulcal effusions 


 
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 
ARIA-H:  ARIAs suggestive of microhemorrhages and/or hemosiderin deposits 
 
Please refer also to Section 5.3.5.2 for further details on how to report ARIA events. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.45.6.  
The investigator is also responsible for reporting medical device complaints 
(see Section 5.4.4). 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each participant contact.  
All adverse events, whether reported by the participant, caregiver, or noted by study 
personnel, will be recorded in the participant's medical record and on the Adverse Event 
eCRF. 
After informed consent has been obtained: 
 
All adverse events occurring while the participant is in the parent Study WN29922 or 
WN39658 will be reported on the parent Adverse Event eCRF until the participant’s 
final visit/last assessment in the parent study. 
 
All adverse events occurring after the participant’s final visit/last assessment in the 
parent Study WN29922 or WN39658 will be reported on the Study WN42171 
Adverse Event eCRF until the participant’s final visit/last assessment in 
Study WN42171 (including long-term follow-up visits). 
 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all participant evaluation timepoints.  Examples of 
non--directive questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?" 
 


 
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5.3.3 
Assessment of Severity of Adverse Events 
Table 3 provides guidance for assessing adverse event severity. 
Table 3 
Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating with inability to work or to perform normal daily activity 
Note:  Regardless of severity, some events may also meet seriousness criteria.  Refer to 
definition of a serious adverse event (see Section 5.2.2). 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether an adverse event is considered to be related to the study drug, 
indicating "yes" or "no" accordingly.  The following guidance should be taken into 
consideration: 
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
 
Known association of the event with the study drug or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the participant or use of concomitant medications known 
to increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Injection Reactions 
Injection reactions (local and systemic) are defined as adverse events that occur during 
or within 24 hours after study drug administration that are judged to be related to the 
study drug injection. 


 
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For local reactions, the diagnosis of injection site reaction should be captured on the 
Adverse Event eCRF and associated signs and symptoms (e.g., erythema at injection 
site) should be recorded on the dedicated Injection Site Reaction eCRF. 
Systemic reactions should be recorded as a single diagnosis on the Adverse Event 
eCRF (e.g., anaphylactic reaction).  If possible, avoid ambiguous terms such as 
“systemic reaction.” 
5.3.5.2 
ARIA Findings 
Not every ARIA finding qualifies as an adverse event.  An ARIA finding must be reported 
as an adverse event if it meets any of the following criteria: 
 
Symptomatic ARIA-E (onset or worsening of CNS symptom[s] attributable to 
ARIA-E MRI findings in the judgement of the investigator) 
 
ARIA findings that result in a change in study treatment (e.g., dosage modification, 
treatment interruption, or treatment discontinuation) 
 
Findings that are otherwise clinically significant in the investigator’s judgment 
 
Any accompanying symptom(s) should also be captured as separate adverse events.  
It is the investigator’s responsibility to review all ARIA findings.  Observations of the 
same clinically significant ARIA finding should only be recorded once on the Adverse 
Event eCRF (see Section 5.3.5.5 for details on recording persistent adverse events). 
5.3.5.3 
Diagnosis versus Signs and Symptoms 
For adverse events other than ISRs or ARIA (see Sections 5.3.5.1 and 5.3.5.2, 
respectively), a diagnosis (if known) should be recorded on the Adverse Event eCRF 
rather than individual signs and symptoms (e.g., record only liver failure or hepatitis 
rather than jaundice, asterixis, and elevated transaminases).  However, if a constellation 
of signs and/or symptoms cannot be medically characterized as a single diagnosis or 
syndrome at the time of reporting, each individual event should be recorded on the 
Adverse Event eCRF.  If a diagnosis is subsequently established, all previously reported 
adverse events based on signs and symptoms should be nullified and replaced by one 
adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis. 
5.3.5.4 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 


 
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 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
However, for a serious or severe secondary event such as a fracture following a fall, 
both events should be reported separately on the eCRF because a fracture is not a 
typical expected consequence of a fall. 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.5 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
participant evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between participant evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.6 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment. 
 


 
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It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5  ULN [upper limit of normal] associated with cholestasis), only 
the diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment 
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for 
details on recording persistent adverse events). 
5.3.5.8 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 


 
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causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy’s Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.3) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2). 
5.3.5.9 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
This includes death attributed to progression of AD. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
If the death is attributed solely to progression of AD, “Alzheimer’s disease progression” 
should be recorded on the Adverse Event eCRF. 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.10 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for the parent 
study and at the beginning of this study.  Conditions reported on the General 
Medical History eCRF in the parent study do not need to be re-entered.  They will be 
reassessed if they are ongoing at the beginning of this study. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 


 
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that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.11 
Lack of Efficacy or Worsening of Alzheimer’s Disease 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an adverse event. 
5.3.5.12 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the parent study baseline (WN29922 
and WN39658) or was scheduled during the study when elective surgery 
became necessary because of the expected normal progression of the disease 
The participant has not experienced an adverse event 
 
5.3.5.13 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug 
 
In some cases, a medication error may be intercepted prior to administration of the 
drug. 
 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 
 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
 


 
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Special situations are not in themselves adverse events but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For gantenerumab and [18F]GTP1, adverse events 
associated with special situations should be recorded as described below for each 
situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the 
"Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 
In addition, all special situations associated with gantenerumab and [18F]GTP1, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 


 
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 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
 
Drug administered to someone other than the participant:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries 
5.3.5.14 
Clinical Outcome Assessment Data 
Adverse event reports will not be derived from clinical outcome assessment (COA) data 
by the Sponsor, and safety analyses will not be performed using COA data.  Sites are 
not expected to review the COA data for adverse events. 
5.3.5.15 
Safety Biomarker Data 
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on participant 
management. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2) for details on 
reporting requirements) 


 
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 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2) for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
Medical device complaints (see Section 5.4.4 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study participants, an Emergency Medical Call Center Help Desk 
will access the Roche Medical Emergency List, escalate emergency medical calls, 
provide medical translation service (if necessary), connect the investigator with a 
Roche Medical Responsible (listed on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
After informed consent has been obtained: 
 
All serious adverse events and adverse events of special interest occurring while 
the participant is in the parent Study (WN29922 or WN39658) will be reported on 
the parent Adverse Event eCRF until the participant’s final visit/last assessment in 
the parent Study (WN29922 or WN39658). 
 
All serious adverse events and adverse events of special interest occurring after the 
participant’s final visit/last assessment in the parent Study (WN29922 or WN39658) 
will be reported on the Study WN42171 Adverse Event eCRF until the participant’s 
final visit/last assessment in Study WN42171 (including long-term follow-up visits). 
 
Investigators should record all case details that can be gathered immediately (i.e., within 
24 hours after learning of the event) on the Adverse Event eCRF and submit the report 


 
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via the electronic data capture (EDC) system.  A report will be generated and sent to 
Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system. 
Instructions for reporting serious adverse events that occur after the adverse event 
reporting period are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Participants 
Female participants of childbearing potential will be instructed through the Informed 
Consent Form to immediately inform the investigator if they become pregnant during the 
study or within 16 weeks after the final dose of study drug.  A paper Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study drug and counsel the 
participant, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the participant should continue until conclusion of the pregnancy.  Any 
serious adverse events associated with the pregnancy (e.g., an event in the fetus, an 
event in the mother during or after the pregnancy, or a congenital anomaly/birth defect in 
the child) should be reported on the Adverse Event eCRF.  In addition, the investigator 
will submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available. 
5.4.3.2 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic 
or elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 


 
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All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female participant exposed to 
study drug should be classified as a serious adverse event, recorded on the 
Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.4.2). 
5.4.4 
Reporting Requirements for Medical Device Complaints 
The investigator must report all medical device complaints (e.g., devices for study drug 
administration) to the Sponsor.  The investigator should document as much information 
as possible on the IMP Deviation Form, including the product batch number, and forward 
the form to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event) (refer to the pharmacy manual for further details).  If the medical device results in 
an adverse event to the study participant, the event must be reported on the 
Adverse Event eCRF and submitted through the EDC system.  If the event is serious, 
the Adverse Event eCRF must be completed immediately (i.e., no more than 24 hours 
after learning of the event), as outlined in Section 5.4.2. 
5.5 
FOLLOW-UP OF PARTICIPANTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the 
participant is lost to follow-up, or the participant withdraws consent.  Every effort should 
be made to follow all serious adverse events considered to be related to study drug or 
trial-related procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the participant's medical record to facilitate source 
data verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
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5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE 
ADVERSE EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
participant’s final visit/last assessment in Study WN42171) if the event is believed to be 
related to prior study drug treatment.  These events should be reported through use of 
the Adverse Event eCRF.  However, if the EDC system is not available, the investigator 
should report these events directly to the Sponsor or its designee, either by faxing or by 
scanning and emailing the paper Clinical Trial Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
Gantenerumab 
Gantenerumab Investigator’s Brochure 
Florbetaben [18F] (Neuraceq) 
Florbetaben [18F] Investigator’s Brochure 
Flutemetamol [18F] (Vizamyl) 
Flutemetamol [18F] Investigator’s Brochure 
[18F] GTP1 
[18F] GTP1 Investigator’s Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The purpose of this study is to assess the safety, tolerability, and efficacy of long-term 
administration of open-label gantenerumab in participants with AD who completed 
Study WN29922 or WN39658. 


 
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Data from OLE baseline (see Section 4.5.2 for definition) to the end of study will be 
summarized. Consequently, where appropriate, data from the parent studies will be 
combined with data from this protocol. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The sample size will include all eligible participants who consent to this study.  
The sample size is expected to be no more than approximately 2032 participants but will 
be determined by the number of participants who complete parent Studies (WN29922 
and WN39658) and enroll in this study. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, participant disposition, and incidence of protocol deviations will be 
summarized using descriptive statistics for all enrolled participants. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (such as age, sex, race, disease stage, 
APOE 4 status, and use and non-use of background therapy for AD) will be 
summarized descriptively for all enrolled participants. 
Descriptive summaries of continuous data will present the mean, standard deviation, 
median, and minimum and maximum.  Descriptive summaries of discrete data will 
include frequencies expressed in terms of number and percentage of participants. 
6.4 
SAFETY ANALYSES 
The safety analysis population will include all enrolled participants who received at least 
one dose of study drug in this protocol. 
The following safety outcome measures will be summarized using descriptive statistics: 
 
Nature, frequency, severity, timing, and outcomes of adverse events and serious 
adverse events 
 
Physical examinations (including neurological systems), vital signs, ECG, laboratory 
tests, and C-SSRS 
 
Nature, frequency, severity, and timing of ARIA-E and ARIA-H 
 
Nature, frequency, severity, timing, and outcomes of injection-site reactions 
 
Incidence of treatment discontinuations for adverse events 
 
Incidence of adverse events of special interest 
 
Statistical methods, endpoint definitions, and analyses of the safety endpoints will be 
described in a SAP. 


 
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6.5 
EFFICACY ANALYSES 
The secondary and exploratory efficacy analyses will use all enrolled participants to 
investigate both the long-term efficacy and potential disease modifying effect of 
long-term gantenerumab.  Associated estimands, including those pertaining to a delayed 
start analysis, will be described in detail in a Statistical Analysis Plan (SAP).  
The efficacy endpoints collected during both the double-blind and OLE parts of the 
parent Study (WN29922 or WN39658) may be combined with data from this study in 
order to evaluate the long-term effect of gantenerumab. 
6.6 
PHARMACOKINETIC ANALYSES 
Plasma concentration data for gantenerumab will be tabulated and summarized.  
Descriptive summary statistics will include the arithmetic mean, median, range, standard 
deviation, and coefficient of variation, as appropriate.  Because a sparse PK sampling 
design is being used, population (non-linear mixed-effects) modeling will be used to 
analyze the dose concentrationtime data of gantenerumab.  Information from other 
clinical studies may be incorporated to establish the PK model.  The selection of 
parameters and the derivation of individual measures of exposure, such as area under 
the concentration–time curve, maximum plasma concentration observed (Cmax), and 
trough plasma concentration, will depend on the final PK model used for this analysis.  
The results of this modeling analysis may be reported separately from the clinical study 
report.  Cerebrospinal fluid concentrations of gantenerumab may be tabulated and 
summarized as appropriate. 
Prior to the completion of the study, one or more separate cutoff date(s) for PK samples 
may be established to allow expedient sample analyses and early access by third party 
vendors. 
Additional PK analyses will be conducted as appropriate and may be reported separately 
from the clinical study report. 
6.7 
IMMUNOGENICITY ANALYSES 
The immunogenicity analysis population will consist of all participants with at least one 
ADA assessment.  The numbers and proportions of ADA-positive participants and 
ADA-negative participants prior to OLE drug administration and after OLE drug 
administration will be summarized using descriptive statistics. 
Prior to completion of the study, one or more separate cutoff date(s) for ADA samples 
may be established to allow expedient samples analyses and early access by third party 
vendors. 
6.8 
BIOMARKER ANALYSES 
Exploratory PD and biomarker endpoints will be analyzed using descriptive statistics, 
subgroup analysis, or statistical models if appropriate.  For longitudinally measured 


 
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endpoints, the change from baseline will be estimated if appropriate.  Prior to the 
completion of the study, one or more separate cutoff date(s) for PD biomarker samples 
may be established to allow expedient sample analyses and early access by third party 
vendors.  Exploratory biomarkers may be reported separately. 
6.9 
HEALTH STATUS UTILITY ANALYSES 
Change over time in EQ-5D health utility index-based will be calculated.  EQ-5D will be 
summarized using descriptive statistics.  Details will be provided in a SAP.  EQ-5D will 
be used to estimate health state utility values needed for economic modeling.  Such 
analyses will be reported separately. 
6.10 
INTERIM ANALYSES 
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one or more interim analysis(es) which may include efficacy, 
safety and biomarker outcomes.  An interim analysis may be considered when the 
parent pivotal Studies WN29922 and WN39658 are completed and the submission 
folder is under preparation.  Details will be pre-specified in a SAP. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  All electronic data from external vendors 
will be sent directly to the Sponsor, using the Sponsor's standard procedures to handle 
and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
COA data will be collected through the use of an electronic device (tablet) provided by a 
vendor (see Section 7.3 for details).  Some COA data may be audio recorded for quality 
assurance purposes.  The device is designed for entry of data in a way that is 
attributable, secure, and accurate, in compliance with U.S. Food and Drug 
Administration (FDA) regulations for electronic records (21 CFR, Part 11).  
The electronic data are available for view access only via secure access to an online 
web portal.  Only identified and trained users may view the data, and their actions 
become part of the audit trail.  The Sponsor will have view access only.  System 


 
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backups for data stored by the Sponsor and records retention for the study data will be 
consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
The eCRFs are to be completed through use of a Sponsor-designated EDC system.  
Sites will receive training and have access to a manual for appropriate eCRF 
completion.  The eCRFs will be submitted electronically to the Sponsor and should be 
handled in accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  The eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive participant data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
ELECTRONIC REPORTED OUTCOME DATA 
An electronic device will be used by participants, caregivers, and appropriate site staff to 
capture COA data.  The device is designed for entry of data in a way that is attributable, 
secure, and accurate, in compliance with FDA regulations for electronic records (21 CFR 
Part 11).  The data will be transmitted to a centralized database maintained by the 
electronic device vendor. 
The electronic data will be available for view access only, via a secure online web portal.  
Only identified and trained users may view the data, and their actions will become part of 
the audit trail.  The Sponsor will have view access only.  System backups for data stored 
by the Sponsor and records retention for the study data will be consistent with the 
Sponsor's standard procedures. 
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive participant data for the site in both human- and 
machine-readable formats that must be kept with the study records as source data.  
Acknowledgement of receipt of the data is required.  In addition, the Sponsor will receive 
all data in a machine-readable format. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which participant data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, participant-reported outcomes, 
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instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
participant files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper COA data, Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 


 
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Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for 
Good Clinical Practice and the principles of the Declaration of Helsinki, or the applicable 
laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual.  The study will comply with the 
requirements of the ICH E2A guideline (Clinical Safety Data Management:  
Definitions and Standards for Expedited Reporting).  Studies conducted in the 
United States or under a U.S. Investigational New Drug (IND) Application will comply 
with U.S. FDA regulations and applicable local, state, and federal laws.  Studies 
conducted in the European Union or European Economic Area will comply with the 
E.U. Clinical Trial Directive (2001/20/EC) and applicable local, regional, and national 
laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before 
IRB/EC submission.  The final IRB/ECapproved Consent Forms must be provided to 
the Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each participant the 
objectives, methods, and potential risks associated with each optional procedure.  
Participants will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a participant's agreement to participate in optional procedures.  Participants 
who decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the participant or the participant's 
legally authorized representative before his or her participation in the study.  The case 
history or clinical records for each participant shall document the informed consent 
process and that written informed consent was obtained prior to participation in the 
study. 


 
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The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
participant to participate.  The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) while a 
participant is participating in the study, the participant or a legally authorized 
representative must re-consent by signing the most current version of the Consent 
Forms or the addendum, in accordance with applicable laws and IRB/EC policy.  For any 
updated or revised Consent Forms, the case history or clinical records for each 
participant shall document the informed consent process and that written informed 
consent was obtained using the updated/revised Consent Forms for continued 
participation in the study. 
A copy of each signed Consent Form must be provided to the participant or the 
participant's legally authorized representative.  All signed and dated Consent Forms 
must remain in each participant's study file or in the site file and must be available for 
verification by study monitors at any time. 
For sites in the United States, each Consent Form may also include participant 
authorization to allow use and disclosure of personal health information in compliance 
with the U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the 
site utilizes a separate Authorization Form for participant authorization for use and 
disclosure of personal health information under the HIPAA regulations, the review, 
approval, and other processes outlined above apply except that IRB review and approval 
may not be required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the 
participant, and relevant supporting information must be submitted to the IRB/EC by the 
Principal Investigator and reviewed and approved by the IRB/EC before the study is 
initiated.  In addition, any participant recruitment materials must be approved by the 
IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments 
(see Section 9.7). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 


 
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for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file. 
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each participant enrolled in 
the study through assignment of a unique patient identification number.  This means that 
participant names are not included in data sets that are transmitted to any Sponsor 
location. 
Participant medical information obtained by this study is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
participant, unless permitted or required by law. 
Medical information may be given to a participant's personal physician or other 
appropriate medical personnel responsible for the participant's welfare, for treatment 
purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication (see Section 9.6). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.6). 
8.5 
FINANCIAL DISCLOSURE 
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 (see definition of end of 
study in Section 3.2). 


 
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100/Protocol WN42171, Version 4 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the participant data, including an audit trail containing a complete record of all changes 
to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on participant safety 
and data integrity to the Sponsor and to the IRB/EC in accordance with established 
IRB/EC policies and procedures.  The Sponsor will review all protocol deviations and 
assess whether any represent a serious breach of Good Clinical Practice guidelines and 
require reporting to health authorities.  As per the Sponsor's standard operating 
procedures, prospective requests to deviate from the protocol, including requests to 
waive protocol eligibility criteria, are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring participant safety and data integrity.  
Prior to study initiation, the Sponsor will identify potential risks associated with critical 
trial processes and data and will implement plans for evaluating and controlling these 
risks.  Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters.  Detection of deviations from quality tolerance 
limits will trigger an evaluation to determine if action is needed.  Details on the 
establishment and monitoring of quality tolerance limits will be provided in a Quality 
Tolerance Limit Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, participants' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
The overall procedures for quality assurance of clinical study data are described in 
Roche standard operating procedures.  This study will be sponsored by F. Hoffmann-La 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
101/Protocol WN42171, Version 4 
Roche Ltd.  The Sponsor will provide clinical operations oversight, site monitoring and 
management, data management support, and medical monitoring. 
Study drug distribution may occur through an IxRS (see Section 4.2).  Central facilities 
may be used for study assessments (i.e., ECG, lumbar puncture, specified laboratory 
tests, PK, rating scales, and MRI and PET imaging), as applicable. 
9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in participants involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical trial results within 6 months after the 
availability of the respective Clinical Study Report.  In addition, for all clinical trials in 
participants involving an IMP for which a marketing authorization application has been 
filed or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and statistically 
sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
102/Protocol WN42171, Version 4 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to participants or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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10. 
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Appendix 1 
 
Schedule of Activities 
Table 1 
Schedule of Activities for Participants Who Did Not Participate in the OLE Part of Parent 
Study WN29922 or WN39658  
Assessment/Procedure 
Screening 
BL 
 
OLE (week) 
UVa 
 
Including 
While in 
parent study 
to 1 Day 
OLE 
Day  
1 
OLE 
Day  
4 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
 
Dose number in the 
Study WN42171 
 
1 b 
 
2 
3 
4 
5 
6 
7 
8 
9 c 
10 c 11 c 12 c 13 d 14 c 15 c 16 c 17 c 18 c 
 
Dose level for participants 
previously on active 
 
510 mg Q2W 
 
Dose level for participants 
previously on placebo 
 
120 mg 
255 mg 
510 mg 
 
Informed consent(s) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of inclusion and 
exclusion criteria 
x 
B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, personal 
status, and demographic 
data 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height e 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Clinical RNA samples 
 
x b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Urinalysis  
 
x r 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation (PT) 
 
B b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG  
 
B b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Plasma PK sample f 
 
B 
x 
 
 
 
 
 
 
 
 
 
 
 
B 
 
 
 
 
 
x 
Plasma ADA sample 
 
B 
 
 
 
 
 
 
 
 
 
 
 
 
B 
 
 
 
 
 
x 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
109/Protocol WN42171, Version 4 
Assessment/Procedure 
Screening 
BL 
 
OLE (week) 
UVa 
 
Including 
While in 
parent study 
to 1 Day 
OLE 
Day  
1 
OLE 
Day  
4 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
 
Dose number in the 
Study WN42171 
 
1 b 
 
2 
3 
4 
5 
6 
7 
8 
9 c 
10 c 11 c 12 c 13 d 14 c 15 c 16 c 17 c 18 c 
 
Dose level for participants 
previously on active 
 
510 mg Q2W 
 
Dose level for participants 
previously on placebo 
 
120 mg 
255 mg 
510 mg 
 
Serum chemistry g and  
hematology h 
 
B b 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Plasma biomarker sample 
 
x b 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Complete physical 
examination (includes 
neurologic systems) i 
 
Bb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Limited physical 
examination j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
MRI scan k 
 
B b, l 
 
 
 
 
 
 
B 
 
 
 
 
 
B 
 
 
 
 
 
x 
CSF and matching serum 
samples m 
 
x b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CDR 
 
P& 
CG b 
 
 
 
 
 
 
 
 
 
 
 
 
P&
CG 
 
 
 
 
 
P& 
CG 
ADAS-Cog13 
 
P b 
 
 
 
 
 
 
 
 
 
 
 
 
P 
 
 
 
 
 
P 
Verbal Fluency Task 
 
P b 
 
 
 
 
 
 
 
 
 
 
 
 
P 
 
 
 
 
 
P 
Coding 
 
P b 
 
 
 
 
 
 
 
 
 
 
 
 
P 
 
 
 
 
 
P 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
110/Protocol WN42171, Version 4 
Assessment/Procedure 
Screening 
BL 
 
OLE (week) 
UVa 
 
Including 
While in 
parent study 
to 1 Day 
OLE 
Day  
1 
OLE 
Day  
4 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
 
Dose number in the 
Study WN42171 
 
1 b 
 
2 
3 
4 
5 
6 
7 
8 
9 c 
10 c 11 c 12 c 13 d 14 c 15 c 16 c 17 c 18 c 
 
Dose level for participants 
previously on active 
 
510 mg Q2W 
 
Dose level for participants 
previously on placebo 
 
120 mg 
255 mg 
510 mg 
 
ADCS-ADL 
 
CG b 
 
 
 
 
 
 
 
 
 
 
 
 
CG 
 
 
 
 
 
CG 
FAQ 
 
CG b 
 
 
 
 
 
 
 
 
 
 
 
 
CG 
 
 
 
 
 
CG 
MMSE 
 
P b 
 
 
 
 
 
 
 
 
 
 
 
 
P 
 
 
 
 
 
P 
EQ-5D 
 
CG b 
 
 
 
 
 
 
 
 
 
 
 
 
CG 
 
 
 
 
 
CG 
QoL-AD 
 
P& 
CG b 
 
 
 
 
 
 
 
 
 
 
 
 
P&
CG 
 
 
 
 
 
P& 
CG 
ZCI-AD 
 
CG b 
 
 
 
 
 
 
 
 
 
 
 
 
CG 
 
 
 
 
 
CG 
RUD-Lite 
 
CG b 
 
 
 
 
 
 
 
 
 
 
 
 
CG 
 
 
 
 
 
CG 
NPI-Q 
 
CG b 
 
 
 
 
 
 
 
 
 
 
 
 
CG 
 
 
 
 
 
CG 
C-SSRS SLV 
 
P b 
 
 
 
 
 
 
 
 
 
 
 
 
P 
 
 
 
 
 
P 
Vital signs n 
 
B 
x 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events o 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine pregnancy test p 
 
B 
 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
B 
 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
111/Protocol WN42171, Version 4 
Assessment/Procedure 
Screening 
BL 
 
OLE (week) 
UVa 
 
Including 
While in 
parent study 
to 1 Day 
OLE 
Day  
1 
OLE 
Day  
4 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
 
Dose number in the 
Study WN42171 
 
1 b 
 
2 
3 
4 
5 
6 
7 
8 
9 c 
10 c 11 c 12 c 13 d 14 c 15 c 16 c 17 c 18 c 
 
Dose level for participants 
previously on active 
 
510 mg Q2W 
 
Dose level for participants 
previously on placebo 
 
120 mg 
255 mg 
510 mg 
 
Study drug  
administration q 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
112/Protocol WN42171, Version 4 
A  amyloid beta; ADA  anti-drug antibody; ADAS-Cog13  Alzheimer’s Disease Assessment ScaleCognition, Subscale 13; 
ADCS-ADL  Alzheimer’s Disease Cooperative Study GroupActivities of Daily Living; ARIA-E  amyloid-related imaging 
abnormalityedema/effusion; ARIA-H  amyloid-related imaging abnormalitymicrohemorrhage/hemosiderin deposition; BL  baseline; 
CDR  Clinical Dementia Rating; CSF  cerebrospinal fluid; C-SSRS  ColumbiaSuicide Severity Rating Scale; DTI  diffusion tensor imaging; 
eCRFelectronic Case Report Form; EQ-5D  EuroQol 5-Dimension Questionnaire; FAQ  Functional Activities Questionnaire; MMSE  Mini-Mental 
State Examination; MRI  magnetic resonance imaging; NPI-Q  Neuropsychiatric Inventory Questionnaire; OLE  open-label extension; 
PK  pharmacokinetic; Q2W  every 2 weeks; QoLAD  Quality of LifeAlzheimer's Disease; RUD-Lite  Resource Utilization in DementiaLite; 
SLV  since last visit; T4  thyroxine; UV  unscheduled visit; ZCI-AD  Zarit Caregiver Interview for Alzheimer’s Disease. 
B  before study drug administration; CG  caregiver completion; P  participant completion; P&CG  participant and caregiver completion. 
Notes:  The participant, the site, and the Sponsor will be kept blinded to the dose level given in order to keep the previous treatment assignment 
blinded.  The visit window is  3 days and  3 days for OLE non-dosing Day 4.  It is recommended that not more than 2 dosing visits are given 
(i.e., 2  510 mg Q2W) within 28 days.  Participants should return to initial planned schedule per baseline visit (OLE Day 1) for subsequent visits. 
a The relevant assessments will be determined by the Principal Investigator per clinical judgment, not necessary to include all assessments listed 
above.  An additional plasma and RNA blood sample for the assessment of exploratory biomarkers will be obtained as soon as practicable 
(e.g., at an unscheduled visit or the next study visit) following each MRI scan showing ARIA-E until and including ARIA-E resolution (i.e., new, 
worsened, stable, improved, resolved ARIA-E); following new or worsened ARIA-E. 
b Results of standard-of-care tests or examinations (coagulation, ECG, serum chemistry, and hematology; complete physical examination) 
performed within 4 weeks prior to Day 1 may be used.  MRI, C-SSRS, and cognitive scale results may be used if they have been performed at 
final efficacy and safety visit of the parent study and within 6 months prior to OLE Day 1.  MRI must have been performed after the last dose 
in the parent study.  If a clinical RNA sample or plasma biomarker or CSF and matching serum sample (where applicable) was collected at the 
final efficacy and safety visit of the parent study, another one does not have to be collected. 
c At applicable sites, administration of gantenerumab may be performed by a mobile nursing professional at the participant's home or another 
suitable location, such as a nursing center, to improve access and convenience for participants participating in the study. 
d Visit may be split over 2 consecutive days.  All cognitive and functional assessments should be completed first.  All safety assessments 
(e.g., vital signs, blood tests, and ECGs) should be completed on the day of dosing.  Whenever possible, cognitive and functional assessments 
should be performed at the visit timepoints stipulated in the schedule of activities.  However, in exceptional circumstances, if the caregiver, the 
primary rater, or even the participant cannot perform these assessments as per the schedule of activities, they may be performed up to 4 weeks 
out of window. 
e Height will be assessed only at the first dosing visit in Study WN42171. 
f Accurate recording of the date and time of study drug administration and PK sampling is critical.  A PK sample will be obtained as soon as 
practicable (e.g., at an unscheduled visit or the next study visit) following a MRI scan showing new occurrence or worsening of ARIAE or ARIA-
H that meets the discontinuation criteria (e.g., during an unscheduled visit). 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
113/Protocol WN42171, Version 4 
g Serum chemistry includes AST, ALT, ALP, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, potassium, calcium, 
BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).  Hemoglobin A1c, glucose, insulin, total cholesterol, 
HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin B-12, T4, free T4, and thyroid-stimulating hormone levels will also be assessed 
and should ideally be collected at least 4 hours after a meal. 
h Hematology includes WBC count, RBC count (with morphology), hemoglobin, hematocrit, platelet count, and differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). 
i A complete physical examination, performed at specified visits, should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems; genitourinary examinations may be 
performed if clinically indicated. 
j Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes. 
k MRI should be performed at least 7 days before dosing, and results must be available for review by site staff before dosing can proceed.  MRI 
should be performed before or at least 3 days following a lumbar puncture. 
l Includes resting-state functional MRI and DTI outcome measures, where available. 
m Lumbar puncture will be performed only in participants who were randomized in Studies WN29922 or WN39658 based on CSF A and tau level 
results.  It must be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal variation of CSF parameters and should 
be performed prior to dosing (if applicable). 
n Vital signs include measurements of pulse rate, respiratory rate, systolic and diastolic blood pressure while the participant is in a seated position, 
and temperature.  Blood pressure and pulse rate should be taken when the participant is at rest and should not be measured unless at least 
15 minutes have elapsed since the last blood draw.  The same arm should be used for all blood pressure measurements.  Pulse rate will be 
determined and will be recorded as beats per minute.  If obtained manually, the pulse rate should be counted for a minimum of 20 seconds at 
each assessment. 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
114/Protocol WN42171, Version 4 
o After informed consent has been obtained, all adverse events occurring while the participant is in the parent Study WN29922 or WN39658 will 
be reported on the parent Adverse Event eCRF until the participant’s final visit/last assessment in the parent study.  After the participant’s final 
visit/last assessment in the parent Study WN29922 or WN39658, all adverse events will be reported on the WN42171 Adverse Event eCRF until 
the participant’s final visit (including long-term follow-up visits). 
p Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to 
each dose administration.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.  
Results are to be recorded only in the source documents. 
q Study drug administration should be performed only after all assessments and rating scales for the participant are completed (unless indicated 
otherwise).  Study drug will be administered to participants by SC injection (full details are provided in the pharmacy manual).  Participants 
should be observed for at least 2 hours after the first 8 dosing visits.  From the ninth dose, this observation time may be reduced to 1 hour.  
Study personnel preparing and administering study drug must not be involved with any efficacy assessments or safety evaluations. 
r If deemed necessary by the investigator, urinalysis may be performed at the site by dipstick for blood, protein, glucose, and pH.  Microscopic 
examination will be performed by the central laboratory if blood and/or protein results are positive or strongly positive. 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
115/Protocol WN42171, Version 4 
Table 2 
Schedule of Activities for Participants Who Have Completed Uptitration in Study WN42171 
(continuation of Table 1) 
Assessment/Procedure 
Treatment Period 
Early 
Term 
Visit c 
UV a 
 
OLE (week) 
Study schedule 
36   
38 b 
40 b 
41 
4250 b 
52 c 
5474 b 
76 c 
78102 b 
103 
 
 
Dose number in the 
Study WN42171 
19 
20 
21 
 
2226 
27 
2838 
39 
4052 
 
 
 
Dose level in milligrams (mg)  
510 Q2W 
Weight  
 
 
 
 
 
x 
 
x 
 
 
x 
x 
Clinical RNA samples 
 
 
 
 
 
 
 
 
 
 
x 
x 
12-Lead ECG 
 
 
 
 
 
 
 
 
 
 
x 
x 
Plasma PK sample d 
 
 
 
x 
(Site 
visit) 
 
B 
 
B 
 
x  
(Site 
visit) 
x 
x 
Plasma ADA sample 
 
 
 
 
 
B 
 
B 
 
 
x 
x 
Serum chemistry e and 
hematology f 
 
 
 
 
 
x 
 
x 
 
 
x 
x 
Plasma biomarker sample 
 
 
 
 
 
x 
 
 
 
 
x 
x 
Complete physical 
examination (includes 
neurologic systems) g 
 
 
 
 
 
 
 
 
 
 
x 
x 
Limited physical examination h 
B 
 
 
 
 
B 
 
B 
 
 
 
x  
MRI scan i 
B 
 
 
 
B 
W48 j 
 
 
B 
 
 
x j 
x 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
116/Protocol WN42171, Version 4 
Assessment/Procedure 
Treatment Period 
Early 
Term 
Visit c 
UV a 
 
OLE (week) 
Study schedule 
36   
38 b 
40 b 
41 
4250 b 
52 c 
5474 b 
76 c 
78102 b 
103 
 
 
Dose number in the 
Study WN42171 
19 
20 
21 
 
2226 
27 
2838 
39 
4052 
 
 
 
Dose level in milligrams (mg)  
510 Q2W 
CSF and matching serum 
samples k 
 
 
 
 
 
x 
 
 
 
 
x 
 
CDR  
 
 
 
 
 
P&CG 
 
P&CG 
 
 
P&CG 
P&CG 
ADAS-Cog13 
 
 
 
 
 
P 
 
P 
 
 
P 
P 
Verbal Fluency Task 
 
 
 
 
 
P 
 
P 
 
 
P 
P 
Coding 
 
 
 
 
 
P 
 
P 
 
 
P 
P 
ADCS-ADL 
 
 
 
 
 
CG 
 
CG 
 
 
CG 
CG 
FAQ 
 
 
 
 
 
CG 
 
CG 
 
 
CG 
CG 
MMSE 
 
 
 
 
 
P 
 
P 
 
 
P 
P 
EQ-5D 
 
 
 
 
 
CG 
 
CG 
 
 
CG 
CG 
QoL-AD 
 
 
 
 
 
P&CG 
 
P&CG 
 
 
P&CG 
P&CG 
ZCI-AD 
 
 
 
 
 
CG 
 
CG 
 
 
CG 
CG 
RUD-Lite 
 
 
 
 
 
CG 
 
CG 
 
 
CG 
CG 
NPI-Q 
 
 
 
 
 
CG 
 
CG 
 
 
CG 
CG 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
117/Protocol WN42171, Version 4 
Assessment/Procedure 
Treatment Period 
Early 
Term 
Visit c 
UV a 
 
OLE (week) 
Study schedule 
36   
38 b 
40 b 
41 
4250 b 
52 c 
5474 b 
76 c 
78102 b 
103 
 
 
Dose number in the 
Study WN42171 
19 
20 
21 
 
2226 
27 
2838 
39 
4052 
 
 
 
Dose level in milligrams (mg)  
510 Q2W 
C-SSRS SLV 
 
 
 
 
 
P 
 
P 
 
 
P 
P 
Vital signs l 
B 
B 
B 
B 
B 
B 
B 
B 
B 
 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events m 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine pregnancy test n 
B 
B 
B 
 
B 
B 
B 
B 
B 
 
x 
x 
Study drug administration o  
x 
x 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
118/Protocol WN42171, Version 4 
 
A  amyloid beta; ADA  anti-drug antibody; ADAS-Cog13  Alzheimer’s Disease Assessment ScaleCognition, Subscale 13; 
ADCS-ADL  Alzheimer’s Disease Cooperative Study GroupActivities of Daily Living; ARIA-E  amyloid-related imaging 
abnormalityedema/effusion; ARIA-H  amyloid-related imaging abnormalitymicrohemorrhage/hemosiderin deposition; Assess  assessment; 
CDR  Clinical Dementia Rating; CSF  cerebrospinal fluid; C-SSRS  ColumbiaSuicide Severity Rating Scale; DTI  diffusion tensor imaging; 
eCRF  electronic Case report Form; EQ-5D  EuroQol-5 Dimension Questionnaire; FAQ  Functional Activities Questionnaire; MMSE  Mini-
Mental State Examination; MRI  magnetic resonance imaging; NPI-Q  Neuropsychiatric Inventory Questionnaire; OLE  open-label extension; 
PK  pharmacokinetic; Q2W  every 2 weeks; QoL-AD  Quality of LifeAlzheimer's Disease; RUD-Lite  Resource Utilization in DementiaLite; 
T4  thyroxine; Term  termination; UV  unscheduled visit; ZCI-AD  Zarit Caregiver Interview for Alzheimer’s Disease. 
B  before study drug administration; CG  caregiver completion; P  participant completion; P&CG  participant and caregiver completion. 
Notes:  The visit window is  3 days.  It is recommended that not more than 2 doses are given (i.e., 2  510 mg Q2W) within 28 days.  
Participants should return to initial planned schedule for subsequent visits. 
a The relevant assessments will be determined by the Principal Investigator per clinical judgment, not necessary to include all assessments 
listed above.  An additional plasma and RNA blood sample for the assessment of exploratory biomarkers will be obtained as soon as 
practicable (e.g., at an unscheduled visit or the next study visit) following each MRI scan showing ARIA-E until and including ARIA-E 
resolution (i.e., new, worsened, stable, improved, resolved ARIA-E); following new or worsened ARIA-E. 
b At applicable sites, administration of gantenerumab may be performed by a mobile nursing professional at the participant's home or another 
suitable location, such as a nursing center, to improve access and convenience for participants participating in the study. 
c Visit may be split over 2 consecutive days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., 
vital signs, blood tests, and ECGs) should be completed on the day of dosing.  Whenever possible, cognitive and functional assessments 
should be performed at the visit timepoints stipulated in the schedule of activities.  However, in exceptional circumstances, if the caregiver, the 
primary rater, or even the participant cannot perform these assessments as per the schedule of activities, they may be performed up to 
4 weeks out of window. 
d Accurate recording of the date and time of study drug administration and PK sampling is critical.  A PK sample will be obtained as soon as 
practicable (e.g., at an unscheduled visit or the next study visit) following a MRI scan showing new occurrence or worsening of ARIA-E or 
ARIA-H that meets the discontinuation criteria (e.g., during an unscheduled visit). 
e Serum chemistry includes AST, ALT, ALP, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, potassium, calcium, 
BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).  Hemoglobin A1c, glucose, insulin, total cholesterol, 
HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin B-12, T4, free T4, and thyroid-stimulating hormone levels will also be assessed 
and should ideally be collected at least 4 hours after a meal. 
f Hematology includes WBC count, RBC count (with morphology), hemoglobin, hematocrit, platelet count, and differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
119/Protocol WN42171, Version 4 
g A complete physical examination, performed at specified visits, should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems; genitourinary examinations may be 
performed if clinically indicated. 
h Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes. 
i MRI should be performed at least 7 days before dosing and results must be available for review by site staff before dosing can proceed.  MRI 
should be performed before or at least 3 days following a lumbar puncture. 
j Includes resting-state functional MRI and DTI outcome measures, where available. 
k Lumbar puncture will be performed only in participants who were randomized in the WN29922 or WN39658 studies based on CSF A and tau 
level results.  It must be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal variation of CSF parameters 
and should be performed prior to dosing (if applicable). 
l Vital signs include measurements of pulse rate, respiratory rate, systolic and diastolic blood pressure while the participant is in a seated 
position, and temperature.  Blood pressure and pulse rate should be taken when the participant is at rest and should not be measured unless 
at least 15 minutes have elapsed since the last blood draw.  The same arm should be used for all blood pressure measurements.  Pulse rate 
will be determined and will be recorded as beats per minute.  If obtained manually, the pulse rate should be counted for a minimum of 20 
seconds at each assessment. 
m After informed consent has been obtained, all adverse events occurring while the participant is in the parent Study WN29922 or WN39658 will 
be reported on the parent Adverse Event eCRF until the participant’s final visit/last assessment in the parent study.  After the participant’s final 
visit/last assessment in the parent Study WN29922 or WN39658 all adverse events will be reported on the Study WN42171 Adverse Event 
eCRF until the participant’s final visit (including long-term follow-up visits). 
n Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior 
to each dose administration.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.  
Results are to be recorded only in the source documents. 
o Study drug administration should be performed only after all assessments and rating scales for the participant are completed (unless indicated 
otherwise).  Study drug will be administered to participants by SC injection (full details are provided in the pharmacy manual).  Participants 
should be observed for at least 1 hour after dosing.  Study personnel preparing and administering study drug must not be involved with any 
efficacy assessments or safety evaluations. 
 
 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
120/Protocol WN42171, Version 4 
Table 3 
Schedule of Activities for Participants Who Have Completed the OLE Part of Parent Study WN29922 or 
WN39658 
Assessment/ 
Procedure 
Screening 
Treatment Period 
Early 
Term. 
Visit c 
UV a 
 
 
OLE (week) 
 
 
Study schedule  
Including 
while in 
parent study 
to  1 day 
before first 
dosing visit 
36 
38 b 40 b 
41 
42 
50 b 
52 c 
54 
74 b 
76 c 
78 
102 b 
103 
 
 
Dose number in the 
Study WN42171 
 
1 
2 
3 
 
48 
9 
1020 
21 
22 
34 
 
 
 
Dose level in milligrams 
(mg) 
 
510 Q2W 
Informed consent(s)  
x 
 
 
 
 
 
 
 
 
 
 
 
 
Review of inclusion and 
exclusion criteria 
x 
B e 
 
 
 
 
 
 
 
 
 
 
 
Medical history, personal 
status, and demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and height d 
 
x e 
 
 
 
 
x 
 
x 
 
 
x 
x 
Clinical RNA samples 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Urinalysis 
 
x r 
 
 
 
 
 
 
 
 
 
 
 
Coagulation (PT) 
 
B e 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
 
B e 
 
 
 
 
 
 
 
 
 
x 
x 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
121/Protocol WN42171, Version 4 
Assessment/ 
Procedure 
Screening 
Treatment Period 
Early 
Term. 
Visit c 
UV a 
 
 
OLE (week) 
 
 
Study schedule  
Including 
while in 
parent study 
to  1 day 
before first 
dosing visit 
36 
38 b 40 b 
41 
42 
50 b 
52 c 
54 
74 b 
76 c 
78 
102 b 
103 
 
 
Dose number in the 
Study WN42171 
 
1 
2 
3 
 
48 
9 
1020 
21 
22 
34 
 
 
 
Dose level in milligrams 
(mg) 
 
510 Q2W 
Plasma PK sample f 
 
B 
 
 
x 
(Site 
visit) 
 
B 
 
B 
 
x (Site 
visit) 
x 
x  
Plasma ADA sample 
 
B 
 
 
 
 
B 
 
B 
 
 
x 
x 
Serum chemistry g and 
hematology h 
 
B e 
 
 
 
 
x 
 
x 
 
 
x 
x 
Plasma biomarker sample 
 
 
 
 
 
 
x 
 
 
 
 
x 
x 
Complete physical 
examination (includes 
neurologic systems) i 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Limited physical 
examination j 
 
B e 
 
 
 
 
B 
 
B 
 
 
 
x 
MRI scan k 
 
B e, l 
 
 
 
B 
W48 l 
 
 
B 
 
 
x i 
x 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
122/Protocol WN42171, Version 4 
Assessment/ 
Procedure 
Screening 
Treatment Period 
Early 
Term. 
Visit c 
UV a 
 
 
OLE (week) 
 
 
Study schedule  
Including 
while in 
parent study 
to  1 day 
before first 
dosing visit 
36 
38 b 40 b 
41 
42 
50 b 
52 c 
54 
74 b 
76 c 
78 
102 b 
103 
 
 
Dose number in the 
Study WN42171 
 
1 
2 
3 
 
48 
9 
1020 
21 
22 
34 
 
 
 
Dose level in milligrams 
(mg) 
 
510 Q2W 
CSF and matching serum 
samples m 
 
 
 
 
 
 
x 
 
 
 
 
x 
 
CDR  
 
P&CG e 
 
 
 
 
P&CG 
 
P&CG 
 
 
P&CG 
P&CG 
ADAS-Cog13 
 
P e 
 
 
 
 
P 
 
P 
 
 
P 
P 
Verbal Fluency Task 
 
P e 
 
 
 
 
P 
 
P 
 
 
P 
P 
Coding 
 
P e 
 
 
 
 
P 
 
P 
 
 
P 
P 
ADCS-ADL 
 
CG e 
 
 
 
 
CG 
 
CG 
 
 
CG 
CG 
FAQ 
 
CG e 
 
 
 
 
CG 
 
CG 
 
 
CG 
CG 
MMSE 
 
P e 
 
 
 
 
P 
  
P 
 
 
P 
P 
EQ-5D 
 
CG e 
 
 
 
 
CG 
 
CG 
 
 
CG 
CG 
QoL-AD 
 
P&CG e 
 
 
 
 
P&CG 
 
P&CG 
 
 
P&CG 
P&CG 
ZCI-AD 
 
CG e 
 
 
 
 
CG 
 
CG 
 
 
CG 
CG 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
123/Protocol WN42171, Version 4 
Assessment/ 
Procedure 
Screening 
Treatment Period 
Early 
Term. 
Visit c 
UV a 
 
 
OLE (week) 
 
 
Study schedule  
Including 
while in 
parent study 
to  1 day 
before first 
dosing visit 
36 
38 b 40 b 
41 
42 
50 b 
52 c 
54 
74 b 
76 c 
78 
102 b 
103 
 
 
Dose number in the 
Study WN42171 
 
1 
2 
3 
 
48 
9 
1020 
21 
22 
34 
 
 
 
Dose level in milligrams 
(mg) 
 
510 Q2W 
RUD-Lite 
 
CG e 
 
 
 
 
CG 
 
CG 
 
 
CG 
CG 
NPI-Q 
 
CG e 
 
 
 
 
CG 
 
CG 
 
 
CG 
CG 
C-SSRS SLV 
 
P e 
 
 
 
 
P 
 
P 
 
 
P 
P 
Vital signs n 
 
B 
B 
B 
B 
B 
B 
B 
B 
B 
 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events o 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine pregnancy test p 
 
B 
B 
B 
 
B 
B 
B 
B 
B 
 
x 
x 
Study drug administration q 
 
x 
x 
x 
 
x 
x 
x 
x 
x 
 
 
 
 
 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
124/Protocol WN42171, Version 4 
ADAS-Cog13  Alzheimer’s Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL  Alzheimer Disease Cooperative Study 
GroupActivities of Daily Living; ARIA-E  amyloid-related imaging abnormalityedema/effusion; ARIA-H  amyloid-related imaging 
abnormalitymicrohemorrhage/hemosiderin deposition; assess  assessment; CDR  Clinical Dementia Rating; CSF  cerebrospinal fluid; 
C-SSRS  ColumbiaSuicide Severity Rating Scale; DTI  diffusion tensor imaging; eCRF  electronic Case Report Form; EQ-5D  EuroQol-Five 
Dimensions; FAQ  Functional Activities Questionnaire; FU  follow-up; MMSE  Mini-Mental State Examination; MRI  magnetic resonance 
imaging; NPI-Q  Neuropsychiatric Inventory Questionnaire; PK  pharmacokinetic; Q2W  every 2 weeks; QoLAD  Quality of LifeAlzheimer's 
Disease; RUD-Lite  Resource Utilization in DementiaLite; term  termination; UV  unscheduled visit; ZCI-AD  Zarit Caregiver Interview for 
Alzheimer’s Disease. 
B  before study drug administration; CG  caregiver completion P  participant completion; P&CG  participant and caregiver completion. 
Notes:  The visit window is  3 days and  3 days for OLE non-dosing Day 4.  It is recommended that not more than 2 administrations are given 
(i.e., 2  510 mg Q2W) within 28 days.  Participants should return to initial planned schedule per randomization for subsequent visits. 
For participants for whom the uptitration in the parent study took longer than 34 weeks to complete, the first visit in Study WN42171 will be 
adapted according to the schedule of the visits they had in the parent study. 
 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
125/Protocol WN42171, Version 4 
a The relevant assessments will be determined by the Principal Investigator per clinical judgment, not necessary to include all assessments listed 
above.  An additional plasma and RNA blood sample for the assessment of exploratory biomarkers will be obtained as soon as practicable 
(e.g., at an unscheduled visit or the next study visit) following each MRI scan showing ARIA-E until and including ARIA-E resolution (i.e., new, 
worsened, stable, improved, resolved ARIA-E); following new or worsened ARIA-E. 
b At applicable sites, administration of gantenerumab may be performed by a mobile nursing professional at the participant's home or another 
suitable location, such as a nursing center, to improve access and convenience for participants participating in the study. 
c Visit may be split over 2 consecutive days.  All cognitive and functional assessments should be completed first.  All safety assessments 
(e.g., vital signs, blood tests, and ECGs) should be completed on the day of dosing.  Whenever possible, cognitive and functional assessments 
should be performed at the visit timepoints stipulated in the schedule of activities.  However, in exceptional circumstances, if the caregiver, the 
primary rater, or even the participant cannot perform these assessments as per schedule of activities they may be performed up to 4 weeks out 
of window. 
d Height will be assessed only at the first dosing visit in Study WN42171. 
e Only for participants who participated in the OLE part of the parent study who are rolling over to this study:  Results of standard-of-care tests or 
examinations (coagulation, ECG, serum chemistry and hematology, complete physical examination) performed in the parent studies within 
4 weeks prior to the visit may be used.  MRI, C-SSRS, and cognitive scale results may be used if they have been performed within 6 months 
prior to the first dosing visit.  MRI must have been performed after the last dose in the parent study. 
f Accurate recording of the date and time of study drug administration and PK sampling is critical.  A PK sample will be obtained as soon as 
practicable (e.g., at an unscheduled visit or the next study visit) following a MRI scan showing new occurrence or worsening of ARIA-E or 
ARIA-H that meets the discontinuation criteria (e.g., during an unscheduled visit). 
g Serum chemistry includes AST, ALT, ALP, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, potassium, calcium, 
BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).  Hemoglobin A1c, glucose, insulin, total cholesterol, 
HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin B-12, T4, free T4, and thyroid-stimulating hormone levels will also be assessed 
and should ideally be collected at least 4 hours after a meal. 
h Hematology includes WBC count, RBC count (with morphology), hemoglobin, hematocrit, platelet count, and differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). 
i A complete physical examination, performed at specified visits, should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems; genitourinary examinations may be 
performed if clinically indicated. 
j Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes. 
k MRI should be performed at least 7 days before dosing, and results must be available for review by site staff before dosing can proceed.  MRI 
should be performed before or at least 3 days following a lumbar puncture. 
l Includes resting-state functional MRI and DTI outcome measures, where available. 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
126/Protocol WN42171, Version 4 
m Lumbar puncture will be performed only in participants who were randomized in Studies WN29922 or WN39658 based on CSF A and 
tau level results.  It must be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal variation of CSF parameters 
and should be performed prior to dosing (if applicable). 
n Vital signs include measurements of pulse rate, respiratory rate, systolic and diastolic blood pressure while the participant is in a seated 
position, and temperature.  Blood pressure and pulse rate should be taken when the participant is at rest and should not be measured unless at 
least 15 minutes have elapsed since the last blood draw.  The same arm should be used for all blood pressure measurements.  Pulse rate will 
be determined and will be recorded as beats per minute.  If obtained manually, the pulse rate should be counted for a minimum of 20 seconds 
at each assessment. 
o After informed consent has been obtained, all adverse events occurring while the participant is in the parent study WN29922 or WN39658 will 
be reported on the parent Adverse Event eCRF until the participant’s final visit/last assessment in the parent study.  After the participant’s final 
visit/last assessment in the parent study WN29922 or WN39658 all adverse events will be reported on the Study WN42171 Adverse Event 
eCRF until the participant’s final visit (including long-term follow-up visits). 
p Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to 
each dose administration.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.  
Results are to be recorded only in the source documents. 
q Study drug administration should be performed only after all assessments and rating scales for the participant are completed (unless indicated 
otherwise).  Study drug will be administered to participants by SC injection (full details are provided in the pharmacy manual).  Participants 
should be observed for at least 1 hour after dosing.  Study personnel preparing and administering study drug must not be involved with any 
efficacy assessments or safety evaluations. 
r If deemed necessary by the investigator, urinalysis may be performed at the site by dipstick for blood, protein, glucose, and pH.  Microscopic 
examination will be performed by the central laboratory if blood and/or protein results are positive or strongly positive. 
 
 
 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
127/Protocol WN42171, Version 4 
Table 4 
Schedule of Activities for Participants Who Have Completed Uptitration in Study WN42171 
(2-year extension) 
 
Assessment/ 
Procedure 
Treatment Period 
Final Safety and 
Efficacy 
Assessment 
Follow-
Up 
Period 
Early 
Term. 
Visit 
UV a 
 
OLE (week) 
 
 
 
 
Study schedule 
104 c 
106 
128 b 
130 c 
132 
154 b 
156 c 
158 
180 b 
182 c 
184 
204 b 
206 b 
208 c 
220 
 
 
Dose number in 
Study WN42171 
53 
5465 
66 
6778 
79 
8091 
92 
93103 
104 
 
 
 
 
Dose level in 
milligrams (mg) 
510 Q2W 
Weight 
x 
 
x 
 
x 
 
x 
 
 
x 
x 
x 
x 
Clinical RNA 
samples 
x 
 
 
 
 
 
 
 
 
x 
 
x 
x 
12-lead ECG 
x 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Coagulation (PT) 
B 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 
sample d 
 
 
 
 
B 
 
 
 
 
x 
x 
x 
x 
Plasma ADA 
sample 
B 
 
 
 
B 
 
 
 
 
x 
x 
x 
x 
Serum chemistry e 
and hematology f 
x 
 
x 
 
x 
 
x 
 
 
x 
x 
x 
x 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
128/Protocol WN42171, Version 4 
Assessment/ 
Procedure 
Treatment Period 
Final Safety and 
Efficacy 
Assessment 
Follow-
Up 
Period 
Early 
Term. 
Visit 
UV a 
 
OLE (week) 
 
 
 
 
Study schedule 
104 c 
106 
128 b 
130 c 
132 
154 b 
156 c 
158 
180 b 
182 c 
184 
204 b 
206 b 
208 c 
220 
 
 
Dose number in 
Study WN42171 
53 
5465 
66 
6778 
79 
8091 
92 
93103 
104 
 
 
 
 
Dose level in 
milligrams (mg) 
510 Q2W 
Plasma biomarker 
sample 
x 
 
 
 
x 
 
 
 
 
x 
 
x 
x 
Complete physical 
examination 
(includes 
neurologic 
systems) g 
B 
 
 
 
 
 
 
 
 
x 
 
x 
x 
Limited physical 
examination h 
 
 
B 
 
B 
 
B 
 
 
 
 
 
x 
MRI scan i 
B j 
 
B 
 
B j 
 
B  
 
 
x j 
 
x j 
x 
CSF and 
matching serum 
samples k 
x 
 
 
 
x 
 
 
 
 
x 
 
x 
 
CDR 
P&CG 
 
P&CG 
 
P&CG 
 
P&CG 
 
 
P&CG 
 
P&CG 
P&CG 
ADAS-Cog13 
P 
 
P 
 
P 
 
P 
 
 
P 
 
P 
P 
Verbal Fluency 
Task 
P 
 
P 
 
P 
 
P 
 
 
P 
 
P 
P 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
129/Protocol WN42171, Version 4 
Assessment/ 
Procedure 
Treatment Period 
Final Safety and 
Efficacy 
Assessment 
Follow-
Up 
Period 
Early 
Term. 
Visit 
UV a 
 
OLE (week) 
 
 
 
 
Study schedule 
104 c 
106 
128 b 
130 c 
132 
154 b 
156 c 
158 
180 b 
182 c 
184 
204 b 
206 b 
208 c 
220 
 
 
Dose number in 
Study WN42171 
53 
5465 
66 
6778 
79 
8091 
92 
93103 
104 
 
 
 
 
Dose level in 
milligrams (mg) 
510 Q2W 
Coding 
P 
 
P 
 
P 
 
P 
 
 
P 
 
P 
P 
ADCS-ADL 
CG 
 
CG 
 
CG 
 
CG 
 
 
CG 
 
CG 
CG 
FAQ 
CG 
 
CG 
 
CG 
 
CG 
 
 
CG 
 
CG 
CG 
MMSE 
P 
 
P 
 
P 
 
P 
 
 
P 
 
P 
P 
EQ-5D 
CG 
 
 
 
CG 
 
 
 
 
CG 
 
CG 
CG 
QoL-AD 
P&CG 
 
 
 
P&CG 
 
 
 
 
P&CG 
 
P&CG 
P&CG 
ZCI-AD 
CG 
 
 
 
CG 
 
 
 
 
CG 
 
CG 
CG 
RUD-Lite 
CG 
 
 
 
CG 
 
 
 
 
CG 
 
CG 
CG 
NPI-Q 
CG 
 
 
 
CG 
 
 
 
 
CG 
 
CG 
CG 
C-SSRS SLV 
P 
 
P 
 
P 
 
P 
 
 
P 
 
P 
P 
Vital signs l 
B 
B 
B 
B 
B 
B 
B 
B 
B 
x 
x 
x 
x 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events m 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
130/Protocol WN42171, Version 4 
Assessment/ 
Procedure 
Treatment Period 
Final Safety and 
Efficacy 
Assessment 
Follow-
Up 
Period 
Early 
Term. 
Visit 
UV a 
 
OLE (week) 
 
 
 
 
Study schedule 
104 c 
106 
128 b 
130 c 
132 
154 b 
156 c 
158 
180 b 
182 c 
184 
204 b 
206 b 
208 c 
220 
 
 
Dose number in 
Study WN42171 
53 
5465 
66 
6778 
79 
8091 
92 
93103 
104 
 
 
 
 
Dose level in 
milligrams (mg) 
510 Q2W 
Urine pregnancy 
test n 
B 
B 
B 
B 
B 
B 
B 
B 
B 
x 
x 
x 
x 
Study drug 
administration o 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
A  amyloid beta; ADA  anti-drug antibody; ADAS-Cog13  Alzheimer’s Disease Assessment Scale−Cognition, Subscale 13; ADCS-
ADL  Alzheimer’s Disease Cooperative Study Group−Activities of Daily Living; ARIA-E  amyloid-related imaging abnormality−edema/effusion; 
ARIA-H  amyloid-related imaging abnormality−microhemorrhage/hemosiderin deposition; Assess   assessment; B  before study drug administration; 
CDR  Clinical Dementia Rating; CG  caregiver completion; CSF  cerebrospinal fluid; C-SSRS  Columbia−Suicide Severity Rating Scale; 
DTI  diffusion tensor imaging; eCRF  electronic Case report Form; EQ-5D  EuroQol-5 Dimension Questionnaire; FAQ  Functional Activities 
Questionnaire; MMSE  Mini-Mental State Examination; MRI  magnetic resonance imaging; NPI-Q  Neuropsychiatric Inventory Questionnaire; 
OLE  open-label extension; P&CG  participant and caregiver completion; P   participant completion; PK  pharmacokinetic; Q2W  every 2 weeks; 
QoL-AD  Quality of Life−Alzheimer's Disease; RUD-Lite  Resource Utilization in Dementia−Lite; T4   thyroxine; Term  termination; 
UV  unscheduled visit; ZCI-AD  Zarit Caregiver Interview for Alzheimer’s Disease. 
Notes:  The visit window is  3 days.  It is recommended that not more than 2 doses are given (i.e., 2   510 mg Q2W) within 28 days.  Participants 
should return to initial planned schedule per randomization for subsequent visits.  


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
131/Protocol WN42171, Version 4 
a The relevant assessments will be determined by the Principal Investigator per clinical judgment, not necessary to include all assessments listed 
above.  An additional plasma and RNA blood sample for the assessment of exploratory biomarkers will be obtained as soon as pr acticable (e.g., at an 
unscheduled visit or the next study visit) following each MRI scan showing ARIA-E until and including ARIA-E resolution (i.e., new, worsened, 
stable, improved, resolved ARIA-E); following new or worsened ARIA-E. 
b At applicable sites, administration of gantenerumab may be performed by a mobile nursing professional at the participant's home or another suitable 
location, such as a nursing center, to improve access and convenience for participants participating in the study.  
c Visit may be split over 2 consecutive days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vital 
signs, blood tests, and ECGs) should be completed on the day of dosing.  Whenever possible, cognitive and functional assessme nts should be 
performed at the visit timepoints stipulated in the schedule of activities.  However, in exceptional circumstances, if the caregiver, the primary rat er, 
or even the participant cannot perform these assessments as per the schedule of activities, they may be performed up to 4 wee ks out of window. 
d Accurate recording of the date and time of study drug administration and PK sampling is critical.  A PK sample will be obtain ed as soon as 
practicable (e.g., at an unscheduled visit or the next study visit) following a MRI scan showing ne w occurrence or worsening of ARIA-E or ARIA-H 
that meets the discontinuation criteria (e.g., during an unscheduled visit). 
e Serum chemistry includes AST, ALT, ALP, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, potass ium, calcium, 
BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).  Hemoglobin A1c, glucose, insulin,  total cholesterol, 
HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin B-12, T4, free T4, and thyroid-stimulating hormone levels will also be assessed and 
should ideally be collected at least 4 hours after a meal. 
f Hematology includes WBC count, RBC count (with morphology), hemoglobin, hematocrit, platelet count, and differential count (n eutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells). 
g A complete physical examination, performed at specified visits, should include an evaluation of the head, eyes, ears, nose, a nd throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems; genitourinary examinations may be performed 
if clinically indicated. 
h Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  
i MRI should be performed at least 7 days before dosing and results must be available for review by site staff before dosing can proceed.  MRI  should 
be performed before or at least 3 days following a lumbar puncture. 
j Includes resting-state functional MRI and DTI outcome measures, where available. 
k Lumbar puncture will be performed only in participants who were randomized in the WN29922 or WN39658 studies based on CSF Aβ and tau level 
results.  It must be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal variation of CSF parameters and should 
be performed prior to dosing (if applicable). 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
132/Protocol WN42171, Version 4 
l Vital signs include measurements of pulse rate, respiratory rate, systolic and diastolic blood pressure while the participant  is in a seated position, 
and temperature.  Blood pressure and pulse rate should be taken when the participant is at rest and should not be measured un less at least 15 
minutes have elapsed since the last blood draw.  The same arm should be used for all blood pressure measurements.  Pulse rate will be determined 
and will be recorded as beats per minute.  If obtained manually, the pulse rate should be counted for a minimum of 20 seconds  at each assessment. 
m After informed consent has been obtained, all adverse events occurring while the participant is in the parent Study WN29922 or WN39658 will be 
reported on the parent Adverse Event eCRF until the participant’s final visit/last assessment in the parent study.  After the  participant’s final 
visit/last assessment in the parent Study WN29922 or WN39658 all adverse events will be reported on the Study WN42171 Adverse Event eCRF 
until the participant’s final visit (including long-term follow-up visits). 
n Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to 
each dose administration.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the centr al laboratory.  Results 
are to be recorded only in the source documents. 
o Study drug administration should be performed only after all assessments and rating scales for the participant are completed (unless indicated 
otherwise).  Study drug will be administered to participants by SC injection (full details are provided in t he pharmacy manual).  Participants 
should be observed for at least 1 hour after dosing.  Study personnel preparing and administering study drug must not be invo lved with any efficacy 
assessments or safety evaluations. 
 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
133/Protocol WN42171, Version 4 
Table 5 
Schedule of Activities for Participants Who Have Completed the OLE Part of Parent Study WN29922 
or WN39658 (2-Year Extension) 
Assessment/ 
Procedure 
Treatment Period 
Final Safety and 
Efficacy 
Assessment 
Follow-
Up 
Period 
Early 
Term. 
Visit 
UV a 
 
OLE (week) 
 
 
 
 
Study schedule 
104 c 
106 
128 b 
130 c 
132 
154 b 
156 c 
158 
180 b 
182 c 
184 
204 b 
206 b 
208 c 
220 
 
 
Dose number in 
Study WN42171 
35 
3647 
48 
4960 
61 
6273 
74 
7585 
86 
 
 
 
 
Dose level in 
milligrams (mg) 
510 Q2W 
Weight 
x 
 
x 
 
x 
 
x 
 
 
x 
x 
x 
x 
Clinical RNA 
samples 
x 
 
 
 
 
 
 
 
 
x 
 
x 
x 
12-lead ECG 
x 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Coagulation (PT) 
B 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK 
sample d 
 
 
 
 
B 
 
 
 
 
x 
x 
x 
x 
Plasma ADA 
sample 
B 
 
 
 
B 
 
 
 
 
x 
x 
x 
x 
Serum 
chemistry e and 
hematology f 
x 
 
x 
 
x 
 
x 
 
 
x 
x 
x 
x 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
134/Protocol WN42171, Version 4 
Assessment/ 
Procedure 
Treatment Period 
Final Safety and 
Efficacy 
Assessment 
Follow-
Up 
Period 
Early 
Term. 
Visit 
UV a 
 
OLE (week) 
 
 
 
 
Study schedule 
104 c 
106 
128 b 
130 c 
132 
154 b 
156 c 
158 
180 b 
182 c 
184 
204 b 
206 b 
208 c 
220 
 
 
Dose number in 
Study WN42171 
35 
3647 
48 
4960 
61 
6273 
74 
7585 
86 
 
 
 
 
Dose level in 
milligrams (mg) 
510 Q2W 
Plasma biomarker 
sample 
x 
 
 
 
x 
 
 
 
 
x 
 
x 
x 
Complete 
physical 
examination 
(includes 
neurologic 
systems) g 
B 
 
 
 
 
 
 
 
 
x 
 
x 
x 
Limited physical 
examination h 
 
 
B 
 
B 
 
B 
 
 
 
 
 
x 
MRI scan i 
B j 
 
B 
 
B j 
 
B  
 
 
x j 
 
x j 
x 
CSF and 
matching serum 
samples k 
x 
 
 
 
x 
 
 
 
 
x 
 
x 
 
CDR 
P&CG 
 
P&CG 
 
P&CG 
 
P&CG 
 
 
P&CG 
 
P&CG 
P&CG 
ADAS-Cog13 
P 
 
P 
 
P 
 
P 
 
 
P 
 
P 
P 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
135/Protocol WN42171, Version 4 
Assessment/ 
Procedure 
Treatment Period 
Final Safety and 
Efficacy 
Assessment 
Follow-
Up 
Period 
Early 
Term. 
Visit 
UV a 
 
OLE (week) 
 
 
 
 
Study schedule 
104 c 
106 
128 b 
130 c 
132 
154 b 
156 c 
158 
180 b 
182 c 
184 
204 b 
206 b 
208 c 
220 
 
 
Dose number in 
Study WN42171 
35 
3647 
48 
4960 
61 
6273 
74 
7585 
86 
 
 
 
 
Dose level in 
milligrams (mg) 
510 Q2W 
Verbal Fluency 
Task 
P 
 
P 
 
P 
 
P 
 
 
P 
 
P 
P 
Coding 
P 
 
P 
 
P 
 
P 
 
 
P 
 
P 
P 
ADCS-ADL 
CG 
 
CG 
 
CG 
 
CG 
 
 
CG 
 
CG 
CG 
FAQ 
CG 
 
CG 
 
CG 
 
CG 
 
 
CG 
 
CG 
CG 
MMSE 
P 
 
P 
 
P 
 
P 
 
 
P 
 
P 
P 
EQ-5D 
CG 
 
 
 
CG 
 
 
 
 
CG 
 
CG 
CG 
QoL-AD 
P&CG 
 
 
 
P&CG 
 
 
 
 
P&CG 
 
P&CG 
P&CG 
ZCI-AD 
CG 
 
 
 
CG 
 
 
 
 
CG 
 
CG 
CG 
RUD-Lite 
CG 
 
 
 
CG 
 
 
 
 
CG 
 
CG 
CG 
NPI-Q 
CG 
 
 
 
CG 
 
 
 
 
CG 
 
CG 
CG 
C-SSRS SLV 
P 
 
P 
 
P 
 
P 
 
 
P 
 
P 
P 
Vital signs l 
B 
B 
B 
B 
B 
B 
B 
B 
B 
x 
x 
x 
x 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
136/Protocol WN42171, Version 4 
Assessment/ 
Procedure 
Treatment Period 
Final Safety and 
Efficacy 
Assessment 
Follow-
Up 
Period 
Early 
Term. 
Visit 
UV a 
 
OLE (week) 
 
 
 
 
Study schedule 
104 c 
106 
128 b 
130 c 
132 
154 b 
156 c 
158 
180 b 
182 c 
184 
204 b 
206 b 
208 c 
220 
 
 
Dose number in 
Study WN42171 
35 
3647 
48 
4960 
61 
6273 
74 
7585 
86 
 
 
 
 
Dose level in 
milligrams (mg) 
510 Q2W 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events m 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine pregnancy 
test n 
B 
B 
B 
B 
B 
B 
B 
B 
B 
x 
x 
x 
x 
Study drug 
administration o 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
137/Protocol WN42171, Version 4 
A  amyloid beta; ADA  anti-drug antibody; ADAS-Cog13  Alzheimer’s Disease Assessment Scale−Cognition, Subscale 13; 
ADCS-ADL  Alzheimer’s Disease Cooperative Study Group−Activities of Daily Living; ARIA-E  amyloid-related imaging 
abnormality−edema/effusion; ARIA-H  amyloid-related imaging abnormality−microhemorrhage/hemosiderin deposition; Assess   assessment; 
B  before study drug administration; CDR  Clinical Dementia Rating; CG  caregiver completion; CSF  cerebrospinal fluid; 
C-SSRS  Columbia−Suicide Severity Rating Scale; DTI   diffusion tensor imaging; eCRF  electronic Case report Form; EQ-5D  EuroQol-5 
Dimension Questionnaire; FAQ  Functional Activities Questionnaire; MMSE   Mini-Mental State Examination; MRI   magnetic resonance 
imaging; NPI-Q  Neuropsychiatric Inventory Questionnaire; OLE   open-label extension; P&CG  participant and caregiver completion; 
P  participant completion; PK  pharmacokinetic; Q2W  every 2 weeks; QoL-AD  Quality of Life−Alzheimer's Disease; 
RUD-Lite  Resource Utilization in Dementia−Lite; T4   thyroxine; Term  termination; UV  unscheduled visit; ZCI-AD  Zarit Caregiver 
Interview for Alzheimer’s Disease. 
Notes:  The visit window is  3 days.  It is recommended that not more than 2 doses are given (i.e., 2   510 mg Q2W) within 28 days.  
Participants should return to initial planned schedule per randomization for subsequent  visits. 
a The relevant assessments will be determined by the Principal Investigator per clinical judgment, not necessary to include all  assessments 
listed above.  An additional plasma and RNA blood sample for the assessment of exploratory biomarkers will be obtained as soon as 
practicable (e.g., at an unscheduled visit or the next study visit) following each MRI scan showing ARIA -E until and including ARIA-E 
resolution (i.e., new, worsened, stable, improved, resolved ARIA-E); following new or worsened ARIA-E. 
b At applicable sites, administration of gantenerumab may be performed by a mobile nursing professional at the participant's ho me or 
another suitable location, such as a nursing center, to improve access and convenience for participants participating in the study. 
c Visit may be split over 2 consecutive days.  All cognitive and functional assessments should be completed first.  All safety assessments 
(e.g., vital signs, blood tests, and ECGs) should be completed on the day of dosing.  Whenever possible , cognitive and functional 
assessments should be performed at the visit timepoints stipulated in the schedule of activities.  However, in exceptional ci rcumstances, if 
the caregiver, the primary rater, or even the participant cannot perform these assessments as per the schedule of activities, they may be 
performed up to 4 weeks out of window. 
d Accurate recording of the date and time of study drug administration and PK sampling is critical.  A PK sample will be obtain ed as soon as 
practicable (e.g., at an unscheduled visit or the next study visit) following a MRI scan showing new occurrence or worsening of ARIA -E or 
ARIA-H that meets the discontinuation criteria (e.g., during an unscheduled visit). 
e Serum chemistry includes AST, ALT, ALP, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, potassium, 
calcium, BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).  Hemoglobin A1c, glucose,  insulin, 
total cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin B-12, T4, free T4, and thyroid-stimulating hormone levels 
will also be assessed and should ideally be collected at least 4 hours after a meal.  


Appendix 1: Schedule of Activities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
138/Protocol WN42171, Version 4 
f Hematology includes WBC count, RBC count (with morphology), hemoglobin, hematocrit, platelet count, and differential count 
(neutrophils, eosinophils, basophils, monocytes, lymphocytes, other cells). 
g A complete physical examination, performed at specified visits, should include an evaluation of the head, eyes, ears, nose, a nd throat, and 
the cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems; genitourinary exami nations may 
be performed if clinically indicated. 
h Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes. 
i MRI should be performed at least 7 days before dosing and results must be available for review by site staff before dosing ca n proceed.  MRI 
should be performed before or at least 3 days following a lumbar puncture. 
j Includes resting-state functional MRI and DTI outcome measures, where available. 
k Lumbar puncture will be performed only in participants who were randomized in the WN29922 or WN39658 studies based on CSF Aβ and 
tau level results.  It must be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal variation of CSF 
parameters and should be performed prior to dosing (if applicable). 
l Vital signs include measurements of pulse rate, respiratory rate, systolic and diastolic blood pressure while the participant is in a seated 
position, and temperature.  Blood pressure and pulse rate should be taken when the participant is at rest and should not be m easured unless 
at least 15 minutes have elapsed since the last blood draw.  The same arm should be used for all blood pressure measurements.  Pulse rate 
will be determined and will be recorded as beats per minute.  If obtained manually, the pulse rate should be counted for a mi nimum of 20 
seconds at each assessment. 
m After informed consent has been obtained, all adverse events occurring while the participant is in the parent Study WN29922 or WN 39658 
will be reported on the parent Adverse Event eCRF until the participant’s final visit/last assessment in the parent study.  A fter the 
participant’s final visit/last assessment in the parent Study WN29922 or WN39658 all adverse events will be reported on the S tudy 
WN42171 Adverse Event eCRF until the participant’s final visit (including long-term follow-up visits). 
n Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site 
prior to each dose administration.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central 
laboratory.  Results are to be recorded only in the source documents. 
o Study drug administration should be performed only after all assessments and rating scales for the pa rticipant are completed (unless 
indicated otherwise.  Study drug will be administered to participants by SC injection (full details are provided in the pharmacy manual).  
Participants should be observed for at least 1 hour after dosing.  Study personnel preparing and administering study drug mus t not be 
involved with any efficacy assessments or safety evaluations. 
 
 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
139/Protocol WN42171, Version 4 
Appendix 2 
Management Rules for Amyloid-Related Imaging 
Abnormalities 
Event 
Characteristic 
Action to Be Taken 
ARIA-E 
Asymptomatic and mild (Bioclinica 
severity 1) 
 Continue study drug according to the 
schedule of administration (including 
uptitration). 
 Perform MRI scans at 4-week intervals until 
ARIA-E resolves. 
 Then, resume the standard MRI schedule. 
Asymptomatic and mild + 
(Bioclinica severity 2) or moderate 
(Bioclinica severity 3) 
During uptitration period: 
 Continue study drug at the same dose level 
and do not uptitrate. 
 Perform MRI scans at 4-week intervals until 
ARIA-E resolves. 
 Once ARIA-E resolves, continue uptitration 
and resume the standard MRI schedule. 
 
During treatment period (at target dose): 
 Continue study drug according to the 
schedule of administration. 
 Perform MRI scans at 4-week intervals until 
ARIA-E resolves. Then, resume the 
standard MRI schedule. 
Asymptomatic and moderate + 
(Bioclinica severity 4) or severe 
(Bioclinica severity 5) 
Or 
Symptomatic ARIA-E a of any 
severity (Bioclinica severity 15) 
During uptitration period: 
 Temporarily interrupt study drug. 
 Perform MRI scans at 4-week intervals until 
ARIA-E (and any ARIA-E symptom/s) 
resolves. 
 Once ARIA-E (and any ARIA-E symptom/s) 
resolves, reintroduce study drug at the dose 
level given at the time the event was 
detected. 
 Perform an MRI scan after two consecutive 
dosing visits. 
 If no new ARIA-E is detected, continue 
uptitration and resume the standard MRI 
schedule. 
 
During treatment period (at target dose): 
 Temporarily interrupt study drug. 
 Perform MRI scans at 4-week intervals until 
ARIA-E (and any ARIA-E symptom/s) 
resolves. 
  Once ARIA-E (and any ARIA-E symptom/s) 
resolves, reintroduce study drug. 
 Perform an MRI scan after two consecutive 
dosing visits. 
 If no new ARIA-E is detected, resume the 
standard MRI schedule. 
Any recurrence of ARIA-E 
 Treat as above. 


 
Appendix 2: Management Rules for Amyloid-Related Imaging Abnormalities 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
140/Protocol WN42171, Version 4 
Event 
Characteristic 
Action to Be Taken 
ARIA-H 
Without disseminated LH 
 Continue study drug according to the 
schedule of administration (including 
uptitration). 
 Perform MRI scans according to the 
standard MRI schedule. 
Disseminated LH 
 Permanently discontinue study drug. 
ARIA-E  amyloid-related imaging abnormalityedema/effusion; ARIA-H  amyloid-related 
imaging abnormalitymicrohemorrhage/hemosiderin deposition; LH  leptomeningeal 
hemosiderosis; MRI  magnetic resonance imaging; PK  pharmacokinetic; Q4W  every 
4 weeks. 
Notes: 
 
Disseminated LH is defined as more than three focal leptomeningeal hemosiderosis 
cumulatively. 
 
If ARIA-E and disseminated LH co-occur, the more conservative management rule will 
apply. 
 
The investigator may choose to perform additional MRI monitoring for ARIA at any time. 
 
In exceptional cases of 1) an ARIA-E that is asymptomatic with Bioclinica severity 1 and 
considered stable over consecutive MRI images by the Sponsor and investigator; or 
2) symptomatic ARIA-E for which the imaging evidence of ARIA-E has resolved but the 
CNS symptoms continue, gantenerumab can be either reintroduced or uptitrated, as 
applicable, and Q4W MRI monitoring may no longer be necessary, as determined by the 
Sponsor and investigator. 
 
A PK sample will be obtained as soon as soon as practicable (e.g., at an unscheduled visit 
or the next study visit) following a MRI scan showing new occurrence or worsening of 
ARIA-E or ARIA-H that meets the discontinuation criteria (e.g., during an 
unscheduled visit). 
 
An additional plasma and RNA sample for the assessment of exploratory biomarkers will 
be obtained as soon as practicable (e.g., at an unscheduled visit or the next study visit) 
following each MRI scan showing ARIA-E until and including ARIA-E resolution (i.e., new, 
worsened, stable, improved, resolved ARIA-E). 
 
a Symptomatic ARIA-E is defined as onset or worsening of CNS symptom(s) that is/are 
attributable to ARIA-E MRI findings in the judgement of the Principal Investigator or 
appropriately medically qualified subinvestigator. 
 


Signature Page for: System identifier:RIM-CLIN-439857
Protocol - WN42171 - GANTENERUMAB (MAIN) - v4 - Global/Core - Published
Approval Task
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11-May-2022 21:47:01 GMT+0000

SAP_001.pdf: 
 
Offi ci al Titl e:  
A n O p e n -L a b el, M ulti c e nt er, R oll o v er St u d y t o E v al u at e t h e S af et y, 
T ol er a bilit y, a n d Effi c a c y of L o n g -T er m G a nt e n er u m a b A d mi ni str ati o n 
i n P arti ci p a nt s Wit h Al z h ei m er' s Di s e a s e 
N C T N u m b er:  N C T 0 4 3 7 4 2 5 3  
D o c u m e nt  D at e : S A P V er si o n 1. 0: 3 0 -N o v e m b er -2 0 2 3  
 
 
 


S T A TI S TI C A L A N A L Y SI S P L A N A P P R O V A L  
S P O N S O R:  
L E G A L R E GI S T E R E D 
A D D R E S S:  
F. H off m a n n -L a R o c h e Lt d  
Gr e n z a c h er str a s s e 1 2 4  
4 0 7 0 B a s el, S wit z erl a n d  
D A T E FI N A L:  
S e e el e ctr o ni c d at e st a m p o n t h e l a st p a g e of t hi s 
d o c u m e nt  
C O N FI D E N TI A L  
 
T hi s i s a n F. H off m a n n -L a R o c h e Lt d  d o c u m e nt t h at c o nt ai n s c o nfi d e nti al i nf or m ati o n.  N ot hi n g 
h er ei n i s t o b e di s cl o s e d wit h o ut writt e n c o n s e nt fr o m F. H off m a n n -L a R o c h e Lt d . 
 
G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n W N 4 2 1 7 1, v 1. 0  
S T A TI S TI C A L A N A L Y SI S  P L A N  
S T U D Y TI T L E:  
A N O P E N -L A B E L, M U L TI C E N T E R, R O L L O V E R 
S T U D Y T O E V A L U A T E T H E S A F E T Y, 
T O L E R A BI LI T Y, A N D E F FI C A C Y O F L O N G -T E R M 
G A N T E N E R U M A B A D MI NI S T R A TI O N I N 
P A R TI CI P A N T S WI T H A L Z H EI M E R' S DI S E A S E  
S T U D Y  N U M B E R:  
W N 4 2 1 7 1  
S T U D Y N A M E:   
P O S T G R A D U A T E  
V E R SI O N N U M B E R:  
1. 0  
R O C H E C O M P O U N D ( S): 
G a nt e n er u m a b  
(R O 4 9 0 9 8 3 2 ) 
E U D R A C T N U M B E R:  
2 0 2 0 -0 0 0 7 6 6 -4 2  
I N D N U M B E R: 
1 0 2, 2 6 6  
N C T N U M B E R:  
N C T 0 4 3 7 4 2 5 3  
P L A N P R E P A R E D B Y:  
 P h. D. , 
 M. S c. ,  
 P h. D.  
 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
1


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
2  
S T A TI S TI C A L A N A L Y SI S  P L A N V E R SI O N  HI S T O R Y  
T hi s S A P w a s d e v el o p e d  b a s e d o n R o c h e S A P m o d el d o c u m e nt  v 2. 0, r e vi s e d 2 6 
O ct o b er 2 0 2 0.  
S A P V er si o n  
A p pr o v al D at e  
B a s e d o n Pr ot o c ol   
( V er si o n, A p pr o v al D at e)  
1  
s e e el e ctr o n i c d at e st a m p 
o n t h e l a st p a g e of t hi s 
d o c u m e nt  
V er si o n 4 . 0, 1 1 M a y, 2 0 2 2  
 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
2


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
3  
 
T A B L E O F C O N T E N T S  
1.  
I N T R O D U C TI O N ............................................................................. 8  
1. 1  
O bj e cti v e s a n d E n d p oi nt s  .......................................................... 8  
1. 2  
St u d y D e si g n  ........................................................................... 1 0  
1. 2. 1  
Tr e at m e nt A s si g n m e nt a n d Bli n di n g  ........................................ 1 4  
1. 2. 2  
I n d e p e n d e nt R e vi e w F a cilit y .................................................... 1 5  
1. 2. 3  
D at a M o nit ori n g  ....................................................................... 1 6  
1. 2. 4  
A RI A M a n a g e m e nt  .................................................................. 1 6  
2.  
S T A TI S TI C A L H Y P O T H E S E S  ...................................................... 1 7  
3.  
S A M P L E SI Z E D E T E R MI N A TI O N  ................................................ 1 7  
4.  
A N A L Y SI S S E T S  .......................................................................... 1 7  
5.  
S T A TI S TI C A L A N A L Y S E S  ........................................................... 1 8  
5. 1  
G e n er al C o n si d er ati o n  ............................................................. 1 8  
5. 1. 1  
D efi niti o n of B a s eli n e  ............................................................... 1 9  
5. 2  
P arti ci p a nt Di s p o siti o n  ............................................................. 1 9  
5. 3  
Pri m ar y E n d p oi nt s A n al y si s  ..................................................... 1 9  
5. 3. 1  
D efi niti o n of Pri m ar y E n d p oi nt s  ................................................ 1 9  
5. 3. 2  
M ai n A n al yti c al A p pr o a c h f or Pri m ar y E n d p oi nt( s)  ................... 2 0  
5. 3. 3  
A d v er s e E v e nt s  ........................................................................ 2 0  
5. 3. 4  
M a g n eti c R e s o n a n c e I m a gi n g S af et y Fi n di n g s  ........................ 2 2  
5. 3. 4. 1  
C N S S y m pt o m s T e m p or all y A s s o ci at e d wit h a n d 
Attri b ut a bl e t o A RI A -E M RI Fi n di n g s  ........................................ 2 2  
5. 3. 5  
L a b or at or y D at a  ....................................................................... 2 3  
5. 3. 6  
Vit al Si g n s  ................................................................................ 2 3  
5. 3. 7  
E C G s  ....................................................................................... 2 3  
5. 3. 8  
C ol u m bi a -S ui ci d e S e v erit y R ati n g S c al e ( C -S S R S)  ................. 2 4  
5. 4  
S e c o n d ar y E n d p oi nt s A n al y s e s  ............................................... 2 4  
5. 4. 1  
S e c o n d ar y Effi c a c y E n d p oi nt s  ................................................. 2 4  
5. 4. 1. 1  
Cli ni c al D e m e nti a R ati n g  ......................................................... 2 5  
5. 4. 1. 2  
M M S E  ...................................................................................... 2 5  
5. 4. 1. 3  
A D A S -C o g 1 1 a n d A D A S -C o g 1 3  .............................................. 2 5  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
3


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
4  
5. 4. 1. 4  
V er b al Fl u e n c y T a s k  ................................................................ 2 6  
5. 4. 1. 5  
C o di n g  ..................................................................................... 2 6  
5. 4. 1. 6  
F A Q  ......................................................................................... 2 6  
5. 4. 1. 7  
A D C S -A D L ............................................................................... 2 6  
5. 5  
E x pl or at or y E n d p oi nt s A n al y si s  ............................................... 2 6  
5. 5. 1  
E x pl or at or y Effi c a c y E n d p oi nt s  ................................................ 2 6  
5. 5. 1. 1  
Q o L -A D  .................................................................................... 2 7  
5. 5. 1. 2  
N PI -Q  ....................................................................................... 2 7  
5. 5. 1. 3  
Z CI -A D  ..................................................................................... 2 7  
5. 6  
Ot h er S af e t y A n al y s e s ............................................................. 2 7  
5. 6. 1  
E xt e nt of E x p o s ur e  .................................................................. 2 7  
5. 7  
Ot h er A n al y s e s  ........................................................................ 2 8  
5. 7. 1  
S u m m ari e s of C o n d u ct of St u d y  .............................................. 2 8  
5. 7. 2  
S u m m ari e s of D e m o gr a p hi c s a n d B a s eli n e C h ar a ct eri sti c s  .... 2 8  
5. 7. 3  
S u m m ari e s of C O VI D -1 9 I m p a ct o n t h e Tri al s  ......................... 2 8  
5. 7. 4  
I m m u n o g e ni cit y A n al y s e s ........................................................ 2 9  
5. 7. 5  
Bi o m ar k er A n al y s e s  ................................................................. 2 9  
5. 7. 6  
A m yl oi d P E T S u b st u d y  ............................................................ 3 0  
5. 7. 6. 1  
Br ai n A m yl oi d L o a d A n al y si s  ................................................... 3 0  
5. 7. 6. 2  
G e n er al C o n si d er ati o n s o n A m yl oi d P E T St ati sti c al 
A n al y s e s  .................................................................................. 3 0  
5. 7. 6. 3  
S u m m ari e s of C o n d u ct of S u b st u d y  ........................................ 3 2  
5. 7. 6. 4  
S u m m ari e s of D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s  ...... 3 2  
5. 7. 6. 5  
S af et y A n al y s e s  ....................................................................... 3 2  
5. 7. 6. 6  
I nt eri m A n al y si s ....................................................................... 3 3  
5. 7. 7  
T a u P E T S u b st u d y  ................................................................... 3 3  
5. 7. 7. 1  
Br ai n T a u L o a d A n al y si s  .......................................................... 3 3  
5. 7. 7. 2  
G e n er al C o n si d er ati o n s o n T a u P E T St ati sti c al A n al y s e s  ....... 3 3  
5. 7. 7. 3  
S u m m ari e s of C o n d u ct of S u b st u d y  ........................................ 3 4  
5. 7. 7. 4  
S u m m ari e s of D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s  ...... 3 5  
5. 7. 7. 5  
S af et y A n al y s e s  ....................................................................... 3 5  
5. 7. 7. 6  
I nt eri m A n al y si s ....................................................................... 3 5  
5. 8  
I nt eri m A n al y s e s ...................................................................... 3 5  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
4


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
5  
5. 8. 1  
Pl a n n e d I nt eri m A n al y s e s  ........................................................ 3 5  
5. 8. 2  
O pti o n al I nt eri m A n al y s e s  ........................................................ 3 6  
6.  
S U P P O R TI N G D O C U M E N T A TI O N  .............................................. 3 6  
7.  
R E F E R E N C E S .............................................................................. 3 9  
 
 
LI S T O F T A B L E S  
T a bl e  1  
O bj e cti v e s a n d C orr e s p o n di n g E n d p oi nt s  ..................................... 9  
T a bl e  2  
Ti m e Wi n d o w s f or A m yl oi d P E T E n d p oi nt s  ................................. 3 1  
T a bl e  3  
Pri m ar y C e ntil oi d E q u ati o n P ar a m et er s  ...................................... 3 2  
T a bl e  4  
Ti m e Wi n d o w s f or T a u P E T E n d p oi nt s  ....................................... 3 4  
 
 
 
LI S T O F A P P E N DI C E S  
A p p e n di x  1  
C h a n g e s t o Pr ot o c ol -Pl a n n e d A n al y s e s  ...................................... 3 7  
A p p e n di x  2  
Bi o cli ni c a S e v erit y S c or e  ............................................................ 3 8  
 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
5


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
6  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  
A b br e vi ati o n or T er m  
D e s cri pti o n  
[1 8 F] G T P 1  G e n e nt e c h T a u Pr o b e 1  
A D  Al z h ei m er’ s Di s e a s e  
A D A  a nti -dr u g a nti b o d y  
A D A S -C o g  Al z h ei m er Di s e a s e A s s e s s m e nt S c al e -C o g niti o n  
A D C S -A D L  Al z h ei m er Di s e a s e C o o p er ati v e St u d y Gr o u p -A cti viti e s of D ail y Li vi n g  
A E  a d v er s e e v e nt  
A RI A -E  a m yl oi d -r el at e d i m a gi n g a b n or m aliti e s –  e d e m a/ eff u si o n  
A RI A -H  a m yl oi d -r el at e d i m a gi n g a b n or m aliti e s –  h e m o si d eri n d e p o siti o n  
B G T S  B ar k h of Gr a n d T ot al S c or e  
C D R  Cli ni c al D e m e nti a R ati n g  
C S R  Cli ni c al St u d y R e p ort  
C -S S R S  C ol u m bi a -s ui ci d e s e v erit y r ati n g s c al e  
D S S T  Di git S y m b ol S u b stit uti o n T e st  
E Q -5 D  E ur o Q ol 5 -Di m e n si o n Q u e sti o n n air e  
F A Q  F u n cti o n al A cti viti e s Q u e sti o n n air e  
i D M C i n d e p e n d e nt D at a M o nit ori n g C o m mitt e e 
I M C I nt er n al M o nit ori n g C o m mitt e e 
I S R i nj e cti o n sit e r e a cti o n 
I T T int e nt  t o tr e at 
I x RS  i nt er a cti v e v oi c e/ w e b-b a s e d r e s p o n s e s y st e m  
M e d D R A  M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s  
M M S E  Mi ni -M e nt al St at e E x a mi n ati o n  
M RI  m a g n eti c r e s o n a n c e i m a gi n g  
N M P A  N ati o n al M e di c al Pr o d u ct s A d mi ni str ati o n  
N PI -Q  N e ur o p s y c hi atri c I n v e nt or y Q u e sti o n n air e  
O L E  o p e n -l a b el e xt e n si o n 
P E T  p o sitr o n e mi s si o n  t o m o gr a p h y 
P D  P h ar m a c o d y n a mi c  
P K  P h ar m a c o ki n eti c  
Q 2 W  E v er y t w o w e e k s  
Q o L -A D  Q u alit y of Lif e -Al z h ei m er' s Di s e a s e  
R U D -Lit e  R e s o ur c e Utili z ati o n i n D e m e nti a -Lit e  
S A E  s eri o u s a d v er s e e v e nt s  
S A P  St ati sti c al A n al y si s Pl a n  
S C  S u b c ut a n e o u s  
S U V R  st a n d ar d u pt a k e v al u e r ati o  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
6


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
7  
Z CI -A D  Z arit C ar e gi v er I nt er vi e w f or Al z h ei m er' s Di s e a s e  
 
 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
7


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
8  
1.  
I NT R O D U C TI O N  
T hi s d o c u m e nt d e s cri b e s t h e st ati sti c al a n al y s e s t h at will b e r e p ort e d i n t h e Cli ni c al 
St u d y R e p ort ( C S R) of S t u d y W N 4 2 1 7 1 ( h er e aft er r ef err e d t o a s “ P O S T G R A D U A T E ”).  
T hi s d o c u m e nt will f o c u s o n t h e st ati sti c al m et h o d ol o g y u n d erl yi n g t h e r e p ort  t h at will 
i n cl u d e p arti ci p a nt di s p o siti o n, b a s eli n e d e m o gr a p hi c s , d e s cri pti v e effi c a c y a n d st a n d ar d 
s af et y o ut p ut s al o n g wit h t h e a n al y si s s et s .   
T hi s St ati sti c al A n al y si s P l a n ( S A P) c o v er s a n al y s e s pl a n n e d f or P O S T G R A D U A T E  
s t u d y o nl y.  A n al y s e s pl a n n e d a cr o s s t h e d o u bl e -bli n d p eri o d i n t h e pi v ot al p ar e nt 
st u di e s W N 2 9 9 2 2 a n d W N 3 9 6 5 8  (h er e aft er r ef err e d t o a s “ G R A D U A T E  I” a n d 
“G R A D U A T E  II”, r e s p e cti v el y), t h e o p e n-l a b el e xt e n si o n ( O L E) p eri o d i n t h e G R A D U A T E 
st u di e s a n d P O S T G R A D U A T E  ar e d e s cri b e d s e p ar at el y  a n d n ot t h e s u bj e ct of t hi s S A P. 
A n al y s e s pl a n n e d f or t h e l o n git u di n al a m yl oi d p o sitr o n e mi s si o n t o m o gr a p h y ( P E T ) a n d 
t a u-P E T s u b st u di e s ar e pr o vi d e d i n S e cti o n s  5. 7. 6  a n d  5. 7. 7 .  T h e p h ar m a c o ki n eti c 
( P K) d at a a n d P K/ P D m o d elli n g  will b e r e p ort e d i n t h e p o p ul ati o n P K r e p ort a n d ar e 
t h er ef or e n ot c o v er e d i n t hi s d o c u m e nt.  Si mil arl y, h e alt h e c o n o mi c d at a ( s u c h a s utilit y 
v al u e s d eri v e d fr o m t h e E ur o Q o L– 5 Di m e n si o n s [ E Q -5 D ] a n d t h e R e s o ur c e Utili z ati o n i n 
D e m e nti a S c al e – Lit e [ R U D -Lit e ]) will b e a n al y z e d a n d r e p ort e d s e p ar at el y fr o m t h e C S R  
a n d ar e t h er ef or e n ot c o v er e d h er e.  Si mil ar ly, t h e e x pl or at or y bi o m ar k er e n d p oi nt s of 
c h a n g e s i n f u n cti o n al br ai n c o n n e cti vit y or c h a n g e s i n t h e i nt e grit y of w hit e m att er will b e 
a n al y z e d a n d r e p ort e d s e p ar at el y fr o m t h e C S R a n d ar e t h er ef or e n ot c o v er e d h er e.  
T h e d e s cri pti o n of l a y o ut s f or t h e C S R o ut p ut s, t h e d et ail s a b o ut t h e u n d erl yi n g a n al y si s 
d at a s et s a n d pr o gr a m s, a n d t h e li n ki n g of pr o d u cti o n o ut p ut s t o s e cti o n s i n t h e C S R ar e 
n ot wit hi n t h e s c o p e of t hi s d o c u m e nt a n d will b e c o v er e d i n t h e D at a A n al y si s Pl a n 
M o d ul e 2 a n d 3.  
T h e l a n g u a g e u s e d i n t hi s S A P s u p er s e d e s t h at i n  t h e pr ot o c ol a n d pr ot o c ol s y n o p si s.  
T hi s S A P i s b a s e d o n Pr ot o c ol v er si o n 4 , i s s u e d o n M a y 1 1, 2 0 2 2 . 
1. 1  
O B J E C TI V E S A N D E N D P OI N T S  
T hi s st u d y will e v al u at e t h e s af et y, t ol er a bilit y, a n d effi c a c y of l o n g -t er m a d mi ni str ati o n of 
o p e n ‑l a b el g a nt e n er u m a b i n p arti ci p a nt s wit h  Al z h ei m er’ s Di s e a s e ( A D ) w h o c o m pl et e d 
G R A D U A T E I  or G R A D U A T E II st u d y .  S p e cifi c o bj e cti v e s a n d c orr e s p o n di n g e n d p oi nt s 
f or t h e st u d y ar e o utli n e d b el o w.
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
8


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
9  
T a bl e  1  
O bj e cti v e s a n d C orr e s p o n di n g E n d p oi nt s  
Pri m ar y O bj e cti v e ( s) 
C orr e s p o n di n g E n d p oi nt ( s) 
 
T o e v al u at e t h e s af et y a n d 
t ol er a bilit y of l o n g-t er m 
g a nt e n er u m a b a d mi ni st er e d b y 
S C i nj e cti o n  
 
N at ur e, fr e q u e n c y, s e v erit y, ti mi n g, a n d 
o ut c o m e s of a d v er s e e v e nt s a n d s eri o u s 
a d v er s e e v e nt s  
 
P h y si c al e x a mi n ati o n s (i n cl u di n g n e ur ol o gi c 
s y st e m s), vit al si g n s, E C G, l a b or at or y  t e st s, 
a n d C ol u m bi a -S ui ci d e S e v erit y R ati n g S c al e 
( C-S S R S)  
 
N at ur e, fr e q u e n c y, s e v erit y, a n d ti mi n g of 
A RI A -E a n d A RI A -H  
 
N at ur e, fr e q u e n c y, s e v erit y, ti mi n g, a n d 
o ut c o m e s of I S R s  
 
I n cid e n c e of tr e at m e nt di s c o nti n u ati o n s f or 
a d v er s e e v e nt s  
 
I n ci d e n c e of a d v er s e e v e nt s of s p e ci al 
i nt er e st 
S e c o n d ar y O bj e cti v e (s ) 
C orr e s p o n di n g E n d p oi nt s  
 
T o e v al u at e t h e effi c a c y of l o n g -
t er m g a nt e n er u m a b 
a d mi ni st er e d b y S C i nj e cti o n  
C h a n g e o v er ti m e i n c o g niti o n  a n d/ or  f u n cti o n, a s 
m e a s ur e d b y t h e f oll o wi n g:  
 
Cli ni c al D e m e nti a R ati n g ( C D R)  
 
Mi ni -M e nt al St at e E x a mi n ati o n ( M M S E)  
 
Al z h ei m er Di s e a s e A s s e s s m e nt S c al e -
C o g niti o n, S u b s c al e 1 1 ( A D A S -C o g 1 1) a n d 
Al z h ei m er Di s e a s e A s s e s s m e nt S c al e -
C o g niti o n, S u b s c al e 1 3 ( A D A S -C o g 1 3)  
 
V er b al Fl u e n c y T a s k  
 
C o di n g  
 
F u n cti o n al A cti viti e s Q u e sti o n n air e ( F A Q)  
 
Al z h ei m er Di s e a s e C o o p er ati v e St u d y 
Gr o u p -A cti viti e s of D ail y Li vi n g ( A D C S -A D L)  
E x pl or at or y O bj e cti v e( s): Effi c a c y  
C orr e s p o n di n g E n d p oi nt s  
 
T o e v al u at e t h e effi c a c y of l o n g-
t er m g a nt e n er u m a b 
a d mi ni st er e d b y S C i nj e cti o n  
C h a n g e o v er ti m e i n:  
 
H e alt h -r el at e d q u alit y of lif e, a s a s s e s s e d b y 
t h e Q u alit y of Lif e-Al z h ei m er' s Di s e a s e 
( Q o L-A D) s c al e  
 
B e h a vi or al a n d n e ur o p s y c hi atri c s y m pt o m s 
of A D, a s m e a s ur e d b y t h e N e ur o p s y c hi atri c 
I n v e nt or y Q u e sti o n n air e ( N PI-Q)  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
9


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
1 0  
 
C ar e gi v er b ur d e n, a s a s s e s s e d b y t h e Z arit 
C ar e gi v er I nt er vi e w f or Al z h ei m er' s Di s e a s e 
( Z CI-A D) s c al e  
 
El e m e nt s of r e s o ur c e utili z ati o n, a s 
a s s e s s e d b y t h e R e s o ur c e Utili z ati o n i n 
D e m e nti a -Lit e ( R U D -Lit e)  
E x pl or at or y P h ar m a c o ki n eti c 
O bj e cti v e( s)  
C orr e s p o n di n g E n d p oi nt s  
 
T o c h ar a ct eri z e t h e P K pr ofil e 
of g a nt e n er u m a b a d mi ni st er e d 
b y S C i nj e cti o n  
 
Pl a s m a c o n c e ntr ati o n of g a nt e n er u m a b 
a d mi ni st er e d S C at s p e cifi e d ti m e p oi nt s  
I m m u n o g e ni cit y O bj e cti v e( s) 
C orr e s p o n di n g E n d p oi nt s  
 
T o e v al u at e t h e i m m u n e 
r e s p o n s e t o g a nt e n er u m a b 
a d mi ni st er e d b y S C i nj e cti o n  
 
Pr e v al e n c e of a nti -dr u g a nti b o di e s ( A D A s) 
at b a s eli n e a n d i n ci d e n c e of A D A s d uri n g 
t h e st u d y 
E x pl or at or y Bi o m ar k er 
O bj e cti v e( s)  
C orr e s p o n di n g E n d p oi nt s  
 
T o e v al u at e t h e l o n g -t er m 
eff e ct s of g a nt e n er u m a b 
a d mi ni st er e d b y S C i nj e cti o n  
 
Br ai n a m yl oi d l o a d o v er ti m e, a s m e a s ur e d 
b y a m yl oi d P E T s c a n i n a s u b s et of 
p arti ci p a nt s  
 
Br ai n t a u l o a d o v er ti m e, a s m e a s ur e d b y 
t a u P E T s c a n i n a s u b s et of p arti ci p a nt s 
 
C S F m ar k er s of di s e a s e o v er ti m e i n a 
s u b s et of p arti ci p a nt s, i n cl u di n g, b ut n ot 
li mit e d t o, Aβ 1 −4 2 , t ot al t a u (t-t a u), a n d 
p h o s p h or yl at e d t a u ( p -t a u) 
 
M RI -d eri v e d m e a s ur e m e nt s o v er ti m e, s u c h 
a s v ol u m etri c c h a n g e s i n w h ol e br ai n, 
v e ntri cl e s, hi p p o c a m p u s, or ot h er str u ct ur e s; 
c h a n g e s i n f u n cti o n al br ai n c o n n e cti vit y; or 
c h a n g e s i n t h e i nt e grit y of w hit e m att er i n all 
p arti ci p a nt s  
 
Bl o o d a n d Pl a s m a m ar k er s o v er ti m e  
E x pl or at or y H e alt h St at u s Utilit y 
O bj e cti v e( s)  
C orr e s p o n di n g E n d p oi nt s  
 
T o e v al u at e t h e h e alt h st at u s 
utilit y s c or e s of p arti ci p a nt s 
tr e at e d wit h g a nt e n er u m a b 
 
H e alt h o ut c o m e s i n p arti ci p a nt a n d 
c ar e gi v er, a s m e a s ur e d b y E ur o Q ol 
5 ‑Di m e n si o n Q u e sti o n n air e ( E Q -5 D)  
  
1. 2  
S T U D Y D E SI G N  
T h e P O S T G R A D U A T E s t u d y i s a n o p e n-l a b el, m ulti c e nt er, r oll o v er st u d y t o e v al u at e t h e 
s af et y, t ol er a bilit y, a n d effi c a c y of l o n g -t er m a d mi ni str ati o n of o p e n-l a b el g a nt e n er u m a b 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
1 0


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
1 1  
i n p arti ci p a nt s wit h A D w h o c o m pl et e d G R A D U A T E  I or G R A D U A T E  II, eit h er t h e 
d o u bl e -bli n d or O L E p ar t, a s a p pli c a bl e ( p ar e nt st u d y).   
T o pr ot e ct st u d y d at a i nt e grit y a n d t o ai d t h e a s s e s s m e nt of t h e l o n g -t er m eff e ct s of 
g a nt e n er u m a b, tr e at m e nt a s si g n m e nt i nf or m ati o n fr o m t h e d o u bl e -bli n d p h a s e of t h e 
p ar e nt G R A D U A T E I or G R A D U A T E II st u di e s will r e m ai n bli n d e d t o t h e S p o n s or, 
i n v e sti g at or, a n d p arti ci p a nt at l e a st u ntil d at a b a s e l o c k of t h e p ar e nt st u di e s, w hi c h will 
h a p p e n w hil e t hi s st u d y i s o n g oi n g . 
P arti ci p a nt s w h o h a v e c o m pl et e d t h e p ar e nt st u d y G R A D U A T E  I or G R A D U A T E II, 
eit h er t h e d o u bl e -bli n d or O L E p art a s a p pli c a bl e, will b e eli gi bl e t o p arti ci p at e i n t hi s 
st u d y.  P arti ci p a nt s w h o di s c o nti n u e d e arl y fr o m st u d y tr e at m e nt d uri n g t h e p ar e nt st u d y 
G R A D U A T E  I or GR A D U A T E  II, r e g ar dl e s s of t h e r e a s o n, will n ot b e eli gi bl e f or t hi s 
st u d y.  
I nf or m e d c o n se nt s h o ul d b e o bt ai n e d fr o m p arti ci p a nt s w hil e t h e y ar e i n t h e p ar e nt s t u d y 
(G R A D U A T E  I or GR A D U A T E  II) i n cl u di n g t h e s af et y f oll o w-u p, u ntil a d a y b ef or e t h e 
fir st d o s e i n P O S T G R A D U A T E .  I n s p e ci al sit u ati o n s, i nf or m e d c o n s e nt c a n b e o bt ai n e d 
at a l at er t i m e p oi nt u p o n pr o vi di n g a n a p pr o pri at e r ati o n al e t o t h e S p o n s or, a n d it m u st 
b e o bt ai n e d b ef or e a n y st u d y pr o c e d ur e s i n t hi s st u d y ar e p erf or m e d.  
T h e fir st a d mi ni str ati o n of st u d y dr u g i n t hi s st u d y will b e a s f oll o w s: 
 
F or p arti ci p a nt s w h o c o m pl et e d t h e d o u bl e -bli n d p art a n d di d n ot e nt er t h e O L E 
p art of G R A D U A T E  I or GR A D U A T E  II: T h e fir st a d mi ni str ati o n of o p e n-l a b el 
st u d y dr u g s h o ul d t a k e pl a c e a p pr o xi m at el y 2 w e e k s aft er t h e l a st effi c a c y a n d 
s af et y vi sit of t h e d o u b l e-bli n d p art of t h e p ar e nt s t u d y (G R A D U A T E  I or 
G R A D U A T E II) a n d will b e c o n si d er e d t h e O L E b a s eli n e vi sit ( O L E D a y 1). 
 
F or p arti ci p a nt s w h o c o m pl et e d t h e d o u bl e -bli n d p art a n d t h e O L E p art of 
G R A D U A T E I or G R A D U A T E II , t h e fir st a d mi ni str ati o n of st u d y d r u g i n t hi s st u d y 
s h o ul d t a k e pl a c e a p pr o xi m at el y 2 w e e k s aft er t h e O L E W e e k 3 4 vi sit or t h e fi n al 
d o s e vi sit i n t h e G R A D U A T E  I or GR A D U A T E  II O L E.  P arti ci p a nt s w h o h a v e a 
g a p i n t h eir tr a n siti o n b et w e e n t h e O L E p art of t h e p ar e nt s t u d y (G R A D U A T E  I or 
G R A D U A T E  II) a n d t hi s st u d y, f or u nf or e s e e n r e a s o n s, will r oll o v er t o t hi s st u d y 
c o nti n ui n g t h e s c h e d ul e of a cti viti e s a s p er t h eir l a st vi sit i n t h e O L E p art of t h e 
p ar e nt st u d y ( G R A D U A T E  I or GR A D U A T E  II).  Di s c u s si o n wit h t h e S p o n s or i s 
r e c o m m e n d e d. 
P arti ci p a nt s wit h e vi d e n c e of a m yl oi d -r el at e d i m a gi n g a b n or m aliti e s –  e d e m a/ eff u si o n 
(A RI A -E ) o n t h e l a st p er -pr ot o c ol st u d y m a g n eti c r e s o n a n c e i m a gi n g ( M RI)  s c a n r e p ort 
i n G R A D U A T E  I or GR A D U A T E  II, eit h er it s d o u bl e-bli n d or O L E p art, a s a p pli c a bl e, will  
b e r et ai n e d i n G R A D U A T E  I or GR A D U A T E  II u ntil t h e A RI A -E fi n di n g i s r e s ol v e d.  T h e y 
m a y t h e n e nr oll i n P O S T G R A D U A T E .  F or t h o s e e nr olli n g fr o m t h e O L E p art , t h e fir st 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
1 1


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
1 2  
vi sit of t h e p arti ci p a nt s i n P O S T G R A D U A T E  will b e a d a pt e d a c c or di n g t o t h e s c h e d ul e of 
t h e vi sit s of e a c h p arti ci p a nt i n t h e p ar e nt st u d y. 
T h e d at a fr o m t h e l a st vi sit i n G R A D U A T E  I or GR A D U A T E  II ( e. g., fi n al effi c a c y a n d 
s af et y vi sit of t h e d o u bl e -bli n d p art or l a st vi sit i n t h e G R A D U A T E  I or GR A D U A T E  II 
O L E p art) will b e u s e d a s t h e d at a f or t h e fir st vi sit i n t hi s st u d y if t h e t w o vi sit s t a k e pl a c e 
wit hi n 4 w e e k s of e a c h ot h er.  All c o g niti v e s c al e s, a n d t h e C ol u m bi a -s ui ci d e s e v erit y 
r ati n g s c al e (C -S S R S ) d o n ot n e e d t o b e r e p e at e d if t h e y w er e p erf or m e d wit hi n 6 
m o nt h s i n t h e pr e vi o u s p a r e nt st u d y.  T h e M RI s c a n d o e s n ot n e e d t o b e r e p e at e d if 
p erf or m e d wit hi n 6 m o nt h s i n t h e pr e vi o u s p ar e nt s t u d y (G R A D U A T E  I or GR A D U A T E  II) 
a n d f oll o wi n g t h e fi n al st u d y dr u g d o s e i n t h e p ar e nt st u d y.  Vit al si g n s a n d uri n e 
pr e g n a n c y t e st will h a v e t o b e p erf or m e d at t h e fir st vi sit i n t hi s st u d y b ef or e d o si n g.  M RI 
a n d uri n e pr e g n a n c y t e st r e s ult s m u st b e a v ail a bl e b ef or e d o si n g.  
I n t hi s st u d y, p arti ci p a nt s w h o w er e i n t h e a cti v e d o u bl e-bli n d ar m i n t h e p ar e nt s t u d y 
(G R A D U A T E  I or GR A D U A T E  II) will c o nti nu e r e c ei vi n g o p e n -l a b el g a nt e n er u m a b 
5 1 0  m g s u b c ut a n e o u sl y ( S C ) e v er y t w o w e e k s (Q 2 W ), a n d t h o s e p arti ci p a nt s w h o w er e 
i n t h e pl a c e b o d o u bl e-bli n d ar m will g o t hr o u g h a f ull u p titr ati o n  s c h e m e w hil e r et ai ni n g 
t h e bli n di n g t o t h e pr e vi o u s tr e at m e nt all o c ati o n.  D et ail s of t h e d o si n g s c h e m e ar e 
d e s cri b e d i n S e cti o n 4. 3. 2 of t h e st u d y pr ot o c ol .  If t h er e i s a d el a y i n a p arti ci p a nt’ s 
tr a n siti o n b et w e e n t h e O L E p art of t h e p ar e nt s t u d y (G R A D U A T E  I or GR A D U A T E  II) 
a n d t hi s st u d y (f or i n st a n c e, d u e t o d el a y s i n t h e a p pr o v al of t hi s st u d y at a sit e) t h at 
g o e s b e y o n d a r e a s o n a bl e ti m e fr a m e a s d et er mi n e d b y t h e S p o n s or, t h e p arti ci p a nt 
m a y b e a s k e d t o st art at t h e d o s e t h e y w er e at pr e vi o u sl y w h e n t h e y c o m pl et e d t h e 
p ar e nt st u d y a n d t o p erf or m a s af et y M RI b ef or e r e c ei vi n g t h e t ar g et d o s e.  I n t hi s c a s e, 
s u c h d e ci si o n s will b e m a d e aft er di s c u s si o n wit h t h e S p o n s or.  
T h e d o si n g s c h e d ul e a n d t h e s c h e d ul e of a cti viti e s will b e diff er e nt f or p arti ci p a nt s, 
d e p e n di n g o n w h e t h er t h e y c o m pl et e d t h e O L E p art of G R A D U A T E  I or GR A D U A T E  II 
st u d y , w hi c h c o v er s t h e u p titr ati o n  p h a s e f or t h e p arti ci p a nt s i n t h e pl a c e b o ar m, or if 
t h e y c o m pl et e d o nl y t h e d o u bl e-bli n d p art.  D et ail s ar e d e s cri b e d i n A p p e n di x 1 of t h e 
st u d y pr ot o c ol . 
F oll o wi n g b a s eli n e a s s e s s m e nt s (i. e., O L E D a y 1 eit h er i n t hi s pr ot o c ol or i n t h e p ar e nt 
pr ot o c ol), e a c h p arti ci p a nt will b e tr e at e d f or 4  y e ar s.  T h e st u d y d ur ati o n h a s b e e n 
e xt e n d e d fr o m 2 t o 4 y e ar s t o c oll e ct m or e i nf or m ati o n o n t h e l o n g -t er m s af et y a n d 
t ol er a bilit y of g a nt e n er u m a b i n A D a n d it s effi c a c y i n t h e c o nt e xt of l o n g-t er m e x p o s ur e 
a n d t o i n cr e a s e t h e o v er all n u m b er of p arti ci p a nt -y e ar s of e x p o s ur e, t h u s i n cr e a si n g 
u n d er st a n di n g of g a nt e n er u m a b’ s l o n g -t er m s af et y a n d effi c a c y pr ofil e s.  U nl e s s 
p arti ci p a nt s ar e eli gi bl e a n d c h o o s e t o e nr oll i n a n alt er n ati v e g a nt e n er u m a b O L E st u d y 
t h at b e c o m e s a v ail a bl e, th e fi n al d o s e of st u d y dr u g will b e a d mi ni st er e d at O L E 
W e e k  2 0 6 .  At t h e e n d of t h e tr e at m e nt p eri o d, all p arti c i p a nt s will u n d er g o a n O L E 
W e e k  2 0 8  vi sit.  P arti ci p a nt s will b e a s k e d t o c o m e b a c k f or a f oll o w -u p vi sit at O L E 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
1 2


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
1 3  
W e e k  2 2 0  u nl e s s t h e y ar e tr a n siti o ni n g t o a n alt er n ati v e g a nt e n er u m a b O L E st u d y t h at 
b e c o m e s a v ail a bl e . 
P arti ci p a nt s w h o di s c o nti n u e st u d y dr u g at a n y ti m e d uri n g t hi s st u d y will b e a s k e d t o 
c o m pl et e a n e arl y t er mi n ati o n vi sit 2 w e e k s aft er t h eir fi n al d o s e a n d al s o r et ur n f or 
c oll e cti o n of s af et y d at a ( e x c e pt s af et y M RI) a n d li mit e d effi c a c y d at a (i. e., s e c o n d ar y 
e n d p oi nt s) ( s e e S e cti o n 4. 6. 1  of t h e st u d y pr ot o c ol ) or t o c o m p l et e t h e s af et y f oll o w-u p 
p eri o d a n d all r el at e d a s s e s s m e nt s . 
P arti ci p a nt s w h o d o n ot m e et t h e crit eri a f or p arti ci p ati o n i n t hi s st u d y ( s cr e e ni n g f ail ur e) 
m a y b e r e -s cr e e n e d.  T h e i n v e sti g at or will r e c or d r e a s o n s f or s cr e e ni n g f ail ur e i n t h e 
s cr e e ni n g l o g  ( S e cti o n 4. 5. 1 of t h e st u d y pr ot o c ol ). 
A n i nt eri m a n al y si s will b e c o n d u ct e d at t h e ti m e of t h e pri m ar y a n al y si s f or t h e 
G R A D U A T E p ar e nt st u di e s,  t o s u p p ort a p ot e nti al fili n g of g a nt e n er u m a b i n c a s e of 
p o siti v e r e a d -o ut of t h e pi v ot al st u di e s.  T h e a n al y si s will b e c o n si d er e d stri ctl y 
a d mi ni str ati v e  a n d will n ot i m p a ct t h e c o n d u ct of t h e st u d y, i. e., e arl y t er mi n ati o n f or 
f utilit y or effi c a c y will n ot b e c o n si d er e d.  T h e fi n al a n al y si s will t a k e pl a c e aft er t h e l a st 
p arti ci p a nt, l a st vi sit, o c c ur s or t h e d at e at w hi c h t h e l a st d at a p oi nt r e q uir e d f or st ati sti c al 
a n al y si s or s af et y f oll o w -u p i s r e c ei v e d fr o m t h e l a st p arti ci p a nt, w hi c h e v er o c c ur s l at er.  
C hi n a E nr oll m e nt Pl a n  
B a s e d o n hi st ori c al d at a, p arti ci p a nt r e cr uit m e nt i s e x p e ct e d t o t a k e l o n g er i n C hi n a; 
t h er ef or e, a s p e cifi c C hi n a e nr oll m e nt pl a n h a s b e e n e st a bli s h e d i n t h e G R A D U A T E  
p ar e nt st u di e s.   
I n t h e G R A D U A T E I st u d y, aft er c o m pl eti o n of t h e gl o b al e nr oll m e nt p h a s e, a d diti o n al 
p arti ci p a nt s ar e b ei n g e nr oll e d i n a n e xt e n d e d C hi n a e xt e n s i o n p h a s e at C hi n a' s sit e s i n 
m ai nl a n d C hi n a t o i n v e sti g at e t h e c o n si st e n c y i n tr e at m e nt eff e ct b et w e e n t h e C hi n a 
s u b p o p ul ati o n a n d t h e gl o b al p o p ul ati o n f or t h e p ur p o s e of r e gi str ati o n i n C hi n a.  
T h e gl o b al p o p ul ati o n will i n cl u d e all p arti ci p a nt s e nr oll e d  d uri n g t h e gl o b al e nr oll m e nt 
p h a s e (i n cl u di n g p arti ci p a nt s e nr oll e d at C hi n a’ s sit e s i n m ai nl a n d C hi n a,  H o n g K o n g, 
a n d T ai w a n, d uri n g t h at p h a s e), a n d t h e C hi n a s u b p o p ul ati o n will i n cl u d e all p arti ci p a nt s 
at C hi n a’ s sit e s (i. e. , d uri n g b ot h t h e gl o b al e nr oll m e nt p h a s e a n d t h e e xt e n d e d C hi n a 
e nr oll m e nt p h a s e).  
S e p ar at e a n al y s e s will b e p erf or m e d f or t h e gl o b al p o p ul ati o n a n d t h e C hi n a 
s u b p o p ul ati o n.  T h e a n al y si s of t h e C hi n a s u b p o p ul ati o n will b e c o n d u ct e d a n d r e p ort e d 
s e p ar at el y fr o m t h e a n al y si s d et ail e d  i n t hi s S A P. 
 
 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
1 3


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
1 4  
S u b st u di e s  
T h e s u b st u di e s a s s o ci at e d wit h P O S T G R A D U A T E  will b e d e s cri b e d i n s e p ar at e 
pr ot o c ol s, a n d p arti ci p a nt s c o n s e nti n g t o e nr oll i n t h e s e s u b st u di e s will b e a s k e d t o si g n 
t h e a s s o ci at e d I nf or m e d C o n s e nt F or m s.  T o d at e, t w o o pti o n al s u b st u di e s ar e 
a s s o ci at e d wit h P O S T G R A D U A T E : a l o n git u di n al a m yl oi d P E T s u b st u d y a n d a 
l o n git u di n al t a u P E T s u b st u d y. 
T h e a m yl oi d a n d t a u P E T a s s e s s m e nt s will e n a bl e a l o n git u di n al e v al u ati o n of t h e eff e ct 
of g a nt e n er u m a b o n br ai n a m y l oi d d e p o siti o n a s m e a s ur e d b y fl or b et a b e n or 
fl ut e m et a m ol P E T r a di oli g a n d s a n d t a u b ur d e n a s m e a s ur e d b y [1 8 F] G T P 1 ( G e n e nt e c h 
T a u Pr o b e 1; a n i n v e sti g ati o n al r a di oli g a n d f or i n vi v o i m a gi n g of t a u pr ot ei n a g gr e g at e s) 
i n p arti ci p a nt s wit h A D. 
T h e c oll e ct e d  P E T d at a ar e e x p e ct e d t o h el p i n u n d er st a n di n g t h e eff e ct s of 
g a nt e n er u m a b o n a m yl oi d a n d t a u p at h ol o g y o v er ti m e a s w ell a s t h e r el ati o n s hi p 
b et w e e n c h a n g e s i n fl or b et a b e n/fl ut e m et a m ol/[ 1 8 F] G T P 1 -P E T a n d c h a n g e s i n ot h er 
e n d p oi nt s i n P O S T G R A D U A T E . 
1. 2. 1  
Tr e at m e nt A s si g n m e nt  a n d Bli n di n g  
T hi s i s a n o n -r a n d o mi z e d, o p e n-l a b el st u d y.  A n i nt er a cti v e v oi c e or w e b -b a s e d 
r e s p o n s e s y st e m (I x R S) will b e u s e d t o m a n a g e p arti ci p a nt e nr oll m e nt a n d dr u g s u p pl y.  
Aft er i niti al writt e n i nf or m e d c o n s e nt h a s b e e n o bt ai n e d , t h e st u d y sit e m a y o bt ai n t h e 
p arti ci p a nt’ s i d e ntifi c ati o n n u m b er.  Aft er all s cr e e ni n g pr o c e d ur e s a n d a s s e s s m e nt s 
h a v e b e e n c o m pl et e d, a n d eli gi bilit y h a s b e e n e st a bli s h e d f or a p arti ci p a nt, t h e st u d y sit e 
will o bt ai n t h e p arti ci p a nt' s tr e at m e nt a s si g n m e nt fr o m t h e I x R S.  
P arti ci p a nt s r a n d o mi z e d t o t h e a cti v e tr e at m e nt ar m i n t h e p ar e nt s t u d y (G R A D U A T E  I 
or G R A D U A T E  II) will c o nti n u e t o b e a d mi ni st er e d t h e st u d y dr u g e v er y 2 w e e k s ( Q 2 W 
a d mi ni str ati o n of 5 1 0 m g S C g a nt e n er u m a b).  P arti ci p a nt s r a n d o mi z e d t o  t h e pl a c e b o 
ar m i n t h e p ar e nt s t u d y (G R A D U A T E  I or GR A D U A T E  II) will h a v e t o g o t hr o u g h at l e a st 
3 4 w e e k s of u ptitr ati o n.  P arti ci p a nt s, sit e s, a n d S p o n s or will r e m ai n bli n d e d t o pr e vi o u s 
tr e at m e nt all o c ati o n i n t h e p ar e nt s t u d y (G R A D U A T E  I or GR A D U A T E  II) t o pr ot e ct st u d y 
i nt e grit y. 
T o pr ot e ct st u d y d at a i nt e grit y a n d t o ai d t h e a s s e s s m e nt of t h e l o n g -t er m eff e ct s of 
g a nt e n er u m a b, st u d y sit e p er s o n n el a n d p arti ci p a nt s will b e bli n d e d t o pr e vi o u s 
tr e at m e nt a s si g n m e nt i n t h e p ar e nt s t u di e s (G R A D U A T E  I or GR A D U A T E  II).  T h e 
S p o n s or a n d it s a g e nt s will al s o b e bli n d e d t o pr e vi o u s tr e at m e nt a s si g n m e nt, at l e a st 
u ntil u n bli n di n g of t h e p ar e nt s t u di e s (G R A D U A T E  I a n d GR A D U A T E  II), w hi c h will 
h a p p e n w hil e t hi s st u d y i s o n g oi n g, wit h t h e e x c e pti o n of i n di vi d u al s w h o r e q uir e a c c e s s 
t o p arti ci p a nt’ s tr e at m e nt a s si g n m e nt s t o f ulfill t h eir j o b r ol e s d uri n g a cli ni c al tri al.  T h e s e 
r ol e s i n cl u d e t h e u n bli n di n g gr o u p r e s p o n si bl e, cli ni c al s u p pl y c h ai n m a n a g er s, 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
1 4


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
1 5  
o p er ati o n al a s s a y gr o u p p er s o n n el, I x R S s er vi c e pr o vi d er, a n d i n d e p e n d e nt D at a 
M o nit ori n g C o m mitt e e ( i D M C) m e m b er s.  
P h ar m a c o ki n eti c s a n d i m m u n o g e ni cit y s a m pl e s will b e c oll e ct e d fr o m all p arti ci p a nt s, 
r e g ar dl e s s of t h e tr e at m e nt a s si g n m e nt.  L a b or at ori e s r e s p o n si bl e f or p erf or mi n g st u d y 
dr u g P K a n d a nti -dr u g a nti b o d y ( A D A ) a s s a y s will b e u n bli n d e d t o p arti ci p a nt s’ tr e at m e nt 
a s si g n m e nt s.  B a s eli n e i m m u n o g e ni cit y s a m pl e s will b e a n al y z e d f or all p arti ci p a nt s.  
If u n bli n di n g i s n e c e s s ar y f or a m e di c al e m er g e n c y ( e. g., i n t h e c a s e of a s eri o u s 
a d v er s e e v e nt f or w hi c h p a rti ci p a nt m a n a g e m e nt mi g ht b e aff e ct e d b y k n o wl e d g e of 
tr e at m e nt a s si g n m e nt), t h e i n v e sti g at or will b e a bl e t o br e a k t h e tr e at m e nt c o d e b y 
c o nt a cti n g t h e I x R S.  T h e i n v e sti g at or i s n ot r e q uir e d t o c o nt a ct t h e M e di c al M o nit or pri or 
t o br e a ki n g t h e tr e at m e nt c o d e; h o w e v er, t h e tr e at m e nt c o d e s h o ul d n ot b e br o k e n 
e x c e pt i n e m er g e n c y sit u ati o n s.  
If t h e i n v e sti g at or wi s h e s t o k n o w t h e i d e ntit y of t h e st u d y dr u g f or a n y r e a s o n ot h er t h a n 
a m e di c al e m er g e n c y, h e or s h e s h o ul d c o nt a ct t h e M e di c al M o nit or dir e ctl y.  T h e 
i n v e sti g at or s h o ul d d o c u m e nt a n d pr o vi d e a n e x pl a n ati o n f or a n y n o n-e m er g e n c y 
u n bli n di n g.   If t h e M e di c al M o nit or a gr e e s t o p arti ci p a nt u n bli n di n g, t h e i n v e sti g at or will 
b e a bl e t o br e a k t h e tr e at m e nt c o d e s b y c o nt a cti n g t h e I x R S.  
A s p er h e alt h a ut h or it y r e p orti n g r e q uir e m e nt s, t h e S p o n s or' s Dr u g S af et y r e pr e s e nt ati v e 
will br e a k t h e tr e at m e nt a s si g n m e nt c o d e f or all s eri o u s, u n e x p e ct e d s u s p e ct e d a d v er s e 
r e a cti o n s ( s e e S e cti o n 5. 7 of t h e st u d y pr ot o c ol) t h at ar e c o n si d er e d b y t h e i n v e sti g at or 
or S p o n s or  t o b e r el at e d t o st u d y dr u g.  T h e p arti ci p a nt m a y c o nti n u e t o r e c ei v e 
tr e at m e nt, a n d t h e i n v e sti g at or, p arti ci p a nt, a n d S p o n s or p er s o n n el, wit h t h e e x c e pti o n of 
t h e Dr u g S af et y r e pr e s e nt ati v e a n d p er s o n n el w h o m u st h a v e a c c e s s t o p arti ci p a nt 
tr e at m e nt a s si g n m e nt s t o f ulfill t h eir r ol e s ( a s d efi n e d a b o v e), will r e m ai n bli n d e d t o 
tr e at m e nt a s si g n m e nt. 
1. 2. 2  
I n d e p e n d e nt R e vi e w F a cilit y 
M RI s c a n s will b e r e vi e w e d b y a c e ntr al M RI c or e l a b or at or y, w hi c h will p erf or m t h e 
di a g n o sti c r e a d s a n d a s s e s s m e nt s of M RI o ut c o m e  m e a s ur e s.  M RI s c a n s s h o ul d 
pr ef er a bl y b e tr a n sf err e d t o t h e c e ntr al M RI c or e l a b or at or y el e ctr o ni c all y.  D at a tr a n sf er 
fr o m i n di vi d u al st u d y sit e s t o t h e c e ntr al M RI c or e l a b or at or y m a y t a k e u p t o 7‑1 0 d a y s, if 
n ot d o n e el e ctr o ni c all y.  U p o n r e c ei pt of t h e M RI s c a n s fr o m t h e st u d y sit e s, t h e c e ntr al 
M RI c or e l a b or at or y will pr o vi d e t h e di a g n o sti c r e a d s.   M RI r e s ult s m u st b e m a d e 
a v ail a bl e t o i n v e sti g at or s pri or t o t h e d o si n g vi sit t h at t h e M RI c orr e s p o n d s t o (r ef er t o 
S e cti o n 5. 1. 2 of t h e st u d y pr ot o c ol f or a d diti o n al d et ail s o n M RI s af et y m a n a g e m e nt).  
M RI f a cilit y q u alifi c ati o n a n d s c a n q u alit y c o ntr ol will b e p erf or m e d b y t h e c e ntr al M RI 
c or e l a b or at or y.  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
1 5


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
1 6  
I n a d diti o n t o a n y l o c al r e a di n g a c c or di n g t o l o c al pr o c e d ur e s a n d r e q uir e m e nt s, all M RI 
s c a n s will b e r e vi e w e d b y a n e x p ert c e ntr al r e a d er wit hi n a p pr o xi m at el y 1 w e e k of 
r e c ei pt a n d a r e p ort pr o vi d e d t o t h e sit e.  F or t h e p ur p o s e s of o v er all st u d y r el e v a nt 
d e ci si o n s a n d r e c o m m e n d ati o n s, r e s ult s fr o m t h e e x p ert c e ntr al r e a d er will b e u s e d.  
A n y ti m e t h e c e ntr al r e a d er i d e ntifi e s a n e w M RI fi n di n g, t h e st u d y c e nt er m e di c al st aff 
a n d t h e S p o n s or will b e r a pi dl y n otifi e d ( s e e S e cti o n 5. 1. 2 of t h e st u d y pr ot o c ol).  
All M RI r e a d i n gs a n d v ol u m e m e a s ur e s will b e c o n d u ct e d b y t h e c e ntr al r e a d er.  
1. 2. 3  
D at a M o nit ori n g  
T h e i D M C will e v al u at e p arti ci p a nt s af et y o n a r e g ul ar b a si s.  I n a d diti o n t o t h e d at a 
d efi n e d i n t h e i D M C C h art er ( e. g., t h e i n ci d e n c e a n d n at ur e of a d v er s e e v e nt s, s eri o u s 
a d v er s e e v e nt s, a d v er s e e v e nt s of s p e ci al i nt er e st, A RI A -E, a m yl oi d -r el at e d i m a gi ng 
a b n or m aliti e s –  h e m o si d eri n d e p o siti o n [ A RI A -H ], a n d i nj e cti o n sit e r e a cti o n s [I S R s]), t h e 
i D M C will r e vi e w all n e c e s s ar y c u m ul ati v e d at a, i n cl u di n g effi c a c y d at a if n e c e s s ar y, at 
r e g ul ar i nt er v al s d uri n g t h e st u d y.  It i s a nti ci p at e d t h at t h e s e a s s e s s m ent s will o c c ur 
a p pr o xi m at el y e v er y 3 m o nt h s  or a s d et ail e d i n t h e i D M C c h art er .  At t h e ti m e of e a c h 
r e vi e w, t h e i D M C will m a k e a p pr o pri at e r e c o m m e n d ati o n s ( e. g., t h e st u d y s h o ul d 
c o nti n u e a s pl a n n e d, t h e s af et y ri s k m a n a g e m e nt s h o ul d b e m o difi e d, t h e pr ot o c ol 
s h o ul d ot h er wi s e b e a m e n d e d, a n d e nr oll m e nt s h o ul d b e h el d p e n di n g f urt h er s af et y 
e v al u ati o n s).  
D e ci si o n s will b e m a d e aft er c o n si d eri n g t h e t ot alit y of t h e a v ail a bl e d at a.  A d -h o c 
m e eti n g s m a y b e c all e d i n a d diti o n t o s c h e d ul e d m e eti n g s, a s n e c e s s ar y , t o pr o vi d e 
r e c o m m e n d ati o n s o n m a n a g e m e nt of a n y n e w s af et y i s s u e s.  S p e cifi c o p er ati o n al 
d et ail s, s u c h a s t h e c o m mitt e e' s c o m p o siti o n, fr e q u e n c y a n d ti mi n g of m e eti n g s, a n d 
m e m b er s' r ol e s a n d r e s p o n si biliti e s ar e d et ail e d i n t h e i D M C C h art er.  
Fi n al d e ci s i o n s will r e st wit h t h e S p o n s or. 
I n t h e e v e nt t h e i D M C w hi c h r e vi e w s s af et y i n b ot h t h e p ar e nt s t u di e s (G R A D U A T E  I 
a n d G R A D U A T E II) a n d P O S T G R A D U A T E  i s n o l o n g er r e q uir e d (f or i n st a n c e aft er t h e 
u n bli n di n g of t h e p ar e nt st u di e s) e v al u ati o n of p arti ci p a nt s af et y m a y b e t a k e n o v er b y 
t h e S p o n s or' s I nt er n al M o nit ori n g C o m mitt e e (I M C), wit h d et ail s d o c u m e nt e d i n a n I M C 
C h art er.  
1. 2. 4  
A RI A M a n a g e m e nt  
I n P O S T G R A D U A T E , t a ki n g i nt o a c c o u nt t h e e v ol vi n g e x p eri e n c e wit h m a n a gi n g A RI A 
fi n di n g s, i n cl u di n g t h e fi n di n g t h at c onti n u e d g a nt e n er u m a b tr e at m e nt d uri n g e pi s o d e s of 
a s y m pt o m ati c mil d A RI A -E w a s n ot a s s o ci at e d wit h cli ni c all y u nf a v or a bl e o ut c o m e s, t h e 
S p o n s or i nt e n d s t o e x a mi n e t h e s af et y of c o nti n ui n g g a nt e n er u m a b tr e at m e nt t hr o u g h 
mil d t o m o d er at e a s y m pt o m ati c A RI A -E fi n di n g s a n d t o e x a mi n e t h e s af et y of 
g a nt e n er u m a b t h er a p y i n t h e pr e s e n c e of a n i n cr e a s e d n u m b er of A RI A -H  
(mi cr o h e m orr h a g e s ).  I n t h e p ar e nt st u di e s, tr e at m e nt w a s i nt err u pt e d f or p arti ci p a nt s 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
1 6


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
1 7  
wit h a s y m pt o m ati c A RI A -E wit h a B G T S  4 or s y m pt o m ati c A RI A -E a n d di s c o nti n u e d f or 
p arti ci p a nt s wit h m or e t h a n 1 5 A RI A -H  or wit h di s s e mi n at e d l e pt o m e ni n g e al 
h e m o si d er o si s .  I n t hi s st u d y, A RI A m a n a g e m e nt r ul e s ar e b a s e d o n t h e Bi o cli ni c a 
5 ‑p oi nt s e v erit y s c or e  (r e n a m e d a s S e v erit y S c al e of A RI A -E ( S S A E) si n c e t h e writi n g of 
t h e st u d y pr ot o c ol) a n d tr e at m e nt i s i nt err u pt e d f or a s y m pt o m ati c A RI A -E wit h a 
Bi o cli ni c a s c or e    4 or s y m pt o m ati c A RI A -E of a n y s e v erit y  wit h C N S s y m pt o m s 
attri b ut a bl e t o A RI A -E i n t h e j u d g e m e nt of t h e i n v e sti g at or  a n d di s c o nti n u e d f or A R I A-H 
wit h di s s e mi n at e d l e pt o m e ni n g e al h e m o si d er o si s.   Di s s e mi n at e d l e pt o m e ni n g e al 
h e m o si d er o si s i s d efi n e d a s m or e t h a n t hr e e f o c al l e pt o m e ni n g e al h e m o si d er o si s 
c u m ul ati v el y.  
2.  
S T A TI S TI C A L H Y P O T H E S E S  
All a n al y s e s pr o vi d e d i n t hi s d o c u m e nt ar e d e s cri pti v e, t h u s n o st ati sti c al h y p ot h e si s will 
b e t e st e d i n t h e s e a n al y s e s.   
3.  
S A M P L E SI Z E D E T E R MI N A TI O N  
T h e s a m pl e si z e will b e d et er mi n e d b y t h e n u m b er of p arti ci p a nt s w h o c o m pl et e t h e 
p ar e nt s t u di e s (G R A D U A T E  I a n d GR A D U A T E  II) a n d e nr oll i n t hi s st u d y.  T h e s a m pl e 
si z e i s e x p e ct e d t o b e n o m or e t h a n a p pr o xi m at el y 2 0 3 2 p arti ci p a nt s .  
4.  
A N A L Y SI S S E T S  
T h e f oll o wi n g a n al y si s s et s  ar e d efi n e d:  
A n al y si s S et  
D efi niti o n  
All e nr oll e d p arti ci p a nt s  
All e nr oll e d p arti ci p a nt s (i. e.; w h o si g n e d t h e i nf or m e d c o n s e nt 
f or m a n d ar e m ar k e d a s e nr oll e d i n I x R S), w h et h er or n ot t h e 
p arti ci p a nt r e c ei v e d t h e a s si g n e d tr e at m e nt.  
I TT ( i nt e nt t o tr e at) 
All e nr oll e d  p arti ci p a nt s , w h o r e c ei v e d at l e a st o n e d o s e of st u d y 
dr u g .  P arti ci p a nt s will b e a n al y z e d b y t h e tr e at m e nt t h e y w er e 
r a n d o mi z e d t o i n t h e p ar e nt st u di e s. 
S af et y -e v al u a bl e  ( S E) 
All p arti ci p a nt s  e nr oll e d  w h o r e c ei v e d at l e a st o n e d o s e of st u d y 
dr u g i n t hi s st u d y  or i n t h e O L E p art of t h e p ar e nt st u di e s .   A n y 
p arti ci p a nt r a n d o mi z e d t o pl a c e b o i n t h e p ar e nt st u di e s w h o 
r e c ei v e d at l e a st o n e d o s e ( a n y d o s e) of a cti v e dr u g  d uri n g t h e 
d o u bl e -bli n d tr e at m e nt i n t h e p ar e nt st u di e s  will b e s u m m ari z e d 
a s h a vi n g r e c ei v e d t h e a cti v e dr u g i n t h e p ar e nt st u di e s. 
M RI s a f et y-e v al u a bl e 
( M-S E)  
All p arti ci p a nt s i n t h e s af et y -e v al u a bl e a n al y si s s et  w h o h a d at 
l e a st o n e p o st-b a s eli n e s af et y M RI s c a n.  
I m m u n o g e ni cit y 
All e nr oll e d p arti ci p a nt s wit h at l e a st o n e A D A a s s e s s m e nt.  
M RI  m o difi e d i nt e nt -t o-
tr e at ( M RI-mI T T)  
All p arti ci p a nt s i n t h e I T T a n al y si s s et w h o h a d at l e a st o n e v ali d 
v ol u m etri c M RI q u a ntit ati v e m e a s ur e m e nt.  
C S F m o difi e d i nt e nt-t o-
tr e at ( C S F-m I T T) 
All p arti ci p a nt s i n t h e I T T a n al y si s s et  w h o h a d at l e a st o n e  v ali d 
q u a ntit ati v e  c er e br o s pi n al fl ui d ( C S F) m e a s ur e m e nt .  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
1 7


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
1 8  
A m yl oi d P E T m o difi e d 
I T T ( a P E T-mI T T)  
All e nr oll e d p arti ci p a nt s of t h e I T T a n al y si s s et  w h o c o n s e nt e d t o 
t h e A m yl oi d P E T s u b st u d y, di d n ot wit h dr a w c o n s e nt b ef or e 
e nr ol m e nt i n t h e s u b st u d y  a n d h a d at l e a st o n e a m yl o i d P E T 
s c a n wit h a v ali d q u a ntit ati v e m e a s ur e m e nt . 
T a u P E T  m o difi e d  I T T 
(t P E T-mI T T)  
All e nr oll e d p arti ci p a nt s of t h e I T T a n al y si s s et  w h o c o n s e nt e d t o 
t h e T a u P E T s u b st u d y, di d n ot wit h dr a w c o n s e nt b ef or e 
e nr ol m e nt i n t h e s u b st u d y  a n d h a d at l e a st o n e t a u P E T s c a n 
wit h a v ali d q u a ntit ati v e m e a s ur e m e nt . 
I T T  i nt e nt t o tr e at; S E   s af et y -e v al u a bl e ; M -S E   M RI s af et y -e v al u a bl e.  
  
5.  
S T A TI S TI C A L A N A L Y S E S  
5. 1  
G E N E R A L C O N SI D E R A TI O N  
T h e p ur p o s e of t hi s st u d y i s t o a s s e s s t h e s af et y, t ol er a bilit y, a n d effi c a c y of l o n g -t er m 
a d mi ni str ati o n of o p e n -l a b el g a nt e n er u m a b i n p arti ci p a nt s wit h A D w h o c o m pl et e d 
G R A D U A T E  I or GR A D U A T E  II. 
T h e p eri o d of t h e P O S T G R A D U A T E  st u d y a n d t h e O L E p eri o d fr o m t h e p ar e nt st u di e s 
will h e n c ef ort h b e r ef err e d t o a s t h e O L E p eri o d.  D at a fr o m t h e O L E p eri o d, i. e., fr o m 
O L E b a s eli n e ( s e e  S e cti o n  5. 1. 1  b el o w  f or d efi niti o n) t o t h e e n d of st u d y, will b e 
s u m m ari z e d.  C o n s e q u e ntl y, f or p arti ci p a nt s w h o c o m pl et e d t h e O L E p art of t h e p ar e nt 
st u di e s  a n d g a v e i nf or m e d c o n s e nt f or t h e P O S T G R A D U A T E st u d y , t h e d at a c oll e ct e d 
i n t h e O L E p eri o d of t h e p ar e nt st u di e s will b e i n cl u d e d i n t h e C S R  of P O S T G R A D U A T E .  
T hi s will e n s ur e t h at d at a fr o m b a s eli n e a n d u ptitr ati o n ar e i n cl u d e d i n t h e a n al y s e s f or 
all p arti ci p a nt s of P O S T G R A D U A T E .  P arti ci p a nt s o f t h e O L E p eri o d of t h e p ar e nt 
st u di e s w it h o ut i nf or m e d c o n s e nt t o P O S T G R A D U A T E  c a n n ot b e i n cl u d e d i n t h e 
a n al y s e s f or t h e C S R of P O S T G R A D U A T E  a n d will i n st e a d b e i n cl u d e d i n t h e a n al y s e s 
wit hi n t h e p ar e nt st u di e s’ C S R s . 
All a n al y s e s will b e p ur el y d e s cri p ti v e a n d n o i m p ut ati o n of mi s si n g d at a will b e 
p erf or m e d.   F or c o nti n u o u s d at a, d e s cri pti v e st ati sti c s of m e a n, st a n d ar d d e vi ati o n, 
m e di a n, 1
st a n d 3 r d q u artil e a s w ell a s mi ni m u m a n d m a xi m u m a n d n u m b er of a v ail a bl e 
d at a will b e pr o vi d e d.   F or c at e g ori c al d at a, n u m b er a n d fr e q u e n c y will b e pr o vi d e d f or 
e a c h c at e g or y a s w ell a s t h e n u m b er of a v ail a bl e d at a.  
All a n al y s e s of s af et y e n d p oi nt s will b e b a s e d o n t h e S E a n al y si s s et  u nl e s s m e nti o n e d 
ot h er wi s e w hil e all a n al y s e s of effi c a c y e n d p oi nt s will b e p erf or m e d f or t h e I T T a n al y si s 
s et .  T h e i m m u n o g e ni cit y a n al y si s s et  will b e u s e d f or i m m u n o g e ni cit y a n al y s e s.  
R e s ult s will b e s h o w n s e p ar at el y b a s e d o n pr e vi o u s tr e at m e nt i n t h e G R A D U A T E  p ar e nt 
st u di e s G R A D U A T E  I a n d GR A D U A T E  II, a n d b y p arti ci p ati o n / n o n -p arti ci p ati o n i n t h e 
O L E p art of t h e p ar e nt st u di e s  a n d o v er all .  F or a n al y s e s u si n g t h e I T T a n al y si s s et , t hi s 
will b e t h e tr e at m e nt a s r a n d o mi z e d i n t h e p ar e nt st u di e s; f or a n al y s e s u si n g t h e S E 
a n al y si s s et , t hi s will b e t h e tr e at m e nt a ct u all y r e c ei v e d i n t h e p ar e nt st u di e s. 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
1 8


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
1 9  
T h e r e s ult s ar e s h o w n s e p ar at el y b y p arti ci p ati o n / n o n -p arti ci p ati o n i n t h e O L E p art of 
t h e p ar e nt st u di e s t o miti g at e t h e i ntr o d u cti o n of bi a s i nt o t h e o v er all r e s ult s.  T h e 
n o n ‑i n cl u si o n of p arti ci p a nt s w h o di s c o nti n u ed d uri n g t h e O L E p art of t h e p ar e nt st u di e s 
a n d d o  n o t h a v e a n i nf or m e d c o n s e nt t o P O S T G R A D U A T E  i ntr o d u c e s a n i m m ort al ti m e 
bi a s  i n c ert ai n a n al y s e s f or t hi s gr o u p of p arti ci p a nt s f or t h e O L E p art of t h e p ar e nt 
st u di e s.  T h e s e p ar ati o n i s f urt h er r e q uir e d d u e t o diff er e nt A RI A m a n a g e m e nt r ul e s i n 
t h e p ar e nt st u di e s a n d t hi s st u d y.  
5. 1. 1  
D efi niti o n of B a s eli n e  
T h e fir st d o si n g vi sit i n t h e O L E will b e c o n si d er e d a s b a s eli n e ( O L E D a y 1).  T h e l a st 
a v ail a bl e a s s e s s m e nt m a d e b ef or e or o n O L E D a y 1 will b e c o n si d er e d  t h e b a s eli n e 
a s s e s s m e nt if o c c urri n g  wit hi n 1 2  w e e k s b ef or e or o n O L E D a y 1  a n d pri or t o fir st d o s e  
f or st a n d ar d-of -c ar e e x a mi n ati o n s or wit hi n 6 m o nt h s f or C -S S R S, c o g niti v e s c al e r e s ult s 
a n d M RI s c a n s.   F or A D A d at a, b a s eli n e will b e t h e b a s eli n e v al u e of t h e p ar e nt st u di e s  
t o e n s ur e t h at t h e b a s eli n e v al u e i s b ef or e a n y d o s e of t h e i n v e sti g ati o n al pr o d u ct.  
5. 2  
P A R TI CI P A N T DI S P O SI TI O N  
T h e a n al y si s of p arti ci p a nt di s p o siti o n will b e b a s e d o n all e nr oll e d  p arti ci p a nt s ( s e e 
a n al y si s s et s i n  S e cti o n  4 ).  T h e n u m b er of p arti ci p a nt s e nr oll e d will b e t a b ul at e d b y 
c o u ntr y  a n d  sit e.  P arti ci p a nt di s p o siti o n (t h e n u m b er of p arti ci p a nt s e nr oll e d , tr e at e d, 
a n d c o m pl eti n g  t h e st u d y) will b e t a b ul at e d.  Pr e m at ur e st u d y dr u g di s c o nti n u ati o n a n d 
st u d y di s c o nti n u ati o n, a s w ell a s r e a s o n s f or di s c o nti n u ati o n s, will b e s u m m ari z e d.  
M aj or pr ot o c ol d e vi ati o n s, i n cl u di n g m aj or d e vi ati o n s wit h r e g ar d t o t h e i n cl u si o n a n d 
e x cl u si o n crit eri a, will b e s u m m ari z e d.  S e p ar at e t a bl e s will b e pr o vi d e d f or C O VI D -
1 9 ‑r el at e d m aj or pr ot o c ol d e vi ati o n s a n d r e a s o n s f or C O VI D-1 9 -r el at e d m aj or pr ot o c ol 
d e vi ati o n s.  
5. 3  
P RI M A R Y E N D P OI N T S A N A L Y SI S  
5. 3. 1  
D efi niti o n of Pri m ar y E n d p oi nt s  
 
T h e  pri m ar y o bj e cti v e f or t hi s st u d y i s t o e v al u at e t h e s af et y a n d t ol er a bilit y of l o n g -t er m 
g a nt e n er u m a b a d mi ni st er e d b y S C i nj e cti o n o n t h e b a si s of a d v er s e e v e nt s ( A E s), 
p h y si c al e x a mi n ati o n s, vit al si g n s, E C G s, l a b or at or y t e st s, C -S S R S, A RI A -E a n d 
A RI A ‑H,  I S R s, tr e at m e nt di s c o nti n u ati o n s f or A E s, a n d i n ci d e n c e of A E s of s p e ci al 
i nt er e st. 
T h e c orr e s p o n di n g pri m ar y e n d p oi nt s ar e:  
 
N at ur e, fr e q u e n c y, s e v erit y, ti mi n g, a n d o ut c o m e s of a d v er s e e v e nt s a n d s eri o u s 
a d v er s e e v e nt s  
 
P h y si c al e x a mi n ati o n s (i n cl u di n g n e ur ol o gi c s y st e m s), vit al si g n s, E C G, l a b or at or y 
t e st s, a n d C ol u m bi a-S ui ci d e S e v erit y R ati n g S c al e ( C -S S R S)  
 
N at ur e, fr e q u e n c y, s e v erit y, a n d ti mi n g of A RI A -E a n d A RI A -H  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
1 9


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
2 0  
 
N at ur e, fr e q u e n c y, s e v erit y, ti mi n g, a n d o ut c o m e s of I S R s  
 
I n ci d e n c e of tr e at m e nt di s c o nti n u ati o n s f or a d v er s e e v e nt s 
 
I n ci d e n c e of a d v er s e e v e nt s of s p e ci al i nt er e st 
T h e a n al yti c al a p pr o a c h e s ar e d e s cri b e d i n p erti n e nt s u b s e cti o n f or e a c h e n d p oi nt 
b el o w.  
5. 3. 2  
M ai n A n al yti c al A p pr o a c h  f or Pri m ar y E n d p oi nt( s) 
All t h e s e s af et y a n al y s e s will b e p erf or m e d i n t h e S E  a n al y si s s et , e x c e pt f or a n al y s e s of 
A RI A -E or A RI A -H , C N S s y m pt o m s t e m p or all y a s s o ci at e d wit h A RI A e v e nt s  or ot h er 
M RI s af et y fi n di n g s  t h at will b e b a s e d o n t h e M-S E a n al y si s s et . 
P arti ci p a nt s will b e a n al y z e d a c c or di n g t o t h e  pr e vi o u s  tr e at m e nt t h e y a ct u all y r e c ei v e d 
i n t h e p ar e nt st u di e s a n d b y p arti ci p ati o n / n o n -p arti ci p ati o n i n t h e O L E p art of t h e p ar e nt 
st u di e s .  
D e s cri pti v e st ati sti c s will b e u s e d t o a n al y z e all s af et y d at a c oll e ct e d i n t h e st u d y  i n t h e 
S E  a n al y si s s et , u nl e s s ot h er wi s e s p e cifi e d.  
S af et y a n al y s e s will pr o vi d e s u m m ari e s of e x p o s ur e t o st u d y tr e at m e nt, a d v er s e e v e nt s, 
c h a n g e s i n l a b or at or y t e st r e s ult s  (i n cl u di n g s hift t a bl e s), M RI fi n di n g s, c h a n g e s i n vit al 
si g n s a n d E C G s, a n d c h a n g e s i n C -S S R S s c or e s a s d e s cri b e d i n p erti n e nt s e cti o n s 
b el o w.  
5. 3. 3  
A d v er s e E v e nt s  
All v er b ati m A E t er m s will b e c o d e d u si n g t h e M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s 
( M e d D R A) v er si o n t h at i s c urr e nt at t h e ti m e of t h e a n al y si s ( V er si o n 2 5 . 0 or hi g h er), a n d 
A E s e v erit y will b e gr a d e d a c c or di n g t o t h e s c al e d efi n e d i n T a bl e 3 i n S e cti o n 5. 3. 3 of 
t h e st u d y pr ot o c ol ( mil d/ m o d er at e/ s e v er e).  F or e a c h di s pl a y e d p arti ci p a nt gr o u p , t h e 
fr e q u e n c y of e a c h A E pr ef err e d t er m will b e d efi n e d a s t h e n u m b er of p arti cip a nt s 
e x p eri e n ci n g at l e a st o n e o c c urr e n c e of t h e e v e nt.  E a c h t a bl e will pr e s e nt t h e o v er all 
n u m b er a n d p er c e nt a g e of p arti ci p a nt s e x p eri e n ci n g at l e a st o n e  A E a n d t h e t ot al 
n u m b er of A E s r e p ort e d.  P er c e nt a g e s will b e b a s e d o n t h e n u m b er of p arti ci p a nt s i n t h e 
S E  a n al y si s s et .  I n s u m m ar y t a bl e s, A E s will b e s ort e d b y b o d y s y st e m (i n d e cr e a si n g 
or d er of o v er all i n ci d e n c e), t h e n b y pr ef err e d t er m (i n d e cr e a si n g or d er of o v er all 
i n ci d e n c e).  T h e s u m m ar y t a bl e s will b e r e stri ct e d t o tr e at m e nt -e m er g e nt A E s, i. e., A E s 
t h at o c c ur or w or s e n  o n or aft er t h e d a y of fir st O L E d o s e , wit h o n s et n o l at er t h a n 1 4 
w e e k s aft er l a st d o s e .  N o n -tr e at m e nt-e m er g e nt A E s  (A E s o n g oi n g at O L E D a y 1 wit h 
o n s et b ef or e t h e fir st O L E d o s e) a n d A E s o c c urri n g m or e t h a n 1 4 w e e k s aft er t h e l a st 
d o s e will b e li st e d. 
T h e f oll o wi n g s af et y i nf or m ati o n will b e s u m m ari z e d:   
 
A E s , A E s b y i nt e n sit y, A E s r el at e d t o st u d y dr u g 
 
A E s wit h f at al o ut c o m e  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
2 0


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
2 1  
 
S eri o u s A E s ( S A E s) , S A E s b y i nt e n sit y, S A E s r el at e d t o st u d y dr u g 
 
A E s l e a di n g t o di s c o nti n u ati o n of  st u d y tr e at m e nt  
 
A E s l e a di n g t o d o s e m o difi c ati o n s ( d o s e i nt err u pti o n, d o s e r e d u cti o n, or d el a y e d  u p -
titr ati o n).  D el a y e d u p -titr ati o n at a n y gi v e n vi sit i s d efi n e d a s t h e si m ult a n e o u s 
o c c urr e n c e of t h e f oll o wi n g t w o ti c k b o x e s i n t h e e C R F A d v er s e E v e nt f or m: 
o  A cti o n t a k e n wit h o p e n l a b el g a nt e n er u m a b d u e t o S A E/ A E : D o s e N ot 
C h a n g e d  
o  If D o s e n ot c h a n g e d, w a s o p e n l a b el d o s e r e gi m e n m o difi e d fr o m pr ot o c ol 
s c h e d ul e d u e t o S A E/ A E ? Y e s  
 
Inj e cti o n sit e r e a cti o n (I S R) si g n s a n d s y m pt o m s  
 
S y st e mi c i nj e cti o n r e a cti o n s ( A E s wit h “ s y st e mi c r e a cti o n” s el e ct e d) 
Pr ot o c ol -s p e cifi e d a d v er s e e v e nt s of s p e ci al i nt er e st ( A E SI) will b e li st e d.  
T h e i m p a ct of t h e C O VI D -1 9 p a n d e mi c o n t h e s af et y d at a will b e a s s e s s e d b y r e vi e wi n g  
t h e f oll o wi n g: 
 
C o nfir m e d or s u s p e ct e d C O VI D -1 9 A E s  
 
A E s a s s o ci at e d wit h C O VI D -1 9  
 
P ot e nti al l o n g C O VI D -1 9 s y m pt o m s  
T h e f oll o wi n g d at a h a n dli n g r ul e s will b e a p pli e d f or all  A E s u m m ar y t a bl e s:  
 
E v e nt s t h at ar e mi s si n g b ot h o n s et a n d e n d d at e s will b e c o n si d er e d t o h a v e st art e d 
aft er t h e fir st d o s e of st u d y dr u g a n d t h e d ur ati o n will b e s et t o mi s si n g.  
 
If t h e o n s et d at e i s mi s si n g, a n d t h e e n d d at e i s o n or aft er t h e fir st d o si n g d at e or 
u nr e s ol v e d or mi s si n g, t h e n t h e e v e nt will b e c o n si d er e d t o h a v e st art e d aft er t h e 
fir st d o s e of st u d y dr u g. 
T h e f oll o wi n g d at a h a n dli n g r ul e s will al s o b e a p pli e d f or s p e cifi c t a bl e s:  
 
A n A E will b e i n cl u d e d i n t h e s u m m ar y t a bl e of A E s l e a di n g t o st u d y dr u g 
di s c o n ti n u ati o n if t h e “ a cti o n t a k e n wit h o p e n l a b el  g a nt e n er u m a b” dr o p -d o w n m e n u 
o n t h e A E e C R F i s c h e c k e d “ dr u g wit h dr a w n”.  
 
I n t h e s u m m ar y t a bl e of A E s b y i nt e n sit y, if a p arti ci p a nt h a s m or e t h a n o n e 
o c c urr e n c e of a n e v e nt, t h e e v e nt wit h t h e m o st s e v er e i nt e n sit y will b e c o u nt e d.  If 
t h e i nt e n sit y of a n A E i s mi s si n g, t h e n t h e A E will b e i n cl u d e d o nl y i n t h e t ot al 
n u m b er of e v e nt s c ol u m n, a n d n ot i n t h e c o u nt of p arti ci p a nt s wit h t h e e v e nt b y 
i nt e n sit y. 
 
I n t h e s u m m ar y t a bl e of A E s r el at e d t o st u d y dr u g, if a p arti ci p a nt h a s m or e t h a n 
o n e o c c urr e n c e of a n e v e nt, t h e r el at e d e v e nt will b e c o u nt e d if a p pli c a bl e.  If t h e 
r el ati o n s hi p of a n A E i s mi s si n g, t h e n t h e A E will n ot b e i n cl u d e d i n t h e c o u nt of 
p arti ci p a nt s wit h t h e e v e nt b y r el ati o n s hi p  
 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
2 1


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
2 2  
5. 3. 4  
M a g n eti c R e s o n a n c e I m a gi n g S af et y Fi n di n g s  
A RI A -E a n d A RI A -H ar e i d e ntifi e d ri s k s a s s o ci at e d wit h g a nt e n er u m a b.  Sit e s w er e 
a s k e d t o c a pt ur e A RI A  fi n di n g s a s A E s i n t h e P O S T G R A D U A T E e C R F if t h e y m et a n y of 
t h e f oll o wi n g crit eri a: 
 
S y m pt o m ati c A RI A -E ( o n s et or w or s e ni n g of C N S s y m pt o m[ s] attri b ut a bl e t o  A RI A -E 
M RI fi n di n g s i n t h e j u d g e m e nt of t h e i n v e sti g at or), a n d/ or  
 
A RI A fi n di n g s t h at r e s ult i n a c h a n g e i n st u d y tr e at m e nt ( e. g., d o s a g e m o difi c ati o n, 
tr e at m e nt i nt err u pti o n, or tr e at m e nt di s c o nti n u ati o n), a n d/ or 
 
Fi n di n g s t h at ar e ot h er wi s e cli ni c all y si g nifi c a nt i n t h e i n v e sti g at or’ s j u d g m e nt  
N ot all A RI A M RI fi n d i n g s q u alif y a s A E.  A RI A a n al y s e s will b e m ai nl y b a s e d o n A RI A 
M RI fi n di n g s.  A RI A A E s will al s o b e r e p ort e d.   A RI A a n al y s e s will b e r e stri ct e d t o A RI A s 
d o c u m e nt e d d uri n g t hi s st u d y or t h e O L E p art of t h e p ar e nt st u di e s.  
B a s e d o n M RI d at a, t h e i n ci d e n c e, s e v erit y ( b a s e d o n t h e Bi o cli ni c a s e v erit y s c al e  ( s e e 
A p p e n di x  2 ) a n d t h e  B ar k h of Gr a n d T ot al S c or e [ B G T S]) a n d ti mi n g of A RI A -E a n d  t h e 
i n ci d e n c e a n d ti mi n g of A RI A -H will b e s u m m ari z e d o v er all a n d al s o b y A P O E ε 4 
g e n ot y p e ( b y n u m b er of all el e s ) a n d b y d o s e l e v el.  F or p arti ci p a nt s fr o m t h e O L E p art of 
t h e p ar e nt st u di e s, o nl y A RI A-E s e v erit y m e a s ur e d b y t h e B G T S i s a v ail a bl e f or e v e nt s 
t h at o c c urr e d d uri n g t h e O L E p art of t h e p ar e nt st u di e s.  T h e ti mi n g of A RI A -E a n d 
A RI A -H m a y b e s u m m ari z e d b y d e s cri pti v e st ati sti c s.  R e c urr e n c e of A RI A -E wit hi n t hi s 
st u d y or t h e O L E p art of t h e p ar e nt st u di e s  will b e s u m m ari z e d.  A RI A -E wit h a s s o ci at e d 
a n d attri b ut a bl e  C N S s y m pt o m s ( s e e S e cti o n  5. 3. 4. 1 ) a n d s eri o u s a s s o ci at e d a n d 
attri b ut a bl e  C N S s y m pt o m s will b e s u m m ari z e d o v er all a n d al s o b y A P O E ε 4 g e n ot y p e  
( b y n u m b er of all el e s).  T e m p or al c o-o c c urr e n c e of A RI A -E a n d A RI A -H will b e 
s u m m ari z e d o v er all a n d al s o b y A P O E ε 4 g e n ot y p e.  T e m p or al c o -o c c urr e n c e i s d efi n e d 
a s a n M RI s c a n s h o wi n g n e w A RI A -H t h at o c c ur s b et w e e n A RI A -E o n s et a n d r e s ol uti o n 
(i n cl u si v e), irr e s p e cti v e of t h e br ai n r e gi o n. 
M RI fi n di n g s ot h er t h a n A RI A will al s o b e s u m m ari z e d.  
5. 3. 4. 1  
C N S S y m pt o m s T e m p or all y A s s o ci at e d wit h a n d Attri b ut a bl e 
t o A RI A -E M RI Fi n di n g s  
C N S s y m pt o m s t e m p or all y a s s o ci at e d wit h a n d attri b ut a bl e t o A RI A -E ar e d efi n e d a s 
o n s et or w or s e ni n g of C N S s y m pt o m( s) t h at i s/ ar e t e m p or all y a s s o ci at e d wit h A RI A -E 
M RI fi n di n g s  a n d c o n si d er e d b y t h e i n v e sti g at or t o b e attri b ut a bl e t o A RI A -E .  C N S 
s y m pt o m s e x p eri e n c e d b y t h e p arti ci p a nt t h at ar e n e w or w or s e n e d si n c e t h e l a st M RI 
wit h o ut A RI A -E ar e c oll e ct e d i n a C N S S y m pt o m s R e q u e st F or m.  T o i d e ntif y C N S 
s y m pt o m s t e m p or all y a s s o ci at e d wit h a n d attri b ut a bl e t o A RI A -E M RI fi n d i n g s, t h e 
f oll o wi n g d efi niti o n s will b e u s e d:  
N E W C N S s y m pt o m s: If t h er e i s a n y A E r e p ort e d i n t h e e C R F wit h ‘ R e p ort e d o n t hi s 
st u d y' s C N S S y m pt o m C oll e cti o n F or m ’  Y e s  t h at i s [ n e w si n c e d at e of m o st r e c e nt M RI 
s c a n s h o wi n g n o A RI A -E fi n di n g s] A N D i s [ o n g oi n g or e n d s b et w e e n t h e d at e of m o st 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
2 2


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
2 3  
r e c e nt sit e vi sit pri or t o d at e of M RI s c a n s h o wi n g n e w A RI A-E ( M RI) a n d d at e of M RI 
s c a n s h o wi n g A RI A -E r e s ol uti o n ( M RI)]  A N D h a s t h e q u e sti o n “I s t hi s A E attri b ut a bl e t o 
A RI A -E ?” a n s w er e d wit h Y e s i n t h e e C R F A E p a g e,  t h e n A RI A-E s h o ul d b e cl a s sifi e d a s 
a s s o ci at e d wit h attri b ut a bl e C N S s y m pt o m s  
 
O R  
 
W O R S E N E D C N S s y m pt o m s: If t h er e i s a n y A E r e p ort e d i n t h e e C R F wit h ‘ R e p ort e d o n 
t hi s st u d y' s C N S S y m pt o m C oll e cti o n F or m’ = Ye s  t h at i s [ st art e d b ef or e t h e d at e of 
m o st  r e c e nt M RI s c a n s h o wi n g n o A RI A-E fi n di n g s ] A N D i s [ o n g oi n g or e n d s b et w e e n 
t h e d at e of m o st r e c e nt sit e vi sit pri or t o d at e of M RI s c a n s h o wi n g n e w A RI A-E ( M RI) 
a n d d at e of M RI s c a n s h o wi n g A RI A -E r e s ol uti o n fr o m M RI d at a ] A N D [t h er e i s a n 
i n cr e a s e i n s e v erit y gr a di n g]  A N D h a s t h e q u e sti o n “I s t hi s A E attri b ut a bl e t o A RI A -E ?” 
a n s w er e d wit h Y e s i n t h e e C R F A E p a g e,  t h e n A RI A-E s h o ul d b e cl a s sifi e d a s 
a s s o ci at e d wit h attri b ut a bl e C N S s y m pt o m s.  
T h e C N S s y m pt o m s t e m p or all y a s s o ci at e d wit h a n d attri b ut a bl e t o A RI A -E M RI fi n di n g s 
will b e li st e d a n d s u m m ari z e d  o v er all a n d al s o b y A P O E ε 4 g e n ot y p e ( b y n u m b er of 
all el e s ).  T h e s a m e s u m m ar y a n d li sti n g will b e pr o d u c e d f or all  C N S s y m pt o m s 
t e m p or all y a s s o ci at e d wit h ( b ut n ot n e c e s s aril y attri b ut a bl e t o)  A RI A -E M RI fi n di n g s.  
5. 3. 5  
L a b or at or y D at a  
L a b or at or y d at a will b e s u m m ari z e d f or e a c h a s s e s s m e nt vi sit u si n g d e s cri pti v e st ati sti c s 
of a b s ol ut e v al u e s  a n d  c h a n g e fr o m b a s eli n e v al u e s.  I n a d diti o n, t h e fr e q u e n c y of 
p ati e nt s wit h a b n or m al l a b or at or y v al u e s will  b e s u m m ari z e d.  
5. 3. 6  
Vit al Si g n s  
Vit al si g n s a s s e s s m e nt s i n cl u d e s y st oli c bl o o d pr e s s ur e, di a st oli c bl o o d pr e s s ur e, a n d 
p ul s e r at e m e a s ur e d t hr o u g h o ut t h e st u d y.  Vit al si g n m e a s ur e m e nt s will b e s u m m ari z e d 
f or e a c h a s s e s s m e nt vi sit u si n g d e s cri pti v e st ati sti c s of a b s ol ut e v al u e s  a n d  c h a n g e fr o m 
b a s eli n e v al u e s.  I n a d diti o n, t h e fr e q u e n c y of p ati e nt s wit h a b n or m al r e s ult s will b e 
s u m m ari z e d.  
5. 3. 7  
E C G s  
E C G d at a will b e s u m m ari z e d b y pr e vi o u s tr e at m e nt gr o u p a n d p arti ci p ati o n / n o n -
p arti ci p ati o n i n t h e O L E p art of t h e p ar e nt st u di e s  f or e a c h a s s e s s m e nt vi sit u si n g 
d e s cri pti v e st ati sti c s of a b s ol ut e v al u e s  a n d  c h a n g e fr o m b a s eli n e v al u e s f or t h e 
f oll o wi n g p ar a m et er s:  
 
H e art r at e  
 
Q R S d ur ati o n  
 
R R i nt er v al  
 
P R i nt er v al  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
2 3


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
2 4  
 
Q T i nt er v al  
 
I n a d diti o n, E C G o v er all i nt er pr et ati o n s will b e s u m m ari z e d b y pr e vi o u s tr e at m e nt gr o u p, 
p arti ci p ati o n / n o n -p arti ci p ati o n i n t h e O L E p art of t h e p ar e nt st u di e s  a n d vi sit.  
 
5. 3. 8  
C ol u m bi a -S ui ci d e S e v erit y R ati n g S c al e ( C -S S R S)  
T h e C -S S R S  i s a t o ol u s e d t o a s s e s s t h e lif eti m e s ui ci d alit y of a p arti ci p a nt ( C-S S R S at 
b a s eli n e) a s w ell a s a n y n e w i n st a n c e s of s ui ci d alit y ( C -S S R S si n c e l a st vi sit).  T h e 
str u ct ur e d i nt er vi e w pr o m pt s r e c oll e cti o n of s ui ci d al i d e ati o n, i n cl u di n g t h e i nt e n sit y of 
t h e i d e ati o n, b e h a vi or, a n d att e m pt s wit h a ct u al or p ot e nti al l et h alit y. 
S ui ci d al i d e ati o n, s ui ci d al b e h a vi or, a n d s elf -i nj uri o u s b e h a vi or wit h o ut s ui ci d al i nt e nt will 
b e s u m m ari z e d b y pr e vi o u s tr e at m e nt gr o u p a n d p arti ci p ati o n / n o n -p arti ci p ati o n i n t h e 
O L E p art of t h e p ar e nt st u di e s .  I n a d diti o n, c h a n g e fr o m b a s eli n e t o w or st p o st-b a s eli n e 
a s s e s s m e nt i n s ui ci d alit y c at e g ori e s will b e s u m m ari z e d b y  pr e vi o u s  tr e at m e nt gr o u p 
a n d p arti ci p ati o n / n o n -p arti ci p ati o n i n t h e O L E p art of t h e p ar e nt st u di e s . 
5. 4  
S E C O N D A R Y E N D P OI N T S A N A L Y S E S  
A c c or di n g t o t h e st u d y pr ot o c ol, s e cti o n 6. 5, t h e s e c o n d ar y effi c a c y a n al y s e s ar e 
pl a n n e d t o  u s e all e nr oll e d p arti ci p a nt s t o i n v e sti g at e b ot h t h e l o n g -t er m effi c a c y a n d 
p ot e nti al di s e a s e m o dif yi n g eff e ct of l o n g -t er m g a nt e n er u m a b.  H o w e v er, a ll a n al y s e s i n 
t hi s S A P will b e r e stri ct e d t o effi c a c y e n d p oi nt s c oll e ct e d u n d er t hi s st u d y or d uri n g t h e 
O L E p art of t h e p ar e nt st u di e s  a n d will b e p ur el y  d e s cri pti v e .  N o e sti m a n d s  will b e 
d efi n e d.  
A n al y s e s of l o n g -t er m eff e ct of t h e st u d y dr u g ( a cr o s s t h e d o u bl e-bli n d a n d o p e n l a b el 
p h a s e s fr o m t h e p ar e nt S t u d y [ GR A D U A T E  I or GR A D U A T E II]) a s w ell a s effi c a c y 
a n al y s e s of d el a y e d st art of tr e at m e nt ar e n ot s u bj e ct t o t hi s S A P a n d will b e d e s cri b e d 
el s e w h er e.  
5. 4. 1  
S e c o n d ar y Effi c a c y E n d p oi nt s  
T h e s e c o n d ar y o bj e cti v e f or t hi s st u d y i s t o e v al u at e t h e effi c a c y of l o n g -t er m 
g a nt e n er u m a b a d mi ni st er e d b y S C i nj e cti o n o n t h e b a si s of c h a n g e o v er ti m e i n 
c o g niti o n, f u n cti o n, a n d ot h er o ut c o m e s a s m e a s ur e d b y t h e f oll o wi n g:  
 
Cli ni c al D e m e nti a R ati n g ( C D R)  
 
Mi ni -M e nt al St at e E x a mi n ati o n ( M M S E)  
 
Al z h ei m er Di s e a s e A s s e s s m e nt S c al e -C o g niti o n, S u b s c al e 1 1 ( A D A S -C o g 1 1) a n d 
Al z h ei m er Di s e a s e A s s e s s m e nt S c al e -C o g niti o n, S u b s c al e 1 3 ( A D A S -C o g 1 3)  
 
V er b al Fl u e n c y T a s k  
 
C o di n g  
 
F u n cti o n al A cti viti e s Q u e sti o n n air e ( F A Q)  
 
Al z h ei m er Di s e a s e C o o p er ati v e St u d y Gr o u p -A cti viti e s of D ail y Li vi n g ( A D C S -A D L)  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
2 4


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
2 5  
D e s cri pti v e st ati sti c s will b e pr o vi d e d f or e a c h of t h e s e e n d p oi nt s, s u m m ari zi n g a b s ol ut e 
v al u e s a n d c h a n g e fr o m b a s eli n e f or e a c h a s s e s s m e nt ti m e p oi nt  b y pr e vi o u s tr e at m e nt 
g r o u p a n d p arti ci p ati o n / n o n-p arti ci p ati o n i n t h e O L E p art of t h e p ar e nt st u di e s . 
5. 4. 1. 1  
Cli ni c al D e m e nti a R ati n g  
T h e C D R -Gl o b al S c or e ( C D R -G S) c h ar a ct eri z e s a p arti ci p a nt’ s l e v el of i m p air m e nt 
a c c or di n g t o t h e f oll o wi n g c at e g ori e s: 0 ( n or m al), 0. 5 ( v er y mil d d e m e nti a), 1 ( mil d 
d e m e nti a), 2 ( m o d er at e d e m e nti a), a n d 3 ( s e v er e d e m e nti a).  T h e C D R -S u m of B o x e s 
( C D R-S O B) s c or e i s a d et ail e d q u a ntit ati v e g e n er al i n d e x t h at pr o vi d e s m or e i nf or m ati o n 
t h a n t h e C D R-G S i n p arti ci p a nt s wit h mil d d e m e nti a ( B er g 1 9 8 8 ; M orri s et al. 2 0 0 1 , 
O' Br y a nt et al. 2 0 1 0 ) a n d i s s c or e d fr o m 0 t o 1 8 wit h hi g h er s c or e s i n di c ati n g gr e at er 
i m p air m e nt.  T h e C D R c h ar a ct eri z e s si x d o m a i n s: m e m or y, ori e nt ati o n, j u d g m e nt a n d 
pr o bl e m s ol vi n g, c o m m u nit y aff air s, h o m e a n d h o b bi e s, a n d p er s o n al c ar e.  T h e 
n e c e s s ar y i nf or m ati o n t o m a k e e a c h r ati n g i s o bt ai n e d t hr o u g h a s e mi -str u ct ur e d 
i nt er vi e w wit h t h e p arti ci p a nt a n d a r eli a bl e i nf or m a nt or c oll at er al s o ur c e ( e. g., a 
c ar e gi v er).  
D e s cri pti v e st ati sti c s will b e pr o vi d e d f or t h e C D R -S O B  a n d t h e  C D R -G S .  
5. 4. 1. 2  
M M S E  
T h e M M S E i s a s et of st a n d ar di z e d q u e sti o n s u s e d t o e v al u at e p o s si bl e c o g niti v e 
i m p air m e nt a n d h el p st a g e t h e s e v erit y l e v el of t hi s i m p air m e nt (F ol st ei n et al. 1 9 7 5 ).  
T h e q u e sti o n s t ar g et si x ar e a s: ori e nt ati o n, r e gi str ati o n, att e nti o n, s h ort -t er m r e c all, 
l a n g u a g e, a n d c o n str u cti o n al pr a xi s/ vi s u o s p ati al a biliti e s.  T h e M M S E i s a 
p arti ci p a nt ‑b a s e d a s s e s s m e nt.   T h e s c or e r a n g e s fr o m 0  t o 3 0, wit h l o w er v al u e s 
i n di c ati n g a gr e at er i m p air m e nt. 
5. 4. 1. 3  
A D A S -C o g 1 1 a n d A D A S -C o g 1 3  
T h e A D A S -C o g i s t h e m o st fr e q u e ntl y u s e d s c al e t o a s s e s s c o g niti o n i n cli ni c al tri al s f or 
mil d t o m o d er at e A D d e m e nti a ( R o z zi ni et al. 2 0 0 7 ; C o n n or a n d S a b b a g h 2 0 0 8 ; I hl et al. 
2 0 1 2 ).  M or e s p e cifi c all y, t h e A D A S -C o g i s a p arti ci p a nt -b a s e d a s s e s s m e nt t h at 
m e a s ur e s l e ar ni n g a n d  m e m or y, l a n g u a g e pr o d u cti o n, l a n g u a g e c o m pr e h e n si o n, 
c o n str u cti o n al pr a xi s, i d e ati o n al pr a xi s, a n d ori e nt ati o n.  T h e m o difi e d v er si o n will b e 
u s e d; it h a s 1 3 it e m s a n d i n cl u d e s t h e a d diti o n of d el a y e d w or d r e c all a n d a n u m b er of 
c a n c ell ati o n s u bt e st s, a s w ell a s u s e of o nl y o n e tri al f or w or d r e c o g niti o n 
(M o h s  et  al.  1 9 9 7 ).  E q ui v al e nt alt er n at e f or m s of t h e w or d r e c all, w or d r e c o g niti o n, a n d 
n u m b er c a n c ell ati o n s u bt e st s will b e u s e d i n s u c c e s si v e t e st a d mi ni str ati o n s.   T h e 
A D A S -C o g 1 1 a n d 1 3 will b e u s e d i n t hi s st u d y.  I n di vi d u al it e m s c or e s ar e b a s e d o n 
err or s a n d g e n er all y r a n g e fr o m 1 t o 5, alt h o u g h s o m e it e m s h a v e s m all er or l ar g er s c or e 
r a n g e s.  T h e A D A S-C o g 1 3 t ot al s c or e r a n g e s fr o m 0  t o 8 5, wit h hi g h er s c or e s r efl e cti n g 
gr e at er i m p air m e nt.   It t a k e s a p pr o xi m at el y 4 5 mi nut e s  t o a d mi ni st er t h e A D A S-C o g 1 3.  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
2 5


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
2 6  
5. 4. 1. 4  
V er b al Fl u e n c y T a s k  
T h e c at e g or y v er b al fl u e n c y ( e. g., a ni m al s) i s a p arti ci p a nt -b a s e d a s s e s s m e nt t h at 
m e a s ur e s s p e e d a n d fl e xi bilit y of v er b al t h o u g ht.  V er b a l fl u e n c y t e st s ar e s e n siti v e t o ol s 
f or d et e cti n g d e m e nti a (P a s q ui er et al. 1 9 9 5 ; L e z a k  et al. 2 0 0 4 ) a n d f or m o nit ori n g 
d e cli n e o v er ti m e ( Cl ar k et al. 2 0 0 9 ). 
5. 4. 1. 5  
C o di n g  
T h e C o di n g, al s o c all e d Di git S y m b ol S u b stit uti o n T e st ( or D S S T), i s a s u bt e st fr o m t h e 
W e c h sl er A d ult I nt elli g e n c e S c al e -F o urt h E diti o n ( W AI S -I V; W e c h sl er 2 0 0 8 ).  T h e 
C o di n g i s a p arti ci p a nt -b a s e d a s s e s s m e nt t h at m e a s ur e s s p e e d of pr o c e s si n g a n d 
a s s o ci ati v e m e m or y.  T h e t e st i s k n o w n t o b e s e n siti v e t o di s e a s e pr o gr e s si o n 
(L e z a k  et  al. 2 0 0 4 ).  T h e 1 2 0 -s e c o n d v er si o n of t h e t e st will b e u s e d i n t hi s st u d y.  
5. 4. 1. 6  
F A Q  
T h e F A Q ( Pf eff er et al. 1 9 8 2 ) i s a n i nf or m a nt-b a s e d m e a s ur e of f u n cti o n al a biliti e s.  
I nf or m a nt s pr o vi d e p erf or m a n c e r ati n g s of t h e t ar g et p er s o n o n t e n c o m pl e x hi g h er-or d er 
a cti viti e s.   T h e F A Q i s a 3 0 -p oi nt s c al e, t h e hi g h er t h e  s c or e t h e w or s e t h e p erf or m a n c e.  
5. 4. 1. 7  
A D C S -A D L  
T h e A D C S -A D L ( G al a s k o et al. 1 9 9 7 ) i s t h e s c al e m o st wi d el y u s e d t o a s s e s s f u n cti o n al 
o ut c o m e i n p arti ci p a nt s wit h A D (V ell a s et al. 2 0 0 8 ).  T h e A D C S -A D L i s a 2 3 -it e m 
i nf or m a nt-b a s e d q u e sti o n n air e t h at c o v er s b ot h b a si c a cti viti e s of d ail y li vi n g ( A D L) ( e. g., 
e ati n g a n d t oil eti n g) a n d m or e c o m pl e x A D L or i n str u m e nt al A D L ( e. g., u si n g t h e 
t el e p h o n e, m a n a gi n g fi n a n c e s, pr e p ari n g a m e al).  It h a s a 4-w e e k r e c all p eri o d.  T ot al 
s c or e s r a n g e fr o m 0  t o 7 8, wit h hi g h er s c or e s i n di c ati n g b ett er f u n cti o ni n g . 
5. 5  
E X P L O R A T O R Y E N D P OI N T S A N A L Y SI S  
T h e e x pl or at or y effi c a c y a n al y s e s will b e b a s e d o n t h e I T T a n al y si s s et a n d will b e 
r e stri ct e d t o effi c a c y e n d p oi nt s c oll e ct e d u n d er t hi s st u d y or d uri n g t h e O L E p art of t h e 
p ar e nt st u di e s .  T h er ef or e, a n al y s e s of l o n g -t er m eff e ct of t h e st u d y dr u g ( a cr o s s t h e 
d o u bl e -bli n d a n d o p e n l a b el p h a s e s fr o m t h e p ar e nt st u d y [ GR A D U A T E  I or 
G R A D U A T E  II]) ar e n ot s u bj e ct t o t hi s S A P a n d will b e d e s cri b e d el s e w h er e. 
5. 5. 1  
E x pl or at or y Effi c a c y E n d p oi nt s  
T h e e x pl or at or y effi c a c y o bj e cti v e i s t o e v al u at e t h e effi c a c y of l o n g -t er m g a nt e n er u m a b 
a d mi ni st er e d b y S C i nj e cti o n i n t er m s of c h a n g e o v er ti m e i n:  
 
H e alt h -r el at e d q u alit y of lif e, a s a s s e s s e d b y t h e Q u alit y of Lif e-Al z h ei m er' s Di s e a s e 
( Q o L-A D) s c al e  
 
B e h a vi or al a n d n e ur o p s y c hi atri c s y m pt o m s of  A D, a s m e a s ur e d b y t h e 
N e ur o p s y c hi atri c I n v e nt or y Q u e sti o n n air e ( N PI -Q)  
 
C ar e gi v er b ur d e n, a s a s s e s s e d b y t h e Z arit C ar e gi v er I nt er vi e w f or Al z h ei m er' s 
Di s e a s e ( Z CI -A D) s c al e  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
2 6


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
2 7  
 
El e m e nt s of r e s o ur c e utili z ati o n, a s a s s e s s e d b y t h e R e s o ur c e Utili z ati o n i n 
D e m e nti a -Lit e ( R U D -Lit e)  
T h e R U D -Lit e will b e u s e d i n t hi s st u d y f or i nf or mi n g p h ar m a c o e c o n o mi c e v al u ati o n s 
a n d will b e r e p ort e d s e p ar at el y.   F or t h e ot h er e n d p oi nt s, d e s cri pti v e st ati sti c s will b e 
pr o vi d e d f or t h e s e e n d p oi nt s b y pr e vi o u s tr e at m e nt gr o u p, p arti ci p ati o n / n o n p arti ci p ati o n 
i n t h e O L E p art of t h e p ar e nt st u di e s a n d a s s e s s m e nt ti m e p oi nt.  
 
5. 5. 1. 1  
Q o L -A D  
T h e Q o L -A D w a s d e v el o p e d t o a s s e s s q u alit y of lif e ( Q o L) i n p arti ci p a nt s w h o h a v e 
d e m e nti a ( L o g s d o n et al. 1 9 9 9 , 2 0 0 2 ).  T h e Q o L -A D c o n si st s of 1 3 it e m s c o v eri n g 
a s p e ct s of p arti ci p a nt s’ r el ati o n s hi p s wit h fri e n d s a n d f a mil y, p h y si c al c o n diti o n, m o o d, 
c o n c er n s a b o ut fi n a n c e s, a n d o v er all a s s e s s m e nt of Q o L.  T h e t ot al s c or e i s t h e s u m of 
t h e 1 3 it e m s a n d r a n g e s fr o m 1 3 t o 5 2, wit h hi g h er s c or e s i n di c ati n g b ett er h e alt h -r el at e d 
Q o L.   I n t hi s st u d y, t h e Q o L-A D will b e a d mi ni st er e d i n a st a n d ar di z e d, str u ct ur e d 
i nt er vi e w f or m at t o p arti ci p a nt s b y i n v e sti g ati v e st aff i n or d er t o g at her p arti ci p a nt 
r e s p o n s e s a b o ut Q o L.  T h e c ar e gi v er will al s o c o m pl et e t h e c ar e gi v er v er si o n of t h e 
q u e sti o n n air e t o e n a bl e pr o x y r e s p o n s e s fr o m t h e c ar e gi v er.  
5. 5. 1. 2  
N PI -Q  
T h e N PI -Q ( K a uf er et al. 2 0 0 0 ) w a s d e v el o p e d t o a s s e ss a wi d e r a n g e of b e h a vi or s 
e n c o u nt er e d i n p ati e nt s wit h d e m e nti a, t o pr o vi d e a m e a n s of di sti n g ui s hi n g s e v erit y of 
b e h a vi or al c h a n g e s, a n d t o f a cilit at e r a pi d b e h a vi or al a s s e s s m e nt t hr o u g h t h e u s e of 
s cr e e ni n g q u e sti o n s.  It i s a n i nf or m a nt -b a s e d i n str u m e nt i n w hi c h 1 2 b e h a vi or al 
d o m ai n s ar e e v al u at e d.  T h e r e c all p eri o d i s t h e p a st m o nt h, a n d s e v erit y s c or e s r a n g e 
fr o m 0 t o 3 6, wit h hi g h er s c or e s i n di c ati n g gr e at er s e v erit y.  T h e c ar e gi v er' s di str e s s 
p orti o n of t h e s c al e will n ot b e u s e d i n t hi s st u d y.  
5. 5. 1. 3  
Z C I-A D  
Z CI -A D i s a m o difi e d v er si o n of t h e Z arit B ur d e n I nt er vi e w, w hi c h w a s ori gi n all y 
d e si g n e d t o r efl e ct t h e str e s s e s e x p eri e n c e d b y c ar e gi v er s f or p e o pl e wit h d e m e nti a 
(Z arit a n d Z arit 1 9 9 0 ).  T h e m o difi e d v er si o n i n cl u d e s sli g ht m o difi c ati o n s i n it e m a n d titl e 
w or di n g ( e. g., r e m o v al of “ y o ur r el ati v e” t o r ef er dir e ctl y t o t h e p arti ci p a nt, r e m o v al of 
“ b ur d e n” fr o m titl e) a n d t h e u s e of 1 1-p oi nt n u m eri c al r ati n g s c al e s.  T h e Z CI -A D s c al e 
c o n si st s  of 3 0 it e m s a n d i s c o m pl et e d b y t h e c ar e gi v er wit h o ut i n v ol v e m e nt fr o m t h e sit e 
st aff.  It h a s a 4-w e e k r e c all p eri o d.  
5. 6  
O T H E R S A F E T Y A N A L Y S E S  
5. 6. 1  
E xt e nt of E x p o s ur e  
E x p o s ur e t o st u d y dr u g i nf or m ati o n will b e s u m m ari z e d d e s cri pti v el y a s f oll o w s: 
 
Tr e at m e nt d ur ati o n (i n w e e k s)  
 
T ot al n u m b er of a d mi ni str ati o n s  
 
T ot al c u m ul ati v e d o s e ( m g)  
 
N u m b er of p arti ci p a nt s wit h a n y d o s e a d mi ni str ati o n, s e p ar at el y f or e a c h d o s e l e v el  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
2 7


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
2 8  
 
5. 7  
O T H E R A N A L Y S E S  
5. 7. 1  
S u m m ari e s of C o n d u ct of St u d y  
T h e s u m m ar y of st u d y c o n d u ct will i n cl u d e a d e s cri pti o n of t h e f oll o wi n g it e m s b y 
pr e vi o u s tr e at m e nt gr o u p a n d p arti ci p ati o n / n o n -p arti ci p ati o n i n t h e O L E p art of t h e 
p ar e nt st u di e s : 
 
N u m b er of p arti ci p a nt s e nr oll e d  
 
N u m b er of p arti ci p a nt s i n cl u d e d i n e a c h a n al y si s s et  
 
N u m b er a n d p er c e nt a g e of p arti ci p a nt s w h o pr e m at ur el y wit h dr e w fr o m t h e st u d y or 
fr o m st u d y tr e at m e nt (i n cl u di n g t h e r e a s o n s f or di s c o nti n u ati o n a n d t h e di stri b uti o n 
of t h e s e di s c o nti n u ati o n s b y ti m e -wi n d o w e d vi sit)  
 
I n ci d e n c e of pr ot o c ol d e vi ati o n s –  o v er all a n d b y f o ur m ai n c at e g ori e s (i n cl u si o n 
crit eri a, e x cl u si o n crit eri a, m e di c ati o n a n d pr o c e d ur al)  
 
N u m b er of p arti ci p a nt s wit h h o m e n ur si n g  
 
M aj or pr ot o c ol d e vi ati o n s a n d pr e m at ur e wit h dr a w al s will b e li st e d.    
5. 7. 2  
S u m m ari e s of D e m o gr a p hi c s a n d B a s eli n e C h ar a ct eri sti c s  
D e m o gr a p hi c a n d b a s eli n e c h ar a ct eri sti c s ( s u c h a s a g e, s e x, r a c e, di s e a s e st a g e  at 
e nr ol m e nt i n t h e p ar e nt st u di e s , str atifi c ati o n f a ct or s a s r e p ort e d i n I x R S at 
r a n d o mi z ati o n i n t h e p ar e nt st u di e s, A P O E e 4 st at u s  ( c arri er v s n o n-c a rri er s a n d A P O e 4 
all el e’ s st at u s ), pr e s e n c e a n d c u m ul ati v e n u m b er of A RI A -H (d uri n g t h e  s cr e e ni n g a n d  
d o u bl e -bli n d p art of t h e p ar e nt st u di e s ), hi st or y  of A RI A -E  i n t h e d o u bl e-bli n d p art of t h e 
p ar e nt st u di e s , a n d u s e a n d n o n -u s e of b a c k gr o u n d t h er a p y f or A D  at O L E b a s eli n e , 
p arti ci p ati o n i n P O S T G R A D U A T E  P E T s u b st u di e s ) will b e s u m m ari z e d d e s cri pti v el y f or 
t h e I T T a n d S E a n al y si s s et s .  
D e s cri pti v e s u m m ari e s of c o nti n u o u s d at a will pr e s e nt t h e m e a n, st a n d ar d d e vi ati o n, 
m e di a n, a n d mi ni m u m a n d m a xi m u m.  D e s cri pti v e s u m m ari e s of di s cr et e d at a will 
i n cl u d e fr e q u e n ci e s e x pr e s s e d i n t er m s of n u m b er a n d p er c e nt a g e of p arti ci p a nt s. 
5. 7. 3  
S u m m ari e s of C O VI D -1 9 I m p a ct o n t h e Tri al s  
T h e P O S T G R A D U A T E st u d y  i s o n g oi n g d uri n g t h e C O VI D-1 9 p a n d e mi c.  C o n s e q u e ntl y, 
t o m o nit or t h e p ot e nti al i m p a ct of t h e p a n d e mi c o n t h e tri al, w e will pr o vi d e a s p e cifi c s et 
of d e s cri pti v e a n al y s e s r el at e d t o C O VI D -1 9  b y pr e vi o u s tr e at m e nt ar m a n d p arti ci p ati o n 
/ n o n-p arti ci p ati o n i n t h e O L E p art of t h e p ar e nt st u di e s  f or t h e I T T a n al y si s s et  (s e e 
S e cti o n  4 ), i n cl u di n g: 
 
D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s i n P arti ci p a nt s wit h C o nfir m e d/ 
S u s p e ct e d C O VI D -1 9 ( s e e S e cti o n  5. 7. 2 ) 
 
C O VI D -1 9 A E s ( s e e S e cti o n  5. 3. 3 ) 
 
C O VI D -1 9 r el at e d Pr ot o c ol D e vi ati o n s ( s e e S e cti o n  5. 2 ) 
 
Mi s s e d d o s e s  d u e t o C O VI D -1 9  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
2 8


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
2 9  
 
St u d y di s c o nti n u ati o n s d u e t o C O VI D -1 9  
 
R e m ot e s c al e a d mi ni str ati o n s  
 
5. 7. 4  
I m m u n o g e ni cit y A n al y s e s  
I m m u n o g e ni cit y a n al y s e s i n cl u d e t h e e v al u ati o n f or a nti b o di e s a g ai n st g a nt e n er u m a b 
(i. e., A D A s) , i n cl u di n g t h e d et er mi n ati o n of a nti b o d y tit er s if a p pr o pri at e.  T h e 
i m m u n o g e ni cit y a n al y si s s et will c o n si st of all p arti ci p a nt s wit h at l e a st o n e  A D A 
a s s e s s m e nt.  T h e r e s ult s of t h e c o nfir m at or y a s s a y will b e pr e s e nt e d a s a fr e q u e n c y 
t a bl e s u m m ari zi n g r e s ult s at p ar e nt st u d y b a s eli n e  a n d  d uri n g  t hi s st u d y or t h e O L E  p art 
of t h e p ar e nt st u di e s . 
A li sti n g of p arti ci p a nt s wit h p o siti v e A D A st at u s p er c o nfir m at or y a s s a y a n d tit er r e s ult 
will b e pr o vi d e d.  
Pri or t o c o m pl eti o n of t h e st u d y, o n e or m or e s e p ar at e c ut off d at e( s) f or A D A s a m pl e s  
m a y b e e st a bli s h e d t o all o w e x p e di e nt s a m pl e s a n al y s e s a n d e arl y a c c e s s b y t hir d p art y  
v e n d or s.  
5. 7. 5  
Bi o m ar k er A n al y s e s  
Bi o m ar k er d at a will b e s u m m ari z e d f or e a c h a s s e s s m e nt vi sit u si n g d e s cri pti v e st ati sti c s 
of a b s ol ut e v al u e s a s w ell a s c h a n g e fr o m b a s eli n e v al u e s.  Pl a s m a bi o m ar k er r e p ort s 
will b e b a s e d o n t h e I T T a n al y si s s et .  All a n al y si s i n cl u di n g C S F bi o m ar k er s will b e 
b a s e d o n t h e C S F -m I T T a n al y si s s et .  T h e f oll o wi n g p h ar m a c o d y n a mi c bi o m ar k er s will 
b e a n al y z e d:  
 
C er e br o s pi n al Fl ui d ( C S F):  
–  
T ot al t a u (t T a u)  
–  
P h o s p h or yl at e d t a u ( p T a u 1 8 1)  
–  
N e ur o gr a ni n  
–  
N e ur ofil a m e nt ( N F L)  
 
Pl a s m a:   
–  
P h o s p h or yl at e d t a u ( p T a u 1 8 1)  
–  
 A m y loi d -b et a  4 2 ( A b et a -4 2)  
 
M RI -d eri v e d m e a s ur e m e nt s, i n cl u di n g:  
–  
V ol u m etri c c h a n g e s i n w h ol e br ai n, v e ntri cl e s, hi p p o c a m p u s, c orti c al gr a y 
or ot h er str u ct ur e s  
I n a d diti o n, ot h er e x pl or at or y bi o m ar k er s will b e r e p ort e d s e p ar at el y. 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
2 9


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
3 0  
5. 7. 6  
A m yl oi d P E T S u b st u d y  
T h e m ai n o bj e cti v e  of t h e P O S T G R A D U A T E  l o n git u di n al a m yl oi d P E T s u b st u d y i s t o 
a s s e s s  c h a n g e s i n br ai n a m yl oi d l o a d ( a s m e a s ur e d b y fl or b et a b e n or fl ut e m et a m ol) 
o v er ti m e  d uri n g t h e tr e at m e nt wit h g a nt e n er u m a b . 
T h e a n al y s e s d e s cri b e d h er e ar e r e stri ct e d t o a n al y s e s of d at a a s s e s s e d d uri n g t hi s 
st u d y or d uri n g t h e O L E p art of t h e p ar e nt st u di e s.  A n al y s e s a cr o s s t h e d o u bl e -bli n d 
p art of t h e p ar e nt st u di e s a n d t hi s st u d y will b e r e p ort e d s e p ar at el y a n d ar e n ot s u bj e ct 
of t hi s S A P.  T hi s d o c u m e nt will f o c u s o n a m yl oi d  P E T d at a a s s e s s e d d uri n g t hi s st u d y 
or d uri n g t h e O L E p art of t h e p ar e nt st u di e s.  
5. 7. 6. 1  
Br ai n A m yl oi d L o a d A n al y si s  
T w o a m yl oi d P E T li g a n d s ar e all o w e d i n t hi s s u b st u d y a c c or di n g t o c o u ntr y a n d sit e 
a v ail a bilit y: fl or b et a b e n a n d fl ut e m et a m ol.  H o w e v er, t h e s a m e li g a n d h a s t o b e u s e d f or 
t h e s a m e p arti ci p a nt t hr o u g h o ut t h e st u d y.  F or all p arti ci p a nt s, t h e li g a n d t h at i s  u s e d 
h a s t o r e m ai n t h e s a m e a s t h at u s e d pr e vi o u sl y ( e. g., if a p arti ci p a nt h a s b e e n e nr oll e d 
i n t h e p ar e nt s t u d y (G R A D U A T E  I or GR A D U A T E  II) wit h a p o siti v e fl or b et a b e n P E T 
s c a n, o nl y fl or b et a b e n will b e all o w e d a n d u s e d f or t h e l o n git u di n al f oll o w -u p s c a n s f or 
t hi s p arti ci p a nt i n t hi s st u d y). 
C e ntil oi d m a p pi n g will b e c o m pl et e d f or t h e St a n d ar d U pt a k e V al u e R ati o ( S U V R) d at a 
fr o m t h e t w o a m yl oi d P E T li g a n d s.  T h e a P E T -m I T T a n al y si s s et  will b e u s e d t o 
s u m m ari z e  a m yl oi d l o a d i n c e ntil oi d b y d e s cri pti v e stati sti c s f or e a c h a s s e s s m e nt ti m e 
p oi nt a s w ell a s t h e c h a n g e fr o m b a s eli n e  b y pr e vi o u s tr e at m e nt . 
5. 7. 6. 2  
G e n er al C o n si d er ati o n s o n A m yl oi d P E T St ati sti c al A n al y s e s  
T h e b a s eli n e a s s e s s m e nt will b e t h e l a st a m yl oi d P E T s c a n b ef or e or o n O L E D a y 4 3 
(ti m e wi n d o w f or d a y 1 i s + 4 2 d a y s)  t h at w a s p erf or m e d wit hi n 6 m o nt h s b ef or e O L E 
D a y  1 . 
Wit h t h e C e ntil oi d e n d p oi nt, d at a fr o m b ot h tr a c er s will b e p o ol e d a n d a n al y z e d t o g et h er.  
S e p ar at e a n al y si s b y tr a c er wit h t h e C e ntil oi d e n d p oi nt m a y al s o b e c o n d u ct e d a s 
a p pr o pri at e . 
Mi s si n g v al u e s will n ot b e i m p ut e d.  
Vi sit Wi n d o wi n g  
T h e a n al y si s of a m yl oi d P E T d at a will b e u n d ert a k e n u si n g r e p orti n g wi n d o w s a s d efi n e d 
i n  
T a bl e  2 .  I n c a s e of m or e t h a n o n e a s s e s s m e nt wit hi n a ti m e wi n d o w, t h e a s s e s s m e nt 
wit h t h e d at e cl o s e st t o t h e t ar g et ( s c h e d ul e d) d a y will b e s el e ct e d.   T h e ti m e wi n d o w s 
ar e b a s e d o n st u d y d a y s , d efi n e d a s d a y s o n st u d y si n c e fir st O L E d o s e, wit h t h e d ay of 
fir st O L E d o s e b ei n g st u d y D a y 1 a n d t h e d a y b ef or e fir st d o s e b ei n g st u d y D a y -1  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
3 0


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
3 1  
B e c a u s e of vi sit wi n d o wi n g, d at a c oll e ct e d at a n e arl y t er mi n ati o n vi sit will b e 
s u m m ari z e d at t h e a p pr o pri at e ti m e i n t h e tri al.  F or p arti ci p a nt s w h o h a v e di s c o nti n u e d  
tr e at m e nt e arl y, if a P E T s c a n i s p erf or m e d m or e t h a n 5 6 d a y s (e arl y t er mi n ati o n vi sit 
e x p e ct e d 1 4 d a y s aft er l a st d o s e, f oll o w e d b y ti m e wi n d o w p er pr ot o c ol f or e arl y 
t er mi n ati o n i s ± 4 2 d a y s) aft er t h e d at e of l a st d o s e, t h e P E T s c a n will n ot b e u s e d f or t h e 
a n al y si s  
T a bl e  2  
Ti m e Wi n d o w s f or A m yl oi d P E T E n d p oi nt s  
Vi sit  
T ar g et st u d y d a y  
Ti m e wi n d o w  
B a s eli n e  
1  
-1 8 3,  4 3  
W e e k 5 2  
3 6 5  
2 8 1, 4 4 9  
W e e k 1 0 4  
7 2 9  
6 4 5, 8 1 3  
W e e k 1 5 6  
1 0 9 3  
1 0 0 9, 1 1 7 7  
W e e k 2 0 8  
1 4 5 7  
1 3 7 3, 1 5 4 1  
  
D et ail s f or D efi niti o n of V ari a bl e  
T h e C e ntil oi d v ari a bl e will b e u s e d r at h er t h a n t h e ori gi n al S U V R, b e c a u s e it all o w s d at a 
t o b e c o m bi n e d fr o m diff er e nt tr a c er s, b y m a p pi n g S U V R v al u e s t o a st a n d ar di z e d s c al e.  
T h e C e ntil oi d v ari a bl e i s t h e c urr e nt c o m m o n st a n d ar d i n t h e s ci e ntifi c c o m m u nit y.  
T h e pri m ar y S U V R m e a s ur e of i nt er e st i s c o m p ut e d u si n g a w ei g ht e d c o m p o sit e t ar g et 
r e gi o n a n d w h ol e c er e b ell u m a s r ef er e n c e r e gi o n.  T h e w ei g ht e d c o m p o sit e t ar g et r e gi o n 
i s c o m p o s e d of ( b ot h l eft a n d ri g ht si d e): 
 
fr ont al l o b e,  
 
p ari et al l o b e,  
 
t e m p or al l o b e l at er al, 
 
ci n g ul u m p o st eri or a n d  
 
a nt eri or ci n g ul at e g yr u s  
 
E a c h r e gi o n i s w ei g ht e d b y it s o w n v ol u m e.  T h e C e ntil oi d c o n v er si o n i s a li n e ar 
tr a n sf or m ati o n of S U V R wit h tr a c er-s p e cifi c p ar a m et er s t h at ar e gi v e n b el o w  in T a bl e  3 : 
C e ntil oi d E q u ati o n : 
C L
  Sl o p e C L   S U V R   I nt er c e pt C L 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
3 1


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
3 2  
C L C e ntil oi d s; Sl o p e C L sl o p e; S U V R st a n d ar d u pt a k e v al u e r ati o of t h e t ar g et r e gi o n; 
I nt er c e pt C Li nt er c e pt. 
T h e p erti n e nt v al u e s f or t h e t w o tr a c er s ar e:  
T a bl e  3  
Pri m ar y C e ntil oi d E q u ati o n P ar a m et er s  
Tr a c er  
R ef er e n c e  
Sl o p e  
I nt er c e pt 
Fl or b et a b e n -F 1 8  
w h ol e c er e b ell u m  
1 7 5. 6  
-1 7 4. 2  
Fl ut e m et a m ol -F 1 8  
w h ol e c er e b ell u m  
1 4 3. 5  
-1 4 1. 1  
  
5. 7. 6. 3  
S u m m ari e s of C o n d u ct of S u b st u d y  
T h e s u m m ar y of st u d y c o n d u ct will i n cl u d e a d e s cri pti o n of t h e f oll o wi n g it e m s b y 
pr e vi o u s tr e at m e nt ar m: 
 
N u m b er of p arti ci p a nt s e nr oll e d  
 
N u m b er of p arti ci p a nt s i n cl u d e d i n e a c h s u b st u d y a n al y si s s et  
 
N u m b er a n d p er c e nt a g e of p arti ci p a nt s w h o pr e m at ur el y wit h dr e w fr o m t h e st u d y , 
s u b st u d y  or fr o m st u d y tr e at m e nt (i n cl u di n g t h e r e a s o n s f or di s c o nti n u ati o n a n d t h e 
di stri b uti o n of t h e s e di s c o nti n u ati o n s b y ti m e -wi n d o w e d vi sit)  
 
I n ci d e n c e of pr ot o c ol d e vi ati o n s –  o v er all a n d b y f o ur m ai n c at e g ori e s (i n cl u si o n 
crit eri a, e x cl u si o n crit eri a, m e di c ati o n a n d pr o c e d ur al)  
M aj or pr ot o c ol d e vi ati o n s, i n cl u di n g m aj or d e vi ati o n s wit h r e g ar d t o t h e i n cl u si o n a n d 
e x cl u si o n crit eri a, will b e s u m m ari z e d a n d li st e d.  S e p ar at e t a bl e s will b e pr o vi d e d f or 
C O VI D -1 9 -r el at e d m aj or pr ot o c ol d e vi ati o n s a n d r e a s o n s f or C O VI D-1 9 -r el at e d m aj or 
pr ot o c ol d e vi ati o n s.  
Pr e m at ur e st u d y dr u g di s c o nti n u ati o n a n d st u d y  or s u b st u d y  di s c o nti n u ati o n, a s w ell a s 
r e a s o n s f or di s c o nti n u ati o n s, will b e s u m m ari z e d a n d li st e d.  
T h e o ut p ut s will b e p erf or m e d o n t h e A m yl oi d I T T a n al y si s s et . 
5. 7. 6. 4  
S u m m ari e s of D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s  
D e m o gr a p hi c a n d b a s eli n e c h ar a ct eri sti c s of t h e p arti ci p a nt s w h o p arti ci p at e i n t hi s 
s u b st u d y will b e s u m m ari z e d f or t h e a m yl oi d I T T a n al y si s s et  a s d e s cri b e d i n 
S e cti o n  5. 7. 2 . 
5. 7. 6. 5  
S af et y A n al y s e s  
T h e s af et y a n al y s e s f or t h e p arti ci p a nt s i n t h e a m yl oi d P E T s u b st u d y will b e c o n d u ct e d 
a s p art of t h e m ai n st u d y ( P O S T G R A D U A T E  or O L E p art of t h e p ar e nt st u d y) s af et y 
a n al y s e s .  T h er e will n ot b e a s e p ar at e a n al y si s of p arti ci p a nt s i n t hi s s u b st u d y.  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
3 2


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
3 3  
5. 7. 6. 6  
I nt eri m A n al y si s 
T o a d a pt t o i nf or m ati o n t h at m a y e m er g e d uri n g t h e c o ur s e of t hi s st u d y, t h e S p o n s or 
m a y c h o o s e t o c o n d u ct o n e or m or e i nt eri m a n al y s e s  f or a d mi ni str ati v e r e a s o n s w hi c h 
m a y i n cl u d e effi c a c y, s af et y, a n d bi o m ar k er o ut c o m e s.  N o i nt eri m a n al y si s  of t h e 
s u b st u d y  i s pl a n n e d f or t h e ti m e of t h e c o m pl eti o n of p ar e nt st u di e s. 
5. 7. 7  
T a u P E T S u b st u d y  
T h e m ai n o bj e cti v e of t h e P O S T G R A D U A T E  l o n git u di n al t a u P E T s u b st u d y i s t o a s s e s s 
c h a n g e s  i n br ai n t a u l oa d ( a s m e a s ur e d wit h [ 1 8 F] G T P 1) o v er ti m e d uri n g tr e at m e nt wit h  
g a nt e n er u m a b.  
T h e a n al y s e s d e s cri b e d h er e ar e r e stri ct e d t o a n al y s e s of d at a a s s e s s e d d uri n g t hi s 
st u d y  or d uri n g t h e O L E p art of t h e p ar e nt st u di e s .  A n al y s e s a cr o s s t h e d o u bl e -bli n d 
p art of t h e p ar e nt st u di e s a n d t hi s st u d y will b e r e p ort e d s e p ar at el y a n d ar e n ot s u bj e ct 
of t hi s S A P.   T hi s d o c u m e nt will f o c u s o n t a u P E T d at a a s s e s s e d d uri n g t hi s st u d y or 
d uri n g t h e O L E p art of t h e p ar e nt st u di e s.  
5. 7. 7. 1  
Br ai n T a u L o a d A n al y si s  
T h e s u b st u d y i s p erf or m e d wit h a n i ntr a v e n o u s (I V) i nj e cti o n of a mi ni m u m of 1 8 5 M B q 
( 5 m Ci) a n d u p t o 2 5 9 M B q ( n ot m or e t h a n 7 m Ci) of [1 8 F] G T P 1 a n d i m a gi n g f or a 
3 0 ‑mi n ut e s c a n, b e gi n ni n g 6 0 mi n ut e s f oll o wi n g i nj e cti o n p er P E T s c a n.  
T h e T a u  I T T a n al y si s s et  will b e u s e d t o s u m m ari z e t a u b ur d e n i n S U V R b y d e s cri pti v e 
st ati sti c s f or e a c h a s s e s s m e nt ti m e p oi nt a s w ell a s t h e c h a n g e fr o m b a s eli n e  b y 
pr e vi o u s tr e at m e nt . 
5. 7. 7. 2  
G e n er al C o n si d er ati o n s o n T a u P E T St ati sti c al A n al y s e s  
T h e b a s eli n e a s s e s s m e nt f or t a u P E T i s s c h e d ul e d f or t h e O L E D a y 1 vi sit (  4 2 d a y s).  
N ot e t h at t h e r e s ult s of t h e t a u P E T s c a n d o n ot n e e d t o b e a v ail a bl e b ef or e d o si n g.  
T h e l a st t a u P E T s c a n a v ail a bl e wit hi n 6 m o nt h s b ef or e O L E D a y 1 a n d u p t o O L E 
D a y  4 3 will b e c o n si d er e d t h e b a s eli n e a s s e s s m e nt.  
Vi sit Wi n d o wi n g  
F or t a u P E T a s s e s s m e nt s, d u e t o t h e l o n g ti m e b et w e e n s c h e d ul e d a s s e s s m e nt s, ti m e 
wi n d o w s, a s d efi n e d i n T a bl e  4 , will b e u s e d.
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
3 3


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
3 4  
T a bl e  4  
Ti m e Wi n d o w s f or T a u P E T E n d p oi nt s  
Vi sit  
T ar g et st u d y d a y  
Ti m e wi n d o w  
B a s eli n e  
1  
-1 8 3,  4 3  
W e e k 5 2  
3 6 5  
2 8 1, 4 4 9  
W e e k 1 0 4  
7 2 9  
6 4 5, 8 1 3  
W e e k 1 5 6  
1 0 9 3  
1 0 0 9, 1 1 7 7  
W e e k 2 0 8  
1 4 5 7  
1 3 7 3, 1 5 4 1  
  
D et ail s f or D efi niti o n of V ari a bl e  
St ati sti c al a n al y s e s will b e c o n d u ct e d o n t a u P E T M e di a n St a n d ar di z e d U pt a k e V al u e 
R ati o s ( S U V R) i n t h e f oll o wi n g f o ur t ar g et r e gi o n s of i nt er e st.  I n c o m p o sit e t ar g et 
r e gi o n s, e a c h r e gi o n i s w ei g ht e d b y it s o w n v ol u m e.  
 
A t e m p or al c o m p o sit e t ar g et r e gi o n.  T hi s r e gi o n i s c o m p o s e d of ( b ot h l eft a n d ri g ht):  
–  
a nt eri or a n d p o st eri or s u p eri or t e m p or al g yr u s,  
–  
p o st eri or t e m p or al l o b e,  
–  
f u sif or m g yr u s, 
–  
mi d dl e a n d i nf eri or t e m p or al g yr u s . 
 
A m e di al t e m p or al c o m p o sit e r e g i o n n ot i n cl u di n g t h e hi p p o c a m p u s, c o m p o s e d of 
( b ot h l eft a n d ri g ht): 
–  
A m y g d al a,  
–  
P ar a hi p p o c a m p u s,  
–  
A nt eri or m e di al a n d l at er al t e m p or al l o b e . 
 
Fr o nt al l o b e ( b ot h l eft a n d ri g ht)  
 
P ari et al l o b e ( b ot h l eft a n d ri g ht)  
 
T h e i nf eri or c er e b ell ar gr e y m att er will b e u s e d a s r ef er e n c e r e gi o n f or t h e c al c ul ati o n of 
m e di a n S U V R s f or all f o ur t ar g et r e gi o n s c o n si d er e d.  
5. 7. 7. 3  
S u m m ari e s of C o n d u ct of S u b st u d y  
T h e s u m m ar y of st u d y c o n d u ct will i n cl u d e a d e s cri pti o n of t h e f oll o wi n g it e m s b y 
pr e vi o u s tr e at m e nt ar m: 
 
N u m b er of p arti ci p a nt s e nr oll e d  
 
N u m b er of p arti ci p a nt s i n cl u d e d i n e a c h s u b st u d y a n al y si s s et  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
3 4


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
3 5  
 
N u m b er a n d p er c e nt a g e of p arti ci p a nt s w h o pr e m at ur el y wit h dr e w fr o m t h e st u d y, 
s u b st u d y or fr o m st u d y tr e at m e nt (i n cl u di n g t h e r e a s o n s f or di s c o nti n u ati o n a n d t h e 
di stri b ut i o n of t h e s e di s c o nti n u ati o n s b y ti m e-wi n d o w e d vi sit)  
 
N u m b er a n d p er c e nt a g e of p arti ci p a nt s w h o c o m pl et e d tr e at m e nt, t h e s u b st u d y, t h e 
st u d y  
 
I n ci d e n c e of pr ot o c ol d e vi ati o n s –  o v er all a n d b y f o ur m ai n c at e g ori e s (i n cl u si o n 
crit eri a, e x cl u si o n crit eri a, m e di c ati o n a n d pr o c e d ur al)  
M aj or pr ot o c ol d e vi ati o n s, i n cl u di n g m aj or d e vi ati o n s wit h r e g ar d t o t h e i n cl u si o n a n d 
e x cl u si o n crit eri a, will b e s u m m ari z e d a n d li st e d.  S e p ar at e t a bl e s will b e pr o vi d e d f or 
C O VI D -1 9 -r el at e d m aj or pr ot o c ol d e vi ati o n s a n d r e a s o ns f or C O VI D -1 9 -r el at e d m aj or 
pr ot o c ol d e vi ati o n s.  
Pr e m at ur e st u d y dr u g di s c o nti n u ati o n a n d st u d y or s u b st u d y di s c o nti n u ati o n, a s w ell a s 
r e a s o n s f or di s c o nti n u ati o n s, will b e s u m m ari z e d a n d li st e d. 
T h e o u t p ut s will b e p erf or m e d o n t h e Ta u I T T a n al y si s s et . 
5. 7. 7. 4  
S u m m ari e s of D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s  
D e m o gr a p hi c a n d b a s eli n e c h ar a ct eri sti c s of t h e p arti ci p a nt s w h o p arti ci p at e i n t hi s 
s u b st u d y will b e s u m m ari z e d f or t h e T a u I T T a n al y si s s et  a s d e s cri b e d i n S e cti o n  5. 7. 2 . 
5. 7. 7. 5  
S af et y A n al y s e s  
T h e s af et y a n al y s e s f or t h e p arti ci p a nt s i n t h e t a u P E T s u b st u d y will b e c o n d u ct e d a s 
p art of t h e m ai n st u d y ( P O S T G R A D U A T E  or O L E p art of t h e p ar e nt st u d y) s af et y 
a n al y s e s.  T h er e will n ot b e a s e p ar at e a n al y si s of p arti ci p a nt s i n t hi s s u b st u d y.  
5. 7. 7. 6  
I nt eri m A n al y si s 
T o a d a pt t o i nf or m ati o n t h at m a y e m er g e d uri n g t h e c o ur s e of t hi s st u d y, t h e S p o n s or 
m a y c h o o s e t o c o n d u ct o n e or m o r e i nt eri m a n al y s e s f or a d mi ni str ati v e r e a s o n s w hi c h 
m a y i n cl u d e effi c a c y, s af et y, a n d bi o m ar k er o ut c o m e s.  N o i nt eri m a n al y si s i s pl a n n e d 
f or t h e s u b st u d y f or t h e ti m e of t h e c o m pl eti o n of p ar e nt st u di e s. 
5. 8  
I N T E RI M A N A L Y S E S  
5. 8. 1  
Pl a n n e d I nt eri m A n al y s e s  
A  fir st i nt eri m a n al y si s will b e c o n d u ct e d at t h e ti m e of t h e pri m ar y a n al y si s f or  t h e p ar e nt 
pi v ot al s t u di e s G R A D U A T E  I a n d GR A D U A T E  II, t o s u p p ort a p ot e nti al fili n g of 
g a nt e n er u m a b i n c a s e of p o siti v e r e a d -o ut of t h e pi v ot al st u di e s.  A s e c o n d i nt eri m 
a n al y si s  m a y b e c o n d u ct e d f or a n u p d at e o n s af et y d at a i n t h e fili n g d o s si er.  T h e 
a n al y s e s will b e stri ctl y d e s cri pti v e a n d will n ot i m p a ct t h e c o n d u ct of t h e st u d y, i. e., e arl y 
t er mi n ati o n f or f utilit y or effi c a c y will n ot b e c o n si d er e d.  A s t hi s st u d y i s o p e n -l a b el a n d 
all a n al y s e s ar e d e s cri pti v e, t h e i nt eri m  a n al y s e s ar e  c o n si d er e d of a n a d mi ni str ati v e 
n at ur e a n d will n ot h a v e a n i m p a ct o n t h e fi n al st u d y r e s ult s.    
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
3 5


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
3 6  
T h e f oll o wi n g will b e i n cl u d e d i n t h e i nt eri m a n al y s e s:  
 
P arti ci p a nt di s p o siti o n ( s e e S e cti o n  5. 2 ) 
 
D e m o gr a p hi c s a n d b a s eli n e c h ar a ct eri sti c s ( s e e S e cti o n  5. 7. 2 ) 
 
E xt e nt of e x p o s ur e ( s e e S e cti o n  5. 6. 1 ) 
 
A d v er s e E v e nt s ( s e e S e cti o n  5. 3. 3 ) 
 
M RI s af et y fi n di n g s ( s e e S e cti o n  5. 3. 4 , e x cl u di n g a n al y s e s of ti m e t o o n s et  or ti m e 
t o r e c urr e n c e of A RI A,  a n d  a n al y s e s b y d o s e l e v e l.  N ot  all a n al y s e s will b e r u n b y 
A P O E ε 4 g e n ot y p e .) 
 
L a b or at or y d at a ( s e e S e cti o n  5. 3. 5 ) 
 
Vit al si g n s ( s e e S e cti o n  5. 3. 6 ) 
 
E C G d at a ( s e e S e cti o n  5. 3. 7 ) 
 
C -S S R S d at a ( s e e S e cti o n  5. 3. 8 ) 
I m m u n o g e ni cit y a n al y s e s m a y al s o b e p erf or m e d at t h e i nt eri m a n al y si s.   
N o i nt eri m a n al y s e s of effi c a c y d at a will b e d o n e.  
5. 8. 2  
O pti o n al I nt eri m A n al y s e s  
T o a d a pt t o i nf or m ati o n t h at m a y e m er g e d uri n g t h e c o ur s e of t hi s st u d y, t h e S p o n s or 
m a y c h o o s e t o c o n d u ct o n e or m or e  a d diti o n al  i nt eri m a n al y si s( e s) w hi c h m a y i n cl u d e 
effi c a c y, s af et y , a n d bi o m ar k er o ut c o m e s . 
6.  
S U P P O R TI N G D O C U M E N T A TI O N  
R ef er t o A p p e n di x  1  a n d A p p e n di x  2  b el o w.  
 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
3 6


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
3 7  
A p p e n di x  1  C h a n g e s t o Pr ot o c ol -Pl a n n e d A n al y s e s  
A ll a n al y s e s i n t hi s S A P will b e r e stri ct e d t o d at a  c oll e ct e d u n d er t hi s st u d y or d uri n g t h e 
O L E p art of t h e p ar e nt st u di e s a n d will b e p ur el y d e s cri pti v e.   N o e sti m a n d s will b e 
d efi n e d.  
A n al y s e s of a n y l o n g -t er m eff e ct of t h e st u d y dr u g ( a cr o s s t h e d o u bl e-bli n d a n d o p e n 
l a b el p h a s e s fr o m t h e p ar e nt s t u d y [ G R A D U A T E I or G R A D U A T E II] a n d t hi s st u d y) ar e 
n ot s u bj e ct t o t hi s S A P a n d will b e d e s cri b e d el s e w h er e.  
 
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
3 7


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
3 8  
A p p e n di x  2  Bi o cli ni c a S e v erit y S c or e  
I n or d er t o d eter mi n e t h e r a di ol o gi c al s e v erit y of a n A RI A -E e v e nt, t h e  Bi o cli ni c a 5 -p oi nt 
s c al e ( Br a c o u d et al. 2 0 1 7 ) will b e u s e d w hi c h h a s b e e n r e n a m e d a s S e v erit y S c al e of 
A RI A -E ( S S A E) si n c e t h e writi n g of t h e pr ot o c ol.  Pl e a s e n ot e t h at i n a d diti o n t o t h e 
5 ‑p oi nt s c al e b ei n g u s e d f or t hi s st u d y, a 3 -p oi nt s c al e al s o e xi st s.  
T a bl e  1  b el o w d et ail s t h e d efi niti o n of b o t h t h e 5-p oi nt a n d 3 -p oi nt s e v erit y s c al e s . 
T a bl e  1  
Bi o cli ni c a 3 -P oi nt a n d 5 -P oi nt S c al e D efi niti o n  
A RI A -E E xt e nt  
A RI A -E F o c alit y  
3 -P oi nt S c al e 
( S S A E-3)  
5 -P oi nt S c al e 
( S S A E-5)  
N o A RI A -E  
N/ A  
0  
0  
< 5 c m  
M o n of o c al  
1 ( Mil d)  
1 ( Mil d)  
M ultif o c al  
2 ( M o d er at e)  
2 ( Mil d + ) 
5 −1 0 c m  
M o n of o c al  
3 ( M o d er at e)  
M ultif o c al  
4 ( M o d er at e + ) 
> 1 0 c m  
M o n of o c al  
3 ( S e v er e)  
5 ( S e v er e)  
M ultif o c al  
N/ A = n ot a p pli c a bl e.  
Pr ot o c ol N u m b er: 
 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
W N 4 2 1 7 1
1 1 1 5 9 8 0
3 8


G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
St ati sti c al A n al y si s Pl a n  W N 4 2 1 7 1 , v 1. 0  
3 9  
7.  
R E F E R E N C E S  
B er g L. Cli ni c al D e m e nti a R ati n g ( C D R). P s y c h o p h ar m a c ol B ull 1 9 8 8; 2 4: 6 3 7 -9.  
Br a c o u d L, Fi e b a c h J B, P ur c ell D D, et al. V ali d ati o n of a si m pl e s e v erit y s c al e f or  
a s s e s si n g A R EI A -E. Al z h ei m er s D e m e nt 2 0 1 7; 1 3( P art 5): P 2 5 3 -4.  
Cl ar k L J, G at z M, Z h e n g L, et al. L o n git u di n al v er b al fl u e n c y i n n or m al a gi n g, pr e cli ni c al, 
a n d pr e v al e nt Al z h ei m er' s di s e a s e. A m J Al z h ei m er s Di s Ot h er D e m e n 
2 0 0 9; 2 4: 4 6 1 -8.  
C ol u m bi a -S ui ci d e S e v erit y R ati n g S c al e ( C -S S R S; C ol u m bi a Pr ot o c ol). T h e C ol u m bi a  
Li g ht h o u s e Pr oj e ct [r e s o ur c e o n t h e  I nt er n et]. 2 0 1 6 [ A c c e s s e d: 2 8 J ul y 2 0 2 2]. 
A v ail a bl e fr o m: htt p s:// c s sr s. c ol u m bi a. e d u/  
C o n n or D J, S a b b a g h M N. A d mi ni str ati o n a n d s c ori n g v ari a n c e o n t h e A D A S -C o g. J 
Al z h ei m er s Di s 2 0 0 8; 1 5: 4 6 1 -4.  
F ol st ei n M F, F ol st ei n S E, M c H u g h P R. “ Mi ni -m e nt al st at e.” A p r a cti c al m et h o d f or 
gr a di n g t h e c o g niti v e st at e of p ati e nt s f or t h e cli ni ci a n. J P s y c hi atr R e s 
1 9 7 5; 1 2: 1 8 9 -9 8.  
G al a s k o D, B e n n ett D, S a n o M, et al. A n i n v e nt or y t o a s s e s s a cti viti e s of d ail y li vi n g f or 
cli ni c al tri al s i n Al z h ei m er’ s di s e a s e. T h e Al z h ei m er' s Di s e a s e C o o p er ati v e St u d y. 
Al z h ei m er Di s A s s o c Di s or d 1 9 9 7; 1 1( S u p pl 2): S 3 3 -9.  
I hl R, F erri s S, R o b ert P, et al. D et e cti n g tr e at m e nt eff e ct s wit h c o m bi n ati o n s of t h e 
A D A S -C o g it e m s i n p ati e nt s wit h mil d a n d m o d er at e Al z h ei m er' s di s e a s e. I nt J 
G eri atr P s y c hi atr y 2 0 1 2; 2 7: 1 5 -2 1.  
K a uf er DI, C u m mi n g s J L, K et c h el P, et al. V ali d ati o n of t h e N PI -Q, a bri ef cli ni c al f or m of 
t h e N e ur o p s y c hi atri c I n v e nt or y. J N e ur o p s y c hi atr y Cli n N e ur o s ci 2 0 0 0; 1 2: 2 3 3-9.  
L e z a k M D, H o wi e s o n D B, L ori n g D W. N e ur o p s y c h ol o gi c al a s s e s s m e nt  ( 4t h r e vi s e d 
e diti o n). N e w Y or k: O xf or d U ni v er sit y Pr e s s, 2 0 0 4.  
L o g s d o n R G, Gi b b o n s L E, M c C urr y S M, et al. Q u alit y of lif e i n Al z h ei m er' s di s e a s e: 
p ati e nt a n d c ar e gi v er r e p ort s. J M e nt al H e alt h A gi n g 1 9 9 9; 5: 2 1 -3 2.  
L o g s d o n R G, Gi b b o n s L E, M c C urr y S M, et al . A s s e s si n g q u alit y of lif e i n ol d er a d ult s 
wit h c o g niti v e i m p air m e nt. P s y c h o s o m M e d 2 0 0 2; 6 4: 5 1 0 -9.  
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W N 4 2 1 7 1
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G a nt e n er u m a b — F. H off m a n n -L a R o c h e Lt d  
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4 0  
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 R e p ort N u m b er: 
Cli ni c al St u d y R e p ort: g a nt e n er u m a b - F. H off m a n n- L a R o c h e Lt d
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Si g nat ure Pa ge f or 1 1 1 5 9 8 0-csr- w n 4 2 1 7 1- 1 6 1 9
S yste m i de ntifier: RI M- C LI N- 5 1 1 9 9 7
A p pr o val Tas k
C o m pa n y Si g nat or y
3 0- N o v- 2 0 2 3 1 5: 5 7: 5 9 G M T + 0 0 0 0